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Sample records for mediates cardiac specification

  1. Raf-mediated cardiac hypertrophy in adult Drosophila

    Directory of Open Access Journals (Sweden)

    Lin Yu

    2013-07-01

    In response to stress and extracellular signals, the heart undergoes a process called cardiac hypertrophy during which cardiomyocytes increase in size. If untreated, cardiac hypertrophy can progress to overt heart failure that causes significant morbidity and mortality. The identification of molecular signals that cause or modify cardiomyopathies is necessary to understand how the normal heart progresses to cardiac hypertrophy and heart failure. Receptor tyrosine kinase (RTK signaling is essential for normal human cardiac function, and the inhibition of RTKs can cause dilated cardiomyopathies. However, neither investigations of activated RTK signaling pathways nor the characterization of hypertrophic cardiomyopathy in the adult fly heart has been previously described. Therefore, we developed strategies using Drosophila as a model to circumvent some of the complexities associated with mammalian models of cardiovascular disease. Transgenes encoding activated EGFRA887T, Ras85DV12 and Ras85DV12S35, which preferentially signal to Raf, or constitutively active human or fly Raf caused hypertrophic cardiomyopathy as determined by decreased end diastolic lumen dimensions, abnormal cardiomyocyte fiber morphology and increased heart wall thicknesses. There were no changes in cardiomyocyte cell numbers. Additionally, activated Raf also induced an increase in cardiomyocyte ploidy compared with control hearts. However, preventing increases in cardiomyocyte ploidy using fizzy-related (Fzr RNAi did not rescue Raf-mediated cardiac hypertrophy, suggesting that Raf-mediated polyploidization is not required for cardiac hypertrophy. Similar to mammals, the cardiac-specific expression of RNAi directed against MEK or ERK rescued Raf-mediated cardiac hypertrophy. However, the cardiac-specific expression of activated ERKD334N, which promotes hyperplasia in non-cardiac tissues, did not cause myocyte hypertrophy. These results suggest that ERK is necessary, but not sufficient, for Raf-mediated

  2. Toll-like receptor 9 mediated responses in cardiac fibroblasts.

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    Ingrid Kristine Ohm

    Full Text Available Altered cardiac Toll-like receptor 9 (TLR9 signaling is important in several experimental cardiovascular disorders. These studies have predominantly focused on cardiac myocytes or the heart as a whole. Cardiac fibroblasts have recently been attributed increasing significance in mediating inflammatory signaling. However, putative TLR9-signaling through cardiac fibroblasts remains non-investigated. Thus, our aim was to explore TLR9-signaling in cardiac fibroblasts and investigate the consequence of such receptor activity on classical cardiac fibroblast cellular functions. Cultivated murine cardiac fibroblasts were stimulated with different TLR9 agonists (CpG A, B and C and assayed for the secretion of inflammatory cytokines (tumor necrosis factor α [TNFα], CXCL2 and interferon α/β. Expression of functional cardiac fibroblast TLR9 was proven as stimulation with CpG B and -C caused significant CXCL2 and TNFα-release. These responses were TLR9-specific as complete inhibition of receptor-stimulated responses was achieved by co-treatment with a TLR9-antagonist (ODN 2088 or chloroquine diphosphate. TLR9-stimulated responses were also found more potent in cardiac fibroblasts when compared with classical innate immune cells. Stimulation of cardiac fibroblasts TLR9 was also found to attenuate migration and proliferation, but did not influence myofibroblast differentiation in vitro. Finally, results from in vivo TLR9-stimulation with subsequent fractionation of specific cardiac cell-types (cardiac myocytes, CD45+ cells, CD31+ cells and cardiac fibroblast-enriched cell-fractions corroborated our in vitro data and provided evidence of differentiated cell-specific cardiac responses. Thus, we conclude that cardiac fibroblast may constitute a significant TLR9 responder cell within the myocardium and, further, that such receptor activity may impact important cardiac fibroblast cellular functions.

  3. Indirect imaging of cardiac-specific transgene expression using a bidirectional two-step transcriptional amplification strategy

    DEFF Research Database (Denmark)

    Chen, I Y; Gheysens, O; Ray, S

    2010-01-01

    in a cardiac cell line and the myocardium, while minimizing expression in non-cardiac cell lines and the liver. In vitro, the TSTA system significantly enhanced cTnT-mediated reporter gene expression with moderate preservation of cardiac specificity. After intramyocardial and hydrodynamic tail vein delivery...... genes, firefly luciferase (fluc) and Renilla luciferase (hrluc), driven by the cardiac troponin T (cTnT) promoter. The vector was characterized in vitro and in living mice using luminometry and bioluminescence imaging to assess its ability to mediate strong, correlated reporter gene expression...

  4. MicroRNA-133 mediates cardiac diseases: Mechanisms and clinical implications

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    Liu, Yi; Liang, Yan [Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang 524023, Guangdong (China); Zhang, Jin-fang [Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (China); Fu, Wei-ming, E-mail: fuweiming76@smu.edu.cn [School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515 (China)

    2017-05-15

    MicroRNAs (miRNAs) belong to the family of small non-coding RNAs that mediate gene expression by post-transcriptional regulation. Increasing evidence have demonstrated that miR-133 is enriched in muscle tissues and myogenic cells, and its aberrant expression could induce the occurrence and development of cardiac disorders, such as cardiac hypertrophy, heart failure, etc. In this review, we summarized the regulatory roles of miR-133 in cardiac disorders and the underlying mechanisms, which suggest that miR-133 may be a potential diagnostic and therapeutic tool for cardiac disorders. - Highlights: • miR-218 is frequently downregulated in multiple cancers. • miR-218 plays pivotal roles in carcinogenesis. • miR-218 mediates proliferation, apoptosis, metastasis, invasion, etc. • miR-218 mediates tumorigenesis and metastasis via multiple pathways.

  5. MicroRNA-133 mediates cardiac diseases: Mechanisms and clinical implications

    International Nuclear Information System (INIS)

    Liu, Yi; Liang, Yan; Zhang, Jin-fang; Fu, Wei-ming

    2017-01-01

    MicroRNAs (miRNAs) belong to the family of small non-coding RNAs that mediate gene expression by post-transcriptional regulation. Increasing evidence have demonstrated that miR-133 is enriched in muscle tissues and myogenic cells, and its aberrant expression could induce the occurrence and development of cardiac disorders, such as cardiac hypertrophy, heart failure, etc. In this review, we summarized the regulatory roles of miR-133 in cardiac disorders and the underlying mechanisms, which suggest that miR-133 may be a potential diagnostic and therapeutic tool for cardiac disorders. - Highlights: • miR-218 is frequently downregulated in multiple cancers. • miR-218 plays pivotal roles in carcinogenesis. • miR-218 mediates proliferation, apoptosis, metastasis, invasion, etc. • miR-218 mediates tumorigenesis and metastasis via multiple pathways.

  6. Cardiomyocyte specific expression of Acyl-coA thioesterase 1 attenuates sepsis induced cardiac dysfunction and mortality

    Energy Technology Data Exchange (ETDEWEB)

    Xia, Congying [Departments of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Dong, Ruolan [Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 (China); Chen, Chen [Departments of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Wang, Hong, E-mail: hong.wang1988@yahoo.com [Departments of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Wang, Dao Wen, E-mail: dwwang@tjh.tjmu.edu.cn [Departments of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China)

    2015-12-25

    Compromised cardiac fatty acid oxidation (FAO) induced energy deprivation is a critical cause of cardiac dysfunction in sepsis. Acyl-CoA thioesterase 1 (ACOT1) is involved in regulating cardiac energy production via altering substrate metabolism. This study aims to clarify whether ACOT1 has a potency to ameliorate septic myocardial dysfunction via enhancing cardiac FAO. Transgenic mice with cardiomyocyte specific expression of ACOT1 (αMHC-ACOT1) and their wild type (WT) littermates were challenged with Escherichia coli lipopolysaccharide (LPS; 5 mg/kg i.p.) and myocardial function was assessed 6 h later using echocardiography and hemodynamics. Deteriorated cardiac function evidenced by reduction of the percentage of left ventricular ejection fraction and fractional shortening after LPS administration was significantly attenuated by cardiomyocyte specific expression of ACOT1. αMHC-ACOT1 mice exhibited a markedly increase in glucose utilization and cardiac FAO compared with LPS-treated WT mice. Suppression of cardiac peroxisome proliferator activated receptor alpha (PPARa) and PPARγ-coactivator-1α (PGC1a) signaling observed in LPS-challenged WT mice was activated by the presence of ACOT1. These results suggest that ACOT1 has potential therapeutic values to protect heart from sepsis mediated dysfunction, possibly through activating PPARa/PGC1a signaling. - Highlights: • ACOT1 has potential therapeutic values to protect heart from sepsis mediated dysfunction. • ACOT1 can regulate PPARa/PGC1a signaling pathway. • We first generate the transgenic mice with cardiomyocyte specific expression of ACOT1.

  7. Cardiomyocyte specific expression of Acyl-coA thioesterase 1 attenuates sepsis induced cardiac dysfunction and mortality

    International Nuclear Information System (INIS)

    Xia, Congying; Dong, Ruolan; Chen, Chen; Wang, Hong; Wang, Dao Wen

    2015-01-01

    Compromised cardiac fatty acid oxidation (FAO) induced energy deprivation is a critical cause of cardiac dysfunction in sepsis. Acyl-CoA thioesterase 1 (ACOT1) is involved in regulating cardiac energy production via altering substrate metabolism. This study aims to clarify whether ACOT1 has a potency to ameliorate septic myocardial dysfunction via enhancing cardiac FAO. Transgenic mice with cardiomyocyte specific expression of ACOT1 (αMHC-ACOT1) and their wild type (WT) littermates were challenged with Escherichia coli lipopolysaccharide (LPS; 5 mg/kg i.p.) and myocardial function was assessed 6 h later using echocardiography and hemodynamics. Deteriorated cardiac function evidenced by reduction of the percentage of left ventricular ejection fraction and fractional shortening after LPS administration was significantly attenuated by cardiomyocyte specific expression of ACOT1. αMHC-ACOT1 mice exhibited a markedly increase in glucose utilization and cardiac FAO compared with LPS-treated WT mice. Suppression of cardiac peroxisome proliferator activated receptor alpha (PPARa) and PPARγ-coactivator-1α (PGC1a) signaling observed in LPS-challenged WT mice was activated by the presence of ACOT1. These results suggest that ACOT1 has potential therapeutic values to protect heart from sepsis mediated dysfunction, possibly through activating PPARa/PGC1a signaling. - Highlights: • ACOT1 has potential therapeutic values to protect heart from sepsis mediated dysfunction. • ACOT1 can regulate PPARa/PGC1a signaling pathway. • We first generate the transgenic mice with cardiomyocyte specific expression of ACOT1.

  8. TNNI3K is a novel mediator of myofilament function and phosphorylates cardiac troponin I

    International Nuclear Information System (INIS)

    Wang, Hui; Wang, Lin; Song, Li; Zhang, Yan-Wan; Ye, Jue; Xu, Rui-Xia; Shi, Na; Meng, Xian-Min

    2013-01-01

    The phosphorylation of cardiac troponin I (cTnI) plays an important role in the contractile dysfunction associated with heart failure. Human cardiac troponin I-interacting kinase (TNNI3K) is a novel cardiac-specific functional kinase that can bind to cTnI in a yeast two-hybrid screen. The purpose of this study was to investigate whether TNNI3K can phosphorylate cTnI at specific sites and to examine whether the phosphorylation of cTnI caused by TNNI3K can regulate cardiac myofilament contractile function. Co-immunoprecipitation was performed to confirm that TNNI3K could interact with cTnI. Kinase assays further indicated that TNNI3K did not phosphorylate cTnI at Ser23/24 and Ser44, but directly phosphorylated Ser43 and Thr143 in vitro. The results obtained for adult rat cardiomyocytes also indicated that enhanced phosphorylation of cTnI at Ser43 and Thr143 correlated with rTNNI3K (rat TNNI3K) overexpression, and phosphorylation was reduced when rTNNI3K was knocked down. To determine the contractile function modulated by TNNI3K-mediated phosphorylation of cTnI, cardiomyocyte contraction was studied in adult rat ventricular myocytes. The contraction of cardiomyocytes increased with rTNNI3K overexpression and decreased with rTNNI3K knockdown. We conclude that TNNI3K may be a novel mediator of cTnI phosphorylation and contribute to the regulation of cardiac myofilament contraction function

  9. Depression and reduced heart rate variability after cardiac surgery: the mediating role of emotion regulation.

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    Patron, Elisabetta; Messerotti Benvenuti, Simone; Favretto, Giuseppe; Gasparotto, Renata; Palomba, Daniela

    2014-02-01

    Heart rate variability (HRV), as an index of autonomic nervous system (ANS) functioning, is reduced by depression after cardiac surgery, but the underlying mechanisms of this relationship are poorly understood. Poor emotion regulation as a core symptom of depression has also been associated with altered ANS functioning. The present study aimed to examine whether emotion dysregulation could be a mediator of the depression-reduced HRV relationship observed after cardiac surgery. Self-reported emotion regulation and four-minute HRV were measured in 25 depressed and 43 nondepressed patients after cardiac surgery. Mediation analysis was conducted to evaluate emotion regulation as a mediator of the depression-reduced HRV relationship. Compared to nondepressed patients, those with depression showed lower standard deviation of normal-to-normal (NN) intervals (pbehavior partially mediated the effect of depression on LF n.u. and HF n.u. Results confirmed previous findings showing that depression is associated with reduced HRV, especially a reduced vagal tone and a sympathovagal imbalance, after cardiac surgery. This study also provides preliminary evidence that increased trait levels of suppression of emotion-expressive behavior may mediate the depression-related sympathovagal imbalance after cardiac surgery. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Proteomic analysis reveals new cardiac-specific dystrophin-associated proteins.

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    Eric K Johnson

    Full Text Available Mutations affecting the expression of dystrophin result in progressive loss of skeletal muscle function and cardiomyopathy leading to early mortality. Interestingly, clinical studies revealed no correlation in disease severity or age of onset between cardiac and skeletal muscles, suggesting that dystrophin may play overlapping yet different roles in these two striated muscles. Since dystrophin serves as a structural and signaling scaffold, functional differences likely arise from tissue-specific protein interactions. To test this, we optimized a proteomics-based approach to purify, identify and compare the interactome of dystrophin between cardiac and skeletal muscles from as little as 50 mg of starting material. We found selective tissue-specific differences in the protein associations of cardiac and skeletal muscle full length dystrophin to syntrophins and dystrobrevins that couple dystrophin to signaling pathways. Importantly, we identified novel cardiac-specific interactions of dystrophin with proteins known to regulate cardiac contraction and to be involved in cardiac disease. Our approach overcomes a major challenge in the muscular dystrophy field of rapidly and consistently identifying bona fide dystrophin-interacting proteins in tissues. In addition, our findings support the existence of cardiac-specific functions of dystrophin and may guide studies into early triggers of cardiac disease in Duchenne and Becker muscular dystrophies.

  11. Patient-specific models of cardiac biomechanics

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    Krishnamurthy, Adarsh; Villongco, Christopher T.; Chuang, Joyce; Frank, Lawrence R.; Nigam, Vishal; Belezzuoli, Ernest; Stark, Paul; Krummen, David E.; Narayan, Sanjiv; Omens, Jeffrey H.; McCulloch, Andrew D.; Kerckhoffs, Roy C. P.

    2013-07-01

    Patient-specific models of cardiac function have the potential to improve diagnosis and management of heart disease by integrating medical images with heterogeneous clinical measurements subject to constraints imposed by physical first principles and prior experimental knowledge. We describe new methods for creating three-dimensional patient-specific models of ventricular biomechanics in the failing heart. Three-dimensional bi-ventricular geometry is segmented from cardiac CT images at end-diastole from patients with heart failure. Human myofiber and sheet architecture is modeled using eigenvectors computed from diffusion tensor MR images from an isolated, fixed human organ-donor heart and transformed to the patient-specific geometric model using large deformation diffeomorphic mapping. Semi-automated methods were developed for optimizing the passive material properties while simultaneously computing the unloaded reference geometry of the ventricles for stress analysis. Material properties of active cardiac muscle contraction were optimized to match ventricular pressures measured by cardiac catheterization, and parameters of a lumped-parameter closed-loop model of the circulation were estimated with a circulatory adaptation algorithm making use of information derived from echocardiography. These components were then integrated to create a multi-scale model of the patient-specific heart. These methods were tested in five heart failure patients from the San Diego Veteran's Affairs Medical Center who gave informed consent. The simulation results showed good agreement with measured echocardiographic and global functional parameters such as ejection fraction and peak cavity pressures.

  12. Cardiac Subtype-Specific Modeling of Kv1.5 Ion Channel Deficiency Using Human Pluripotent Stem Cells

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    Maike Marczenke

    2017-07-01

    Full Text Available The ultrarapid delayed rectifier K+ current (IKur, mediated by Kv1.5 channels, constitutes a key component of the atrial action potential. Functional mutations in the underlying KCNA5 gene have been shown to cause hereditary forms of atrial fibrillation (AF. Here, we combine targeted genetic engineering with cardiac subtype-specific differentiation of human induced pluripotent stem cells (hiPSCs to explore the role of Kv1.5 in atrial hiPSC-cardiomyocytes. CRISPR/Cas9-mediated mutagenesis of integration-free hiPSCs was employed to generate a functional KCNA5 knockout. This model as well as isogenic wild-type control hiPSCs could selectively be differentiated into ventricular or atrial cardiomyocytes at high efficiency, based on the specific manipulation of retinoic acid signaling. Investigation of electrophysiological properties in Kv1.5-deficient cardiomyocytes compared to isogenic controls revealed a strictly atrial-specific disease phentoype, characterized by cardiac subtype-specific field and action potential prolongation and loss of 4-aminopyridine sensitivity. Atrial Kv1.5-deficient cardiomyocytes did not show signs of arrhythmia under adrenergic stress conditions or upon inhibiting additional types of K+ current. Exposure of bulk cultures to carbachol lowered beating frequencies and promoted chaotic spontaneous beating in a stochastic manner. Low-frequency, electrical stimulation in single cells caused atrial and mutant-specific early afterdepolarizations, linking the loss of KCNA5 function to a putative trigger mechanism in familial AF. These results clarify for the first time the role of Kv1.5 in atrial hiPSC-cardiomyocytes and demonstrate the feasibility of cardiac subtype-specific disease modeling using engineered hiPSCs.

  13. Gender specific pattern of left ventricular cardiac adaptation to ...

    African Journals Online (AJOL)

    EB

    2013-09-03

    Sep 3, 2013 ... Some gender specific associations with left ventricular structure and function have been described ... used for analysis. ... risk due to LVH and that cardiac adaptation to ... had history taking, physical examination and ..... between the gender specific differences in cardiac ... A metaanalysis of individual.

  14. Co-regulation of the atrial natriuretic factor and cardiac myosin light chain-2 genes during alpha-adrenergic stimulation of neonatal rat ventricular cells. Identification of cis sequences within an embryonic and a constitutive contractile protein gene which mediate inducible expression.

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    Knowlton, K U; Baracchini, E; Ross, R S; Harris, A N; Henderson, S A; Evans, S M; Glembotski, C C; Chien, K R

    1991-04-25

    To study the mechanisms which mediate the transcriptional activation of cardiac genes during alpha adrenergic stimulation, the present study examined the regulated expression of three cardiac genes, a ventricular embryonic gene (atrial natriuretic factor, ANF), a constitutively expressed contractile protein gene (cardiac MLC-2), and a cardiac sodium channel gene. alpha 1-Adrenergic stimulation activates the expression and release of ANF from neonatal ventricular cells. As assessed by RNase protection analyses, treatment with alpha-adrenergic agonists increases the steady-state levels of ANF mRNA by greater than 15-fold. However, a rat cardiac sodium channel gene mRNA is not induced, indicating that alpha-adrenergic stimulation does not lead to an increase in the expression of all cardiac genes. Studies employing a series of rat ANF luciferase and rat MLC-2 luciferase fusion genes identify 315- and 92-base pair cis regulatory sequences within an embryonic gene (ANF) and a constitutively expressed contractile protein gene (MLC-2), respectively, which mediate alpha-adrenergic-inducible gene expression. Transfection of various ANF luciferase reporters into neonatal rat ventricular cells demonstrated that upstream sequences which mediate tissue-specific expression (-3003 to -638) can be segregated from those responsible for inducibility. The lack of inducibility of a cardiac Na+ channel gene, and the segregation of ANF gene sequences which mediate cardiac specific from those which mediate inducible expression, provides further insight into the relationship between muscle-specific and inducible expression during cardiac myocyte hypertrophy. Based on these results, a testable model is proposed for the induction of embryonic cardiac genes and constitutively expressed contractile protein genes and the noninducibility of a subset of cardiac genes during alpha-adrenergic stimulation of neonatal rat ventricular cells.

  15. Cardiomyocyte-Specific Ablation of Med1 Subunit of the Mediator Complex Causes Lethal Dilated Cardiomyopathy in Mice.

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    Jia, Yuzhi; Chang, Hsiang-Chun; Schipma, Matthew J; Liu, Jing; Shete, Varsha; Liu, Ning; Sato, Tatsuya; Thorp, Edward B; Barger, Philip M; Zhu, Yi-Jun; Viswakarma, Navin; Kanwar, Yashpal S; Ardehali, Hossein; Thimmapaya, Bayar; Reddy, Janardan K

    2016-01-01

    Mediator, an evolutionarily conserved multi-protein complex consisting of about 30 subunits, is a key component of the polymerase II mediated gene transcription. Germline deletion of the Mediator subunit 1 (Med1) of the Mediator in mice results in mid-gestational embryonic lethality with developmental impairment of multiple organs including heart. Here we show that cardiomyocyte-specific deletion of Med1 in mice (csMed1-/-) during late gestational and early postnatal development by intercrossing Med1fl/fl mice to α-MyHC-Cre transgenic mice results in lethality within 10 days after weaning due to dilated cardiomyopathy-related ventricular dilation and heart failure. The csMed1-/- mouse heart manifests mitochondrial damage, increased apoptosis and interstitial fibrosis. Global gene expression analysis revealed that loss of Med1 in heart down-regulates more than 200 genes including Acadm, Cacna1s, Atp2a2, Ryr2, Pde1c, Pln, PGC1α, and PGC1β that are critical for calcium signaling, cardiac muscle contraction, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy and peroxisome proliferator-activated receptor regulated energy metabolism. Many genes essential for oxidative phosphorylation and proper mitochondrial function such as genes coding for the succinate dehydrogenase subunits of the mitochondrial complex II are also down-regulated in csMed1-/- heart contributing to myocardial injury. Data also showed up-regulation of about 180 genes including Tgfb2, Ace, Atf3, Ctgf, Angpt14, Col9a2, Wisp2, Nppa, Nppb, and Actn1 that are linked to cardiac muscle contraction, cardiac hypertrophy, cardiac fibrosis and myocardial injury. Furthermore, we demonstrate that cardiac specific deletion of Med1 in adult mice using tamoxifen-inducible Cre approach (TmcsMed1-/-), results in rapid development of cardiomyopathy and death within 4 weeks. We found that the key findings of the csMed1-/- studies described above are highly reproducible in TmcsMed1-/- mouse heart

  16. Circulating Histones Are Major Mediators of Cardiac Injury in Patients With Sepsis.

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    Alhamdi, Yasir; Abrams, Simon T; Cheng, Zhenxing; Jing, Shengjie; Su, Dunhao; Liu, Zhiyong; Lane, Steven; Welters, Ingeborg; Wang, Guozheng; Toh, Cheng-Hock

    2015-10-01

    To investigate the impact of circulating histones on cardiac injury and dysfunction in a murine model and patients with sepsis. Prospective, observational clinical study with in vivo and ex vivo translational laboratory investigations. General ICU and university research laboratory. Sixty-five septic patients and 27 healthy volunteers. Twelve-week-old male C57BL/6N mice. Serial blood samples from 65 patients with sepsis were analyzed, and left ventricular function was assessed by echocardiography. Patients' sera were incubated with cultured cardiomyocytes in the presence or absence of antihistone antibody, and cellular viability was assessed. Murine sepsis was initiated by intraperitoneal Escherichia coli injection (10(8) colony-forming unit/mouse) in 12-week-old male C57BL/6N mice, and the effect of antihistone antibody (10 mg/kg) was studied. Murine blood samples were collected serially, and left ventricular function was assessed by intraventricular catheters and electrocardiography. Circulating histones and cardiac troponins in human and murine plasma were quantified. In 65 patients with sepsis, circulating histones were significantly elevated compared with healthy controls (n = 27) and linearly correlated with cardiac troponin T levels (rs = 0.650; p histone levels were significantly associated with new-onset left ventricular dysfunction (p = 0.001) and arrhythmias (p = 0.01). Left ventricular dysfunction only predicted adverse outcomes when combined with elevated histones or cardiac troponin levels. Furthermore, patients' sera directly induced histone-specific cardiomyocyte death ex vivo, which was abrogated by antihistone antibodies. In vivo studies on septic mice confirmed the cause-effect relationship between circulating histones and the development of cardiac injury, arrhythmias, and left ventricular dysfunction. Circulating histones are novel and important mediators of septic cardiomyopathy, which can potentially be utilized for prognostic and therapeutic

  17. Cardiac-specific overexpression of aldehyde dehydrogenase 2 exacerbates cardiac remodeling in response to pressure overload

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    Sujith Dassanayaka

    2018-07-01

    Full Text Available Pathological cardiac remodeling during heart failure is associated with higher levels of lipid peroxidation products and lower abundance of several aldehyde detoxification enzymes, including aldehyde dehydrogenase 2 (ALDH2. An emerging idea that could explain these findings concerns the role of electrophilic species in redox signaling, which may be important for adaptive responses to stress or injury. The purpose of this study was to determine whether genetically increasing ALDH2 activity affects pressure overload-induced cardiac dysfunction. Mice subjected to transverse aortic constriction (TAC for 12 weeks developed myocardial hypertrophy and cardiac dysfunction, which were associated with diminished ALDH2 expression and activity. Cardiac-specific expression of the human ALDH2 gene in mice augmented myocardial ALDH2 activity but did not improve cardiac function in response to pressure overload. After 12 weeks of TAC, ALDH2 transgenic mice had larger hearts than their wild-type littermates and lower capillary density. These findings show that overexpression of ALDH2 augments the hypertrophic response to pressure overload and imply that downregulation of ALDH2 may be an adaptive response to certain forms of cardiac pathology. Keywords: Heart failure, Hypertrophy, Oxidative stress, Aldehydes, Cardiac remodeling, Hormesis

  18. Carvedilol-mediated antioxidant protection against doxorubicin-induced cardiac mitochondrial toxicity

    International Nuclear Information System (INIS)

    Oliveira, Paulo J.; Bjork, James A.; Santos, Maria S.; Leino, Richard L.; Froberg, M. Kent; Moreno, Antonio J.; Wallace, Kendall B.

    2004-01-01

    The cardiotoxicity associated with doxorubicin (DOX) therapy limits the total cumulative dose and therapeutic success of active anticancer chemotherapy. Cardiac mitochondria are implicated as primary targets for DOX toxicity, which is believed to be mediated by the generation of highly reactive free radical species of oxygen from complex I of the mitochondrial electron transport chain. The objective of this study was to determine if the protection demonstrated by carvedilol (CV), a β-adrenergic receptor antagonist with strong antioxidant properties, against DOX-induced mitochondrial-mediated cardiomyopathy [Toxicol. Appl. Pharmacol. 185 (2002) 218] is attributable to its antioxidant properties or its β-adrenergic receptor antagonism. Our results confirm that DOX induces oxidative stress, mitochondrial dysfunction, and histopathological lesions in the cardiac tissue, all of which are inhibited by carvedilol. In contrast, atenolol (AT), a β-adrenergic receptor antagonist lacking antioxidant properties, preserved phosphate energy charge but failed to protect against any of the indexes of DOX-induced oxidative mitochondrial toxicity. We therefore conclude that the cardioprotective effects of carvedilol against DOX-induced mitochondrial cardiotoxicity are due to its inherent antioxidant activity and not to its β-adrenergic receptor antagonism

  19. Cardiac-specific activation of Cre expression at late fetal development

    International Nuclear Information System (INIS)

    Opherk, Jan P.; Yampolsky, Peter; Hardt, Stefan E.; Schoels, Wolfgang; Katus, Hugo A.; Koenen, Michael; Zehelein, Joerg

    2007-01-01

    In a first step towards dissecting molecular mechanisms that contribute to the development of cardiac diseases, we have generated transgenic mice that express a Cre-GFP fusion protein under the transcriptional control of a 4.3 kb murine cardiac Troponin I gene (cTnI) promoter. Cre-GFP expression, similar in three transgenic lines, is described in one line. In mouse embryos, transgenic for the Cre-GFP and ROSA lacZ reporter allele, first Cre-mediated recombination appeared at 16.5 dpc selectively at the heart. Like the endogenous cTnI gene, transgenic Cre expression showed a slow rise through fetal development that increased neonatally. Bitransgenic hearts, stained at 30 days of age, showed intense signals in ventricular and atrial myocytes while no recombination occurred in other tissues. The delayed onset of Cre activity in cTnI-Cre mice could provide a useful genetic tool to evaluate the function of loxP targeted cardiac genes without interference of recombination during early heart development

  20. Wnt inhibition promotes vascular specification of embryonic cardiac progenitors.

    Science.gov (United States)

    Reichman, David E; Park, Laura; Man, Limor; Redmond, David; Chao, Kenny; Harvey, Richard P; Taketo, Makoto M; Rosenwaks, Zev; James, Daylon

    2018-01-08

    Several studies have demonstrated a multiphasic role for Wnt signaling during embryonic cardiogenesis and developed protocols that enrich for cardiac derivatives during in vitro differentiation of human pluripotent stem cells (hPSCs). However, few studies have investigated the role of Wnt signaling in the specification of cardiac progenitor cells (CPCs) toward downstream fates. Using transgenic mice and hPSCs, we tracked endothelial cells (ECs) that originated from CPCs expressing NKX2.5. Analysis of EC-fated CPCs at discrete phenotypic milestones during hPSC differentiation identified reduced Wnt activity as a hallmark of EC specification, and the enforced activation or inhibition of Wnt reduced or increased, respectively, the degree of vascular commitment within the CPC population during both hPSC differentiation and mouse embryogenesis. Wnt5a, which has been shown to exert an inhibitory influence on Wnt signaling during cardiac development, was dynamically expressed during vascular commitment of hPSC-derived CPCs, and ectopic Wnt5a promoted vascular specification of hPSC-derived and mouse embryonic CPCs. © 2018. Published by The Company of Biologists Ltd.

  1. Construction and Development of a Cardiac Tissue-Specific and Hypoxia-Inducible Expression Vector

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    Shahrooz Ghaderi

    2018-03-01

    Full Text Available Purpose: Cardiovascular gene therapy is a sophisticated approach, thanks to the safety of vectors, stable transgene expression, delivery method, and different layers of the heart. To date, numerous expression vectors have been introduced in biotechnology and biopharmacy industries in relation to genetic manipulation. Despite the rapid growth of these modalities, they must be intelligently designed, addressing the cardiac-specific transgene expression and less side effects. Herein, we conducted a pilot project aiming to design a cardiac-specific hypoxia-inducible expression cassette. Methods: We explored a new approach to design an expression cassette containing cardiac specific enhancer, hypoxia response elements (HRE, cardiac specific promoter, internal ribosome entry site (IRES, and beta globin poly A sequence to elicit specific and inducible expression of the gene of interest. Enhanced green fluorescent protein (eGFP was sub-cloned by BglII and NotI into the cassette. The specificity and inducible expression of the cassette was determined in both mouse myoblast C2C12 and mammary glandular tumor 4T1 as ‘twin’ cells. eGFP expression was evaluated by immunofluorescence microscope and flow cytometry at 520 nm emission peak. Results: Our data revealed that the designed expression cassette provided tissue specific and hypoxia inducible (O2<1% transgene expression. Conclusion: It is suggested that cardiac-specific enhancer combined with cardiac-specific promoter are efficient for myoblast specific gene expression. As well, this is for the first time that HRE are derived from three well known hypoxia-regulated promoters. Therefore, there is no longer need to overlap PCR process for one repeated sequence just in one promoter.

  2. Patient-specific cardiac phantom for clinical training and preprocedure surgical planning.

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    Laing, Justin; Moore, John; Vassallo, Reid; Bainbridge, Daniel; Drangova, Maria; Peters, Terry

    2018-04-01

    Minimally invasive mitral valve repair procedures including MitraClip ® are becoming increasingly common. For cases of complex or diseased anatomy, clinicians may benefit from using a patient-specific cardiac phantom for training, surgical planning, and the validation of devices or techniques. An imaging compatible cardiac phantom was developed to simulate a MitraClip ® procedure. The phantom contained a patient-specific cardiac model manufactured using tissue mimicking materials. To evaluate accuracy, the patient-specific model was imaged using computed tomography (CT), segmented, and the resulting point cloud dataset was compared using absolute distance to the original patient data. The result, when comparing the molded model point cloud to the original dataset, resulted in a maximum Euclidean distance error of 7.7 mm, an average error of 0.98 mm, and a standard deviation of 0.91 mm. The phantom was validated using a MitraClip ® device to ensure anatomical features and tools are identifiable under image guidance. Patient-specific cardiac phantoms may allow for surgical complications to be accounted for preoperative planning. The information gained by clinicians involved in planning and performing the procedure should lead to shorter procedural times and better outcomes for patients.

  3. The changes in beta-adrenoceptor-mediated cardiac function in experimental hypothyroidism: the possible contribution of cardiac beta3-adrenoceptors.

    Science.gov (United States)

    Arioglu, E; Guner, S; Ozakca, I; Altan, V M; Ozcelikay, A T

    2010-02-01

    Thyroid hormone deficiency has been reported to decrease expression and function of both beta(1)- and beta(2)-adrenoceptor in different tissues including heart. The purpose of this study was to examine the possible contribution of beta(3)-adrenoceptors to cardiac dysfunction in hypothyroidism. In addition, effect of this pathology on beta(1)- and beta(2)-adrenoceptor was investigated. Hypothyroidism was induced by adding methimazole (300 mg/l) to drinking water of rats for 8 weeks. Cardiac hemodynamic parameters were measured in anesthetised rats in vivo. Responses to beta-adrenoceptor agonists were examined in rat papillary muscle in vitro. We also studied the effect of hypotyroidism on mRNA expression of beta-adrenoceptors, Gialpha, GRK, and eNOS in rat heart. All of the hemodynamic parameters (systolic, diastolic and mean arterial pressure, left ventricular pressure, heart rate, +dp/dt, and -dp/dt) were significantly reduced by the methimazole treatment. The negative inotropic effect elicited by BRL 37344 (a beta(3)-adrenoceptor preferential agonist) and positive inotropic effects produced by isoprenaline and noradrenaline, respectively, were significantly decreased in papillary muscle of hypothyroid rats as compared to those of controls. On the other hand, hypothyroidism resulted in increased cardiac beta(2)- and beta(3)-adrenoceptor, Gialpha(2), Gialpha(3), GRK3, and eNOS mRNA expressions. However, beta(1)-adrenoceptor and GRK2 mRNA expressions were not changed significantly in this pathology. These results show that mRNA expression of beta(3)-adrenoceptors as well as the signalling pathway components mediated through beta(3)-adrenoceptors are significantly increased in hypothyroid rat heart. Since we could not correlate these alternates with the decreased negative inotropic response mediated by this receptor subtype, it is not clear whether these changes are important for hypothyroid induced reduction in cardiac function.

  4. Gender specific pattern of left ventricular cardiac adaptation to ...

    African Journals Online (AJOL)

    Background: Cardiac adaptation to hypertension and obesity may be related to many factors such as race, gender and haemodynamic status. Some gender specific associations with left ventricular structure and function have been described among Caucasians. Objectives: To describe the sex specific pattern of left ...

  5. Wnt signaling balances specification of the cardiac and pharyngeal muscle fields

    Science.gov (United States)

    Mandal, Amrita; Holowiecki, Andrew; Song, Yuntao Charlie; Waxman, Joshua S.

    2017-01-01

    Canonical Wnt/β-catenin (Wnt) signaling plays multiple conserved roles during fate specification of cardiac progenitors in developing vertebrate embryos. Although lineage analysis in ascidians and mice has indicated there is a close relationship between the cardiac second heart field (SHF) and pharyngeal muscle (PM) progenitors, the signals underlying directional fate decisions of the cells within the cardio-pharyngeal muscle field in vertebrates are not yet understood. Here, we examined the temporal requirements of Wnt signaling in cardiac and PM development. In contrast to a previous report in chicken embryos that suggested Wnt inhibits PM development during somitogenesis, we find that in zebrafish embryos Wnt signaling is sufficient to repress PM development during anterior-posterior patterning. Importantly, the temporal sensitivity of dorso-anterior PMs to increased Wnt signaling largely overlaps with when Wnt signaling promotes specification of the adjacent cardiac progenitors. Furthermore, we find that excess early Wnt signaling can cell autonomously promote expansion of the first heart field (FHF) progenitors at the expense of PM and SHF within the anterior lateral plate mesoderm (ALPM). Our study provides insight into an antagonistic developmental mechanism that balances the sizes of the adjacent cardiac and PM progenitor fields in early vertebrate embryos. PMID:28087459

  6. Salacia oblonga root improves cardiac lipid metabolism in Zucker diabetic fatty rats: Modulation of cardiac PPAR-α-mediated transcription of fatty acid metabolic genes

    International Nuclear Information System (INIS)

    Huang, Tom H.-W.; Yang Qinglin; Harada, Masaki; Uberai, Jasna; Radford, Jane; Li, George Q.; Yamahara, Johji; Roufogalis, Basil D.; Li Yuhao

    2006-01-01

    Excess cardiac triglyceride accumulation in diabetes and obesity induces lipotoxicity, which predisposes the myocytes to death. On the other hand, increased cardiac fatty acid (FA) oxidation plays a role in the development of myocardial dysfunction in diabetes. PPAR-α plays an important role in maintaining homeostasis of lipid metabolism. We have previously demonstrated that the extract from Salacia oblonga root (SOE), an Ayurvedic anti-diabetic and anti-obesity medicine, improves hyperlipidemia in Zucker diabetic fatty (ZDF) rats (a genetic model of type 2 diabetes and obesity) and possesses PPAR-α activating properties. Here we demonstrate that chronic oral administration of SOE reduces cardiac triglyceride and FA contents and decreases the Oil red O-stained area in the myocardium of ZDF rats, which parallels the effects on plasma triglyceride and FA levels. Furthermore, the treatment suppressed cardiac overexpression of both FA transporter protein-1 mRNA and protein in ZDF rats, suggesting inhibition of increased cardiac FA uptake as the basis for decreased cardiac FA levels. Additionally, the treatment also inhibited overexpression in ZDF rat heart of PPAR-α mRNA and protein and carnitine palmitoyltransferase-1, acyl-CoA oxidase and 5'-AMP-activated protein kinase mRNAs and restored the downregulated acetyl-CoA carboxylase mRNA. These results suggest that SOE inhibits cardiac FA oxidation in ZDF rats. Thus, our findings suggest that improvement by SOE of excess cardiac lipid accumulation and increased cardiac FA oxidation in diabetes and obesity occurs by reduction of cardiac FA uptake, thereby modulating cardiac PPAR-α-mediated FA metabolic gene transcription

  7. Cardiac-specific catalase overexpression rescues anthrax lethal toxin-induced cardiac contractile dysfunction: role of oxidative stress and autophagy

    OpenAIRE

    Kandadi, Machender R; Yu, Xuejun; Frankel, Arthur E; Ren, Jun

    2012-01-01

    Abstract Background Lethal and edema toxins secreted by Bacillus anthracis during anthrax infection were found to incite serious cardiovascular complications. However, the underlying mechanisms in anthrax lethal toxin-induced cardiac anomalies remain unknown. This study was designed to evaluate the impact of antioxidant enzyme catalase in anthrax lethal toxin-induced cardiomyocyte contractile dysfunction. Methods Wild type (WT) and cardiac-specific catalase overexpression mice were challenged...

  8. Biomarkers for cardiac cachexia: reality or utopia.

    Science.gov (United States)

    Martins, Telma; Vitorino, Rui; Amado, Francisco; Duarte, José Alberto; Ferreira, Rita

    2014-09-25

    Cardiac cachexia is a serious complication of chronic heart failure, characterized by significant weight loss and body wasting. Chronic heart failure-related muscle wasting results from a chronic imbalance in the activation of anabolic or catabolic pathways, caused by a series of immunological, metabolic, and neurohormonal processes. In spite of the high morbidity and mortality associated to this condition, there is no universally accepted definition or specific biomarkers for cardiac cachexia, which makes its diagnosis and treatment difficult. Several hormonal, inflammatory and oxidative stress molecules have been proposed as serological markers of prognosis in cardiac cachexia but with doubtful success. As individual biomarkers may have limited sensitivity and specificity, multimarker strategies involving mediators of the biological processes modulated by cardiac cachexia will strongly contribute for the diagnosis and management of the disease, as well as for the establishment of new therapeutic targets. An integrated analysis of the biomarkers proposed so far for cardiac cachexia is made in the present review, highlighting the biological processes to which they are related. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Trait anxiety mediates the effect of stress exposure on post-traumatic stress disorder and depression risk in cardiac surgery patients.

    Science.gov (United States)

    Kok, Lotte; Sep, Milou S; Veldhuijzen, Dieuwke S; Cornelisse, Sandra; Nierich, Arno P; van der Maaten, Joost; Rosseel, Peter M; Hofland, Jan; Dieleman, Jan M; Vinkers, Christiaan H; Joëls, Marian; van Dijk, Diederik; Hillegers, Manon H

    2016-12-01

    Post-traumatic stress disorder (PTSD) and depression are common after cardiac surgery. Lifetime stress exposure and personality traits may influence the development of these psychiatric conditions. Self-reported rates of PTSD and depression and potential determinants (i.e., trait anxiety and stress exposure) were established 1.5 to 4 years after cardiac surgery. Data was available for 1125 out of 1244 (90.4%) participants. Multivariable linear regressions were conducted to investigate mediating and/or moderating effects of trait anxiety on the relationship between stress exposure, and PTSD and depression. Pre-planned subgroup analyses were performed for both sexes. PTSD and depression symptoms were present in 10.2% and 13.1% of the participants, respectively. Trait anxiety was a full mediator of the association between stress exposure and depression in both the total cohort and female and male subgroups. Moreover, trait anxiety partially mediated the relationship between stress exposure and PTSD in the full cohort and the male subgroup, whereas trait anxiety fully mediated this relationship in female patients. Trait anxiety did not play a moderating role in the total patient sample, nor after stratification on gender. The unequal distribution of male (78%) and female patients (22%) might limit the generalizability of our findings. Furthermore, risk factors were investigated retrospectively and with variable follow-up time. In cardiac surgery patients, trait anxiety was found to be an important mediator of postoperative PTSD and depression. Prospective research is necessary to verify whether these factors are reliable screening measures of individuals' vulnerability for psychopathology development after cardiac surgery. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Egr-1 mediated cardiac miR-99 family expression diverges physiological hypertrophy from pathological hypertrophy.

    Science.gov (United States)

    Ramasamy, Subbiah; Velmurugan, Ganesan; Rekha, Balakrishnan; Anusha, Sivakumar; Shanmugha Rajan, K; Shanmugarajan, Suresh; Ramprasath, Tharmarajan; Gopal, Pandi; Tomar, Dhanendra; Karthik, Karuppusamy V; Verma, Suresh Kumar; Garikipati, Venkata Naga Srikanth; Sudarsan, Rajan

    2018-04-01

    The physiological cardiac hypertrophy is an adaptive condition without myocyte cell death, while pathological hypertrophy is a maladaptive condition associated with myocyte cell death. This study explores the miRNome of α-2M-induced physiologically hypertrophied cardiomyocytes and the role of miRNA-99 family during cardiac hypertrophy. Physiological and pathological cardiac hypertrophy was induced in H9c2 cardiomyoblast cell lines using α-2M and isoproterenol respectively. Total RNA isolation and small RNA sequencing were executed for physiological hypertrophy model. The differentially expressed miRNAs and its target mRNAs were validated in animal models. Transcription factor binding sites were predicted in the promoter of specific miRNAs and validated by ChIP-PCR. Subsequently, the selected miRNA was functionally characterized by overexpression and silencing. The effects of silencing of upstream regulator and downstream target gene were studied. Analysis of small RNA reads revealed the differential expression of a large set of miRNAs during hypertrophy, of which miR-99 family was highly downregulated upon α-2M treatment. However, this miR-99 family expression was upregulated during pathological hypertrophy and confirmed in animal models. ChIP-PCR confirms the binding of Egr-1 transcription factor to the miR-99 promoter. Further, silencing of Egr-1 decreased the expression of miR-99. The overexpression or silencing of miR-99 diverges the physiological hypertrophy to pathological hypertrophy and vice versa by regulating Akt-1 pathway. Silencing of Akt-1 replicates the effect of overexpression of miR-99. The results proved Egr-1 mediated regulation of miR-99 family that plays a key role in determining the fate of cardiac hypertrophy by regulating Akt-1 signaling. Copyright © 2018 Elsevier Inc. All rights reserved.

  11. Expression of a novel cardiac-specific tropomyosin isoform in humans

    International Nuclear Information System (INIS)

    Denz, Christopher R.; Narshi, Aruna; Zajdel, Robert W.; Dube, Dipak K.

    2004-01-01

    Tropomyosins are a family of actin binding proteins encoded by a group of highly conserved genes. Humans have four tropomyosin-encoding genes: TPM1, TPM2, TPM3, and TPM4, each of which is known to generate multiple isoforms by alternative splicing, promoters, and 3 ' end processing. TPM1 is the most versatile and encodes a variety of tissue specific isoforms. The TPM1 isoform specific to striated muscle, designated TPM1α, consists of 10 exons: 1a, 2b, 3, 4, 5, 6b, 7, 8, and 9a/b. In this study, using RT-PCR with adult and fetal human RNAs, we present evidence for the expression of a novel isoform of the TPM1 gene that is specifically expressed in cardiac tissues. The new isoform is designated TPM1κ and contains exon 2a instead of 2b. Ectopic expression of human GFP.TPM1κ fusion protein can promote myofibrillogenesis in cardiac mutant axolotl hearts that are lacking in tropomyosin

  12. Pim-1 Kinase Phosphorylates Cardiac Troponin I and Regulates Cardiac Myofilament Function

    Directory of Open Access Journals (Sweden)

    Ni Zhu

    2018-03-01

    Full Text Available Background/Aims: Pim-1 is a serine/threonine kinase that is highly expressed in the heart, and exerts potent cardiac protective effects through enhancing survival, proliferation, and regeneration of cardiomyocytes. Its myocardial specific substrates, however, remain unknown. In the present study, we aim to investigate whether Pim-1 modulates myofilament activity through phosphorylation of cardiac troponin I (cTnI, a key component in regulating myofilament function in the heart. Methods: Coimmunoprecipitation and immunofluorescent assays were employed to investigate the interaction of Pim-1 with cTnI in cardiomyocytes. Biochemical, site directed mutagenesis, and mass spectrometric analyses were utilized to identify the phosphorylation sites of Pim1 in cTnI. Myofilament functional assay using skinned cardiac fiber was used to assess the effect of Pim1-mediated phosphorylation on cardiac myofilament activity. Lastly, the functional significance of Pim1-mediated cTnI in heart disease was determined in diabetic mice. Results: We found that Pim-1 specifically interacts with cTnI in cardiomyocytes and this interaction leads to Pim1-mediated cTnI phosphorylation, predominantly at Ser23/24 and Ser150. Furthermore, our functional assay demonstrated that Pim-1 induces a robust phosphorylation of cTnI within the troponin complex, thus leading to a decreased Ca2+ sensitivity. Insulin-like growth factor 1 (IGF-1, a peptide growth factor that has been shown to stimulate myocardial contractility, markedly induces cTnI phosphorylation at Ser23/24 and Ser150 through increasing Pim-1 expression in cardiomyocytes. In a high-fat diabetic mice model, the expression of Pim1 in the heart is significantly decreased, which is accompanied by a decreased phosphorylation of cTnI at Ser23/24 and Ser150, further implicating the pathological significance of the Pim1/cTnI axis in the development of diabetic cardiomyopathy. Conclusion: Our results demonstrate that Pim-1 is a

  13. Regulation of basal and reserve cardiac pacemaker function by interactions of cAMP mediated PKA-dependent Ca2+ cycling with surface membrane channels

    Science.gov (United States)

    Vinogradova, Tatiana M.; Lakatta, Edward G.

    2009-01-01

    Decades of intensive research of primary cardiac pacemaker, the sinoatrial node, have established potential roles of specific membrane channels in the generation of the diastolic depolarization, the major mechanism allowing sinoatrial node cells generate spontaneous beating. During the last three decades, multiple studies made either in the isolated sinoatrial node or sinoatrial node cells have demonstrated a pivotal role of Ca2+ and, specifically Ca2+-release from sarcoplasmic reticulum, for spontaneous beating of cardiac pacemaker. Recently, spontaneous, rhythmic local subsarcolemmal Ca2+ releases from ryanodine receptors during late half of the diastolic depolarization have been implicated as a vital factor in the generation of sinoatrial node cells spontaneous firing. Local Ca2+ releases are driven by a unique combination of high basal cAMP production by adenylyl cyclases, high basal cAMP degradation by phosphodiesterases and a high level of cAMP-mediated PKA-dependent phosphorylation. These local Ca2+ releases activate an inward Na+-Ca2+ exchange current which accelerates the terminal diastolic depolarization rate and, thus, controls the spontaneous pacemaker firing. Both the basal primary pacemaker beating rate and its modulation via β-adrenergic receptor stimulation appear to be critically dependent upon intact RyR function and local subsarcolemmal sarcoplasmic reticulum generated Ca2+ releases. This review aspires to integrate the traditional viewpoint that has emphasized the supremacy of the ensemble of surface membrane ion channels in spontaneous firing of the primary cardiac pacemaker, and these novel perspectives of cAMP-mediated PKA-dependent Ca2+ cycling in regulation of the heart pacemaker clock, both in the basal state and during β-adrenergic receptor stimulation. PMID:19573534

  14. Importance of leptin signaling and signal transducer and activator of transcription-3 activation in mediating the cardiac hypertrophy associated with obesity.

    Science.gov (United States)

    Leifheit-Nestler, Maren; Wagner, Nana-Maria; Gogiraju, Rajinikanth; Didié, Michael; Konstantinides, Stavros; Hasenfuss, Gerd; Schäfer, Katrin

    2013-07-11

    The adipokine leptin and its receptor are expressed in the heart, and leptin has been shown to promote cardiomyocyte hypertrophy in vitro. Obesity is associated with hyperleptinemia and hypothalamic leptin resistance as well as an increased risk to develop cardiac hypertrophy and heart failure. However, the role of cardiac leptin signaling in mediating the cardiomyopathy associated with increased body weight is unclear, in particular, whether it develops subsequently to cardiac leptin resistance or overactivation of hypertrophic signaling pathways via elevated leptin levels. The cardiac phenotype of high-fat diet (HFD)-induced obese wildtype (WT) mice was examined and compared to age-matched genetically obese leptin receptor (LepR)-deficient (LepRdb/db) or lean WT mice. To study the role of leptin-mediated STAT3 activation during obesity-induced cardiac remodeling, mice in which tyrosine residue 1138 within LepR had been replaced with a serine (LepRS1138) were also analyzed. Obesity was associated with hyperleptinemia and elevated cardiac leptin expression in both diet-induced and genetically obese mice. Enhanced LepR and STAT3 phosphorylation levels were detected in hearts of obese WT mice, but not in those with LepR mutations. Moreover, exogenous leptin continued to induce cardiac STAT3 activation in diet-induced obese mice. Although echocardiography revealed signs of cardiac hypertrophy in all obese mice, the increase in left ventricular (LV) mass and diameter was significantly more pronounced in LepRS1138 animals. LepRS1138 mice also exhibited an increased activation of signaling proteins downstream of LepR, including Jak2 (1.8-fold), Src kinase (1.7-fold), protein kinase B (1.3-fold) or C (1.6-fold). Histological analysis of hearts revealed that the inability of leptin to activate STAT3 in LepRdb/db and LepRS1138 mice was associated with reduced cardiac angiogenesis as well as increased apoptosis and fibrosis. Our findings suggest that hearts from obese mice

  15. Transgenic over-expression of YY1 induces pathologic cardiac hypertrophy in a sex-specific manner

    Science.gov (United States)

    Stauffer, Brian L.; Dockstader, Karen; Russell, Gloria; Hijmans, Jamie; Walker, Lisa; Cecil, Mackenzie; Demos-Davies, Kimberly; Medway, Allen; McKinsey, Timothy A.; Sucharov, Carmen C.

    2015-01-01

    YY1 can activate or repress transcription of various genes. In cardiac myocytes in culture YY1 has been shown to regulate expression of several genes involved in myocyte pathology. YY1 can also acutely protect the heart against detrimental changes in gene expression. In this study we show that cardiac over-expression of YY1 induces pathologic cardiac hypertrophy in male mice, measured by changes in gene expression and lower ejection fraction/fractional shortening. In contrast, female animals are protected against pathologic gene expression changes and cardiac dysfunction. Furthermore, we show that YY1 regulates, in a sex-specific manner, the expression of mammalian enable (Mena), a factor that regulates cytoskeletal actin dynamics and whose expression is increased in several models of cardiac pathology, and that Mena expression in humans with heart failure is sex-dependent. Finally, we show that sex differences in YY1 expression are also observed in human heart failure. In summary, this is the first work to show that YY1 has a sex-specific effect in the regulation of cardiac pathology. PMID:25935483

  16. Kruppel-like factor 15 is required for the cardiac adaptive response to fasting.

    Science.gov (United States)

    Sugi, Keiki; Hsieh, Paishiun N; Ilkayeva, Olga; Shelkay, Shamanthika; Moroney, Bridget; Baadh, Palvir; Haynes, Browning; Pophal, Megan; Fan, Liyan; Newgard, Christopher B; Prosdocimo, Domenick A; Jain, Mukesh K

    2018-01-01

    Cardiac metabolism is highly adaptive in response to changes in substrate availability, as occur during fasting. This metabolic flexibility is essential to the maintenance of contractile function and is under the control of a group of select transcriptional regulators, notably the nuclear receptor family of factors member PPARα. However, the diversity of physiologic and pathologic states through which the heart must sustain function suggests the possible existence of additional transcriptional regulators that play a role in matching cardiac metabolism to energetic demand. Here we show that cardiac KLF15 is required for the normal cardiac response to fasting. Specifically, we find that cardiac function is impaired upon fasting in systemic and cardiac specific Klf15-null mice. Further, cardiac specific Klf15-null mice display a fasting-dependent accumulation of long chain acylcarnitine species along with a decrease in expression of the carnitine translocase Slc25a20. Treatment with a diet high in short chain fatty acids relieves the KLF15-dependent long chain acylcarnitine accumulation and impaired cardiac function in response to fasting. Our observations establish KLF15 as a critical mediator of the cardiac adaptive response to fasting through its regulation of myocardial lipid utilization.

  17. Characterization and validation of new tools for measuring site-specific cardiac troponin I phosphorylation.

    Science.gov (United States)

    Thoemmes, Stephen F; Stutzke, Crystal A; Du, Yanmei; Browning, Michael D; Buttrick, Peter M; Walker, Lori A

    2014-01-31

    Phosphorylation of cardiac troponin I is a well established mechanism by which cardiac contractility is modulated. However, there are a number of phosphorylation sites on TnI which contribute singly or in combination to influence cardiac function. Accordingly, methods for accurately measuring site-specific TnI phosphorylation are needed. Currently, two strategies are employed: mass spectrometry, which is costly, difficult and has a low throughput; and Western blotting using phospho-specific antibodies, which is limited by the availability of reagents. In this report, we describe a cohort of new site-specific TnI phosphoantibodies, generated against physiologically relevant phosphorylation sites, that are superior to the current commercially available antibodies: to phospho-serine 22/23 which shows a >5-fold phospho-specificity for phosphorylated TnI; to phospho-serine 43, which has >3-fold phospho-specificity for phosphorylated TnI; and phospho-serine 150 which has >2-fold phospho-specificity for phosphorylated TnI. These new antibodies demonstrated greater sensitivity and specificity for the phosphorylated TnI than the most widely used commercially available reagents. For example, at a protein load of 20 μg of total cardiac extract, a commercially available antibody recognized both phosphorylated and dephosphorylated TnI to the same degree. At the same protein load our phospho-serine 22/23 antibody exhibited no cross-reactivity with dephosphorylated TnI. These new tools should allow a more accurate assessment and a better understanding of the role of TnI phosphorylation in the response of the heart to pathologic stress. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivo.

    Science.gov (United States)

    Bueno, O F; De Windt, L J; Lim, H W; Tymitz, K M; Witt, S A; Kimball, T R; Molkentin, J D

    2001-01-19

    Mitogen-activated protein kinase (MAPK) signaling pathways are important regulators of cell growth, proliferation, and stress responsiveness. A family of dual-specificity MAP kinase phosphatases (MKPs) act as critical counteracting factors that directly regulate the magnitude and duration of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) activation. Here we show that constitutive expression of MKP-1 in cultured primary cardiomyocytes using adenovirus-mediated gene transfer blocked the activation of p38, JNK1/2, and ERK1/2 and prevented agonist-induced hypertrophy. Transgenic mice expressing physiological levels of MKP-1 in the heart showed (1) no activation of p38, JNK1/2, or ERK1/2; (2) diminished developmental myocardial growth; and (3) attenuated hypertrophy in response to aortic banding and catecholamine infusion. These results provide further evidence implicating MAPK signaling factors as obligate regulators of cardiac growth and hypertrophy and demonstrate the importance of dual-specificity phosphatases as counterbalancing regulatory factors in the heart.

  19. Repetitive Transient Ischemia-Induced Cardiac Angiogenesis is Mediated by Camkii Activation

    Directory of Open Access Journals (Sweden)

    Zhuobin Chen

    2018-05-01

    Full Text Available Background/Aims: Coronary angiogenesis is an important protective mechanism in response to myocardial ischemia in coronary artery disease. However, the underlying mechanisms remain largely unclear. Here, we investigated the role of CaMKII activation in ischemia-induced cardiac angiogenesis. Methods: Repetitive transient ischemia model was established in C57/BL6 mice by daily multiple episodes (3 times/day of short time (5 min occlusion of the left anterior descending coronary artery for 7 days. Coronary angiogenesis was detected by immunofluorescent staining. RT-qPCR and Western blot analyses were used to detect the mRNA and protein levels of CaMKII, p-CaMKII and VEGF. Primary cardiac microvascular endothelial cells (CMECs were isolated to investigate the effects of KN93 on cell proliferation and migration in hypoxic condition. Results: We found that angiogenesis was induced in the ischemic myocardium and suppressed by chronic intraperitoneal injection of CaMKII inhibitor KN93. RT-qPCR and Western blot analyses showed that myocardial ischemia induced an increased expression and autophosphorylation of CaMKII. VEGF expression was increased in the ischemia model but blunted by KN93. Moreover, KN93 suppressed the proliferation and migration of cardiac endothelial cells in hypoxic condition in which the protein expression of CaMKII, p-CaMKII and VEGF was increased. Conclusion: CaMKII is an important mediator for the ischemia-induced coronary angiogenesis, in which CaMKII-triggered VEGF expression plays a key role.

  20. GATA4-mediated cardiac hypertrophy induced by D-myo-inositol 1,4,5-tris-phosphate

    International Nuclear Information System (INIS)

    Zhu Zhiming; Zhu Shanjun; Liu Daoyan; Yu Zengping; Yang Yongjian; Giet, Markus van der; Tepel, Martin

    2005-01-01

    We evaluated the effects of D-myo-inositol 1,4,5-tris-phosphate on cardiac hypertrophy. D-myo-inositol 1,4,5-tris-phosphate augmented cardiac hypertrophy as evidenced by its effects on DNA synthesis, protein synthesis, and expression of immediate-early genes c-myc and c-fos, β-myosin heavy chain, and α-actin. The administration of D-myo-inositol 1,4,5-tris-phosphate increased the expression of nuclear factor of activated T-cells and cardiac-restricted zinc finger transcription factor (GATA4). Real-time quantitative RT-PCR showed that D-myo-inositol 1,4,5-tris-phosphate-induced GATA4 mRNA was significantly enhanced even in the presence of the calcineurin inhibitor, cyclosporine A. The effect of D-myo-inositol 1,4,5-tris-phosphate was blocked after inhibition of inositol-trisphosphate receptors but not after inhibition of c-Raf/mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (ERK) or p38 mitogen-activated protein kinase pathways. The study shows that D-myo-inositol 1,4,5-tris-phosphate-induced cardiac hypertrophy is mediated by GATA4 but independent from the calcineurin pathway

  1. Establishment of a PRKAG2 cardiac syndrome disease model and mechanism study using human induced pluripotent stem cells.

    Science.gov (United States)

    Zhan, Yongkun; Sun, Xiaolei; Li, Bin; Cai, Huanhuan; Xu, Chen; Liang, Qianqian; Lu, Chao; Qian, Ruizhe; Chen, Sifeng; Yin, Lianhua; Sheng, Wei; Huang, Guoying; Sun, Aijun; Ge, Junbo; Sun, Ning

    2018-04-01

    PRKAG2 cardiac syndrome is a distinct form of human cardiomyopathy characterized by cardiac hypertrophy, ventricular pre-excitation and progressive cardiac conduction disorder. However, it remains unclear how mutations in the PRKAG2 gene give rise to such a complicated disease. To investigate the underlying molecular mechanisms, we generated disease-specific hiPSC-derived cardiomyocytes from two brothers both carrying a heterozygous missense mutation c.905G>A (R302Q) in the PRKAG2 gene and further corrected the R302Q mutation with CRISPR-Cas9 mediated genome editing. Disease-specific hiPSC-cardiomyocytes recapitulated many phenotypes of PRKAG2 cardiac syndrome including cellular enlargement, electrophysiological irregularities and glycogen storage. In addition, we found that the PRKAG2-R302Q mutation led to increased AMPK activities, resulting in extensive glycogen deposition and cardiomyocyte hypertrophy. Finally we confirmed that disrupted phenotypes of PRKAG2 cardiac syndrome caused by the specific PRKAG2-R302Q mutation can be alleviated by small molecules inhibiting AMPK activity and be rescued with CRISPR-Cas9 mediated genome correction. Our results showed that disease-specific hiPSC-CMs and genetically-corrected hiPSC-cardiomyocytes would be a very useful platform for understanding the pathogenesis of, and testing autologous cell-based therapies for, PRKAG2 cardiac syndrome. Copyright © 2018. Published by Elsevier Ltd.

  2. Pathological effects of chronic myocardial infarction on peripheral neurons mediating cardiac neurotransmission.

    Science.gov (United States)

    Nakamura, Keijiro; Ajijola, Olujimi A; Aliotta, Eric; Armour, J Andrew; Ardell, Jeffrey L; Shivkumar, Kalyanam

    2016-05-01

    To determine whether chronic myocardial infarction (MI) induces structural and neurochemical changes in neurons within afferent and efferent ganglia mediating cardiac neurotransmission. Neuronal somata in i) right atrial (RAGP) and ii) ventral interventricular ganglionated plexi (VIVGP), iii) stellate ganglia (SG) and iv) T1-2 dorsal root ganglia (DRG) bilaterally derived from normal (n=8) vs. chronic MI (n=8) porcine subjects were studied. We examined whether the morphology and neuronal nitric oxide synthase (nNOS) expression in soma of RAGP, VIVGP, DRG and SG neurons were altered as a consequence of chronic MI. In DRG, we also examined immunoreactivity of calcitonin gene related peptide (CGRP), a marker of afferent neurons. Chronic MI increased neuronal size and nNOS immunoreactivity in VIVGP (but not RAGP), as well as in the SG bilaterally. Across these ganglia, the increase in neuronal size was more pronounced in nNOS immunoreactive neurons. In the DRG, chronic MI also caused neuronal enlargement, and increased CGRP immunoreactivity. Further, DRG neurons expressing both nNOS and CGRP were increased in MI animals compared to controls, and represented a shift from double negative neurons. Chronic MI impacts diverse elements within the peripheral cardiac neuraxis. That chronic MI imposes such widespread, diverse remodeling of the peripheral cardiac neuraxis must be taken into consideration when contemplating neuronal regulation of the ischemic heart. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. PATHOLOGICAL EFFECTS OF CHRONIC MYOCARDIAL INFARCTION ON PERIPHERAL NEURONS MEDIATING CARDIAC NEUROTRANSMISSION

    Science.gov (United States)

    Nakamura, Keijiro; Ajijola, Olujimi A.; Aliotta, Eric; Armour, J. Andrew; Ardell, Jeffrey L.; Shivkumar, Kalyanam

    2016-01-01

    Objective To determine whether chronic myocardial infarction (MI) induces structural and neurochemical changes in neurons within afferent and efferent ganglia mediating cardiac neurotransmission. Methods Neuronal somata in i) right atrial (RAGP) and ii) ventral interventricular ganglionated plexi (VIVGP), iii) stellate ganglia (SG) and iv) T1-2 dorsal root ganglia (DRG) bilaterally derived from normal (n = 8) vs. chronic MI (n = 8) porcine subjects were studied. We examined whether the morphology and neuronal nitric oxide synthase (nNOS) expression in soma of RAGP, VIVGP, DRG and SG neurons were altered as a consequence of chronic MI. In DRG, we also examined immunoreactivity of calcitonin gene related peptide (CGRP), a marker of afferent neurons. Results Chronic MI increased neuronal size and nNOS immunoreactivity in VIVGP (but not RAGP), as well as in the SG bilaterally. Across these ganglia, the increase in neuronal size was more pronounced in nNOS immunoreacitive neurons. In the DRG, chronic MI also caused neuronal enlargement, and increased CGRP immunoreactivity. Further, DRG neurons expressing both nNOS and CGRP were increased in MI animals compared to controls, and represented a shift from double negative neurons. Conclusions Chronic MI impacts diverse elements within the peripheral cardiac neuraxis. That chronic MI imposes such widespread, diverse remodeling of the peripheral cardiac neuraxis must be taken into consideration when contemplating neuronal regulation of the ischemic heart. PMID:27209472

  4. Posttraumatic growth in patients who survived cardiac surgery: the predictive and mediating roles of faith-based factors.

    Science.gov (United States)

    Ai, Amy L; Hall, Daniel; Pargament, Kenneth; Tice, Terrence N

    2013-04-01

    Despite the growing knowledge of posttraumatic growth, only a few studies have examined personal growth in the context of cardiac health. Similarly, longitudinal research is lacking on the implications of religion/spirituality for patients with advanced cardiac diseases. This paper aims to explore the effect of preoperative religious coping on long-term postoperative personal growth and potential mediation in this effect. Analyses capitalized on a preoperative survey and medical indices from the Society of Thoracic Surgeons' National Database of patients undergoing cardiac surgery. Participants in the current follow-up study completed a mailed survey 30 months after surgery. Hierarchical regression analysis was performed to evaluate the extent to which preoperative use of religious coping predicted growth at follow-up, after controlling for key demographics, medical indices, mental health, and protective factors. Predictors of posttraumatic growth at follow-up were positive religious coping and a living status without a partner. Medical indices, optimistic expectations, social support, and other religious factors were unrelated to posttraumatic growth. Including religious factors diminished effects of gender, age, and race. Including perceived spiritual support completely eliminated the role of positive religious coping, indicating mediation. Preoperative positive religious coping may have a long-term effect on postoperative personal growth, explainable by higher spiritual connections as a part of significance-making. These results suggest that spirituality may play a favorable role in cardiac patients' posttraumatic growth after surviving a life-altering operation. The elimination of demographic effects may help explain previously mixed findings concerning the association between these factors and personal growth.

  5. Aging and the cardiac collagen matrix: Novel mediators of fibrotic remodelling.

    Science.gov (United States)

    Horn, Margaux A; Trafford, Andrew W

    2016-04-01

    Cardiovascular disease is a leading cause of death worldwide and there is a pressing need for new therapeutic strategies to treat such conditions. The risk of developing cardiovascular disease increases dramatically with age, yet the majority of experimental research is executed using young animals. The cardiac extracellular matrix (ECM), consisting predominantly of fibrillar collagen, preserves myocardial integrity, provides a means of force transmission and supports myocyte geometry. Disruptions to the finely balanced control of collagen synthesis, post-synthetic deposition, post-translational modification and degradation may have detrimental effects on myocardial functionality. It is now well established that the aged heart is characterized by fibrotic remodelling, but the mechanisms responsible for this are incompletely understood. Furthermore, studies using aged animal models suggest that interstitial remodelling with disease may be age-dependent. Thus with the identification of new therapeutic strategies targeting fibrotic remodelling, it may be necessary to consider age-dependent mechanisms. In this review, we discuss remodelling of the cardiac collagen matrix as a function of age, whilst highlighting potential novel mediators of age-dependent fibrotic pathways. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  6. Growth factors mediated differentiation of mesenchymal stem cells to cardiac polymicrotissue using hanging drop and bioreactor.

    Science.gov (United States)

    Konstantinou, Dimitrios; Lei, Ming; Xia, Zhidao; Kanamarlapudi, Venkateswarlu

    2015-04-01

    Heart disease is the major leading cause of death worldwide and the use of stem cells promises new ways for its treatment. The relatively easy and quick acquisition of human umbilical cord matrix mesenchymal stem cells (HUMSCs) and their properties make them useful for the treatment of cardiac diseases. Therefore, the main aim of this investigation was to create cardiac polymicrotissue from HUMSCs using a combination of growth factors [sphingosine-1-phosphate (S1P) and suramin] and techniques (hanging drop and bioreactor). Using designated culture conditions of the growth factors (100 nM S1P and 500 µM suramin), cardiomyocyte differentiation medium (CDM), hanging drop, bioreactor and differentiation for 7 days, a potential specific cardiac polymicrotissue was derived from HUMSCs. The effectiveness of growth factors alone or in combination in differentiation of HUMSCs to cardiac polymicrotissue was analysed by assessing the presence of cardiac markers by immunocytochemistry. This analysis demonstrated the importance of those growth factors for the differentiation. This study for the first time demonstrated the formation of a cardiac polymicrotissue under specific culture conditions. The polymicrotissue thus obtained may be used in future as a 'patch' to cover the injured cardiac region and would thereby be useful for the treatment of heart diseases. © 2014 International Federation for Cell Biology.

  7. Mitragynine and its potential blocking effects on specific cardiac potassium channels

    Energy Technology Data Exchange (ETDEWEB)

    Tay, Yea Lu; Teah, Yi Fan; Chong, Yoong Min [Malaysian Institute of Pharmaceuticals & Nutraceuticals, NIBM, Ministry of Science, Technology & Innovation (MOSTI), Pulau Pinang (Malaysia); Jamil, Mohd Fadzly Amar [Clinical Research Center, Hospital Seberang Jaya, Kementerian Kesihatan Malaysia, Pulau Pinang (Malaysia); Kollert, Sina [Institute of Physiology, University of Wurzburg, Wurzburg (Germany); Adenan, Mohd Ilham [Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Selangor Darul Ehsan (Malaysia); Wahab, Habibah Abdul [Pharmaceutical Design & Simulation (PhDS) Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Pulau Pinang (Malaysia); Döring, Frank; Wischmeyer, Erhard [Institute of Physiology, University of Wurzburg, Wurzburg (Germany); Tan, Mei Lan, E-mail: tanml@usm.my [Malaysian Institute of Pharmaceuticals & Nutraceuticals, NIBM, Ministry of Science, Technology & Innovation (MOSTI), Pulau Pinang (Malaysia); Advanced Medical and Dental Institute, Universiti Sains Malaysia, Pulau Pinang (Malaysia)

    2016-08-15

    Mitragyna speciosa Korth is known for its euphoric properties and is frequently used for recreational purposes. Several poisoning and fatal cases involving mitragynine have been reported but the underlying causes remain unclear. Human ether-a-go-go-related gene (hERG) encodes the cardiac I{sub Kr} current which is a determinant of the duration of ventricular action potentials and QT interval. On the other hand, I{sub K1}, a Kir current mediated by Kir2.1 channel and I{sub KACh}, a receptor-activated Kir current mediated by GIRK channel are also known to be important in maintaining the cardiac function. This study investigated the effects of mitragynine on the current, mRNA and protein expression of hERG channel in hERG-transfected HEK293 cells and Xenopus oocytes. The effects on Kir2.1 and GIRK channels currents were also determined in the oocytes. The hERG tail currents following depolarization pulses were inhibited by mitragynine with an IC{sub 50} value of 1.62 μM and 1.15 μM in the transfected cell line and Xenopus oocytes, respectively. The S6 point mutations of Y652A and F656A attenuated the inhibitor effects of mitragynine, indicating that mitragynine interacts with these high affinity drug-binding sites in the hERG channel pore cavity which was consistent with the molecular docking simulation. Interestingly, mitragynine does not affect the hERG expression at the transcriptional level but inhibits the protein expression. Mitragynine is also found to inhibit I{sub KACh} current with an IC{sub 50} value of 3.32 μM but has no significant effects on I{sub K1}. Blocking of both hERG and GIRK channels may cause additive cardiotoxicity risks. - Highlights: • The potential cardiac potassium channel blocking properties of mitragynine were investigated. • Mitragynine blocks hERG channel and I{sub Kr} in hERG-transfected HEK293 cells and hERG cRNA-injected Xenopus oocytes. • Mitragynine inhibits the hERG protein but not the mRNA expression. • Mitragynine

  8. Mitragynine and its potential blocking effects on specific cardiac potassium channels

    International Nuclear Information System (INIS)

    Tay, Yea Lu; Teah, Yi Fan; Chong, Yoong Min; Jamil, Mohd Fadzly Amar; Kollert, Sina; Adenan, Mohd Ilham; Wahab, Habibah Abdul; Döring, Frank; Wischmeyer, Erhard; Tan, Mei Lan

    2016-01-01

    Mitragyna speciosa Korth is known for its euphoric properties and is frequently used for recreational purposes. Several poisoning and fatal cases involving mitragynine have been reported but the underlying causes remain unclear. Human ether-a-go-go-related gene (hERG) encodes the cardiac I Kr current which is a determinant of the duration of ventricular action potentials and QT interval. On the other hand, I K1 , a Kir current mediated by Kir2.1 channel and I KACh , a receptor-activated Kir current mediated by GIRK channel are also known to be important in maintaining the cardiac function. This study investigated the effects of mitragynine on the current, mRNA and protein expression of hERG channel in hERG-transfected HEK293 cells and Xenopus oocytes. The effects on Kir2.1 and GIRK channels currents were also determined in the oocytes. The hERG tail currents following depolarization pulses were inhibited by mitragynine with an IC 50 value of 1.62 μM and 1.15 μM in the transfected cell line and Xenopus oocytes, respectively. The S6 point mutations of Y652A and F656A attenuated the inhibitor effects of mitragynine, indicating that mitragynine interacts with these high affinity drug-binding sites in the hERG channel pore cavity which was consistent with the molecular docking simulation. Interestingly, mitragynine does not affect the hERG expression at the transcriptional level but inhibits the protein expression. Mitragynine is also found to inhibit I KACh current with an IC 50 value of 3.32 μM but has no significant effects on I K1 . Blocking of both hERG and GIRK channels may cause additive cardiotoxicity risks. - Highlights: • The potential cardiac potassium channel blocking properties of mitragynine were investigated. • Mitragynine blocks hERG channel and I Kr in hERG-transfected HEK293 cells and hERG cRNA-injected Xenopus oocytes. • Mitragynine inhibits the hERG protein but not the mRNA expression. • Mitragynine inhibits GIRK channel. • Simultaneous

  9. Cyclin D2 is a critical mediator of exercise-induced cardiac hypertrophy.

    Science.gov (United States)

    Luckey, Stephen W; Haines, Chris D; Konhilas, John P; Luczak, Elizabeth D; Messmer-Kratzsch, Antke; Leinwand, Leslie A

    2017-12-01

    induced cardiac growth in all of the transgenic mice except for the mice deficient in cyclin D2. In the cyclin D2 null mice, cardiac function was not impacted even though the hypertrophic response was blunted and a number of signaling pathways are differentially regulated by exercise. These data provide the field with an understanding that cyclin D2 is a key mediator of physiological hypertrophy.

  10. Novel mechanism of cardiac protection by valsartan: synergetic roles of TGF-β1 and HIF-1α in Ang II-mediated fibrosis after myocardial infarction.

    Science.gov (United States)

    Sui, Xizhong; Wei, Hongchao; Wang, Dacheng

    2015-08-01

    Transforming growth factor (TGF)-β1 is a known factor in angiotensin II (Ang II)-mediated cardiac fibrosis after myocardial infarction (MI). Hypoxia inducible factor-1 (Hif-1α) was recently demonstrated to involve in the tissue fibrosis and influenced by Ang II. However, whether Hif-1α contributed to the Ang II-mediated cardiac fibrosis after MI, and whether interaction or synergetic roles between Hif-1α and TGF-β pathways existed in the process was unclear. In vitro, cardiac cells were incubated under hypoxia or Ang II to mimic ischaemia. In vivo, valsartan was intravenously injected into Sprague-Dawley rats with MI daily for 1 week; saline and hydralazine (another anti-hypertensive agent like valsartan) was used as control. The fibrosis-related proteins were detected by Western blotting. Cardiac structure and function were assessed with multimodality methods. We demonstrated in vitro that hypoxia would induce the up-regulation of Ang II, TGF-β/Smad and Hif-1α, which further induced collagen accumulation. By blocking with valsartan, a blocker of Ang II type I (AT1) receptor, we confirmed that the up-regulation of TGF-β/Smad and Hif-1α was through the Ang II-mediated pathway. By administering TGF-β or dimethyloxalylglycine, we determined that both TGF-β/Smad and Hif-1α contributed to Ang II-mediated collagen accumulation and a synergetic effect between them was observed. Consistent with in vitro results, valsartan significantly attenuated the expression of TGF-β/Smad, Hif-1α and fibrosis-related protein in rats after MI. Heart function, infarcted size, wall thickness as well as myocardial vascularization of ischaemic hearts were also significantly improved by valsartan compared with saline and hydralazine. Our study may provide novel insights into the mechanisms of Ang II-induced cardiac fibrosis as well as into the cardiac protection of valsartan. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and

  11. Immunosuppression in cardiac graft rejection: A human in vitro model to study the potential use of new immunomodulatory drugs

    International Nuclear Information System (INIS)

    Crescioli, Clara; Squecco, Roberta; Cosmi, Lorenzo; Sottili, Mariangela; Gelmini, Stefania; Borgogni, Elisa; Sarchielli, Erica; Scolletta, Sabino; Francini, Fabio; Annunziato, Francesco; Vannelli, Gabriella Barbara; Serio, Mario

    2008-01-01

    CXCL10-CXCR3 axis plays a pivotal role in cardiac allograft rejection, so that targeting CXCL10 without inducing generalized immunosuppression may be of therapeutic significance in allotransplantation. Since the role of resident cells in cardiac rejection is still unclear, we aimed to establish reliable human cardiomyocyte cultures to investigate Th1 cytokine-mediated response in allograft rejection. We used human fetal cardiomyocytes (Hfcm) isolated from fetal hearts, obtained after legal abortions. Hfcm expressed specific cardiac lineage markers, specific cardiac structural proteins, typical cardiac currents and generated ventricular action potentials. Thus, Hfcm represent a reliable in vitro tool for allograft rejection research, since they resemble the features of mature cells. Hfcm secreted CXCL10 in response to IFNγ and TNFαα; this effect was magnified by cytokine combination. Cytokine synergy was associated to a significant TNFα-induced up-regulation of IFNγR. The response of Hfcm to some currently used immunosuppressive drugs compared to rosiglitazone, a peroxisome proliferator-activated receptor γ agonist and Th1-mediated response inhibitor, was also evaluated. Only micophenolic acid and rosiglitazone halved CXCL10 secretion by Hfcm. Given the pivotal role of IFNγ-induced chemokines in Th1-mediated allograft rejection, these preliminary results suggest that the combined effects of immunosuppressive agents and rosiglitazone could be potentially beneficial to patients receiving heart transplants

  12. Cardiac-Specific Overexpression of Catalase Attenuates Lipopolysaccharide-Induced Myocardial Contractile Dysfunction: Role of Autophagy

    OpenAIRE

    Turdi, Subat; Han, Xuefeng; Huff, Anna F.; Roe, Nathan D.; Hu, Nan; Gao, Feng; Ren, Jun

    2012-01-01

    Lipopolysaccharide (LPS) from Gram-negative bacteria is a major initiator of sepsis, leading to cardiovascular collapse. Accumulating evidence has indicated a role of reactive oxygen species (ROS) in cardiovascular complication in sepsis. This study was designed to examine the effect of cardiac-specific overexpression of catalase in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Catalase transgenic and wild-type FVB mice were challenged ...

  13. Cardiac integrins the ties that bind.

    Science.gov (United States)

    Simpson, D G; Reaves, T A; Shih, D T; Burgess, W; Borg, T K; Terracio, L

    1998-01-01

    An elaborate series of morphogenetic events must be precisely coordinated during development to promote the formation of the elaborate three-dimensional structure of the normal heart. In this study we focus on discussing how interconnections between the cardiac myocyte and its surrounding environment regulate cardiac form and function. In vitro experiments from our laboratories provide direct evidence that cardiac cell shape is regulated by a dynamic interaction between constituents of the extracellular matrix (ECM) and by specific members of the integrin family of matrix receptors. Our data indicates that phenotypic information is stored in the tertiary structure and chemical identity of the ECM. This information appears to be actively communicated and transduced by the α1β1 integrin molecule into an intracellular signal that regulates cardiac cell shape and myofibrillar organization. In this study we have assessed the phenotypic consequences of suppressing the expression and accumulation of the α1 integrin molecule in aligned cultures of cardiac myocytes. In related experiments we have examined how the overexpression of α2 and α5 integrin, integrins normally not present or present at very low copy number on the cell surface of neonatal cardiac myocytes, affect cardiac protein metabolism. We also consider how biochemical signals and the mechanical signals mediated by the integrins may converge on common intracellular signaling pathways in the heart. Experiments with the whole embryo culture system indicate that angiotensin II, a peptide that carries information concerning cardiac load, plays a role in controling cardiac looping and the proliferation of myofibrils during development.

  14. Serial measurement of neuron specific enolase improves prognostication in cardiac arrest patients treated with hypothermia: A prospective study

    Directory of Open Access Journals (Sweden)

    Storm Christian

    2012-01-01

    Full Text Available Abstract Background Neuron specific enolase (NSE has repeatedly been evaluated for neurological prognostication in patients after cardiac arrest. However, it is unclear whether current guidelines for NSE cutoff levels also apply to cardiac arrest patients treated with hypothermia. Thus, we investigated the prognostic significance of absolute NSE levels and NSE kinetics in cardiac arrest patients treated with hypothermia. Methods In a prospective study of 35 patients resuscitated from cardiac arrest, NSE was measured daily for four days following admission. Outcome was assessed at ICU discharge using the CPC score. All patients received hypothermia treatment for 24 hours at 33°C with a surface cooling device according to current guidelines. Results The cutoff for absolute NSE levels in patients with unfavourable outcome (CPC 3-5 72 hours after cardiac arrest was 57 μg/l with an area under the curve (AUC of 0.82 (sensitivity 47%, specificity 100%. The cutoff level for NSE kinetics in patients with unfavourable outcome (CPC 3-5 was an absolute increase of 7.9 μg/l (AUC 0.78, sensitivity 63%, specificity 100% and a relative increase of 33.1% (AUC 0.803, sensitivity 67%, specificity 100% at 48 hours compared to admission. Conclusion In cardiac arrest patients treated with hypothermia, prognostication of unfavourable outcome by NSE kinetics between admission and 48 hours after resuscitation may be superior to prognostication by absolute NSE levels.

  15. Toll‐Like Receptor‐2 Mediates Adaptive Cardiac Hypertrophy in Response to Pressure Overload Through Interleukin‐1β Upregulation via Nuclear Factor κB Activation

    Science.gov (United States)

    Higashikuni, Yasutomi; Tanaka, Kimie; Kato, Megumi; Nureki, Osamu; Hirata, Yasunobu; Nagai, Ryozo; Komuro, Issei; Sata, Masataka

    2013-01-01

    Background Inflammation is induced in the heart during the development of cardiac hypertrophy. The initiating mechanisms and the role of inflammation in cardiac hypertrophy, however, remain unclear. Toll‐like receptor‐2 (TLR2) recognizes endogenous molecules that induce noninfectious inflammation. Here, we examined the role of TLR2‐mediated inflammation in cardiac hypertrophy. Methods and Results At 2 weeks after transverse aortic constriction, Tlr2−/− mice showed reduced cardiac hypertrophy and fibrosis with greater left ventricular dilatation and impaired systolic function compared with wild‐type mice, which indicated impaired cardiac adaptation in Tlr2−/− mice. Bone marrow transplantation experiment revealed that TLR2 expressed in the heart, but not in bone marrow–derived cells, is important for cardiac adaptive response to pressure overload. In vitro experiments demonstrated that TLR2 signaling can induce cardiomyocyte hypertrophy and fibroblast and vascular endothelial cell proliferation through nuclear factor–κB activation and interleukin‐1β upregulation. Systemic administration of a nuclear factor–κB inhibitor or anti–interleukin‐1β antibodies to wild‐type mice resulted in impaired adaptive cardiac hypertrophy after transverse aortic constriction. We also found that heat shock protein 70, which was increased in murine plasma after transverse aortic constriction, can activate TLR2 signaling in vitro and in vivo. Systemic administration of anti–heat shock protein 70 antibodies to wild‐type mice impaired adaptive cardiac hypertrophy after transverse aortic constriction. Conclusions Our results demonstrate that TLR2‐mediated inflammation induced by extracellularly released heat shock protein 70 is essential for adaptive cardiac hypertrophy in response to pressure overload. Thus, modulation of TLR2 signaling in the heart may provide a novel strategy for treating heart failure due to inadequate adaptation to hemodynamic

  16. Egr-1 Upregulates Siva-1 Expression and Induces Cardiac Fibroblast Apoptosis

    Directory of Open Access Journals (Sweden)

    Karin Zins

    2014-01-01

    Full Text Available The early growth response transcription factor Egr-1 controls cell specific responses to proliferation, differentiation and apoptosis. Expression of Egr-1 and downstream transcription is closely controlled and cell specific upregulation induced by processes such as hypoxia and ischemia has been previously linked to multiple aspects of cardiovascular injury. In this study, we showed constitutive expression of Egr-1 in cultured human ventricular cardiac fibroblasts, used adenoviral mediated gene transfer to study the effects of continuous Egr-1 overexpression and studied downstream transcription by Western blotting, immunohistochemistry and siRNA transfection. Apoptosis was assessed by fluorescence microscopy and flow cytometry in the presence of caspase inhibitors. Overexpression of Egr-1 directly induced apoptosis associated with caspase activation in human cardiac fibroblast cultures in vitro assessed by fluorescence microscopy and flow cytometry. Apoptotic induction was associated with a caspase activation associated loss of mitochondrial membrane potential and transient downstream transcriptional up-regulation of the pro-apoptotic gene product Siva-1. Suppression of Siva-1 induction by siRNA partially reversed Egr-1 mediated loss of cell viability. These findings suggest a previously unknown role for Egr-1 and transcriptional regulation of Siva-1 in the control of cardiac accessory cell death.

  17. IL-34 is a Treg-specific cytokine and mediates transplant tolerance

    OpenAIRE

    Bézie, Séverine; Picarda, Elodie; Ossart, Jason; Tesson, Laurent; Usal, Claire; Renaudin, Karine; Anegon, Ignacio; Guillonneau, Carole

    2015-01-01

    Cytokines and metabolic pathway–controlling enzymes regulate immune responses and have potential as powerful tools to mediate immune tolerance. Blockade of the interaction between CD40 and CD40L induces long-term cardiac allograft survival in rats through a CD8+CD45RClo Treg potentiation. Here, we have shown that the cytokine IL-34, the immunoregulatory properties of which have not been previously studied in transplantation or T cell biology, is expressed by rodent CD8+CD45RClo Tregs and huma...

  18. Small Engine, Big Power: MicroRNAs as Regulators of Cardiac Diseases and Regeneration

    Directory of Open Access Journals (Sweden)

    Darukeshwara Joladarashi

    2014-09-01

    Full Text Available Cardiac diseases are the predominant cause of human mortality in the United States and around the world. MicroRNAs (miRNAs are small non-coding RNAs that have been shown to modulate a wide range of biological functions under various pathophysiological conditions. miRNAs alter target expression by post-transcriptional regulation of gene expression. Numerous studies have implicated specific miRNAs in cardiovascular development, pathology, regeneration and repair. These observations suggest that miRNAs are potential therapeutic targets to prevent or treat cardiovascular diseases. This review focuses on the emerging role of miRNAs in cardiac development, pathogenesis of cardiovascular diseases, cardiac regeneration and stem cell-mediated cardiac repair. We also discuss the novel diagnostic and therapeutic potential of these miRNAs and their targets in patients with cardiac diseases.

  19. Deregulated Cardiac Specific MicroRNAs in Postnatal Heart Growth

    Directory of Open Access Journals (Sweden)

    Pujiao Yu

    2016-01-01

    Full Text Available The heart is recognized as an organ that is terminally differentiated by adulthood. However, during the process of human development, the heart is the first organ with function in the embryo and grows rapidly during the postnatal period. MicroRNAs (miRNAs, miRs, as regulators of gene expression, play important roles during the development of multiple systems. However, the role of miRNAs in postnatal heart growth is still unclear. In this study, by using qRT-PCR, we compared the expression of seven cardiac- or muscle-specific miRNAs that may be related to heart development in heart tissue from mice at postnatal days 0, 3, 8, and 14. Four miRNAs—miR-1a-3p, miR-133b-3p, miR-208b-3p, and miR-206-3p—were significantly decreased while miR-208a-3p was upregulated during the postnatal heart growth period. Based on these results, GeneSpring GX was used to predict potential downstream targets by performing a 3-way comparison of predictions from the miRWalk, PITA, and microRNAorg databases. Gene Ontology (GO and Kyoto Encyclopedia of Genes and Genomes (KEGG analysis were used to identify potential functional annotations and signaling pathways related to postnatal heart growth. This study describes expression changes of cardiac- and muscle-specific miRNAs during postnatal heart growth and may provide new therapeutic targets for cardiovascular diseases.

  20. The relative contribution of paracine effect versus direct differentiation on adipose-derived stem cell transplantation mediated cardiac repair.

    Directory of Open Access Journals (Sweden)

    Dezhong Yang

    Full Text Available BACKGROUND: Recent studies have demonstrated that transplantation of adipose-derived stem cell (ADSC can improve cardiac function in animal models of myocardial infarction (MI. However, the mechanisms underlying the beneficial effect are not fully understood. In this study, we characterized the paracrine effect of transplanted ADSC and investigated its relative importance versus direct differentiation in ADSC transplantation mediated cardiac repair. METHODOLOGY/PRINCIPAL FINDINGS: MI was experimentally induced in mice by ligation of the left anterior descending coronary artery. Either human ADSC, conditioned medium (CM collected from the same amount of ADSC or control medium was injected into the peri-infarct region immediately after MI. Compared with the control group, both ADSC and ADSC-CM significantly reduced myocardial infarct size and improved cardiac function. The therapeutic efficacy of ADSC was moderately superior to ADSC-CM. ADSC-CM significantly reduced cardiomyocyte apoptosis in the infarct border zone, to a similar degree with ADSC treatment. ADSC enhanced angiogenesis in the infarct border zone, but to a stronger degree than that seen in the ADSC-CM treatment. ADSC was able to differentiate to endothelial cell and smooth muscle cell in post-MI heart; these ADSC-derived vascular cells amount to about 9% of the enhanced angiogenesis. No cardiomyocyte differentiated from ADSC was found. CONCLUSIONS: ADSC-CM is sufficient to improve cardiac function of infarcted hearts. The therapeutic function of ADSC transplantation is mainly induced by paracrine-mediated cardioprotection and angiogenesis, while ADSC differentiation contributes a minor benefit by being involved in angiogenesis. Highlights 1 ADSC-CM is sufficient to exert a therapeutic potential. 2. ADSC was able to differentiate to vascular cells but not cardiomyocyte. 3. ADSC derived vascular cells amount to about 9% of the enhanced angiogenesis. 4. Paracrine effect is the major

  1. TRPA1 mediates changes in heart rate variability and cardiac mechanical function in mice exposed to acrolein

    Energy Technology Data Exchange (ETDEWEB)

    Kurhanewicz, Nicole [Curriculum in Toxicology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599 (United States); McIntosh-Kastrinsky, Rachel [Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599 (United States); Tong, Haiyan; Ledbetter, Allen; Walsh, Leon; Farraj, Aimen [Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27711 (United States); Hazari, Mehdi, E-mail: hazari.mehdi@epa.gov [Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27711 (United States)

    2017-06-01

    Short-term exposure to ambient air pollution is linked with adverse cardiovascular effects. While previous research focused primarily on particulate matter-induced responses, gaseous air pollutants also contribute to cause short-term cardiovascular effects. Mechanisms underlying such effects have not been adequately described, however the immediate nature of the response suggests involvement of irritant neural activation and downstream autonomic dysfunction. Thus, this study examines the role of TRPA1, an irritant sensory receptor found in the airways, in the cardiac response of mice to acrolein and ozone. Conscious unrestrained wild-type C57BL/6 (WT) and TRPA1 knockout (KO) mice implanted with radiotelemeters were exposed once to 3 ppm acrolein, 0.3 ppm ozone, or filtered air. Heart rate (HR) and electrocardiogram (ECG) were recorded continuously before, during and after exposure. Analysis of ECG morphology, incidence of arrhythmia and heart rate variability (HRV) were performed. Cardiac mechanical function was assessed using a Langendorff perfusion preparation 24 h post-exposure. Acrolein exposure increased HRV independent of HR, as well as incidence of arrhythmia. Acrolein also increased left ventricular developed pressure in WT mice at 24 h post-exposure. Ozone did not produce any changes in cardiac function. Neither gas produced ECG effects, changes in HRV, arrhythmogenesis, or mechanical function in KO mice. These data demonstrate that a single exposure to acrolein causes cardiac dysfunction through TRPA1 activation and autonomic imbalance characterized by a shift toward parasympathetic modulation. Furthermore, it is clear from the lack of ozone effects that although gaseous irritants are capable of eliciting immediate cardiac changes, gas concentration and properties play important roles. - Highlights: • Acute acrolein exposure causes autonomic imbalance and altered CV function in mice. • TRPA1 mediates acrolein-induced autonomic nervous system cardiac

  2. TRPA1 mediates changes in heart rate variability and cardiac mechanical function in mice exposed to acrolein

    International Nuclear Information System (INIS)

    Kurhanewicz, Nicole; McIntosh-Kastrinsky, Rachel; Tong, Haiyan; Ledbetter, Allen; Walsh, Leon; Farraj, Aimen; Hazari, Mehdi

    2017-01-01

    Short-term exposure to ambient air pollution is linked with adverse cardiovascular effects. While previous research focused primarily on particulate matter-induced responses, gaseous air pollutants also contribute to cause short-term cardiovascular effects. Mechanisms underlying such effects have not been adequately described, however the immediate nature of the response suggests involvement of irritant neural activation and downstream autonomic dysfunction. Thus, this study examines the role of TRPA1, an irritant sensory receptor found in the airways, in the cardiac response of mice to acrolein and ozone. Conscious unrestrained wild-type C57BL/6 (WT) and TRPA1 knockout (KO) mice implanted with radiotelemeters were exposed once to 3 ppm acrolein, 0.3 ppm ozone, or filtered air. Heart rate (HR) and electrocardiogram (ECG) were recorded continuously before, during and after exposure. Analysis of ECG morphology, incidence of arrhythmia and heart rate variability (HRV) were performed. Cardiac mechanical function was assessed using a Langendorff perfusion preparation 24 h post-exposure. Acrolein exposure increased HRV independent of HR, as well as incidence of arrhythmia. Acrolein also increased left ventricular developed pressure in WT mice at 24 h post-exposure. Ozone did not produce any changes in cardiac function. Neither gas produced ECG effects, changes in HRV, arrhythmogenesis, or mechanical function in KO mice. These data demonstrate that a single exposure to acrolein causes cardiac dysfunction through TRPA1 activation and autonomic imbalance characterized by a shift toward parasympathetic modulation. Furthermore, it is clear from the lack of ozone effects that although gaseous irritants are capable of eliciting immediate cardiac changes, gas concentration and properties play important roles. - Highlights: • Acute acrolein exposure causes autonomic imbalance and altered CV function in mice. • TRPA1 mediates acrolein-induced autonomic nervous system cardiac

  3. Exercise and type 2 diabetes mellitus: changes in tissue-specific fat distribution and cardiac function.

    Science.gov (United States)

    Jonker, Jacqueline T; de Mol, Pieter; de Vries, Suzanna T; Widya, Ralph L; Hammer, Sebastiaan; van Schinkel, Linda D; van der Meer, Rutger W; Gans, Rijk O B; Webb, Andrew G; Kan, Hermien E; de Koning, Eelco J P; Bilo, Henk J G; Lamb, Hildo J

    2013-11-01

    To prospectively assess the effects of an exercise intervention on organ-specific fat accumulation and cardiac function in type 2 diabetes mellitus. Written informed consent was obtained from all participants, and the study protocol was approved by the medical ethics committee. The study followed 12 patients with type 2 diabetes mellitus (seven men; mean age, 46 years ± 2 [standard error]) before and after 6 months of moderate-intensity exercise, followed by a high-altitude trekking expedition with exercise of long duration. Abdominal, epicardial, and paracardial fat volume were measured by using magnetic resonance (MR) imaging. Cardiac function was quantified with cardiac MR, and images were analyzed by a researcher who was supervised by a senior researcher (4 and 21 years of respective experience in cardiac MR). Hepatic, myocardial, and intramyocellular triglyceride (TG) content relative to water were measured with proton MR spectroscopy at 1.5 and 7 T. Two-tailed paired t tests were used for statistical analysis. Exercise reduced visceral abdominal fat volume from 348 mL ± 57 to 219 mL ± 33 (P Exercise decreased hepatic TG content from 6.8% ± 2.3 to 4.6% ± 1.6 (P Exercise did not change epicardial fat volume (P = .9), myocardial TG content (P = .9), intramyocellular lipid content (P = .3), or cardiac function (P = .5). A 6-month exercise intervention in type 2 diabetes mellitus decreased hepatic TG content and visceral abdominal and paracardial fat volume, which are associated with increased cardiovascular risk, but cardiac function was unaffected. Tissue-specific exercise-induced changes in body fat distribution in type 2 diabetes mellitus were demonstrated in this study. RSNA, 2013

  4. Pre-transplantation specification of stem cells to cardiac lineage for regeneration of cardiac tissue.

    Science.gov (United States)

    Mayorga, Maritza; Finan, Amanda; Penn, Marc

    2009-03-01

    Myocardial infarction (MI) is a lead cause of mortality in the Western world. Treatment of acute MI is focused on restoration of antegrade flow which inhibits further tissue loss, but does not restore function to damaged tissue. Chronic therapy for injured myocardial tissue involves medical therapy that attempts to minimize pathologic remodeling of the heart. End stage therapy for chronic heart failure (CHF) involves inotropic therapy to increase surviving cardiac myocyte function or mechanical augmentation of cardiac performance. Not until the point of heart transplantation, a limited resource at best, does therapy focus on the fundamental problem of needing to replace injured tissue with new contractile tissue. In this setting, the potential for stem cell therapy has garnered significant interest for its potential to regenerate or create new contractile cardiac tissue. While to date adult stem cell therapy in clinical trials has suggested potential benefit, there is waning belief that the approaches used to date lead to regeneration of cardiac tissue. As the literature has better defined the pathways involved in cardiac differentiation, preclinical studies have suggested that stem cell pretreatment to direct stem cell differentiation prior to stem cell transplantation may be a more efficacious strategy for inducing cardiac regeneration. Here we review the available literature on pre-transplantation conditioning of stem cells in an attempt to better understand stem cell behavior and their readiness in cell-based therapy for myocardial regeneration.

  5. Quality specification and status of internal quality control of cardiac biomarkers in China from 2011 to 2016.

    Science.gov (United States)

    Li, Tingting; Wang, Wei; Zhao, Haijian; He, Falin; Zhong, Kun; Yuan, Shuai; Wang, Zhiguo

    2017-09-07

    This study aimed to investigate the status of internal quality control (IQC) for cardiac biomarkers from 2011 to 2016 so that we can have overall knowledge of the precision level of measurements in China and set appropriate precision specifications. Internal quality control data of cardiac biomarkers, including creatinine kinase MB (CK-MB) (μg/L), CK-MB(U/L), myoglobin (Mb), cardiac troponin I (cTnI), cardiac troponin T (cTnT), and homocysteines (HCY), were collected by a web-based external quality assessment (EQA) system. Percentages of laboratories meeting five precision quality specifications for current coefficient of variations (CVs) were calculated. Then, appropriate precision specifications were chosen for these six analytes. Finally, the CVs and IQC practice were further analyzed with different grouping methods. The current CVs remained nearly constant for 6 years. cTnT had the highest pass rates every year against five specifications, whereas HCY had the lowest pass rates. Overall, most analytes had a satisfactory performance (pass rates >80%), except for HCY, if one-third TEa or the minimum specification were employed. When the optimal specification was applied, the performance of most analytes was frustrating (pass rates < 60%) except for cTnT. The appropriate precision specifications of Mb, cTnI, cTnT and HCY were set as current CVs less than 9.20%, 9.90%, 7.50%, 10.54%, 7.63%, and 6.67%, respectively. The data of IQC practices indicated wide variation and substantial progress. The precision performance of cTnT was already satisfying, while the other five analytes, especially HCY, were still frustrating; thus, ongoing investigation and continuous improvement for IQC are still needed. © 2017 Wiley Periodicals, Inc.

  6. Cardiac Sirt1 mediates the cardioprotective effect of caloric restriction by suppressing local complement system activation after ischemia-reperfusion.

    Science.gov (United States)

    Yamamoto, Tsunehisa; Tamaki, Kayoko; Shirakawa, Kohsuke; Ito, Kentaro; Yan, Xiaoxiang; Katsumata, Yoshinori; Anzai, Atsushi; Matsuhashi, Tomohiro; Endo, Jin; Inaba, Takaaki; Tsubota, Kazuo; Sano, Motoaki; Fukuda, Keiichi; Shinmura, Ken

    2016-04-15

    Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion (I/R) injury. We previously found the essential roles of endothelial nitric oxide synthase in the development of CR-induced cardioprotection and Sirt1 activation during CR (Shinmura K, Tamaki K, Ito K, Yan X, Yamamoto T, Katsumata Y, Matsuhashi T, Sano M, Fukuda K, Suematsu M, Ishii I. Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury.Am J Physiol Heart Circ Physiol 308: H894-H903, 2015). However, the exact mechanism by which Sirt1 in cardiomyocytes mediates the cardioprotective effect of CR remains undetermined. We subjected cardiomyocyte-specific Sirt1 knockout (CM-Sirt1(-/-)) mice and the corresponding control mice to either 3-mo ad libitum feeding or CR (-40%). Isolated perfused hearts were subjected to 25-min global ischemia, followed by 60-min reperfusion. The recovery of left ventricle function after I/R was improved, and total lactate dehydrogenase release into the perfusate during reperfusion was attenuated in the control mice treated with CR, but a similar cardioprotective effect of CR was not observed in the CM-Sirt1(-/-)mice. The expression levels of cardiac complement component 3 (C3) at baseline and the accumulation of C3 and its fragments in the ischemia-reperfused myocardium were attenuated by CR in the control mice, but not in the CM-Sirt1(-/-)mice. Resveratrol treatment also attenuated the expression levels of C3 protein in cultured neonatal rat ventricular cardiomyocytes. Moreover, the degree of myocardial I/R injury in conventional C3 knockout (C3(-/-)) mice treated with CR was similar to that in the ad libitum-fed C3(-/-)mice, although the expression levels of Sirt1 were enhanced by CR. These results demonstrate that cardiac Sirt1 plays an essential role in CR-induced cardioprotection against I/R injury by suppressing cardiac C3 expression. This is the first report suggesting

  7. Psychosocial mediation of religious coping styles: a study of short-term psychological distress following cardiac surgery.

    Science.gov (United States)

    Ai, Amy L; Park, Crystal L; Huang, Bu; Rodgers, Willard; Tice, Terrence N

    2007-06-01

    Although religiousness and religious coping styles are well-documented predictors of well-being, research on the mechanisms through which religious coping styles operate is sparse. This prospective study examined religious coping styles, hope, and social support as pathways of the influence of general religiousness (religious importance and involvement) on the reduced postoperative psychological distress of 309 cardiac patients. Results of structural equation modeling indicated that controlling for preoperative distress, gender, and education, religiousness contributed to positive religious coping, which in turn was associated with less distress via a path fully mediated by the secular factors of social support and hope. Furthermore, negative religious coping styles, although correlated at the bivariate level with preoperative distress but not with religiousness, were associated both directly and indirectly with greater post-operative distress via the same mediators.

  8. Glutaredoxin-2 is required to control oxidative phosphorylation in cardiac muscle by mediating deglutathionylation reactions.

    Science.gov (United States)

    Mailloux, Ryan J; Xuan, Jian Ying; McBride, Skye; Maharsy, Wael; Thorn, Stephanie; Holterman, Chet E; Kennedy, Christopher R J; Rippstein, Peter; deKemp, Robert; da Silva, Jean; Nemer, Mona; Lou, Marjorie; Harper, Mary-Ellen

    2014-05-23

    Glutaredoxin-2 (Grx2) modulates the activity of several mitochondrial proteins in cardiac tissue by catalyzing deglutathionylation reactions. However, it remains uncertain whether Grx2 is required to control mitochondrial ATP output in heart. Here, we report that Grx2 plays a vital role modulating mitochondrial energetics and heart physiology by mediating the deglutathionylation of mitochondrial proteins. Deletion of Grx2 (Grx2(-/-)) decreased ATP production by complex I-linked substrates to half that in wild type (WT) mitochondria. Decreased respiration was associated with increased complex I glutathionylation diminishing its activity. Tissue glucose uptake was concomitantly increased. Mitochondrial ATP output and complex I activity could be recovered by restoring the redox environment to that favoring the deglutathionylated states of proteins. Grx2(-/-) hearts also developed left ventricular hypertrophy and fibrosis, and mice became hypertensive. Mitochondrial energetics from Grx2 heterozygotes (Grx2(+/-)) were also dysfunctional, and hearts were hypertrophic. Intriguingly, Grx2(+/-) mice were far less hypertensive than Grx2(-/-) mice. Thus, Grx2 plays a vital role in modulating mitochondrial metabolism in cardiac muscle, and Grx2 deficiency leads to pathology. As mitochondrial ATP production was restored by the addition of reductants, these findings may be relevant to novel redox-related therapies in cardiac disease. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Functions of PDE3 Isoforms in Cardiac Muscle

    Science.gov (United States)

    Movsesian, Matthew; Ahmad, Faiyaz

    2018-01-01

    Isoforms in the PDE3 family of cyclic nucleotide phosphodiesterases have important roles in cyclic nucleotide-mediated signalling in cardiac myocytes. These enzymes are targeted by inhibitors used to increase contractility in patients with heart failure, with a combination of beneficial and adverse effects on clinical outcomes. This review covers relevant aspects of the molecular biology of the isoforms that have been identified in cardiac myocytes; the roles of these enzymes in modulating cAMP-mediated signalling and the processes mediated thereby; and the potential for targeting these enzymes to improve the profile of clinical responses. PMID:29415428

  10. CARDIAC TRANSPLANT REJECTION AND NON-INVASIVE COMON CAROTID ARTERY WALL FUNCTIONAL INDICES

    Directory of Open Access Journals (Sweden)

    A. O. Shevchenko

    2015-01-01

    Full Text Available Allograft rejection would entail an increase in certain blood biomarkers and active substances derived from activated inflammatory cells which could influence entire vascular endothelial function and deteriorate arterial wall stiffness. We propose that carotid wall functional indices measured with non-invasive ultrasound could we valuable markers of the subclinical cardiac allograft rejection. Aim. Our goal was to analyze the clinical utility of functional common carotid wall (CCW variables measured with high-resolution Doppler ultrasound as a non-invasive screening tool for allograft rejection in cardiac transplant patients (pts. Methods. One hundred and seventy one pts included 93 cardiac recipients, 30 dilated cardiomyopathy waiting list pts, and 48 stable coronary artery disease (SCAD pts without decompensated heart failure were included. Along with resistive index (Ri, pulsative index (Pi, and CCW intima-media thickness (IMT, CCW rigidity index (iRIG was estimated using empirical equation. Non-invasive evaluation was performed in cardiac transplant recipients prior the endomyo- cardial biopsy. Results. Neither of Ri, Pi, or CCW IMT were different in studied subgroups. iRIG was signifi- cantly lower in SCAD pts when compared to the dilated cardiomyopathy subgroup. The later had similar values with cardiac transplant recipients without rejection. Antibody-mediated and cellular rejection were found in 22 (23.7% and 17 (18.3% cardiac recipients, respectively. Mean iRIG in pts without rejection was significantly lower in comparison to antibody-mediated rejection and cell-mediated (5514.7 ± 2404.0 vs 11856.1 ± 6643.5 and 16071.9 ± 10029.1 cm/sec2, respectively, p = 0.001. Area under ROC for iRIG was 0.90 ± 0.03 units2. Analysis showed that iRIG values above estimated treshold 7172 cm/sec2 suggested relative risk of any type of rejection 17.7 (95%CI = 6.3–49.9 sensitivity 80.5%, specificity – 81.1%, negative predictive value – 84

  11. Interaction between cardiac myosin-binding protein C and formin Fhod3.

    Science.gov (United States)

    Matsuyama, Sho; Kage, Yohko; Fujimoto, Noriko; Ushijima, Tomoki; Tsuruda, Toshihiro; Kitamura, Kazuo; Shiose, Akira; Asada, Yujiro; Sumimoto, Hideki; Takeya, Ryu

    2018-05-08

    Mutations in cardiac myosin-binding protein C (cMyBP-C) are a major cause of familial hypertrophic cardiomyopathy. Although cMyBP-C has been considered to regulate the cardiac function via cross-bridge arrangement at the C-zone of the myosin-containing A-band, the mechanism by which cMyBP-C functions remains unclear. We identified formin Fhod3, an actin organizer essential for the formation and maintenance of cardiac sarcomeres, as a cMyBP-C-binding protein. The cardiac-specific N-terminal Ig-like domain of cMyBP-C directly interacts with the cardiac-specific N-terminal region of Fhod3. The interaction seems to direct the localization of Fhod3 to the C-zone, since a noncardiac Fhod3 variant lacking the cMyBP-C-binding region failed to localize to the C-zone. Conversely, the cardiac variant of Fhod3 failed to localize to the C-zone in the cMyBP-C-null mice, which display a phenotype of hypertrophic cardiomyopathy. The cardiomyopathic phenotype of cMyBP-C-null mice was further exacerbated by Fhod3 overexpression with a defect of sarcomere integrity, whereas that was partially ameliorated by a reduction in the Fhod3 protein levels, suggesting that Fhod3 has a deleterious effect on cardiac function under cMyBP-C-null conditions where Fhod3 is aberrantly mislocalized. Together, these findings suggest the possibility that Fhod3 contributes to the pathogenesis of cMyBP-C-related cardiomyopathy and that Fhod3 is critically involved in cMyBP-C-mediated regulation of cardiac function via direct interaction.

  12. Sensitivity and Specificity of Cardiac Tissue Discrimination Using Fiber-Optics Confocal Microscopy.

    Science.gov (United States)

    Huang, Chao; Sachse, Frank B; Hitchcock, Robert W; Kaza, Aditya K

    2016-01-01

    Disturbances of the cardiac conduction system constitute a major risk after surgical repair of complex cases of congenital heart disease. Intraoperative identification of the conduction system may reduce the incidence of these disturbances. We previously developed an approach to identify cardiac tissue types using fiber-optics confocal microscopy and extracellular fluorophores. Here, we applied this approach to investigate sensitivity and specificity of human and automated classification in discriminating images of atrial working myocardium and specialized tissue of the conduction system. Two-dimensional image sequences from atrial working myocardium and nodal tissue of isolated perfused rodent hearts were acquired using a fiber-optics confocal microscope (Leica FCM1000). We compared two methods for local application of extracellular fluorophores: topical via pipette and with a dye carrier. Eight blinded examiners evaluated 162 randomly selected images of atrial working myocardium (n = 81) and nodal tissue (n = 81). In addition, we evaluated the images using automated classification. Blinded examiners achieved a sensitivity and specificity of 99.2 ± 0.3% and 98.0 ± 0.7%, respectively, with the dye carrier method of dye application. Sensitivity and specificity was similar for dye application via a pipette (99.2 ± 0.3% and 94.0 ± 2.4%, respectively). Sensitivity and specificity for automated methods of tissue discrimination were similarly high. Human and automated classification achieved high sensitivity and specificity in discriminating atrial working myocardium and nodal tissue. We suggest that our findings facilitate clinical translation of fiber-optics confocal microscopy as an intraoperative imaging modality to reduce the incidence of conduction disturbances during surgical correction of congenital heart disease.

  13. Effects of PPARs agonists on cardiac metabolism in littermate and cardiomyocyte-specific PPAR-γ-knockout (CM-PGKO mice.

    Directory of Open Access Journals (Sweden)

    Michelangela Barbieri

    Full Text Available Understanding the molecular regulatory mechanisms controlling for myocardial lipid metabolism is of critical importance for the development of new therapeutic strategies for heart diseases. The role of PPARγ and thiazolidinediones in regulation of myocardial lipid metabolism is controversial. The aim of our study was to assess the role of PPARγ on myocardial lipid metabolism and function and differentiate local/from systemic actions of PPARs agonists using cardiomyocyte-specific PPARγ -knockout (CM-PGKO mice. To this aim, the effect of PPARγ, PPARγ/PPARα and PPARα agonists on cardiac function, intra-myocyte lipid accumulation and myocardial expression profile of genes and proteins, affecting lipid oxidation, uptake, synthesis, and storage (CD36, CPT1MIIA, AOX, FAS, SREBP1-c and ADPR was evaluated in cardiomyocyte-specific PPARγ-knockout (CM-PGKO and littermate control mice undergoing standard and high fat diet (HFD. At baseline, protein levels and mRNA expression of genes involved in lipid uptake, oxidation, synthesis, and accumulation of CM-PGKO mice were not significantly different from those of their littermate controls. At baseline, no difference in myocardial lipid content was found between CM-PGKO and littermate controls. In standard condition, pioglitazone and rosiglitazone do not affect myocardial metabolism while, fenofibrate treatment significantly increased CD36 and CPT1MIIA gene expression. In both CM-PGKO and control mice submitted to HFD, six weeks of treatment with rosiglitazone, fenofibrate and pioglitazone lowered myocardial lipid accumulation shifting myocardial substrate utilization towards greater contribution of glucose. In conclusion, at baseline, PPARγ does not play a crucial role in regulating cardiac metabolism in mice, probably due to its low myocardial expression. PPARs agonists, indirectly protect myocardium from lipotoxic damage likely reducing fatty acids delivery to the heart through the actions on adipose

  14. Short-term exercise worsens cardiac oxidative stress and fibrosis in 8-month-old db/db mice by depleting cardiac glutathione.

    Science.gov (United States)

    Laher, Ismail; Beam, Julianne; Botta, Amy; Barendregt, Rebekah; Sulistyoningrum, Dian; Devlin, Angela; Rheault, Mark; Ghosh, Sanjoy

    2013-01-01

    Moderate exercise improves cardiac antioxidant status in young humans and animals with Type-2 diabetes (T2D). Given that both diabetes and advancing age synergistically decrease antioxidant expression in most tissues, it is unclear whether exercise can upregulate cardiac antioxidants in chronic animal models of T2D. To this end, 8-month-old T2D and normoglycemic mice were exercised for 3 weeks, and cardiac redox status was evaluated. As expected, moderate exercise increased cardiac antioxidants and attenuated oxidative damage in normoglycemic mice. In contrast, similar exercise protocol in 8-month-old db/db mice worsened cardiac oxidative damage, which was associated with a specific dysregulation of glutathione (GSH) homeostasis. Expression of enzymes for GSH biosynthesis [γ-glutamylcysteine synthase, glutathione reductase] as well as for GSH-mediated detoxification (glutathione peroxidase, glutathione-S-transferase) was lower, while toxic metabolites dependent on GSH for clearance (4-hydroxynonenal) were increased in exercised diabetic mice hearts. To validate GSH loss as an important factor for such aggravated damage, daily administration of GSH restored cardiac GSH levels in exercised diabetic mice. Such supplementation attenuated both oxidative damage and fibrotic changes in the myocardium. Expression of transforming growth factor beta (TGF-β) and its regulated genes which are responsible for such profibrotic changes were also attenuated with GSH supplementation. These novel findings in a long-term T2D animal model demonstrate that short-term exercise by itself can deplete cardiac GSH and aggravate cardiac oxidative stress. As GSH administration conferred protection in 8-month-old diabetic mice undergoing exercise, supplementation with GSH-enhancing agents may be beneficial in elderly diabetic patients undergoing exercise.

  15. Different protein kinase C isoenzymes mediate inhibition of cardiac rapidly activating delayed rectifier K+ current by different G-protein coupled receptors.

    Science.gov (United States)

    Liu, Xueli; Wang, Yuhong; Zhang, Hua; Shen, Li; Xu, Yanfang

    2017-12-01

    Elevated angiotensin II (Ang II) and sympathetic activity contributes to a high risk of ventricular arrhythmias in heart disease. The rapidly activating delayed rectifier K + current (I Kr ) carried by the hERG channels plays a critical role in cardiac repolarization, and decreased I Kr is involved in increased cardiac arrhythmogenicity. Stimulation of α 1A -adrenoreceptors or angiotensin II AT 1 receptors is known to inhibit I Kr via PKC. Here, we have identified the PKC isoenzymes mediating the inhibition of I Kr by activation of these two different GPCRs. The whole-cell patch-clamp technique was used to record I Kr in guinea pig cardiomyocytes and HEK293 cells co-transfected with hERG and α 1A -adrenoreceptor or AT 1 receptor genes. A broad spectrum PKC inhibitor Gö6983 (not inhibiting PKCε), a selective cPKC inhibitor Gö6976 and a PKCα-specific inhibitor peptide, blocked the inhibition of I Kr by the α 1A -adrenoreceptor agonist A61603. However, these inhibitors did not affect the reduction of I Kr by activation of AT 1 receptors, whereas the PKCε-selective inhibitor peptide did block the effect. The effects of angiotensin II and the PKCε activator peptide were inhibited in mutant hERG channels in which 17 of the 18 PKC phosphorylation sites were deleted, whereas a deletion of the N-terminus of the hERG channels selectively prevented the inhibition elicited by A61603 and the cPKC activator peptide. Our results indicated that inhibition of I Kr by activation of α 1A -adrenoreceptors or AT 1 receptors were mediated by PKCα and PKCε isoforms respectively, through different molecular mechanisms. © 2017 The British Pharmacological Society.

  16. Improved bioavailability of targeted Curcumin delivery efficiently regressed cardiac hypertrophy by modulating apoptotic load within cardiac microenvironment

    International Nuclear Information System (INIS)

    Ray, Aramita; Rana, Santanu; Banerjee, Durba; Mitra, Arkadeep; Datta, Ritwik; Naskar, Shaon; Sarkar, Sagartirtha

    2016-01-01

    Cardiomyocyte apoptosis acts as a prime modulator of cardiac hypertrophy leading to heart failure, a major cause of human mortality worldwide. Recent therapeutic interventions have focussed on translational applications of diverse pharmaceutical regimes among which, Curcumin (from Curcuma longa) is known to have an anti-hypertrophic potential but with limited pharmacological efficacies due to low aqueous solubility and poor bioavailability. In this study, Curcumin encapsulated by carboxymethyl chitosan (CMC) nanoparticle conjugated to a myocyte specific homing peptide was successfully delivered in bioactive form to pathological myocardium for effective regression of cardiac hypertrophy in a rat (Rattus norvegicus) model. Targeted nanotization showed higher cardiac bioavailability of Curcumin at a low dose of 5 mg/kg body weight compared to free Curcumin at 35 mg/kg body weight. Moreover, Curcumin/CMC-peptide treatment during hypertrophy significantly improved cardiac function by downregulating expression of hypertrophy marker genes (ANF, β-MHC), apoptotic mediators (Bax, Cytochrome-c) and activity of apoptotic markers (Caspase 3 and PARP); whereas free Curcumin in much higher dose showed minimal improvement during compromised cardiac function. Targeted Curcumin treatment significantly lowered p53 expression and activation in diseased myocardium via inhibited interaction of p53 with p300-HAT. Thus attenuated acetylation of p53 facilitated p53 ubiquitination and reduced the apoptotic load in hypertrophied cardiomyocytes; thereby limiting cardiomyocytes' need to enter the regeneration cycle during hypertrophy. This study elucidates for the first time an efficient targeted delivery regimen for Curcumin and also attributes towards probable mechanistic insight into its therapeutic potential as a cardio-protective agent for regression of cardiac hypertrophy. - Highlights: • Cardiomyocyte targeted Curcumin/CMC-peptide increases bioavailability of the drug.

  17. Isometric exercise: cardiovascular responses in normal and cardiac populations.

    Science.gov (United States)

    Hanson, P; Nagle, F

    1987-05-01

    Isometric exercise produces a characteristic pressor increase in blood pressure which may be important in maintaining perfusion of muscle during sustained contraction. This response is mediated by combined central and peripheral afferent input to medullary cardiovascular centers. In normal individuals the increase in blood pressure is mediated by a rise in cardiac output with little or no change in systemic vascular resistance. However, the pressor response is also maintained during pharmacologic blockade or surgical denervation by increasing systemic vascular resistance. Left ventricular function is normally maintained or improves in normal subjects and cardiac patients with mild impairment of left ventricular contractility. Patients with poor left ventricular function may show deterioration during isometric exercise, although this pattern of response is difficult to predict from resting studies. Recent studies have shown that patients with uncomplicated myocardial infarction can perform submaximum isometric exercise such as carrying weights in the range of 30 to 50 lb without difficulty or adverse responses. In addition, many patients who show ischemic ST depression or angina during dynamic exercise may have a reduced ischemic response during isometric or combined isometric and dynamic exercise. Isometric exercises are frequently encountered in activities of daily living and many occupational tasks. Cardiac patients should be gradually exposed to submaximum isometric training in supervised cardiac rehabilitation programs. Specific job tasks that require isometric or combined isometric and dynamic activities may be evaluated by work simulation studies. This approach to cardiac rehabilitation may facilitate patients who wish to return to a job requiring frequent isometric muscle contraction. Finally, there is a need for additional research on the long-term effects of isometric exercise training on left ventricular hypertrophy and performance. The vigorous training

  18. Cardiac-specific inducible overexpression of human plasma membrane Ca2+ ATPase 4b is cardioprotective and improves survival in mice following ischemic injury.

    Science.gov (United States)

    Sadi, Al Muktafi; Afroze, Talat; Siraj, M Ahsan; Momen, Abdul; White-Dzuro, Colin; Zarrin-Khat, Dorrin; Handa, Shivalika; Ban, Kiwon; Kabir, M Golam; Trivieri, Maria G; Gros, Robert; Backx, Peter; Husain, Mansoor

    2018-03-30

    Background: Heart failure (HF) is associated with reduced expression of plasma membrane Ca 2+ -ATPase 4 (PMCA4). Cardiac-specific overexpression of human PMCA4b in mice inhibited nNOS activity and reduced cardiac hypertrophy by inhibiting calcineurin. Here we examine temporally regulated cardiac-specific overexpression of hPMCA4b in mouse models of myocardial ischemia reperfusion injury (IRI) ex vivo , and HF following experimental myocardial infarction (MI) in vivo Methods and results: Doxycycline-regulated cardiomyocyte-specific overexpression and activity of hPMCA4b produced adaptive changes in expression levels of Ca 2+ -regulatory genes, and induced hypertrophy without significant differences in Ca 2+ transients or diastolic Ca 2+ concentrations. Total cardiac NOS and nNOS-specific activities were reduced in mice with cardiac overexpression of hPMCA4b while nNOS, eNOS and iNOS protein levels did not differ. hMPCA4b-overexpressing mice also exhibited elevated systolic blood pressure vs. controls, with increased contractility and lusitropy in vivo In isolated hearts undergoing IRI, hPMCA4b overexpression was cardioprotective. NO donor-treated hearts overexpressing hPMCA4b showed reduced LVDP and larger infarct size versus vehicle-treated hearts undergoing IRI, demonstrating that the cardioprotective benefits of hPMCA4b-repressed nNOS are lost by restoring NO availability. Finally, both pre-existing and post-MI induction of hPMCA4b overexpression reduced infarct expansion and improved survival from HF. Conclusions: Cardiac PMCA4b regulates nNOS activity, cardiac mass and contractility, such that PMCA4b overexpression preserves cardiac function following IRI, heightens cardiac performance and limits infarct progression, cardiac hypertrophy and HF, even when induced late post-MI. These data identify PMCA4b as a novel therapeutic target for IRI and HF. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  19. Myocardial gene delivery using molecular cardiac surgery with recombinant adeno-associated virus vectors in vivo

    Science.gov (United States)

    White, JD; Thesier, DM; Swain, JBD; Katz, MG; Tomasulo, C; Henderson, A; Wang, L; Yarnall, C; Fargnoli, A; Sumaroka, M; Isidro, A; Petrov, M; Holt, D; Nolen-Walston, R; Koch, WJ; Stedman, HH; Rabinowitz, J; Bridges, CR

    2013-01-01

    We use a novel technique that allows for closed recirculation of vector genomes in the cardiac circulation using cardiopulmonary bypass, referred to here as molecular cardiac surgery with recirculating delivery (MCARD). We demonstrate that this platform technology is highly efficient in isolating the heart from the systemic circulation in vivo. Using MCARD, we compare the relative efficacy of single-stranded (ss) adeno-associated virus (AAV)6, ssAAV9 and self-complimentary (sc)AAV6-encoding enhanced green fluorescent protein, driven by the constitutive cytomegalovirus promoter to transduce the ovine myocardium in situ. MCARD allows for the unprecedented delivery of up to 48 green fluorescent protein genome copies per cell globally in the sheep left ventricular (LV) myocardium. We demonstrate that scAAV6-mediated MCARD delivery results in global, cardiac-specific LV gene expression in the ovine heart and provides for considerably more robust and cardiac-specific gene delivery than other available delivery techniques such as intramuscular injection or intracoronary injection; thus, representing a potential, clinically translatable platform for heart failure gene therapy. PMID:21228882

  20. Cardiac-Specific Overexpression of Catalase Attenuates Lipopolysaccharide-Induced Myocardial Contractile Dysfunction: Role of Autophagy

    Science.gov (United States)

    Turdi, Subat; Han, Xuefeng; Huff, Anna F.; Roe, Nathan D.; Hu, Nan; Gao, Feng; Ren, Jun

    2012-01-01

    Lipopolysaccharide (LPS) from Gram-negative bacteria is a major initiator of sepsis, leading to cardiovascular collapse. Accumulating evidence has indicated a role of reactive oxygen species (ROS) in cardiovascular complication in sepsis. This study was designed to examine the effect of cardiac-specific overexpression of catalase in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Catalase transgenic and wild-type FVB mice were challenged with LPS (6 mg/kg) and cardiac function was evaluated. Levels of oxidative stress, autophagy, apoptosis and protein damage were examined using fluorescence microscopy, Western blot, TUNEL assay, caspase-3 activity and carbonyl formation. Kaplan-Meier curve was constructed for survival following LPS treatment. Our results revealed a lower mortality in catalase mice compared with FVB mice following LPS challenge. LPS injection led to depressed cardiac contractile capacity as evidenced by echocardiography and cardiomyocyte contractile function, the effect of which was ablated by catalase overexpression. LPS treatment induced elevated TNF-α level, autophagy, apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), production of ROS and O2−, and protein carbonyl formation, the effects of which were significantly attenuated by catalase overexpression. Electron microscopy revealed focal myocardial damage characterized by mitochondrial injury following LPS treatment, which was less severe in catalase mice. Interestingly, LPS-induced cardiomyocyte contractile dysfunction was prevented by antioxidant NAC and the autophagy inhibitor 3-methyladenine. Taken together, our data revealed that catalase protects against LPS-induced cardiac dysfunction and mortality, which may be associated with inhibition of oxidative stress and autophagy. PMID:22902401

  1. Exercise and Type 2 Diabetes Mellitus : Changes in Tissue-specific Fat Distribution and Cardiac Function

    NARCIS (Netherlands)

    Jonker, Jacqueline T.; de Mol, Pieter; de Vries, Suzanna T.; Widya, Ralph L.; Hammer, Sebastiaan; van Schinkel, Linda D.; van der Meer, Rutger W.; Gans, Rijk O. B.; Webb, Andrew G.; Kan, Hermien E.; de Koning, Eelco J. P.; Bilo, Henk J. G.; Lamb, Hildo J.

    2013-01-01

    Purpose: To prospectively assess the effects of an exercise intervention on organ-specific fat accumulation and cardiac function in type 2 diabetes mellitus. Materials and Methods: Written informed consent was obtained from all participants, and the study protocol was approved by the medical ethics

  2. Cardiac-specific overexpression of catalase attenuates lipopolysaccharide-induced myocardial contractile dysfunction: role of autophagy.

    Science.gov (United States)

    Turdi, Subat; Han, Xuefeng; Huff, Anna F; Roe, Nathan D; Hu, Nan; Gao, Feng; Ren, Jun

    2012-09-15

    Lipopolysaccharide (LPS) from gram-negative bacteria is a major initiator of sepsis, leading to cardiovascular collapse. Accumulating evidence has indicated a role of reactive oxygen species (ROS) in cardiovascular complications in sepsis. This study was designed to examine the effect of cardiac-specific overexpression of catalase in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Catalase transgenic and wild-type FVB mice were challenged with LPS (6 mg/kg) and cardiac function was evaluated. Levels of oxidative stress, autophagy, apoptosis, and protein damage were examined using fluorescence microscopy, Western blot, TUNEL assay, caspase-3 activity, and carbonyl formation. A Kaplan-Meier curve was constructed for survival after LPS treatment. Our results revealed a lower mortality in catalase mice compared with FVB mice after LPS challenge. LPS injection led to depressed cardiac contractile capacity as evidenced by echocardiography and cardiomyocyte contractile function, the effect of which was ablated by catalase overexpression. LPS treatment induced elevated TNF-α level, autophagy, apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), production of ROS and O(2)(-), and protein carbonyl formation, the effects of which were significantly attenuated by catalase overexpression. Electron microscopy revealed focal myocardial damage characterized by mitochondrial injury after LPS treatment, which was less severe in catalase mice. Interestingly, LPS-induced cardiomyocyte contractile dysfunction was prevented by the antioxidant N-acetylcysteine and the autophagy inhibitor 3-methyladenine. Taken together, our data revealed that catalase protects against LPS-induced cardiac dysfunction and mortality, which may be associated with inhibition of oxidative stress and autophagy. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. The HEART mobile phone trial: The partial mediating effects of self-efficacy on physical activity among cardiac patients

    Directory of Open Access Journals (Sweden)

    Ralph eMaddison

    2014-05-01

    Full Text Available Background: The ubiquitous use of mobile phones provides an ideal opportunity to deliver interventions to increase physical activity levels. Understanding potential mediators of such interventions is needed to increase their effectiveness. A recent randomized controlled trial of a mobile phone and Internet (mHealth intervention was conducted in New Zealand to determine the effectiveness on exercise capacity and physical activity levels in addition to current cardiac rehabilitation (CR services for people (n=171 with ischaemic heart disease (IHD. Significant intervention effect was observed for self-reported leisure time physical activity and walking, but not peak oxygen uptake (PVO2 at 24 weeks. There was also significant improvement in self-efficacy.Objective: To evaluate the mediating effect of self-efficacy on physical activity levels in an mHealth delivered exercise CR programme. Methods: Treatment evaluations were performed on the principle of intention to treat (ITT. Adjusted regression analyses were conducted to evaluate the main treatment effect on leisure time physical activity and walking at 24 weeks, with and without change in self-efficacy as the mediator of interest. Results: Change in self-efficacy at 24 weeks significantly mediated the treatment effect on leisure time physical activity by 13%, but only partially mediated the effect on walking by 4% at 24 weeks. Conclusion: An mHealth intervention involving text messaging and Internet support had a positive treatment effect on leisure time physical activity and walking at 24 weeks, and this effect was likely mediated through changes in self-efficacy. Future trials should examine other potential mediators related to this type of intervention.

  4. Cardiac-Specific Gene Expression Facilitated by an Enhanced Myosin Light Chain Promoter

    Directory of Open Access Journals (Sweden)

    Wolfgang Boecker

    2004-04-01

    Full Text Available Background: Adenoviral gene transfer has been shown to be effective in cardiac myocytes in vitro and in vivo. A major limitation of myocardial gene therapy is the extracardiac transgene expression. Methods: To minimize extracardiac gene expression, we have constructed a tissue-specific promoter for cardiac gene transfer, namely, the 250-bp fragment of the myosin light chain-2v (MLC-2v gene, which is known to be expressed in a tissue-specific manner in ventricular myocardium followed by a luciferase (luc reporter gene (Ad.4 × MLC250.Luc. Rat cardiomyocytes, liver and kidney cells were infected with Ad.4 × MLC.Luc or control vectors. For in vivo testing, Ad.4 × MLC250.Luc was injected into the myocardium or in the liver of rats. Kinetics of promoter activity were monitored over 8 days using a cooled CCD camera. Results: In vitro: By infecting hepatic versus cardiomyocyte cells, we found that the promoter specificity ratio (luc activity in cardiomyocytes per liver cells was 20.4 versus 0.9 (Ad.4 × MLC250.Luc vs. Ad.CMV. In vivo: Ad.4 × MLC250.Luc significantly reduced luc activity in liver (38.4-fold, lung (16.1-fold, and kidney (21.8-fold versus Ad.CMV (p = .01; whereas activity in the heart was only 3.8-fold decreased. The gene expression rate of cardiomyocytes versus hepatocytes was 7:1 (Ad.4 × MLC.Luc versus 1:1.4 (Ad.CMV.Luc. Discussion: This new vector may be useful to validate therapeutic approaches in animal disease models and offers the perspective for selective expression of therapeutic genes in the diseased heart.

  5. Novel protective role of endogenous cardiac myocyte P2X4 receptors in heart failure.

    Science.gov (United States)

    Yang, Tiehong; Shen, Jian-bing; Yang, Ronghua; Redden, John; Dodge-Kafka, Kimberly; Grady, James; Jacobson, Kenneth A; Liang, Bruce T

    2014-05-01

    Heart failure (HF), despite continuing progress, remains a leading cause of mortality and morbidity. P2X4 receptors (P2X4R) have emerged as potentially important molecules in regulating cardiac function and as potential targets for HF therapy. Transgenic P2X4R overexpression can protect against HF, but this does not explain the role of native cardiac P2X4R. Our goal is to define the physiological role of endogenous cardiac myocyte P2X4R under basal conditions and during HF induced by myocardial infarction or pressure overload. Mice established with conditional cardiac-specific P2X4R knockout were subjected to left anterior descending coronary artery ligation-induced postinfarct or transverse aorta constriction-induced pressure overload HF. Knockout cardiac myocytes did not show P2X4R by immunoblotting or by any response to the P2X4R-specific allosteric enhancer ivermectin. Knockout hearts showed normal basal cardiac function but depressed contractile performance in postinfarct and pressure overload models of HF by in vivo echocardiography and ex vivo isolated working heart parameters. P2X4R coimmunoprecipitated and colocalized with nitric oxide synthase 3 (eNOS) in wild-type cardiac myocytes. Mice with cardiac-specific P2X4R overexpression had increased S-nitrosylation, cyclic GMP, NO formation, and were protected from postinfarct and pressure overload HF. Inhibitor of eNOS, L-N(5)-(1-iminoethyl)ornithine hydrochloride, blocked the salutary effect of cardiac P2X4R overexpression in postinfarct and pressure overload HF as did eNOS knockout. This study establishes a new protective role for endogenous cardiac myocyte P2X4R in HF and is the first to demonstrate a physical interaction between the myocyte receptor and eNOS, a mediator of HF protection. © 2014 American Heart Association, Inc.

  6. Histone Deacetylase Inhibitors Prolong Cardiac Repolarization through Transcriptional Mechanisms.

    Science.gov (United States)

    Spence, Stan; Deurinck, Mark; Ju, Haisong; Traebert, Martin; McLean, LeeAnne; Marlowe, Jennifer; Emotte, Corinne; Tritto, Elaine; Tseng, Min; Shultz, Michael; Friedrichs, Gregory S

    2016-09-01

    Histone deacetylase (HDAC) inhibitors are an emerging class of anticancer agents that modify gene expression by altering the acetylation status of lysine residues of histone proteins, thereby inducing transcription, cell cycle arrest, differentiation, and cell death or apoptosis of cancer cells. In the clinical setting, treatment with HDAC inhibitors has been associated with delayed cardiac repolarization and in rare instances a lethal ventricular tachyarrhythmia known as torsades de pointes. The mechanism(s) of HDAC inhibitor-induced effects on cardiac repolarization is unknown. We demonstrate that administration of structurally diverse HDAC inhibitors to dogs causes delayed but persistent increases in the heart rate corrected QT interval (QTc), an in vivo measure of cardiac repolarization, at timepoints far removed from the Tmax for parent drug and metabolites. Transcriptional profiling of ventricular myocardium from dogs treated with various HDAC inhibitors demonstrated effects on genes involved in protein trafficking, scaffolding and insertion of various ion channels into the cell membrane as well as genes for specific ion channel subunits involved in cardiac repolarization. Extensive in vitro ion channel profiling of various structural classes of HDAC inhibitors (and their major metabolites) by binding and acute patch clamp assays failed to show any consistent correlations with direct ion channel blockade. Drug-induced rescue of an intracellular trafficking-deficient mutant potassium ion channel, hERG (G601S), and decreased maturation (glycosylation) of wild-type hERG expressed by CHO cells in vitro correlated with prolongation of QTc intervals observed in vivo The results suggest that HDAC inhibitor-induced prolongation of cardiac repolarization may be mediated in part by transcriptional changes of genes required for ion channel trafficking and localization to the sarcolemma. These data have broad implications for the development of these drug classes and

  7. Cardiac-Specific Conversion Factors to Estimate Radiation Effective Dose From Dose-Length Product in Computed Tomography.

    Science.gov (United States)

    Trattner, Sigal; Halliburton, Sandra; Thompson, Carla M; Xu, Yanping; Chelliah, Anjali; Jambawalikar, Sachin R; Peng, Boyu; Peters, M Robert; Jacobs, Jill E; Ghesani, Munir; Jang, James J; Al-Khalidi, Hussein; Einstein, Andrew J

    2018-01-01

    -factors for all scanners and protocols are considerably higher than the k-factor currently used to estimate ED of cardiac CT studies, suggesting that radiation doses from cardiac CT have been significantly and systematically underestimated. Using cardiac-specific factors can more accurately inform the benefit-risk calculus of cardiac-imaging strategies. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Searching for a job: Cardiac responses to acute stress and the mediating role of threat appraisal in young people.

    Science.gov (United States)

    Zandara, M; Garcia-Lluch, M; Villada, C; Hidalgo, V; Salvador, A

    2018-02-01

    Being unemployed and looking for a job has become a source of stress for many people in several European countries. However, little attention has been paid to the impact of this stressful situation on the individuals' psychophysiological stress responses. The aim of this study was to investigate the effect of being an unemployed job seeker on cognitive threat appraisal and cardiac responses to a psychosocial stressor. We exposed a group of unemployed job seekers (N = 42) and a matched group of unemployed non-job seekers (N = 40) to a standardized social stressor in form of job interview, the Trier Social Stress Test. Our results showed that unemployed job seekers manifest lower cardiac responses, along with a lower cognitive threat appraisal, compared to non-job seekers. Moreover, we observed a full mediating role of cognitive threat appraisal on the relationship between being an unemployed job seeker and cardiac responses to stress. These findings reveal that being unemployed and looking for a job has an effect on physiological responses to acute stress, as well as the importance of psychological process related to the situation. These responses might lead to negative health and motivational consequences. Theoretical and practical implications are discussed. Copyright © 2017 John Wiley & Sons, Ltd.

  9. Compliant Buckled Foam Actuators and Application in Patient-Specific Direct Cardiac Compression.

    Science.gov (United States)

    Mac Murray, Benjamin C; Futran, Chaim C; Lee, Jeanne; O'Brien, Kevin W; Amiri Moghadam, Amir A; Mosadegh, Bobak; Silberstein, Meredith N; Min, James K; Shepherd, Robert F

    2018-02-01

    We introduce the use of buckled foam for soft pneumatic actuators. A moderate amount of residual compressive strain within elastomer foam increases the applied force ∼1.4 × or stroke ∼2 × compared with actuators without residual strain. The origin of these improved characteristics is explained analytically. These actuators are applied in a direct cardiac compression (DCC) device design, a type of implanted mechanical circulatory support that avoids direct blood contact, mitigating risks of clot formation and stroke. This article describes a first step toward a pneumatically powered, patient-specific DCC design by employing elastomer foam as the mechanism for cardiac compression. To form the device, a mold of a patient's heart was obtained by 3D printing a digitized X-ray computed tomography or magnetic resonance imaging scan into a solid model. From this model, a soft, robotic foam DCC device was molded. The DCC device is compliant and uses compressed air to inflate foam chambers that in turn apply compression to the exterior of a heart. The device is demonstrated on a porcine heart and is capable of assisting heart pumping at physiologically relevant durations (∼200 ms for systole and ∼400 ms for diastole) and stroke volumes (∼70 mL). Although further development is necessary to produce a fully implantable device, the material and processing insights presented here are essential to the implementation of a foam-based, patient-specific DCC design.

  10. Specificity in mediated pathways by anxiety symptoms linking adolescent stress profiles to depressive symptoms: Results of a moderated mediation approach.

    Science.gov (United States)

    Anyan, Frederick; Bizumic, Boris; Hjemdal, Odin

    2018-03-01

    We investigated the specificity in mediated pathways that separately link specific stress dimensions through anxiety to depressive symptoms and the protective utility of resilience. Thus, this study goes beyond lumping together potential mediating and moderating processes that can explain the relations between stress and (symptoms of) psychopathology and the buffering effect of resilience. Ghanaian adolescents between 13 and 17 years (female = 285; male = 244) completed the Adolescent Stress Questionnaire (ASQ), Spielberger State Anxiety Inventory (STAI), Short Mood Feeling Questionnaire (SMFQ) and the Resilience Scale for Adolescents (READ). Independent samples t-test, multivariate analysis of covariance with follow-up tests and moderated mediation analyses were performed. Evidences were found for specificity in the associations between dimensions of adolescent stressors and depressive symptoms independent of transient anxiety. Transient anxiety partly accounted for the indirect effects of eight stress dimensions on depressive symptoms. Except stress of school attendance and school/leisure conflict, resilience moderated the indirect effects of specific stress dimensions on depressive symptoms. Results suggested differences in how Ghanaian adolescents view the various stress dimensions, and mediated pathways associated with anxiety and depressive symptoms. Use of cross-sectional data does not show causal process and temporal changes over time. Findings support and clarify the specificity in the interrelations and mediated pathways among dimensions of adolescent stress, transient anxiety, and depressive symptoms. Conditional process analyses shows that resilience does not only buffer direct, but also indirect psychological adversities. Interventions for good mental health may focus on low resilience subgroups in specific stress dimensions while minimizing transient anxiety. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Transient receptor potential cation channel A1 (TRPA1) mediates decrements in cardiac mechanical function and dysrhythmia caused by a single air pollution exposure in mice

    Science.gov (United States)

    This work, which will be presented at SOT 2014, demonstrates that a single exposure to either ozone or acrolein causes decrements in cardiac function and altered electrical activity (i.e. arrhythmia). The results suggest that this effect is mediated by the airway sensor TRPA1. ...

  12. Specific residues of the cytoplasmic domains of cardiac inward rectifier potassium channels are effective antifibrillatory targets

    Science.gov (United States)

    Noujaim, Sami F.; Stuckey, Jeanne A.; Ponce-Balbuena, Daniela; Ferrer-Villada, Tania; López-Izquierdo, Angelica; Pandit, Sandeep; Calvo, Conrado J.; Grzeda, Krzysztof R.; Berenfeld, Omer; Sánchez Chapula, José A.; Jalife, José

    2010-01-01

    Atrial and ventricular tachyarrhythmias can be perpetuated by up-regulation of inward rectifier potassium channels. Thus, it may be beneficial to block inward rectifier channels under conditions in which their function becomes arrhythmogenic (e.g., inherited gain-of-function mutation channelopathies, ischemia, and chronic and vagally mediated atrial fibrillation). We hypothesize that the antimalarial quinoline chloroquine exerts potent antiarrhythmic effects by interacting with the cytoplasmic domains of Kir2.1 (IK1), Kir3.1 (IKACh), or Kir6.2 (IKATP) and reducing inward rectifier potassium currents. In isolated hearts of three different mammalian species, intracoronary chloroquine perfusion reduced fibrillatory frequency (atrial or ventricular), and effectively terminated the arrhythmia with resumption of sinus rhythm. In patch-clamp experiments chloroquine blocked IK1, IKACh, and IKATP. Comparative molecular modeling and ligand docking of chloroquine in the intracellular domains of Kir2.1, Kir3.1, and Kir6.2 suggested that chloroquine blocks or reduces potassium flow by interacting with negatively charged amino acids facing the ion permeation vestibule of the channel in question. These results open a novel path toward discovering antiarrhythmic pharmacophores that target specific residues of the cytoplasmic domain of inward rectifier potassium channels.—Noujaim, S. F., Stuckey, J. A., Ponce-Balbuena, D., Ferrer-Villada, T., López-Izquierdo, A., Pandit, S., Calvo, C. J., Grzeda, K. R., Berenfeld, O., Sánchez Chapula, J. A., Jalife, J. Specific residues of the cytoplasmic domains of cardiac inward rectifier potassium channels are effective antifibrillatory targets. PMID:20585026

  13. The accuracy of chest radiographs in the detection of congenital heart disease and in the diagnosis of specific congenital cardiac lesions

    International Nuclear Information System (INIS)

    Laya, Bernard F.; Goske, Marilyn J.; Morrison, Stuart; Reid, Janet R.; Swischuck, Leonard; Ey, Elizabeth H.; Murphy, Daniel J.; Lieber, Michael; Obuchowski, Nancy

    2006-01-01

    Congenital heart disease (CHD) is a significant cause of morbidity and mortality in pediatric patients. Traditional teaching holds that specific types of CHD can be diagnosed on the chest radiograph (CXR) through pattern recognition. To determine the accuracy of radiologists in detecting CHD on the CXR. This study was a blinded retrospective review of chest radiographs from 281 patients (<12 years) by five pediatric radiologists from three institutions. Thirteen groups were evaluated that included 12 categories of CHD and a control group of patients without heart disease. Radiographs were assessed for heart size, heart and mediastinal shape and vascularity. Clinical information, angiography, echocardiograms and surgery were used as the gold standard for definitive diagnosis. The average accuracy of the five readers in distinguishing normal from CHD patients was 78% (range of 72% to 82%). The overall measure of accuracy in distinguishing specific congenital cardiac lesions among 13 groups of patients was 71% (range of 63% to 79%). CXR alone is not diagnostic of specific cardiac lesions, with a low accuracy of only 71%. We believe that less emphasis should be placed on the use of radiographs alone in diagnosing specific congenital cardiac lesions. (orig.)

  14. Type of treatment of cardiac disorders--quality of life and heart-focused anxiety: The mediating role of illness perceptions.

    Science.gov (United States)

    Panzaru, Gabriela Monica; Holman, Andrei

    2015-01-01

    The aim of the present research was to investigate the impact of illness perceptions on quality of life and heart-focused anxiety, in patients with cardiovascular disease (N = 106) admitted in the hospital, undergoing medication or who had undergone surgery. The influence of the type of treatment on the heart-focused anxiety and on the quality of life was mediated by illness perceptions. Consequently, patients who have undergone cardiac surgery have a better quality of life and lower levels of heart-focused anxiety than those relying only on medication to treat their illness.

  15. Involvement of atypical protein kinase C in the regulation of cardiac glucose and long-chain fatty acid uptake

    Directory of Open Access Journals (Sweden)

    Daphna D.J. Habets

    2012-09-01

    Full Text Available Aim: The signaling pathways involved in the regulation of cardiac GLUT4 translocation/glucose uptake and CD36 translocation/ long-chain fatty acid uptake are not fully understood. We compared in heart/muscle-specific PKC-λ knockout mice the roles of atypical PKCs (PKC-ζ and PKC-λ in regulating cardiac glucose and fatty acid uptake. Results: Neither insulin-stimulated nor AMPK-mediated glucose and fatty acid uptake were inhibited upon genetic PKC-λ ablation in cardiomyocytes. In contrast, myristoylated PKC-ζ pseudosubstrate inhibited both insulin-stimulated and AMPK-mediated glucose and fatty acid uptake by >80% in both wild-type and PKC-λ-knockout cardiomyocytes. In PKC-λ knockout cardiomyocytes, PKC-ζ is the sole remaining atypical PKC isoform, and its expression level is not different from wild-type cardiomyocytes, in which it contributes to 29% and 17% of total atypical PKC expression and phosphorylation, respectively. Conclusion: Taken together, atypical PKCs are necessary for insulin-stimulated and AMPK-mediated glucose uptake into the heart, as well as for insulin-stimulated and AMPK-mediated fatty acid uptake. However, the residual PKC-ζ activity in PKC-λ-knockout cardiomyocytes is sufficient to allow optimal stimulation of glucose and fatty acid uptake, indicating that atypical PKCs are necessary but not rate-limiting in the regulation of cardiac substrate uptake and that PKC-λ and PKC-ζ have interchangeable functions in these processes.

  16. Anxiety and depression among amyloid light-chain cardiac amyloidosis patients: The role of life satisfaction.

    Science.gov (United States)

    Smorti, Martina; Guarnieri, Silvia; Bergesio, Franco; Perfetto, Federico; Cappelli, Francesco

    2016-06-01

    The present study aimed to provide a contribution to the study of a rare disease, amyloid light-chain (AL) cardiac amyloidosis, which is the most common type of systemic amyloidosis. In AL amyloidosis prognosis is determined by cardiac involvement. Although the association between psychological distress (e.g. anxiety and depression) and AL cardiac amyloidosis is documented, very little is known about the psychosocial variables that may mediate the association. The aim of the study is therefore to examine the potential mediating role of life satisfaction in the relationship between cardiac symptom severity (independent variable) and anxious and depressive symptoms (dependent variables) in AL patients. Forty-three AL amyloidosis patients (57.1% males) with cardiac amyloidosis were administered the Satisfaction with Life Scale, the State-Trait Anxiety Inventory and the Centre for Epidemiological Study-Depression Scale. Clinical variables such as months since cardiac symptom onset and cardiac symptom severity were collected. Findings showed significant relationships between symptom severity and psychological disorders (e.g. anxiety and depression) and these were mediated by life satisfaction. Overall, findings highlight the importance of subjective well-being (e.g. life satisfaction) to reduce anxious and depressive symptoms and to improve general health in AL patients. © The European Society of Cardiology 2015.

  17. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets.

    Science.gov (United States)

    Tham, Yow Keat; Bernardo, Bianca C; Ooi, Jenny Y Y; Weeks, Kate L; McMullen, Julie R

    2015-09-01

    The onset of heart failure is typically preceded by cardiac hypertrophy, a response of the heart to increased workload, a cardiac insult such as a heart attack or genetic mutation. Cardiac hypertrophy is usually characterized by an increase in cardiomyocyte size and thickening of ventricular walls. Initially, such growth is an adaptive response to maintain cardiac function; however, in settings of sustained stress and as time progresses, these changes become maladaptive and the heart ultimately fails. In this review, we discuss the key features of pathological cardiac hypertrophy and the numerous mediators that have been found to be involved in the pathogenesis of cardiac hypertrophy affecting gene transcription, calcium handling, protein synthesis, metabolism, autophagy, oxidative stress and inflammation. We also discuss new mediators including signaling proteins, microRNAs, long noncoding RNAs and new findings related to the role of calcineurin and calcium-/calmodulin-dependent protein kinases. We also highlight mediators and processes which contribute to the transition from adaptive cardiac remodeling to maladaptive remodeling and heart failure. Treatment strategies for heart failure commonly include diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and β-blockers; however, mortality rates remain high. Here, we discuss new therapeutic approaches (e.g., RNA-based therapies, dietary supplementation, small molecules) either entering clinical trials or in preclinical development. Finally, we address the challenges that remain in translating these discoveries to new and approved therapies for heart failure.

  18. Regulation of cardiac remodeling by cardiac Na/K-ATPase isoforms

    Directory of Open Access Journals (Sweden)

    Lijun Catherine Liu

    2016-09-01

    Full Text Available Cardiac remodeling occurs after cardiac pressure/volume overload or myocardial injury during the development of heart failure and is a determinant of heart failure. Preventing or reversing remodeling is a goal of heart failure therapy. Human cardiomyocyte Na+/K+-ATPase has multiple α isoforms (1-3. The expression of the α subunit of the Na+/K+-ATPase is often altered in hypertrophic and failing hearts. The mechanisms are unclear. There are limited data from human cardiomyocytes. Abundant evidences from rodents show that Na+/K+-ATPase regulates cardiac contractility, cell signaling, hypertrophy and fibrosis. The α1 isoform of the Na+/K+-ATPase is the ubiquitous isoform and possesses both pumping and signaling functions. The α2 isoform of the Na+/K+-ATPase regulates intracellular Ca2+ signaling, contractility and pathological hypertrophy. The α3 isoform of the Na+/K+-ATPase may also be a target for cardiac hypertrophy. Restoration of cardiac Na+/K+-ATPase expression may be an effective approach for prevention of cardiac remodeling. In this article, we will overview: (1 the distribution and function of isoform specific Na+/K+-ATPase in the cardiomyocytes. (2 the role of cardiac Na+/K+-ATPase in the regulation of cell signaling, contractility, cardiac hypertrophy and fibrosis in vitro and in vivo. Selective targeting of cardiac Na+/K+-ATPase isoform may offer a new target for the prevention of cardiac remodeling.

  19. Specific efficacy expectations mediate exercise compliance in patients with COPD.

    Science.gov (United States)

    Kaplan, R M; Atkins, C J; Reinsch, S

    1984-01-01

    Social learning theory has generated two different approaches for the assessment of expectancies. Bandura argues that expectancies are specific and do not generalize. Therefore, he prefers measures of specific efficacy expectations. Others endorse the role of generalized expectancies measured by locus of control scales. The present study examines specific versus generalized expectancies as mediators of changes in exercise behavior among 60 older adult patients with Chronic Obstructive Pulmonary Disease. The patients were given a prescription to increase exercise and randomly assigned to experimental groups or control groups. All groups received attention but only experimental groups received training to increase their exercise. After 3 months, groups given specific training for compliance with walking significantly increased their activity in comparison to the control group receiving only attention. These changes were mediated by changes in perceived efficacy for walking, with efficacy expectations for other behaviors changing as a function of their similarity to walking. A generalized health locus of control expectancy measure was less clearly associated with behavior change. The results are interpreted as supporting Bandura's version of social theory.

  20. Methyl-CpG binding-protein 2 function in cholinergic neurons mediates cardiac arrhythmogenesis.

    Science.gov (United States)

    Herrera, José A; Ward, Christopher S; Wehrens, Xander H T; Neul, Jeffrey L

    2016-11-15

    Sudden unexpected death occurs in one quarter of deaths in Rett Syndrome (RTT), a neurodevelopmental disorder caused by mutations in Methyl-CpG-binding protein 2 (MECP2). People with RTT show a variety of autonomic nervous system (ANS) abnormalities and mouse models show similar problems including QTc interval prolongation and hypothermia. To explore the role of cardiac problems in sudden death in RTT, we characterized cardiac rhythm in mice lacking Mecp2 function. Male and female mutant mice exhibited spontaneous cardiac rhythm abnormalities including bradycardic events, sinus pauses, atrioventricular block, premature ventricular contractions, non-sustained ventricular arrhythmias, and increased heart rate variability. Death was associated with spontaneous cardiac arrhythmias and complete conduction block. Atropine treatment reduced cardiac arrhythmias in mutant mice, implicating overactive parasympathetic tone. To explore the role of MeCP2 within the parasympathetic neurons, we selectively removed MeCP2 function from cholinergic neurons (MeCP2 ChAT KO), which recapitulated the cardiac rhythm abnormalities, hypothermia, and early death seen in RTT male mice. Conversely, restoring MeCP2 only in cholinergic neurons rescued these phenotypes. Thus, MeCP2 in cholinergic neurons is necessary and sufficient for autonomic cardiac control, thermoregulation, and survival, and targeting the overactive parasympathetic system may be a useful therapeutic strategy to prevent sudden unexpected death in RTT.

  1. Automated segmentation and reconstruction of patient-specific cardiac anatomy and pathology from in vivo MRI

    International Nuclear Information System (INIS)

    Ringenberg, Jordan; Deo, Makarand; Devabhaktuni, Vijay; Filgueiras-Rama, David; Pizarro, Gonzalo; Ibañez, Borja; Berenfeld, Omer; Boyers, Pamela; Gold, Jeffrey

    2012-01-01

    This paper presents an automated method to segment left ventricle (LV) tissues from functional and delayed-enhancement (DE) cardiac magnetic resonance imaging (MRI) scans using a sequential multi-step approach. First, a region of interest (ROI) is computed to create a subvolume around the LV using morphological operations and image arithmetic. From the subvolume, the myocardial contours are automatically delineated using difference of Gaussians (DoG) filters and GSV snakes. These contours are used as a mask to identify pathological tissues, such as fibrosis or scar, within the DE-MRI. The presented automated technique is able to accurately delineate the myocardium and identify the pathological tissue in patient sets. The results were validated by two expert cardiologists, and in one set the automated results are quantitatively and qualitatively compared with expert manual delineation. Furthermore, the method is patient-specific, performed on an entire patient MRI series. Thus, in addition to providing a quick analysis of individual MRI scans, the fully automated segmentation method is used for effectively tagging regions in order to reconstruct computerized patient-specific 3D cardiac models. These models can then be used in electrophysiological studies and surgical strategy planning. (paper)

  2. Signaling factors in stem cell-mediated repair of infarcted myocardium

    NARCIS (Netherlands)

    Vandervelde, S; van Luyn, MJA; Tio, RA; Harmsen, MC

    Myocardial infarction leads to scar formation and subsequent reduced cardiac performance. The ultimate therapy after myocardial infarction would pursue stem cell-based regeneration. The aim of stem cell-mediated cardiac repair embodies restoration of cardiac function by regeneration of healthy

  3. Extracellular high-mobility group box 1 mediates pressure overload-induced cardiac hypertrophy and heart failure.

    Science.gov (United States)

    Zhang, Lei; Liu, Ming; Jiang, Hong; Yu, Ying; Yu, Peng; Tong, Rui; Wu, Jian; Zhang, Shuning; Yao, Kang; Zou, Yunzeng; Ge, Junbo

    2016-03-01

    Inflammation plays a key role in pressure overload-induced cardiac hypertrophy and heart failure, but the mechanisms have not been fully elucidated. High-mobility group box 1 (HMGB1), which is increased in myocardium under pressure overload, may be involved in pressure overload-induced cardiac injury. The objectives of this study are to determine the role of HMGB1 in cardiac hypertrophy and cardiac dysfunction under pressure overload. Pressure overload was imposed on the heart of male wild-type mice by transverse aortic constriction (TAC), while recombinant HMGB1, HMGB1 box A (a competitive antagonist of HMGB1) or PBS was injected into the LV wall. Moreover, cardiac myocytes were cultured and given sustained mechanical stress. Transthoracic echocardiography was performed after the operation and sections for histological analyses were generated from paraffin-embedded hearts. Relevant proteins and genes were detected. Cardiac HMGB1 expression was increased after TAC, which was accompanied by its translocation from nucleus to both cytoplasm and intercellular space. Exogenous HMGB1 aggravated TAC-induced cardiac hypertrophy and cardiac dysfunction, as demonstrated by echocardiographic analyses, histological analyses and foetal cardiac genes detection. Nevertheless, the aforementioned pathological change induced by TAC could partially be reversed by HMGB1 inhibition. Consistent with the in vivo observations, mechanical stress evoked the release and synthesis of HMGB1 in cultured cardiac myocytes. This study indicates that the activated and up-regulated HMGB1 in myocardium, which might partially be derived from cardiac myocytes under pressure overload, may be of crucial importance in pressure overload-induced cardiac hypertrophy and cardiac dysfunction. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  4. Chronic hydrocephalus-induced changes in cerebral blood flow: mediation through cardiac effects.

    Science.gov (United States)

    Dombrowski, Stephen M; Schenk, Soren; Leichliter, Anna; Leibson, Zack; Fukamachi, Kiyotaka; Luciano, Mark G

    2006-10-01

    Decreased cerebral blood flow (CBF) in hydrocephalus is believed to be related to increased intracranial pressure (ICP), vascular compression as the result of enlarged ventricles, or impaired metabolic activity. Little attention has been given to the relationship between cardiac function and systemic blood flow in chronic hydrocephalus (CH). Using an experimental model of chronic obstructive hydrocephalus developed in our laboratory, we investigated the relationship between the duration and severity of hydrocephalus and cardiac output (CO), CBF, myocardial tissue perfusion (MTP), and peripheral blood flow (PBF). Blood flow measures were obtained using the microsphere injection method under controlled hemodynamic conditions in experimental CH (n=23) and surgical control (n=8) canines at baseline and at 2, 4, 8, 12, and 16 weeks. Cardiac output measures were made using the Swan-Ganz thermodilution method. Intracranial compliance (ICC) via cerebrospinal fluid (CSF) bolus removal and infusion, and oxygen delivery in CSF and prefrontal cortex (PFC) were also investigated. We observed an initial surgical effect relating to 30% CO reduction and approximately 50% decrease in CBF, MTP, and PBF in both groups 2 weeks postoperatively, which recovered in control animals but continued to decline further in CH animals at 16 weeks. Cerebral blood flow, which was positively correlated with CO (P=0.028), showed no significant relationship with either CSF volume or pressure. Decreased CBF correlated with oxygen deprivation in PFC (P=0.006). Cardiac output was inversely related with ventriculomegaly (P=0.019), but did not correlate with ICP. Decreased CO corresponded to increased ICC, as measured by CSF infusion (P=0.04). Our results suggest that CH may have more of an influence on CO and CBF in the chronic stage than in the early condition, which was dominated by surgical effect. The cause of this late deterioration of cardiac function in hydrocephalus is uncertain, but may reflect

  5. Cardiac-specific catalase overexpression rescues anthrax lethal toxin-induced cardiac contractile dysfunction: role of oxidative stress and autophagy.

    Science.gov (United States)

    Kandadi, Machender R; Yu, Xuejun; Frankel, Arthur E; Ren, Jun

    2012-11-07

    Lethal and edema toxins secreted by Bacillus anthracis during anthrax infection were found to incite serious cardiovascular complications. However, the underlying mechanisms in anthrax lethal toxin-induced cardiac anomalies remain unknown. This study was designed to evaluate the impact of antioxidant enzyme catalase in anthrax lethal toxin-induced cardiomyocyte contractile dysfunction. Wild type (WT) and cardiac-specific catalase overexpression mice were challenged with lethal toxin (2 μg/g, intraperotineally (i.p.)). Cardiomyocyte contractile and intracellular Ca(2+) properties were assessed 18 h later using an IonOptix edge-detection system. Proteasome function was assessed using chymotrypsin-like and caspase-like activities. GFP-LC3 puncta and Western blot analysis were used to evaluate autophagy and protein ubiquitination. Lethal toxin exposure suppressed cardiomyocyte contractile function (suppressed peak shortening, maximal velocity of shortening/re-lengthening, prolonged duration of shortening/re-lengthening, and impaired intracellular Ca(2+) handling), the effects of which were alleviated by catalase. In addition, lethal toxin triggered autophagy, mitochondrial and ubiquitin-proteasome defects, the effects of which were mitigated by catalase. Pretreatment of cardiomyocytes from catalase mice with the autophagy inducer rapamycin significantly attenuated or ablated catalase-offered protection against lethal toxin-induced cardiomyocyte dysfunction. On the other hand, the autophagy inhibitor 3-MA ablated or significantly attenuated lethal toxin-induced cardiomyocyte contractile anomalies. Our results suggest that catalase is protective against anthrax lethal toxin-induced cardiomyocyte contractile and intracellular Ca(2+) anomalies, possibly through regulation of autophagy and mitochondrial function.

  6. SUCCESSFUL APPLICATION OF PERIPHERAL VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION FOR CARDIAC ALLOGRAFT ANTIBODY-MEDIATED REJECTION WITH SEVERE HEMODYNAMIC COMPROMISE

    Directory of Open Access Journals (Sweden)

    V. N. Poptsov

    2015-01-01

    Full Text Available Introduction. Acute antibody-mediated rejection (AMR is one of the severe complications of early and late period after heart transplantation (HT. Only few case reports and studies presented of mechanical circulatory support (MCS application for refractory acute rejection causing hemodynamic compromise. Aim. We report the case of a woman with cardiogenic shock caused by severe AMR that was successfully treatment by peripheral venoarterial extracorporeal membrane oxygenation (VA ECMO. Material and methods. In december 2014, a 60-year-old woman with dilated cardiomyopathy was operated for HT. The patient had a good initial cardiac allograft function and no and was discharged from ICU on the 4th day after HT. 1st endomyocardial biopsy (EMB (the 7th day after HT showed absence of acute cellular and antibody-mediated rejection. On the 11th day after HT patient aggravated and presented clinical signs of life-threatening acute cardiac allograft dysfunction: arterial blood pressure 78/49/38 mm Hg, HR 111 in min, CVP 20 mm Hg, PAP 47/34/25 mm Hg, PCWP 25 mm Hg, CI 1.5 l/min/m2, adrenalin 110 ng/kg/min, dopamine 15 mcg/kg/min. ECG showed impairment of systolic left (LVEF 25% and right (RVEF 15% ventricle function, left and right ventricle diffuse hypokinesis, thickness of IVS, LV and RV wall 1.7, 1.4 and 0.8 cm, tricuspid and mitral valve regurgitation 2–3 degrees. EMB presented AMR. In conscience peripheral VA ECMO was installed. We used peripheral transcutaneous cannulation technique via femoral vessels – arterial cannula 15 F, venous cannula – 23 F, vascular catheter 14 G for anterograde leg’s perfusion. ACT 130–150 sec. AMR therapy included: methylprednisolon pulse-therapy (10 mg/kg for 5 day, IgG, plasmapheresis (No 7, rituximab. Results. Under MCS by VA ECMO we noted quick improvement of hemodynamic, metabolic homeostasis and organ functions. On the 6th day of VA ECMO (blood flow 1.8 l/min: arterial blood pressure 133/81/54 mm Hg, CVP 5 mm

  7. Cardiac-specific overexpression of insulin-like growth factor I (IGF-1) rescues lipopolysaccharide-induced cardiac dysfunction and activation of stress signaling in murine cardiomyocytes.

    Science.gov (United States)

    Zhao, Peng; Turdi, Subat; Dong, Feng; Xiao, Xiaoyan; Su, Guohai; Zhu, Xinglei; Scott, Glenda I; Ren, Jun

    2009-07-01

    Lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, plays a key role in cardiac dysfunction in sepsis. Low circulating levels of insulin-like growth factor 1 (IGF-1) are found in sepsis, although the influence of IGF-1 on septic cardiac defect is unknown. This study was designed to examine the impact of IGF-1 on LPS-induced cardiac contractile and intracellular Ca2+ dysfunction, activation of stress signal and endoplasmic reticulum (ER) stress. Mechanical and intracellular Ca2+ properties were examined in cardiomyocytes from Fast Violet B and cardiac-specific IGF-1 overexpression mice treated with or without LPS (4 mg kg(-1), 6 h). Reactive oxygen species (ROS), protein carbonyl formation and apoptosis were measured. Activation of mitogen-activated protein kinase pathways (p38, c-jun N-terminal kinase [JNK] and extracellular signal-related kinase [ERK]), ER stress and apoptotic markers were evaluated using Western blot analysis. Our results revealed decreased peak shortening and maximal velocity of shortening/relengthening and prolonged duration of relengthening in LPS-treated Fast Violet B cardiomyocytes associated with reduced intracellular Ca2+ decay. Accumulation of ROS protein carbonyl and apoptosis were elevated after LPS treatment. Western blot analysis revealed activated p38 and JNK, up-regulated Bax, and the ER stress markers GRP78 and Gadd153 in LPS-treated mouse hearts without any change in ERK and Bcl-2. Total protein expression of p38, JNK, and ERK was unaffected by either LPS or IGF-1. Interestingly, these LPS-induced changes in mechanical and intracellular Ca2+ properties, ROS, protein carbonyl, apoptosis, stress signal activation, and ER stress markers were effectively ablated by IGF-1. In vitro LPS exposure (1 microg mL(-1)) produced cardiomyocyte mechanical dysfunction reminiscent of the in vivo setting, which was alleviated by exogenous IGF-1 (50 nM). These data collectively suggested a beneficial of IGF-1 in

  8. Evaluating the Cancer Therapeutic Potential of Cardiac Glycosides

    Directory of Open Access Journals (Sweden)

    José Manuel Calderón-Montaño

    2014-01-01

    Full Text Available Cardiac glycosides, also known as cardiotonic steroids, are a group of natural products that share a steroid-like structure with an unsaturated lactone ring and the ability to induce cardiotonic effects mediated by a selective inhibition of the Na+/K+-ATPase. Cardiac glycosides have been used for many years in the treatment of cardiac congestion and some types of cardiac arrhythmias. Recent data suggest that cardiac glycosides may also be useful in the treatment of cancer. These compounds typically inhibit cancer cell proliferation at nanomolar concentrations, and recent high-throughput screenings of drug libraries have therefore identified cardiac glycosides as potent inhibitors of cancer cell growth. Cardiac glycosides can also block tumor growth in rodent models, which further supports the idea that they have potential for cancer therapy. Evidence also suggests, however, that cardiac glycosides may not inhibit cancer cell proliferation selectively and the potent inhibition of tumor growth induced by cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact caused by their ability to selectively kill human cells versus rodent cells. This paper reviews such evidence and discusses experimental approaches that could be used to reveal the cancer therapeutic potential of cardiac glycosides in preclinical studies.

  9. Activity and specificity of TRV-mediated gene editing in plants

    KAUST Repository

    Ali, Zahir; Abulfaraj, Aala A.; Piatek, Marek J.; Mahfouz, Magdy M.

    2015-01-01

    editing in Nicotiana benthamiana. TRV infects the growing points and possesses small genome size; which facilitate cloning, multiplexing, and agroinfections. Here, we report on the persistent activity and specificity of the TRV-mediated CRISPR/Cas9 system

  10. Gender-specific issues in cardiac rehabilitation: do women with ischaemic heart disease need specially tailored programmes?

    Science.gov (United States)

    Bjarnason-Wehrens, Birna; Grande, Gesine; Loewel, Hannelore; Völler, Heinz; Mittag, Oskar

    2007-04-01

    Ischaemic heart disease (IHD) has changed from a disease of middle-aged men in the late 1970s to a disease of elderly women in the 2000s. Most clinical studies during the past three decades have been conducted with men. Cardiac rehabilitation programmes were also developed with special regard to improving the rate of return to work in middle-aged men. The rehabilitation needs of older patients and women in particular have been largely neglected. The aim of this review is briefly to outline our present knowledge on gender issues in cardiac rehabilitation, and to specify barriers with regard to physical activities especially in (older) women. Coping with a cardiac event, women tend to minimize or play down the impact of their health situation and avoid burdening their social contacts. After a first cardiac event, women report greater psychological distress and lower self-efficacy and self-esteem. In addition, older age, lower exercise levels and reduced functional capacity or co-morbid conditions such as osteoporosis and urinary incontinence are barriers to physical activities in women with IHD. Recent studies on psychosocial intervention revealed less favourable results in women compared with men. These findings have not yet been well explained. This emphasizes our current lack of knowledge about the processes and determinants of successful psychosocial interventions in men and women with IHD. A large (European) trial on gender-specific coping styles, needs, and preferences of older women, and the effects of psychosocial intervention is proposed.

  11. Age- and gender-specific differences in left and right ventricular cardiac function and mass determined by cine magnetic resonance imaging

    International Nuclear Information System (INIS)

    Sandstede, J.; Lipke, C.; Beer, M.; Hofmann, S.; Pabst, T.; Kenn, W.; Hahn, D.; Neubauer, S.

    2000-01-01

    We examined possible age- and gender-specific differences in the function and mass of left (LV) and right (RV) ventricles in 36 healthy volunteers using cine gradient-recalled echo magnetic resonance imaging. Subjects were divided into four groups (nine men and nine women in each): men aged under 45 years (32 ± 7), women aged under 45 (27 ± 6), men aged over 45 (59 ± 8), and women aged over 45 (57 ± 9). Functional analysis of cardiac volume and mass and of LV wall motion was performed by manual segmentation of the endocardial and epicardial borders of the end-diastolic and end-systolic frame; both absolute and normalized (per square meter body surface area) values were evaluated. With age there was a significant decrease in both absolute and normalized LV and RV chamber volumes (EDV, ESV), while LV and RV masses remained unchanged. Gender-specific differences were found in cardiac mass and volume (for men and women, respectively: LV mass, 155 ± 18 and 110 ± 16 g; LV EDV, 118 ± 27 and 96 ± 21 ml; LV ESV, 40 ± 13 and 29 ± 9 ml; RV mass, 52 ± 10 and 39 ± 5 g; RV EDV, 131 ± 28 and 100 ± 23 ml; RV ESV, 53 ± 17 and 33 ± 15 ml). Normalization to body surface area eliminated differences in LV volumes but not those in LV mass, RV mass, or RV function. Functional parameters such as cardiac output and LV ejection fraction showed nonsignificant or only slight differences and were thus largely independent of age and gender. Intra- and interobserver variability ranged between 1.4 % and 5.9 % for all parameters. Cine magnetic resonance imaging thus shows age- and gender-specific differences in cardiac function, and therefore the evaluation of cardiac function in patients should consider age- and gender-matched normative values. (orig.)

  12. Boosters and barriers for direct cardiac reprogramming.

    Science.gov (United States)

    Talkhabi, Mahmood; Zonooz, Elmira Rezaei; Baharvand, Hossein

    2017-06-01

    Heart disease is currently the most significant cause of morbidity and mortality worldwide, which accounts for approximately 33% of all deaths. Recently, a promising and alchemy-like strategy has been developed called direct cardiac reprogramming, which directly converts somatic cells such as fibroblasts to cardiac lineage cells such as cardiomyocytes (CMs), termed induced CMs or iCMs. The first in vitro cardiac reprogramming study, mediated by cardiac transcription factors (TFs)-Gata4, Tbx5 and Mef2C-, was not enough efficient to produce an adequate number of fully reprogrammed, functional iCMs. As a result, numerous combinations of cardiac TFs exist for direct cardiac reprogramming of mouse and human fibroblasts. However, the efficiency of direct cardiac reprogramming remains low. Recently, a number of cellular and molecular mechanisms have been identified to increase the efficiency of direct cardiac reprogramming and the quality of iCMs. For example, microgrooved substrate, cardiogenic growth factors [VEGF, FGF, BMP4 and Activin A], and an appropriate stoichiometry of TFs boost the direct cardiac reprogramming. On the other hand, serum, TGFβ signaling, activators of epithelial to mesenchymal transition, and some epigenetic factors (Bmi1 and Ezh2) are barriers for direct cardiac reprogramming. Manipulating these mechanisms by the application of boosters and removing barriers can increase the efficiency of direct cardiac reprogramming and possibly make iCMs reliable for cell-based therapy or other potential applications. In this review, we summarize the latest trends in cardiac TF- or miRNA-based direct cardiac reprogramming and comprehensively discuses all molecular and cellular boosters and barriers affecting direct cardiac reprogramming. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Tissue-specific and substrate-specific mitochondrial bioenergetics in feline cardiac and skeletal muscles

    DEFF Research Database (Denmark)

    Christiansen, Liselotte Bruun; Dela, Flemming; Koch, Jørgen

    2015-01-01

    fibers. Biopsies of left ventricular cardiac muscle and soleus muscle, a type I-rich oxidative skeletal muscle, were obtained from 15 healthy domestic cats. Enzymatic activity of citrate synthase (CS), a biomarker of mitochondrial content, was measured. Mitochondrial OXPHOS capacity with various kinds...

  14. The distressed (Type D) personality mediates the relationship between remembered parenting and psychological distress in cardiac patients

    DEFF Research Database (Denmark)

    Damen, Nikki L; Versteeg, Henneke; van Helmondt, Sanne J

    2013-01-01

    Objective: Both the distressed (Type D) personality (i.e. the combination of negative affectivity and social inhibition traits) and dysfunctional parenting styles are associated with anxiety and depression. As parenting styles have been related to personality development, dysfunctional parenting...... styles may also be associated with Type D personality. We examined whether remembered parenting was associated with anxiety and depression in cardiac patients and whether Type D personality mediated this relationship. Methods: Our sample comprised 435 patients treated with percutaneous coronary...... intervention (PCI) and 123 patients with congestive heart failure (CHF). Patients completed the Hospital Anxiety and Depression Scale, Type D Scale (DS14), and Remembered Relationship with Parents (RRP(10)) scale. Results: Remembered parenting was significantly associated with higher anxiety and depression...

  15. Donor-specific anti-HLA antibodies with antibody-mediated rejection and long-term outcomes following heart transplantation.

    Science.gov (United States)

    Clerkin, Kevin J; Farr, Maryjane A; Restaino, Susan W; Zorn, Emmanuel; Latif, Farhana; Vasilescu, Elena R; Marboe, Charles C; Colombo, Paolo C; Mancini, Donna M

    2017-05-01

    Donor-specific anti-HLA antibodies (DSA) are common after heart transplantation and are associated with rejection, cardiac allograft vasculopathy, and mortality. A noninvasive diagnostic test for pathologic antibody-mediated rejection (pAMR) does not exist. From January 1, 2010, through August 31, 2013, 221 consecutive adult patients underwent heart transplantation and were followed through October 1, 2015. The primary objective was to determine whether the presence of DSA could detect AMR at the time of pathologic diagnosis. Secondary analyses included association of DSA (stratified by major histocompatibility complex class and de novo status) during AMR with new graft dysfunction, graft loss (mortality or retransplantation), and development of cardiac allograft vasculopathy. During the study period, 69 patients (31.2%) had DSA (24% had de novo DSA), and there were 74 episodes of pAMR in 38 patients. Sensitivity of DSA at any mean fluorescence intensity to detect concurrent pAMR was only 54.3%. The presence of any DSA during pAMR increased the odds of graft dysfunction (odds ratio = 5.37; 95% confidence interval [CI], 1.34-21.47; p = 0.018), adjusting for age, sex, and timing of AMR. Circulating class II DSA after transplantation increased risk of future pAMR (hazard ratio = 2.97; 95% CI, 1.31-6.73; p = 0.009). Patients who developed de novo class II DSA had 151% increased risk of graft loss (contingent on 30-day survival) compared with patients who did not have DSA (95% CI, 1.11-5.69; p = 0.027). DSA were inadequate to diagnose pAMR. Class II DSA provided prognostic information regarding future pAMR, graft dysfunction with pAMR, and graft loss. Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  16. Redox regulation of calcium release in skeletal and cardiac muscle

    Directory of Open Access Journals (Sweden)

    CECILIA HIDALGO

    2002-01-01

    Full Text Available In skeletal and cardiac muscle cells, specific isoforms of the Ryanodine receptor channels mediate Ca2+ release from the sarcoplasmic reticulum. These channels are highly susceptible to redox modifications, which regulate channel activity. In this work, we studied the effects of Ca2+ (endogenous agonist and Mg2+ (endogenous inhibitor on the kinetics of Ca2+ release from sarcoplasmic reticulum vesicles isolated from skeletal or cardiac mammalian muscle. Native skeletal vesicles exhibited maximal stimulation of release kinetics by 10-20 µM [Ca2+], whereas in native cardiac vesicles, maximal stimulation of release required only 1 µM [Ca2+]. In 10 µM [Ca2+], free [Mg2+] < 0.1 mM produced marked inhibition of release from skeletal vesicles but free [Mg2+] ­ 0.8 mM did not affect release from cardiac vesicles. Incubation of skeletal or cardiac vesicles with the oxidant thimerosal increased their susceptibility to stimulation by Ca2+ and decreased the inhibitory effect of Mg2+ in skeletal vesicles. Sulfhydryl-reducing agents fully reversed the effects of thimerosal. The endogenous redox species, glutathione disulfide and S-nitrosoglutathione, also stimulated release from skeletal sarcoplasmic reticulum vesicles. In 10 µM [Ca2+], 35S-nitrosoglutathione labeled a protein fraction enriched in release channels through S-glutathiolation. Free [Mg2+] 1 mM or decreasing free [Ca2+] to the nM range prevented this reaction. Possible physiological and pathological consequences of redox modification of release channels on Ca2+ signaling in heart and muscle cells are discussed

  17. Topical thrombin preparations and their use in cardiac surgery

    Directory of Open Access Journals (Sweden)

    Brianne L Dunn

    2009-10-01

    Full Text Available Brianne L Dunn1, Walter E Uber1, John S Ikonomidis21Department of Pharmacy Services and 2Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina, USAAbstract: Coagulopathic bleeding may lead to increased morbidity and mortality after cardiac surgery. Topical bovine thrombin has been used to promote hemostasis after surgical procedures for over 60 years and is used frequently as a topical hemostatic agent in cardiac surgery. Recently, use of bovine thrombin has been reported to be associated with increased risk for anaphylaxis, thrombosis, and immune-mediated coagulopathy thought secondary to the production of antifactor V and antithrombin antibodies. In patients who develop bovine thrombin-induced immune-mediated coagulopathy, clinical manifestations may range from asymptomatic alterations in coagulation tests to severe hemorrhage and death. Patients undergoing cardiac surgical procedures may be at increased risk for development of antibodies to bovine thrombin products and associated complications. This adverse immunologic profile has led to the development of alternative preparations including a human and a recombinant thrombin which have been shown to be equally efficacious to bovine thrombin and have reduced antigenicity. However, the potential benefit associated with reduced antigenicity is not truly known secondary to the lack of long-term experience with these products. Given the potentially higher margin of safety and less stringent storage concerns compared to human thrombin, recombinant thrombin may be the most reasonable approach in cardiac surgery.Keywords: bovine thrombin, human thrombin, recombinant thrombin, immune-mediated coagulopathy, topical hemostatic agents, thrombin 

  18. Patient-Specific Induced Pluripotent Stem Cell Models: Generation and Characterization of Cardiac Cells.

    Science.gov (United States)

    Zanella, Fabian; Sheikh, Farah

    2016-01-01

    The generation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes has been of utmost interest for the study of cardiac development, cardiac disease modeling, and evaluation of cardiotoxic effects of novel candidate drugs. Several protocols have been developed to guide human stem cells toward the cardiogenic path. Pioneering work used serum to promote cardiogenesis; however, low cardiogenic throughputs, lack of chemical definition, and batch-to-batch variability of serum lots constituted a considerable impediment to the implementation of those protocols to large-scale cell biology. Further work focused on the manipulation of pathways that mouse genetics indicated to be fundamental in cardiac development to promote cardiac differentiation in stem cells. Although extremely elegant, those serum-free protocols involved the use of human recombinant cytokines that tend to be quite costly and which can also be variable between lots. The latest generation of cardiogenic protocols aimed for a more cost-effective and reproducible definition of the conditions driving cardiac differentiation, using small molecules to manipulate cardiogenic pathways overriding the need for cytokines. This chapter details methods based on currently available cardiac differentiation protocols for the generation and characterization of robust numbers of hiPSC-derived cardiomyocytes under chemically defined conditions.

  19. Cardiac-specific catalase overexpression rescues anthrax lethal toxin-induced cardiac contractile dysfunction: role of oxidative stress and autophagy

    Directory of Open Access Journals (Sweden)

    Kandadi Machender R

    2012-11-01

    Full Text Available Abstract Background Lethal and edema toxins secreted by Bacillus anthracis during anthrax infection were found to incite serious cardiovascular complications. However, the underlying mechanisms in anthrax lethal toxin-induced cardiac anomalies remain unknown. This study was designed to evaluate the impact of antioxidant enzyme catalase in anthrax lethal toxin-induced cardiomyocyte contractile dysfunction. Methods Wild type (WT and cardiac-specific catalase overexpression mice were challenged with lethal toxin (2 μg/g, intraperotineally (i.p.. Cardiomyocyte contractile and intracellular Ca2+ properties were assessed 18 h later using an IonOptix edge-detection system. Proteasome function was assessed using chymotrypsin-like and caspase-like activities. GFP-LC3 puncta and Western blot analysis were used to evaluate autophagy and protein ubiquitination. Results Lethal toxin exposure suppressed cardiomyocyte contractile function (suppressed peak shortening, maximal velocity of shortening/re-lengthening, prolonged duration of shortening/re-lengthening, and impaired intracellular Ca2+ handling, the effects of which were alleviated by catalase. In addition, lethal toxin triggered autophagy, mitochondrial and ubiquitin-proteasome defects, the effects of which were mitigated by catalase. Pretreatment of cardiomyocytes from catalase mice with the autophagy inducer rapamycin significantly attenuated or ablated catalase-offered protection against lethal toxin-induced cardiomyocyte dysfunction. On the other hand, the autophagy inhibitor 3-MA ablated or significantly attenuated lethal toxin-induced cardiomyocyte contractile anomalies. Conclusions Our results suggest that catalase is protective against anthrax lethal toxin-induced cardiomyocyte contractile and intracellular Ca2+ anomalies, possibly through regulation of autophagy and mitochondrial function.

  20. Antigen-specific and nonspecific mediators of T cell/B cell cooperation. III. Characterization of the nonspecific mediator(s) from different sources.

    Science.gov (United States)

    Harwell, L; Kappler, J W; Marrack, P

    1976-05-01

    T cell-containing lymphoid populations produce a nonantigen-specific mediator(s) (NSM) which can replace T cell helper function in vitro in the response of B cells to sheep red blood cells (SRBC), but not to the hapten-protein conjugate, trinitrophenyl-keyhole limpet hemocyanin, (TNP-KLH). NSM produced under three conditions: 1) stimulation of KLH-primed cells with KLH; 2) allogeneic stimulation of normal spleen cells; and 3) stimulation of normal spleen cells with Con A (but not PHA) are indistinguishable on the basis of their biologic activity and m.w., estimated as 30 to 40,000 daltons by G-200 chromatography. Production of NSM is dependent on the presence of T cells. The action of NSM on B cells responding to SRBC in the presence of 2-mercaptoethanol is unaffected by severe macrophage depletion. Extensive absorption of NSM with SRBC failed to remove its activity, confirming its nonantigen-specific nature.

  1. Mitochondrial Reactive Oxygen Species Mediate Cardiac Structural, Functional, and Mitochondrial Consequences of Diet-Induced Metabolic Heart Disease.

    Science.gov (United States)

    Sverdlov, Aaron L; Elezaby, Aly; Qin, Fuzhong; Behring, Jessica B; Luptak, Ivan; Calamaras, Timothy D; Siwik, Deborah A; Miller, Edward J; Liesa, Marc; Shirihai, Orian S; Pimentel, David R; Cohen, Richard A; Bachschmid, Markus M; Colucci, Wilson S

    2016-01-11

    Mitochondrial reactive oxygen species (ROS) are associated with metabolic heart disease (MHD). However, the mechanism by which ROS cause MHD is unknown. We tested the hypothesis that mitochondrial ROS are a key mediator of MHD. Mice fed a high-fat high-sucrose (HFHS) diet develop MHD with cardiac diastolic and mitochondrial dysfunction that is associated with oxidative posttranslational modifications of cardiac mitochondrial proteins. Transgenic mice that express catalase in mitochondria and wild-type mice were fed an HFHS or control diet for 4 months. Cardiac mitochondria from HFHS-fed wild-type mice had a 3-fold greater rate of H2O2 production (P=0.001 versus control diet fed), a 30% decrease in complex II substrate-driven oxygen consumption (P=0.006), 21% to 23% decreases in complex I and II substrate-driven ATP synthesis (P=0.01), and a 62% decrease in complex II activity (P=0.002). In transgenic mice that express catalase in mitochondria, all HFHS diet-induced mitochondrial abnormalities were ameliorated, as were left ventricular hypertrophy and diastolic dysfunction. In HFHS-fed wild-type mice complex II substrate-driven ATP synthesis and activity were restored ex vivo by dithiothreitol (5 mmol/L), suggesting a role for reversible cysteine oxidative posttranslational modifications. In vitro site-directed mutation of complex II subunit B Cys100 or Cys103 to redox-insensitive serines prevented complex II dysfunction induced by ROS or high glucose/high palmitate in the medium. Mitochondrial ROS are pathogenic in MHD and contribute to mitochondrial dysfunction, at least in part, by causing oxidative posttranslational modifications of complex I and II proteins including reversible oxidative posttranslational modifications of complex II subunit B Cys100 and Cys103. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  2. Nanotized PPARα Overexpression Targeted to Hypertrophied Myocardium Improves Cardiac Function by Attenuating the p53-GSK3β-Mediated Mitochondrial Death Pathway.

    Science.gov (United States)

    Rana, Santanu; Datta, Ritwik; Chaudhuri, Ratul Datta; Chatterjee, Emeli; Chawla-Sarkar, Mamta; Sarkar, Sagartirtha

    2018-05-09

    Metabolic remodeling of cardiac muscles during pathological hypertrophy is characterized by downregulation of fatty acid oxidation (FAO) regulator, peroxisome proliferator-activated receptor alpha (PPARα). Thereby, we hypothesized that a cardiac-specific induction of PPARα might restore the FAO-related protein expression and resultant energy deficit. In the present study, consequences of PPARα augmentation were evaluated for amelioration of chronic oxidative stress, myocyte apoptosis, and cardiac function during pathological cardiac hypertrophy. Nanotized PPARα overexpression targeted to myocardium was done by a stearic acid-modified carboxymethyl-chitosan (CMC) conjugated to a 20-mer myocyte-targeted peptide (CMCP). Overexpression of PPARα ameliorated pathological hypertrophy and improved cardiac function. Augmented PPARα in hypertrophied myocytes revealed downregulated p53 acetylation (lys 382), leading to reduced apoptosis. Such cells showed increased binding of PPARα with p53 that in turn reduced interaction of p53 with glycogen synthase kinase-3β (GSK3β), which upregulated inactive phospho-GSK3β (serine [Ser]9) expression within mitochondrial protein fraction. Altogether, the altered molecular milieu in PPARα-overexpressed hypertrophy groups restored mitochondrial structure and function both in vitro and in vivo. Cardiomyocyte-targeted overexpression of a protein of interest (PPARα) by nanotized plasmid has been described for the first time in this study. Our data provide a novel insight towards regression of pathological hypertrophy by ameliorating mitochondrial oxidative stress in targeted PPARα-overexpressed myocardium. PPARα-overexpression during pathological hypertrophy showed substantial betterment of mitochondrial structure and function, along with downregulated apoptosis. Myocardium-targeted overexpression of PPARα during pathological cardiac hypertrophy led to an overall improvement of cardiac energy deficit and subsequent cardiac

  3. Activity and specificity of TRV-mediated gene editing in plants

    KAUST Repository

    Ali, Zahir

    2015-06-03

    © 2015 Taylor and Francis Group, LLC. Plant trait engineering requires efficient targeted genome-editing technologies. Clustered regularly interspaced palindromic repeats (CRISPRs)/ CRISPR associated (Cas) type II system is used for targeted genome-editing applications across eukaryotic species including plants. Delivery of genome engineering reagents and recovery of mutants remain challenging tasks for in planta applications. Recently, we reported the development of Tobacco rattle virus (TRV)-mediated genome editing in Nicotiana benthamiana. TRV infects the growing points and possesses small genome size; which facilitate cloning, multiplexing, and agroinfections. Here, we report on the persistent activity and specificity of the TRV-mediated CRISPR/Cas9 system for targeted modification of the Nicotiana benthamiana genome. Our data reveal the persistence of the TRVmediated Cas9 activity for up to 30 d post-agroinefection. Further, our data indicate that TRV-mediated genome editing exhibited no off-target activities at potential off-targets indicating the precision of the system for plant genome engineering. Taken together, our data establish the feasibility and exciting possibilities of using virus-mediated CRISPR/Cas9 for targeted engineering of plant genomes.

  4. Progression in sensing cardiac troponin biomarker charge transductions on semiconducting nanomaterials

    Energy Technology Data Exchange (ETDEWEB)

    Fathil, M.F.M., E-mail: faris.fathil@gmail.com [Institute of Nano Electronic Engineering (INEE), Universiti Malaysia Perlis, 01000, Kangar, Perlis (Malaysia); Md Arshad, M.K., E-mail: mohd.khairuddin@unimap.edu.my [Institute of Nano Electronic Engineering (INEE), Universiti Malaysia Perlis, 01000, Kangar, Perlis (Malaysia); School of Microelectronic Engineering, Universiti Malaysia Perlis, 01000, Kangar, Perlis (Malaysia); Ruslinda, A.R., E-mail: ruslinda@unimap.edu.my [Institute of Nano Electronic Engineering (INEE), Universiti Malaysia Perlis, 01000, Kangar, Perlis (Malaysia); Nuzaihan, M.N.M., E-mail: m.nuzaihan@unimap.edu.my [Institute of Nano Electronic Engineering (INEE), Universiti Malaysia Perlis, 01000, Kangar, Perlis (Malaysia); Gopinath, Subash C.B., E-mail: subash@unimap.edu.my [Institute of Nano Electronic Engineering (INEE), Universiti Malaysia Perlis, 01000, Kangar, Perlis (Malaysia); School of Bioprocess Engineering, Universiti Malaysia Perlis, 02600, Arau, Perlis (Malaysia); Adzhri, R., E-mail: adzhri@gmail.com [Institute of Nano Electronic Engineering (INEE), Universiti Malaysia Perlis, 01000, Kangar, Perlis (Malaysia); Hashim, U., E-mail: uda@unimap.edu.my [Institute of Nano Electronic Engineering (INEE), Universiti Malaysia Perlis, 01000, Kangar, Perlis (Malaysia); School of Microelectronic Engineering, Universiti Malaysia Perlis, 01000, Kangar, Perlis (Malaysia)

    2016-09-07

    A real-time ability to interpret the interaction between targeted biomolecules and the surface of semiconductors (metal transducers) into readable electrical signals, without biomolecular modification involving fluorescence dyes, redox enzymes, and radioactive labels, created by label-free biosensors has been extensively researched. Field-effect transistor (FET)- and capacitor-based biosensors are among the diverse electrical charge biosensing architectures that have drawn much attention for having charge transduction; thus, enabling the early and rapid diagnosis of the appropriate cardiac biomarkers at lower concentrations. These semiconducting material-based transducers are very suitable to be integrated with portable electronic devices for future online collection, transmission, reception, analysis, and reporting. This overview elucidates and clarifies two major electrical label-free systems (FET- and capacitor-based biosensors) with cardiac troponin (cTn) biomarker-mediated charge transduction for acute myocardial infarction (AMI) diagnosis. Advances in these systems are highlighted by their progression in bridging the laboratory and industry; the foremost technologies have made the transition from benchtop to bedside and beyond. - Highlights: • The progression of cardiac troponin detection from past to future are presented. • Electrical label-free biosensors for cardiac troponin are discussed. • The discussion focused on field-effect transistor-and capacitor-based devices. • Surface functionalization, sensitivity, and innovation of devices are highlighted. • They presented high sensitivity and specificity of real-time AMI determination.

  5. Macrophage migration inhibitory factor (MIF) knockout preserves cardiac homeostasis through alleviating Akt-mediated myocardial autophagy suppression in high-fat diet-induced obesity.

    Science.gov (United States)

    Xu, X; Ren, J

    2015-03-01

    Macrophage migration inhibitory factor (MIF) has a role in the development of obesity and diabetes. However, whether MIF has a role in fat diet-induced obesity and associated cardiac anomalies still remains unknown. The aim of this study was to examine the impact of MIF knockout on high-fat diet-induced obesity, obesity-associated cardiac anomalies and the underlying mechanisms involved with a focus on Akt-mediated autophagy. Adult male wild-type (WT) and MIF knockout (MIF(-/-)) mice were placed on 45% high-fat diet for 5 months. Oxygen consumption, CO2 production, respiratory exchange ratio, locomotor activity and heat generation were measured using energy calorimeter. Echocardiographic, cardiomyocyte mechanical and intracellular Ca2+ properties were assessed. Apoptosis was examined using terminal dUTP nick end labeling staining and western blot analysis. Akt signaling pathway and autophagy markers were evaluated. Cardiomyocytes isolated from WT and MIF(-/-) mice were treated with recombinant mouse MIF (rmMIF). High-fat diet feeding elicited increased body weight gain, insulin resistance and caloric disturbance in WT and MIF(-/-) mice. High-fat diet induced unfavorable geometric, contractile and histological changes in the heart, the effects of which were alleviated by MIF knockout. In addition, fat diet-induced cardiac anomalies were associated with Akt activation and autophagy suppression, which were nullified by MIF deficiency. In cardiomyocytes from WT mice, autophagy was inhibited by exogenous rmMIF through Akt activation. In addition, MIF knockout rescued palmitic acid-induced suppression of cardiomyocyte autophagy, the effect of which was nullified by rmMIF. These results indicate that MIF knockout preserved obesity-associated cardiac anomalies without affecting fat diet-induced obesity, probably through restoring myocardial autophagy in an Akt-dependent manner. Our findings provide new insights for the role of MIF in obesity and associated cardiac

  6. Sirtuins as Mediator of the Anti-Ageing Effects of Calorie Restriction in Skeletal and Cardiac Muscle

    Directory of Open Access Journals (Sweden)

    Alberto Zullo

    2018-03-01

    Full Text Available Fighting diseases and controlling the signs of ageing are the major goals of biomedicine. Sirtuins, enzymes with mainly deacetylating activity, could be pivotal targets of novel preventive and therapeutic strategies to reach such aims. Scientific proofs are accumulating in experimental models, but, to a minor extent, also in humans, that the ancient practice of calorie restriction could prove an effective way to prevent several degenerative diseases and to postpone the detrimental signs of ageing. In the present review, we summarize the evidence about the central role of sirtuins in mediating the beneficial effects of calorie restriction in skeletal and cardiac muscle since these tissues are greatly damaged by diseases and advancing years. Moreover, we entertain the possibility that the identification of sirtuin activators that mimic calorie restriction could provide the benefits without the inconvenience of this dietary style.

  7. Arakeri’s Reflex: an Alternative Pathway for Dento-Cardiac Reflex Mediated Syncope

    Directory of Open Access Journals (Sweden)

    Veena Arali

    2010-03-01

    Full Text Available Introduction: Dentocardiac reflex, a variant of trigeminocardiac reflex elicited specifically during tooth extraction procedures in den-tal/maxillofacial surgery and is believed to cause syncope with an afferent link mediated by posterior superior alveolar nerve. Another variant of trigeminocardiac reflex which is also of interest to the oral and maxillofacial surgeon is oculocardiac reflex which can be triggered by direct or indirect manipulation of eye globe or muscles around it.The hypothesis: Excessive or injudicious pressure or manipulations around the maxillary first molars during extraction procedure are as-sociated with maximum incidence of bradycardia and hypotension than around incisor/ canine/ third molars. This is because; the pressure on eye globe and ophthalmic rectus muscle is maximum during extraction of first molar than incisor/canine and third molars. This observation led us to postulate an alternative pathway for dentocardiac reflex mediated syncope which may possibly justify the maxillary first molar region as a prone factor for the trigger. Evaluation of the hypothesis: Present hypothesis may not confer the specific factor responsible for switch in autonomic response in syncope origin during the tooth extraction procedure, but may provide a clue to where we should be looking.

  8. Cardiac CT

    International Nuclear Information System (INIS)

    Dewey, Marc

    2011-01-01

    Computed tomography of the heart has become a highly accurate diagnostic modality that is attracting increasing attention. This extensively illustrated book aims to assist the reader in integrating cardiac CT into daily clinical practice, while also reviewing its current technical status and applications. Clear guidance is provided on the performance and interpretation of imaging using the latest technology, which offers greater coverage, better spatial resolution, and faster imaging. The specific features of scanners from all four main vendors, including those that have only recently become available, are presented. Among the wide range of applications and issues to be discussed are coronary artery bypass grafts, stents, plaques, and anomalies, cardiac valves, congenital and acquired heart disease, and radiation exposure. Upcoming clinical uses of cardiac CT, such as plaque imaging and functional assessment, are also explored. (orig.)

  9. Cardiac CT

    Energy Technology Data Exchange (ETDEWEB)

    Dewey, Marc [Charite - Universitaetsmedizin Berlin (Germany). Inst. fuer Radiologie

    2011-07-01

    Computed tomography of the heart has become a highly accurate diagnostic modality that is attracting increasing attention. This extensively illustrated book aims to assist the reader in integrating cardiac CT into daily clinical practice, while also reviewing its current technical status and applications. Clear guidance is provided on the performance and interpretation of imaging using the latest technology, which offers greater coverage, better spatial resolution, and faster imaging. The specific features of scanners from all four main vendors, including those that have only recently become available, are presented. Among the wide range of applications and issues to be discussed are coronary artery bypass grafts, stents, plaques, and anomalies, cardiac valves, congenital and acquired heart disease, and radiation exposure. Upcoming clinical uses of cardiac CT, such as plaque imaging and functional assessment, are also explored. (orig.)

  10. Laminar shear stress modulates endothelial luminal surface stiffness in a tissue-specific manner.

    Science.gov (United States)

    Merna, Nick; Wong, Andrew K; Barahona, Victor; Llanos, Pierre; Kunar, Balvir; Palikuqi, Brisa; Ginsberg, Michael; Rafii, Shahin; Rabbany, Sina Y

    2018-04-17

    Endothelial cells form vascular beds in all organs and are exposed to a range of mechanical forces that regulate cellular phenotype. We sought to determine the role of endothelial luminal surface stiffness in tissue-specific mechanotransduction of laminar shear stress in microvascular mouse cells and the role of arachidonic acid in mediating this response. Microvascular mouse endothelial cells were subjected to laminar shear stress at 4 dynes/cm 2 for 12 hours in parallel plate flow chambers that enabled real-time optical microscopy and atomic force microscopy measurements of cell stiffness. Lung endothelial cells aligned parallel to flow, while cardiac endothelial cells did not. This rapid alignment was accompanied by increased cell stiffness. The addition of arachidonic acid to cardiac endothelial cells increased alignment and stiffness in response to shear stress. Inhibition of arachidonic acid in lung endothelial cells and embryonic stem cell-derived endothelial cells prevented cellular alignment and decreased cell stiffness. Our findings suggest that increased endothelial luminal surface stiffness in microvascular cells may facilitate mechanotransduction and alignment in response to laminar shear stress. Furthermore, the arachidonic acid pathway may mediate this tissue-specific process. An improved understanding of this response will aid in the treatment of organ-specific vascular disease. © 2018 John Wiley & Sons Ltd.

  11. Placental Growth Factor Promotes Cardiac Muscle Repair via Enhanced Neovascularization

    Directory of Open Access Journals (Sweden)

    Jianfeng Zhang

    2015-06-01

    Full Text Available Background/Aims: Transplantation of mesenchymal stem cells (MSCs improves post-injury cardiac muscle repair using ill-defined mechanisms. Recently, we have shown that production and secretion of placental growth factor (PLGF by MSCs play a critical role in the MSCs-mediated post-injury cardiac muscle repair. In this study, we addressed the underlying molecular mechanisms, focusing specifically on the interactions between MSCs, macrophages and endothelial cells. Methods: We isolated macrophages (BM-MΦ from mouse bone-marrow derived cells based on F4/80 expression by flow cytometry. BM-MΦ were treated with different doses of PLGF. Cell number was analyzed by a MTT assay. Macrophage polarization was examined based on CD206 expression by flow cytometry. PLGF levels in macrophage subpopulations were analyzed by RT-qPCR and ELISA. Effects of macrophages on vascularization were evaluated by a collagen gel assay using Human umbilical vein endothelial cells (HUVECs co-cultured with PLGF-treated macrophages. Results: PLGF did not increase macrophage number, but dose-dependently polarized macrophages into a M2 subpopulation. M2 macrophages expressed high levels of PLGF. PLGF-polarized M2 macrophages significantly increased tubular structures in the collagen gel assay. Conclusion: Our data suggest that MSCs-derived PLGF may induce macrophage polarization into a M2 subpopulation, which in turn releases more PLGF to promote local neovascularization for augmenting post-injury cardiac muscle repair. This study thus sheds novel light on the role of PLGF in cardiac muscle regeneration.

  12. FET-biosensor for cardiac troponin biomarker

    Directory of Open Access Journals (Sweden)

    Md Arshad Mohd Khairuddin

    2017-01-01

    Full Text Available Acute myocardial infarction or myocardial infarction (MI is a major health problem, due to diminished flow of blood to the heart, leads to higher rates of mortality and morbidity. The most specific markers for cardiac injury are cardiac troponin I (cTnI and cardiac troponin T (cTnT which have been considered as ‘gold standard’. Due to higher specificity, determination of the level of cardiac troponins became a predominant indicator for MI. Currently, field-effect transistor (FET-based biosensors have been main interest to be implemented in portable sensors with the ultimate application in point-of-care testing (POCT. In this paper, we review on the FET-based biosensor based on its principle of operation, integration with nanomaterial, surface functionalization as well as immobilization, and the introduction of additional gate (for ambipolar conduction on the device architecture for the detection of cardiac troponin I (cTnI biomarker.

  13. Solving the cardiac hypertrophy riddle: The angiotensin II-mechanical stress connection.

    Science.gov (United States)

    Zablocki, Daniela; Sadoshima, Junichi

    2013-11-08

    A series of studies conducted 20 years ago, documenting the cardiac hypertrophy phenotype and its underlying signaling mechanism induced by angiotensin II (Ang II) and mechanical stress, showed a remarkable similarity between the effect of the Gαq agonist and that of mechanical forces on cardiac hypertrophy. Subsequent studies confirmed the involvement of autocrine/paracrine mechanisms, including stretch-induced release of Ang II in load-induced cardiac hypertrophy. Recent studies showed that the Ang II type 1 (AT1) receptor is also directly activated by mechanical forces, suggesting that AT1 receptors play an important role in mediating load-induced cardiac hypertrophy through both ligand- and mechanical stress-dependent mechanisms.

  14. Distinct trajectories of disease-specific health status in heart failure patients undergoing cardiac resynchronization therapy

    DEFF Research Database (Denmark)

    Mastenbroek, Mirjam H.; Pedersen, Susanne S.; Meine, Mathias

    2016-01-01

    of beta-blockers, use of psychotropic medication, anxiety, depression, and type D personality were found to be associated with poorer health status in unadjusted analyses. Interestingly, subgroups of patients (12-20 %) who experienced poor health status at baseline improved to stable good health status....... The timely identification of CRT-D patients who present with poor disease-specific health status (i.e., KCCQ score anxiety, depression, and/or type D personality) is paramount, as they may benefit from cardiac rehabilitation in combination...

  15. AAV-mediated knock-down of HRC exacerbates transverse aorta constriction-induced heart failure.

    Directory of Open Access Journals (Sweden)

    Chang Sik Park

    Full Text Available Histidine-rich calcium binding protein (HRC is located in the lumen of sarcoplasmic reticulum (SR that binds to both triadin (TRN and SERCA affecting Ca(2+ cycling in the SR. Chronic overexpression of HRC that may disrupt intracellular Ca(2+ homeostasis is implicated in pathogenesis of cardiac hypertrophy. Ablation of HRC showed relatively normal phenotypes under basal condition, but exhibited a significantly increased susceptibility to isoproterenol-induced cardiac hypertrophy. In the present study, we characterized the functions of HRC related to Ca(2+ cycling and pathogenesis of cardiac hypertrophy using the in vitro siRNA- and the in vivo adeno-associated virus (AAV-mediated HRC knock-down (KD systems, respectively.AAV-mediated HRC-KD system was used with or without C57BL/6 mouse model of transverse aortic constriction-induced failing heart (TAC-FH to examine whether HRC-KD could enhance cardiac function in failing heart (FH. Initially we expected that HRC-KD could elicit cardiac functional recovery in failing heart (FH, since predesigned siRNA-mediated HRC-KD enhanced Ca(2+ cycling and increased activities of RyR2 and SERCA2 without change in SR Ca(2+ load in neonatal rat ventricular cells (NRVCs and HL-1 cells. However, AAV9-mediated HRC-KD in TAC-FH was associated with decreased fractional shortening and increased cardiac fibrosis compared with control. We found that phospho-RyR2, phospho-CaMKII, phospho-p38 MAPK, and phospho-PLB were significantly upregulated by HRC-KD in TAC-FH. A significantly increased level of cleaved caspase-3, a cardiac cell death marker was also found, consistent with the result of TUNEL assay.Increased Ca(2+ leak and cytosolic Ca(2+ concentration due to a partial KD of HRC could enhance activity of CaMKII and phosphorylation of p38 MAPK, causing the mitochondrial death pathway observed in TAC-FH. Our results present evidence that down-regulation of HRC could deteriorate cardiac function in TAC-FH through

  16. A cardiac-specific health-related quality of life module for young adults with congenital heart disease: development and validation

    NARCIS (Netherlands)

    Kamphuis, M.; Zwinderman, K.A.H.; Vogels, T.; Vliegen, H.W.; Kamphuis, R.P.; Ottenkamp, J.; Verloove-Vanhorick, S.P.; Bruil, J.

    2004-01-01

    This study represents the development and validation of a cardiac-specific module of the generic health-related quality of life (HRQoL) instrument, the TAAQOL (TNO/AZL Adult Quality Of Life), for young adults with congenital heart disease (CHD). Items were selected based on literature, an

  17. Rationale and design of the Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research Trial (MANTICORE 101 - Breast): a randomized, placebo-controlled trial to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer using cardiac MRI

    International Nuclear Information System (INIS)

    Pituskin, Edith; Paterson, Ian; Haykowsky, Mark; Mackey, John R; Thompson, Richard B; Ezekowitz, Justin; Koshman, Sheri; Oudit, Gavin; Chow, Kelvin; Pagano, Joseph J

    2011-01-01

    MANTICORE 101 - Breast (Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research) is a randomized trial to determine if conventional heart failure pharmacotherapy (angiotensin converting enzyme inhibitor or beta-blocker) can prevent trastuzumab-mediated left ventricular remodeling, measured with cardiac MRI, among patients with HER2+ early breast cancer. One hundred and fifty-nine patients with histologically confirmed HER2+ breast cancer will be enrolled in a parallel 3-arm, randomized, placebo controlled, double-blind design. After baseline assessments, participants will be randomized in a 1:1:1 ratio to an angiotensin-converting enzyme inhibitor (perindopril), beta-blocker (bisoprolol), or placebo. Participants will receive drug or placebo for 1 year beginning 7 days before trastuzumab therapy. Dosages for all groups will be systematically up-titrated, as tolerated, at 1 week intervals for a total of 3 weeks. The primary objective of this randomized clinical trial is to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer, as measured by 12 month change in left ventricular end-diastolic volume using cardiac MRI. Secondary objectives include 1) determine the evolution of left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer, 2) understand the mechanism of trastuzumab mediated cardiac toxicity by assessing for the presence of myocardial injury and apoptosis on serum biomarkers and cardiac MRI, and 3) correlate cardiac biomarkers of myocyte injury and extra-cellular matrix remodeling with left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer. Cardiac toxicity as a result of cancer therapies is now recognized as a significant health problem of increasing prevalence. To our knowledge, MANTICORE will be the first randomized trial testing proven heart failure pharmacotherapy in

  18. CCR2+ Monocyte-Derived Infiltrating Macrophages Are Required for Adverse Cardiac Remodeling During Pressure Overload

    Directory of Open Access Journals (Sweden)

    Bindiya Patel, PhD

    2018-04-01

    Full Text Available Summary: Although chronic inflammation is a central feature of heart failure (HF, the immune cell profiles differ with different underlying causes. This suggests that for immunomodulatory therapy in HF to be successful, it needs to be tailored to the specific etiology. Here, the authors demonstrate that monocyte-derived C-C chemokine receptor 2 (CCR2+ macrophages infiltrate the heart early during pressure overload in mice, and that blocking this response either pharmacologically or with antibody-mediated CCR2+ monocyte depletion alleviates late pathological left ventricular remodeling and dysfunction, T-cell expansion, and cardiac fibrosis. Hence, suppression of CCR2+ monocytes/macrophages may be an important immunomodulatory therapeutic target to ameliorate pressure-overload HF. Key Words: cardiac remodeling, heart failure, inflammation, macrophages, T cells

  19. Measurement of functional capacity requirements of police officers to aid in development of an occupation-specific cardiac rehabilitation training program.

    Science.gov (United States)

    Adams, Jenny; Schneider, Jonna; Hubbard, Matthew; McCullough-Shock, Tiffany; Cheng, Dunlei; Simms, Kay; Hartman, Julie; Hinton, Paul; Strauss, Danielle

    2010-01-01

    This study was designed to measure the functional capacity of healthy subjects during strenuous simulated police tasks, with the goal of developing occupation-specific training for cardiac rehabilitation of police officers. A calibrated metabolic instrument and an oxygen consumption data collection mask were used to measure the oxygen consumption and heart rates of 30 Dallas Police Academy officers and cadets as they completed an 8-event obstacle course that simulated chasing, subduing, and handcuffing a suspect. Standard target heart rates (85% of age-predicted maximum heart rate, or 0.85 x [220 - age]) and metabolic equivalents (METs) were calculated; a matched-sample t test based on differences between target and achieved heart rate and MET level was used for statistical analysis. Peak heart rates during the obstacle course simulation were significantly higher than the standard target heart rates (those at which treadmill stress tests in physicians' offices are typically stopped) (t(29) = 12.81, P requires a functional capacity greater than that typically attained in traditional cardiac rehabilitation programs. Rehabilitation professionals should consider performing maximal stress tests and increasing the intensity of cardiac rehabilitation workouts to effectively train police officers who have had a cardiac event.

  20. Burnout versus work engagement in their effects on 24-hour ambulatory monitored cardiac autonomic function

    NARCIS (Netherlands)

    L.J.P. van Doornen (Lorenz); J.H. Houtveen (Jan); S. Langelaan (Saar); A.B. Bakker (Arnold); W. van Rhenen (Willem); W.B. Schaufeli (Wilmar)

    2009-01-01

    textabstractBurnout has been associated with increased risk of cardiovascular disease. This relationship may be mediated by a stress-related disruption in cardiac autonomic activity. The aim of the present study was to assess cardiac autonomic activity (sympathetic and parasympathetic) during a

  1. Defective branched chain amino acid catabolism contributes to cardiac dysfunction and remodeling following myocardial infarction.

    Science.gov (United States)

    Wang, Wei; Zhang, Fuyang; Xia, Yunlong; Zhao, Shihao; Yan, Wenjun; Wang, Helin; Lee, Yan; Li, Congye; Zhang, Ling; Lian, Kun; Gao, Erhe; Cheng, Hexiang; Tao, Ling

    2016-11-01

    Cardiac metabolic remodeling is a central event during heart failure (HF) development following myocardial infarction (MI). It is well known that myocardial glucose and fatty acid dysmetabolism contribute to post-MI cardiac dysfunction and remodeling. However, the role of amino acid metabolism in post-MI HF remains elusive. Branched chain amino acids (BCAAs) are an important group of essential amino acids and function as crucial nutrient signaling in mammalian animals. The present study aimed to determine the role of cardiac BCAA metabolism in post-MI HF progression. Utilizing coronary artery ligation-induced murine MI models, we found that myocardial BCAA catabolism was significantly impaired in response to permanent MI, therefore leading to an obvious elevation of myocardial BCAA abundance. In MI-operated mice, oral BCAA administration further increased cardiac BCAA levels, activated the mammalian target of rapamycin (mTOR) signaling, and exacerbated cardiac dysfunction and remodeling. These data demonstrate that BCAAs act as a direct contributor to post-MI cardiac pathologies. Furthermore, these BCAA-mediated deleterious effects were improved by rapamycin cotreatment, revealing an indispensable role of mTOR in BCAA-mediated adverse effects on cardiac function/structure post-MI. Of note, pharmacological inhibition of branched chain ketoacid dehydrogenase kinase (BDK), a negative regulator of myocardial BCAA catabolism, significantly improved cardiac BCAA catabolic disorders, reduced myocardial BCAA levels, and ameliorated post-MI cardiac dysfunction and remodeling. In conclusion, our data provide the evidence that impaired cardiac BCAA catabolism directly contributes to post-MI cardiac dysfunction and remodeling. Moreover, improving cardiac BCAA catabolic defects may be a promising therapeutic strategy against post-MI HF. Copyright © 2016 the American Physiological Society.

  2. Disease-specific health-related quality of life instruments for IgE-mediated food allergy

    DEFF Research Database (Denmark)

    Salvilla, S A; Dubois, A E J; Flokstra-de Blok, B M J

    2014-01-01

    of the impact of, and investigations and interventions for, IgE-mediated food allergy on health-related quality of life (HRQL). Using a sensitive search strategy, we searched seven electronic bibliographic databases to identify disease-specific quality of life (QOL) tools relating to IgE-mediated food allergy...

  3. Overexpression of Cardiac-Specific Kinase TNNI3K Promotes Mouse Embryonic Stem Cells Differentiation into Cardiomyocytes.

    Science.gov (United States)

    Wang, Yin; Wang, Shi-Qiang; Wang, Li-Peng; Yao, Yu-Hong; Ma, Chun-Yan; Ding, Jin-Feng; Ye, Jue; Meng, Xian-Min; Li, Jian-Jun; Xu, Rui-Xia

    2017-01-01

    Backgroud/Aims: The biological function of cardiac troponin I-interacting kinase (TNNI3K), a cardiac-specific functional kinase, is largely unknown. We investigated the effect of human TNNI3K (hTNNI3K) on the differentiation of mouse embryonic stem cells (mESCs) into cardiomyocytes. First, the time-space expression of endogenous Tnni3k was detected by real-time polymerase chain reaction (PCR) and western blotting at 16 different time-points over a period of 28 days. Further, action potentials and calcium current with/without 5 µM nifedipine were measured by patch clamp for mESC-derived cardiomyocytes. HTNNI3K and mouse-derived siRNA were transfected into mESC using lentivirus vector to induce hTNNI3K overexpression and knock-down, respectively. The number of troponin-T (cTnT) positive cells was greater in the group with TNNI3K overexpression as compared to that in control group, while less such cells were detected in the mTnni3k knock-down group as evaluated on flow cytometry (FCM) and ImageXpress Micro system. After upregulation of connexin43, cardiac troponin-I (Ctni), Ctni, Gata4 were detected in mESCs with TNNI3K overexpression; however, overexpression of α-Actinin and Mlc2v was not detected. Interestingly, Ctnt, connexin40 and connexin45, the markers of ventricular, atrial, and pacemaker cells, respectively, were detected in by real-time PCR in TNNI3K overexpression group. our study indicated that TNNI3K overexpression promoted mESC differentiating into beating cardiomyocytes and induced up-regulating expression of cTnT by PKCε signal pathway, which suggested a modulation of TNNI3K activity as a potential therapeutic approach for ischemic cardiac disease. © 2017 The Author(s) Published by S. Karger AG, Basel.

  4. Functional role of peripheral opioid receptors in the regulation of cardiac spinal afferent nerve activity during myocardial ischemia

    Science.gov (United States)

    Longhurst, John C.

    2013-01-01

    Thinly myelinated Aδ-fiber and unmyelinated C-fiber cardiac sympathetic (spinal) sensory nerve fibers are activated during myocardial ischemia to transmit the sensation of angina pectoris. Although recent observations showed that myocardial ischemia increases the concentrations of opioid peptides and that the stimulation of peripheral opioid receptors inhibits chemically induced visceral and somatic nociception, the role of opioids in cardiac spinal afferent signaling during myocardial ischemia has not been studied. The present study tested the hypothesis that peripheral opioid receptors modulate cardiac spinal afferent nerve activity during myocardial ischemia by suppressing the responses of cardiac afferent nerve to ischemic mediators like bradykinin and extracellular ATP. The nerve activity of single unit cardiac afferents was recorded from the left sympathetic chain (T2–T5) in anesthetized cats. Forty-three ischemically sensitive afferent nerves (conduction velocity: 0.32–3.90 m/s) with receptive fields in the left and right ventricles were identified. The responses of these afferent nerves to repeat ischemia or ischemic mediators were further studied in the following protocols. First, epicardial administration of naloxone (8 μmol), a nonselective opioid receptor antagonist, enhanced the responses of eight cardiac afferent nerves to recurrent myocardial ischemia by 62%, whereas epicardial application of vehicle (PBS) did not alter the responses of seven other cardiac afferent nerves to ischemia. Second, naloxone applied to the epicardial surface facilitated the responses of seven cardiac afferent nerves to epicardial ATP by 76%. Third, administration of naloxone enhanced the responses of seven other afferent nerves to bradykinin by 85%. In contrast, in the absence of naloxone, cardiac afferent nerves consistently responded to repeated application of ATP (n = 7) or bradykinin (n = 7). These data suggest that peripheral opioid peptides suppress the

  5. Acute effects of sex steroid hormones on susceptibility to cardiac arrhythmias: a simulation study.

    Directory of Open Access Journals (Sweden)

    Pei-Chi Yang

    2010-01-01

    Full Text Available Acute effects of sex steroid hormones likely contribute to the observation that post-pubescent males have shorter QT intervals than females. However, the specific role for hormones in modulating cardiac electrophysiological parameters and arrhythmia vulnerability is unclear. Here we use a computational modeling approach to incorporate experimentally measured effects of physiological concentrations of testosterone, estrogen and progesterone on cardiac ion channel targets. We then study the hormone effects on ventricular cell and tissue dynamics comprised of Faber-Rudy computational models. The "female" model predicts changes in action potential duration (APD at different stages of the menstrual cycle that are consistent with clinically observed QT interval fluctuations. The "male" model predicts shortening of APD and QT interval at physiological testosterone concentrations. The model suggests increased susceptibility to drug-induced arrhythmia when estradiol levels are high, while testosterone and progesterone are apparently protective. Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval. The simulations also indicate that acute effects of estrogen are not alone sufficient to cause arrhythmia triggers and explain the increased risk of females to Torsades de Pointes. Our results suggest that acute effects of sex steroid hormones on cardiac ion channels are sufficient to account for some aspects of gender specific susceptibility to long-QT linked arrhythmias.

  6. Measurement of functional capacity requirements to aid in development of an occupation-specific rehabilitation training program to help firefighters with cardiac disease safely return to work.

    Science.gov (United States)

    Adams, Jenny; Roberts, Joanne; Simms, Kay; Cheng, Dunlei; Hartman, Julie; Bartlett, Charles

    2009-03-15

    We designed a study to measure the functional capacity requirements of firefighters to aid in the development of an occupation-specific training program in cardiac rehabilitation; 23 healthy male firefighters with no history of heart disease completed a fire and rescue obstacle course that simulated 7 common firefighting tasks. They wore complete personal protective equipment and portable metabolic instruments that included a data collection mask. We monitored each subject's oxygen consumption (VO(2)) and working heart rate, then calculated age-predicted maximum heart rates (220 - age) and training target heart rates (85% of age-predicted maximum heart rate). During performance of the obstacle course, the subjects' mean working heart rates and peak heart rates were higher than the calculated training target heart rates (t(22) = 5.69 [working vs target, p functional capacity greatly exceeded that typically attained by patients in traditional cardiac rehabilitation programs (5 to 8 METs). In conclusion, our results indicate the need for intense, occupation-specific cardiac rehabilitation training that will help firefighters safely return to work after a cardiac event.

  7. The Impact of Ventricular Assist Device Prior to Transplantation on Morphological Parameters in Cardiac Allografts

    DEFF Research Database (Denmark)

    Wassilew, Katharina

    2017-01-01

    . The Cochran-Mantel-Haenzsel test was applied to assess significance of the differences in interactions between groups. To evaluate the impact of bridge- to- transplant mechanical circulatory support on development on transplant vasculopathy in cardiac allografts, the intramyocardial terminal arterial network...... allograft dysfunction, as MCS patients show a higher frequency of antibody-mediated rejection (AMR) episodes. We aimed to analyze the effects of MCS on cardiac AMR with regards to capillary C3d and C4d depositions. Regarding the functional parameters, both acute cellular rejection (ACR) and an increase...... of interstitial fibrosis (IF) often correlate with impaired ventricular function. The innate immune system, in particular macrophages, plays an important role in the resorptive process of ACR and is, on the other hand, known to promote IF. In this study we aimed to analyze the effect of ACR and specifically...

  8. HaloTag protein-mediated specific labeling of living cells with quantum dots

    International Nuclear Information System (INIS)

    So, Min-kyung; Yao Hequan; Rao Jianghong

    2008-01-01

    Quantum dots emerge as an attractive alternative to small molecule fluorophores as fluorescent tags for in vivo cell labeling and imaging. This communication presents a method for specific labeling of live cells using quantum dots. The labeling is mediated by HaloTag protein expressed at the cell surface which forms a stable covalent adduct with its ligand (HaloTag ligand). The labeling can be performed in one single step with quantum dot conjugates that are functionalized with HaloTag ligand, or in two steps with biotinylated HaloTag ligand first and followed by streptavidin coated quantum dots. Live cell fluorescence imaging indicates that the labeling is specific and takes place at the cell surface. This HaloTag protein-mediated cell labeling method should facilitate the application of quantum dots for live cell imaging

  9. Age-specific prognostication after out-of-hospital cardiac arrest - The ethical dilemma between 'life-sustaining treatment' and 'the right to die' in the elderly.

    Science.gov (United States)

    Sulzgruber, Patrick; Sterz, Fritz; Poppe, Michael; Schober, Andreas; Lobmeyr, Elisabeth; Datler, Philip; Keferböck, Markus; Zeiner, Sebastian; Nürnberger, Alexander; Hubner, Pia; Stratil, Peter; Wallmueller, Christian; Weiser, Christoph; Warenits, Alexandra-Maria; van Tulder, Raphael; Zajicek, Andreas; Buchinger, Angelika; Testori, Christoph

    2017-03-01

    While prognostic values on survival after out-of-hospital cardiac arrest have been well investigated, less attention has been paid to their age-specific relevance. Therefore, we aimed to identify suitable age-specific early prognostication in elderly patients suffering out-of-hospital cardiac arrest in order to reduce the burden of unnecessary treatment and harm. In a prospective population-based observational trial on individuals suffering out-of-hospital cardiac arrest, a total of 2223 patients receiving resuscitation attempts by the local emergency medical service in Vienna, Austria, were enrolled. Patients were stratified according to age as follows: young and middle-aged individuals (85 years). There was an increasing rate of 30-day mortality (+21.8%, p 85-year-olds. Frailty was directly associated with mortality (HR 1.22, 95% CI 1.01-1.51, p = 0.049), showing a 30-day survival of 5.6% and a favourable neurological outcome of 1.1% among elderly individuals. An initially shockable electrocardiogram proved to be a suitable tool for risk assessment and decision making in order to predict a successful outcome in elderly victims of out-of-hospital cardiac arrest. However, the outcomes of elderly patients seemed to be exceptionally poor in frail individuals and need to be considered in order to reduce unnecessary treatment decisions.

  10. The Impact of a Non-Functional Thyroid Receptor Beta upon Triiodotironine-Induced Cardiac Hypertrophy in Mice

    Directory of Open Access Journals (Sweden)

    Güínever Eustáquio do Império

    2015-08-01

    Full Text Available Background/Aims: Thyroid hormone (TH signalling is critical for heart function. The heart expresses thyroid hormone receptors (THRs; THRα1 and THRβ1. We aimed to investigate the regulation mechanisms of the THRβ isoform, its association with gene expression changes and implications for cardiac function. Methods: The experiments were performed using adult male mice expressing TRβΔ337T, which contains the Δ337T mutation of the human THRB gene and impairs ligand binding. Cardiac function and RNA expression were studied after hypo-or hyperthyroidism inductions. T3-induced cardiac hypertrophy was not observed in TRβΔ337T mice, showing the fundamental role of THRβ in cardiac hypertrophy. Results: We identified a group of independently regulated THRβ genes, which includes Adrb2, Myh7 and Hcn2 that were normally regulated by T3 in the TRβΔ337T group. However, Adrb1, Myh6 and Atp2a2 were regulated via THRβ. The TRβΔ337T mice exhibited a contractile deficit, decreased ejection fraction and stroke volume, as assessed by echocardiography. In our model, miR-208a and miR-199a may contribute to THRβ-mediated cardiac hypertrophy, as indicated by the absence of T3-regulated ventricular expression in TRβΔ337T mice. Conclusion: THRβ has important role in the regulation of specific mRNA and miRNA in T3-induced cardiac hypertrophic growth and in the alteration of heart functions.

  11. Postnatal ablation of Foxm1 from cardiomyocytes causes late onset cardiac hypertrophy and fibrosis without exacerbating pressure overload-induced cardiac remodeling.

    Directory of Open Access Journals (Sweden)

    Craig Bolte

    Full Text Available Heart disease remains a leading cause of morbidity and mortality in the industrialized world. Hypertrophic cardiomyopathy is the most common genetic cardiovascular disorder and the most common cause of sudden cardiac death. Foxm1 transcription factor (also known as HFH-11B, Trident, Win or MPP2 plays an important role in the pathogenesis of various cancers and is a critical mediator of post-injury repair in multiple organs. Foxm1 has been previously shown to be essential for heart development and proliferation of embryonic cardiomyocytes. However, the role of Foxm1 in postnatal heart development and in cardiac injury has not been evaluated. To delete Foxm1 in postnatal cardiomyocytes, αMHC-Cre/Foxm1(fl/fl mice were generated. Surprisingly, αMHC-Cre/Foxm1(fl/fl mice exhibited normal cardiomyocyte proliferation at postnatal day seven and had no defects in cardiac structure or function but developed cardiac hypertrophy and fibrosis late in life. The development of cardiomyocyte hypertrophy and cardiac fibrosis in aged Foxm1-deficient mice was associated with reduced expression of Hey2, an important regulator of cardiac homeostasis, and increased expression of genes critical for cardiac remodeling, including MMP9, αSMA, fibronectin and vimentin. We also found that following aortic constriction Foxm1 mRNA and protein were induced in cardiomyocytes. However, Foxm1 deletion did not exacerbate cardiac hypertrophy or fibrosis following chronic pressure overload. Our results demonstrate that Foxm1 regulates genes critical for age-induced cardiomyocyte hypertrophy and cardiac fibrosis.

  12. The Role of Nrf2-Mediated Pathway in Cardiac Remodeling and Heart Failure

    Directory of Open Access Journals (Sweden)

    Shanshan Zhou

    2014-01-01

    Full Text Available Heart failure (HF is frequently the consequence of sustained, abnormal neurohormonal, and mechanical stress and remains a leading cause of death worldwide. The key pathophysiological process leading to HF is cardiac remodeling, a term referring to maladaptation to cardiac stress at the molecular, cellular, tissue, and organ levels. HF and many of the conditions that predispose one to HF are associated with oxidative stress. Increased generation of reactive oxygen species (ROS in the heart can directly lead to increased necrosis and apoptosis of cardiomyocytes which subsequently induce cardiac remodeling and dysfunction. Nuclear factor-erythroid-2- (NF-E2- related factor 2 (Nrf2 is a transcription factor that controls the basal and inducible expression of a battery of antioxidant genes and other cytoprotective phase II detoxifying enzymes that are ubiquitously expressed in the cardiovascular system. Emerging evidence has revealed that Nrf2 and its target genes are critical regulators of cardiovascular homeostasis via the suppression of oxidative stress, which is the key player in the development and progression of HF. The purpose of this review is to summarize evidence that activation of Nrf2 enhances endogenous antioxidant defenses and counteracts oxidative stress-associated cardiac remodeling and HF.

  13. Cardiac Gene Expression Knockdown Using Small Inhibitory RNA-Loaded Microbubbles and Ultrasound.

    Directory of Open Access Journals (Sweden)

    Jonathan A Kopechek

    Full Text Available RNA interference has potential therapeutic value for cardiac disease, but targeted delivery of interfering RNA is a challenge. Custom designed microbubbles, in conjunction with ultrasound, can deliver small inhibitory RNA to target tissues in vivo. The efficacy of cardiac RNA interference using a microbubble-ultrasound theranostic platform has not been demonstrated in vivo. Therefore, our objective was to test the hypothesis that custom designed microbubbles and ultrasound can mediate effective delivery of small inhibitory RNA to the heart. Microbubble and ultrasound mediated cardiac RNA interference was tested in transgenic mice displaying cardiac-restricted luciferase expression. Luciferase expression was assayed in select tissues of untreated mice (n = 14. Mice received intravenous infusion of cationic microbubbles bearing small inhibitory RNA directed against luciferase (n = 9 or control RNA (n = 8 during intermittent cardiac-directed ultrasound at mechanical index of 1.6. Simultaneous echocardiography in a separate group of mice (n = 3 confirmed microbubble destruction and replenishment during treatment. Three days post treatment, cardiac luciferase messenger RNA and protein levels were significantly lower in ultrasound-treated mice receiving microbubbles loaded with small inhibitory RNA directed against luciferase compared to mice receiving microbubbles bearing control RNA (23±7% and 33±7% of control mice, p<0.01 and p = 0.03, respectively. Passive cavitation detection focused on the heart confirmed that insonification resulted in inertial cavitation. In conclusion, small inhibitory RNA-loaded microbubbles and ultrasound directed at the heart significantly reduced the expression of a reporter gene. Ultrasound-targeted destruction of RNA-loaded microbubbles may be an effective image-guided strategy for therapeutic RNA interference in cardiac disease.

  14. Investigating β-adrenergic-induced cardiac hypertrophy through computational approach: classical and non-classical pathways.

    Science.gov (United States)

    Khalilimeybodi, Ali; Daneshmehr, Alireza; Sharif-Kashani, Babak

    2018-07-01

    The chronic stimulation of β-adrenergic receptors plays a crucial role in cardiac hypertrophy and its progression to heart failure. In β-adrenergic signaling, in addition to the well-established classical pathway, Gs/AC/cAMP/PKA, activation of non-classical pathways such as Gi/PI3K/Akt/GSK3β and Gi/Ras/Raf/MEK/ERK contribute in cardiac hypertrophy. The signaling network of β-adrenergic-induced hypertrophy is very complex and not fully understood. So, we use a computational approach to investigate the dynamic response and contribution of β-adrenergic mediators in cardiac hypertrophy. The proposed computational model provides insights into the effects of β-adrenergic classical and non-classical pathways on the activity of hypertrophic transcription factors CREB and GATA4. The results illustrate that the model captures the dynamics of the main signaling mediators and reproduces the experimental observations well. The results also show that despite the low portion of β2 receptors out of total cardiac β-adrenergic receptors, their contribution in the activation of hypertrophic mediators and regulation of β-adrenergic-induced hypertrophy is noticeable and variations in β1/β2 receptors ratio greatly affect the ISO-induced hypertrophic response. The model results illustrate that GSK3β deactivation after β-adrenergic receptor stimulation has a major influence on CREB and GATA4 activation and consequent cardiac hypertrophy. Also, it is found through sensitivity analysis that PKB (Akt) activation has both pro-hypertrophic and anti-hypertrophic effects in β-adrenergic signaling.

  15. Discovery and progress of direct cardiac reprogramming.

    Science.gov (United States)

    Kojima, Hidenori; Ieda, Masaki

    2017-06-01

    Cardiac disease remains a major cause of death worldwide. Direct cardiac reprogramming has emerged as a promising approach for cardiac regenerative therapy. After the discovery of MyoD, a master regulator for skeletal muscle, other single cardiac reprogramming factors (master regulators) have been sought. Discovery of cardiac reprogramming factors was inspired by the finding that multiple, but not single, transcription factors were needed to generate induced pluripotent stem cells (iPSCs) from fibroblasts. We first reported a combination of cardiac-specific transcription factors, Gata4, Mef2c, and Tbx5 (GMT), that could convert mouse fibroblasts into cardiomyocyte-like cells, which were designated as induced cardiomyocyte-like cells (iCMs). Following our first report of cardiac reprogramming, many researchers, including ourselves, demonstrated an improvement in cardiac reprogramming efficiency, in vivo direct cardiac reprogramming for heart regeneration, and cardiac reprogramming in human cells. However, cardiac reprogramming in human cells and adult fibroblasts remains inefficient, and further efforts are needed. We believe that future research elucidating epigenetic barriers and molecular mechanisms of direct cardiac reprogramming will improve the reprogramming efficiency, and that this new technology has great potential for clinical applications.

  16. Area-Specific Cell Stimulation via Surface-Mediated Gene Transfer Using Apatite-Based Composite Layers

    Directory of Open Access Journals (Sweden)

    Yushin Yazaki

    2015-04-01

    Full Text Available Surface-mediated gene transfer systems using biocompatible calcium phosphate (CaP-based composite layers have attracted attention as a tool for controlling cell behaviors. In the present study we aimed to demonstrate the potential of CaP-based composite layers to mediate area-specific dual gene transfer and to stimulate cells on an area-by-area basis in the same well. For this purpose we prepared two pairs of DNA–fibronectin–apatite composite (DF-Ap layers using a pair of reporter genes and pair of differentiation factor genes. The results of the area-specific dual gene transfer successfully demonstrated that the cells cultured on a pair of DF-Ap layers that were adjacently placed in the same well showed specific gene expression patterns depending on the gene that was immobilized in theunderlying layer. Moreover, preliminary real-time PCR results indicated that multipotential C3H10T1/2 cells may have a potential to change into different types of cells depending on the differentiation factor gene that was immobilized in the underlying layer, even in the same well. Because DF-Ap layers have a potential to mediate area-specific cell stimulation on their surfaces, they could be useful in tissue engineering applications.

  17. Micro and Nano-mediated 3D Cardiac Tissue Engineering

    Science.gov (United States)

    2010-10-01

    dilated cardiomyopathy . Critical Care Medicine. 2009;37:1197-1205 21. Leor J. Bioengineered cardiac grafts: A new approach to repair the infarcted...chamber and while the atrium “helps” during inner flow. Since increase of amplitude as response to synchronism is a measure of contraction and dilation ...optimal pump function in canine hearts. Journal of the American College of Cardiology. 2003;41:1218-1226 4. Storaa C. Tissue motion imaging of the left

  18. Imaging in cardiac mass lesions

    International Nuclear Information System (INIS)

    Mundinger, A.; Gruber, H.P.; Dinkel, E.; Geibel, A.; Beck, A.; Wimmer, B.; Schlosser, V.

    1992-01-01

    In 26 patients with cardiac mass lesions confirmed by surgery, diagnostic imaging was performed preoperatively by means of two-dimensional echocardiography (26 patients), angiography (12 patients), correlative computed tomography (CT, 8 patients), and magnetic resonance imaging (MRI, 3 patients). Two-dimensional echocardiography correctly identified the cardiac masses in all patients. Angiography missed two of 12 cardiac masses; CT missed one of eight. MRI identified three of three cardiac masses. Although the sensitivity of two-dimensional echocardiography was high (100%), all methods lacked specificity. None of the methods allowed differentiation between myxoma (n=13) and thrombus (n=7). Malignancy of the lesions was successfully predicted by noninvasive imaging methods in all six patients. However, CT and MRI provided additional information concerning cardiac mural infiltration, pericardial involvement, and extracardiac tumor extension, and should be integrated within a preoperative imaging strategy. Thus two-dimensional echocardiography is the method of choice for primary assessment of patients with suspected cardiac masses. Further preoperative imaging by CT or MRI can be limited to patients with malignancies suspected on the grounds of pericardial effusion or other clinical results. (author)

  19. Beneficial effects of combined benazepril-amlodipine on cardiac nitric oxide, cGMP, and TNF-alpha production after cardiac ischemia.

    Science.gov (United States)

    Siragy, Helmy M; Xue, Chun; Webb, Randy L

    2006-05-01

    The aim of this study was to determine if myocardial inflammation is increased after myocardial ischemia and whether angiotensin-converting enzyme inhibitors, calcium channel blockers, or diuretics decrease mediators of inflammation in rats with induced myocardial ischemia. Changes in cardiac interstitial fluid (CIF) levels of nitric oxide metabolites (NOX), cyclic guanosine 3',5'-monophosphate (cGMP), angiotensin II (Ang II), and tumor necrosis factor-alpha (TNF-alpha) were monitored with/without oral administration of benazepril, amlodipine, combined benazepril-amlodipine, or hydrochlorothiazide. Using a microdialysis technique, levels of several mediators of inflammation were measured after sham operation or 30-minute occlusion of the left anterior descending coronary artery. Compared with sham animals, levels of CIF NOX and cGMP were decreased in animals with ischemia (P Benazepril or amlodipine significantly increased NOX levels (P benazepril significantly increased cGMP (P benazepril-amlodipine further increased CIF NOX and cGMP (P benazepril alone, or combined benazepril-amlodipine significantly reduced TNF-alpha (P benazepril-amlodipine may be beneficial for managing cardiac ischemia.

  20. Mechanical stretch up-regulates the B-type natriuretic peptide system in human cardiac fibroblasts: a possible defense against transforming growth factor-ß mediated fibrosis

    LENUS (Irish Health Repository)

    Watson, Chris J

    2012-07-07

    AbstractBackgroundMechanical overload of the heart is associated with excessive deposition of extracellular matrix proteins and the development of cardiac fibrosis. This can result in reduced ventricular compliance, diastolic dysfunction, and heart failure. Extracellular matrix synthesis is regulated primarily by cardiac fibroblasts, more specifically, the active myofibroblast. The influence of mechanical stretch on human cardiac fibroblasts’ response to pro-fibrotic stimuli, such as transforming growth factor beta (TGFβ), is unknown as is the impact of stretch on B-type natriuretic peptide (BNP) and natriuretic peptide receptor A (NPRA) expression. BNP, acting via NPRA, has been shown to play a role in modulation of cardiac fibrosis.Methods and resultsThe effect of cyclical mechanical stretch on TGFβ induction of myofibroblast differentiation in primary human cardiac fibroblasts and whether differences in response to stretch were associated with changes in the natriuretic peptide system were investigated. Cyclical mechanical stretch attenuated the effectiveness of TGFβ in inducing myofibroblast differentiation. This finding was associated with a novel observation that mechanical stretch can increase BNP and NPRA expression in human cardiac fibroblasts, which could have important implications in modulating myocardial fibrosis. Exogenous BNP treatment further reduced the potency of TGFβ on mechanically stretched fibroblasts.ConclusionWe postulate that stretch induced up-regulation of the natriuretic peptide system may contribute to the observed reduction in myofibroblast differentiation.

  1. Association of cardiac myosin binding protein-C with the ryanodine receptor channel: putative retrograde regulation?

    Science.gov (United States)

    Stanczyk, Paulina J; Seidel, Monika; White, Judith; Viero, Cedric; George, Christopher H; Zissimopoulos, Spyros; Lai, F Anthony

    2018-06-21

    The cardiac muscle ryanodine receptor-Ca 2+ release channel (RyR2) constitutes the sarcoplasmic reticulum (SR) Ca 2+ efflux mechanism that initiates myocyte contraction, while cardiac myosin binding protein-C (cMyBP-C) mediates regulation of acto-myosin cross-bridge cycling. In this report, we provide the first evidence for the presence of direct interaction between these two proteins, forming a RyR2:cMyBP-C complex. The C-terminus of cMyBP-C binds with the RyR2 N-terminus in mammalian cells and is not mediated by a fibronectin-like domain. Notably, we detected complex formation between both recombinant cMyBP-C and RyR2, as well as with the native proteins in cardiac tissue. Cellular Ca 2+ dynamics in HEK293 cells is altered upon co-expression of cMyBP-C and RyR2, with lowered frequency of RyR2-mediated spontaneous Ca 2+ oscillations, suggesting cMyBP-C exerts a potential inhibitory effect on RyR2-dependent Ca 2+ release. Discovery of a functional RyR2 association with cMyBP-C provides direct evidence for a putative mechanistic link between cytosolic soluble cMyBP-C and SR-mediated Ca 2+ release, via RyR2. Importantly, this interaction may have clinical relevance to the observed cMyBP-C and RyR2 dysfunction in cardiac pathologies, such as hypertrophic cardiomyopathy. © 2018. Published by The Company of Biologists Ltd.

  2. Diabetes-specific emotional distress mediates the association between depressive symptoms and glycaemic control in Type 1 and Type 2 diabetes

    DEFF Research Database (Denmark)

    van Bastelaar, Kim M P; Pouwer, F; Geelhoed-Duijvestijn, P H L M

    2010-01-01

    and diabetes-specific emotional distress respectively. Linear regression was performed to examine the mediating effect of diabetes-distress. RESULTS: Complete data were available for 627 outpatients with Type 1 (n = 280) and Type 2 (n = 347) diabetes. Analyses showed that diabetes-distress mediated......OBJECTIVES: To investigate whether diabetes-specific emotional distress mediates the relationship between depression and glycaemic control in patients with Type 1 and Type 2 diabetes. RESEARCH DESIGN AND METHODS: Data were derived from the baseline assessment of a depression in diabetes screening...... and glycaemic control, diabetes-specific emotional distress appears to be an important mediator. Addressing diabetes-specific emotional problems as part of depression treatment in diabetes patients may help improve glycaemic outcomes....

  3. Adiponectin mediated MHC class II mismatched cardiac graft rejection in mice is IL-4 dependent.

    Directory of Open Access Journals (Sweden)

    Daxu Li

    Full Text Available BACKGROUND: Adiponectin regulates glucose and fatty-acid metabolism but its role in chronic graft rejection mediated by Th2 cytokines remains ill-defined. METHODOLOGY/PRINCIPAL FINDINGS: Wild type and adiponectin-null mice were used as graft recipients in mouse MHC class II disparate cardiac transplantation (bm12 toB6 and the graft rejection was monitored. In adiponectin-null mice we observed that the cellular infiltrate of eosinophils, CD4(+ and CD8(+ T cells was reduced in grafts compared to the controls as was collagen deposition and vessel occlusion. A similar outcome was observed for skin transplants except that neutrophil infiltration was increased. Low levels of IL-4 were detected in the grafts and serum. The effect of adiponectin signaling on IL-4 expression was further investigated. Treatment with AMPK and p38 MAPK inhibitors blocked adiponectin enhanced T cell proliferation in mixed lymphocyte reactions. Inhibition of AMPK reduced eosinophil infiltration in skin grafts in wild type recipients and in contrast AMPK activation increased eosinophils in adiponectin-null recipients. The addition of adiponectin increased IL-4 production by the T cell line EL4 with augmented nuclear GATA-3 and phospho-STAT6 expression which were suppressed by knockdown of adiponectin receptor 1 and 2. CONCLUSIONS: Our results demonstrate a direct effect of adiponectin on IL-4 expression which contributes to Th2 cytokine mediated rejection in mouse MHC class II histoincompatible transplants. These results add to our understanding of the interrelationship of metabolism and immune regulation and raise the possibility that AMPK inhibitors may be beneficial in selected types of rejection.

  4. Recruitment of Mediator Complex by Cell Type and Stage-Specific Factors Required for Tissue-Specific TAF Dependent Gene Activation in an Adult Stem Cell Lineage.

    Science.gov (United States)

    Lu, Chenggang; Fuller, Margaret T

    2015-12-01

    Onset of terminal differentiation in adult stem cell lineages is commonly marked by robust activation of new transcriptional programs required to make the appropriate differentiated cell type(s). In the Drosophila male germ line stem cell lineage, the switch from proliferating spermatogonia to spermatocyte is accompanied by one of the most dramatic transcriptional changes in the fly, as over 1000 new transcripts turn on in preparation for meiosis and spermatid differentiation. Here we show that function of the coactivator complex Mediator is required for activation of hundreds of new transcripts in the spermatocyte program. Mediator appears to act in a sequential hierarchy, with the testis activating Complex (tMAC), a cell type specific form of the Mip/dREAM general repressor, required to recruit Mediator subunits to the chromatin, and Mediator function required to recruit the testis TAFs (tTAFs), spermatocyte specific homologs of subunits of TFIID. Mediator, tMAC and the tTAFs co-regulate expression of a major set of spermatid differentiation genes. The Mediator subunit Med22 binds the tMAC component Topi when the two are coexpressed in S2 cells, suggesting direct recruitment. Loss of Med22 function in spermatocytes causes meiosis I maturation arrest male infertility, similar to loss of function of the tMAC subunits or the tTAFs. Our results illuminate how cell type specific versions of the Mip/dREAM complex and the general transcription machinery cooperate to drive selective gene activation during differentiation in stem cell lineages.

  5. Metoclopramide-induced cardiac arrest

    Directory of Open Access Journals (Sweden)

    Martha M. Rumore

    2011-11-01

    Full Text Available The authors report a case of cardiac arrest in a patient receiving intravenous (IV metoclopramide and review the pertinent literature. A 62-year-old morbidly obese female admitted for a gastric sleeve procedure, developed cardiac arrest within one minute of receiving metoclopramide 10 mg via slow intravenous (IV injection. Bradycardia at 4 beats/min immediately appeared, progressing rapidly to asystole. Chest compressions restored vital function. Electrocardiogram (ECG revealed ST depression indicative of myocardial injury. Following intubation, the patient was transferred to the intensive care unit. Various cardiac dysrrhythmias including supraventricular tachycardia (SVT associated with hypertension and atrial fibrillation occurred. Following IV esmolol and metoprolol, the patient reverted to normal sinus rhythm. Repeat ECGs revealed ST depression resolution without pre-admission changes. Metoclopramide is a non-specific dopamine receptor antagonist. Seven cases of cardiac arrest and one of sinus arrest with metoclopramide were found in the literature. The metoclopramide prescribing information does not list precautions or adverse drug reactions (ADRs related to cardiac arrest. The reaction is not dose related but may relate to the IV administration route. Coronary artery disease was the sole risk factor identified. According to Naranjo, the association was possible. Other reports of cardiac arrest, severe bradycardia, and SVT were reviewed. In one case, five separate IV doses of 10 mg metoclopramide were immediately followed by asystole repeatedly. The mechanism(s underlying metoclopramide’s cardiac arrest-inducing effects is unknown. Structural similarities to procainamide may play a role. In view of eight previous cases of cardiac arrest from metoclopramide having been reported, further elucidation of this ADR and patient monitoring is needed. Our report should alert clinicians to monitor patients and remain diligent in surveillance and

  6. Inhibition of the Unfolded Protein Response Mechanism Prevents Cardiac Fibrosis.

    Directory of Open Access Journals (Sweden)

    Jody Groenendyk

    Full Text Available Cardiac fibrosis attributed to excessive deposition of extracellular matrix proteins is a major cause of heart failure and death. Cardiac fibrosis is extremely difficult and challenging to treat in a clinical setting due to lack of understanding of molecular mechanisms leading to cardiac fibrosis and effective anti-fibrotic therapies. The objective in this study was to examine whether unfolded protein response (UPR pathway mediates cardiac fibrosis and whether a pharmacological intervention to modulate UPR can prevent cardiac fibrosis and preserve heart function.We demonstrate here that the mechanism leading to development of fibrosis in a mouse with increased expression of calreticulin, a model of heart failure, stems from impairment of endoplasmic reticulum (ER homeostasis, transient activation of the unfolded protein response (UPR pathway and stimulation of the TGFβ1/Smad2/3 signaling pathway. Remarkably, sustained pharmacologic inhibition of the UPR pathway by tauroursodeoxycholic acid (TUDCA is sufficient to prevent cardiac fibrosis, and improved exercise tolerance.We show that the mechanism leading to development of fibrosis in a mouse model of heart failure stems from transient activation of UPR pathway leading to persistent remodelling of cardiac tissue. Blocking the activation of the transiently activated UPR pathway by TUDCA prevented cardiac fibrosis, and improved prognosis. These findings offer a window for additional interventions that can preserve heart function.

  7. Impact of ethnicity on cardiac adaptation to exercise.

    Science.gov (United States)

    Sheikh, Nabeel; Sharma, Sanjay

    2014-04-01

    The increasing globalization of sport has resulted in athletes from a wide range of ethnicities emerging onto the world stage. Fuelled by the untimely death of a number of young professional athletes, data generated from the parallel increase in preparticipation cardiovascular evaluation has indicated that ethnicity has a substantial influence on cardiac adaptation to exercise. From this perspective, the group most intensively studied comprises athletes of African or Afro-Caribbean ethnicity (black athletes), an ever-increasing number of whom are competing at the highest levels of sport and who often exhibit profound electrical and structural cardiac changes in response to exercise. Data on other ethnic cohorts are emerging, but remain incomplete. This Review describes our current knowledge on the impact of ethnicity on cardiac adaptation to exercise, starting with white athletes in whom the physiological electrical and structural changes--collectively termed the 'athlete's heart'--were first described. Discussion of the differences in the cardiac changes between ethnicities, with a focus on black athletes, and of the challenges that these variations can produce for the evaluating physician is also provided. The impact of ethnically mediated changes on preparticipation cardiovascular evaluation is highlighted, particularly with respect to false positive results, and potential genetic mechanisms underlying racial differences in cardiac adaptation to exercise are described.

  8. Development of an organ-specific insert phantom generated using a 3D printer for investigations of cardiac computed tomography protocols.

    Science.gov (United States)

    Abdullah, Kamarul A; McEntee, Mark F; Reed, Warren; Kench, Peter L

    2018-04-30

    An ideal organ-specific insert phantom should be able to simulate the anatomical features with appropriate appearances in the resultant computed tomography (CT) images. This study investigated a 3D printing technology to develop a novel and cost-effective cardiac insert phantom derived from volumetric CT image datasets of anthropomorphic chest phantom. Cardiac insert volumes were segmented from CT image datasets, derived from an anthropomorphic chest phantom of Lungman N-01 (Kyoto Kagaku, Japan). These segmented datasets were converted to a virtual 3D-isosurface of heart-shaped shell, while two other removable inserts were included using computer-aided design (CAD) software program. This newly designed cardiac insert phantom was later printed by using a fused deposition modelling (FDM) process via a Creatbot DM Plus 3D printer. Then, several selected filling materials, such as contrast media, oil, water and jelly, were loaded into designated spaces in the 3D-printed phantom. The 3D-printed cardiac insert phantom was positioned within the anthropomorphic chest phantom and 30 repeated CT acquisitions performed using a multi-detector scanner at 120-kVp tube potential. Attenuation (Hounsfield Unit, HU) values were measured and compared to the image datasets of real-patient and Catphan ® 500 phantom. The output of the 3D-printed cardiac insert phantom was a solid acrylic plastic material, which was strong, light in weight and cost-effective. HU values of the filling materials were comparable to the image datasets of real-patient and Catphan ® 500 phantom. A novel and cost-effective cardiac insert phantom for anthropomorphic chest phantom was developed using volumetric CT image datasets with a 3D printer. Hence, this suggested the printing methodology could be applied to generate other phantoms for CT imaging studies. © 2018 The Authors. Journal of Medical Radiation Sciences published by John Wiley & Sons Australia, Ltd on behalf of Australian Society of Medical

  9. Concise Review: Pluripotent Stem Cell-Derived Cardiac Cells, A Promising Cell Source for Therapy of Heart Failure: Where Do We Stand?

    Science.gov (United States)

    Gouadon, Elodie; Moore-Morris, Thomas; Smit, Nicoline W; Chatenoud, Lucienne; Coronel, Ruben; Harding, Sian E; Jourdon, Philippe; Lambert, Virginie; Rucker-Martin, Catherine; Pucéat, Michel

    2016-01-01

    Heart failure is still a major cause of hospitalization and mortality in developed countries. Many clinical trials have tested the use of multipotent stem cells as a cardiac regenerative medicine. The benefit for the patients of this therapeutic intervention has remained limited. Herein, we review the pluripotent stem cells as a cell source for cardiac regeneration. We more specifically address the various challenges of this cell therapy approach. We question the cell delivery systems, the immune tolerance of allogenic cells, the potential proarrhythmic effects, various drug mediated interventions to facilitate cell grafting and, finally, we describe the pathological conditions that may benefit from such an innovative approach. As members of a transatlantic consortium of excellence of basic science researchers and clinicians, we propose some guidelines to be applied to cell types and modes of delivery in order to translate pluripotent stem cell cardiac derivatives into safe and effective clinical trials. © 2015 AlphaMed Press.

  10. Cardiac expression of microsomal triglyceride transfer protein is increased in obesity and serves to attenuate cardiac triglyceride accumulation

    DEFF Research Database (Denmark)

    Bartels, Emil D; Nielsen, Jan M; Hellgren, Lars I

    2009-01-01

    Obesity causes lipid accumulation in the heart and may lead to lipotoxic heart disease. Traditionally, the size of the cardiac triglyceride pool is thought to reflect the balance between uptake and beta-oxidation of fatty acids. However, triglycerides can also be exported from cardiomyocytes via...... secretion of apolipoproteinB-containing (apoB) lipoproteins. Lipoprotein formation depends on expression of microsomal triglyceride transfer protein (MTP); the mouse expresses two isoforms of MTP, A and B. Since many aspects of the link between obesity-induced cardiac disease and cardiac lipid metabolism...... remain unknown, we investigated how cardiac lipoprotein synthesis affects cardiac expression of triglyceride metabolism-controlling genes, insulin sensitivity, and function in obese mice. Heart-specific ablation of MTP-A in mice using Cre-loxP technology impaired upregulation of MTP expression...

  11. Postnatal Cardiac Gene Editing Using CRISPR/Cas9 With AAV9-Mediated Delivery of Short Guide RNAs Results in Mosaic Gene Disruption.

    Science.gov (United States)

    Johansen, Anne Katrine; Molenaar, Bas; Versteeg, Danielle; Leitoguinho, Ana Rita; Demkes, Charlotte; Spanjaard, Bastiaan; de Ruiter, Hesther; Akbari Moqadam, Farhad; Kooijman, Lieneke; Zentilin, Lorena; Giacca, Mauro; van Rooij, Eva

    2017-10-27

    CRISPR/Cas9 (clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9)-based DNA editing has rapidly evolved as an attractive tool to modify the genome. Although CRISPR/Cas9 has been extensively used to manipulate the germline in zygotes, its application in postnatal gene editing remains incompletely characterized. To evaluate the feasibility of CRISPR/Cas9-based cardiac genome editing in vivo in postnatal mice. We generated cardiomyocyte-specific Cas9 mice and demonstrated that Cas9 expression does not affect cardiac function or gene expression. As a proof-of-concept, we delivered short guide RNAs targeting 3 genes critical for cardiac physiology, Myh6 , Sav1 , and Tbx20 , using a cardiotropic adeno-associated viral vector 9. Despite a similar degree of DNA disruption and subsequent mRNA downregulation, only disruption of Myh6 was sufficient to induce a cardiac phenotype, irrespective of short guide RNA exposure or the level of Cas9 expression. DNA sequencing analysis revealed target-dependent mutations that were highly reproducible across mice resulting in differential rates of in- and out-of-frame mutations. Finally, we applied a dual short guide RNA approach to effectively delete an important coding region of Sav1 , which increased the editing efficiency. Our results indicate that the effect of postnatal CRISPR/Cas9-based cardiac gene editing using adeno-associated virus serotype 9 to deliver a single short guide RNA is target dependent. We demonstrate a mosaic pattern of gene disruption, which hinders the application of the technology to study gene function. Further studies are required to expand the versatility of CRISPR/Cas9 as a robust tool to study novel cardiac gene functions in vivo. © 2017 American Heart Association, Inc.

  12. Conditional shape models for cardiac motion estimation

    DEFF Research Database (Denmark)

    Metz, Coert; Baka, Nora; Kirisli, Hortense

    2010-01-01

    We propose a conditional statistical shape model to predict patient specific cardiac motion from the 3D end-diastolic CTA scan. The model is built from 4D CTA sequences by combining atlas based segmentation and 4D registration. Cardiac motion estimation is, for example, relevant in the dynamic...

  13. Recruitment of Mediator Complex by Cell Type and Stage-Specific Factors Required for Tissue-Specific TAF Dependent Gene Activation in an Adult Stem Cell Lineage.

    Directory of Open Access Journals (Sweden)

    Chenggang Lu

    2015-12-01

    Full Text Available Onset of terminal differentiation in adult stem cell lineages is commonly marked by robust activation of new transcriptional programs required to make the appropriate differentiated cell type(s. In the Drosophila male germ line stem cell lineage, the switch from proliferating spermatogonia to spermatocyte is accompanied by one of the most dramatic transcriptional changes in the fly, as over 1000 new transcripts turn on in preparation for meiosis and spermatid differentiation. Here we show that function of the coactivator complex Mediator is required for activation of hundreds of new transcripts in the spermatocyte program. Mediator appears to act in a sequential hierarchy, with the testis activating Complex (tMAC, a cell type specific form of the Mip/dREAM general repressor, required to recruit Mediator subunits to the chromatin, and Mediator function required to recruit the testis TAFs (tTAFs, spermatocyte specific homologs of subunits of TFIID. Mediator, tMAC and the tTAFs co-regulate expression of a major set of spermatid differentiation genes. The Mediator subunit Med22 binds the tMAC component Topi when the two are coexpressed in S2 cells, suggesting direct recruitment. Loss of Med22 function in spermatocytes causes meiosis I maturation arrest male infertility, similar to loss of function of the tMAC subunits or the tTAFs. Our results illuminate how cell type specific versions of the Mip/dREAM complex and the general transcription machinery cooperate to drive selective gene activation during differentiation in stem cell lineages.

  14. Overexpression of the human angiotensin II type 1 receptor in the rat heart augments load induced cardiac hypertrophy

    NARCIS (Netherlands)

    Hoffmann, S.; Krause, T.; van Geel, P. P.; Willenbrock, R.; Pagel, I.; Pinto, Y. M.; Buikema, H.; van Gilst, W. H.; Lindschau, C.; Paul, M.; Inagami, T.; Ganten, D.; Urata, H.

    2001-01-01

    Angiotensin II is known to stimulate cardiac hypertrophy and contractility. Most angiotensin II effects are mediated via membrane bound AT1 receptors. However, the role of myocardial AT1 receptors in cardiac hypertrophy and contractility is still rarely defined. To address the hypothesis that

  15. Overexpression of the human angiotensin II type 1 receptor in the rat heart augments load induced cardiac hypertrophy

    NARCIS (Netherlands)

    Hoffmann, S; van Geel, PP; Willenbrock, R; Pagel, [No Value; Pinto, YM; Buikema, H; van Gilst, WH; Lindschau, C; Paul, M; Inagami, T; Ganten, D; Urata, H

    2001-01-01

    Angiotensin II is known to stimulate cardiac hypertrophy and contractility. Most angiotensin II effects are mediated via membrane bound AT(1) receptors. However, the role of myocardial AT(1) receptors in cardiac hypertrophy and contractility is still rarely defined. To address the hypothesis that

  16. GSK-3β/NFAT Signaling Is Involved in Testosterone-Induced Cardiac Myocyte Hypertrophy.

    Directory of Open Access Journals (Sweden)

    Javier Duran

    Full Text Available Testosterone induces cardiac hypertrophy through a mechanism that involves a concerted crosstalk between cytosolic and nuclear signaling pathways. Nuclear factor of activated T-cells (NFAT is associated with the promotion of cardiac hypertrophy, glycogen synthase kinase-3β (GSK-3β is considered to function as a negative regulator, mainly by modulating NFAT activity. However, the role played by calcineurin-NFAT and GSK-3β signaling in testosterone-induced cardiac hypertrophy has remained unknown. Here, we determined that testosterone stimulates cardiac myocyte hypertrophy through NFAT activation and GSK-3β inhibition. Testosterone increased the activity of NFAT-luciferase (NFAT-Luc in a time- and dose-dependent manner, with the activity peaking after 24 h of stimulation with 100 nM testosterone. NFAT-Luc activity induced by testosterone was blocked by the calcineurin inhibitors FK506 and cyclosporine A and by 11R-VIVIT, a specific peptide inhibitor of NFAT. Conversely, testosterone inhibited GSK-3β activity as determined by increased GSK-3β phosphorylation at Ser9 and β-catenin protein accumulation, and also by reduction in β-catenin phosphorylation at residues Ser33, Ser37, and Thr41. GSK-3β inhibition with 1-azakenpaullone or a GSK-3β-targeting siRNA increased NFAT-Luc activity, whereas overexpression of a constitutively active GSK-3β mutant (GSK-3βS9A inhibited NFAT-Luc activation mediated by testosterone. Testosterone-induced cardiac myocyte hypertrophy was established by increased cardiac myocyte size and [3H]-leucine incorporation (as a measurement of cellular protein synthesis. Calcineurin-NFAT inhibition abolished and GSK-3β inhibition promoted the hypertrophy stimulated by testosterone. GSK-3β activation by GSK-3βS9A blocked the increase of hypertrophic markers induced by testosterone. Moreover, inhibition of intracellular androgen receptor prevented testosterone-induced NFAT-Luc activation. Collectively, these results

  17. Novel PET and Near Infrared Imaging Probes for the Specific Detection of Bacterial Infections Associated With Cardiac Devices.

    Science.gov (United States)

    Takemiya, Kiyoko; Ning, Xinghai; Seo, Wonewoo; Wang, Xiaojian; Mohammad, Rafi; Joseph, Giji; Titterington, Jane S; Kraft, Colleen S; Nye, Jonathan A; Murthy, Niren; Goodman, Mark M; Taylor, W Robert

    2018-04-13

    The aim of this study was to develop imaging agents to detect early stage infections in implantable cardiac devices. Bacteria ingest maltodextrins through the specific maltodextrin transporter. We developed probes conjugated with either a fluorescent dye (maltohexaose fluorescent dye probe [MDP]) or a F-18 (F18 fluoromaltohexaose) and determined their usefulness in a model of infections associated with implanted cardiac devices. Stainless steel mock-ups of medical devices were implanted subcutaneously in rats. On post-operative day 4, animals were injected with either Staphylococcus aureus around the mock-ups to induce a relatively mild infection or oil of turpentine to induce noninfectious inflammation. Animals with a sterile implant were used as control subjects. On post-operative day 6, either the MDP or F18 fluoromaltohexaose was injected intravenously, and the animals were scanned with the appropriate imaging device. Additional positron emission tomography imaging studies were performed with F18-fluorodeoxyglucose as a comparison of the specificity of our probes (n = 5 to 9 per group). The accumulation of the MDP in the infected rats was significantly increased at 1 h after injection when compared with the control and noninfectious inflammation groups (intensity ratio 1.54 ± 0.07 vs. 1.26 ± 0.04 and 1.20 ± 0.05, respectively; p F18 fluoromaltohexaose and F18 fluorodeoxyglucose significantly accumulated in the infected area 30 min after the injection (maximum standard uptake value ratio 4.43 ± 0.30 and 4.87 ± 0.28, respectively). In control rats, there was no accumulation of imaging probes near the device. In the noninfectious inflammation rats, no significant accumulation was observed with F18 fluoromaltohexaose, but F18 fluorodeoxyglucose accumulated in the mock-up area (maximum standard uptake value 2.53 ± 0.39 vs. 4.74 ± 0.46, respectively; p < 0.05). Our results indicate that maltohexaose-based imaging probes are potentially useful for the

  18. Disease-specific health-related quality of life instruments for IgE-mediated food allergy.

    Science.gov (United States)

    Salvilla, S A; Dubois, A E J; Flokstra-de Blok, B M J; Panesar, S S; Worth, A; Patel, S; Muraro, A; Halken, S; Hoffmann-Sommergruber, K; DunnGalvin, A; Hourihane, J O'B; Regent, L; de Jong, N W; Roberts, G; Sheikh, A

    2014-07-01

    This is one of seven interlinked systematic reviews undertaken on behalf of the European Academy of Allergy and Clinical Immunology as part of their Guidelines for Food Allergy and Anaphylaxis, which focuses on instruments developed for IgE-mediated food allergy. Disease-specific questionnaires are significantly more sensitive than generic ones in measuring the response to interventions or future treatments, as well as estimating the general burden of food allergy. The aim of this systematic review was therefore to identify which disease-specific, validated instruments can be employed to enable assessment of the impact of, and investigations and interventions for, IgE-mediated food allergy on health-related quality of life (HRQL). Using a sensitive search strategy, we searched seven electronic bibliographic databases to identify disease-specific quality of life (QOL) tools relating to IgE-mediated food allergy. From the 17 eligible studies, we identified seven disease-specific HRQL instruments, which were then subjected to detailed quality appraisal. This revealed that these instruments have undergone formal development and validation processes, and have robust psychometric properties, and therefore provide a robust means of establishing the impact of food allergy on QOL. Suitable instruments are now available for use in children, adolescents, parents/caregivers, and adults. Further work must continue to develop a clinical minimal important difference for food allergy and for making these instruments available in a wider range of European languages. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Patient-specific coronary blood supply territories for quantitative perfusion analysis

    Science.gov (United States)

    Zakkaroff, Constantine; Biglands, John D.; Greenwood, John P.; Plein, Sven; Boyle, Roger D.; Radjenovic, Aleksandra; Magee, Derek R.

    2018-01-01

    Abstract Myocardial perfusion imaging, coupled with quantitative perfusion analysis, provides an important diagnostic tool for the identification of ischaemic heart disease caused by coronary stenoses. The accurate mapping between coronary anatomy and under-perfused areas of the myocardium is important for diagnosis and treatment. However, in the absence of the actual coronary anatomy during the reporting of perfusion images, areas of ischaemia are allocated to a coronary territory based on a population-derived 17-segment (American Heart Association) AHA model of coronary blood supply. This work presents a solution for the fusion of 2D Magnetic Resonance (MR) myocardial perfusion images and 3D MR angiography data with the aim to improve the detection of ischaemic heart disease. The key contribution of this work is a novel method for the mediated spatiotemporal registration of perfusion and angiography data and a novel method for the calculation of patient-specific coronary supply territories. The registration method uses 4D cardiac MR cine series spanning the complete cardiac cycle in order to overcome the under-constrained nature of non-rigid slice-to-volume perfusion-to-angiography registration. This is achieved by separating out the deformable registration problem and solving it through phase-to-phase registration of the cine series. The use of patient-specific blood supply territories in quantitative perfusion analysis (instead of the population-based model of coronary blood supply) has the potential of increasing the accuracy of perfusion analysis. Quantitative perfusion analysis diagnostic accuracy evaluation with patient-specific territories against the AHA model demonstrates the value of the mediated spatiotemporal registration in the context of ischaemic heart disease diagnosis. PMID:29392098

  20. Cardiac expression of microsomal triglyceride transfer protein is increased in obesity and serves to attenuate cardiac triglyceride accumulation.

    Directory of Open Access Journals (Sweden)

    Emil D Bartels

    Full Text Available Obesity causes lipid accumulation in the heart and may lead to lipotoxic heart disease. Traditionally, the size of the cardiac triglyceride pool is thought to reflect the balance between uptake and beta-oxidation of fatty acids. However, triglycerides can also be exported from cardiomyocytes via secretion of apolipoproteinB-containing (apoB lipoproteins. Lipoprotein formation depends on expression of microsomal triglyceride transfer protein (MTP; the mouse expresses two isoforms of MTP, A and B. Since many aspects of the link between obesity-induced cardiac disease and cardiac lipid metabolism remain unknown, we investigated how cardiac lipoprotein synthesis affects cardiac expression of triglyceride metabolism-controlling genes, insulin sensitivity, and function in obese mice. Heart-specific ablation of MTP-A in mice using Cre-loxP technology impaired upregulation of MTP expression in response to increased fatty acid availability during fasting and fat feeding. This resulted in cardiac triglyceride accumulation but unaffected cardiac insulin-stimulated glucose uptake. Long-term fat-feeding of male C57Bl/6 mice increased cardiac triglycerides, induced cardiac expression of triglyceride metabolism-controlling genes and attenuated heart function. Abolishing cardiac triglyceride accumulation in fat-fed mice by overexpression of an apoB transgene in the heart prevented the induction of triglyceride metabolism-controlling genes and improved heart function. The results suggest that in obesity, the physiological increase of cardiac MTP expression serves to attenuate cardiac triglyceride accumulation albeit without major effects on cardiac insulin sensitivity. Nevertheless, the data suggest that genetically increased lipoprotein secretion prevents development of obesity-induced lipotoxic heart disease.

  1. A novel theory: biological processes mostly involve two types of mediators, namely general and specific mediators Endogenous small radicals such as superoxide and nitric oxide may play a role of general mediator in biological processes.

    Science.gov (United States)

    Mo, Jian

    2005-01-01

    A great number of papers have shown that free radicals as well as bioactive molecules can play a role of mediator in a wide spectrum of biological processes, but the biological actions and chemical reactivity of the free radicals are quite different from that of the bioactive molecules, and that a wide variety of bioactive molecules can be easily modified by free radicals due to having functional groups sensitive to redox, and the significance of the interaction between the free radicals and the bioactive molecules in biological processes has been confirmed by the results of some in vitro and in vivo studies. Based on these evidence, this article presented a novel theory about the mediators of biological processes. The essentials of the theory are: (a) mediators of biological processes can be classified into general and specific mediators; the general mediators include two types of free radicals, namely superoxide and nitric oxide; the specific mediators include a wide variety of bioactive molecules, such as specific enzymes, transcription factors, cytokines and eicosanoids; (b) a general mediator can modify almost any class of the biomolecules, and thus play a role of mediator in nearly every biological process via diverse mechanisms; a specific mediator always acts selectively on certain classes of the biomolecules, and may play a role of mediator in different biological processes via a same mechanism; (c) biological processes are mostly controlled by networks of their mediators, so the free radicals can regulate the last consequence of a biological process by modifying some types of the bioactive molecules, or in cooperation with these bioactive molecules; the biological actions of superoxide and nitric oxide may be synergistic or antagonistic. According to this theory, keeping the integrity of these networks and the balance between the free radicals and the bioactive molecules as well as the balance between the free radicals and the free radical scavengers

  2. Leptin induces cardiac fibrosis through galectin-3, mTOR and oxidative stress: potential role in obesity.

    Science.gov (United States)

    Martínez-Martínez, Ernesto; Jurado-López, Raquel; Valero-Muñoz, María; Bartolomé, María Visitación; Ballesteros, Sandra; Luaces, María; Briones, Ana María; López-Andrés, Natalia; Miana, María; Cachofeiro, Victoria

    2014-05-01

    Leptin acts as a cardiac profibrotic factor. However, the mechanisms underlying this effect are unclear. Therefore, we sought to elucidate the mediators involved in this process and the potential role of leptin in cardiac fibrosis associated with obesity. Male Wistar rats were fed either a high-fat diet (HFD; 33.5% fat), or a standard diet (3.5% fat) for 6 weeks. HFD animals show cardiac hypertrophy, fibrosis and an increase in O2- production as evaluated by dihydroethidium. Echocardiographic parameters of cardiac structure and systolic function were similar in both groups. Cardiac levels of leptin, collagen I, galectin-3 and transforming growth factor β (TGF-β) were higher in HFD than in controls. In cardiac myofibroblasts, leptin (10-100 ng/ml) increased O2-, collagen I, galectin-3, TGF-β and connective tissue growth factor production (CTGF). These effects were prevented by the presence of either melatonin (10 mmol/l) or the inhibitor of mTOR, rapamycin (10 mmol/l). Blockage of galectin-3 activity by N-acetyllactosamine (LacNac 10 mmol/l) reduced both collagen I and O2(*-) production induced by leptin. The p70S6 kinase activation/phosphorylation, the downstream mediator of mTOR, induced by leptin was not modified by melatonin. Leptin reduced the metalloproteinase (MMP) 2 activity and the presence of melatonin, rapamycin or LacNac were unable to prevent it. The data suggest that leptin locally produced in the heart could participate in the fibrosis observed in HFD by affecting collagen turnover. Collagen synthesis induced by leptin seems to be mediated by the production of galectin-3, TGF-β and CTGF through oxidative stress increased by activation of mTOR pathway.

  3. Study on the effect of hypoxia on apoptosis of cultured newly born rat cardiac myocytes

    International Nuclear Information System (INIS)

    Su Weidong; Li Huiqiang; Yao Zhi

    2005-01-01

    Objective: To investigate the possible hypoxia-mediated cellular apoptosis after ischemic cardiac injury via a model of cultured newly born rat cardiac myocytes. Methods: Cardiac myocytes cultures from newly born rats (1-3d) were examined for apoptosis with HE stain and flow cytometry after cultured 96h and again examined after exposure to hypoxic environment for 16h. Results: Apoptotic changes were evident in the hypoxic culture cells. The HE stain revealed cellular shrinkage, nuclear chromosomal condensation with cytoplasmic eosinophilia. Also, distinct apoptosis peak was observed in the flow cytometry. Conclusion: This experiment proved that hypoxic model of cardiac myocyte culture showed definite apoptosis of the cells. (authors)

  4. Cardiac effects of electrically induced intrathoracic autonomic reflexes.

    Science.gov (United States)

    Armour, J A

    1988-06-01

    Electrical stimulation of the afferent components in one cardiopulmonary nerve (the left vagosympathetic complex at a level immediately caudal to the origin of the left recurrent laryngeal nerve) in acutely decentralized thoracic autonomic ganglionic preparations altered cardiac chronotropism and inotropism in 17 of 44 dogs. Since these neural preparations were acutely decentralized, the effects were mediated presumably via intrathoracic autonomic reflexes. The lack of consistency of these reflexly generated cardiac responses presumably were due in part to anatomical variation of afferent axons in the afferent nerve stimulated. As stimulation of the afferent components in the same neural structure caudal to the heart (where cardiopulmonary afferent axons are not present) failed to elicit cardiac responses in any dog, it is presumed that when cardiac responses were elicited by the more cranially located stimulations, these were due to activation of afferent axons arising from the heart and (or) lungs. When cardiac responses were elicited, intramyocardial pressures in the right ventricular conus as well as the ventral and lateral walls of the left ventricle were augmented. Either bradycardia or tachycardia was elicited. Following hexamethonium administration no responses were produced, demonstrating that nicotonic cholinergic synaptic mechanisms were involved in these intrathoracic cardiopulmonary-cardiac reflexes. In six of the animals, when atropine was administered before hexamethonium, reflexly generated responses were attenuated. The same thing occurred when morphine was administered in four animals. In contrast, in four animals following administration of phentolamine, the reflexly generated changes were enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Obesity, metabolic dysfunction and cardiac fibrosis: pathophysiologic pathways, molecular mechanisms and therapeutic opportunities

    Science.gov (United States)

    Cavalera, Michele; Wang, Junhong; Frangogiannis, Nikolaos G

    2014-01-01

    Cardiac fibrosis is strongly associated with obesity and metabolic dysfunction and may contribute to the increased incidence of heart failure, atrial arrhythmias and sudden cardiac death in obese subjects. Our review discusses the evidence linking obesity and myocardial fibrosis in animal models and human patients, focusing on the fundamental pathophysiologic alterations that may trigger fibrogenic signaling, the cellular effectors of fibrosis and the molecular signals that may regulate the fibrotic response. Obesity is associated with a wide range of pathophysiologic alterations (such as pressure and volume overload, metabolic dysregulation, neurohumoral activation and systemic inflammation); their relative role in mediating cardiac fibrosis is poorly defined. Activation of fibroblasts likely plays a major role in obesity-associated fibrosis; however, inflammatory cells, cardiomyocytes and vascular cells may also contribute to fibrogenic signaling. Several molecular processes have been implicated in regulation of the fibrotic response in obesity. Activation of the Renin-Angiotensin-Aldosterone System, induction of Transforming Growth Factor-β, oxidative stress, advanced glycation end-products (AGEs), endothelin-1, Rho-kinase signaling, leptin-mediated actions and upregulation of matricellular proteins (such as thrombospondin-1) may play a role in the development of fibrosis in models of obesity and metabolic dysfunction. Moreover, experimental evidence suggests that obesity and insulin resistance profoundly affect the fibrotic and remodeling response following cardiac injury. Understanding the pathways implicated in obesity-associated fibrosis may lead to development of novel therapies to prevent heart failure and to attenuate post-infarction cardiac remodeling in obese patients. PMID:24880146

  6. How is cardiac troponin released from injured myocardium?

    DEFF Research Database (Denmark)

    Mair, Johannes; Lindahl, Bertil; Hammarsten, Ola

    2017-01-01

    Cardiac troponin I and cardiac troponin T are nowadays the criterion biomarkers for the laboratory diagnosis of acute myocardial infarction due to their very high sensitivities and specificities for myocardial injury. However, still many aspects of their degradation, tissue release and eliminatio...

  7. "Just-In-Time" Simulation Training Using 3-D Printed Cardiac Models After Congenital Cardiac Surgery.

    Science.gov (United States)

    Olivieri, Laura J; Su, Lillian; Hynes, Conor F; Krieger, Axel; Alfares, Fahad A; Ramakrishnan, Karthik; Zurakowski, David; Marshall, M Blair; Kim, Peter C W; Jonas, Richard A; Nath, Dilip S

    2016-03-01

    High-fidelity simulation using patient-specific three-dimensional (3D) models may be effective in facilitating pediatric cardiac intensive care unit (PCICU) provider training for clinical management of congenital cardiac surgery patients. The 3D-printed heart models were rendered from preoperative cross-sectional cardiac imaging for 10 patients undergoing congenital cardiac surgery. Immediately following surgical repair, a congenital cardiac surgeon and an intensive care physician conducted a simulation training session regarding postoperative care utilizing the patient-specific 3D model for the PCICU team. After the simulation, Likert-type 0 to 10 scale questionnaire assessed participant perception of impact of the training session. Seventy clinicians participated in training sessions, including 22 physicians, 38 nurses, and 10 ancillary care providers. Average response to whether 3D models were more helpful than standard hand off was 8.4 of 10. Questions regarding enhancement of understanding and clinical ability received average responses of 9.0 or greater, and 90% of participants scored 8 of 10 or higher. Nurses scored significantly higher than other clinicians on self-reported familiarity with the surgery (7.1 vs. 5.8; P = .04), clinical management ability (8.6 vs. 7.7; P = .02), and ability enhancement (9.5 vs. 8.7; P = .02). Compared to physicians, nurses and ancillary providers were more likely to consider 3D models more helpful than standard hand off (8.7 vs. 7.7; P = .05). Higher case complexity predicted greater enhancement of understanding of surgery (P = .04). The 3D heart models can be used to enhance congenital cardiac critical care via simulation training of multidisciplinary intensive care teams. Benefit may be dependent on provider type and case complexity. © The Author(s) 2016.

  8. HIV-1-Specific IgA Monoclonal Antibodies from an HIV-1 Vaccinee Mediate Galactosylceramide Blocking and Phagocytosis

    Science.gov (United States)

    2018-01-01

    ABSTRACT Vaccine-elicited humoral immune responses comprise an array of antibody forms and specificities, with only a fraction contributing to protective host immunity. Elucidation of antibody effector functions responsible for protective immunity against human immunodeficiency virus type 1 (HIV-1) acquisition is a major goal for the HIV-1 vaccine field. Immunoglobulin A (IgA) is an important part of the host defense against pathogens; however, little is known about the role of vaccine-elicited IgA and its capacity to mediate antiviral functions. To identify the antiviral functions of HIV-1-specific IgA elicited by vaccination, we cloned HIV-1 envelope-specific IgA monoclonal antibodies (MAbs) by memory B cell cultures from peripheral blood mononuclear cells from an RV144 vaccinee and produced two IgA clonal cell lines (HG129 and HG130) producing native, nonrecombinant IgA MAbs. The HG129 and HG130 MAbs mediated phagocytosis by monocytes, and HG129 blocked HIV-1 Env glycoprotein binding to galactosylceramide, an alternative HIV-1 receptor. These findings elucidate potential antiviral functions of vaccine-elicited HIV-1 envelope-specific IgA that may act to block HIV-1 acquisition at the portal of entry by preventing HIV-1 binding to galactosylceramide and mediating antibody Fc receptor-mediated virion phagocytosis. Furthermore, these findings highlight the complex and diverse interactions of vaccine-elicited IgA with pathogens that depend on IgA fine specificity and form (e.g., multimeric or monomeric) in the systemic circulation and mucosal compartments. IMPORTANCE Host-pathogen interactions in vivo involve numerous immune mechanisms that can lead to pathogen clearance. Understanding the nature of antiviral immune mechanisms can inform the design of efficacious HIV-1 vaccine strategies. Evidence suggests that both neutralizing and nonneutralizing antibodies can mediate some protection against HIV in animal models. Although numerous studies have characterized the

  9. Seismocardiography-Based Cardiac Computed Tomography Gating Using Patient-Specific Template Identification and Detection.

    Science.gov (United States)

    Yao, Jingting; Tridandapani, Srini; Wick, Carson A; Bhatti, Pamela T

    2017-01-01

    To more accurately trigger cardiac computed tomography angiography (CTA) than electrocardiography (ECG) alone, a sub-system is proposed as an intermediate step toward fusing ECG with seismocardiography (SCG). Accurate prediction of quiescent phases is crucial to prospectively gating CTA, which is susceptible to cardiac motion and, thus, can affect the diagnostic quality of images. The key innovation of this sub-system is that it identifies the SCG waveform corresponding to heart sounds and determines their phases within the cardiac cycles. Furthermore, this relationship is modeled as a linear function with respect to heart rate. For this paper, B-mode echocardiography is used as the gold standard for identifying the quiescent phases. We analyzed synchronous ECG, SCG, and echocardiography data acquired from seven healthy subjects (mean age: 31; age range: 22-48; males: 4) and 11 cardiac patients (mean age: 56; age range: 31-78; males: 6). On average, the proposed algorithm was able to successfully identify 79% of the SCG waveforms in systole and 68% in diastole. The simulated results show that SCG-based prediction produced less average phase error than that of ECG. It was found that the accuracy of ECG-based gating is more susceptible to increases in heart rate variability, while SCG-based gating is susceptible to high cycle to cycle variability in morphology. This pilot work of prediction using SCG waveforms enriches the framework of a comprehensive system with multiple modalities that could potentially, in real time, improve the image quality of CTA.

  10. Gcn4-Mediator Specificity Is Mediated by a Large and Dynamic Fuzzy Protein-Protein Complex.

    Science.gov (United States)

    Tuttle, Lisa M; Pacheco, Derek; Warfield, Linda; Luo, Jie; Ranish, Jeff; Hahn, Steven; Klevit, Rachel E

    2018-03-20

    Transcription activation domains (ADs) are inherently disordered proteins that often target multiple coactivator complexes, but the specificity of these interactions is not understood. Efficient transcription activation by yeast Gcn4 requires its tandem ADs and four activator-binding domains (ABDs) on its target, the Mediator subunit Med15. Multiple ABDs are a common feature of coactivator complexes. We find that the large Gcn4-Med15 complex is heterogeneous and contains nearly all possible AD-ABD interactions. Gcn4-Med15 forms via a dynamic fuzzy protein-protein interface, where ADs bind the ABDs in multiple orientations via hydrophobic regions that gain helicity. This combinatorial mechanism allows individual low-affinity and specificity interactions to generate a biologically functional, specific, and higher affinity complex despite lacking a defined protein-protein interface. This binding strategy is likely representative of many activators that target multiple coactivators, as it allows great flexibility in combinations of activators that can cooperate to regulate genes with variable coactivator requirements. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Drug-Induced Rhabdomyolysis with Elevated Cardiac Troponin T

    Directory of Open Access Journals (Sweden)

    Gro Egholm

    2015-01-01

    Full Text Available The essential role of cardiac troponin in the diagnosis of acute myocardial infarction has led to the development of high-sensitivity assays, which are able to detect very small amounts of myocardial necrosis. The high-sensitivity cardiac troponin T assay, however, is not entirely specific for myocardial injury. This case report describes a 48-year-old woman, who, two years after cardiac transplantation, presented with rhabdomyolysis. During the course of the disease, her troponin T level was elevated on repeated occasions, but other definitive evidence of myocardial injury was not found. Asymptomatic cardiac troponin T elevations during rhabdomyolysis may be due to either cardiac involvement or false positive results stemming from skeletal muscle injury.

  12. Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules.

    Directory of Open Access Journals (Sweden)

    Takanobu Nagata

    Full Text Available Myocardial ischemia reperfusion injury (IRI adversely affects cardiac performance and the prognosis of patients with acute myocardial infarction. Although myocardial signal transducer and activator of transcription (STAT 3 is potently cardioprotective during IRI, the inhibitory mechanism responsible for its activation is largely unknown. The present study aimed to investigate the role of the myocardial suppressor of cytokine signaling (SOCS-3, an intrinsic negative feedback regulator of the Janus kinase (JAK-STAT signaling pathway, in the development of myocardial IRI. Myocardial IRI was induced in mice by ligating the left anterior descending coronary artery for 1 h, followed by different reperfusion times. One hour after reperfusion, the rapid expression of JAK-STAT-activating cytokines was observed. We precisely evaluated the phosphorylation of cardioprotective signaling molecules and the expression of SOCS3 during IRI and then induced myocardial IRI in wild-type and cardiac-specific SOCS3 knockout mice (SOCS3-CKO. The activation of STAT3, AKT, and ERK1/2 rapidly peaked and promptly decreased during IRI. This decrease correlated with the induction of SOCS3 expression up to 24 h after IRI in wild-type mice. The infarct size 24 h after reperfusion was significantly reduced in SOCS3-CKO compared with wild-type mice. In SOCS3-CKO mice, STAT3, AKT, and ERK1/2 phosphorylation was sustained, myocardial apoptosis was prevented, and the expression of anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1 was augmented. Cardiac-specific SOCS3 deletion led to the sustained activation of cardioprotective signaling molecules including and prevented myocardial apoptosis and injury during IRI. Our findings suggest that SOCS3 may represent a key factor that exacerbates the development of myocardial IRI.

  13. [Cardiac cachexia].

    Science.gov (United States)

    Miján, Alberto; Martín, Elvira; de Mateo, Beatriz

    2006-05-01

    Chronic heart failure (CHF), especially affecting the right heart, frequently leads to malnutrition. If the latter is severe and is combined to other factors, it may lead to cardiac cachexia. This one is associated to increased mortality and lower survival of patients suffering from it. The causes of cardiac cachexia are diverse, generally associated to maintenance of a negative energy balance, with increasing evidence of its multifactorial origin. Neurohumoral, inflammatory, immunological, and metabolic factors, among others, are superimposed in the patient with CHF, leading to involvement and deterioration of several organs and systems, since this condition affects both lean (or active cellular) mass and adipose and bone tissue osteoporosis. Among all, the most pronounced deterioration may be seen at skeletal muscle tissue, at both structural and functional levels, the heart not being spared. As for treatment, it should be based on available scientific evidence. Assessment of nutritional status of any patient with CHF is a must, with the requirement of nutritional intervention in case of malnutrition. In this situation, especially if accompanied by cardiac cachexia, it is required to modify energy intake and oral diet quality, and to consider the indication of specific complementary or alternative artificial nutrition. Besides, the causal relationship of the beneficial role of moderate physical exertion is increasing, as well as modulation of metabolic and inflammatory impairments observed in cardiac cachexia with several drugs, leading to a favorable functional and structural response in CHF patients.

  14. Cardiac ablation

    Directory of Open Access Journals (Sweden)

    Kelly Ratheal

    2016-01-01

    Full Text Available Cardiac ablation is a procedure that uses either radiofrequency or cryothermal energy to destroy cells in the heart to terminate and/or prevent arrhythmias. The indications for cardiac catheter ablation include refractory, symptomatic arrhythmias, with more specific guidelines for atrial fibrillation in particular. The ablation procedure itself involves mapping the arrhythmia and destruction of the aberrant pathway in an effort to permanently prevent the arrhythmia. There are many types of arrhythmias, and they require individualized approaches to ablation based on their innately different electrical pathways. Ablation of arrhythmias, such as Wolff-Parkinson-White syndrome, AV nodal reentrant tachycardia, and atrial-fibrillation, is discussed in this review. Ablation has a high success rate overall and minimal complication rates, leading to improved quality of life in many patients.

  15. Pathological links between stroke and cardiac arrest

    Institute of Scientific and Technical Information of China (English)

    Shaila Ghanekar; Sydney Corey; Trenton Lippert; Cesar V.Borlongan

    2017-01-01

    There may be a pathological connection between cardiac failure and ischemic stroke.In this article we describe pertinent research that demonstrates subsequent death of cardiac and neural myocytes in the post ischemic stroke brain.Current stroke therapy overlooks the connection between cardiac and cerebrovascular events and fails to address the shared risk factors.Current pre-clinical stroke investigations have provided evidence that suggests the presence of an indirect cell death pathway in which toxic molecules emanate from the stroke brain and trigger cardiac cell death.On the other hand,other studies highlight the presence of a reverse cell death cascade in which toxic molecules from the heart,following cardiac arrest,travel to the brain and induce ischemic cell death.Further examination of these putative cell death pathways between ischemic stroke and cardiac arrest will prompt the advancement of innovative treatments specifically targeting both diseases,leading to ameliorated clinical results of patients diagnosed with heart failure and ischemic stroke.

  16. The definition of exertion-related cardiac events.

    Science.gov (United States)

    Rai, M; Thompson, P D

    2011-02-01

    Vigorous physical activity increases the risk of sudden cardiac death (SCD) and acute myocardial infarction (AMI) but there is no standard definition as to what constitutes an exertion-related cardiac event, specifically the time interval between physical exertion and cardiac event. A systematic review of studies related to exertion-related cardiac events was performed and the time interval between exertion and the event or the symptoms leading to the event was looked for in all the articles selected for inclusion. A total of 12 of 26 articles "suggested" or "defined" exertion-related events as those events whose symptoms started during or within 1 h of exertion. Others used definitions of 0.5 h, 2 h, "during exertion", "during or immediately post exertion" and "during or within several hours after exertion". It is suggested, therefore, that the definition of an exertion-related cardiac event be established as a cardiac event in which symptoms started during or within 1 h of physical exertion.

  17. Specificity of secreted proteomes from cardiac stem cells and neonatal myocytes

    Czech Academy of Sciences Publication Activity Database

    Šťastná, Miroslava; Chimenti, I.; Marban, E.; Van Eyk, J.

    2009-01-01

    Roč. 276, Suppl.1 (2009), s. 346 ISSN 1742-464X. [FEBS Congress /34./. 04.07.2009-09.07.2009, Prague] Institutional research plan: CEZ:AV0Z40310501 Keywords : cardiac stem cells * secreted paracrine/autocrine factors * proteomics Subject RIV: CB - Analytical Chemistry, Separation

  18. Urotensin II promotes vagal-mediated bradycardia by activating cardiac-projecting parasympathetic neurons of nucleus ambiguus.

    Science.gov (United States)

    Brailoiu, Gabriela Cristina; Deliu, Elena; Rabinowitz, Joseph E; Tilley, Douglas G; Koch, Walter J; Brailoiu, Eugen

    2014-05-01

    Urotensin II (U-II) is a cyclic undecapeptide that regulates cardiovascular function at central and peripheral sites. The functional role of U-II nucleus ambiguus, a key site controlling cardiac tone, has not been established, despite the identification of U-II and its receptor at this level. We report here that U-II produces an increase in cytosolic Ca(2+) concentration in retrogradely labeled cardiac vagal neurons of nucleus ambiguus via two pathways: (i) Ca(2+) release from the endoplasmic reticulum via inositol 1,4,5-trisphosphate receptor; and (ii) Ca(2+) influx through P/Q-type Ca(2+) channels. In addition, U-II depolarizes cultured cardiac parasympathetic neurons. Microinjection of increasing concentrations of U-II into nucleus ambiguus elicits dose-dependent bradycardia in conscious rats, indicating the in vivo activation of the cholinergic pathway controlling the heart rate. Both the in vitro and in vivo effects were abolished by the urotensin receptor antagonist, urantide. Our findings suggest that, in addition, to the previously reported increase in sympathetic outflow, U-II activates cardiac vagal neurons of nucleus ambiguus, which may contribute to cardioprotection. © 2014 International Society for Neurochemistry.

  19. Mathematical Models of Cardiac Pacemaking Function

    Science.gov (United States)

    Li, Pan; Lines, Glenn T.; Maleckar, Mary M.; Tveito, Aslak

    2013-10-01

    Over the past half century, there has been intense and fruitful interaction between experimental and computational investigations of cardiac function. This interaction has, for example, led to deep understanding of cardiac excitation-contraction coupling; how it works, as well as how it fails. However, many lines of inquiry remain unresolved, among them the initiation of each heartbeat. The sinoatrial node, a cluster of specialized pacemaking cells in the right atrium of the heart, spontaneously generates an electro-chemical wave that spreads through the atria and through the cardiac conduction system to the ventricles, initiating the contraction of cardiac muscle essential for pumping blood to the body. Despite the fundamental importance of this primary pacemaker, this process is still not fully understood, and ionic mechanisms underlying cardiac pacemaking function are currently under heated debate. Several mathematical models of sinoatrial node cell membrane electrophysiology have been constructed as based on different experimental data sets and hypotheses. As could be expected, these differing models offer diverse predictions about cardiac pacemaking activities. This paper aims to present the current state of debate over the origins of the pacemaking function of the sinoatrial node. Here, we will specifically review the state-of-the-art of cardiac pacemaker modeling, with a special emphasis on current discrepancies, limitations, and future challenges.

  20. The evaluation-mediation hypothesis: does the specification of potential side effects influence the perceived risk of medication?

    International Nuclear Information System (INIS)

    Reimer, T.

    1998-01-01

    Full text of publication follows: starting from the assumptions of support theory, this project analyzed the extent to which the specification of potential side effects influences the perceived risk associated, with a particular medication. Respondents were presented with an instruction leaflet for a medication which indicated (a) the overall probability that a side effect will occur or (b) the probability of occurrence of several specific side effects. Support theory predicts that the cognitive availability of potential side effects and therefore the perceived risk increases as a function of the specificity with which the side effects are presented. In contrast the evaluation-mediation hypothesis predicts that a more detailed presentation of potential side effects enhances the perceived quality of the information leaflet and thereby leads to a reduction of perceived risk. Support for the evaluation-mediation hypothesis was found in a series of studies which included the editing hypothesis and the elaboration likelihood model as additional explanations: the more detailed the information about potential side effects, the lower the estimated risk of suffering a side effect on taking the medication. As predicted, the influence of presentation specificity on perceived risk was mediated almost exclusively by the perceived quality of the information leaflet. A current series of studies seeks to support the evaluation-mediation hypothesis in a completely different domain, the perceived risk of environmental pollution by motor vehicles. (author)

  1. Dark chocolate receptors: epicatechin-induced cardiac protection is dependent on delta-opioid receptor stimulation.

    Science.gov (United States)

    Panneerselvam, Mathivadhani; Tsutsumi, Yasuo M; Bonds, Jacqueline A; Horikawa, Yousuke T; Saldana, Michelle; Dalton, Nancy D; Head, Brian P; Patel, Piyush M; Roth, David M; Patel, Hemal H

    2010-11-01

    Epicatechin, a flavonoid, is a well-known antioxidant linked to a variety of protective effects in both humans and animals. In particular, its role in protection against cardiovascular disease has been demonstrated by epidemiologic studies. Low-dose epicatechin, which does not have significant antioxidant activity, is also protective; however, the mechanism by which low-dose epicatechin induces this effect is unknown. Our laboratory tested the hypothesis that low-dose epicatechin mediates cardiac protection via opioid receptor activation. C57BL/6 mice were randomly assigned to 1 of 10 groups: control, epicatechin, naloxone (nonselective opioid receptor antagonist), epicatechin + naloxone, naltrindole (δ-specific opioid receptor antagonist), epicatechin + naltrindole, norbinaltorphimine (nor-BNI, κ-specific opioid receptor antagonist), epicatechin + nor-BNI, 5-hydroxydecanoic acid [5-HD, ATP-sensitive potassium channel antagonist], and epicatechin + 5-HD. Epicatechin (1 mg/kg) or other inhibitors (5 mg/kg) were administered by oral gavage or intraperitoneal injection, respectively, daily for 10 days. Mice were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion, and infarct size was determined via planimetry. Whole heart homogenates were assayed for downstream opioid receptor signaling targets. Infarct size was significantly reduced in epicatechin- and epicatechin + nor-BNI-treated mice compared with control mice. This protection was blocked by naloxone, naltrindole, and 5-HD. Epicatechin and epicatechin + nor-BNI increased the phosphorylation of Src, Akt, and IκBα, while simultaneously decreasing the expression of c-Jun NH(2)-terminal kinase and caspase-activated DNase. All signaling effects are consistent with opioid receptor stimulation and subsequent cardiac protection. Naloxone, naltrindole, and 5-HD attenuated these effects. In conclusion, epicatechin acts via opioid receptors and more specifically through the δ-opioid receptor to

  2. NUCLEAR IMAGING IN THE DIAGNOSIS OF CARDIAC AMYLOIDOSIS

    Directory of Open Access Journals (Sweden)

    V. B. Sergienko

    2018-01-01

    Full Text Available Histological analysis of endomyocardial tissue is still the gold standard for the diagnosis of cardiac amyloidosis but has its limitations. Accordingly, there is a need for noninvasive techniques to cardiac amyloidosis diagnostics. Echocardiography and magnetic resonance imaging can show characteristics which may not be very specific for cardiac amyloid. Recently, new opportunities of nuclear imaging in risk stratification and assessment of prognosis for patients with cardiac amyloidosis have appeared. During the last two decades different classes of radiopharmaceuticals have been developed based on compounds tropic to the components of amyloid infiltrates. In this paper we describe the current possibilities and perspectives of nuclear medicine techniques in patients with cardiac amyloidosis, including osteotropic and neurotropic scintigraphy, single-photon and positron emission tomography

  3. Cardiac Glycoside Glucoevatromonoside Induces Cancer Type-Specific Cell Death

    Directory of Open Access Journals (Sweden)

    Naira F. Z. Schneider

    2018-03-01

    Full Text Available Cardiac glycosides (CGs are natural compounds used traditionally to treat congestive heart diseases. Recent investigations repositioned CGs as potential anticancer agents. To discover novel cytotoxic CG scaffolds, we selected the cardenolide glucoevatromonoside (GEV out of 46 CGs for its low nanomolar anti-lung cancer activity. GEV presented reduced toxicity toward non-cancerous cell types (lung MRC-5 and PBMC and high-affinity binding to the Na+/K+-ATPase α subunit, assessed by computational docking. GEV-induced cell death was caspase-independent, as investigated by a multiparametric approach, and culminates in severe morphological alterations in A549 cells, monitored by transmission electron microscopy, live cell imaging and flow cytometry. This non-canonical cell death was not preceded or accompanied by exacerbation of autophagy. In the presence of GEV, markers of autophagic flux (e.g. LC3I-II conversion were impacted, even in presence of bafilomycin A1. Cell death induction remained unaffected by calpain, cathepsin, parthanatos, or necroptosis inhibitors. Interestingly, GEV triggered caspase-dependent apoptosis in U937 acute myeloid leukemia cells, witnessing cancer-type specific cell death induction. Differential cell cycle modulation by this CG led to a G2/M arrest, cyclin B1 and p53 downregulation in A549, but not in U937 cells. We further extended the anti-cancer potential of GEV to 3D cell culture using clonogenic and spheroid formation assays and validated our findings in vivo by zebrafish xenografts. Altogether, GEV shows an interesting anticancer profile with the ability to exert cytotoxic effects via induction of different cell death modalities.

  4. Cardiac Delayed Rectifier Potassium Channels in Health and Disease

    Science.gov (United States)

    Chen, Lei; Sampson, Kevin J.; Kass, Robert S.

    2016-01-01

    Cardiac delayed rectifier potassium channels conduct outward potassium currents during the plateau phase of action potentials and play pivotal roles in cardiac repolarization. These include IKs, IKr and the atrial specific IKur channels. In this chapter, we will review the molecular identities and biophysical properties of these channels. Mutations in the genes encoding delayed rectifiers lead to loss- or gain-of-function phenotypes, disrupt normal cardiac repolarization and result in various cardiac rhythm disorders, including congenital Long QT Syndrome, Short QT Syndrome and familial atrial fibrillation. We will also discuss the possibility and prospect of using delayed rectifier channels as therapeutic targets to manage cardiac arrhythmia. PMID:27261823

  5. Cardiac Delayed Rectifier Potassium Channels in Health and Disease.

    Science.gov (United States)

    Chen, Lei; Sampson, Kevin J; Kass, Robert S

    2016-06-01

    Cardiac delayed rectifier potassium channels conduct outward potassium currents during the plateau phase of action potentials and play pivotal roles in cardiac repolarization. These include IKs, IKr and the atrial specific IKur channels. In this article, we will review their molecular identities and biophysical properties. Mutations in the genes encoding delayed rectifiers lead to loss- or gain-of-function phenotypes, disrupt normal cardiac repolarization and result in various cardiac rhythm disorders, including congenital Long QT Syndrome, Short QT Syndrome and familial atrial fibrillation. We will also discuss the prospect of using delayed rectifier channels as therapeutic targets to manage cardiac arrhythmia. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Wnt/β-Catenin Signaling during Cardiac Development and Repair

    Directory of Open Access Journals (Sweden)

    Jan W. Buikema

    2014-05-01

    Full Text Available Active Wnt/β-catenin signaling is essential for proper cardiac specification, progenitor expansion and myocardial growth. During development, the mass of the embryonic heart increases multiple times to achieve the dimensions of adult ventricular chambers. Cell division in the embryonic heart is fairly present, whereas cell turnover in the adult myocardium is extremely low. Understanding of embryonic cardiomyocyte cell-replication, therefore, could improve strategies for cardiac regenerative therapeutics. Here, we review which role Wnt signaling plays in cardiac development and highlight a selection of attempts that have been made to modulate Wnt signaling after cardiac ischemic injury to improve cardiac function and reduce infarct size.

  7. CRISPR/Cas9-loxP-Mediated Gene Editing as a Novel Site-Specific Genetic Manipulation Tool.

    Science.gov (United States)

    Yang, Fayu; Liu, Changbao; Chen, Ding; Tu, Mengjun; Xie, Haihua; Sun, Huihui; Ge, Xianglian; Tang, Lianchao; Li, Jin; Zheng, Jiayong; Song, Zongming; Qu, Jia; Gu, Feng

    2017-06-16

    Cre-loxP, as one of the site-specific genetic manipulation tools, offers a method to study the spatial and temporal regulation of gene expression/inactivation in order to decipher gene function. CRISPR/Cas9-mediated targeted genome engineering technologies are sparking a new revolution in biological research. Whether the traditional site-specific genetic manipulation tool and CRISPR/Cas9 could be combined to create a novel genetic tool for highly specific gene editing is not clear. Here, we successfully generated a CRISPR/Cas9-loxP system to perform gene editing in human cells, providing the proof of principle that these two technologies can be used together for the first time. We also showed that distinct non-homologous end-joining (NHEJ) patterns from CRISPR/Cas9-mediated gene editing of the targeting sequence locates at the level of plasmids (episomal) and chromosomes. Specially, the CRISPR/Cas9-mediated NHEJ pattern in the nuclear genome favors deletions (64%-68% at the human AAVS1 locus versus 4%-28% plasmid DNA). CRISPR/Cas9-loxP, a novel site-specific genetic manipulation tool, offers a platform for the dissection of gene function and molecular insights into DNA-repair pathways. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  8. Ripk3 induces mitochondrial apoptosis via inhibition of FUNDC1 mitophagy in cardiac IR injury

    Directory of Open Access Journals (Sweden)

    Hao Zhou

    2017-10-01

    Full Text Available Ripk3-required necroptosis and mitochondria-mediated apoptosis are the predominant types of cell death that largely account for the development of cardiac ischemia reperfusion injury (IRI. Here, we explored the effect of Ripk3 on mitochondrial apoptosis. Compared with wild-type mice, the infarcted area in Ripk3-deficient (Ripk3-/- mice had a relatively low abundance of apoptotic cells. Moreover, the loss of Ripk3 protected the mitochondria against IRI and inhibited caspase9 apoptotic pathways. These protective effects of Ripk3 deficiency were relied on mitophagy activation. However, inhibition of mitophagy under Ripk3 deficiency enhanced cardiomyocyte and endothelia apoptosis, augmented infarcted area and induced microvascular dysfunction. Furthermore, ischemia activated mitophagy by modifying FUNDC1 dephosphorylation, which substantively engulfed mitochondria debris and cytochrome-c, thus blocking apoptosis signal. However, reperfusion injury elevated the expression of Ripk3 which disrupted FUNDC1 activation and abated mitophagy, increasing the likelihood of apoptosis. In summary, this study confirms the promotive effect of Ripk3 on mitochondria-mediated apoptosis via inhibition of FUNDC1-dependent mitophagy in cardiac IRI. These findings provide new insight into the roles of Ripk3-related necroptosis, mitochondria-mediated apoptosis and FUNDC1-required mitophagy in cardiac IRI.

  9. Cardiac regeneration therapy: connections to cardiac physiology.

    Science.gov (United States)

    Takehara, Naofumi; Matsubara, Hiroaki

    2011-12-01

    Without heart transplantation, a large number of patients with failing hearts worldwide face poor outcomes. By means of cardiomyocyte regeneration, cardiac regeneration therapy is emerging with great promise as a means for restoring loss of cardiac function. However, the limited success of clinical trials using bone marrow-derived cells and myoblasts with heterogeneous constituents, transplanted at a wide range of cell doses, has led to disagreement on the efficacy of cell therapy. It is therefore essential to reevaluate the evidence for the efficacy of cell-based cardiac regeneration therapy, focusing on targets, materials, and methodologies. Meanwhile, the revolutionary innovation of cardiac regeneration therapy is sorely needed to help the millions of people who suffer heart failure from acquired loss of cardiomyocytes. Cardiac regeneration has been used only in limited species or as a developing process in the rodent heart; now, the possibility of cardiomyocyte turnover in the human heart is being revisited. In the pursuit of this concept, the use of cardiac stem/progenitor stem cells in the cardiac niche must be focused to usher in a second era of cardiac regeneration therapy for the severely injured heart. In addition, tissue engineering and cellular reprogramming will advance the next era of treatment that will enable current cell-based therapy to progress to "real" cardiac regeneration therapy. Although many barriers remain, the prevention of refractory heart failure through cardiac regeneration is now becoming a realistic possibility.

  10. Complete cardiac regeneration in a mouse model of myocardial infarction.

    Science.gov (United States)

    Haubner, Bernhard Johannes; Adamowicz-Brice, Martyna; Khadayate, Sanjay; Tiefenthaler, Viktoria; Metzler, Bernhard; Aitman, Tim; Penninger, Josef M

    2012-12-01

    Cardiac remodeling and subsequent heart failure remain critical issues after myocardial infarction despite improved treatment and reperfusion strategies. Recently, complete cardiac regeneration has been demonstrated in fish and newborn mice following resection of the cardiac apex. However, it remained entirely unclear whether the mammalian heart can also completely regenerate following a complex cardiac ischemic injury. We established a protocol to induce a severe heart attack in one-day-old mice using left anterior descending artery (LAD) ligation. LAD ligation triggered substantial cardiac injury in the left ventricle defined by Caspase 3 activation and massive cell death. Ischemia-induced cardiomyocyte death was also visible on day 4 after LAD ligation. Remarkably, 7 days after the initial ischemic insult, we observed complete cardiac regeneration without any signs of tissue damage or scarring. This tissue regeneration translated into long-term normal heart functions as assessed by echocardiography. In contrast, LAD ligations in 7-day-old mice resulted in extensive scarring comparable to adult mice, indicating that the regenerative capacity for complete cardiac healing after heart attacks can be traced to the first week after birth. RNAseq analyses of hearts on day 1, day 3, and day 10 and comparing LAD-ligated and sham-operated mice surprisingly revealed a transcriptional programme of major changes in genes mediating mitosis and cell division between days 1, 3 and 10 postnatally and a very limited set of genes, including genes regulating cell cycle and extracellular matrix synthesis, being differentially regulated in the regenerating hearts. We present for the first time a mammalian model of complete cardiac regeneration following a severe ischemic cardiac injury. This novel model system provides the unique opportunity to uncover molecular and cellular pathways that can induce cardiac regeneration after ischemic injury, findings that one day could be translated

  11. Effect of ultraviolet-B-irradiated donor-specific blood transfusions and peritransplant immunosuppression with cyclosporine on rat cardiac allograft survival

    International Nuclear Information System (INIS)

    Oluwole, S.F.; Lau, H.T.; Reemtsma, K.; Hardy, M.A.

    1988-01-01

    We have previously demonstrated that pretreatment of ACI recipients with ultraviolet-irradiated donor-specific blood transfusion (UV-DST) leads to permanent cardiac allograft survival without further host immunosuppression (ACI rats are weak responders to Lewis lymphocytes in mixed-lymphocyte reaction). This study examines the effect of UV-DST and the timing of transfusions on ACI cardiac allograft survival in Lewis recipients with and without the addition of peritransplant cyclosporine (CsA) (20 mg/kg i.m.) given on days 0, +1, and +2 in relation to the time of transplantation. The mean survival time (MST) of ACI cardiac allografts in Lewis recipients was significantly increased to 33.6 +/- 5.7 days (P less than 0.001) by CsA treatment alone as compared to 6.5 +/- 0.5 days survival in control. When DST was given on day -3 combined with CsA, graft survival was increased to 42.0 +/- 9.3 days (P less than 0.01), as compared to 5.8 +/- 1.3 days when DST alone was used. When DST was irradiated with ultraviolet B (UV-DST) and administered on day -3 combined with peritransplant CsA, the MST was increased to 68.83 +/- 16.1 days as compared to an MST of 10.0 +/- 1.0 days in controls treated with UV-DST alone. When UV-DST was given on day -7 and combined with peritransplant CsA immunosuppression, the results were similar. However, when UV-DST was peritransplant CsA course, 4 of 6 recipients maintained their ACI heart allografts indefinitely (greater than 300 days) in contrast to the effect of UV-DST alone (MST of 13.5 days). Third-party (W/F) UV-irradiated blood transfusions were ineffective in prolonging ACI cardiac allografts in Lewis rats, regardless of whether the transfusions were given alone or in combination with peritransplant immunosuppression with CsA

  12. The Trw type IV secretion system of Bartonella mediates host-specific adhesion to erythrocytes.

    Directory of Open Access Journals (Sweden)

    Muriel Vayssier-Taussat

    2010-06-01

    Full Text Available Bacterial pathogens typically infect only a limited range of hosts; however, the genetic mechanisms governing host-specificity are poorly understood. The alpha-proteobacterial genus Bartonella comprises 21 species that cause host-specific intraerythrocytic bacteremia as hallmark of infection in their respective mammalian reservoirs, including the human-specific pathogens Bartonella quintana and Bartonella bacilliformis that cause trench fever and Oroya fever, respectively. Here, we have identified bacterial factors that mediate host-specific erythrocyte colonization in the mammalian reservoirs. Using mouse-specific Bartonella birtlesii, human-specific Bartonella quintana, cat-specific Bartonella henselae and rat-specific Bartonella tribocorum, we established in vitro adhesion and invasion assays with isolated erythrocytes that fully reproduce the host-specificity of erythrocyte infection as observed in vivo. By signature-tagged mutagenesis of B. birtlesii and mutant selection in a mouse infection model we identified mutants impaired in establishing intraerythrocytic bacteremia. Among 45 abacteremic mutants, five failed to adhere to and invade mouse erythrocytes in vitro. The corresponding genes encode components of the type IV secretion system (T4SS Trw, demonstrating that this virulence factor laterally acquired by the Bartonella lineage is directly involved in adherence to erythrocytes. Strikingly, ectopic expression of Trw of rat-specific B. tribocorum in cat-specific B. henselae or human-specific B. quintana expanded their host range for erythrocyte infection to rat, demonstrating that Trw mediates host-specific erythrocyte infection. A molecular evolutionary analysis of the trw locus further indicated that the variable, surface-located TrwL and TrwJ might represent the T4SS components that determine host-specificity of erythrocyte parasitism. In conclusion, we show that the laterally acquired Trw T4SS diversified in the Bartonella lineage

  13. Cardiac Anxiety - When the heart is (thought to be) in danger-

    NARCIS (Netherlands)

    Beek, M.H.C.T. van

    2016-01-01

    When the heart is (thought to be) in danger - like after a myocardial infarction (MI) or in patients with Non Cardiac Chest Pain (NCCP)- , this may provoke specific fears related to the heart: cardiac anxiety. This anxiety is often not acknowledged nor treated. The present thesis showed that cardiac

  14. GPR30 decreases cardiac chymase/angiotensin II by inhibiting local mast cell number

    International Nuclear Information System (INIS)

    Zhao, Zhuo; Wang, Hao; Lin, Marina; Groban, Leanne

    2015-01-01

    Chronic activation of the novel estrogen receptor GPR30 by its agonist G1 mitigates the adverse effects of estrogen (E2) loss on cardiac structure and function. Using the ovariectomized (OVX) mRen2.Lewis rat, an E2-sensitive model of diastolic dysfunction, we found that E2 status is inversely correlated with local cardiac angiotensin II (Ang II) levels, likely via Ang I/chymase-mediated production. Since chymase is released from cardiac mast cells during stress (e.g., volume/pressure overload, inflammation), we hypothesized that GPR30-related cardioprotection after E2 loss might occur through its opposing actions on cardiac mast cell proliferation and chymase production. Using real-time quantitative PCR, immunohistochemistry, and immunoblot analysis, we found mast cell number, chymase expression, and cardiac Ang II levels were significantly increased in the hearts of OVX-compared to ovary-intact mRen2.Lewis rats and the GPR30 agonist G1 (50 mg/kg/day, s.c.) administered for 2 weeks limited the adverse effects of estrogen loss. In vitro studies revealed that GPR30 receptors are expressed in the RBL-2H3 mast cell line and G1 inhibits serum-induced cell proliferation in a dose-dependent manner, as determined by cell counting, BrdU incorporation assay, and Ki-67 staining. Using specific antagonists to estrogen receptors, blockage of GPR30, but not ERα or ERβ, attenuated the inhibitory effects of estrogen on BrdU incorporation in RBL-2H3 cells. Further study of the mechanism underlying the effect on cell proliferation showed that G1 inhibits cyclin-dependent kinase 1 (CDK1) mRNA and protein expression in RBL-2H3 cells in a dose-dependent manner. - Highlights: • GPR30 activation limits mast cell number in hearts from OVX mRen2.Lewis rats. • GPR30 activation decreases cardiac chymase/angiotensin II after estrogen loss. • GPR30 activation inhibits RBL-2H3 mast cell proliferation and CDK1 expression

  15. GPR30 decreases cardiac chymase/angiotensin II by inhibiting local mast cell number

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Zhuo [Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27159-1009 (United States); Department of Cardiology, Jinan Central Hospital, Affiliated with Shandong University, 105 Jiefang Road, Jinan, 250013 (China); Wang, Hao; Lin, Marina [Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27159-1009 (United States); Groban, Leanne, E-mail: lgroban@wakehealth.edu [Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27159-1009 (United States); Hypertension and Vascular Disease Center, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 (United States); Office of Women in Medicine and Science, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 (United States)

    2015-03-27

    Chronic activation of the novel estrogen receptor GPR30 by its agonist G1 mitigates the adverse effects of estrogen (E2) loss on cardiac structure and function. Using the ovariectomized (OVX) mRen2.Lewis rat, an E2-sensitive model of diastolic dysfunction, we found that E2 status is inversely correlated with local cardiac angiotensin II (Ang II) levels, likely via Ang I/chymase-mediated production. Since chymase is released from cardiac mast cells during stress (e.g., volume/pressure overload, inflammation), we hypothesized that GPR30-related cardioprotection after E2 loss might occur through its opposing actions on cardiac mast cell proliferation and chymase production. Using real-time quantitative PCR, immunohistochemistry, and immunoblot analysis, we found mast cell number, chymase expression, and cardiac Ang II levels were significantly increased in the hearts of OVX-compared to ovary-intact mRen2.Lewis rats and the GPR30 agonist G1 (50 mg/kg/day, s.c.) administered for 2 weeks limited the adverse effects of estrogen loss. In vitro studies revealed that GPR30 receptors are expressed in the RBL-2H3 mast cell line and G1 inhibits serum-induced cell proliferation in a dose-dependent manner, as determined by cell counting, BrdU incorporation assay, and Ki-67 staining. Using specific antagonists to estrogen receptors, blockage of GPR30, but not ERα or ERβ, attenuated the inhibitory effects of estrogen on BrdU incorporation in RBL-2H3 cells. Further study of the mechanism underlying the effect on cell proliferation showed that G1 inhibits cyclin-dependent kinase 1 (CDK1) mRNA and protein expression in RBL-2H3 cells in a dose-dependent manner. - Highlights: • GPR30 activation limits mast cell number in hearts from OVX mRen2.Lewis rats. • GPR30 activation decreases cardiac chymase/angiotensin II after estrogen loss. • GPR30 activation inhibits RBL-2H3 mast cell proliferation and CDK1 expression.

  16. The impact of obesity in the cardiac lipidome and its consequences in the cardiac damage observed in obese rats.

    Science.gov (United States)

    Marín-Royo, Gema; Martínez-Martínez, Ernesto; Gutiérrez, Beatriz; Jurado-López, Raquel; Gallardo, Isabel; Montero, Olimpio; Bartolomé, Mª Visitación; Román, José Alberto San; Salaices, Mercedes; Nieto, María Luisa; Cachofeiro, Victoria

    To explore the impact of obesity on the cardiac lipid profile in rats with diet-induced obesity, as well as to evaluate whether or not the specific changes in lipid species are associated with cardiac fibrosis. Male Wistar rats were fed either a high-fat diet (HFD, 35% fat) or standard diet (3.5% fat) for 6 weeks. Cardiac lipids were analyzed using by liquid chromatography-tandem mass spectrometry. HFD rats showed cardiac fibrosis and enhanced levels of cardiac superoxide anion (O 2 ), HOMA index, adiposity, and plasma leptin, as well as a reduction in those of cardiac glucose transporter (GLUT 4), compared with control animals. Cardiac lipid profile analysis showed a significant increase in triglycerides, especially those enriched with palmitic, stearic, and arachidonic acid. An increase in levels of diacylglycerol (DAG) was also observed. No changes in cardiac levels of diacyl phosphatidylcholine, or even a reduction in total levels of diacyl phosphatidylethanolamine, diacyl phosphatidylinositol, and sphingomyelins (SM) was observed in HFD, as compared with control animals. After adjustment for other variables (oxidative stress, HOMA, cardiac hypertrophy), total levels of DAG were independent predictors of cardiac fibrosis while the levels of total SM were independent predictors of the cardiac levels of GLUT 4. These data suggest that obesity has a significant impact on cardiac lipid composition, although it does not modulate the different species in a similar manner. Nonetheless, these changes are likely to participate in the cardiac damage in the context of obesity, since total DAG levels can facilitate the development of cardiac fibrosis, and SM levels predict GLUT4 levels. Copyright © 2017 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

  17. Virus-specific HLA-restricted lysis of herpes simplex virus-infected human monocytes and macrophages mediated by cytotoxic T lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Torpey, D.J. III

    1987-01-01

    Freshly-isolated peripheral blood human monocytes and 5 day in vitro cultured macrophages were infected with herpes simplex virus type 1 (HSV-1), labeled with /sup 51/Cr, and used as target cells in a 12-14 hour cell-mediated cytotoxicity assay. Mononuclear leukocytes (MNL) from HSV-1 non-immune individuals, whether unstimulated or stimulated with HSV-1 antigen, did not mediate significant lysis of either target cell. HSV-immune MNL, both freshly-isolated and cultured for 5 days without antigen, demonstrated only low levels of natural killer (NK) cell-mediate lysis. MNL from HSV-immune individuals incubated for 5 days in vitro with HSV-1 antigen mediated significant virus-specific lysis of both target cells. Mean virus-specific lysis of autologous monocytes was 8.5(/+-/2.0)% compared to a three-fold greater virus-specific lysis of autologous macrophages. Greater than 70% of this lytic activity was mediated by Leu-11-negative, T3-positive cytotoxic T lymphocytes (CTL). Allogeneic target cells lacking a common HLA determinant were not significantly lysed while T8-positive CTL mediated infrequent lysis of target cells sharing a common HLA-A and/or HLA-B determinant. T4-positive lymphocytes were demonstrated to be the predominant cell mediating lysis of autologous target cells and allogeneic target cells sharing both HLA-A and/or HLA-B plus HLA-DR determinants with the CTL; the T4-positive cell was the sole CTL mediator of lysis of allogeneic target cells having a common HLA-DR determinant.

  18. Virus-specific HLA-restricted lysis of herpes simplex virus-infected human monocytes and macrophages mediated by cytotoxic T lymphocytes

    International Nuclear Information System (INIS)

    Torpey, D.J. III.

    1987-01-01

    Freshly-isolated peripheral blood human monocytes and 5 day in vitro cultured macrophages were infected with herpes simplex virus type 1 (HSV-1), labeled with 51 Cr, and used as target cells in a 12-14 hour cell-mediated cytotoxicity assay. Mononuclear leukocytes (MNL) from HSV-1 non-immune individuals, whether unstimulated or stimulated with HSV-1 antigen, did not mediate significant lysis of either target cell. HSV-immune MNL, both freshly-isolated and cultured for 5 days without antigen, demonstrated only low levels of natural killer (NK) cell-mediate lysis. MNL from HSV-immune individuals incubated for 5 days in vitro with HSV-1 antigen mediated significant virus-specific lysis of both target cells. Mean virus-specific lysis of autologous monocytes was 8.5(/+-/2.0)% compared to a three-fold greater virus-specific lysis of autologous macrophages. Greater than 70% of this lytic activity was mediated by Leu-11-negative, T3-positive cytotoxic T lymphocytes (CTL). Allogeneic target cells lacking a common HLA determinant were not significantly lysed while T8-positive CTL mediated infrequent lysis of target cells sharing a common HLA-A and/or HLA-B determinant. T4-positive lymphocytes were demonstrated to be the predominant cell mediating lysis of autologous target cells and allogeneic target cells sharing both HLA-A and/or HLA-B plus HLA-DR determinants with the CTL; the T4-positive cell was the sole CTL mediator of lysis of allogeneic target cells having a common HLA-DR determinant

  19. Specific expression of bioluminescence reporter gene in cardiomyocyte regulated by tissue specific promoter

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, Vu Hong; Tae, Seong Ho; Le, Nguyen Uyen Chi; Min, Jung Joon [Chonnam National University Medical School, Gwangju (Korea, Republic of)

    2007-07-01

    As the human heart is not capable of regenerating the great numbers of cardiac cells that are lost after myocardial infarction, impaired cardiac function is the inevitable result of ischemic disease. Recently, human embryonic stem cells (hESCs) have gained popularity as a potentially ideal cell candidate for tissue regeneration. In particular, hESCs are capable of cardiac lineage-specific differentiation and confer improvement of cardiac function following transplantation into animal models. Although such data are encouraging, the specific strategy for in vivo and non-invasive detection of differentiated cardiac lineage is still limited. Therefore, in the present study, we established the gene construction in which the optical reporter gene Firefly luciferase was controlled by Myosin Heavy Chain promoter for specific expressing in heart cells. The vector consisting of - MHC promoter and a firefly luciferase coding sequence flanked by full-length bovine growth hormone (BGH) 3'-polyadenylation sequence based on pcDNA3.1- vector backbone. To test the specific transcription of this promoter in g of MHC-Fluc or CMV-Flue (for control) plasmid DNA in myocardial tissue, 20 phosphate-buffered saline was directly injected into mouse myocardium through a midline sternotomy and liver. After 1 week of injection, MHC-Fluc expression was detected from heart region which was observed under cooled CCD camera of in vivo imaging system but not from liver. In control group injected with CMV-Flue, the bioluminescence was detected from all these organs. The expression of Flue under control of Myosin Heavy Chain promoter may become a suitable optical reporter gene for stem cell-derived cardiac lineage differentiation study.

  20. Role of mobile passenger lymphocytes in the rejection of renal and cardiac allografts in the rat. A passenger lymphocyte-mediated graft-versus-host reaction amplifies the host response

    International Nuclear Information System (INIS)

    van Vrieshilfgaarde, R.; Hermans, P.; Terpstra, J.L.; van Breda Viresman, P.J.

    1980-01-01

    It is demonstrated that passenger lymphocytes migrate out of rat renal allografts into host spleens in a radioresistant fashion. These mobile passenger lymphocytes within BN kidney and heart transplants are immunocompetent, since they elicit a graft-versus-host (GVH) reaction in the spleens of (LEW x BN)F2 hybrid hosts. The greater GVH reaction in (LEW x BN)F1 recipients of BN kidneys reflects the greater number of mobile passenger lymphocytes in the kidney when compared to the heart. The mobile passenger lymphocytes within BN renal allografts also cause a proliferative response in the spleens of the LEW hosts as well as an accelerated rejection of BN renal allografts when compared to BN cardiac allografts, for the differences between BN kidney and heart, both in terms of splenomegaly elicited in LEW as well as tempo of rejection, are abolished by total body x-irradiation of the donor with 900 rad. Results indicate that a mobile passenger lymphocyte mediated GVH reaction in the central lymphoid organs of the host augments the host response to allogenic kidneys and contributes materially to first-set renal allograft rejection; this GVH reaction on the other hand is not conspicuously present in LEW recipients of BN cardiac allografts and has therefore little effect on first-set cardiac allograft rejection

  1. Light-sheet fluorescence imaging to localize cardiac lineage and protein distribution

    Science.gov (United States)

    Ding, Yichen; Lee, Juhyun; Ma, Jianguo; Sung, Kevin; Yokota, Tomohiro; Singh, Neha; Dooraghi, Mojdeh; Abiri, Parinaz; Wang, Yibin; Kulkarni, Rajan P.; Nakano, Atsushi; Nguyen, Thao P.; Fei, Peng; Hsiai, Tzung K.

    2017-02-01

    Light-sheet fluorescence microscopy (LSFM) serves to advance developmental research and regenerative medicine. Coupled with the paralleled advances in fluorescence-friendly tissue clearing technique, our cardiac LSFM enables dual-sided illumination to rapidly uncover the architecture of murine hearts over 10 by 10 by 10 mm3 in volume; thereby allowing for localizing progenitor differentiation to the cardiomyocyte lineage and AAV9-mediated expression of exogenous transmembrane potassium channels with high contrast and resolution. Without the steps of stitching image columns, pivoting the light-sheet and sectioning the heart mechanically, we establish a holistic strategy for 3-dimentional reconstruction of the “digital murine heart” to assess aberrant cardiac structures as well as the spatial distribution of the cardiac lineages in neonates and ion-channels in adults.

  2. Cardiac surgery with cardiopulmonary bypass: does aprotinin affect outcome?

    NARCIS (Netherlands)

    van der Linden, P. J.; Hardy, J.-F.; Daper, A.; Trenchant, A.; de Hert, S. G.

    2007-01-01

    BACKGROUND: Aprotinin, a non-specific serine protease inhibitor, has been used for two decades to reduce perioperative blood loss and the risk for allogeneic transfusion in cardiac surgery. This study evaluated the effects of aprotinin on outcome (mortality, cardiac events, renal failure, and

  3. Cardiac Insulin Resistance and MicroRNA Modulators

    Directory of Open Access Journals (Sweden)

    Lakshmi Pulakat

    2012-01-01

    Full Text Available Cardiac insulin resistance is a metabolic and functional disorder that is often associated with obesity and/or the cardiorenal metabolic syndrome (CRS, and this disorder may be accentuated by chronic alcohol consumption. In conditions of over-nutrition, increased insulin (INS and angiotensin II (Ang II activate mammalian target for rapamycin (mTOR/p70 S6 kinase (S6K1 signaling, whereas chronic alcohol consumption inhibits mTOR/S6K1 activation in cardiac tissue. Although excessive activation of mTOR/S6K1 induces cardiac INS resistance via serine phosphorylation of INS receptor substrates (IRS-1/2, it also renders cardioprotection via increased Ang II receptor 2 (AT2R upregulation and adaptive hypertrophy. In the INS-resistant and hyperinsulinemic Zucker obese (ZO rat, a rodent model for CRS, activation of mTOR/S6K1signaling in cardiac tissue is regulated by protective feed-back mechanisms involving mTOR↔AT2R signaling loop and profile changes of microRNA that target S6K1. Such regulation may play a role in attenuating progressive heart failure. Conversely, alcohol-mediated inhibition of mTOR/S6K1, down-regulation of INS receptor and growth-inhibitory mir-200 family, and upregulation of mir-212 that promotes fetal gene program may exacerbate CRS-related cardiomyopathy.

  4. Preoperative cardiac computed tomography for demonstration of congenital cardiac septal defect in adults

    Energy Technology Data Exchange (ETDEWEB)

    Eom, Hye-Joung; Yang, Dong Hyun; Kang, Joon-Won; Lim, Tae-Hwan [University of Ulsan College of Medicine, Department of Radiology and Research Institute of Radiology, Cardiac Imaging Center, Asan Medical Center, Seoul (Korea, Republic of); Kim, Dae-Hee; Song, Jong-Min; Kang, Duk-Hyun; Song, Jae-Kwan [University of Ulsan College of Medicine, Department of Cardiology and Heart Institute, Cardiac Imaging Center, Asan Medical Center, Seoul (Korea, Republic of); Kim, Joon Bum; Jung, Sung-Ho; Choo, Suk Jung; Chung, Cheol Hyun; Lee, Jae Won [University of Ulsan College of Medicine, Department of Cardiothoracic surgery, Cardiac Imaging Center, Asan Medical Center, Seoul (Korea, Republic of)

    2015-06-01

    We aimed to evaluate the role of preoperative cardiac computed tomography (CT) for adults with congenital cardiac septal defect (CSD). Sixty-five consecutive patients who underwent preoperative CT and surgery for CSD were included. The diagnostic accuracy of CT and the concordance rate of the subtype classification of CSD were evaluated using surgical findings as the reference standard. Sixty-five patients without CSD who underwent cardiac valve surgery were used as a control group. An incremental value of CT over echocardiography was described retrospectively. Sensitivity and specificity of CT for diagnosis of CSD were 95 % and 100 %, respectively. The concordance rate of subtype classification was 91 % in CT and 92 % in echocardiography. The maximum size of the defect measured by CT correlated well with surgical measurement (r = 0.82), and the limit of agreement was -0.9 ± 7.42 mm. In comparison with echocardiography, CT was able to detect combined abnormalities in three cases, and exclusively provided correct subtype classification or clarified suspected abnormal findings found on echocardiography in seven cases. Cardiac CT can accurately demonstrates CSD in preoperative adult patients. CT may have an incremental role in preoperative planning, particularly in those with more complex anatomy. (orig.)

  5. Mathematical Models of Cardiac Pacemaking Function

    Directory of Open Access Journals (Sweden)

    Pan eLi

    2013-10-01

    Full Text Available Over the past half century, there has been intense and fruitful interaction between experimental and computational investigations of cardiac function. This interaction has, for example, led to deep understanding of cardiac excitation-contraction coupling; how it works, as well as how it fails. However, many lines of inquiry remain unresolved, among them the initiation of each heartbeat. The sinoatrial node, a cluster of specialized pacemaking cells in the right atrium of the heart, spontaneously generates an electro-chemical wave that spreads through the atria and through the cardiac conduction system to the ventricles, initiating the contraction of cardiac muscle essential for pumping blood to the body. Despite the fundamental importance of this primary pacemaker, this process is still not fully understood, and ionic mechanisms underlying cardiac pacemaking function are currently under heated debate. Several mathematical models of sinoatrial node cell membrane electrophysiology have been constructed as based on different experimental data sets and hypotheses. As could be expected, these differing models offer diverse predictions about cardiac pacemaking activities. This paper aims to present the current state of debate over the origins of the pacemaking function of the sinoatrial node. Here, we will specifically review the state-of-the-art of cardiac pacemaker modeling, with a special emphasis on current discrepancies, limitations, and future challenges.

  6. Effect of Phosphatase and Tensin Homologue on Chromosome 10 on Angiotensin II-Mediated Proliferation, Collagen Synthesis, and Akt/P27 Signaling in Neonatal Rat Cardiac Fibroblasts

    Directory of Open Access Journals (Sweden)

    Ling Nie

    2016-01-01

    Full Text Available Cardiac fibroblasts (CFs play a key role in cardiac fibrosis by regulating the balance between extracellular matrix synthesis and breakdown. Although phosphatase and tensin homologue on chromosome 10 (PTEN has been found to play an important role in cardiovascular disease, it is not clear whether PTEN is involved in functional regulation of CFs. In the present study, PTEN was overexpressed in neonatal rat CFs via recombinant adenovirus-mediated gene transfer. The effects of PTEN overexpression on cell-cycle progression and angiotensin II- (Ang II- mediated regulation of collagen metabolism, synthesis of matrix metalloproteinases, and Akt/P27 signaling were investigated. Compared with uninfected cells and cells infected with green fluorescent protein-expressing adenovirus (Ad-GFP, cells infected with PTEN-expressing adenovirus (Ad-PTEN significantly increased PTEN protein and mRNA levels in CFs (P<0.05. The proportion of CFs in the G1/S cell-cycle phase was significantly higher for PTEN-overexpressing cells. In addition, Ad-PTEN decreased mRNA expression and the protein synthesis rate of collagen types I and III and antagonized Ang II-induced collagen synthesis. Overexpression of PTEN also decreased Ang II-induced matrix metalloproteinase-2 (MMP-2 and tissue inhibitor of metalloproteinase-1 (TIMP-1 production as well as gelatinase activity. Moreover, Ad-PTEN decreased Akt expression and increased P27 expression independent of Ang II stimulation. These results suggest that PTEN could regulate its functional effects in neonatal rat CFs partially via the Akt/P27 signaling pathway.

  7. The articulo-cardiac sympathetic reflex in spinalized, anesthetized rats.

    Science.gov (United States)

    Nakayama, Tomohiro; Suzuki, Atsuko; Ito, Ryuzo

    2006-04-01

    Somatic afferent regulation of heart rate by noxious knee joint stimulation has been proven in anesthetized cats to be a reflex response whose reflex center is in the brain and whose efferent arc is a cardiac sympathetic nerve. In the present study we examined whether articular stimulation could influence heart rate by this efferent sympathetic pathway in spinalized rats. In central nervous system (CNS)-intact rats, noxious articular movement of either the knee or elbow joint resulted in an increase in cardiac sympathetic nerve activity and heart rate. However, although in acutely spinalized rats a noxious movement of the elbow joint resulted in a significant increase in cardiac sympathetic nerve activity and heart rate, a noxious movement of the knee joint had no such effect and resulted in only a marginal increase in heart rate. Because this marginal increase was abolished by adrenalectomy suggests that it was due to the release of adrenal catecholamines. In conclusion, the spinal cord appears to be capable of mediating, by way of cardiac sympathetic nerves, the propriospinally induced reflex increase in heart rate that follows noxious stimulation of the elbow joint, but not the knee joint.

  8. The Role of Oxygen Sensors, Hydroxylases, and HIF in Cardiac Function and Disease

    Directory of Open Access Journals (Sweden)

    W. H. Davin Townley-Tilson

    2015-01-01

    Full Text Available Ischemic heart disease is the leading cause of death worldwide. Oxygen-sensing proteins are critical components of the physiological response to hypoxia and reperfusion injury, but the role of oxygen and oxygen-mediated effects is complex in that they can be cardioprotective or deleterious to the cardiac tissue. Over 200 oxygen-sensing proteins mediate the effects of oxygen tension and use oxygen as a substrate for posttranslational modification of other proteins. Hydroxylases are an essential component of these oxygen-sensing proteins. While a major role of hydroxylases is regulating the transcription factor HIF, we investigate the increasing scope of hydroxylase substrates. This review discusses the importance of oxygen-mediated effects in the heart as well as how the field of oxygen-sensing proteins is expanding, providing a more complete picture into how these enzymes play a multifaceted role in cardiac function and disease. We also review how oxygen-sensing proteins and hydroxylase function could prove to be invaluable in drug design and therapeutic targets for heart disease.

  9. Nitric Oxide Induces Cardiac Protection by Preventing Extracellular Matrix Degradation through the Complex Caveolin-3/EMMPRIN in Cardiac Myocytes.

    Directory of Open Access Journals (Sweden)

    Irene Cuadrado

    Full Text Available Inhibition of Extracellular Matrix degradation by nitric oxide (NO induces cardiac protection against coronary ischemia/reperfusion (IR. Glycosylation of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN stimulates enzymatic activation of matrix metalloproteinases (MMPs in the heart, although the mechanisms leading to EMMPRIN glycosylation are poorly understood. We sought to determine if NO may induce cardiac protection by preventing glycosylation of EMMPRIN in a mouse model of IR. Here we found that Caveolin-3 binds to low glycosylated EMMPRIN (LG-EMMPRIN in cardiac cells and in the hearts of healthy mice, whereas IR disrupted the complex in nitric oxide synthase 2 (NOS2 knockout (KO mice. By contrast, the binding was partially restored when mice were fed with an NO donor (DEA-NO in the drinking water, showing a significant reduction on infarct size (NOS2KO: 34.6±5 vs NOS2KO+DEA-NO: 20.7±9, in expression of matrix metalloproteinases, and cardiac performance was improved (left ventricular ejection fraction (LVEF. NOS2KO: 31±4 vs NOS2KO+DEA-NO: 46±6. The role of Caveolin-3/EMMPRIN in NO-mediated cardiac protection was further assayed in Caveolin-3 KO mice, showing no significant improvement on infarct size (Caveolin-3 KO: 34.8±3 vs Caveolin-3 KO+DEA-NO:33.7±5, or in the expression of MMPs, suggesting that stabilization of the complex Caveolin-3/LG-EMMPRIN may play a significant role in the cardioprotective effect of NO against IR.

  10. Nitric Oxide Induces Cardiac Protection by Preventing Extracellular Matrix Degradation through the Complex Caveolin-3/EMMPRIN in Cardiac Myocytes.

    Science.gov (United States)

    Cuadrado, Irene; Castejon, Borja; Martin, Ana M; Saura, Marta; Reventun-Torralba, Paula; Zamorano, Jose Luis; Zaragoza, Carlos

    2016-01-01

    Inhibition of Extracellular Matrix degradation by nitric oxide (NO) induces cardiac protection against coronary ischemia/reperfusion (IR). Glycosylation of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) stimulates enzymatic activation of matrix metalloproteinases (MMPs) in the heart, although the mechanisms leading to EMMPRIN glycosylation are poorly understood. We sought to determine if NO may induce cardiac protection by preventing glycosylation of EMMPRIN in a mouse model of IR. Here we found that Caveolin-3 binds to low glycosylated EMMPRIN (LG-EMMPRIN) in cardiac cells and in the hearts of healthy mice, whereas IR disrupted the complex in nitric oxide synthase 2 (NOS2) knockout (KO) mice. By contrast, the binding was partially restored when mice were fed with an NO donor (DEA-NO) in the drinking water, showing a significant reduction on infarct size (NOS2KO: 34.6±5 vs NOS2KO+DEA-NO: 20.7±9), in expression of matrix metalloproteinases, and cardiac performance was improved (left ventricular ejection fraction (LVEF). NOS2KO: 31±4 vs NOS2KO+DEA-NO: 46±6). The role of Caveolin-3/EMMPRIN in NO-mediated cardiac protection was further assayed in Caveolin-3 KO mice, showing no significant improvement on infarct size (Caveolin-3 KO: 34.8±3 vs Caveolin-3 KO+DEA-NO:33.7±5), or in the expression of MMPs, suggesting that stabilization of the complex Caveolin-3/LG-EMMPRIN may play a significant role in the cardioprotective effect of NO against IR.

  11. Minocycline attenuates cardiac dysfunction in tumor-burdened mice.

    Science.gov (United States)

    Devine, Raymond D; Eichenseer, Clayton M; Wold, Loren E

    2016-11-01

    Cardiovascular dysfunction as a result of tumor burden is becoming a recognized complication; however, the mechanisms remain unknown. A murine model of cancer cachexia has shown marked increases of matrix metalloproteinases (MMPs), known mediators of cardiac remodeling, in the left ventricle. The extent to which MMPs are involved in remodeling remains obscured. To this end a common antibiotic, minocycline, with MMP inhibitory properties was used to elucidate MMP involvement in tumor induced cardiovascular dysfunction. Tumor-bearing mice showed decreased cardiac function with reduced posterior wall thickness (PWTs) during systole, increased MMP and collagen expression consistent with fibrotic remodeling. Administration of minocycline preserved cardiac function in tumor bearing mice and decreased collagen RNA expression in the left ventricle. MMP protein levels were unaffected by minocycline administration, with the exception of MMP-9, indicating minocycline inhibition mechanisms are directly affecting MMP activity. Cancer induced cardiovascular dysfunction is an increasing concern; novel therapeutics are needed to prevent cardiac complications. Minocycline is a well-known antibiotic and recently has been shown to possess MMP inhibitory properties. Our findings presented here show that minocycline could represent a novel use for a long established drug in the prevention and treatment of cancer induced cardiovascular dysfunction. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Effect of myocardial perfusion and metabolic interventions on cardiac kinetics of phenylpentadecanoic acid (IPPA) I 123

    Energy Technology Data Exchange (ETDEWEB)

    Reske, S.N.; Schoen, S.; Schmitt, W.; Knopp, R.; Winkler, C.; Machulla, H.J.

    1986-08-01

    The effect of regional myocardial perfusion and flow-independent adrenergic stimulation, as well as lactate-mediated inhibition of cardiac lipolysis, on cardiac IPPA uptake and metabolism was examined in canine hearts (flow studies) and in the isolated perfused Langendorff rat heart (metabolic interventions). In both normal and ischaemic myocardium, local perfusion is a major determinant of cardiac IPPA uptake. In pacing-induced hyperaemia, the strict flow-dependence of cardiac IPPA uptake is not preserved. Adrenergic stimulation raises the rate of oxidation of both palmitic acid /sup 14/C and IPPA. This change is reflected by increased metabolite production released into the perfusate and radioactivity clearance recorded externally. Lactate in high concentrations exerts the opposite effect on cardiac free fatty acid oxidation. IPPA is stored in this condition preferentially in tissue phospholipids and triglycerides.

  13. Effect of myocardial perfusion and metabolic interventions on cardiac kinetics of phenylpentadecanoic acid (IPPA) I 123

    International Nuclear Information System (INIS)

    Reske, S.N.; Schoen, S.; Schmitt, W.; Knopp, R.; Winkler, C.; Machulla, H.J.

    1986-01-01

    The effect of regional myocardial perfusion and flow-independent adrenergic stimulation, as well as lactate-mediated inhibition of cardiac lipolysis, on cardiac IPPA uptake and metabolism was examined in canine hearts (flow studies) and in the isolated perfused Langendorff rat heart (metabolic interventions). In both normal and ischaemic myocardium, local perfusion is a major determinant of cardiac IPPA uptake. In pacing-induced hyperaemia, the strict flow-dependence of cardiac IPPA uptake is not preserved. Adrenergic stimulation raises the rate of oxidation of both palmitic acid 14 C and IPPA. This change is reflected by increased metabolite production released into the perfusate and radioactivity clearance recorded externally. Lactate in high concentrations exerts the opposite effect on cardiac free fatty acid oxidation. IPPA is stored in this condition preferentially in tissue phospholipids and triglycerides. (orig.)

  14. Transient gestational and neonatal hypothyroidism-induced specific changes in androgen receptor expression in skeletal and cardiac muscles of adult rat.

    Science.gov (United States)

    Annapoorna, K; Anbalagan, J; Neelamohan, R; Vengatesh, G; Stanley, J; Amudha, G; Aruldhas, M M

    2013-03-01

    The present study aims to identify the association between androgen status and metabolic activity in skeletal and cardiac muscles of adult rats with transient gestational/neonatal-onset hypothyroidism. Pregnant and lactating rats were made hypothyroid by exposing to 0.05% methimazole in drinking water; gestational exposure was from embryonic day 9-14 (group II) or 21 (group III), lactational exposure was from postnatal day 1-14 (group IV) or 29 (group V). Serum was collected for hormone assay. Androgen receptor status, Glu-4 expression, and enzyme activities were assessed in the skeletal and cardiac muscles. Serum testosterone and estradiol levels decreased in adult rats of groups II and III, whereas testosterone remained normal but estradiol increased in group IV and V, when compared to coeval control. Androgen receptor ligand binding activity increased in both muscle phenotypes with a consistent increase in the expression level of its mRNA and protein expressions except in the forelimb of adult rats with transient hypothyroidism (group II-V). Glut-4 expression remained normal in skeletal and cardiac muscle of experimental rats. Specific activity of hexokinase and lactate dehydrogenase increased in both muscle phenotypes whereas, creatine kinase activity increased in skeletal muscles alone. It is concluded that transient gestational/lactational exposure to methimazole results in hypothyroidism during prepuberal life whereas it increases AR status and glycolytic activity in skeletal and cardiac muscles even at adulthood. Thus, the present study suggests that euthyroid status during prenatal and early postnatal life is essential to have optimal AR status and metabolic activity at adulthood. © Georg Thieme Verlag KG Stuttgart · New York.

  15. Cardiac-specific overexpression of catalase prevents diabetes-induced pathological changes by inhibiting NF-κB signaling activation in the heart.

    Science.gov (United States)

    Cong, Weitao; Ruan, Dandan; Xuan, Yuanhu; Niu, Chao; Tao, Youli; Wang, Yang; Zhan, Kungao; Cai, Lu; Jin, Litai; Tan, Yi

    2015-12-01

    Catalase is an antioxidant enzyme that specifically catabolizes hydrogen peroxide (H2O2). Overexpression of catalase via a heart-specific promoter (CAT-TG) was reported to reduce diabetes-induced accumulation of reactive oxygen species (ROS) and further prevent diabetes-induced pathological abnormalities, including cardiac structural derangement and left ventricular abnormity in mice. However, the mechanism by which catalase overexpression protects heart function remains unclear. This study found that activation of a ROS-dependent NF-κB signaling pathway was downregulated in hearts of diabetic mice overexpressing catalase. In addition, catalase overexpression inhibited the significant increase in nitration levels of key enzymes involved in energy metabolism, including α-oxoglutarate dehydrogenase E1 component (α-KGD) and ATP synthase α and β subunits (ATP-α and ATP-β). To assess the effects of the NF-κB pathway activation on heart function, Bay11-7082, an inhibitor of the NF-κB signaling pathway, was injected into diabetic mice, protecting mice against the development of cardiac damage and increased nitrative modifications of key enzymes involved in energy metabolism. In conclusion, these findings demonstrated that catalase protects mouse hearts against diabetic cardiomyopathy, partially by suppressing NF-κB-dependent inflammatory responses and associated protein nitration. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. The new numerology of immunity mediated by virus-specific CD8(+) T cells.

    Science.gov (United States)

    Doherty, P C

    1998-08-01

    Our understanding of virus-specific CD8(+) T cell responses is currently being revolutionized by peptide-based assay systems that allow flow cytometric analysis of effector and memory cytotoxic T lymphocyte populations. These techniques are, for the first time, putting the analysis of T-cell-mediated immunity on a quantitative basis.

  17. Gcn4-Mediator Specificity Is Mediated by a Large and Dynamic Fuzzy Protein-Protein Complex

    Directory of Open Access Journals (Sweden)

    Lisa M. Tuttle

    2018-03-01

    Full Text Available Summary: Transcription activation domains (ADs are inherently disordered proteins that often target multiple coactivator complexes, but the specificity of these interactions is not understood. Efficient transcription activation by yeast Gcn4 requires its tandem ADs and four activator-binding domains (ABDs on its target, the Mediator subunit Med15. Multiple ABDs are a common feature of coactivator complexes. We find that the large Gcn4-Med15 complex is heterogeneous and contains nearly all possible AD-ABD interactions. Gcn4-Med15 forms via a dynamic fuzzy protein-protein interface, where ADs bind the ABDs in multiple orientations via hydrophobic regions that gain helicity. This combinatorial mechanism allows individual low-affinity and specificity interactions to generate a biologically functional, specific, and higher affinity complex despite lacking a defined protein-protein interface. This binding strategy is likely representative of many activators that target multiple coactivators, as it allows great flexibility in combinations of activators that can cooperate to regulate genes with variable coactivator requirements. : Tuttle et al. report a “fuzzy free-for-all” interaction mechanism that explains how seemingly unrelated transcription activators converge on a limited number of coactivator targets. The mechanism provides a rationale for the observation that individually weak and low-specificity interactions can combine to produce biologically critical function without requiring highly ordered structure. Keywords: transcription activation, intrinsically disordered proteins, fuzzy binding

  18. Establishing a clinical cardiac MRI service

    International Nuclear Information System (INIS)

    O'Regan, D.P.; Schmitz, S.A.

    2006-01-01

    After several years of research development cardiovascular MRI has evolved into a widely accepted clinical tool. It offers important diagnostic and prognostic information for a variety of clinical indications, which include ischaemic heart disease, cardiomyopathies, valvular dysfunction and congenital heart disorders. It is a safe non-invasive technique that employs a variety of imaging sequences optimized for temporal or spatial resolution, tissue-specific contrast, flow quantification or angiography. Cardiac MRI offers specific advantages over conventional imaging techniques for a significant number of patients. The demand for cardiac MRI studies from cardiothoracic surgeons, cardiologists and other referrers is likely to continue to rise with pressure for more widespread local service provision. Setting up a cardiac MRI service requires careful consideration regarding funding issues and how it will be integrated with existing service provision. The purchase of cardiac phased array coils, monitoring equipment and software upgrades must also be considered, as well as the training needs of those involved. The choice of appropriate imaging protocols will be guided by operator experience, clinical indication and equipment capability, and is likely to evolve as the service develops. Post-processing and offline analysis form a significant part of the time taken to report studies and an efficient method of providing quantitative reports is an important requirement. Collaboration between radiologists and cardiologists is needed to develop a successful service and multi-disciplinary meetings are key component of this. This review will explore these issues from our perspective of a new clinical cardiac MRI service operating over its first year in a teaching hospital imaging department

  19. FLP recombinase-mediated site-specific recombination in silkworm, Bombyx mori.

    Directory of Open Access Journals (Sweden)

    Ding-Pei Long

    Full Text Available A comprehensive understanding of gene function and the production of site-specific genetically modified mutants are two major goals of genetic engineering in the post-genomic era. Although site-specific recombination systems have been powerful tools for genome manipulation of many organisms, they have not yet been established for use in the manipulation of the silkworm Bombyx mori genome. In this study, we achieved site-specific excision of a target gene at predefined chromosomal sites in the silkworm using a FLP/FRT site-specific recombination system. We first constructed two stable transgenic target silkworm strains that both contain a single copy of the transgene construct comprising a target gene expression cassette flanked by FRT sites. Using pre-blastoderm microinjection of a FLP recombinase helper expression vector, 32 G3 site-specific recombinant transgenic individuals were isolated from five of 143 broods. The average frequency of FLP recombinase-mediated site-specific excision in the two target strains genome was approximately 3.5%. This study shows that it is feasible to achieve site-specific recombination in silkworms using the FLP/FRT system. We conclude that the FLP/FRT system is a useful tool for genome manipulation in the silkworm. Furthermore, this is the first reported use of the FLP/FRT system for the genetic manipulation of a lepidopteran genome and thus provides a useful reference for the establishment of genome manipulation technologies in other lepidopteran species.

  20. Ebola virus glycoprotein-mediated anoikis of primary human cardiac microvascular endothelial cells

    International Nuclear Information System (INIS)

    Ray, Ratna B.; Basu, Arnab; Steele, Robert; Beyene, Aster; McHowat, Jane; Meyer, Keith; Ghosh, Asish K.; Ray, Ranjit

    2004-01-01

    Ebola virus glycoprotein (EGP) has been implicated for the induction of cytotoxicity and injury in vascular cells. On the other hand, EGP has also been suggested to induce massive cell rounding and detachment from the plastic surface by downregulating cell adhesion molecules without causing cytotoxicity. In this study, we have examined the cytotoxic role of EGP in primary endothelial cells by transduction with a replication-deficient recombinant adenovirus expressing EGP (Ad-EGP). Primary human cardiac microvascular endothelial cells (HCMECs) transduced with Ad-EGP displayed loss of cell adhesion from the plastic surface followed by cell death. Transfer of conditioned medium from EGP-transduced HCMEC into naive cells did not induce loss of adhesion or cell death, suggesting that EGP needs to be expressed intracellularly to exert its cytotoxic effect. Subsequent studies suggested that HCMEC death occurred through apoptosis. Results from this study shed light on the EGP-induced anoikis in primary human cardiac endothelial cells, which may have significant pathological consequences

  1. Cardiac complications in diphtheria and predictors of outcomes.

    Science.gov (United States)

    Samdani, Sunil; Jain, Avani; Meena, Vinod; Meena, C B

    2018-01-01

    To study the cardiac complications in diphtheria patients and to study the predictors of outcomes. Single centre prospective analysis of cardiac complications in diphtheria patients. In this study, there were 60 patients diagnosed with diphtheria with ECG changes. The ECG changes seen were sinus tachycardia (68.3%), T wave inversion (20%), ST segment depression (13.3%), right bundle branch block (5%), multiple atrial ectopics (3.3%). The case fatality rate in our study was 25% (15 patients). High CPK-MB, myoglobulin and cardiac troponin levels were associated with cardiac mortality. In our study, cardiac troponin T had the highest sensitivity (80%) and CK-MB had the highest specificity (95.56%). Cardiac involvement is a common complication of infection with C. diphtheria and is associated with high mortality. As diphtheria can be prevented by adequate vaccination, efforts should be maximized for high vaccine coverage with booster doses. Copyright © 2017. Published by Elsevier B.V.

  2. The cardiac patient in Ramadan.

    Science.gov (United States)

    Chamsi-Pasha, Majed; Chamsi-Pasha, Hassan

    2016-01-01

    Ramadan is one of the five fundamental pillars of Islam. During this month, the majority of the 1.6 billion Muslims worldwide observe an absolute fast from dawn to sunset without any drink or food. Our review shows that the impact of fasting during Ramadan on patients with stable cardiac disease is minimal and does not lead to any increase in acute events. Most patients with the stable cardiac disease can fast safely. Most of the drug doses and their regimen are easily manageable during this month and may need not to be changed. Ramadan fasting is a healthy nonpharmacological means for improving cardiovascular risk factors. Most of the Muslims, who suffer from chronic diseases, insist on fasting Ramadan despite being exempted by religion. The Holy Quran specifically exempts the sick from fasting. This is particularly relevant if fasting worsens one's illness or delays recovery. Patients with unstable angina, recent myocardial infarction, uncontrolled hypertension, decompensated heart failure, recent cardiac intervention or cardiac surgery or any debilitating diseases should avoid fasting.

  3. Safe genetic modification of cardiac stem cells using a site-specific integration technique.

    Science.gov (United States)

    Lan, Feng; Liu, Junwei; Narsinh, Kazim H; Hu, Shijun; Han, Leng; Lee, Andrew S; Karow, Marisa; Nguyen, Patricia K; Nag, Divya; Calos, Michele P; Robbins, Robert C; Wu, Joseph C

    2012-09-11

    Human cardiac progenitor cells (hCPCs) are a promising cell source for regenerative repair after myocardial infarction. Exploitation of their full therapeutic potential may require stable genetic modification of the cells ex vivo. Safe genetic engineering of stem cells, using facile methods for site-specific integration of transgenes into known genomic contexts, would significantly enhance the overall safety and efficacy of cellular therapy in a variety of clinical contexts. We used the phiC31 site-specific recombinase to achieve targeted integration of a triple fusion reporter gene into a known chromosomal context in hCPCs and human endothelial cells. Stable expression of the reporter gene from its unique chromosomal integration site resulted in no discernible genomic instability or adverse changes in cell phenotype. Namely, phiC31-modified hCPCs were unchanged in their differentiation propensity, cellular proliferative rate, and global gene expression profile when compared with unaltered control hCPCs. Expression of the triple fusion reporter gene enabled multimodal assessment of cell fate in vitro and in vivo using fluorescence microscopy, bioluminescence imaging, and positron emission tomography. Intramyocardial transplantation of genetically modified hCPCs resulted in significant improvement in myocardial function 2 weeks after cell delivery, as assessed by echocardiography (P=0.002) and MRI (P=0.001). We also demonstrated the feasibility and therapeutic efficacy of genetically modifying differentiated human endothelial cells, which enhanced hind limb perfusion (Pmodification system is a safe, efficient tool to enable site-specific integration of reporter transgenes in progenitor and differentiated cell types.

  4. Mediators of exposure therapy for youth obsessive-compulsive disorder: specificity and temporal sequence of client and treatment factors.

    Science.gov (United States)

    Chu, Brian C; Colognori, Daniela B; Yang, Guang; Xie, Min-ge; Lindsey Bergman, R; Piacentini, John

    2015-05-01

    Behavioral engagement and cognitive coping have been hypothesized to mediate effectiveness of exposure-based therapies. Identifying which specific child factors mediate successful therapy and which therapist factors facilitate change can help make our evidence-based treatments more efficient and robust. The current study examines the specificity and temporal sequence of relations among hypothesized client and therapist mediators in exposure therapy for pediatric Obsessive Compulsive Disorder (OCD). Youth coping (cognitive, behavioral), youth safety behaviors (avoidance, escape, compulsive behaviors), therapist interventions (cognitive, exposure extensiveness), and youth anxiety were rated via observational ratings of therapy sessions of OCD youth (N=43; ages=8 - 17; 62.8% male) who had received Exposure and Response Prevention (ERP). Regression analysis using Generalized Estimation Equations and cross-lagged panel analysis (CLPA) were conducted to model anxiety change within and across sessions, to determine formal mediators of anxiety change, and to establish sequence of effects. Anxiety ratings decreased linearly across exposures within sessions. Youth coping and therapist interventions significantly mediated anxiety change across exposures, and youth-interfering behavior mediated anxiety change at the trend level. In CLPA, youth-interfering behaviors predicted, and were predicted by, changes in anxiety. Youth coping was predicted by prior anxiety change. The study provides a preliminary examination of specificity and temporal sequence among child and therapist behaviors in predicting youth anxiety. Results suggest that therapists should educate clients in the natural rebound effects of anxiety between sessions and should be aware of the negatively reinforcing properties of avoidance during exposure. Copyright © 2015. Published by Elsevier Ltd.

  5. Site-specific recombination in the chicken genome using Flipase recombinase-mediated cassette exchange.

    Science.gov (United States)

    Lee, Hong Jo; Lee, Hyung Chul; Kim, Young Min; Hwang, Young Sun; Park, Young Hyun; Park, Tae Sub; Han, Jae Yong

    2016-02-01

    Targeted genome recombination has been applied in diverse research fields and has a wide range of possible applications. In particular, the discovery of specific loci in the genome that support robust and ubiquitous expression of integrated genes and the development of genome-editing technology have facilitated rapid advances in various scientific areas. In this study, we produced transgenic (TG) chickens that can induce recombinase-mediated gene cassette exchange (RMCE), one of the site-specific recombination technologies, and confirmed RMCE in TG chicken-derived cells. As a result, we established TG chicken lines that have, Flipase (Flp) recognition target (FRT) pairs in the chicken genome, mediated by piggyBac transposition. The transgene integration patterns were diverse in each TG chicken line, and the integration diversity resulted in diverse levels of expression of exogenous genes in each tissue of the TG chickens. In addition, the replaced gene cassette was expressed successfully and maintained by RMCE in the FRT predominant loci of TG chicken-derived cells. These results indicate that targeted genome recombination technology with RMCE could be adaptable to TG chicken models and that the technology would be applicable to specific gene regulation by cis-element insertion and customized expression of functional proteins at predicted levels without epigenetic influence. © FASEB.

  6. A comparison study of Agrobacterium-mediated transformation methods for root-specific promoter analysis in soybean.

    Science.gov (United States)

    Li, Caifeng; Zhang, Haiyan; Wang, Xiurong; Liao, Hong

    2014-11-01

    Both in vitro and in vivo hairy root transformation systems could not replace whole plant transformation for promoter analysis of root-specific and low-P induced genes in soybean. An efficient genetic transformation system is crucial for promoter analysis in plants. Agrobacterium-mediated transformation is the most popular method to produce transgenic hairy roots or plants. In the present study, first, we compared the two different Agrobacterium rhizogenes-mediated hairy root transformation methods using either constitutive CaMV35S or the promoters of root-preferential genes, GmEXPB2 and GmPAP21, in soybean, and found the efficiency of in vitro hairy root transformation was significantly higher than that of in vivo transformation. We compared Agrobacterium rhizogenes-mediated hairy root and Agrobacterium tumefaciens-mediated whole plant transformation systems. The results showed that low-phosphorous (P) inducible GmEXPB2 and GmPAP21 promoters could not induce the increased expression of the GUS reporter gene under low P stress in both in vivo and in vitro transgenic hairy roots. Conversely, GUS activity of GmPAP21 promoter was significantly higher at low P than high P in whole plant transformation. Therefore, both in vitro and in vivo hairy root transformation systems could not replace whole plant transformation for promoter analysis of root-specific and low-P induced genes in soybean.

  7. Halogenated anaesthetics and cardiac protection in cardiac and non-cardiac anaesthesia

    Directory of Open Access Journals (Sweden)

    Landoni Giovanni

    2009-01-01

    Full Text Available Volatile anaesthetic agents have direct protective properties against ischemic myocardial damage. The implementation of these properties during clinical anaesthesia can provide an additional tool in the treatment or prevention, or both, of ischemic cardiac dysfunction in the perioperative period. A recent meta-analysis showed that desflurane and sevoflurane reduce postoperative mortality and incidence of myocardial infarction following cardiac surgery, with significant advantages in terms of postoperative cardiac troponin release, need for inotrope support, time on mechanical ventilation, intensive care unit and overall hospital stay. Multicentre, randomised clinical trials had previously demonstrated that the use of desflurane can reduce the postoperative release of cardiac troponin I, the need for inotropic support, and the number of patients requiring prolonged hospitalisation following coronary artery bypass graft surgery either with and without cardiopulmonary bypass. The American College of Cardiology/American Heart Association Guidelines recommend volatile anaesthetic agents during non-cardiac surgery for the maintenance of general anaesthesia in patients at risk for myocardial infarction. Nonetheless, e vidence in non-coronary surgical settings is contradictory and will be reviewed in this paper together with the mechanisms of cardiac protection by volatile agents.

  8. A specific and sensitive HPLC-MS/MS micromethod for milrinone plasma levels determination after inhalation in cardiac patients.

    Science.gov (United States)

    Gavra, Paul; Nguyen, Anne Q-N; Theoret, Yves; Litalien, Catherine; Denault, André Y; Varin, France

    2014-10-01

    Milrinone administered through inhalation is an emerging method aimed at specifically reducing pulmonary hypertension without affecting systemic pressures. Its administration has been shown to be useful both in patients undergoing cardiac surgery and for persistent pulmonary hypertension of the newborn. These populations are prone to receive many concomitant medications and/or blood sampling may require a low volume quantification method. To address these issues in view of pharmacokinetic studies, this article aims to develop and validate a specific and sensitive analytical assay using high performance liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS) detection for the quantification of milrinone plasma concentrations after inhalation in patients undergoing cardiac surgery. Plasma samples (50 μL) were extracted using ethyl acetate. Milrinone was separated on a C18 analytical column at 50°C. The mobile phase consisted of methanol and 10 mM ammonium acetate (45:55 vol/vol). The electrospray was operated in the negative ionization mode and monitored the following mass transitions: m/z 212.1 → 140.0 at 36 eV for milrinone and m/z 252.1 → 156.1 at 32 eV for olprinone. Calibration curves followed a quadratic regression in the concentration range of 0.3125-640 ng/mL. The lower limit of quantification is 0.3125 ng/mL and is based on a low plasma volume of 50 μL. Mean drug recovery and accuracy were ≥72.3% and 96.0%, respectively. Intraday and interday precision coefficient of variation (%) was ≤7.4% and ≤11.5%, respectively. The specificity allowed milrinone quantification in the multidrug administration conditions of cardiopulmonary bypass. This validated micromethod proved to be highly sensitive and specific while using a low volume of plasma. Its low volume and its lower limit of quantification indicate that this approach is suitable for further characterization of milrinone pharmacokinetics in both adults (inhalation) and neonates.

  9. Promoting safety voice with safety-specific transformational leadership: the mediating role of two dimensions of trust.

    Science.gov (United States)

    Conchie, Stacey M; Taylor, Paul J; Donald, Ian J

    2012-01-01

    Although safety-specific transformational leadership is known to encourage employee safety voice behaviors, less is known about what makes this style of leadership effective. We tested a model that links safety-specific transformational leadership to safety voice through various dimensions of trust. Data from 150 supervisor-employee dyads from the United Kingdom oil industry supported our predictions that the effects of safety-specific transformational leadership are sequentially mediated by affect-based trust beliefs and disclosure trust intentions. Moreover, we found that reliance trust intentions moderated the effect of disclosure: employees' disclosure intentions mediated the effects of affect-based trust on safety voice behaviors only when employees' intention to rely on their leader was moderate to high. These findings suggest that leaders seeking to encourage safety voice behaviors should go beyond "good reason" arguments and develop affective bonds with their employees.

  10. Deficiency of Smad7 enhances cardiac remodeling induced by angiotensin II infusion in a mouse model of hypertension.

    Directory of Open Access Journals (Sweden)

    Li Hua Wei

    Full Text Available Smad7 has been shown to negatively regulate fibrosis and inflammation, but its role in angiotensin II (Ang II-induced hypertensive cardiac remodeling remains unknown. Therefore, the present study investigated the role of Smad7 in hypertensive cardiopathy induced by angiotensin II infusion. Hypertensive cardiac disease was induced in Smad7 gene knockout (KO and wild-type (WT mice by subcutaneous infusion of Ang II (1.46 mg/kg/day for 28 days. Although equal levels of high blood pressure were developed in both Smad7 KO and WT mice, Smad7 KO mice developed more severe cardiac injury as demonstrated by impairing cardiac function including a significant increase in left ventricular (LV mass (P<0.01,reduction of LV ejection fraction(P<0.001 and fractional shortening(P<0.001. Real-time PCR, Western blot and immunohistochemistry detected that deletion of Smad7 significantly enhanced Ang II-induced cardiac fibrosis and inflammation, including upregulation of collagen I, α-SMA, interleukin-1β, TNF-α, and infiltration of CD3(+ T cells and F4/80(+ macrophages. Further studies revealed that enhanced activation of the Sp1-TGFβ/Smad3-NF-κB pathways and downregulation of miR-29 were mechanisms though which deletion of Smad7 promoted Ang II-mediated cardiac remodeling. In conclusions, Smad7 plays a protective role in AngII-mediated cardiac remodeling via mechanisms involving the Sp1-TGF-β/Smad3-NF.κB-miR-29 regulatory network.

  11. Mouse allergen exposure and immunologic responses: IgE-mediated mouse sensitization and mouse specific IgG and IgG4 levels

    NARCIS (Netherlands)

    Matsui, Elizabeth C.; Krop, Esmeralda J. M.; Diette, Gregory B.; Aalberse, Rob C.; Smith, Abigail L.; Eggleston, Peyton A.

    2004-01-01

    Although there is evidence that contact with mice is associated with IgE-mediated mouse sensitization and mouse specific antibody responses, the exposure-response relationships remain unclear. To determine whether IgE-mediated mouse sensitization and mouse specific IgG (mIgG) and mIgG4 levels

  12. Transcription Factors in Heart: Promising Therapeutic Targets in Cardiac Hypertrophy

    OpenAIRE

    Kohli, Shrey; Ahuja, Suchit; Rani, Vibha

    2011-01-01

    Regulation of gene expression is central to cell growth, differentiation and diseases. Context specific and signal dependent regulation of gene expression is achieved to a large part by transcription factors. Cardiac transcription factors regulate heart development and are also involved in stress regulation of the adult heart, which may lead to cardiac hypertrophy. Hypertrophy of cardiac myocytes is an outcome of the imbalance between prohypertrophic factors and anti-hypertrophic factors. Thi...

  13. Cardiac fusion and complex congenital cardiac defects in thoracopagus twins: diagnostic value of cardiac CT

    Energy Technology Data Exchange (ETDEWEB)

    Goo, Hyun Woo [University of Ulsan College of Medicine, Asan Medical Center, Department of Radiology and Research Institute of Radiology, Seoul (Korea, Republic of); Park, Jeong-Jun [University of Ulsan College of Medicine, Asan Medical Center, Department of Pediatric Cardiac Surgery, Seoul (Korea, Republic of); Kim, Ellen Ai-Rhan [University of Ulsan College of Medicine, Asan Medical Center, Division of Neonatology, Department of Pediatrics, Seoul (Korea, Republic of); Won, Hye-Sung [University of Ulsan College of Medicine, Asan Medical Center, Department of Obstetrics and Gynecology, Seoul (Korea, Republic of)

    2014-09-15

    Most thoracopagus twins present with cardiac fusion and associated congenital cardiac defects, and assessment of this anatomy is of critical importance in determining patient care and outcome. Cardiac CT with electrocardiographic triggering provides an accurate and quick morphological assessment of both intracardiac and extracardiac structures in newborns, making it the best imaging modality to assess thoracopagus twins during the neonatal period. In this case report, we highlight the diagnostic value of cardiac CT in thoracopagus twins with an interatrial channel and complex congenital cardiac defects. (orig.)

  14. Stress cardiac magnetic resonance imaging provides effective cardiac risk reclassification in patients with known or suspected stable coronary artery disease.

    Science.gov (United States)

    Shah, Ravi; Heydari, Bobak; Coelho-Filho, Otavio; Murthy, Venkatesh L; Abbasi, Siddique; Feng, Jiazhuo H; Pencina, Michael; Neilan, Tomas G; Meadows, Judith L; Francis, Sanjeev; Blankstein, Ron; Steigner, Michael; di Carli, Marcelo; Jerosch-Herold, Michael; Kwong, Raymond Y

    2013-08-06

    A recent large-scale clinical trial found that an initial invasive strategy does not improve cardiac outcomes beyond optimized medical therapy in patients with stable coronary artery disease. Novel methods to stratify at-risk patients may refine therapeutic decisions to improve outcomes. In a cohort of 815 consecutive patients referred for evaluation of myocardial ischemia, we determined the net reclassification improvement of the risk of cardiac death or nonfatal myocardial infarction (major adverse cardiac events) incremental to clinical risk models, using guideline-based low (3%) annual risk categories. In the whole cohort, inducible ischemia demonstrated a strong association with major adverse cardiac events (hazard ratio=14.66; Pstatistic, 0.81-0.86; P=0.04; adjusted hazard ratio=7.37; PStress cardiac magnetic resonance imaging effectively reclassifies patient risk beyond standard clinical variables, specifically in patients at moderate to high pretest clinical risk and in patients with previous coronary artery disease. http://www.clinicaltrials.gov. Unique identifier: NCT01821924.

  15. Acetylsalicylic acid inhibits IL-18-induced cardiac fibroblast migration through the induction of RECK.

    Science.gov (United States)

    Siddesha, Jalahalli M; Valente, Anthony J; Sakamuri, Siva S V P; Gardner, Jason D; Delafontaine, Patrice; Noda, Makoto; Chandrasekar, Bysani

    2014-07-01

    The pathogenesis of cardiac fibrosis and adverse remodeling is thought to involve the ROS-dependent induction of inflammatory cytokines and matrix metalloproteinases (MMPs), and the activation and migration of cardiac fibroblasts (CF). Here we investigated the role of RECK (reversion-inducing-cysteine-rich protein with Kazal motifs), a unique membrane-anchored MMP regulator, on IL-18-induced CF migration, and the effect of acetylsalicylic acid (ASA) on this response. In a Matrigel invasion assay, IL-18-induced migration of primary mouse CF was dependent on both IKK/NF-κB- and JNK/AP-1-mediated MMP9 induction and Sp1-mediated RECK suppression, mechanisms that required Nox4-dependent H(2)O(2) generation. Notably, forced expression of RECK attenuated IL-18-induced MMP9 activation and CF migration. Further, therapeutic concentrations of ASA inhibited IL-18-induced H(2)O(2) generation, MMP9 activation, RECK suppression, and CF migration. The salicylic acid moiety of ASA similarly attenuated IL-18-induced CF migration. Thus, ASA may exert potential beneficial effect in cardiac fibrosis through multiple protective mechanisms. © 2013 Wiley Periodicals, Inc.

  16. Nonexercise cardiac stress testing

    International Nuclear Information System (INIS)

    Vacek, J.L.; Baldwin, T.

    1989-01-01

    Many patients who require evaluation for coronary artery disease are unable to undergo exercise stress testing because of physiologic or psychological limitations. Drs Vacek and Baldwin describe three alternative methods for assessment of cardiac function in these patients, all of which have high levels of diagnostic sensitivity and specificity. 23 references

  17. Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts.

    Science.gov (United States)

    Lee, Tsung-Ming; Chang, Nen-Chung; Lin, Shinn-Zong

    2017-03-01

    During myocardial infarction, infiltrated macrophages have pivotal roles in cardiac remodeling and delayed M1 toward M2 macrophage phenotype transition is considered one of the major factors for adverse ventricular remodeling. We investigated whether dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, attenuates cardiac fibrosis via regulating macrophage phenotype by a reactive oxygen and nitrogen species (RONS)/STAT3-dependent pathway in postinfarcted rats. Normoglycemic male Wistar rats were subjected to coronary ligation and then randomized to either saline, dapagliflozin (a specific SGLT2 inhibitor), phlorizin (a nonspecific SGLT1/2 inhibitor), dapagliflozin + S3I-201 (a STAT3 inhibitor), or phlorizin + S3I-201 for 4 weeks. There were similar infarct sizes among the infarcted groups at the acute and chronic stages of infarction. At day 3 after infarction, post-infarction was associated with increased levels of superoxide and nitrotyrosine, which can be inhibited by administering either dapagliflozin or phlorizin. SGLT2 inhibitors significantly increased STAT3 activity, STAT3 nuclear translocation, myocardial IL-10 levels and the percentage of M2 macrophage infiltration. At day 28 after infarction, SGLT2 inhibitors were associated with attenuated myofibroblast infiltration and cardiac fibrosis. Although phlorizin decreased myofibroblast infiltration, the effect of dapagliflozin on attenuated myofibroblast infiltration was significantly higher than phlorizin. The effects of SGLT2 inhibitors on cardiac fibrosis were nullified by adding S3I-201. Furthermore, the effects of dapagliflozin on STAT3 activity and myocardial IL-10 levels can be reversed by 3-morpholinosydnonimine, a peroxynitrite generator. Taken together, these observations provide a novel mechanism of SGLT2 inhibitors-mediated M2 polarization through a RONS-dependent STAT3-mediated pathway and selective SGLT2 inhibitors are more effective in attenuating myofibroblast infiltration during

  18. Suppression of Oncolytic Adenovirus-Mediated Hepatotoxicity by Liver-Specific Inhibition of NF-κB

    Directory of Open Access Journals (Sweden)

    Mitsuhiro Machitani

    2017-12-01

    Full Text Available Telomerase-specific replication-competent adenoviruses (Ads, i.e., TRADs, which possess an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, are promising agents for cancer treatment. However, even though oncolytic Ads, including TRAD, are intratumorally administered, they are disseminated from the tumor to systemic circulation, causing concern about oncolytic Ad-mediated hepatotoxicity (due mainly to leaky expression of Ad genes in liver. We reported that inhibition of nuclear factor-κB (NF-κB leads to the suppression of replication-incompetent Ad vector-mediated hepatotoxicity via reduction of the leaky expression of Ad genes in liver. Here, to develop a TRAD with an improved safety profile, we designed a TRAD that carries a liver-specific promoter-driven dominant-negative IκBα (DNIκBα expression cassette (TRAD-DNIκBα. Compared with a conventional TRAD, TRAD-DNIκBα showed hepatocyte-specific inhibition of NF-κB signaling and significantly reduced Ad gene expression and replication in the normal human hepatocyte cell line. TRAD-induced hepatotoxicity was largely suppressed in mice following intravenous administration of TRAD-DNIκBα. However, the replication profiles and oncolytic activities of TRAD-DNIκBα were comparable with those of the conventional TRAD in human non-hepatic tumor cells. These results indicate that oncolytic Ads containing the liver-specific DNIκBα expression cassette have improved safety profiles without inhibiting oncolytic activities.

  19. Substance abuse and criminal thinking: testing the countervailing, mediation, and specificity hypotheses.

    Science.gov (United States)

    Walters, Glenn D

    2012-12-01

    The purpose of this study was to determine (a) which of 2 dimensions of criminal thinking (proactive and/or reactive) correlates with prior substance abuse; (b) whether criminal thinking mediates the relationship between prior substance abuse and recidivism; (c) if a direct relationship exists between specific drugs of abuse and specific criminal thinking styles. First, the reconstructed Proactive (Prc) and Reactive (Rrc) Criminal Thinking scores from the Psychological Inventory of Criminal Thinking Styles (PICTS; Walters, 1995) were correlated with a dichotomous measure of prior substance abuse and a continuous measure of the number of substances abused in a sample of 2877 male federal prisoners (age: M = 34.96, SD = 9.89, range = 18-84; race: 63.6% Black, 17.3% White, 17.6% Hispanic, 1.4% other). The results indicated that only the Rrc score correlated significantly with prior substance abuse when the effect of the alternative measure (Prc in the case of Rrc and Rrc in the case of the Prc) was controlled through partial correlations. Second, reactive criminal thinking was found to mediate the relationship between a history of prior substance abuse and subsequent recidivism in a subsample of 1101 inmates who were released from prison during a 1- to 76-month follow-up. Third, both specific (alcohol with cutoff; marijuana with cognitive indolence) and global (heroin, cocaine, and amphetamine with cutoff, cognitive indolence, and discontinuity) drug-criminal thinking correlations were obtained. These results suggest that reactive criminal thinking plays a potentially important role in the drug-crime relationship.

  20. Quantitative phosphoproteomics using acetone-based peptide labeling: Method evaluation and application to a cardiac ischemia/reperfusion model

    Science.gov (United States)

    Wijeratne, Aruna B.; Manning, Janet R.; Schultz, Jo El J.; Greis, Kenneth D.

    2013-01-01

    Mass spectrometry (MS) techniques to globally profile protein phosphorylation in cellular systems that are relevant to physiological or pathological changes have been of significant interest in biological research. In this report, an MS-based strategy utilizing an inexpensive acetone-based peptide labeling technique known as reductive alkylation by acetone (RABA) for quantitative phosphoproteomics was explored to evaluate its capacity. Since the chemistry for RABA-labeling for phosphorylation profiling had not been previously reported, it was first validated using a standard phosphoprotein and identical phosphoproteomes from cardiac tissue extracts. A workflow was then utilized to compare cardiac tissue phosphoproteomes from mouse hearts not expressing FGF2 vs. hearts expressing low molecular weight fibroblast growth factor-2 (LMW FGF2) to relate low molecular weight fibroblast growth factor-2 (LMW FGF2) mediated cardioprotective phenomena induced by ischemia/reperfusion (I/R) injury of hearts, with downstream phosphorylation changes in LMW FGF2 signaling cascades. Statistically significant phosphorylation changes were identified at 14 different sites on 10 distinct proteins including some with mechanisms already established for LMW FGF2-mediated cardioprotective signaling (e.g. connexin-43), some with new details linking LMW FGF2 to the cardioprotective mechanisms (e.g. cardiac myosin binding protein C or cMyBPC), and also several new downstream effectors not previously recognized for cardio-protective signaling by LMW FGF2. Additionally, one of the phosphopeptides, cMyBPC/pSer-282, identified was further verified with site-specific quantification using an SRM (selected reaction monitoring)-based approach that also relies on isotope labeling of a synthetic phosphopeptide with deuterated acetone as an internal standard. Overall, this study confirms that the inexpensive acetone-based peptide labeling can be used in both exploratory and targeted quantification

  1. The effect of timing and graft dysfunction on survival and cardiac allograft vasculopathy in antibody-mediated rejection.

    Science.gov (United States)

    Clerkin, Kevin J; Restaino, Susan W; Zorn, Emmanuel; Vasilescu, Elena R; Marboe, Charles C; Mancini, Donna M

    2016-09-01

    Antibody-mediated rejection (AMR) has been associated with increased death and cardiac allograft vasculopathy (CAV). Early studies suggested that late AMR was rarely associated with graft dysfunction, whereas recent reports have demonstrated an association with increased mortality. We investigated the timing of AMR and its association with graft dysfunction, death, and CAV. This retrospective cohort study identified all adult orthotopic heart transplant (OHT) recipients (N = 689) at Columbia University Medical Center from 2004 to 2013. There were 68 primary cases of AMR, which were stratified by early ( 1 year post-OHT) AMR. Kaplan-Meier survival analysis and modeling was performed with multivariable logistic regression and Cox proportional hazards regression. From January 1, 2004, through October 1, 2015, early AMR (median 23 days post-OHT) occurred in 43 patients and late AMR (median 1,084 days post-OHT) occurred in 25. Graft dysfunction was less common with early compared with late AMR (25.6% vs 56%, p = 0.01). Patients with late AMR had decreased post-AMR survival compared with early AMR (1 year: 80% vs 93%, 5 years: 51% vs 73%, p < 0.05). When stratified by graft dysfunction, only those with late AMR and graft dysfunction had worse survival (30 days: 79%, 1 year: 64%, 5 years: 36%; p < 0.006). The association remained irrespective of age, sex, donor-specific antibodies, left ventricular assist device use, reason for OHT, and recovery of graft function. Similarly, those with late AMR and graft dysfunction had accelerated development of de novo CAV (50% at 1 year; hazard ratio, 5.42; p = 0.009), whereas all other groups were all similar to the general transplant population. Late AMR is frequently associated with graft dysfunction. When graft dysfunction is present in late AMR, there is an early and sustained increased risk of death and rapid development of de novo CAV despite aggressive treatment. Copyright © 2016 International Society for Heart and Lung

  2. Antibody-Mediated Rejection of the Heart in the Setting of Autoimmune Demyelinating Polyneuropathy: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Kathryn J. Lindley

    2012-01-01

    Full Text Available Background. Antibody-mediated rejection (AMR is caused by the production of donor-specific antibodies (DSA which lead to allograft injury in part via complement activation. The inflammatory demyelinating polyneuropathies (IDP are inflammatory disorders of the nervous system, involving both cellular and humoral immune mechanisms directed against myelin. Case Report. A 58-year-old man five years after heart transplant presented with progressive dyspnea, imbalance, dysphagia, and weakness. Nerve conduction studies and electromyogram were consistent with IDP. Plasmapheresis and high-dose steroids resulted in improvement in neurologic symptoms. Within two weeks, he was readmitted with anasarca and acute renal failure, requiring intravenous furosemide and inotropic support. Echocardiogram and right heart catheterization revealed reduced cardiac function and elevated filling pressures. DSA was positive against HLA DR53, and endomyocardial biopsy revealed grade 1R chronic inflammation, with strong capillary endothelial immunostaining for C4d. Plasmapheresis and intravenous immunoglobulin (IVIG were initiated. His anasarca and renal failure subsequently resolved, echocardiogram showed improved function off inotropes, and anti-DR53 MFI was reduced by 57%. Conclusions. This is an example of a single immune-mediated process causing concurrent IDP and AMR. The improvement in cardiac function and neurologic symptoms with plasmapheresis, IVIG, and high-dose steroids argues for a unifying antibody-mediated mechanism.

  3. Cardiac ankyrin repeat protein attenuates cardiac hypertrophy by inhibition of ERK1/2 and TGF-β signaling pathways.

    Directory of Open Access Journals (Sweden)

    Yao Song

    Full Text Available AIMS: It has been reported that cardiac ankyrin repeat protein is associated with heart development and diseases. This study is aimed to investigate the role of CARP in heart hypertrophy in vivo. METHODS AND RESULTS: We generated a cardiac-specific CARP-overexpressing transgenic mouse. Although such animals did not display any overt physiological abnormality, they developed less cardiac hypertrophy in response to pressure overload than did wildtype mice, as indicated by heart weight/body weight ratios, echocardiographic and histological analyses, and expression of hypertrophic markers. These mice also exhibited less cardiac hypertrophy after infusion of isoproterenol. To gain a molecular insight into how CARP attenuated heart hypertrophy, we examined expression of the mitogen-activated protein kinase cascade and found that the concentrations of phosphorylated ERK1/2 and MEK were markedly reduced in the hearts of transgenic mice subjected to pressure overload. In addition, the expressions of TGF-β and phosphorylated Smad3 were significantly downregulated in the hearts of CARP Tg mice in response to pressure overload. Furthermore, addition of human TGF-β1 could reverse the inhibitory effect of CARP on the hypertrophic response induced by phenylephrine in cardiomyocytes. It was also evidenced that the inhibitory effect of CARP on cardiac hypertrophy was not attributed to apoptosis. CONCLUSION: CARP attenuates cardiac hypertrophy, in which the ERK and TGF-β pathways may be involved. Our findings highlight the significance of CARP as an anti-hypertrophic factor in therapy of cardiac hypertrophy.

  4. DIAGNOSTIC EFFICACY OF CARDIAC TROPONIN-T IN ACUTE MYOCARDIAL INFARCTION PATIENTS ADMITTED IN INTENSIVE CARDIAC CARE UNIT

    Directory of Open Access Journals (Sweden)

    Tapan

    2016-03-01

    Full Text Available INTRODUCTION Myocardial infarction is a common and severe manifestation of ischaemic heart disease (IHD. Acute myocardial infarction (AMI is the result of death of heart muscle cells following either from a prolonged or severe ischaemia. The World Health Organisation emphasises IHD as our "Modern Epidemic" and AMI as common cause of sudden death. AIM The present study has been undertaken with the aim to assess the role of cardiac Troponin-T in early diagnosis of AMI and to evaluate its positive roles over CK-MB and LDH enzyme assays. The study also aims to find out the role of cardiac Troponin-T test, where ECG changes are nondiagnostic and inconclusive for AMI. MATERIAL & METHOD One hundred cases of provisionally diagnosed AMI, who were admitted during June 2012 to July 2015 in ICC Unit of TMC & Dr. BRAM Teaching Hospital, formed the subjects for the study. Those patients reported 2 to 10 hours after onset of chest pain were included in this study. Patients reported beyond 10 hours after onset of chest pain of AMI cases and patients having chest pain of non-AMI causes are excluded from the study. The provisional diagnosis of AMI was done on the basis of the history, chest pain, clinical findings and ECG changes. Trop-T test (Troponin-T sensitive rapid test by Muller Bardoff, et al, 1991 as well as CK-MB (creatine kinase-MB isoenzymeassays were performed immediately for each and every patient. Trop-T test was repeated in some selective cases where the early changes were insignificant and the results were compared with those of CK-MB, at different period of the disease onset. RESULTS The rapid cardiac Troponin-T test (CTn-T has 100% specificity for AMI whereas CK-MB and LDH have specificities of 80% and 60% respectively. The CTn-T has diagnostic efficiency of 92% for AMI but ECG has only 69% sensitivity and 80% specificity. The overall diagnostic efficacy of cardiac Troponin-T is higher than that of CK-MB, LDH and ECG (94% versus 92%, 91 % and 72

  5. Life satisfaction in middle-aged Koreans: mediating effects of domain-specific self-esteem satisfaction, and sex differences.

    Science.gov (United States)

    Park, Hyun-Joo; Lee, Dong-Gwi; Yang, Nan Mee

    2014-08-01

    The current study was an attempt to examine the interplay between domain-specific self-esteem and life satisfaction with middle-aged Koreans. For four domains (Social/Objective Ability, Positive Characteristics, Interpersonal Relationships, and Family), the mediating effects of the satisfaction index of domain-specific self-esteem between the importance index of domain-specific self-esteem and life satisfaction were tested using structural equation modeling. 364 Koreans in their 40s and 50s were recruited through stratified sampling. Overall, the satisfaction index of domain-specific self-esteem was found to be a strong mediator across all the four domains; for middle-aged Koreans, if they appraised their self-esteem in a given domain as important and they felt satisfied in that domain, their life satisfaction was likely to be higher. Additionally, results of multi-group analysis suggested that the strengths of associations in the model were different between men and women in the Interpersonal Relationships domain.

  6. Acquired valvar disease and cardiac tumours

    International Nuclear Information System (INIS)

    Ruttley, M.

    1985-01-01

    Investigation must determine the severity of the valve fault or faults, the effect on cardiac function and the significance of any associated cardiac disease in order that surgical referral can be made when appropriate with knowledge of operative risk and prognosis; radiology plays an important part in this. Radiological features will depend on the valve or valves affected, the type and severity of the haemodynamic disturbance and its time scale of development and duration. They may be modified by embolism or infection and there may be specific radiological manifestations of the underlying disease

  7. Sarcospan Regulates Cardiac Isoproterenol Response and Prevents Duchenne Muscular Dystrophy-Associated Cardiomyopathy.

    Science.gov (United States)

    Parvatiyar, Michelle S; Marshall, Jamie L; Nguyen, Reginald T; Jordan, Maria C; Richardson, Vanitra A; Roos, Kenneth P; Crosbie-Watson, Rachelle H

    2015-12-23

    Duchenne muscular dystrophy is a fatal cardiac and skeletal muscle disease resulting from mutations in the dystrophin gene. We have previously demonstrated that a dystrophin-associated protein, sarcospan (SSPN), ameliorated Duchenne muscular dystrophy skeletal muscle degeneration by activating compensatory pathways that regulate muscle cell adhesion (laminin-binding) to the extracellular matrix. Conversely, loss of SSPN destabilized skeletal muscle adhesion, hampered muscle regeneration, and reduced force properties. Given the importance of SSPN to skeletal muscle, we investigated the consequences of SSPN ablation in cardiac muscle and determined whether overexpression of SSPN into mdx mice ameliorates cardiac disease symptoms associated with Duchenne muscular dystrophy cardiomyopathy. SSPN-null mice exhibited cardiac enlargement, exacerbated cardiomyocyte hypertrophy, and increased fibrosis in response to β-adrenergic challenge (isoproterenol; 0.8 mg/day per 2 weeks). Biochemical analysis of SSPN-null cardiac muscle revealed reduced sarcolemma localization of many proteins with a known role in cardiomyopathy pathogenesis: dystrophin, the sarcoglycans (α-, δ-, and γ-subunits), and β1D integrin. Transgenic overexpression of SSPN in Duchenne muscular dystrophy mice (mdx(TG)) improved cardiomyofiber cell adhesion, sarcolemma integrity, cardiac functional parameters, as well as increased expression of compensatory transmembrane proteins that mediate attachment to the extracellular matrix. SSPN regulates sarcolemmal expression of laminin-binding complexes that are critical to cardiac muscle function and protects against transient and chronic injury, including inherited cardiomyopathy. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  8. Cardiac-Restricted IGF-1Ea Overexpression Reduces the Early Accumulation of Inflammatory Myeloid Cells and Mediates Expression of Extracellular Matrix Remodelling Genes after Myocardial Infarction

    Directory of Open Access Journals (Sweden)

    Enrique Gallego-Colon

    2015-01-01

    Full Text Available Strategies to limit damage and improve repair after myocardial infarct remain a major therapeutic goal in cardiology. Our previous studies have shown that constitutive expression of a locally acting insulin-like growth factor-1 Ea (IGF-1Ea propeptide promotes functional restoration after cardiac injury associated with decreased scar formation. In the current study, we investigated the underlying molecular and cellular mechanisms behind the enhanced functional recovery. We observed improved cardiac function in mice overexpressing cardiac-specific IGF-1Ea as early as day 7 after myocardial infarction. Analysis of gene transcription revealed that supplemental IGF-1Ea regulated expression of key metalloproteinases (MMP-2 and MMP-9, their inhibitors (TIMP-1 and TIMP-2, and collagen types (Col 1α1 and Col 1α3 in the first week after injury. Infiltration of inflammatory cells, which direct the remodelling process, was also altered; in particular there was a notable reduction in inflammatory Ly6C+ monocytes at day 3 and an increase in anti-inflammatory CD206+ macrophages at day 7. Taken together, these results indicate that the IGF-1Ea transgene shifts the balance of innate immune cell populations early after infarction, favouring a reduction in inflammatory myeloid cells. This correlates with reduced extracellular matrix remodelling and changes in collagen composition that may confer enhanced scar elasticity and improved cardiac function.

  9. Toll-Like Receptor 9 Promotes Cardiac Inflammation and Heart Failure during Polymicrobial Sepsis

    Directory of Open Access Journals (Sweden)

    Ralph Lohner

    2013-01-01

    Full Text Available Background. Aim was to elucidate the role of toll-like receptor 9 (TLR9 in cardiac inflammation and septic heart failure in a murine model of polymicrobial sepsis. Methods. Sepsis was induced via colon ascendens stent peritonitis (CASP in C57BL/6 wild-type (WT and TLR9-deficient (TLR9-D mice. Bacterial load in the peritoneal cavity and cardiac expression of inflammatory mediators were determined at 6, 12, 18, 24, and 36 h. Eighteen hours after CASP cardiac function was monitored in vivo. Sarcomere length of isolated cardiomyocytes was measured at 0.5 to 10 Hz after incubation with heat-inactivated bacteria. Results. CASP led to continuous release of bacteria into the peritoneal cavity, an increase of cytokines, and differential regulation of receptors of innate immunity in the heart. Eighteen hours after CASP WT mice developed septic heart failure characterised by reduction of end-systolic pressure, stroke volume, cardiac output, and parameters of contractility. This coincided with reduced cardiomyocyte sarcomere shortening. TLR9 deficiency resulted in significant reduction of cardiac inflammation and a sustained heart function. This was consistent with reduced mortality in TLR9-D compared to WT mice. Conclusions. In polymicrobial sepsis TLR9 signalling is pivotal to cardiac inflammation and septic heart failure.

  10. IGF-1 protects cardiac myocytes from hyperosmotic stress-induced apoptosis via CREB

    International Nuclear Information System (INIS)

    Maldonado, Carola; Cea, Paola; Adasme, Tatiana; Collao, Andres; Diaz-Araya, Guillermo; Chiong, Mario; Lavandero, Sergio

    2005-01-01

    Hyperosmotic stress stimulates a rapid and pronounced apoptosis in cardiac myocytes which is attenuated by insulin-like growth factor-1 (IGF-1). Because in these cells IGF-1 induces intracellular Ca 2+ increase, we assessed whether the cyclic AMP response element-binding protein (CREB) is activated by IGF-1 through Ca 2+ -dependent signalling pathways. In cultured cardiac myocytes, IGF-1 induced phosphorylation (6.5 ± 1.0-fold at 5 min), nuclear translocation (30 min post-stimulus) and DNA binding activity of CREB. IGF-1-induced CREB phosphorylation was mediated by MEK1/ERK, PI3-K, p38-MAPK, as well as Ca 2+ /calmodulin kinase and calcineurin. Exposure of cardiac myocytes to hyperosmotic stress (sorbitol 600 mOsm) decreased IGF-1-induced CREB activation Moreover, overexpression of a dominant negative CREB abolished the anti-apoptotic effects of IGF-1. Our results suggest that IGF-1 activates CREB through a complex signalling pathway, and this transcription factor plays an important role in the anti-apoptotic action of IGF-1 in cultured cardiac myocytes

  11. Sudden Cardiac Arrest during Participation in Competitive Sports.

    Science.gov (United States)

    Landry, Cameron H; Allan, Katherine S; Connelly, Kim A; Cunningham, Kris; Morrison, Laurie J; Dorian, Paul

    2017-11-16

    The incidence of sudden cardiac arrest during participation in sports activities remains unknown. Preparticipation screening programs aimed at preventing sudden cardiac arrest during sports activities are thought to be able to identify at-risk athletes; however, the efficacy of these programs remains controversial. We sought to identify all sudden cardiac arrests that occurred during participation in sports activities within a specific region of Canada and to determine their causes. In this retrospective study, we used the Rescu Epistry cardiac arrest database (which contains records of every cardiac arrest attended by paramedics in the network region) to identify all out-of-hospital cardiac arrests that occurred from 2009 through 2014 in persons 12 to 45 years of age during participation in a sport. Cases were adjudicated as sudden cardiac arrest (i.e., having a cardiac cause) or as an event resulting from a noncardiac cause, on the basis of records from multiple sources, including ambulance call reports, autopsy reports, in-hospital data, and records of direct interviews with patients or family members. Over the course of 18.5 million person-years of observation, 74 sudden cardiac arrests occurred during participation in a sport; of these, 16 occurred during competitive sports and 58 occurred during noncompetitive sports. The incidence of sudden cardiac arrest during competitive sports was 0.76 cases per 100,000 athlete-years, with 43.8% of the athletes surviving until they were discharged from the hospital. Among the competitive athletes, two deaths were attributed to hypertrophic cardiomyopathy and none to arrhythmogenic right ventricular cardiomyopathy. Three cases of sudden cardiac arrest that occurred during participation in competitive sports were determined to have been potentially identifiable if the athletes had undergone preparticipation screening. In our study involving persons who had out-of-hospital cardiac arrest, the incidence of sudden cardiac

  12. Vitamin D attenuates pressure overload-induced cardiac remodeling and dysfunction in mice.

    Science.gov (United States)

    Zhang, Liang; Yan, Xiao; Zhang, Yun-Long; Bai, Jie; Hidru, Tesfaldet Habtemariam; Wang, Qing-Shan; Li, Hui-Hua

    2018-04-01

    Vitamin D (VD) and its analogues play critical roles in metabolic and cardiovascular diseases. Recent studies have demonstrated that VD exerts a protective role in cardiovascular diseases. However, the beneficial effect of VD on pressure overload-induced cardiac remodeling and dysfunction and its underlying mechanisms are not fully elucidated. In this study, cardiac dysfunction and hypertrophic remodeling in mice were induced by pressure overload. Cardiac function was evaluated by echocardiography, and myocardial histology was detected by H&E and Masson's trichrome staining. Cardiomyocyte size was detected by wheat germ agglutinin staining. The protein levels of signaling mediators were examined by western blotting while mRNA expression of hypertrophic and fibrotic markers was examined by qPCR analysis. Oxidative stress was detected by dihydroethidine staining. Our results showed that administration of VD3 significantly ameliorates pressure overload-induced contractile dysfunction, cardiac hypertrophy, fibrosis and inflammation in mice. In addition, VD3 treatment also markedly inhibited cardiac oxidative stress and apoptosis. Moreover, protein levels of calcineurin A, ERK1/2, AKT, TGF-β, GRP78, cATF6, and CHOP were significantly reduced whereas SERCA2 level was upregulated in the VD3-treated hearts compared with control. These results suggest that VD3 attenuates cardiac remodeling and dysfunction induced by pressure overload, and this protective effect is associated with inhibition of multiple signaling pathways. Copyright © 2018 Elsevier Ltd. All rights reserved.

  13. Cardiac allograft immune activation: current perspectives

    Directory of Open Access Journals (Sweden)

    Chang D

    2014-12-01

    Full Text Available David Chang, Jon Kobashigawa Cedars-Sinai Heart Institute, Los Angeles, CA, USA Abstract: Heart transplant remains the most durable option for end-stage heart disease. Cardiac allograft immune activation and heart transplant rejection remain among the main complications limiting graft and recipient survival. Mediators of the immune system can cause different forms of rejection post-heart transplant. Types of heart transplant rejection include hyperacute rejection, cellular rejection, antibody-mediated rejection, and chronic rejection. In this review, we will summarize the innate and adaptive immune responses which influence the post-heart transplant recipient. Different forms of rejection and their clinical presentation, detection, and immune monitoring will be discussed. Treatment of heart transplant rejection will be examined. We will discuss potential treatment strategies for preventing rejection post-transplant in immunologically high-risk patients with antibody sensitization. Keywords: heart transplant, innate immunity, adaptive immunity, rejection, immunosuppression

  14. Sirolimus use and incidence of venous thromboembolism in cardiac transplant recipients.

    Science.gov (United States)

    Thibodeau, Jennifer T; Mishkin, Joseph D; Patel, Parag C; Kaiser, Patricia A; Ayers, Colby R; Mammen, Pradeep P A; Markham, David W; Ring, W Steves; Peltz, Matthias; Drazner, Mark H

    2012-01-01

    Sirolimus is an immunosuppressive agent increasingly used in cardiac transplant recipients in the setting of allograft vasculopathy or worsening renal function. Recently, sirolimus has been associated with increased risk of venous thromboembolism (VTE) in lung transplant recipients. To investigate whether this association is also present in cardiac transplant recipients, we retrospectively reviewed the charts of 67 cardiac transplant recipients whose immunosuppressive regimen included sirolimus and 134 matched cardiac transplant recipients whose regimen did not include sirolimus. Rates of VTE were compared. Multivariable Cox proportional hazards models tested the association of sirolimus use with VTE. A higher incidence of VTE was seen in patients treated with vs. without sirolimus (8/67 [12%] vs. 9/134 [7%], log-rank statistic: 4.66, p=0.03). Lower body mass index (BMI) and total cholesterol levels were also associated with VTE (p<0.05). The association of sirolimus with VTE persisted when adjusting for BMI (hazard ratio [95% confidence interval]: 2.96 [1.13, 7.75], p=0.03) but not when adjusting for total cholesterol (p=0.08). These data suggest that sirolimus is associated with an increased risk of VTE in cardiac transplant recipients, a risk possibly mediated through comorbid conditions. Larger, more conclusive studies are needed. Until such studies are completed, a heightened level of awareness for VTE in cardiac transplant recipients treated with sirolimus appears warranted. © 2012 John Wiley & Sons A/S.

  15. Upregulation of vascular endothelial growth factor receptor-1 contributes to sevoflurane preconditioning–mediated cardioprotection

    Directory of Open Access Journals (Sweden)

    Qian B

    2018-04-01

    Full Text Available Bin Qian,1 Yang Yang,2 Yusheng Yao,3 Yanling Liao,3 Ying Lin3 1Department of Anesthesiology, People’s Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China; 2Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China; 3Department of Anesthesiology, The Shengli Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China Purpose: Sevoflurane preconditioning (SPC can provide myocardial protective effects similar to ischemic preconditioning. However, the exact mechanism of SPC remains unclear. Previous studies indicate that vascular endothelial growth factor receptor 1 (VEGFR-1 is involved in ischemic preconditioning-mediated cardioprotection. This study was designed to determine the significance of VEGFR-1 signaling in SPC-mediated cardioprotection.Materials and methods: Myocardial ischemia–reperfusion (I/R rat model was established using the Langendorff isolated heart perfusion apparatus. Additionally, after 15 min of baseline equilibration, the isolated hearts were pretreated with 2.5% sevoflurane, 2.5% sevoflurane+MF1 10 µmol/L, or 2.5% sevoflurane+placental growth factor 10 µmol/L, and then subjected to 30 min of global ischemia and 120 min of reperfusion. The changes in hemodynamic parameters, myocardial infarct size, and the levels of creatine kinase-MB, lactate dehydrogenase, cardiac troponin-I, tumor necrosis factor-α, and interleukin 6 in the myocardium were evaluated.Results: Compared to the I/R group, pretreatment with 2.5% sevoflurane significantly improved the cardiac function, limited myocardial infarct size, reduced cardiac enzyme release, upregulated VEGFR-1 expression, and decreased inflammation. In addition, the selective VEGFR-1 agonist, placental growth factor, did not enhance the cardioprotection and anti-inflammation effects of sevoflurane, while the specific VEGFR-1 inhibitor, MF1, completely reversed these effects

  16. Associations between specific psychotic symptoms and specific childhood adversities are mediated by attachment styles: an analysis of the National Comorbidity Survey.

    Science.gov (United States)

    Sitko, Katarzyna; Bentall, Richard P; Shevlin, Mark; O'Sullivan, Noreen; Sellwood, William

    2014-07-30

    Accumulated evidence over the past decade consistently demonstrates a relationship between childhood adversity and psychosis in adulthood. There is some evidence of specific associations between childhood sexual abuse and hallucinations, and between insecure attachment and paranoia. Data from the National Comorbidity Survey were used in assessing whether current attachment styles influenced the association between adverse childhood experiences and psychotic symptoms in adulthood. Hallucinations and paranoid beliefs were differentially associated with sexual abuse (rape and sexual molestation) and neglect, respectively. Sexual abuse and neglect were also associated with depression. The relationship between neglect and paranoid beliefs was fully mediated via anxious and avoidant attachment. The relationship between sexual molestation and hallucinations was independent of attachment style. The relationship between rape and hallucinations was partially mediated via anxious attachment; however this effect was no longer present when depression was included as a mediating variable. The findings highlight the importance of addressing and understanding childhood experiences within the context of current attachment styles in clinical interventions for patients with psychosis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  17. Scaffold Free Bio-orthogonal Assembly of 3-Dimensional Cardiac Tissue via Cell Surface Engineering

    Science.gov (United States)

    Rogozhnikov, Dmitry; O'Brien, Paul J.; Elahipanah, Sina; Yousaf, Muhammad N.

    2016-12-01

    There has been tremendous interest in constructing in vitro cardiac tissue for a range of fundamental studies of cardiac development and disease and as a commercial system to evaluate therapeutic drug discovery prioritization and toxicity. Although there has been progress towards studying 2-dimensional cardiac function in vitro, there remain challenging obstacles to generate rapid and efficient scaffold-free 3-dimensional multiple cell type co-culture cardiac tissue models. Herein, we develop a programmed rapid self-assembly strategy to induce specific and stable cell-cell contacts among multiple cell types found in heart tissue to generate 3D tissues through cell-surface engineering based on liposome delivery and fusion to display bio-orthogonal functional groups from cell membranes. We generate, for the first time, a scaffold free and stable self assembled 3 cell line co-culture 3D cardiac tissue model by assembling cardiomyocytes, endothelial cells and cardiac fibroblast cells via a rapid inter-cell click ligation process. We compare and analyze the function of the 3D cardiac tissue chips with 2D co-culture monolayers by assessing cardiac specific markers, electromechanical cell coupling, beating rates and evaluating drug toxicity.

  18. Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction.

    Science.gov (United States)

    Poleshko, Andrey; Shah, Parisha P; Gupta, Mudit; Babu, Apoorva; Morley, Michael P; Manderfield, Lauren J; Ifkovits, Jamie L; Calderon, Damelys; Aghajanian, Haig; Sierra-Pagán, Javier E; Sun, Zheng; Wang, Qiaohong; Li, Li; Dubois, Nicole C; Morrisey, Edward E; Lazar, Mitchell A; Smith, Cheryl L; Epstein, Jonathan A; Jain, Rajan

    2017-10-19

    Progenitor cells differentiate into specialized cell types through coordinated expression of lineage-specific genes and modification of complex chromatin configurations. We demonstrate that a histone deacetylase (Hdac3) organizes heterochromatin at the nuclear lamina during cardiac progenitor lineage restriction. Specification of cardiomyocytes is associated with reorganization of peripheral heterochromatin, and independent of deacetylase activity, Hdac3 tethers peripheral heterochromatin containing lineage-relevant genes to the nuclear lamina. Deletion of Hdac3 in cardiac progenitor cells releases genomic regions from the nuclear periphery, leading to precocious cardiac gene expression and differentiation into cardiomyocytes; in contrast, restricting Hdac3 to the nuclear periphery rescues myogenesis in progenitors otherwise lacking Hdac3. Our results suggest that availability of genomic regions for activation by lineage-specific factors is regulated in part through dynamic chromatin-nuclear lamina interactions and that competence of a progenitor cell to respond to differentiation signals may depend upon coordinated movement of responding gene loci away from the nuclear periphery. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Cardiac tamponade: contrast reflux as an indicator of cardiac chamber equalization

    Directory of Open Access Journals (Sweden)

    Nauta Foeke Jacob

    2012-05-01

    Full Text Available Abstract Background Traumatic hemopericardium remains a rare entity; it does however commonly cause cardiac tamponade which remains a major cause of death in traumatic blunt cardiac injury. Objectives We present a case of blunt chest trauma complicated by cardiac tamponade causing cardiac chamber equalization revealed by reflux of contrast. Case report A 29-year-old unidentified male suffered blunt chest trauma in a motor vehicle collision. Computed tomography (CT demonstrated a periaortic hematoma and hemopericardium. Significant contrast reflux was seen in the inferior vena cava and hepatic veins suggesting a change in cardiac chamber pressures. After intensive treatment including cardiac massage this patient expired of cardiac arrest. Conclusion Reflux of contrast on CT imaging can be an indicator of traumatic cardiac tamponade.

  20. Dealing with existential anxiety in exercise-based cardiac rehabilitation

    DEFF Research Database (Denmark)

    Simonÿ, Charlotte; Pedersen, Birthe D; Dreyer, Pia

    2015-01-01

    rehabilitation. Focus group interviews were conducted at the programme end, and individual interviews were performed one to two months later. The interpretation comprised three methodological steps: naïve reading, structural analysis, and comprehensive interpretation and discussion. Findings Although both......Aims and objectives To investigate patients' lived experiences of exercise-based cardiac rehabilitation. Background Exercise-based cardiac rehabilitation is used to enable patients with cardiac problems to move forward to lead satisfying lives. However, knowledge of patients' concerns while...... it requires specific care. Recognising this anxiety also highlights how participating in the programme can be very demanding, which can help us understand aspects of adherence problems. Of greatest importance is that exercise-based cardiac rehabilitation enables patients to find a new foothold, which...

  1. Living cardiac patch: the elixir for cardiac regeneration.

    Science.gov (United States)

    Lakshmanan, Rajesh; Krishnan, Uma Maheswari; Sethuraman, Swaminathan

    2012-12-01

    A thorough understanding of the cellular and muscle fiber orientation in left ventricular cardiac tissue is of paramount importance for the generation of artificial cardiac patches to treat the ischemic myocardium. The major challenge faced during cardiac patch engineering is to choose a perfect combination of three entities; cells, scaffolds and signaling molecules comprising the tissue engineering triad for repair and regeneration. This review provides an overview of various scaffold materials, their mechanical properties and fabrication methods utilized in cardiac patch engineering. Stem cell therapies in clinical trials and the commercially available cardiac patch materials were summarized in an attempt to provide a recent perspective in the treatment of heart failure. Various tissue engineering strategies employed thus far to construct viable thick cardiac patches is schematically illustrated. Though many strategies have been proposed for fabrication of various cardiac scaffold materials, the stage and severity of the disease condition demands the incorporation of additional cues in a suitable scaffold material. The scaffold may be nanofibrous patch, hydrogel or custom designed films. Integration of stem cells and biomolecular cues along with the scaffold may provide the right microenvironment for the repair of unhealthy left ventricular tissue as well as promote its regeneration.

  2. Impact of Cardiac Contractility during Cerebral Blood Flow in Ischemia

    Directory of Open Access Journals (Sweden)

    Silver, Brian

    2011-05-01

    Full Text Available Objective: In cerebral regions affected by ischemia, intrinsic vascular autoregulation is often lost. Blood flow delivery depends upon cardiac function and may be influenced by neuro-endocrine mediated myocardial suppression. Our objective is to evaluate the relation between ejection fraction (EF and transcranial doppler (TCD peak systolic velocities (PSV in patients with cerebral ischemic events.Methods: We conducted a retrospective cohort study from an existing TCD registry. We evaluated patients admitted within 24 hours of onset of a focal neurological deficit who had an echocardiogram and TCD performed within 72 hours of admission.Results: We identified 58 patients from March to October 2003. Eighty-one percent (n=47 had a hospital discharge diagnosis of ischemic stroke and 18.9% (n=11 had a diagnosis of transient ischemic attack. Fourteen patients had systolic dysfunction (EF50% compared to those with systolic dysfunction (EF<50% was as follows: middle cerebral artery 62.0 + 28.6 cm/s vs. 51.0 + 23.3 cm/s, p=0.11; anterior cerebral artery 52.1 + 21.6 cm/s vs. 45.9 + 22.7 cm/s, p=0.28; internal carotid artery 56.5 + 20.1 cm/s vs. 46.4 + 18.4 cm/s, p=0.04; ophthalmic artery 18.6 + 7.2 cm/s vs. 15.3 + 5.2 cm/s, p=0.11; vertebral artery 34.0 + 13.9 cm/s vs. 31.6 + 15.0 cm/s, p=0.44.Conclusion: Cerebral blood flow in the internal carotid artery territory appears to be higher in cerebral ischemia patients with preserved left ventricular contractility. Our study was unable to differentiate pre-existing cardiac dysfunction from neuro-endocrine mediated myocardial stunning. Future research is necessary to better understand heart-brain interactions in this setting and to further explore the underlying mechanisms and consequences of neuro-endocrine mediated cardiac dysfunction. [West J Emerg Med. 2011;12(2:227-232.

  3. Prediction of tonic parasympathetic cardiac control using respiratory sinus arrhythmia: the need for respiratory control

    NARCIS (Netherlands)

    GROSSMAN, P.; Karemaker, J.; Wieling, W.

    1991-01-01

    Respiratory sinus arrhythmia (RSA) has received much attention in recent years due to the large body of evidence indicating that variations in this phenomenon represent alterations in parasympathetic cardiac control. Although it appears that respiratory sinus arrhythmia is mediated by vagal

  4. Antibody-mediated modulation of cytokinins in tobacco: Organ-specific changes in cytokinin homeostasis

    Czech Academy of Sciences Publication Activity Database

    Gelová, Z.; Hoopen, P.; Novák, Ondřej; Motyka, Václav; Pernisová, M.; Dabravolski, S.; Didi, V.; Tillack, F.; Oklešťková, Jana; Strnad, Miroslav; Hause, B.; Haruštiaková, D.; Conrad, U.; Janda, L.; Hejátko, J.

    2018-01-01

    Roč. 69, č. 3 (2018), s. 441-454 ISSN 0022-0957 R&D Projects: GA MŠk(CZ) LQ1601; GA MŠk(CZ) LO1204; GA MŠk(CZ) LM2015062; GA ČR(CZ) GA16-14649S Institutional support: RVO:61389030 Keywords : Antibody-mediated modulation * biosynthesis * ckx * cytokinin * homeostasis * organ specificity * tobacco Subject RIV: EF - Botanics OBOR OECD: Plant sciences, botany Impact factor: 5.830, year: 2016

  5. EMMPRIN mediates beta-adrenergic receptor-stimulated matrix metalloproteinase activity in cardiac myocytes.

    OpenAIRE

    Siwik Deborah A; Kuster Gabriela M; Brahmbhatt Jamin V; Zaidi Zaheer; Malik Julia; Ooi Henry; Ghorayeb Ghassan

    2008-01-01

    Extracellular matrix metalloproteinase inducer (EMMPRIN) expression is increased in myocardium from patients with dilated cardiomyopathy and animal models of heart failure. However little is known about the regulated expression or functional role of EMMPRIN in the myocardium. In rat cardiac cells EMMPRIN is expressed on myocytes but not endothelial cells or fibroblasts. Therefore we tested the hypothesis that EMMPRIN expression regulates matrix metalloproteinase (MMP) activity in rat ventricu...

  6. Source and specificity of chemical cues mediating shelter preference of Caribbean spiny lobsters (Panulirus argus).

    Science.gov (United States)

    Horner, Amy J; Nickles, Scott P; Weissburg, Marc J; Derby, Charles D

    2006-10-01

    Caribbean spiny lobsters display a diversity of social behaviors, one of the most prevalent of which is gregarious diurnal sheltering. Previous research has demonstrated that shelter selection is chemically mediated, but the source of release and the identity of the aggregation signal are unknown. In this study, we investigated the source and specificity of the aggregation signal in Caribbean spiny lobsters, Panulirus argus. We developed a relatively rapid test of shelter choice in a 5000-l laboratory flume that simulated flow conditions in the spiny lobster's natural environment, and used it to examine the shelter preference of the animals in response to a variety of odorants. We found that both males and females associated preferentially with shelters emanating conspecific urine of either sex, but not with shelters emanating seawater, food odors, or the scent of a predatory octopus. These results demonstrate specificity in the cues mediating sheltering behavior and show that urine is at least one source of the aggregation signal.

  7. Initial Efficacy of a Cardiac Rehabilitation Transition Program: Cardiac TRUST

    Science.gov (United States)

    Zullo, Melissa; Boxer, Rebecca; Moore, Shirley M.

    2012-01-01

    Patients recovering from cardiac events are increasingly using postacute care, such as home health care and skilled nursing facility services. The purpose of this pilot study was to test the initial efficacy, feasibility, and safety of a specially designed postacute care transitional rehabilitation intervention for cardiac patients. Cardiac Transitional Rehabilitation Using Self- Management Techniques (Cardiac TRUST) is a family-focused intervention that includes progressive low-intensity walking and education in self-management skills to facilitate recovery following a cardiac event. Using a randomized two-group design, exercise self-efficacy, steps walked, and participation in an outpatient cardiac rehabilitation program were compared in a sample of 38 older adults; 17 who received the Cardiac TRUST program and 21 who received usual care only. At discharge from postacute care, the intervention group had a trend for higher levels of self-efficacy for exercise outcomes (X=39.1, SD=7.4) than the usual care group (X=34.5; SD=7.0) (t-test 1.9, p=.06). During the 6 weeks following discharge, compared with the usual care group, the intervention group had more attendance in out-patient cardiac rehabilitation (33% compared to 11.8%, F=7.1, p=.03) and a trend toward more steps walked during the first week (X=1,307, SD=652 compared to X=782, SD=544, t-test 1.8, p=.07). The feasibility of the intervention was better for the home health participants than for those in the skilled nursing facility and there were no safety concerns. The provision of cardiac-focused rehabilitation during postacute care has the potential to bridge the gap in transitional services from hospitalization to outpatient cardiac rehabilitation for these patients at high risk for future cardiac events. Further evidence of the efficacy of Cardiac TRUST is warranted. PMID:22084960

  8. Cardiac parasympathetic reactivation following exercise: implications for training prescription.

    Science.gov (United States)

    Stanley, Jamie; Peake, Jonathan M; Buchheit, Martin

    2013-12-01

    The objective of exercise training is to initiate desirable physiological adaptations that ultimately enhance physical work capacity. Optimal training prescription requires an individualized approach, with an appropriate balance of training stimulus and recovery and optimal periodization. Recovery from exercise involves integrated physiological responses. The cardiovascular system plays a fundamental role in facilitating many of these responses, including thermoregulation and delivery/removal of nutrients and waste products. As a marker of cardiovascular recovery, cardiac parasympathetic reactivation following a training session is highly individualized. It appears to parallel the acute/intermediate recovery of the thermoregulatory and vascular systems, as described by the supercompensation theory. The physiological mechanisms underlying cardiac parasympathetic reactivation are not completely understood. However, changes in cardiac autonomic activity may provide a proxy measure of the changes in autonomic input into organs and (by default) the blood flow requirements to restore homeostasis. Metaboreflex stimulation (e.g. muscle and blood acidosis) is likely a key determinant of parasympathetic reactivation in the short term (0-90 min post-exercise), whereas baroreflex stimulation (e.g. exercise-induced changes in plasma volume) probably mediates parasympathetic reactivation in the intermediate term (1-48 h post-exercise). Cardiac parasympathetic reactivation does not appear to coincide with the recovery of all physiological systems (e.g. energy stores or the neuromuscular system). However, this may reflect the limited data currently available on parasympathetic reactivation following strength/resistance-based exercise of variable intensity. In this review, we quantitatively analyse post-exercise cardiac parasympathetic reactivation in athletes and healthy individuals following aerobic exercise, with respect to exercise intensity and duration, and fitness

  9. Regulation of cardiac microRNAs by serum response factor

    Directory of Open Access Journals (Sweden)

    Wei Jeanne Y

    2011-02-01

    Full Text Available Abstract Serum response factor (SRF regulates certain microRNAs that play a role in cardiac and skeletal muscle development. However, the role of SRF in the regulation of microRNA expression and microRNA biogenesis in cardiac hypertrophy has not been well established. In this report, we employed two distinct transgenic mouse models to study the impact of SRF on cardiac microRNA expression and microRNA biogenesis. Cardiac-specific overexpression of SRF (SRF-Tg led to altered expression of a number of microRNAs. Interestingly, downregulation of miR-1, miR-133a and upregulation of miR-21 occurred by 7 days of age in these mice, long before the onset of cardiac hypertrophy, suggesting that SRF overexpression impacted the expression of microRNAs which contribute to cardiac hypertrophy. Reducing cardiac SRF level using the antisense-SRF transgenic approach (Anti-SRF-Tg resulted in the expression of miR-1, miR-133a and miR-21 in the opposite direction. Furthermore, we observed that SRF regulates microRNA biogenesis, specifically the transcription of pri-microRNA, thereby affecting the mature microRNA level. The mir-21 promoter sequence is conserved among mouse, rat and human; one SRF binding site was found to be in the mir-21 proximal promoter region of all three species. The mir-21 gene is regulated by SRF and its cofactors, including myocardin and p49/Strap. Our study demonstrates that the downregulation of miR-1, miR-133a, and upregulation of miR-21 can be reversed by one single upstream regulator, SRF. These results may help to develop novel therapeutic interventions targeting microRNA biogenesis.

  10. What to do when you question cardiac troponin values

    DEFF Research Database (Denmark)

    Mair, Johannes; Lindahl, Bertil; Müller, Christian

    2017-01-01

    High-sensitivity cardiac troponin assays enable cardiac troponin measurement with a high degree of analytical sensitivity and a low level of analytical imprecision at the low measuring range. One of the most important advantages of these new assays is that they allow novel, more rapid approaches...... for ruling in or ruling out acute myocardial infarctions. The increase in the early diagnostic sensitivity of high-sensitivity cardiac troponin assays comes at the cost of a reduced acute myocardial infarction specificity of the biomarker, because more patients with other causes of acute or chronic...... of the work-up for such a clinical setting....

  11. Cardiac computed tomography in patients with acute coronary syndrome

    International Nuclear Information System (INIS)

    Schlett, C.L.; Bamberg, F.

    2014-01-01

    Currently, cardiac computed tomography (CT) is increasingly being implemented into clinical algorithms, primarily due to substantial technical advances over the last decade. Its use in the setting of suspected acute coronary syndrome is of particular relevance, given the high degree of accumulating scientific evidence of improving patient outcomes. Performing cardiac CT requires specific knowledge on the available scan acquisitions and patient preparation. Also, expertise is required in order to interpret the coronary and extra-coronary findings adequately. The present article provides an overview of the different aspects on the use of cardiac CT in the setting of acute coronary syndrome.

  12. Myocardial infarction false alarm: initial electrocardiogram and cardiac enzymes.

    Science.gov (United States)

    Gupta, Esha Das; Sakthiswary, Rajalingham

    2014-05-01

    The objectives of this study were to determine the incidence of a myocardial infarction "false alarm" and evaluate the efficacy of the initial electrocardiogram and cardiac enzymes in diagnosing myocardial infarction in Malaysia. We recruited patients who were admitted with suspected myocardial infarction from June to August 2008. The medical records of these patients were reviewed for the initial electrocardiogram, initial cardiac enzyme levels (creatinine kinase-MB and troponin T), and the final diagnosis upon discharge. The subjects were stratified into 2 groups: true myocardial infarction, and false alarm. 125 patients were enrolled in this study. Following admission and further evaluation, the diagnosis was revised from myocardial infarction to other medical conditions in 48 (38.4%) patients. The sensitivity and specificity of the initial ischemic electrocardiographic changes were 54.5% and 70.8%, respectively. Raised cardiac enzymes had a sensitivity of 44.3% and specificity of 95.8%. A significant proportion of patients in Malaysia are admitted with a false-alarm myocardial infarction. The efficacy of the electrocardiogram in diagnosing myocardial infarction in Malaysia was comparable to the findings of Western studies, but the cardiac enzymes had a much lower sensitivity.

  13. Cardiac damage in athlete's heart: When the "supernormal" heart fails!

    Science.gov (United States)

    Carbone, Andreina; D'Andrea, Antonello; Riegler, Lucia; Scarafile, Raffaella; Pezzullo, Enrica; Martone, Francesca; America, Raffaella; Liccardo, Biagio; Galderisi, Maurizio; Bossone, Eduardo; Calabrò, Raffaele

    2017-06-26

    Intense exercise may cause heart remodeling to compensate increases in blood pressure or volume by increasing muscle mass. Cardiac changes do not involve only the left ventricle, but all heart chambers. Physiological cardiac modeling in athletes is associated with normal or enhanced cardiac function, but recent studies have documented decrements in left ventricular function during intense exercise and the release of cardiac markers of necrosis in athlete's blood of uncertain significance. Furthermore, cardiac remodeling may predispose athletes to heart disease and result in electrical remodeling, responsible for arrhythmias. Athlete's heart is a physiological condition and does not require a specific treatment. In some conditions, it is important to differentiate the physiological adaptations from pathological conditions, such as hypertrophic cardiomyopathy, arrhythmogenic dysplasia of the right ventricle, and non-compaction myocardium, for the greater risk of sudden cardiac death of these conditions. Moreover, some drugs and performance-enhancing drugs can cause structural alterations and arrhythmias, therefore, their use should be excluded.

  14. Alcohol-specific parenting, adolescents' self-control, and alcohol use: a moderated mediation model.

    Science.gov (United States)

    Koning, Ina M; van den Eijnden, Regina J J M; Vollebergh, Wilma A M

    2014-01-01

    There is convincing evidence that parental rules about alcohol are important in curbing adolescents' alcohol use. However, little is known about the mechanisms through which the direct link between alcohol-specific parenting and alcohol use is obtained. In this study, we investigated the mediating effect of adolescent self-control on the relationship between alcohol-specific rules and adolescents' drinking behavior and whether this mediation effect depends on the level of quality of communication. A total of 883 adolescents participated in this longitudinal study at ages 13, 14, and 15 years. Strict rules predicted lower rates of drinking, but no direct effect of the quality of communication on adolescents' alcohol use was found. A higher level of self-control was related to lower rates of drinking in adolescents. The indirect effect of rules about alcohol through adolescents' self-control was statistically significant, yet only in adolescents with high qualitative parent-child communication about alcohol. In adolescents with low quality of parent-child communication, self-control was not related to drinking. These findings imply that strict rule setting in combination with qualitative parent-child communication is an important target for prevention. In addition, findings point at the importance of high qualitative parent-child communication for adolescents' motivation to engage in self-control to avoid drinking.

  15. The relationship between autistic traits and social anxiety, worry, obsessive-compulsive, and depressive symptoms: specific and non-specific mediators in a student sample.

    Science.gov (United States)

    Liew, Shi Min; Thevaraja, Nishta; Hong, Ryan Y; Magiati, Iliana

    2015-03-01

    The high prevalence of anxiety symptoms in individuals with autism spectrum disorders has now been well documented. There is also a positive relationship between autistic traits and anxiety symptoms in unselected samples and individuals with anxiety disorders have more autistic traits compared to those without. Less is known, however, regarding which elements of autistic traits (i.e., social versus non-social/behavioral) or which other variables may mediate this relationship. This study investigated the shared and specific role of five autistic-trait related mediators (social problem-solving, social competence, teasing experiences, prevention from/punishment for preferred repetitive behaviors and aversive sensory experiences) in a non-clinical sample of 252 university students. Autistic traits positively correlated with both anxiety and depressive symptoms. Social competence mediated the relationship between autistic traits and social anxiety symptoms only, while only prevention from preferred repetitive behaviors and frequent aversive sensory experiences mediated the relationship between autistic traits, worry and obsessive-compulsive symptoms. Replication of these findings is required in longitudinal studies and with clinical samples. Limitations of the study are discussed and possible implications for intervention are tentatively suggested.

  16. Animal models of cardiac cachexia.

    Science.gov (United States)

    Molinari, Francesca; Malara, Natalia; Mollace, Vincenzo; Rosano, Giuseppe; Ferraro, Elisabetta

    2016-09-15

    Cachexia is the loss of body weight associated with several chronic diseases including chronic heart failure (CHF). The cachectic condition is mainly due to loss of skeletal muscle mass and adipose tissue depletion. The majority of experimental in vivo studies on cachexia rely on animal models of cancer cachexia while a reliable and appropriate model for cardiac cachexia has not yet been established. A critical issue in generating a cardiac cachexia model is that genetic modifications or pharmacological treatments impairing the heart functionality and used to obtain the heart failure model might likely impair the skeletal muscle, this also being a striated muscle and sharing with the myocardium several molecular and physiological mechanisms. On the other hand, often, the induction of heart damage in the several existing models of heart failure does not necessarily lead to skeletal muscle loss and cachexia. Here we describe the main features of cardiac cachexia and illustrate some animal models proposed for cardiac cachexia studies; they include the genetic calsequestrin and Dahl salt-sensitive models, the monocrotaline model and the surgical models obtained by left anterior descending (LAD) ligation, transverse aortic constriction (TAC) and ascending aortic banding. The availability of a specific animal model for cardiac cachexia is a crucial issue since, besides the common aspects of cachexia in the different syndromes, each disease has some peculiarities in its etiology and pathophysiology leading to cachexia. Such peculiarities need to be unraveled in order to find new targets for effective therapies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Can cardiac surgery cause hypopituitarism?

    Science.gov (United States)

    Francis, Flverly; Burger, Ines; Poll, Eva Maria; Reineke, Andrea; Strasburger, Christian J; Dohmen, Guido; Gilsbach, Joachim M; Kreitschmann-Andermahr, Ilonka

    2012-03-01

    Apoplexy of pituitary adenomas with subsequent hypopituitarism is a rare but well recognized complication following cardiac surgery. The nature of cardiac on-pump surgery provides a risk of damage to the pituitary because the vascular supply of the pituitary is not included in the cerebral autoregulation. Thus, pituitary tissue may exhibit an increased susceptibility to hypoperfusion, ischemia or intraoperative embolism. After on-pump procedures, patients often present with physical and psychosocial impairments which resemble symptoms of hypopituitarism. Therefore, we analyzed whether on-pump cardiac surgery may cause pituitary dysfunction also in the absence of pre-existing pituitary disease. Twenty-five patients were examined 3-12 months after on-pump cardiac surgery. Basal hormone levels for all four anterior pituitary hormone axes were measured and a short synacthen test and a growth hormone releasing hormone plus arginine (GHRH-ARG)-test were performed. Quality of life (QoL), depression, subjective distress for a specific life event, sleep quality and fatigue were assessed by means of self-rating questionnaires. Hormonal alterations were only slight and no signs of anterior hypopituitarism were found except for an insufficient growth hormone rise in two overweight patients in the GHRH-ARG-test. Psychosocial impairment was pronounced, including symptoms of moderate to severe depression in 9, reduced mental QoL in 8, dysfunctional coping in 6 and pronounced sleep disturbances in 16 patients. Hormone levels did not correlate with psychosocial impairment. On-pump cardiac surgery did not cause relevant hypopituitarism in our sample of patients and does not serve to explain the psychosocial symptoms of these patients.

  18. Secoisolariciresinol diglucoside abrogates oxidative stress-induced damage in cardiac iron overload condition.

    Directory of Open Access Journals (Sweden)

    Stephanie Puukila

    Full Text Available Cardiac iron overload is directly associated with cardiac dysfunction and can ultimately lead to heart failure. This study examined the effect of secoisolariciresinol diglucoside (SDG, a component of flaxseed, on iron overload induced cardiac damage by evaluating oxidative stress, inflammation and apoptosis in H9c2 cardiomyocytes. Cells were incubated with 50 μ5M iron for 24 hours and/or a 24 hour pre-treatment of 500 μ M SDG. Cardiac iron overload resulted in increased oxidative stress and gene expression of the inflammatory mediators tumor necrosis factor-α, interleukin-10 and interferon γ, as well as matrix metalloproteinases-2 and -9. Increased apoptosis was evident by increased active caspase 3/7 activity and increased protein expression of Forkhead box O3a, caspase 3 and Bax. Cardiac iron overload also resulted in increased protein expression of p70S6 Kinase 1 and decreased expression of AMP-activated protein kinase. Pre-treatment with SDG abrogated the iron-induced increases in oxidative stress, inflammation and apoptosis, as well as the increased p70S6 Kinase 1 and decreased AMP-activated protein kinase expression. The decrease in superoxide dismutase activity by iron treatment was prevented by pre-treatment with SDG in the presence of iron. Based on these findings we conclude that SDG was cytoprotective in an in vitro model of iron overload induced redox-inflammatory damage, suggesting a novel potential role for SDG in cardiac iron overload.

  19. Specific emotions as mediators of the effect of intergroup contact on prejudice: findings across multiple participant and target groups.

    Science.gov (United States)

    Seger, Charles R; Banerji, Ishani; Park, Sang Hee; Smith, Eliot R; Mackie, Diane M

    2017-08-01

    Emotions are increasingly being recognised as important aspects of prejudice and intergroup behaviour. Specifically, emotional mediators play a key role in the process by which intergroup contact reduces prejudice towards outgroups. However, which particular emotions are most important for prejudice reduction, as well as the consistency and generality of emotion-prejudice relations across different in-group-out-group relations, remain uncertain. To address these issues, in Study 1 we examined six distinct positive and negative emotions as mediators of the contact-prejudice relations using representative samples of U.S. White, Black, and Asian American respondents (N = 639). Admiration and anger (but not other emotions) were significant mediators of the effects of previous contact on prejudice, consistently across different perceiver and target ethnic groups. Study 2 examined the same relations with student participants and gay men as the out-group. Admiration and disgust mediated the effect of past contact on attitude. The findings confirm that not only negative emotions (anger or disgust, based on the specific types of threat perceived to be posed by an out-group), but also positive, status- and esteem-related emotions (admiration) mediate effects of contact on prejudice, robustly across several different respondent and target groups.

  20. Asian consortium on radiation dose of pediatric cardiac CT (ASCI-REDCARD)

    International Nuclear Information System (INIS)

    Hui, Peter K.T.; Goo, Hyun Woo; Du, Jing; Ip, Janice J.K.; Kanzaki, Suzu; Kim, Young Jin; Kritsaneepaiboon, Supika; Lilyasari, Oktavia; Siripornpitak, Suvipaporn

    2017-01-01

    With incremental utilization of pediatric cardiac CT in congenital heart disease, it is imperative to define its current radiation dose levels in clinical practice in order to help imagers optimize CT protocols, particularly in Asia and other developing countries where CT physicists are not readily available. To evaluate current radiation dose levels and influencing factors in cardiac CT in children with congenital heart disease in Asia by conducting a retrospective multi-center, multi-vendor study. We included 1,043 pediatric cardiac CT examinations performed in 8 centers between January 2014 and December 2014 to evaluate congenital heart disease. In five weight groups, we calculated radiation dose metrics including volume CT dose index, size-specific dose estimate, dose-length product and effective dose. Age at CT exam, gender, tube voltage, scan mode, CT indication and image reconstruction algorithm were analyzed to learn whether they influenced CT radiation dose. Volume CT dose index, size-specific dose estimate, dose-length product and effective dose of pediatric cardiac CT showed variations in the range of 4.3-23.8 mGy, 4.9-17.6 mGy, 55.8-501.3 mGy circle cm and 1.5-3.2 mSv, respectively, within five weight groups. Gender, tube voltage, scan mode and cardiac function assessment significantly influenced CT radiation dose. This multi-center, multi-vendor study demonstrated variations in radiation dose metrics of pediatric cardiac CT reflecting current practice in Asia. Gender, tube voltage, scan mode and cardiac function assessment should be considered as essential radiation dose-influencing factors in developing optimal pediatric cardiac CT protocols. (orig.)

  1. Asian consortium on radiation dose of pediatric cardiac CT (ASCI-REDCARD)

    Energy Technology Data Exchange (ETDEWEB)

    Hui, Peter K.T. [Hong Kong Baptist Hospital, Department of Radiology, Hong Kong, SAR (China); Goo, Hyun Woo [University of Ulsan College of Medicine, Asan Medical Center, Seoul (Korea, Republic of); Du, Jing [Beijing Anzhen Hospital, Capital Medical University, Department of Radiology, Beijing (China); Ip, Janice J.K. [Queen Mary Hospital, Department of Radiology, Hong Kong, SAR (China); Kanzaki, Suzu [National Cerebral and Cardiovascular Center, Department of Radiology, Osaka (Japan); Kim, Young Jin [Yonsei University, Shinchon Severance Hospital, Department of Radiology, Seoul (Korea, Republic of); Kritsaneepaiboon, Supika [Songklanagarind Hospital, Prince of Songkla University, Department of Radiology, Hat Yai (Thailand); Lilyasari, Oktavia [University of Indonesia, National Cardiovascular Center Harapan Kita, Department of Cardiology, Jakarta (Indonesia); Siripornpitak, Suvipaporn [Ramathibodi Hospital, Mahidol University, Department of Radiology, Salaya (Thailand)

    2017-07-15

    With incremental utilization of pediatric cardiac CT in congenital heart disease, it is imperative to define its current radiation dose levels in clinical practice in order to help imagers optimize CT protocols, particularly in Asia and other developing countries where CT physicists are not readily available. To evaluate current radiation dose levels and influencing factors in cardiac CT in children with congenital heart disease in Asia by conducting a retrospective multi-center, multi-vendor study. We included 1,043 pediatric cardiac CT examinations performed in 8 centers between January 2014 and December 2014 to evaluate congenital heart disease. In five weight groups, we calculated radiation dose metrics including volume CT dose index, size-specific dose estimate, dose-length product and effective dose. Age at CT exam, gender, tube voltage, scan mode, CT indication and image reconstruction algorithm were analyzed to learn whether they influenced CT radiation dose. Volume CT dose index, size-specific dose estimate, dose-length product and effective dose of pediatric cardiac CT showed variations in the range of 4.3-23.8 mGy, 4.9-17.6 mGy, 55.8-501.3 mGy circle cm and 1.5-3.2 mSv, respectively, within five weight groups. Gender, tube voltage, scan mode and cardiac function assessment significantly influenced CT radiation dose. This multi-center, multi-vendor study demonstrated variations in radiation dose metrics of pediatric cardiac CT reflecting current practice in Asia. Gender, tube voltage, scan mode and cardiac function assessment should be considered as essential radiation dose-influencing factors in developing optimal pediatric cardiac CT protocols. (orig.)

  2. Cardiac tumors: optimal cardiac MR sequences and spectrum of imaging appearances.

    LENUS (Irish Health Repository)

    O'Donnell, David H

    2012-02-01

    OBJECTIVE: This article reviews the optimal cardiac MRI sequences for and the spectrum of imaging appearances of cardiac tumors. CONCLUSION: Recent technologic advances in cardiac MRI have resulted in the rapid acquisition of images of the heart with high spatial and temporal resolution and excellent myocardial tissue characterization. Cardiac MRI provides optimal assessment of the location, functional characteristics, and soft-tissue features of cardiac tumors, allowing accurate differentiation of benign and malignant lesions.

  3. Quadripolar leads in cardiac resynchronization therapy

    NARCIS (Netherlands)

    Van Everdingen, Wouter M.; Cramer, MJ; Doevendans, Pieter A.; Meine, Mathias

    2015-01-01

    Despite the benefit of cardiac resynchronization therapy (CRT) in patients with heart failure and conduction delay, a considerable number of patients do not respond substantially. Left ventricular lead position is an important factor in response, restricted by the patient's specific anatomy and

  4. Cardiac gated ventilation

    International Nuclear Information System (INIS)

    Hanson, C.W. III; Hoffman, E.A.

    1995-01-01

    There are several theoretic advantages to synchronizing positive pressure breaths with the cardiac cycle, including the potential for improving distribution of pulmonary and myocardial blood flow and enhancing cardiac output. The authors evaluated the effects of synchronizing respiration to the cardiac cycle using a programmable ventilator and electron beam CT (EBCT) scanning. The hearts of anesthetized dogs were imaged during cardiac gated respiration with a 50 msec scan aperture. Multi slice, short axis, dynamic image data sets spanning the apex to base of the left ventricle were evaluated to determine the volume of the left ventricular chamber at end-diastole and end-systole during apnea, systolic and diastolic cardiac gating. The authors observed an increase in cardiac output of up to 30% with inspiration gated to the systolic phase of the cardiac cycle in a non-failing model of the heart

  5. Real-time MRI guidance of cardiac interventions.

    Science.gov (United States)

    Campbell-Washburn, Adrienne E; Tavallaei, Mohammad A; Pop, Mihaela; Grant, Elena K; Chubb, Henry; Rhode, Kawal; Wright, Graham A

    2017-10-01

    Cardiac magnetic resonance imaging (MRI) is appealing to guide complex cardiac procedures because it is ionizing radiation-free and offers flexible soft-tissue contrast. Interventional cardiac MR promises to improve existing procedures and enable new ones for complex arrhythmias, as well as congenital and structural heart disease. Guiding invasive procedures demands faster image acquisition, reconstruction and analysis, as well as intuitive intraprocedural display of imaging data. Standard cardiac MR techniques such as 3D anatomical imaging, cardiac function and flow, parameter mapping, and late-gadolinium enhancement can be used to gather valuable clinical data at various procedural stages. Rapid intraprocedural image analysis can extract and highlight critical information about interventional targets and outcomes. In some cases, real-time interactive imaging is used to provide a continuous stream of images displayed to interventionalists for dynamic device navigation. Alternatively, devices are navigated relative to a roadmap of major cardiac structures generated through fast segmentation and registration. Interventional devices can be visualized and tracked throughout a procedure with specialized imaging methods. In a clinical setting, advanced imaging must be integrated with other clinical tools and patient data. In order to perform these complex procedures, interventional cardiac MR relies on customized equipment, such as interactive imaging environments, in-room image display, audio communication, hemodynamic monitoring and recording systems, and electroanatomical mapping and ablation systems. Operating in this sophisticated environment requires coordination and planning. This review provides an overview of the imaging technology used in MRI-guided cardiac interventions. Specifically, this review outlines clinical targets, standard image acquisition and analysis tools, and the integration of these tools into clinical workflow. 1 Technical Efficacy: Stage 5 J

  6. Bystander defibrillation for out-of-hospital cardiac arrest in Public vs Residential Locations

    DEFF Research Database (Denmark)

    Hansen, Steen Møller; Hansen, Carolina Malta; Folke, Fredrik

    2017-01-01

    Importance: Bystander-delivered defibrillation (hereinafter referred to as bystander defibrillation) of patients with out-of-hospital cardiac arrests (OHCAs) remains limited despite the widespread dissemination of automated external defibrillators (AEDs). Objective: To examine calendar changes...... in bystander defibrillation and subsequent survival according to a public or a residential location of the cardiac arrest after nationwide initiatives in Denmark to facilitate bystander-mediated resuscitative efforts, including bystander defibrillation. Design, Setting, and Participants: This nationwide study......, 2016. Exposures: Nationwide initiatives to facilitate bystander resuscitative efforts, including bystander defibrillation, consisted of resuscitation training of Danish citizens, dissemination of on-site AEDs, foundation of an AED registry linked to emergency medical dispatch centers, and dispatcher...

  7. Integrating light-sheet imaging with virtual reality to recapitulate developmental cardiac mechanics.

    Science.gov (United States)

    Ding, Yichen; Abiri, Arash; Abiri, Parinaz; Li, Shuoran; Chang, Chih-Chiang; Baek, Kyung In; Hsu, Jeffrey J; Sideris, Elias; Li, Yilei; Lee, Juhyun; Segura, Tatiana; Nguyen, Thao P; Bui, Alexander; Sevag Packard, René R; Fei, Peng; Hsiai, Tzung K

    2017-11-16

    Currently, there is a limited ability to interactively study developmental cardiac mechanics and physiology. We therefore combined light-sheet fluorescence microscopy (LSFM) with virtual reality (VR) to provide a hybrid platform for 3D architecture and time-dependent cardiac contractile function characterization. By taking advantage of the rapid acquisition, high axial resolution, low phototoxicity, and high fidelity in 3D and 4D (3D spatial + 1D time or spectra), this VR-LSFM hybrid methodology enables interactive visualization and quantification otherwise not available by conventional methods, such as routine optical microscopes. We hereby demonstrate multiscale applicability of VR-LSFM to (a) interrogate skin fibroblasts interacting with a hyaluronic acid-based hydrogel, (b) navigate through the endocardial trabecular network during zebrafish development, and (c) localize gene therapy-mediated potassium channel expression in adult murine hearts. We further combined our batch intensity normalized segmentation algorithm with deformable image registration to interface a VR environment with imaging computation for the analysis of cardiac contraction. Thus, the VR-LSFM hybrid platform demonstrates an efficient and robust framework for creating a user-directed microenvironment in which we uncovered developmental cardiac mechanics and physiology with high spatiotemporal resolution.

  8. Cross-Linking Mast Cell Specific Gangliosides Stimulates the Release of Newly Formed Lipid Mediators and Newly Synthesized Cytokines

    Directory of Open Access Journals (Sweden)

    Edismauro Garcia Freitas Filho

    2016-01-01

    Full Text Available Mast cells are immunoregulatory cells that participate in inflammatory processes. Cross-linking mast cell specific GD1b derived gangliosides by mAbAA4 results in partial activation of mast cells without the release of preformed mediators. The present study examines the release of newly formed and newly synthesized mediators following ganglioside cross-linking. Cross-linking the gangliosides with mAbAA4 released the newly formed lipid mediators, prostaglandins D2 and E2, without release of leukotrienes B4 and C4. The effect of cross-linking these gangliosides on the activation of enzymes in the arachidonate cascade was then investigated. Ganglioside cross-linking resulted in phosphorylation of cytosolic phospholipase A2 and increased expression of cyclooxygenase-2. Translocation of 5-lipoxygenase from the cytosol to the nucleus was not induced by ganglioside cross-linking. Cross-linking of GD1b derived gangliosides also resulted in the release of the newly synthesized mediators, interleukin-4, interleukin-6, and TNF-α. The effect of cross-linking the gangliosides on the MAP kinase pathway was then investigated. Cross-linking the gangliosides induced the phosphorylation of ERK1/2, JNK1/2, and p38 as well as activating both NFκB and NFAT in a Syk-dependent manner. Therefore, cross-linking the mast cell specific GD1b derived gangliosides results in the activation of signaling pathways that culminate with the release of newly formed and newly synthesized mediators.

  9. Interleukin-1 is required for cancer eradication mediated by tumor-specific Th1 cells.

    Science.gov (United States)

    Haabeth, Ole Audun Werner; Lorvik, Kristina Berg; Yagita, Hideo; Bogen, Bjarne; Corthay, Alexandre

    The role of inflammation in cancer is controversial as both tumor-promoting and tumor-suppressive aspects of inflammation have been reported. In particular, it has been shown that pro-inflammatory cytokines, like interleukin-1α (IL-1α), IL-1β, IL-6, and tumor necrosis factor α (TNFα), may either promote or suppress cancer. However, the cellular and molecular basis underlying these opposing outcomes remains enigmatic. Using mouse models for myeloma and lymphoma, we have recently reported that inflammation driven by tumor-specific T helper 1 (Th1) cells conferred protection against B-cell cancer and that interferon-γ (IFN-γ) was essential for this process. Here, we have investigated the contribution of several inflammatory mediators. Myeloma eradication by Th1 cells was not affected by inhibition of TNF-α, TNF-related weak inducer of apoptosis (TWEAK), or TNF-related apoptosis-inducing ligand (TRAIL). In contrast, cancer elimination by tumor-specific Th1 cells was severely impaired by the in vivo neutralization of both IL-1α and IL-1β (collectively named IL-1) with IL-1 receptor antagonist (IL-1Ra). The antitumor functions of tumor-specific Th1 cells and tumor-infiltrating macrophages were both affected by IL-1 neutralization. Secretion of the Th1-derived cytokines IL-2 and IFN-γ at the incipient tumor site was severely reduced by IL-1 blockade. Moreover, IL-1 was shown to synergize with IFN-γ for induction of tumoricidal activity in tumor-infiltrating macrophages. This synergy between IL-1 and IFN-γ may explain how inflammation, when driven by tumor-specific Th1 cells, represses rather than promotes cancer. Collectively, the data reveal a central role of inflammation, and more specifically of the canonical pro-inflammatory cytokine IL-1, in enhancing Th1-mediated immunity against cancer.

  10. Cardiac function and cognition in older community-dwelling cardiac patients.

    Science.gov (United States)

    Eggermont, Laura H P; Aly, Mohamed F A; Vuijk, Pieter J; de Boer, Karin; Kamp, Otto; van Rossum, Albert C; Scherder, Erik J A

    2017-11-01

    Cognitive deficits have been reported in older cardiac patients. An underlying mechanism for these findings may be reduced cardiac function. The relationship between cardiac function as represented by different echocardiographic measures and different cognitive function domains in older cardiac patients remains unknown. An older (≥70 years) heterogeneous group of 117 community-dwelling cardiac patients under medical supervision by a cardiologist underwent thorough echocardiographic assessment including left ventricular ejection fraction, cardiac index, left atrial volume index, left ventricular mass index, left ventricular diastolic function, and valvular calcification. During a home visit, a neuropsychological assessment was performed within 7.1 ± 3.8 months after echocardiographic assessment; the neuropsychological assessment included three subtests of a word-learning test (encoding, recall, recognition) to examine one memory function domain and three executive function tests, including digit span backwards, Trail Making Test B minus A, and the Stroop colour-word test. Regression analyses showed no significant linear or quadratic associations between any of the echocardiographic functions and the cognitive function measures. None of the echocardiographic measures as representative of cardiac function was correlated with memory or executive function in this group of community-dwelling older cardiac patients. These findings contrast with those of previous studies. © 2017 Japanese Psychogeriatric Society.

  11. PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

    Science.gov (United States)

    Knight, Walter E.; Chen, Si; Zhang, Yishuai; Oikawa, Masayoshi; Wu, Meiping; Zhou, Qian; Miller, Clint L.; Cai, Yujun; Mickelsen, Deanne M.; Moravec, Christine; Small, Eric M.; Abe, Junichi; Yan, Chen

    2016-01-01

    Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β–stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance. PMID:27791092

  12. Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

    Science.gov (United States)

    O’Connell, Timothy D.; Jensen, Brian C.; Baker, Anthony J.

    2014-01-01

    Adrenergic receptors (AR) are G-protein-coupled receptors (GPCRs) that have a crucial role in cardiac physiology in health and disease. Alpha1-ARs signal through Gαq, and signaling through Gq, for example, by endothelin and angiotensin receptors, is thought to be detrimental to the heart. In contrast, cardiac alpha1-ARs mediate important protective and adaptive functions in the heart, although alpha1-ARs are only a minor fraction of total cardiac ARs. Cardiac alpha1-ARs activate pleiotropic downstream signaling to prevent pathologic remodeling in heart failure. Mechanisms defined in animal and cell models include activation of adaptive hypertrophy, prevention of cardiac myocyte death, augmentation of contractility, and induction of ischemic preconditioning. Surprisingly, at the molecular level, alpha1-ARs localize to and signal at the nucleus in cardiac myocytes, and, unlike most GPCRs, activate “inside-out” signaling to cause cardioprotection. Contrary to past opinion, human cardiac alpha1-AR expression is similar to that in the mouse, where alpha1-AR effects are seen most convincingly in knockout models. Human clinical studies show that alpha1-blockade worsens heart failure in hypertension and does not improve outcomes in heart failure, implying a cardioprotective role for human alpha1-ARs. In summary, these findings identify novel functional and mechanistic aspects of cardiac alpha1-AR function and suggest that activation of cardiac alpha1-AR might be a viable therapeutic strategy in heart failure. PMID:24368739

  13. Cardiac function and cognition in older community-dwelling cardiac patients

    NARCIS (Netherlands)

    Eggermont, Laura H.P.; Aly, Mohamed F.A.; Vuijk, Pieter J.; de Boer, Karin; Kamp, Otto; van Rossum, Albert C.; Scherder, Erik J.A.

    2017-01-01

    Background: Cognitive deficits have been reported in older cardiac patients. An underlying mechanism for these findings may be reduced cardiac function. The relationship between cardiac function as represented by different echocardiographic measures and different cognitive function domains in older

  14. Post-cardiac injury syndrome: an atypical case following percutaneous coronary intervention.

    Science.gov (United States)

    Paiardi, Silvia; Cannata, Francesco; Ciccarelli, Michele; Voza, Antonio

    2017-12-01

    Post-cardiac injury syndrome (PCIS) is a syndrome characterized by pericardial and/or pleural effusion, triggered by a cardiac injury, usually a myocardial infarction or cardiac surgery, rarely a minor cardiovascular percutaneous procedure. Nowadays, the post-cardiac injury syndrome, is regaining importance and interest as an emerging cause of pericarditis, especially in developed countries, due to a great and continuous increase in the number and complexity of percutaneous cardiologic procedures. The etiopathogenesis seems mediated by the immunitary system producing immune complexes, which deposit in the pericardium and pleura and trigger an inflammatory response. We present the atypical case of a 76-year-old man presenting with a hydro-pneumothorax, low-grade fever and elevated inflammation markers, after two complex percutaneous coronary interventions, executed 30 and 75 days prior. The clinical features of our case are consistent with the diagnostic criteria of PCIS: prior injury of the pericardium and/or myocardium, fever, leucocytosis, elevated inflammatory markers, remarkable steroid responsiveness and latency period. Only one element does not fit with this diagnosis and does not find any further explanation: the air accompanying the pleural effusion, determining a hydro-pneumothorax and requiring a pleural drainage catheter positioning. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Gold nanorod-incorporated gelatin-based conductive hydrogels for engineering cardiac tissue constructs.

    Science.gov (United States)

    Navaei, Ali; Saini, Harpinder; Christenson, Wayne; Sullivan, Ryan Tanner; Ros, Robert; Nikkhah, Mehdi

    2016-09-01

    The development of advanced biomaterials is a crucial step to enhance the efficacy of tissue engineering strategies for treatment of myocardial infarction. Specific characteristics of biomaterials including electrical conductivity, mechanical robustness and structural integrity need to be further enhanced to promote the functionalities of cardiac cells. In this work, we fabricated UV-crosslinkable gold nanorod (GNR)-incorporated gelatin methacrylate (GelMA) hybrid hydrogels with enhanced material and biological properties for cardiac tissue engineering. Embedded GNRs promoted electrical conductivity and mechanical stiffness of the hydrogel matrix. Cardiomyocytes seeded on GelMA-GNR hybrid hydrogels exhibited excellent cell retention, viability, and metabolic activity. The increased cell adhesion resulted in abundance of locally organized F-actin fibers, leading to the formation of an integrated tissue layer on the GNR-embedded hydrogels. Immunostained images of integrin β-1 confirmed improved cell-matrix interaction on the hybrid hydrogels. Notably, homogeneous distribution of cardiac specific markers (sarcomeric α-actinin and connexin 43), were observed on GelMA-GNR hydrogels as a function of GNRs concentration. Furthermore, the GelMA-GNR hybrids supported synchronous tissue-level beating of cardiomyocytes. Similar observations were also noted by, calcium transient assay that demonstrated the rhythmic contraction of the cardiomyocytes on GelMA-GNR hydrogels as compared to pure GelMA. Thus, the findings of this study clearly demonstrated that functional cardiac patches with superior electrical and mechanical properties can be developed using nanoengineered GelMA-GNR hybrid hydrogels. In this work, we developed gold nanorod (GNR) incorporated gelatin-based hydrogels with suitable electrical conductivity and mechanical stiffness for engineering functional cardiac tissue constructs (e.g. cardiac patches). The synthesized conductive hybrid hydrogels properly

  16. PRKAG2 mutation: An easily missed cardiac specific non-lysosomal glycogenosis

    International Nuclear Information System (INIS)

    Aggarwal, Varun; Dobrolet, Nancy; Fishberger, Steven; Zablah, Jenny; Jayakar, Parul; Ammous, Zineb

    2005-01-01

    Mutations in PRKAG2 gene that regulates the γ2 subunit of the adenosine monophosphate (AMP) dependent protein kinase have been associated with the development of atrioventricular (AV) accessory pathways, cardiac hypertrophy, and conduction system abnormalities. These patients can potentially be misdiagnosed as hypertrophic cardiomyopathy (HOCM) and/or Wolf-Parkinson White (WPW) syndrome due to similar clinical phenotype. Early recognition of this disease entity is very important as ablation of suspected accessory pathways is not effective and the natural history of the disease is very different from HOCM and WPW syndrome

  17. Lysyl oxidase overexpression accelerates cardiac remodeling and aggravates angiotensin II-induced hypertrophy.

    Science.gov (United States)

    Galán, María; Varona, Saray; Guadall, Anna; Orriols, Mar; Navas, Miquel; Aguiló, Silvia; de Diego, Alicia; Navarro, María A; García-Dorado, David; Rodríguez-Sinovas, Antonio; Martínez-González, José; Rodriguez, Cristina

    2017-09-01

    Lysyl oxidase (LOX) controls matrix remodeling, a key process that underlies cardiovascular diseases and heart failure; however, a lack of suitable animal models has limited our knowledge with regard to the contribution of LOX to cardiac dysfunction. Here, we assessed the impact of LOX overexpression on ventricular function and cardiac hypertrophy in a transgenic LOX (TgLOX) mouse model with a strong cardiac expression of human LOX. TgLOX mice exhibited high expression of the transgene in cardiomyocytes and cardiofibroblasts, which are associated with enhanced LOX activity and H 2 O 2 production and with cardiofibroblast reprogramming. LOX overexpression promoted an age-associated concentric remodeling of the left ventricle and impaired diastolic function. Furthermore, LOX transgenesis aggravated angiotensin II (Ang II)-induced cardiac hypertrophy and dysfunction, which triggered a greater fibrotic response that was characterized by stronger collagen deposition and cross-linking and high expression of fibrotic markers. In addition, LOX transgenesis increased the Ang II-induced myocardial inflammatory infiltrate, exacerbated expression of proinflammatory markers, and decreased that of cardioprotective factors. Mechanistically, LOX overexpression enhanced oxidative stress and potentiated the Ang II-mediated cardiac activation of p38 MAPK while reducing AMPK activation. Our findings suggest that LOX induces an age-dependent disturbance of diastolic function and aggravates Ang II-induced hypertrophy, which provides novel insights into the role of LOX in cardiac performance.-Galán, M., Varona, S., Guadall, A., Orriols, M., Navas, M., Aguiló, S., de Diego, A., Navarro, M. A., García-Dorado, D., Rodríguez-Sinovas, A., Martínez-González, J., Rodriguez, C. Lysyl oxidase overexpression accelerates cardiac remodeling and aggravates angiotensin II-induced hypertrophy. © FASEB.

  18. Reduction of blood oxygen levels enhances postprandial cardiac hypertrophy in Burmese python (Python bivittatus).

    Science.gov (United States)

    Slay, Christopher E; Enok, Sanne; Hicks, James W; Wang, Tobias

    2014-05-15

    Physiological cardiac hypertrophy is characterized by reversible enlargement of cardiomyocytes and changes in chamber architecture, which increase stroke volume and via augmented convective oxygen transport. Cardiac hypertrophy is known to occur in response to repeated elevations of O2 demand and/or reduced O2 supply in several species of vertebrate ectotherms, including postprandial Burmese pythons (Python bivittatus). Recent data suggest postprandial cardiac hypertrophy in P. bivittatus is a facultative rather than obligatory response to digestion, though the triggers of this response are unknown. Here, we hypothesized that an O2 supply-demand mismatch stimulates postprandial cardiac enlargement in Burmese pythons. To test this hypothesis, we rendered animals anemic prior to feeding, essentially halving blood oxygen content during the postprandial period. Fed anemic animals had heart rates 126% higher than those of fasted controls, which, coupled with a 71% increase in mean arterial pressure, suggests fed anemic animals were experiencing significantly elevated cardiac work. We found significant cardiac hypertrophy in fed anemic animals, which exhibited ventricles 39% larger than those of fasted controls and 28% larger than in fed controls. These findings support our hypothesis that those animals with a greater magnitude of O2 supply-demand mismatch exhibit the largest hearts. The 'low O2 signal' stimulating postprandial cardiac hypertrophy is likely mediated by elevated ventricular wall stress associated with postprandial hemodynamics. © 2014. Published by The Company of Biologists Ltd.

  19. Asymptomatic Changes in Cardiac Function Can Occur in DCIS Patients Following Treatment with HER-2/neu Pulsed Dendritic Cell Vaccines

    Science.gov (United States)

    Bahl, Susan; Roses, Robert; Sharma, Anupama; Koldovsky, Ursula; Xu, Shuwen; Weinstein, Susan; Nisenbaum, Harvey; Fox, Kevin; Pasha, Theresa; Zhang, Paul; Araujo, Louis; Carver, Joseph; Czerniecki, Brian J

    2009-01-01

    Background Targeting HER-2/neu with Trastuzumab has been associated with development of cardiac toxicity. Methods Twenty-seven patients with ductal carcinoma in situ (DCIS) of the breast completed an IRB approved clinical trial of a HER-2/neu targeted dendritic cell based vaccine. Four weekly vaccinations were administered prior to surgical resection. All subjects underwent pre- and post-vaccine cardiac monitoring by MUGA/ECHO scanning allowing for a comparison of cardiac function. Results In 3 of 27 vaccinated patients (11%) transient asymptomatic decrements in ejection fraction of greater than 15% were noted after vaccination. Notably, evidence of circulating anti-HER-2/neu antibody was found prior to vaccination in all three patients, but cardiac toxicity was not noted until induction of cellular mediated immune responses. Conclusions This is the first description of HER-2/neu targeted vaccination associated with an incidence of cardiac changes, and the induction of cellular immune responses combined with antibody may contribute to changes in cardiac function. PMID:19800453

  20. Plant-derived cardiac glycosides: Role in heart ailments and cancer management.

    Science.gov (United States)

    Patel, Seema

    2016-12-01

    Cardiac glycosides, the cardiotonic steroids such as digitalis have been in use as heart ailment remedy since ages. They manipulate the renin-angiotensin axis to improve cardiac output. However; their safety and efficacy have come under scrutiny in recent times, as poisoning and accidental mortalities have been observed. In order to better understand and exploit them as cardiac ionotropes, studies are being pursued using different cardiac glycosides such as digitoxin, digoxin, ouabain, oleandrin etc. Several cardiac glycosides as peruvoside have shown promise in cancer control, especially ovary cancer and leukemia. Functional variability of these glycosides has revealed that not all cardiac glycosides are alike. Apart from their specific affinity to sodium-potassium ATPase, their therapeutic dosage and behavior in poly-morbidity conditions needs to be considered. This review presents a concise account of the key findings in recent years with adequate elaboration of the mechanisms. This compilation is expected to contribute towards management of cardiac, cancer, even viral ailments. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  1. Reactivation of the Nkx2.5 cardiac enhancer after myocardial infarction does not presage myogenesis.

    Science.gov (United States)

    Deutsch, Marcus-André; Doppler, Stefanie A; Li, Xinghai; Lahm, Harald; Santamaria, Gianluca; Cuda, Giovanni; Eichhorn, Stefan; Ratschiller, Thomas; Dzilic, Elda; Dreßen, Martina; Eckart, Annekathrin; Stark, Konstantin; Massberg, Steffen; Bartels, Anna; Rischpler, Christoph; Gilsbach, Ralf; Hein, Lutz; Fleischmann, Bernd K; Wu, Sean M; Lange, Rüdiger; Krane, Markus

    2018-03-20

    The contribution of resident stem or progenitor cells to cardiomyocyte renewal after injury in adult mammalian hearts remains a matter of considerable debate. We evaluated a cell population in the adult mouse heart induced by myocardial infarction (MI) and characterized by an activated Nkx2.5 enhancer element that is specific for multipotent cardiac progenitor cells during embryonic development. We hypothesized that these MI induced cells (MICs) harbor cardiomyogenic properties similar to their embryonic counterparts. MICs reside in the heart and mainly localize to the infarction area and border zone. Interestingly, gene expression profiling of purified MICs one week after infarction revealed increased expression of stem cell markers and embryonic cardiac transcription factors in these cells as compared to the non-mycoyte cell fraction of adult hearts. A subsequent global transcriptome comparison with embryonic cardiac progenitor cells and fibroblasts and in vitro culture of MICs unveiled that (myo-) fibroblastic features predominated and that cardiac transcription factors were only expressed at background levels. Adult injury induced reactivation of a cardiac-specific Nkx2.5 enhancer element known to specifically mark myocardial progenitor cells during embryonic development does not reflect hypothesized embryonic cardiomyogenic properties. Our data suggest a decreasing plasticity of cardiac progenitor (-like) cell populations with increasing age. A re-expression of embryonic, stem or progenitor cell features in the adult heart must be interpreted very carefully with respect to the definition of cardiac resident progenitor cells. Albeit, the abundance of scar formation after cardiac injury suggests a potential to target predestinated activated profibrotic cells to push them towards cardiomyogenic differentiation to improve regeneration.

  2. Churg-Strauss Syndrome with Cardiac Involvement: A Case Report with CT and MRI Findings

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Seong Joo; Cho, Young Jun; Kim, Keum; Hwang, Cheol Mok; Kim, Dae Ho [Dept. of Radiology, Konyang University College of Medicine, Daegu (Korea, Republic of); Choi, Eu Gene [Dept. of Internal Medicine, Konyang University College of Medicine, Daegu (Korea, Republic of)

    2012-02-15

    This is a case report of Churg-Strauss Syndrome (CSS) associated with cardiac involvement which is demonstrated in chest CT and cardiac MRI (CMR) without specific cardiac symptoms. A 32-year-old woman had a 3-year history of bronchial asthma, chronic sinusitis, and otitis media. The patient had various typical findings of CSS. The patient had no specific cardiac symptoms or signs such as chest pain, palpitations, syncope, or murmur, but she had diffuse low attenuation lesions in the inner wall of the left ventricle (LV) in contrast-enhanced CT. This corresponded to the area of subendocardial hyperenhancement in delayed contrast-enhanced CMR images. She was treated with steroids for 2 months. Follow-up delayed contrast-enhanced CMR of the LV showed a decrease in the size of the subendocardial enhancement area, and she had no symptoms. Therefore, the radiologist and clinician both should pay careful attention to observe possible cardiac involvement in case of CSS.

  3. Churg-Strauss Syndrome with Cardiac Involvement: A Case Report with CT and MRI Findings

    International Nuclear Information System (INIS)

    Lim, Seong Joo; Cho, Young Jun; Kim, Keum; Hwang, Cheol Mok; Kim, Dae Ho; Choi, Eu Gene

    2012-01-01

    This is a case report of Churg-Strauss Syndrome (CSS) associated with cardiac involvement which is demonstrated in chest CT and cardiac MRI (CMR) without specific cardiac symptoms. A 32-year-old woman had a 3-year history of bronchial asthma, chronic sinusitis, and otitis media. The patient had various typical findings of CSS. The patient had no specific cardiac symptoms or signs such as chest pain, palpitations, syncope, or murmur, but she had diffuse low attenuation lesions in the inner wall of the left ventricle (LV) in contrast-enhanced CT. This corresponded to the area of subendocardial hyperenhancement in delayed contrast-enhanced CMR images. She was treated with steroids for 2 months. Follow-up delayed contrast-enhanced CMR of the LV showed a decrease in the size of the subendocardial enhancement area, and she had no symptoms. Therefore, the radiologist and clinician both should pay careful attention to observe possible cardiac involvement in case of CSS.

  4. Cardiac Abnormalities in Adult Patients With Polymyositis or Dermatomyositis as Assessed by Noninvasive Modalities

    DEFF Research Database (Denmark)

    Diederichsen, L P; Simonsen, J A; Diederichsen, A C

    2016-01-01

    age (P = 0.001), disease duration (P = 0.004), presence of myositis-specific or -associated autoantibodies (P = 0.05), and high cardiac (99m) Tc-PYP uptake (P = 0.006). In multivariate analysis of the pooled data for patients and HCs, a diagnosis of PM/DM (P .... CONCLUSION: Patients with PM or DM had an increased prevalence of cardiac abnormalities compared to HCs. LVDD was a common occurrence in PM/DM patients and correlated to disease duration. In addition, the association of LVDD with myositis-specific or -associated autoantibodies and high cardiac (99m) Tc...

  5. Twist1 Controls a Cell-Specification Switch Governing Cell Fate Decisions within the Cardiac Neural Crest

    Science.gov (United States)

    Vincentz, Joshua W.; Firulli, Beth A.; Lin, Andrea; Spicer, Douglas B.; Howard, Marthe J.; Firulli, Anthony B.

    2013-01-01

    Neural crest cells are multipotent progenitor cells that can generate both ectodermal cell types, such as neurons, and mesodermal cell types, such as smooth muscle. The mechanisms controlling this cell fate choice are not known. The basic Helix-loop-Helix (bHLH) transcription factor Twist1 is expressed throughout the migratory and post-migratory cardiac neural crest. Twist1 ablation or mutation of the Twist-box causes differentiation of ectopic neuronal cells, which molecularly resemble sympathetic ganglia, in the cardiac outflow tract. Twist1 interacts with the pro-neural factor Sox10 via its Twist-box domain and binds to the Phox2b promoter to repress transcriptional activity. Mesodermal cardiac neural crest trans-differentiation into ectodermal sympathetic ganglia-like neurons is dependent upon Phox2b function. Ectopic Twist1 expression in neural crest precursors disrupts sympathetic neurogenesis. These data demonstrate that Twist1 functions in post-migratory neural crest cells to repress pro-neural factors and thereby regulate cell fate determination between ectodermal and mesodermal lineages. PMID:23555309

  6. Cardiac nuclear medicine, part II: diagnosis of coronary artery diseas

    International Nuclear Information System (INIS)

    Polak, J.F.; Holman, B.L.

    1981-01-01

    Diagnosing coronary artery disease is difficult and requires careful consideration of the roles and limitations of the tests used. Standard ECG tests are not reliable indicators of the presence of disease in asymptomatic patients. Thallium stress testing to assess ischemia and exercise ventriculography to assess functional status of the heart are limited in sensitivity and specificity. This is the second of a three-part series on cardiac nuclear medicine. Part I (Med. Instrum., May-June, 1981) focused on the commonly used examinations in cardiac physiology and pathophysiology. Part III will focus on myocardial infarction and other cardiac diseases

  7. Role of NAD+ and mitochondrial sirtuins in cardiac and renal diseases.

    Science.gov (United States)

    Hershberger, Kathleen A; Martin, Angelical S; Hirschey, Matthew D

    2017-04-01

    The coenzyme nicotinamide adenine dinucleotide (NAD + ) has key roles in the regulation of redox status and energy metabolism. NAD + depletion is emerging as a major contributor to the pathogenesis of cardiac and renal diseases and NAD + repletion strategies have shown therapeutic potential as a means to restore healthy metabolism and physiological function. The pleotropic roles of NAD + enable several possible avenues by which repletion of this coenzyme could have therapeutic efficacy. In particular, NAD + functions as a co-substrate in deacylation reactions carried out by the sirtuin family of enzymes. These NAD + -dependent deacylases control several aspects of metabolism and a wealth of data suggests that boosting sirtuin activity via NAD + supplementation might be a promising therapy for cardiac and renal pathologies. This Review summarizes the role of NAD + metabolism in the heart and kidney, and highlights the mitochondrial sirtuins as mediators of some of the beneficial effects of NAD + -boosting therapies in preclinical animal models. We surmise that modulating the NAD + -sirtuin axis is a clinically relevant approach to develop new therapies for cardiac and renal diseases.

  8. Cardiac troponins in dogs and cats

    DEFF Research Database (Denmark)

    Langhorn, Rebecca; Willesen, Jakob

    2016-01-01

    Cardiac troponins are sensitive and specific markers of myocardial injury. The troponin concentration can be thought of as a quantitative measure of the degree of injury sustained by the heart, however, it provides no information on the cause of injury or the mechanism of troponin release. Conven...

  9. Type 2 diabetes and cardiac autonomic neuropathy screening using dynamic pupillometry

    Science.gov (United States)

    Lerner, Alana G.; Bernabé-Ortiz, Antonio; Ticse, Ray; Hernandez, Arturo; Huaylinos, Yvonne; Pinto, Miguel E.; Málaga, Germán; Checkley, William; Gilman, Robert H.; Miranda, J. Jaime

    2015-01-01

    Aim To determine if changes in pupillary response are useful as a screening tool for diabetes and to assess whether pupillometry is associated with cardiac autonomic neuropathy. Methods We conducted a cross-sectional study with participants drawn from two settings: a hospital and a community site. At the community site, individuals with newly diagnosed diabetes as well as a random sample of control individuals without diabetes, confirmed by oral glucose tolerance test, were selected. Participants underwent an LED light stimulus test and eight pupillometry variables were measured. Outcomes were diabetes, defined by oral glucose tolerance test, and cardiac autonomic dysfunction, determined by a positive readout on two of four diagnostic tests: heart rate response to the Valsalva manoeuvre; orthostatic hypotension; 30:15 ratio; and expiration-to-inspiration ratio. The area under the curve, best threshold, sensitivity and specificity of each pupillometry variable was calculated. Results Data from 384 people, 213 with diabetes, were analysed. The mean (±SD) age of the people with diabetes was 58.6 (±8.2) years and in the control subjects it was 56.1 (±8.6) years. When comparing individuals with and without diabetes, the amplitude of the pupil reaction had the highest area under the curve [0.69 (sensitivity: 78%; specificity: 55%)]. Cardiac autonomic neuropathy was present in 51 of the 138 people evaluated (37.0%; 95% CI 28.8–45.1). To diagnose cardiac autonomic neuropathy, two pupillometry variables had the highest area under the curve: baseline pupil radius [area under the curve: 0.71 (sensitivity: 51%; specificity: 84%)], and amplitude of the pupil reaction [area under the curve: 070 (sensitivity: 82%; specificity: 55%)]. Conclusions Pupillometry is an inexpensive technique to screen for diabetes and cardiac autonomic neuropathy, but it does not have sufficient accuracy for clinical use as a screening tool. PMID:25761508

  10. Technetium-99m labeled 1-(4-fluorobenzyl)-4-(2-mercapto-2-methyl-4-azapentyl)-4- (2-mercapto-2-methylp ropylamino)-piperidine and iodine-123 metaiodobenzylguanidine for studying cardiac adrenergic function: a comparison of the uptake characteristics in vascular smooth muscle cells and neonatal cardiac myocytes, and an investigation in rats

    International Nuclear Information System (INIS)

    Samnick, Samuel; Scheuer, Claudia; Muenks, Sven; El-Gibaly, Amr M.; Menger, Michael D.; Kirsch, Carl-Martin

    2004-01-01

    drugs in lowering cardiac uptake of 99m Tc-FBPBAT. Uptake reduction was more pronounced in myocardium than in other adrenergic-rich organs, including the lung, spleen, kidney, and adrenals, suggesting that the 99m Tc-FBPBAT uptake in myocardium specifically reflects a high degree of α 1 /β 1 -receptor binding to cardiac adrenergic neurons. In comparison, reduction of cardiac and pulmonary uptake of 123 I-MIBG was effective after pretreatment of rats with desipramine and reserpine, confirming distinct neuronal binding sites for 99m Tc-FBPBAT and 123 I-MIBG. 99m Tc-FBPBAT was excreted via urine and to a lower degree via feces. Urine analysis 6 hours p.i. revealed that more than 40% of the total excreted radioactivity was unmetabolized 99m Tc-FBPBAT. In conclusion, the uptake of 99m Tc-FBPBAT in rat myocardium specifically reflects binding to cardiac adrenergic neurons. The 99m Tc-FBPBAT uptake appears to be predominantly mediated via the α 1 /β 1 -adrenoceptor pathway. These data indicate that 99m Tc-FBPBAT, like 123 I-MIBG, may be suitable for mapping cardiac adrenergic innervation by SPET, especially for α 1 /β 1 -adrenoceptors as target in numerous heart diseases

  11. Technetium-99m labeled 1-(4-fluorobenzyl)-4-(2-mercapto-2-methyl-4-azapentyl)-4- (2-mercapto-2-methylp ropylamino)-piperidine and iodine-123 metaiodobenzylguanidine for studying cardiac adrenergic function: a comparison of the uptake characteristics in vascular smooth muscle cells and neonatal cardiac myocytes, and an investigation in rats

    Energy Technology Data Exchange (ETDEWEB)

    Samnick, Samuel E-mail: rassam@uniklinik-saarland.de; Scheuer, Claudia; Muenks, Sven; El-Gibaly, Amr M.; Menger, Michael D.; Kirsch, Carl-Martin

    2004-05-01

    -MIBG, respectively. Prazosin, urapidil, and metoprolol were as effective as treatment with other adrenergic drugs in lowering cardiac uptake of {sup 99m}Tc-FBPBAT. Uptake reduction was more pronounced in myocardium than in other adrenergic-rich organs, including the lung, spleen, kidney, and adrenals, suggesting that the {sup 99m}Tc-FBPBAT uptake in myocardium specifically reflects a high degree of {alpha}{sub 1}/{beta}{sub 1}-receptor binding to cardiac adrenergic neurons. In comparison, reduction of cardiac and pulmonary uptake of {sup 123}I-MIBG was effective after pretreatment of rats with desipramine and reserpine, confirming distinct neuronal binding sites for {sup 99m}Tc-FBPBAT and {sup 123}I-MIBG. {sup 99m}Tc-FBPBAT was excreted via urine and to a lower degree via feces. Urine analysis 6 hours p.i. revealed that more than 40% of the total excreted radioactivity was unmetabolized {sup 99m}Tc-FBPBAT. In conclusion, the uptake of {sup 99m}Tc-FBPBAT in rat myocardium specifically reflects binding to cardiac adrenergic neurons. The {sup 99m}Tc-FBPBAT uptake appears to be predominantly mediated via the {alpha}{sub 1}/{beta}{sub 1}-adrenoceptor pathway. These data indicate that {sup 99m}Tc-FBPBAT, like {sup 123}I-MIBG, may be suitable for mapping cardiac adrenergic innervation by SPET, especially for {alpha}{sub 1}/{beta}{sub 1}-adrenoceptors as target in numerous heart diseases.

  12. Evaluation of microRNAs − 208 and 133a/b as differential biomarkers of acute cardiac and skeletal muscle toxicity in rats

    Energy Technology Data Exchange (ETDEWEB)

    Calvano, Jacqueline, E-mail: Jacqueline.Calvano@bms.com [Drug Safety Evaluation, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903 (United States); Achanzar, William; Murphy, Bethanne [Drug Safety Evaluation, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903 (United States); DiPiero, Janet [Discovery Toxicology, Bristol-Myers Squibb, Route 206 and Province Line Road, Lawrenceville, NJ 08540 (United States); Hixson, Clifford; Parrula, Cecilia; Burr, Holly; Mangipudy, Raja; Tirmenstein, Mark [Drug Safety Evaluation, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903 (United States)

    2016-12-01

    Conventional circulating biomarkers of cardiac and skeletal muscle (SKM) toxicity lack specificity and/or have a short half-life. MicroRNAs (miRNAs) are currently being assessed as biomarkers of tissue injury based on their long half-life in blood and selective expression in certain tissues. To assess the utility of miRNAs as biomarkers of cardiac and SKM injury, male Sprague–Dawley rats received a single dose of isoproterenol (ISO); metaproterenol (MET); allylamine (AAM); mitoxantrone (MIT); acetaminophen (APAP) or vehicle. Blood and tissues were collected from rats in each group at 4, 24 and 48 h. ISO, MET, and AAM induced cardiac and SKM lesions and APAP induced liver specific lesions. There was no evidence of tissue injury with MIT by histopathology. Serum levels of candidate miRNAs were compared to conventional serum biomarkers of SKM/cardiac toxicity. Increases in heart specific miR-208 only occurred in rats with cardiac lesions alone and were increased for a longer duration than cardiac troponin and FABP3 (cardiac biomarkers). ISO, MET and AAM induced increases in MyL3 and skeletal muscle troponin (sTnl) (SKM biomarkers). MIT induced large increases in sTnl indicative of SKM toxicity, but sTnl levels were also increased in APAP-treated rats that lacked SKM toxicity. Serum levels of miR-133a/b (enriched in cardiac and SKM) increased following ISO, MET, AAM and MIT treatments but were absent in APAP-treated rats. Our results suggest that miR-133a/b are sensitive and specific markers of SKM and cardiac toxicity and that miR-208 used in combination with miR-133a/b can be used to differentiate cardiac from SKM toxicity. - Highlights: • MiR-208 is specifically expressed in rat hearts. • MiR-133a/b are enriched in rat cardiac/skeletal muscle. • MiR-133a/b are sensitive and specific markers of muscle/cardiac toxicity. • MiR-208 can be used to differentiate cardiac toxicity from skeletal muscle toxicity.

  13. Dyrk1A-ASF-CaMKIIδ Signaling Is Involved in Valsartan Inhibition of Cardiac Hypertrophy in Renovascular Hypertensive Rats.

    Science.gov (United States)

    Yao, Jian; Qin, Xiaotong; Zhu, Jianhua; Sheng, Hongzhuan

    2016-01-01

    It is known that the expression, activity and alternative splicing of Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) are dysregulated in the cardiac remodeling process. Recently, we found a further signaling pathway, by which dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) regulates the alternative splicing of CaMKIIδ via the alternative splicing factor (ASF), i.e., Dyrk1A-ASF-CaMKIIδ. In this study, we aimed to investigate whether Dyrk1A-ASF-CaMKIIδ signaling was involved in valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats. Rats were subjected to two kidney-one clip (2K1C) surgery and then treated with valsartan (30 mg/kg/day) for 8 weeks. Hypertrophic parameter analysis was then performed. Western blot analysis was used to determine the protein expression of Dyrk1A and ASF and RT-PCR was used to analyze the alternative splicing of CaMKIIδ in the left ventricular (LV) sample. Valsartan attenuated cardiac hypertrophy in 2K1C rats but without impairment of cardiac systolic function. Increased protein expression of Dyrk1A and decreased protein expression of ASF were observed in the LV sample of 2K1C rats. Treatment of 2K1C rats with valsartan reversed the changes in Dyrk1A and ASF expression in the LV sample. Valsartan adjusted the 2K1C-induced imbalance in alternative splicing of CaMKIIδ by upregulating the mRNA expression of CaMKIIδC and downregulating the mRNA expression of CaMKIIδA and CaMKIIδB. Valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats was mediated, at least partly, by Dyrk1A-ASF-CaMKIIδ signaling. © 2015 S. Karger AG, Basel.

  14. MURC, a muscle-restricted coiled-coil protein that modulates the Rho/ROCK pathway, induces cardiac dysfunction and conduction disturbance.

    Science.gov (United States)

    Ogata, Takehiro; Ueyama, Tomomi; Isodono, Koji; Tagawa, Masashi; Takehara, Naofumi; Kawashima, Tsuneaki; Harada, Koichiro; Takahashi, Tomosaburo; Shioi, Tetsuo; Matsubara, Hiroaki; Oh, Hidemasa

    2008-05-01

    We identified a novel muscle-restricted putative coiled-coil protein, MURC, which is evolutionarily conserved from frog to human. MURC was localized to the cytoplasm with accumulation in the Z-line of the sarcomere in the murine adult heart. MURC mRNA expression in the heart increased during the developmental process from the embryonic stage to adulthood. In response to pressure overload, MURC mRNA expression increased in the hypertrophied heart. Using the yeast two-hybrid system, we identified the serum deprivation response (SDPR) protein, a phosphatidylserine-binding protein, as a MURC-binding protein. MURC induced activation of the RhoA/ROCK pathway, which modulated serum response factor-mediated atrial natriuretic peptide (ANP) expression and myofibrillar organization. SDPR augmented MURC-induced transactivation of the ANP promoter in cardiomyocytes, and RNA interference of SDPR attenuated the action of MURC on the ANP promoter. Transgenic mice expressing cardiac-specific MURC (Tg-MURC) exhibited cardiac contractile dysfunction and atrioventricular (AV) conduction disturbances with atrial chamber enlargement, reduced thickness of the ventricular wall, and interstitial fibrosis. Spontaneous episodes of atrial fibrillation and AV block were observed in Tg-MURC mice. These findings indicate that MURC modulates RhoA signaling and that MURC plays an important role in the development of cardiac dysfunction and conduction disturbance with increased vulnerability to atrial arrhythmias.

  15. MURC, a Muscle-Restricted Coiled-Coil Protein That Modulates the Rho/ROCK Pathway, Induces Cardiac Dysfunction and Conduction Disturbance▿

    Science.gov (United States)

    Ogata, Takehiro; Ueyama, Tomomi; Isodono, Koji; Tagawa, Masashi; Takehara, Naofumi; Kawashima, Tsuneaki; Harada, Koichiro; Takahashi, Tomosaburo; Shioi, Tetsuo; Matsubara, Hiroaki; Oh, Hidemasa

    2008-01-01

    We identified a novel muscle-restricted putative coiled-coil protein, MURC, which is evolutionarily conserved from frog to human. MURC was localized to the cytoplasm with accumulation in the Z-line of the sarcomere in the murine adult heart. MURC mRNA expression in the heart increased during the developmental process from the embryonic stage to adulthood. In response to pressure overload, MURC mRNA expression increased in the hypertrophied heart. Using the yeast two-hybrid system, we identified the serum deprivation response (SDPR) protein, a phosphatidylserine-binding protein, as a MURC-binding protein. MURC induced activation of the RhoA/ROCK pathway, which modulated serum response factor-mediated atrial natriuretic peptide (ANP) expression and myofibrillar organization. SDPR augmented MURC-induced transactivation of the ANP promoter in cardiomyocytes, and RNA interference of SDPR attenuated the action of MURC on the ANP promoter. Transgenic mice expressing cardiac-specific MURC (Tg-MURC) exhibited cardiac contractile dysfunction and atrioventricular (AV) conduction disturbances with atrial chamber enlargement, reduced thickness of the ventricular wall, and interstitial fibrosis. Spontaneous episodes of atrial fibrillation and AV block were observed in Tg-MURC mice. These findings indicate that MURC modulates RhoA signaling and that MURC plays an important role in the development of cardiac dysfunction and conduction disturbance with increased vulnerability to atrial arrhythmias. PMID:18332105

  16. Cardiac lipid accumulation associated with diastolic dysfunction in obese mice

    DEFF Research Database (Denmark)

    Christoffersen, Christina; Bollano, Entela; Lindegaard, Marie L S

    2003-01-01

    Obesity may confer cardiac dysfunction due to lipid accumulation in cardiomyocytes. To test this idea, we examined whether obese ob/ob mice display heart lipid accumulation and cardiac dysfunction. Ob/ob mouse hearts had increased expression of genes mediating extracellular generation, transport....../ob mice and 2.5 +/- 0.1 in ob/+ mice (P = 0.0001). In contrast, the indexes of systolic function and heart brain natriuretic peptide mRNA expression were only marginally affected and unaffected, respectively, in ob/ob compared with ob/+ mice. The results suggest that ob/ob mouse hearts have increased...... across the myocyte cell membrane, intracellular transport, mitochondrial uptake, and beta-oxidation of fatty acids compared with ob/+ mice. Accordingly, ob/ob mouse hearts contained more triglyceride (6.8 +/- 0.4 vs. 2.3 +/- 0.4 microg/mg; P hearts. Histological examinations...

  17. Detecting early cardiac dysfunction with radionuclide cardiac blood-pool imaging

    International Nuclear Information System (INIS)

    Wu Kegui; Chen Daguang; Lin Haoxue

    1992-01-01

    Cardiac function was measured by radionuclide cardiac blood-pool imaging in 15 normal persons, 19 cases of hypertension, 32 cases of coronary heart disease, 35 cases of coronary heart disease combined with hypertension and 44 cases of myocardial infarction. Significant differences have been found in indices of cardiac function between normal subjects and patients with coronary heart disease and coronary heart disease combined with hypertension, even though the patients were without any clinical sin of cardiac failure. Lowered regional EF and decreased ventricular was motion were found in 38.8% of patients, while 65.7%of patients revealed marked abnormality in MFR. The results indicate that latent cardiac dysfunction is common in patients with coronary heart disease. The earliest change is diastolic function abnormalities

  18. Modulation of neonatal microbial recognition: TLR-mediated innate immune responses are specifically and differentially modulated by human milk.

    Science.gov (United States)

    LeBouder, Emmanuel; Rey-Nores, Julia E; Raby, Anne-Catherine; Affolter, Michael; Vidal, Karine; Thornton, Catherine A; Labéta, Mario O

    2006-03-15

    The mechanisms controlling innate microbial recognition in the neonatal gut are still to be fully understood. We have sought specific regulatory mechanisms operating in human breast milk relating to TLR-mediated microbial recognition. In this study, we report a specific and differential modulatory effect of early samples (days 1-5) of breast milk on ligand-induced cell stimulation via TLRs. Although a negative modulation was exerted on TLR2 and TLR3-mediated responses, those via TLR4 and TLR5 were enhanced. This effect was observed in human adult and fetal intestinal epithelial cell lines, monocytes, dendritic cells, and PBMC as well as neonatal blood. In the latter case, milk compensated for the low capacity of neonatal plasma to support responses to LPS. Cell stimulation via the IL-1R or TNFR was not modulated by milk. This, together with the differential effect on TLR activation, suggested that the primary effect of milk is exerted upstream of signaling proximal to TLR ligand recognition. The analysis of TLR4-mediated gene expression, used as a model system, showed that milk modulated TLR-related genes differently, including those coding for signal intermediates and regulators. A proteinaceous milk component of > or =80 kDa was found to be responsible for the effect on TLR4. Notably, infant milk formulations did not reproduce the modulatory activity of breast milk. Together, these findings reveal an unrecognized function of human milk, namely, its capacity to influence neonatal microbial recognition by modulating TLR-mediated responses specifically and differentially. This in turn suggests the existence of novel mechanisms regulating TLR activation.

  19. Cardiac Function Remains Impaired Despite Reversible Cardiac Remodeling after Acute Experimental Viral Myocarditis

    Directory of Open Access Journals (Sweden)

    Peter Moritz Becher

    2017-01-01

    Full Text Available Background. Infection with Coxsackievirus B3 induces myocarditis. We aimed to compare the acute and chronic phases of viral myocarditis to identify the immediate effects of cardiac inflammation as well as the long-term effects after resolved inflammation on cardiac fibrosis and consequently on cardiac function. Material and Methods. We infected C57BL/6J mice with Coxsackievirus B3 and determined the hemodynamic function 7 as well as 28 days after infection. Subsequently, we analyzed viral burden and viral replication in the cardiac tissue as well as the expression of cytokines and matrix proteins. Furthermore, cardiac fibroblasts were infected with virus to investigate if viral infection alone induces profibrotic signaling. Results. Severe cardiac inflammation was determined and cardiac fibrosis was consistently colocalized with inflammation during the acute phase of myocarditis. Declined cardiac inflammation but no significantly improved hemodynamic function was observed 28 days after infection. Interestingly, cardiac fibrosis declined to basal levels as well. Both cardiac inflammation and fibrosis were reversible, whereas the hemodynamic function remains impaired after healed viral myocarditis in C57BL/6J mice.

  20. Current role of cardiac and extra-cardiac pathologies in clinically indicated cardiac computed tomography with emphasis on status before pulmonary vein isolation

    Energy Technology Data Exchange (ETDEWEB)

    Sohns, J.M.; Lotz, J. [Goettingen University Medical Center (Germany). Inst. for Diagnostic and Interventional Radiology; German Center for Cardiovascular Research (DZHK), Goettingen (Germany); Menke, J.; Staab, W.; Fasshauer, M.; Kowallick, J.T.; Zwaka, P.A.; Schwarz, A. [Goettingen University Medical Center (Germany). Inst. for Diagnostic and Interventional Radiology; Spiro, J. [Koeln University Hospital (Germany). Radiology; Bergau, L.; Unterberg-Buchwald, C. [Goettingen University Medical Center (Germany). Cardiology and Pneumology

    2014-09-15

    Purpose: The aim of this study was to assess the incidence of cardiac and significant extra-cardiac findings in clinical computed tomography of the heart in patients with atrial fibrillation before pulmonary vein isolation (PVI). Materials and Methods: 224 patients (64 ± 10 years; male 63%) with atrial fibrillation were examined by cardiac 64-slice multidetector CT before PVI. Extra-cardiac findings were classified as 'significant' if they were recommended to additional diagnostics or therapy, and otherwise as 'non-significant'. Additionally, cardiac findings were documented in detail. Results: A total of 724 cardiac findings were identified in 203 patients (91% of patients). Additionally, a total of 619 extra-cardiac findings were identified in 179 patients (80% of patients). Among these extra-cardiac findings 196 (32%) were 'significant', and 423 (68%) were 'non-significant'. In 2 patients (1%) a previously unknown malignancy was detected (esophageal cancer and lung cancer, local stage, no metastasis). 203 additional imaging diagnostics followed to clarify the 'significant' findings (124 additional CT, costs 38,314.69 US dollars). Overall, there were 3.2 cardiac and 2.8 extra-cardiac findings per patient. Extra-cardiac findings appear significantly more frequently in patients over 60 years old, in smokers and in patients with a history of cardiac findings (p < 0.05). Conclusion: Cardiac CT scans before PVI should be screened for extracardiac incidental findings that could have important clinical implications for each patient. (orig.)

  1. Treatment with Fenofibrate plus a low dose of Benznidazole attenuates cardiac dysfunction in experimental Chagas disease

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    Ágata C. Cevey

    2017-12-01

    Full Text Available Trypanosoma cruzi induces serious cardiac alterations during the chronic infection. Intense inflammatory response observed from the beginning of infection, is critical for the control of parasite proliferation and evolution of Chagas disease. Peroxisome proliferator-activated receptors (PPAR-α, are known to modulate inflammation.In this study we investigated whether a PPAR-α agonist, Fenofibrate, improves cardiac function and inflammatory parameters in a murine model of T. cruzi infection. BALB/c mice were sequentially infected with two T. cruzi strains of different genetic background. Benznidazole, commonly used as trypanocidal drug, cleared parasites but did not preclude cardiac pathology, resembling what is found in human chronic chagasic cardiomyopathy. Fenofibrate treatment restored to normal values the ejection and shortening fractions, left ventricular end-diastolic, left ventricular end-systolic diameter, and isovolumic relaxation time. Moreover, it reduced cardiac inflammation and fibrosis, decreased the expression of pro-inflammatory (IL-6, TNF-α and NOS2 and heart remodeling mediators (MMP-9 and CTGF, and reduced serum creatine kinase activity. The fact that Fenofibrate partially inhibited NOS2 expression and NO release in the presence of a PPAR-α non-competitive inhibitor, suggested it also acted through PPAR-α-independent pathways. Since IκBα cytosolic degradation was inhibited by Fenofibrate, it can be concluded that the NFκB pathway has a role in its effects. Thus, we demonstrate that Fenofibrate acts through PPAR-α-dependent and -independent pathways.Our study shows that combined treatment with Fenofibrate plus Benznidazole is able both to reverse the cardiac dysfunction associated with the ongoing inflammatory response and fibrosis and to attain parasite clearance in an experimental model of Chagas disease. Keywords: Trypanosoma cruzi, Heart dysfunction, PPAR-α, Fenofibrate treatment, Inflammatory mediators

  2. Cefditoren and ceftriaxone enhance complement-mediated immunity in the presence of specific antibodies against antibiotic-resistant pneumococcal strains.

    Directory of Open Access Journals (Sweden)

    Elisa Ramos-Sevillano

    Full Text Available BACKGROUND: Specific antibodies mediate humoral and cellular protection against invading pathogens such as Streptococcus pneumoniae by activating complement mediated immunity, promoting phagocytosis and stimulating bacterial clearance. The emergence of pneumococcal strains with high levels of antibiotic resistance is of great concern worldwide and a serious threat for public health. METHODOLOGY/PRINCIPAL FINDINGS: Flow cytometry was used to determine whether complement-mediated immunity against three antibiotic-resistant S. pneumoniae clinical isolates is enhanced in the presence of sub-inhibitory concentrations of cefditoren and ceftriaxone. The binding of acute phase proteins such as C-reactive protein and serum amyloid P component, and of complement component C1q, to pneumococci was enhanced in the presence of serum plus either of these antibiotics. Both antibiotics therefore trigger the activation of the classical complement pathway against S. pneumoniae. C3b deposition was also increased in the presence of specific anti-pneumococcal antibodies and sub-inhibitory concentrations of cefditoren and ceftriaxone confirming that the presence of these antibiotics enhances complement-mediated immunity to S. pneumoniae. CONCLUSIONS/SIGNIFICANCE: Using cefditoren and ceftriaxone to promote the binding of acute phase proteins and C1q to pneumococci, and to increase C3b deposition, when anti-pneumococcal antibodies are present, might help reduce the impact of antibiotic resistance in S. pneumoniae infections.

  3. Desipramine increases cardiac parasympathetic activity via α2-adrenergic mechanism in rats.

    Science.gov (United States)

    Kawada, Toru; Akiyama, Tsuyoshi; Shimizu, Shuji; Fukumitsu, Masafumi; Kamiya, Atsunori; Sugimachi, Masaru

    2017-07-01

    Desipramine (DMI) is a blocker of neuronal norepinephrine (NE) uptake transporter. Although intravenous DMI has been shown to cause centrally-mediated sympathoinhibition and peripheral NE accumulation, its parasympathetic effect remains to be elucidated. We hypothesized that intravenous DMI activates the cardiac vagal nerve via an α 2 -adrenergic mechanism. Using a cardiac microdialysis technique, changes in myocardial interstitial acetylcholine (ACh) levels in the left ventricular free wall in response to intravenous DMI (1mg·kg -1 ) were examined in anesthetized rats. In rats with intact vagi (n=7), intravenous DMI increased ACh from 1.67±0.43 to 2.48±0.66nM (Padrenergic stimulation in experimental settings in vivo. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Specific binding of [3H]LY186126, an analogue of indolidan (LY195115), to cardiac membranes enriched in sarcoplasmic reticulum vesicles

    International Nuclear Information System (INIS)

    Kauffman, R.F.; Utterback, B.G.; Robertson, D.W.

    1989-01-01

    LY186126 was found to be a potent inhibitor of type IV cyclic AMP phosphodiesterase located in the sarcoplasmic reticulum of canine cardiac muscle. This compound, a close structural analogue of indolidan (LY195115), was prepared in high specific activity, tritiated form to study the positive inotropic receptor(s) for cardiotonic phosphodiesterase inhibitors such as indolidan and milrinone. A high-affinity binding site for [ 3 H]LY186126 was observed (Kd = 4 nM) in purified preparations of canine cardiac sarcoplasmic reticulum vesicles. Binding was proportional to vesicle protein, was inactivated by subjecting membranes to proteolysis or boiling, and was dependent on added Mg2+. Scatchard analysis suggested the presence of a single class of binding sites in the membrane preparation. Indolidan, milrinone, and LY186126 (all at 1 microM) produced essentially complete displacement of bound [ 3 H]LY186126, while nifedipine, propranolol, and prazosin had little or no effect at this concentration. This represents the first reported use of a radioactive analogue to label the inotropic receptor for cardiotonic phosphodiesterase inhibitors. The results suggest that [ 3 H]LY186126 is a useful radioligand for examining the subcellular site(s) responsible for positive inotropic effects of these drugs

  5. Cardiac MRI in restrictive cardiomyopathy

    Energy Technology Data Exchange (ETDEWEB)

    Gupta, A. [Department of Cardiovascular Radiology, All India Institute of Medical Sciences, Ansari Nagar, Delhi (India); Singh Gulati, G., E-mail: gulatigurpreet@rediffmail.com [Department of Cardiovascular Radiology, All India Institute of Medical Sciences, Ansari Nagar, Delhi (India); Seth, S. [Department of Cardiology, All India Institute of Medical Sciences, Ansari Nagar, Delhi (India); Sharma, S. [Department of Cardiovascular Radiology, All India Institute of Medical Sciences, Ansari Nagar, Delhi (India)

    2012-02-15

    Restrictive cardiomyopathy (RCM) is a specific group of heart muscle disorders characterized by inadequate ventricular relaxation during diastole. This leads to diastolic dysfunction with relative preservation of systolic function. Although short axis systolic function is usually preserved in RCM, the long axis systolic function may be severely impaired. Confirmation of diagnosis and information regarding aetiology, extent of myocardial damage, and response to treatment requires imaging. Importantly, differentiation from constrictive pericarditis (CCP) is needed, as only the latter is managed surgically. Echocardiography is the initial cardiac imaging technique but cannot reliably suggest a tissue diagnosis; although recent advances, especially tissue Doppler imaging and spectral tracking, have improved its ability to differentiate RCM from CCP. Cardiac catheterization is the reference standard, but is invasive, two-dimensional, and does not aid myocardial characterization. Cardiac magnetic resonance (CMR) is a versatile technique providing anatomical, morphological and functional information. In recent years, it has been shown to provide important information regarding disease mechanisms, and also been found useful to guide treatment, assess its outcome and predict patient prognosis. This review describes the CMR features of RCM, appearances in various diseases, its overall role in patient management, and how it compares with other imaging techniques.

  6. Deriving a cardiac ageing signature to reveal MMP-9-dependent inflammatory signalling in senescence.

    Science.gov (United States)

    Ma, Yonggang; Chiao, Ying Ann; Clark, Ryan; Flynn, Elizabeth R; Yabluchanskiy, Andriy; Ghasemi, Omid; Zouein, Fouad; Lindsey, Merry L; Jin, Yu-Fang

    2015-06-01

    Cardiac ageing involves the progressive development of cardiac fibrosis and diastolic dysfunction coordinated by MMP-9. Here, we report a cardiac ageing signature that encompasses macrophage pro-inflammatory signalling in the left ventricle (LV) and distinguishes biological from chronological ageing. Young (6-9 months), middle-aged (12-15 months), old (18-24 months), and senescent (26-34 months) mice of both C57BL/6J wild type (WT) and MMP-9 null were evaluated. Using an identified inflammatory pattern, we were able to define individual mice based on their biological, rather than chronological, age. Bcl6, Ccl24, and Il4 were the strongest inflammatory markers of the cardiac ageing signature. The decline in early-to-late LV filling ratio was most strongly predicted by Bcl6, Il1r1, Ccl24, Crp, and Cxcl13 patterns, whereas LV wall thickness was most predicted by Abcf1, Tollip, Scye1, and Mif patterns. With age, there was a linear increase in cardiac M1 macrophages and a decrease in cardiac M2 macrophages in WT mice; of which, both were prevented by MMP-9 deletion. In vitro, MMP-9 directly activated young macrophage polarization to an M1/M2 mid-transition state. Our results define the cardiac ageing inflammatory signature and assign MMP-9 roles in mediating the inflammaging profile by indirectly and directly modifying macrophage polarization. Our results explain early mechanisms that stimulate ageing-induced cardiac fibrosis and diastolic dysfunction. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  7. Andrographolide Attenuates LPS-Induced Cardiac Malfunctions Through Inhibition of IκB Phosphorylation and Apoptosis in Mice

    Directory of Open Access Journals (Sweden)

    Jinlong Zhang

    2015-11-01

    Full Text Available Background/Aims: Cardiac malfunction is a common complication in sepsis and significantly increases the mortality of patients in septic shock. However, no studies have examined whether andrographolide (And reduces LPS-induced myocardial malfunction. Methods: Left ventricular systolic and diastolic functions were examined using echocardiography. TNF-a and IL-1ß protein levels were detected by an enzyme-linked immunosorbent assay (ELISA. NO oxidation products were determined using Griess reagent. Protein expression levels of inhibitors of NF-κBa (IκB and phospho-IκB were determined via Western blot. Oxidative injury was determined by measuring myocardial lipid peroxidation and superoxide dismutase activity. Cardiac apoptosis was examined by terminal deoxynucleotidyl transferase-mediated dUTP nickend-labeling (TUNEL and cardiac caspase 3/7 activity. Results: And blunted LPS-induced myocardial malfunctions in mice. LPS induced TNF-a, IL-1ß, and NO production as well as I-κB phosphorylation. Cardiac apoptosis was attenuated via incubation with And, but the extent of oxidative injury remained unaffected. Conclusion: And prevents LPS-induced cardiac malfunctions in mice by inhibiting TNF-a, IL-1ß, and NO production, IκB phosphorylation, and cardiac apoptosis, indicating that And may be a potential agent for preventing myocardial malfunction during sepsis.

  8. Loss of microRNA-22 prevents high-fat diet induced dyslipidemia and increases energy expenditure without affecting cardiac hypertrophy.

    Science.gov (United States)

    Diniz, Gabriela Placoná; Huang, Zhan-Peng; Liu, Jianming; Chen, Jinghai; Ding, Jian; Fonseca, Renata Inzinna; Barreto-Chaves, Maria Luiza; Donato, Jose; Hu, Xiaoyun; Wang, Da-Zhi

    2017-12-15

    Obesity is associated with development of diverse diseases, including cardiovascular diseases and dyslipidemia. MiRNA-22 (miR-22) is a critical regulator of cardiac function and targets genes involved in metabolic processes. Previously, we generated miR-22 null mice and we showed that loss of miR-22 blunted cardiac hypertrophy induced by mechanohormornal stress. In the present study, we examined the role of miR-22 in the cardiac and metabolic alterations promoted by high-fat (HF) diet. We found that loss of miR-22 attenuated the gain of fat mass and prevented dyslipidemia induced by HF diet, although the body weight gain, or glucose intolerance and insulin resistance did not seem to be affected. Mechanistically, loss of miR-22 attenuated the increased expression of genes involved in lipogenesis and inflammation mediated by HF diet. Similarly, we found that miR-22 mediates metabolic alterations and inflammation induced by obesity in the liver. However, loss of miR-22 did not appear to alter HF diet induced cardiac hypertrophy or fibrosis in the heart. Our study therefore establishes miR-22 as an important regulator of dyslipidemia and suggests it may serve as a potential candidate in the treatment of dyslipidemia associated with obesity. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  9. Epidemiology and Outcomes After In-Hospital Cardiac Arrest After Pediatric Cardiac Surgery

    Science.gov (United States)

    Gupta, Punkaj; Jacobs, Jeffrey P.; Pasquali, Sara K.; Hill, Kevin D.; Gaynor, J. William; O’Brien, Sean M.; He, Max; Sheng, Shubin; Schexnayder, Stephen M.; Berg, Robert A.; Nadkarni, Vinay M.; Imamura, Michiaki; Jacobs, Marshall L.

    2014-01-01

    Background Multicenter data regarding cardiac arrest in children undergoing heart operations are limited. We describe epidemiology and outcomes associated with postoperative cardiac arrest in a large multiinstitutional cohort. Methods Patients younger than 18 years in the Society of Thoracic Surgeons Congenital Heart Surgery Database (2007 through 2012) were included. Patient factors, operative characteristics, and outcomes were described for patients with and without postoperative cardiac arrest. Multivariable models were used to evaluate the association of center volume with cardiac arrest rate and mortality after cardiac arrest, adjusting for patient and procedural factors. Results Of 70,270 patients (97 centers), 1,843 (2.6%) had postoperative cardiac arrest. Younger age, lower weight, and presence of preoperative morbidities (all p < 0.0001) were associated with cardiac arrest. Arrest rate increased with procedural complexity across common benchmark operations, ranging from 0.7% (ventricular septal defect repair) to 12.7% (Norwood operation). Cardiac arrest was associated with significant mortality risk across procedures, ranging from 15.4% to 62.3% (all p < 0.0001). In multivariable analysis, arrest rate was not associated with center volume (odds ratio, 1.06; 95% confidence interval, 0.71 to 1.57 in low- versus high-volume centers). However, mortality after cardiac arrest was higher in low-volume centers (odds ratio, 2.00; 95% confidence interval, 1.52 to 2.63). This association was present for both high- and low-complexity operations. Conclusions Cardiac arrest carries a significant mortality risk across the stratum of procedural complexity. Although arrest rates are not associated with center volume, lower-volume centers have increased mortality after cardiac arrest. Further study of mechanisms to prevent cardiac arrest and to reduce mortality in those with an arrest is warranted. PMID:25443018

  10. Combinatorial therapy of exercise-preconditioning and nanocurcumin formulation supplementation improves cardiac adaptation under hypobaric hypoxia.

    Science.gov (United States)

    Nehra, Sarita; Bhardwaj, Varun; Bansal, Anju; Saraswat, Deepika

    2017-09-26

    Chronic hypobaric hypoxia (cHH) mediated cardiac insufficiencies are associated with pathological damage. Sustained redox stress and work load are major causative agents of cardiac insufficiencies under cHH. Despite the advancements made in pharmacological (anti-oxidants, vasodilators) and non-pharmacological therapeutics (acclimatization strategies and schedules), only partial success has been achieved in improving cardiac acclimatization to cHH. This necessitates the need for potent combinatorial therapies to improve cardiac acclimatization at high altitudes. We hypothesize that a combinatorial therapy comprising preconditioning to mild aerobic treadmill exercise and supplementation with nanocurcumin formulation (NCF) consisting of nanocurcumin (NC) and pyrroloquinoline quinone (PQQ) might improve cardiac adaptation at high altitudes. Adult Sprague-Dawley rats pre-conditioned to treadmill exercise and supplemented with NCF were exposed to cHH (7620 m altitude corresponding to pO2~8% at 28±2°C, relative humidity 55%±1%) for 3 weeks. The rat hearts were analyzed for changes in markers of oxidative stress (free radical leakage, lipid peroxidation, manganese-superoxide dismutase [MnSOD] activity), cardiac injury (circulating cardiac troponin I [TnI] and T [cTnT], myocardial creatine kinase [CK-MB]), metabolic damage (lactate dehydrogenase [LDH] and acetyl-coenzyme A levels, lactate and pyruvate levels) and bio-energetic insufficiency (ATP, p-AMPKα). Significant modulations (p≤0.05) in cardiac redox status, metabolic damage, cardiac injury and bio-energetics were observed in rats receiving both NCF supplementation and treadmill exercise-preconditioning compared with rats receiving only one of the treatments. The combinatorial therapeutic strategy showed a tremendous improvement in cardiac acclimatization to cHH compared to either exercise-preconditioning or NCF supplementation alone which was evident from the effective modulation in redox, metabolic, contractile

  11. Inhibition of miR-155 Protects Against LPS-induced Cardiac Dysfunction and Apoptosis in Mice

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    Hui Wang

    2016-01-01

    Full Text Available Sepsis-induced myocardial dysfunction represents a major cause of death in intensive care units. Dysregulated microRNAs (miR-155 has been implicated in multiple cardiovascular diseases and miR-155 can be induced by lipopolysaccharide (LPS. However, the role of miR-155 in LPS-induced cardiac dysfunction is unclear. Septic cardiac dysfunction in mice was induced by intraperitoneal injection of LPS (5 mg/kg and miR-155 was found to be significantly increased in heart challenged with LPS. Pharmacological inhibition of miR-155 using antagomiR improved cardiac function and suppressed cardiac apoptosis induced by LPS in mice as determined by echocardiography, terminal deoxynucleotidyl transferase nick-end labeling (TUNEL assay, and Western blot for Bax and Bcl-2, while overexpression of miR-155 using agomiR had inverse effects. Pea15a was identified as a target gene of miR-155, mediating its effects in controlling apoptosis of cardiomyocytes as evidenced by luciferase reporter assays, quantitative real time-polymerase chain reaction, Western blot, and TUNEL staining. Noteworthy, miR-155 was also found to be upregulated in the plasma of patients with septic cardiac dysfunction compared to sepsis patients without cardiac dysfunction, indicating a potential clinical relevance of miR-155. The receiver-operator characteristic curve indicated that plasma miR-155 might be a biomarker for sepsis patients developing cardiac dysfunction. Therefore, inhibition of miR-155 represents a novel therapy for septic myocardial dysfunction.

  12. Intracellular localisation of proteins to specific cellular areas by nanocapsule mediated delivery.

    Science.gov (United States)

    Wang, Huabin; Chen, Ligang; Sun, Xianchao; Fu, Ailing

    2017-09-01

    Nanocapsules are promising carriers with great potential for intracellular protein transport. Although many studies have intended to improve cell uptake efficacy, there is an increasing interest in understanding of subcellular distribution of cargoes inside cells, which is essential for purposeful delivery of biomolecules into specific sites within cells. Herein, we interrogate the intracellular localisation of exogenous proteins, including fluorescein isothiocyanate (FITC)-labelled bovine serum albumin (BSA) and green fluorescent protein (GFP), mediated by specially designed nanocapsules. The results show that the designed nanocapsules can deliver the two types of fluorescent proteins into different cellular destinations (cytosol, nucleus or the whole cell), depending on the composition of nanocapsules. Meanwhile, several impact factors that influence the distribution of proteins in cells have also been investigated, and the results suggest that the localisation of capsule-mediated proteins in cells is strongly affected by the surface properties of nanocapsules, the types of stabilisers and proteins, and environmental temperatures. The rational control of intracellular localised delivery of exogenous proteins as we demonstrated in this study might open new avenues to obtain desired magnitude of drug effects for modulating cell activity.

  13. [Cardiac rehabilitation: current status and future challenges].

    Science.gov (United States)

    Hahmann, H W

    2012-02-01

    The goal of cardiac rehabilitation is to support heart patients using a multidisciplinary team in order to obtain the best possible physical and mental health and achieve long-term social reintegration. In addition to improving physical fitness, cardiac rehabilitation restores self-confidence, thus better equipping patients to deal with mental illness and improving their social reintegration ("participation"). Once the causes of disease have been identified and treated as effectively as possible, drug and lifestyle changes form the focus of cardiac rehabilitation measures. In particular diseases, rehabilitation offers the opportunity for targeted educational courses for diabetics or drug dose escalation, as well as special training for heart failure patients. A nationwide network of outpatient heart groups is available for targeted follow-up. Cardiac patients predominantly rehabilitated in follow-up rehabilitation are older and have greater morbidity than in the past; moreover, they generally come out of acute clinical care earlier and are discharged from hospital more quickly. The proportion of severely ill and multimorbid patients presents a diagnostic and therapeutic challenge in cardiac rehabilitation, although cardiac rehabilitation was not initially conceived for this patient group. The benefit of cardiac rehabilitation has been a well documented reduction in morbidity and mortality. However, hurdles remain, partly due to the patients themselves, partly due to the health insurers. Some insurance providers still refuse rehabilitation for non-ST-segment elevation infarction. In principle rehabilitation can be carried out in an inpatient or an outpatient setting. Specific allocation criteria have not yet been established, but the structure and process quality of outpatient rehabilitation should correspond to that of the inpatient setting. The choice between the two settings should be based on pragmatic criteria. Both settings should be possible for an individual

  14. Cardiac overexpression of Mammalian enabled (Mena) exacerbates heart failure in mice.

    Science.gov (United States)

    Belmonte, Stephen L; Ram, Rashmi; Mickelsen, Deanne M; Gertler, Frank B; Blaxall, Burns C

    2013-09-15

    Mammalian enabled (Mena) is a key regulator of cytoskeletal actin dynamics, which has been implicated in heart failure (HF). We have previously demonstrated that cardiac Mena deletion produced cardiac dysfunction with conduction abnormalities and hypertrophy. Moreover, elevated Mena expression correlates with HF in human and animal models, yet the precise role of Mena in cardiac pathophysiology is unclear. In these studies, we evaluated mice with cardiac myocyte-specific Mena overexpression (TTA/TgTetMena) comparable to that observed in cardiac pathology. We found that the hearts of TTA/TgTetMena mice were functionally and morphologically comparable to wild-type littermates, except for mildly increased heart mass in the transgenic mice. Interestingly, TTA/TgTetMena mice were particularly susceptible to cardiac injury, as these animals experienced pronounced decreases in ejection fraction and fractional shortening as well as heart dilatation and hypertrophy after transverse aortic constriction (TAC). By "turning off" Mena overexpression in TTA/TgTetMena mice either immediately prior to or immediately after TAC surgery, we discovered that normalizing Mena levels eliminated cardiac hypertrophy in TTA/TgTetMena animals but did not preclude post-TAC cardiac functional deterioration. These findings indicate that hearts with increased levels of Mena fare worse when subjected to cardiac injury and suggest that Mena contributes to HF pathophysiology.

  15. Stimulating endogenous cardiac regeneration

    Directory of Open Access Journals (Sweden)

    Amanda eFinan

    2015-09-01

    Full Text Available The healthy adult heart has a low turnover of cardiac myocytes. The renewal capacity, however, is augmented after cardiac injury. Participants in cardiac regeneration include cardiac myocytes themselves, cardiac progenitor cells, and peripheral stem cells, particularly from the bone marrow compartment. Cardiac progenitor cells and bone marrow stem cells are augmented after cardiac injury, migrate to the myocardium, and support regeneration. Depletion studies of these populations have demonstrated their necessary role in cardiac repair. However, the potential of these cells to completely regenerate the heart is limited. Efforts are now being focused on ways to augment these natural pathways to improve cardiac healing, primarily after ischemic injury but in other cardiac pathologies as well. Cell and gene therapy or pharmacological interventions are proposed mechanisms. Cell therapy has demonstrated modest results and has passed into clinical trials. However, the beneficial effects of cell therapy have primarily been their ability to produce paracrine effects on the cardiac tissue and recruit endogenous stem cell populations as opposed to direct cardiac regeneration. Gene therapy efforts have focused on prolonging or reactivating natural signaling pathways. Positive results have been demonstrated to activate the endogenous stem cell populations and are currently being tested in clinical trials. A potential new avenue may be to refine pharmacological treatments that are currently in place in the clinic. Evidence is mounting that drugs such as statins or beta blockers may alter endogenous stem cell activity. Understanding the effects of these drugs on stem cell repair while keeping in mind their primary function may strike a balance in myocardial healing. To maximize endogenous cardiac regeneration,a combination of these approaches couldameliorate the overall repair process to incorporate the participation ofmultiple cell players.

  16. Autobiographical memory specificity and the persistence of depressive symptoms in HIV-positive patients: rumination and social problem-solving skills as mediators.

    Science.gov (United States)

    Yanes, Paula K; Morse, Gene; Hsiao, Chiu-Bin; Simms, Leonard; Roberts, John E

    2012-01-01

    Individuals infected with human immunodeficiency virus (HIV) are at elevated risk for depressive conditions, which in turn can negatively impact health-related behaviours and the course of illness. The present study tested the role of autobiographical memory specificity and its interaction with perceived stress in the persistence of depressive symptoms among dysphoric HIV-positive individuals. Additionally, we examined whether rumination and social problem solving mediated these effects. Results indicated that memory specificity moderated the impact of perceived stress, such that perceived stress was more strongly associated with follow-up depressive symptoms among those with greater memory specificity. Rumination, but not social problem solving, mediated this effect. Implications of these findings are discussed.

  17. Carbon monoxide exposure enhances arrhythmia after cardiac stress: involvement of oxidative stress.

    Science.gov (United States)

    André, Lucas; Gouzi, Fares; Thireau, Jérôme; Meyer, Gregory; Boissiere, Julien; Delage, Martine; Abdellaoui, Aldja; Feillet-Coudray, Christine; Fouret, Gilles; Cristol, Jean-Paul; Lacampagne, Alain; Obert, Philippe; Reboul, Cyril; Fauconnier, Jérémy; Hayot, Maurice; Richard, Sylvain; Cazorla, Olivier

    2011-11-01

    Arrhythmias following cardiac stress are a key predictor of death in healthy population. Carbon monoxide (CO) is a ubiquitous pollutant promoting oxidative stress and associated with hospitalization for cardiovascular disease and cardiac mortality. We investigated the effect of chronic CO exposure on the occurrence of arrhythmic events after a cardiac stress test and the possible involvement of related oxidative stress. Wistar rats exposed chronically (4 weeks) to sustained urban CO pollution presented more arrhythmic events than controls during recovery after cardiac challenge with isoprenaline in vivo. Sudden death occurred in 22% of CO-exposed rats versus 0% for controls. Malondialdehyde (MDA), an end-product of lipid peroxidation, was increased in left ventricular tissue of CO-exposed rats. Cardiomyocytes isolated from CO-exposed rats showed higher reactive oxygen species (ROS) production (measured with MitoSox Red dye), higher diastolic Ca(2+) resulting from SR calcium leak and an higher occurrence of irregular Ca(2+) transients (measured with Indo-1) in comparison to control cells after a high pacing sequence. Acute treatment with a ROS scavenger (N-acetylcysteine, 20 mmol/L, 1 h) prevented this sequence of alterations and decreased the number of arrhythmic cells following high pacing. Chronic CO exposure promotes oxidative stress that alters Ca(2+) homeostasis (through RYR2 and SERCA defects) and thereby mediates the triggering of ventricular arrhythmia after cardiac stress that can lead to sudden death.

  18. Perspectives on Current Training Guidelines for Cardiac Imaging and Recommendations for the Future.

    Science.gov (United States)

    Arrighi, James A; Kilic, Sena; Haines, Philip G

    2018-04-23

    To summarize current training guidelines for cardiac imaging and provide recommendations for future guidelines. The current structure of training in cardiac imaging is largely dictated by modality-specific guidelines. While there has been debate on how to define the advanced cardiac imager for over a decade, a uniform consensus has not emerged. We report the perspectives of three key stakeholders in this debate: a senior faculty member-former fellowship program director, a cardiology fellow, and an academic junior faculty imaging expert. The observations of these stakeholders suggest that there is no consensus on the definition of advanced cardiac imaging, leading to ambiguity in training guidelines. This may have negative impact on recruitment of fellows into cardiac imaging careers. Based on the current status of training in cardiac imaging, the authors suggest that the relevant professional groups reconvene to form a consensus in defining advanced cardiac imaging, in order to guide future revisions of training guidelines.

  19. High Density Sphere Culture of Adult Cardiac Cells Increases the Levels of Cardiac and Progenitor Markers and Shows Signs of Vasculogenesis

    Directory of Open Access Journals (Sweden)

    Kristina Vukusic

    2013-01-01

    Full Text Available 3D environment and high cell density play an important role in restoring and supporting the phenotypes of cells represented in cardiac tissues. The aim of this study was therefore to investigate the suitability of high density sphere (HDS cultures for studies of cardiomyocyte-, endothelial-, and stem-cell biology. Primary adult cardiac cells from nine human biopsies were cultured using different media for up to 9 weeks. The possibilities to favor a certain cell phenotype and induce production of extra cellular matrix (ECM were studied by histology, immunohistochemistry, and quantitative real-time PCR. Defined media gave significant increase in both cardiac- and progenitor-specific markers and also an intraluminal position of endothelial cells over time. Cardiac media showed indication of differentiation and maturity of HDS considering the ECM production and activities within NOTCH regulation but no additional cardiac differentiation. Endothelial media gave no positive effects on endothelial phenotype but increased proliferation without fibroblast overgrowth. In addition, indications for early vasculogenesis were found. It was also possible to affect the Wnt signaling in HDS by addition of a glycogen synthase kinase 3 (GSK3 inhibitor. In conclusion, these findings show the suitability of HDS as in vitro model for studies of cardiomyocyte-, endothelial-, and stem-cell biology.

  20. Concise Review: Fluorescent Reporters in Human Pluripotent Stem Cells: Contributions to Cardiac Differentiation and Their Applications in Cardiac Disease and Toxicity.

    Science.gov (United States)

    Den Hartogh, Sabine C; Passier, Robert

    2016-01-01

    In the last decade, since the first report of induced pluripotent stem cells, the stem cell field has made remarkable progress in the differentiation to specialized cell-types of various tissues and organs, including the heart. Cardiac lineage- and tissue-specific human pluripotent stem cell (hPSC) reporter lines have been valuable for the identification, selection, and expansion of cardiac progenitor cells and their derivatives, and for our current understanding of the underlying molecular mechanisms. In order to further advance the use of hPSCs in the fields of regenerative medicine, disease modeling, and preclinical drug development in cardiovascular research, it is crucial to identify functionally distinct cardiac subtypes and to study their biological signaling events and functional aspects in healthy and diseased conditions. In this review, we discuss the various strategies that have been followed to generate and study fluorescent reporter lines in hPSCs and provide insights how these reporter lines contribute to a better understanding and improvement of cell-based therapies and preclinical drug and toxicity screenings in the cardiac field. © AlphaMed Press.

  1. Capturing the cardiac effects of racial discrimination: Do the effects "keep going"?

    Science.gov (United States)

    Hoggard, Lori S; Hill, LaBarron K; Gray, DeLeon L; Sellers, Robert M

    2015-08-01

    Racial discrimination negatively impacts cardiac functioning, but few studies examine the more distal cardiac effects of racial discrimination experiences. The present study examined the momentary and prolonged impact of lab-based intergroup and intragroup racial discrimination on heart rate variability (HRV) and heart rate (HR) in a sample (N = 42) of African American (AA) women across two days. On day one, the women were exposed to simulated racial discrimination from either a European American (EA) or AA confederate in the lab. On day two, the women returned to the lab for additional physiological recording and debriefing. Women insulted by the EA confederate exhibited lower HRV on day one and marginally lower HRV on day two. These women also exhibited marginally higher HR on day two. The HRV and HR effects on day two were not mediated by differences in perseveration about the stressor. The findings indicate that racial discrimination - particularly intergroup racial discrimination - may have both momentary and prolonged effects on cardiac activity in AAs. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. The gender specific mediational pathways between parenting styles, neuroticism, pathological reasons for drinking, and alcohol-related problems in emerging adulthood.

    Science.gov (United States)

    Patock-Peckham, Julie A; Morgan-Lopez, Antonio A

    2009-03-01

    Mediational links between parenting styles, neuroticism, pathological reasons for drinking, alcohol use and alcohol-related problems were tested. A two-group SEM path model with 441 (216 female, 225 male) college students was examined. In general, pathological reasons for drinking mediated the impact of neuroticism on alcohol use and alcohol-related problems. A different pattern of relationships was found for each of the two genders. Perceptions of having an authoritarian father were positively linked to higher levels of neuroticism among males but this pattern was not found among females. For males, neuroticism mediated the impact of having an authoritarian father on pathological reasons for drinking with pathological reasons for drinking mediating the impact of neuroticism on alcohol-related problems. Perceptions of having a permissive father were linked to lower levels of neuroticism in females (but have been found as a consistent risk factor for other pathways to alcohol use elsewhere). Compared with other work in this area, these findings indicate parental influences regarding vulnerabilities for alcohol use may be specific to parent-child gender matches for some pathways and specific to one parent (irrespective of child gender) for other pathways.

  3. Cardiac rehabilitation

    Science.gov (United States)

    ... rehab; Heart failure - cardiac rehab References Anderson L, Taylor RS. Cardiac rehabilitation for people with heart disease: ... of Medicine, Division of Cardiology, Harborview Medical Center, University of Washington Medical School, Seattle, WA. Also reviewed ...

  4. Current Pharmacological Advances in the Treatment of Cardiac Arrest

    Directory of Open Access Journals (Sweden)

    Andry Papastylianou

    2012-01-01

    Full Text Available Cardiac arrest is defined as the sudden cessation of spontaneous ventilation and circulation. Within 15 seconds of cardiac arrest, the patient loses consciousness, electroencephalogram becomes flat after 30 seconds, pupils dilate fully after 60 seconds, and cerebral damage takes place within 90–300 seconds. It is essential to act immediately as irreversible damage can occur in a short time. Cardiopulmonary resuscitation (CPR is an attempt to restore spontaneous circulation through a broad range of interventions which are early defibrillation, high-quality and uninterrupted chest compressions, advanced airway interventions, and pharmacological interventions. Drugs should be considered only after initial shocks have been delivered (when indicated and chest compressions and ventilation have been started. During cardiopulmonary resuscitation, no specific drug therapy has been shown to improve survival to hospital discharge after cardiac arrest, and only few drugs have a proven benefit for short-term survival. This paper reviews current pharmacological treatment of cardiac arrest. There are three groups of drugs relevant to the management of cardiac arrest: vasopressors, antiarrhythmics, and other drugs such as sodium bicarbonate, calcium, magnesium, atropine, fibrinolytic drugs, and corticosteroids.

  5. Patient perceptions of experience with cardiac rehabilitation after isolated heart valve surgery

    DEFF Research Database (Denmark)

    Hansen, Tina B; Berg, Selina K; Sibilitz, Kirstine L

    2018-01-01

    in a cardiac rehabilitation programme, and none have analysed their experiences with it. AIMS: The purpose of this qualitative analysis was to gain insight into patients' experiences in cardiac rehabilitation, the CopenHeartVR trial. This trial specifically assesses patients undergoing isolated heart valve...... to take active personal responsibility for their health. Despite these benefits, participants experienced existential and psychological challenges and musculoskeletal problems. Participants also sought additional advice from healthcare professionals both inside and outside the healthcare system....... CONCLUSIONS: Even though the cardiac rehabilitation programme reduced insecurity and helped participants take active personal responsibility for their health, they experienced existential, psychological and physical challenges during recovery. The cardiac rehabilitation programme had several limitations...

  6. Postmortem cardiac imaging in fetuses and children

    International Nuclear Information System (INIS)

    Taylor, Andrew M.; Arthurs, Owen J.; Sebire, Neil J.

    2015-01-01

    Fetal and pediatric cardiac autopsies have a crucial role in the counseling of parents with regard to both the cause of death of their child and the implications of such findings for future pregnancies, as well as for quality assurance of antenatal screening programs and antemortem diagnostic procedures. Postmortem imaging allows an opportunity to investigate the heart in situ prior to dissection, and both postmortem CT and postmortem MRI have shown excellent accuracy in detecting the majority of clinically significant cardiac lesions in the perinatal and pediatric population. As less-invasive autopsy becomes increasingly popular, clinical guidelines for maximal diagnostic yield in specific circumstances can be developed. (orig.)

  7. Postmortem cardiac imaging in fetuses and children

    Energy Technology Data Exchange (ETDEWEB)

    Taylor, Andrew M. [Great Ormond Street Hospital for Children NHS Foundation Trust, Cardiorespiratory Division, Level 7, Old Nurses Home, London (United Kingdom); UCL Institute of Cardiovascular Science, London (United Kingdom); Arthurs, Owen J. [Great Ormond Street Hospital for Children NHS Foundation Trust, Department of Radiology, London (United Kingdom); UCL Institute of Cardiovascular Science, London (United Kingdom); Sebire, Neil J. [UCL Institute of Cardiovascular Science, London (United Kingdom); Great Ormond Street Hospital for Children NHS Foundation Trust, Department of Histopathology, London (United Kingdom)

    2015-04-01

    Fetal and pediatric cardiac autopsies have a crucial role in the counseling of parents with regard to both the cause of death of their child and the implications of such findings for future pregnancies, as well as for quality assurance of antenatal screening programs and antemortem diagnostic procedures. Postmortem imaging allows an opportunity to investigate the heart in situ prior to dissection, and both postmortem CT and postmortem MRI have shown excellent accuracy in detecting the majority of clinically significant cardiac lesions in the perinatal and pediatric population. As less-invasive autopsy becomes increasingly popular, clinical guidelines for maximal diagnostic yield in specific circumstances can be developed. (orig.)

  8. Antimyosin imaging in cardiac transplant rejection

    International Nuclear Information System (INIS)

    Johnson, L.L.; Cannon, P.J.

    1991-01-01

    Fab fragments of antibodies specific for cardiac myosin have been labeled with indium-111 and injected intravenously into animals and into patients with heart transplants. The antibodies, developed by Khaw, Haber, and co-workers, localize in cardiac myocytes that have been damaged irreversibly by ischemia, myocarditis, or the rejection process. After clearance of the labeled antibody from the cardiac blood pool, planar imaging or single photon emission computed tomography is performed. Scintigrams reveal the uptake of the labeled antimyosin in areas of myocardium undergoing transplant rejection. In animal studies, the degree of antimyosin uptake appears to correlate significantly with the degree of rejection assessed at necropsy. In patients, the correlation between scans and pathologic findings from endomyocardial biopsy is not as good, possibly because of sampling error in the endomyocardial biopsy technique. The scan results at 1 year correlate with either late complications (positive) or benign course (negative). Current limitations of the method include slow blood clearance, long half-life of indium-111, and hepatic uptake. Overcoming these limitations represents a direction for current research. It is possible that from these efforts a noninvasive approach to the diagnosis and evaluation of cardiac transplantation may evolve that will decrease the number of endomyocardial biopsies required to evaluate rejection. This would be particularly useful in infants and children. 31 references

  9. Sarcopenia and physical activity in older male cardiac patients.

    Science.gov (United States)

    Izawa, Kazuhiro P; Watanabe, Satoshi; Oka, Koichiro; Kasahara, Yusuke; Morio, Yuji; Hiraki, Koji; Hirano, Yasuyuki; Omori, Yutaka; Suzuki, Norio; Kida, Keisuke; Suzuki, Kengo; Akashi, Yoshihiro J

    2016-11-01

    There is little information on the association of sarcopenia with physical activity in elderly cardiac patients. This study determined differences in physical activity and cutoff values for physical activity according to the presence or absence of sarcopenia in elderly male cardiac patients. Sixty-seven consecutive men aged ≥65 years with cardiac disease were enrolled. We defined sarcopenia using the European Working Group on Sarcopenia in Older People algorithm. Patients were divided into the sarcopenia group (n=25) and the non-sarcopenia group (n=42). In the patients with and without sarcopenia of physical activities were evaluated to determine cutoff values of physical activity. After adjusting for patient characteristics, both the average daily number of steps (3361.43±793.23 vs. 5991.55±583.57 steps, P=0.021) and the average daily energy expenditure of physical activity (71.84±22.19 vs. 154.57±16.18kcal, P=0.009) were significantly lower in the sarcopenia versus non-sarcopenia group. Receiver-operating characteristic analysis identified a cutoff value for steps of physical activity of 3551.80steps/day for 1 week, with a sensitivity of 0.73 and 1-specificity of 0.44 and a cutoff value for energy expenditure of physical activity of 85.17kcal/day for 1 week, with a sensitivity of 0.73 and 1-specificity of 0.27. Physical activity in the male cardiac patients with sarcopenia was significantly lower than that in those without sarcopenia. The cutoff values reported here may be useful values to aid in the identification of elderly male cardiac patients with sarcopenia. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. QTc-prolonging drugs and hospitalizations for cardiac arrhythmias

    DEFF Research Database (Denmark)

    De Bruin, Marie L; Hoes, Arno W; Leufkens, Hubert G M

    2003-01-01

    Cardiac arrhythmia as an adverse effect of noncardiac drugs has been an issue of growing importance during the past few years. In this population-based study, we evaluated the risk for serious cardiac arrhythmias during the use of several noncardiac QTc-prolonging drugs in day-to-day practice......, and subsequently focused on several specific groups of patients who could be extremely vulnerable for drug-induced arrhythmias. We performed a case-control study in which patients (cases), hospitalized for nonatrial cardiac arrhythmias from 1987 to 1998, were compared with their matched controls regarding current...... use of QTc-prolonging drugs. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariate conditional logistic regression, adjusting for potential confounding factors. Data were obtained from the PHARMO record linkage system. We identified 501 cases, 39 of whom used QTc...

  11. Ripk3 regulates cardiac microvascular reperfusion injury: The role of IP3R-dependent calcium overload, XO-mediated oxidative stress and F-action/filopodia-based cellular migration.

    Science.gov (United States)

    Zhou, Hao; Wang, Jin; Zhu, Pingjun; Hu, Shunying; Ren, Jun

    2018-05-01

    Ripk3-mediated cellular apoptosis is a major contributor to the pathogenesis of myocardial ischemia reperfusion (IR) injury. However, the mechanisms by which Ripk3 influences microvascular homeostasis and endothelial apoptosis are not completely understood. In this study, loss of Ripk3 inhibited endothelial apoptosis, alleviated luminal swelling, maintained microvasculature patency, reduced the expression of adhesion molecules and limited the myocardial inflammatory response. In vitro, Ripk3 deficiency protected endothelial cells from apoptosis and migratory arrest induced by HR injury. Mechanistically, Ripk3 had the ability to migrate onto the endoplasmic reticulum (ER), leading to ER damage, as evidenced by increased IP3R and XO expression. The higher IP3R content was associated with cellular calcium overload, and increased XO expression was involved in cellular oxidative injury. Furthermore, IP3R-mediated calcium overload and XO-dependent oxidative damage were able to initiate cellular apoptosis. More importantly, IP3R and XO also caused F-actin degradation into G-actin via post-transcriptional modification of cofilin, impairing the formation of the filopodia and limiting the migratory response of endothelial cells. Altogether, our data confirmed that Ripk3 was involved in microvascular IR injury via regulation of IP3R-mediated calcium overload, XO-dependent oxidative damage and filopodia-related cellular migration, ultimately leading to endothelial apoptosis and migratory inhibition. These findings provide a potential target for treating cardiac microcirculatory IR injury. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. Chronic medical conditions and mental health in older people : disability and psychosocial resources mediate specific mental health effects

    NARCIS (Netherlands)

    Ormel, J; Kempen, GIJM; Penninx, BWJH; Brilman, EI; Beekman, ATF; VanSonderen, E

    Background. This study describes the differences in psychological distress, disability and psychosocial resources between types of major medical conditions and sensory impairments (collectively denoted as CMCs); and tests whether disability and psychosocial resources mediate CMC-specific mental

  13. Cardiac manifestations of GH deficiency after treatment for acromegaly: a comparison to patients with biochemical remission and controls

    NARCIS (Netherlands)

    van der Klaauw, Agatha A.; Bax, Jeroen J.; Bleeker, Gabe B.; Holman, Eduard R.; Delgado, V.; Smit, Johannes W. A.; Romijn, Johannes A.; Pereira, Alberto M.

    2008-01-01

    Both GH excess and GH deficiency (GHD) lead to specific cardiac pathology. The aim of this study was to evaluate cardiac morphology and function in patients with GHD after treatment for acromegaly. Cross-sectional study. Cardiac parameters were studied by conventional two-dimensional

  14. Bisexual-Specific Minority Stressors, Psychological Distress, and Suicidality in Bisexual Individuals: the Mediating Role of Loneliness.

    Science.gov (United States)

    Mereish, Ethan H; Katz-Wise, Sabra L; Woulfe, Julie

    2017-08-01

    Bisexual individuals are at higher risk for poor mental health outcomes compared to heterosexual as well as lesbian and gay individuals and experience minority stressors, such as discrimination, from both heterosexual and sexual minority communities. However, there is little research examining the negative effects of bisexual-specific minority stressors on bisexual individuals' mental health as well as psychological factors that might help explain minority stressors' deleterious effects. This research examined the effects of distal minority stressors (i.e., anti-bisexual experiences from both heterosexual as well as lesbian and gay people) and proximal stressors (i.e., internalized heterosexism and sexual orientation concealment) on psychological distress and suicidality among bisexual adults (N = 503). Building on the relational framing of the minority stress model, we also tested one relational factor (i.e., loneliness) as a mediator of the associations between distal and proximal minority stressors and poor mental health (i.e., psychological distress and suicidality). Structural equation modeling analyses were used to test the mediating effects of loneliness on the associations between minority stressors and psychological distress and suicidality. Although distal and proximal minority stressors were not associated with each other, loneliness mediated the effects of distal and proximal minority stressors on psychological distress and suicidality. The results of this study underscore the importance of targeting bisexual-specific minority stressors as well as loneliness in preventive interventions to improve the mental health of bisexual individuals.

  15. Defining the Intrinsic Cardiac Risks of Operations to Improve Preoperative Cardiac Risk Assessments.

    Science.gov (United States)

    Liu, Jason B; Liu, Yaoming; Cohen, Mark E; Ko, Clifford Y; Sweitzer, Bobbie J

    2018-02-01

    Current preoperative cardiac risk stratification practices group operations into broad categories, which might inadequately consider the intrinsic cardiac risks of individual operations. We sought to define the intrinsic cardiac risks of individual operations and to demonstrate how grouping operations might lead to imprecise estimates of perioperative cardiac risk. Elective operations (based on Common Procedural Terminology codes) performed from January 1, 2010 to December 31, 2015 at hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program were studied. A composite measure of perioperative adverse cardiac events was defined as either cardiac arrest requiring cardiopulmonary resuscitation or acute myocardial infarction. Operations' intrinsic cardiac risks were derived from mixed-effects models while controlling for patient mix. Resultant risks were sorted into low-, intermediate-, and high-risk categories, and the most commonly performed operations within each category were identified. Intrinsic operative risks were also examined using a representative grouping of operations to portray within-group variation. Sixty-six low, 30 intermediate, and 106 high intrinsic cardiac risk operations were identified. Excisional breast biopsy had the lowest intrinsic cardiac risk (overall rate, 0.01%; odds ratio, 0.11; 95% CI, 0.02 to 0.25) relative to the average, whereas aorto-bifemoral bypass grafting had the highest (overall rate, 4.1%; odds ratio, 6.61; 95% CI, 5.54 to 7.90). There was wide variation in the intrinsic cardiac risks of operations within the representative grouping (median odds ratio, 1.40; interquartile range, 0.88 to 2.17). A continuum of intrinsic cardiac risk exists among operations. Grouping operations into broad categories inadequately accounts for the intrinsic cardiac risk of individual operations.

  16. Apocynin improving cardiac remodeling in chronic renal failure disease is associated with up-regulation of epoxyeicosatrienoic acids.

    Science.gov (United States)

    Zhang, Kun; Liu, Yu; Liu, Xiaoqiang; Chen, Jie; Cai, Qingqing; Wang, Jingfeng; Huang, Hui

    2015-09-22

    Cardiac remodeling is one of the most common cardiac abnormalities and associated with a high mortality in chronic renal failure (CRF) patients. Apocynin, a nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase inhibitor, has been showed cardio-protective effects. However, whether apocynin can improve cardiac remodeling in CRF and what is the underlying mechanism are unclear. In the present study, we enrolled 94 participants. In addition, we used 5/6 nephrectomized rats to mimic cardiac remodeling in CRF. Serum levels of epoxyeicosatrienoic acids (EETs) and its mainly metabolic enzyme-soluble epoxide hydrolase (sEH) were measured. The results showed that the serum levels of EETs were significantly decreased in renocardiac syndrome participants (P < 0.05). In 5/6 nephrectomized CRF model, the ratio of left ventricular weight / body weight, left ventricular posterior wall thickness, and cardiac interstitial fibrosis were significantly increased while ejection fraction significantly decreased (P < 0.05). All these effects could partly be reversed by apocynin. Meanwhile, we found during the process of cardiac remodeling in CRF, apocynin significantly increased the reduced serum levels of EETs and decreased the mRNA and protein expressions of sEH in the heart (P < 0.05). Our findings indicated that the protective effect of apocynin on cardiac remodeling in CRF was associated with the up-regulation of EETs. EETs may be a new mediator for the injury of kidney-heart interactions.

  17. Apocynin improving cardiac remodeling in chronic renal failure disease is associated with up-regulation of epoxyeicosatrienoic acids

    Science.gov (United States)

    Chen, Jie; Cai, Qingqing; Wang, Jingfeng; Huang, Hui

    2015-01-01

    Cardiac remodeling is one of the most common cardiac abnormalities and associated with a high mortality in chronic renal failure (CRF) patients. Apocynin, a nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase inhibitor, has been showed cardio-protective effects. However, whether apocynin can improve cardiac remodeling in CRF and what is the underlying mechanism are unclear. In the present study, we enrolled 94 participants. In addition, we used 5/6 nephrectomized rats to mimic cardiac remodeling in CRF. Serum levels of epoxyeicosatrienoic acids (EETs) and its mainly metabolic enzyme-soluble epoxide hydrolase (sEH) were measured. The results showed that the serum levels of EETs were significantly decreased in renocardiac syndrome participants (P < 0.05). In 5/6 nephrectomized CRF model, the ratio of left ventricular weight /body weight, left ventricular posterior wall thickness, and cardiac interstitial fibrosis were significantly increased while ejection fraction significantly decreased (P < 0.05). All these effects could partly be reversed by apocynin. Meanwhile, we found during the process of cardiac remodeling in CRF, apocynin significantly increased the reduced serum levels of EETs and decreased the mRNA and protein expressions of sEH in the heart (P < 0.05). Our findings indicated that the protective effect of apocynin on cardiac remodeling in CRF was associated with the up-regulation of EETs. EETs may be a new mediator for the injury of kidney-heart interactions. PMID:26322503

  18. Optical mapping of optogenetically shaped cardiac action potentials

    Science.gov (United States)

    Park, Sarah A.; Lee, Shin-Rong; Tung, Leslie; Yue, David T.

    2014-01-01

    Light-mediated silencing and stimulation of cardiac excitability, an important complement to electrical stimulation, promises important discoveries and therapies. To date, cardiac optogenetics has been studied with patch-clamp, multielectrode arrays, video microscopy, and an all-optical system measuring calcium transients. The future lies in achieving simultaneous optical acquisition of excitability signals and optogenetic control, both with high spatio-temporal resolution. Here, we make progress by combining optical mapping of action potentials with concurrent activation of channelrhodopsin-2 (ChR2) or halorhodopsin (eNpHR3.0), via an all-optical system applied to monolayers of neonatal rat ventricular myocytes (NRVM). Additionally, we explore the capability of ChR2 and eNpHR3.0 to shape action-potential waveforms, potentially aiding the study of short/long QT syndromes that result from abnormal changes in action potential duration (APD). These results show the promise of an all-optical system to acquire action potentials with precise temporal optogenetics control, achieving a long-sought flexibility beyond the means of conventional electrical stimulation. PMID:25135113

  19. Cardiac magnetic resonance radiofrequency tissue tagging for diagnosis of constrictive pericarditis: A proof of concept study.

    Science.gov (United States)

    Power, John A; Thompson, Diane V; Rayarao, Geetha; Doyle, Mark; Biederman, Robert W W

    2016-05-01

    Invasive cardiac catheterization is the venerable "gold standard" for diagnosing constrictive pericarditis. However, its sensitivity and specificity vary dramatically from center to center. Given the ability to unequivocally define segments of the pericardium with the heart via radiofrequency tissue tagging, we hypothesize that cardiac magnetic resonance has the capability to be the new gold standard. All patients who were referred for cardiac magnetic resonance evaluation of constrictive pericarditis underwent cardiac magnetic resonance radiofrequency tissue tagging to define visceral-parietal pericardial adherence to determine constriction. This was then compared with intraoperative surgical findings. Likewise, all preoperative cardiac catheterization testing was reviewed in a blinded manner. A total of 120 patients were referred for clinical suspicion of constrictive pericarditis. Thirty-nine patients were defined as constrictive pericarditis positive solely via radiofrequency tissue-tagging cardiac magnetic resonance, of whom 21 were positive, 4 were negative, and 1 was equivocal for constrictive pericarditis, as defined by cardiac catheterization. Of these patients, 16 underwent pericardiectomy and were surgically confirmed. There was 100% agreement between cardiac magnetic resonance-defined constrictive pericarditis positivity and postsurgical findings. No patients were misclassified by cardiac magnetic resonance. In regard to the remaining constrictive pericarditis-positive patients defined by cardiac magnetic resonance, 10 were treated medically, declined, were ineligible for surgery, or were lost to follow-up. Long-term follow-up of those who were constrictive pericarditis negative by cardiac magnetic resonance showed no early or late crossover to the surgery arm. Cardiac magnetic resonance via radiofrequency tissue tagging offers a unique, efficient, and effective manner of defining clinically and surgically relevant constrictive pericarditis

  20. Histamine-2 receptor antagonist famotidine modulates cardiac stem cell characteristics in hypertensive heart disease

    Directory of Open Access Journals (Sweden)

    Sherin Saheera

    2017-10-01

    Full Text Available Background Cardiac stem cells (CSCs play a vital role in cardiac homeostasis. A decrease in the efficiency of cardiac stem cells is speculated in various cardiac abnormalities. The maintenance of a healthy stem cell population is essential for the prevention of adverse cardiac remodeling leading to cardiac failure. Famotidine, a histamine-2 receptor antagonist, is currently used to treat ulcers of the stomach and intestines. In repurposing the use of the drug, reduction of cardiac hypertrophy and improvement in cardiac function of spontaneously hypertensive rats (SHR was reported by our group. Given that stem cells are affected in cardiac pathologies, the effect of histamine-2 receptor antagonism on CSC characteristics was investigated. Methods To examine whether famotidine has a positive effect on CSCs, spontaneously hypertensive rats (SHR treated with the drug were sacrificed; and CSCs isolated from atrial appendages was evaluated. Six-month-old male SHRs were treated with famotidine (30 mg/kg/day for two months. The effect of famotidine treatment on migration, proliferation and survival of CSCs was compared with untreated SHRs and normotensive Wistar rats. Results Functional efficiency of CSCs from SHR was compromised relative to that in Wistar rat. Famotidine increased the migration and proliferation potential, along with retention of stemness of CSCs in treated SHRs. Cellular senescence and oxidative stress were also reduced. The expression of H2R was unaffected by the treatment. Discussion As anticipated, CSCs from SHRs were functionally impaired. Stem cell attributes of famotidine-treated SHRs was comparable to that of Wistar rats. Therefore, in addition to being cardioprotective, the histamine 2 receptor antagonist modulated cardiac stem cells characteristics. Restoration of stem cell efficiency by famotidine is possibly mediated by reduction of oxidative stress as the expression of H2R was unaffected by the treatment. Maintenance of

  1. Cardiac involvement in myotonic muscular dystrophy (Steinert's disease): a prospective study of 25 patients

    International Nuclear Information System (INIS)

    Perloff, J.K.; Stevenson, W.G.; Roberts, N.K.; Cabeen, W.; Weiss, J.

    1984-01-01

    The presence, degree and frequency of disorders of cardiac conduction and rhythm and of regional or global myocardial dystrophy or myotonia have not previously been studied prospectively and systematically in the same population of patients with myotonic dystrophy. Accordingly, 25 adults with classic Steinert's disease underwent electrocardiography, 24-hour ambulatory electrocardiography, vectorcardiography, chest x-rays, echocardiography, electrophysiologic studies, and technetium-99m angiography. Clinically important cardiac manifestations of myotonic dystrophy reside in specialized tissues rather than in myocardium. Involvement is relatively specific, primarily assigned to the His-Purkinje system. The cardiac muscle disorder takes the form of dystrophy rather than myotonia, and is not selective, appearing with approximately equal distribution in all 4 chambers. Myocardial dystrophy seldom results in clinically overt ventricular failure, but may be responsible for atrial and ventricular arrhythmias. Since myotonic dystrophy is genetically transmitted, a primary biochemical defect has been proposed with complete expression of the gene toward striated muscle tissue, whether skeletal or cardiac. Specialized cardiac tissue and myocardium have close, if not identical, embryologic origins, so it is not surprising that the genetic marker affects both. Cardiac involvement is therefore an integral part of myotonic dystrophy, targeting particularly the infranodal conduction system, to a lesser extent the sinus node, and still less specifically, the myocardium

  2. Role of the immune system in cardiac tissue damage and repair following myocardial infarction.

    Science.gov (United States)

    Saparov, Arman; Ogay, Vyacheslav; Nurgozhin, Talgat; Chen, William C W; Mansurov, Nurlan; Issabekova, Assel; Zhakupova, Jamilya

    2017-09-01

    The immune system plays a crucial role in the initiation, development, and resolution of inflammation following myocardial infarction (MI). The lack of oxygen and nutrients causes the death of cardiomyocytes and leads to the exposure of danger-associated molecular patterns that are recognized by the immune system to initiate inflammation. At the initial stage of post-MI inflammation, the immune system further damages cardiac tissue to clear cell debris. The excessive production of reactive oxygen species (ROS) by immune cells and the inability of the anti-oxidant system to neutralize ROS cause oxidative stress that further aggravates inflammation. On the other hand, the cells of both innate and adaptive immune system and their secreted factors are critically instrumental in the very dynamic and complex processes of regulating inflammation and mediating cardiac repair. It is important to decipher the balance between detrimental and beneficial effects of the immune system in MI. This enables us to identify better therapeutic targets for reducing the infarct size, sustaining the cardiac function, and minimizing the likelihood of heart failure. This review discusses the role of both innate and adaptive immune systems in cardiac tissue damage and repair in experimental models of MI.

  3. Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease

    Science.gov (United States)

    Ballestri, Stefano; Lonardo, Amedeo; Bonapace, Stefano; Byrne, Christopher D; Loria, Paola; Targher, Giovanni

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) has emerged as a public health problem of epidemic proportions worldwide. Accumulating clinical and epidemiological evidence indicates that NAFLD is not only associated with liver-related morbidity and mortality but also with an increased risk of coronary heart disease (CHD), abnormalities of cardiac function and structure (e.g., left ventricular dysfunction and hypertrophy, and heart failure), valvular heart disease (e.g., aortic valve sclerosis) and arrhythmias (e.g., atrial fibrillation). Experimental evidence suggests that NAFLD itself, especially in its more severe forms, exacerbates systemic/hepatic insulin resistance, causes atherogenic dyslipidemia, and releases a variety of pro-inflammatory, pro-coagulant and pro-fibrogenic mediators that may play important roles in the pathophysiology of cardiac and arrhythmic complications. Collectively, these findings suggest that patients with NAFLD may benefit from more intensive surveillance and early treatment interventions to decrease the risk for CHD and other cardiac/arrhythmic complications. The purpose of this clinical review is to summarize the rapidly expanding body of evidence that supports a strong association between NAFLD and cardiovascular, cardiac and arrhythmic complications, to briefly examine the putative biological mechanisms underlying this association, and to discuss some of the current treatment options that may influence both NAFLD and its related cardiac and arrhythmic complications. PMID:24587651

  4. ASCI 2010 appropriateness criteria for cardiac computed tomography: a report of the Asian Society of Cardiovascular Imaging Cardiac Computed Tomography and Cardiac Magnetic Resonance Imaging Guideline Working Group.

    Science.gov (United States)

    Tsai, I-Chen; Choi, Byoung Wook; Chan, Carmen; Jinzaki, Masahiro; Kitagawa, Kakuya; Yong, Hwan Seok; Yu, Wei

    2010-02-01

    In Asia, the healthcare system, populations and patterns of disease differ from Western countries. The current reports on the criteria for cardiac CT scans, provided by Western professional societies, are not appropriate for Asian cultures. The Asian Society of Cardiovascular Imaging, the only society dedicated to cardiovascular imaging in Asia, formed a Working Group and invited 23 Technical Panel members representing a variety of Asian countries to rate the 51 indications for cardiac CT in clinical practice in Asia. The indications were rated as 'appropriate' (7-9), 'uncertain' (4-6), or 'inappropriate' (1-3) on a scale of 1-9. The median score was used for the final result if there was no disagreement. The final ratings for indications were 33 appropriate, 14 uncertain and 4 inappropriate. And 20 of them are highly agreed (19 appropriate and 1 inappropriate). Specifically, the Asian representatives considered cardiac CT as an appropriate modality for Kawasaki disease and congenital heart diseases in follow up and in symptomatic patients. In addition, except for some specified conditions, cardiac CT was considered to be an appropriate modality for one-stop shop ischemic heart disease evaluation due to its general appropriateness in coronary, structure and function evaluation. This report is expected to have a significant impact on the clinical practice, research and reimbursement policy in Asia.

  5. Severe antiphospholipid syndrome and cardiac surgery: Perioperative management.

    Science.gov (United States)

    Mishra, Pankaj Kumar; Khazi, Fayaz Mohammed; Yiu, Patrick; Billing, John Stephen

    2016-06-01

    Antiphospholipid syndrome is an antiphospholipid antibody-mediated prothrombotic state leading to arterial and venous thrombosis. This condition alters routine in-vitro coagulation tests, making results unreliable. Antiphospholipid syndrome patients requiring cardiac surgery with cardiopulmonary bypass present a unique challenge in perioperative anticoagulation management. We describe 3 patients with antiphospholipid syndrome who had successful heart valve surgery at our institution. We have devised an institutional protocol for antiphospholipid syndrome patients, and all 3 patients were managed according to this protocol. An algorithm-based approach is recommended because it improves team work, optimizes treatment, and improves patient outcome. © The Author(s) 2015.

  6. Aspirin suppresses cardiac fibroblast proliferation and collagen formation through downregulation of angiotensin type 1 receptor transcription

    International Nuclear Information System (INIS)

    Wang, Xianwei; Lu, Jingjun; Khaidakov, Magomed; Mitra, Sona; Ding, Zufeng; Raina, Sameer; Goyal, Tanu; Mehta, Jawahar L.

    2012-01-01

    Aspirin (acetyl salicylic acid, ASA) is a common drug used for its analgesic and antipyretic effects. Recent studies show that ASA not only blocks cyclooxygenase, but also inhibits NADPH oxidase and resultant reactive oxygen species (ROS) generation, a pathway that underlies pathogenesis of several ailments, including hypertension and tissue remodeling after injury. In these disease states, angiotensin II (Ang II) activates NADPH oxidase via its type 1 receptor (AT1R) and leads to fibroblast growth and collagen synthesis. In this study, we examined if ASA would inhibit NADPH oxidase activation, upregulation of AT1R transcription, and subsequent collagen generation in mouse cardiac fibroblasts challenged with Ang II. Mouse heart fibroblasts were isolated and treated with Ang II with or without ASA. As expected, Ang II induced AT1R expression, and stimulated cardiac fibroblast growth and collagen synthesis. The AT1R blocker losartan attenuated these effects of Ang II. Similarly to losartan, ASA, and its SA moiety suppressed Ang II-mediated AT1R transcription and fibroblast proliferation as well as expression of collagens and MMPs. ASA also suppressed the expression of NADPH oxidase subunits (p22 phox , p47 phox , p67 phox , NOX2 and NOX4) and ROS generation. ASA did not affect total NF-κB p65, but inhibited its phosphorylation and activation. These observations suggest that ASA inhibits Ang II-induced NADPH oxidase expression, NF-κB activation and AT1R transcription in cardiac fibroblasts, and fibroblast proliferation and collagen expression. The critical role of NADPH oxidase activity in stimulation of AT1R transcription became apparent in experiments where ASA also inhibited AT1R transcription in cardiac fibroblasts challenged with H 2 O 2 . Since SA had similar effect as ASA on AT1R expression, we suggest that ASA's effect is mediated by its SA moiety. -- Highlights: ► Aspirin in therapeutic concentrations decreases mouse cardiac fibroblast growth and collagen

  7. Aspirin suppresses cardiac fibroblast proliferation and collagen formation through downregulation of angiotensin type 1 receptor transcription

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xianwei, E-mail: XWang2@UAMS.edu; Lu, Jingjun; Khaidakov, Magomed; Mitra, Sona; Ding, Zufeng; Raina, Sameer; Goyal, Tanu; Mehta, Jawahar L., E-mail: MehtaJL@UAMS.edu

    2012-03-15

    Aspirin (acetyl salicylic acid, ASA) is a common drug used for its analgesic and antipyretic effects. Recent studies show that ASA not only blocks cyclooxygenase, but also inhibits NADPH oxidase and resultant reactive oxygen species (ROS) generation, a pathway that underlies pathogenesis of several ailments, including hypertension and tissue remodeling after injury. In these disease states, angiotensin II (Ang II) activates NADPH oxidase via its type 1 receptor (AT1R) and leads to fibroblast growth and collagen synthesis. In this study, we examined if ASA would inhibit NADPH oxidase activation, upregulation of AT1R transcription, and subsequent collagen generation in mouse cardiac fibroblasts challenged with Ang II. Mouse heart fibroblasts were isolated and treated with Ang II with or without ASA. As expected, Ang II induced AT1R expression, and stimulated cardiac fibroblast growth and collagen synthesis. The AT1R blocker losartan attenuated these effects of Ang II. Similarly to losartan, ASA, and its SA moiety suppressed Ang II-mediated AT1R transcription and fibroblast proliferation as well as expression of collagens and MMPs. ASA also suppressed the expression of NADPH oxidase subunits (p22{sup phox}, p47{sup phox}, p67{sup phox}, NOX2 and NOX4) and ROS generation. ASA did not affect total NF-κB p65, but inhibited its phosphorylation and activation. These observations suggest that ASA inhibits Ang II-induced NADPH oxidase expression, NF-κB activation and AT1R transcription in cardiac fibroblasts, and fibroblast proliferation and collagen expression. The critical role of NADPH oxidase activity in stimulation of AT1R transcription became apparent in experiments where ASA also inhibited AT1R transcription in cardiac fibroblasts challenged with H{sub 2}O{sub 2}. Since SA had similar effect as ASA on AT1R expression, we suggest that ASA's effect is mediated by its SA moiety. -- Highlights: ► Aspirin in therapeutic concentrations decreases mouse cardiac

  8. Outside-in HLA class I signaling regulates ICAM-1 clustering and endothelial cell-monocyte interactions via mTOR in transplant antibody-mediated rejection.

    Science.gov (United States)

    Salehi, Sahar; Sosa, Rebecca A; Jin, Yi-Ping; Kageyama, Shoichi; Fishbein, Michael C; Rozengurt, Enrique; Kupiec-Weglinski, Jerzy W; Reed, Elaine F

    2018-05-01

    Antibody-mediated rejection (AMR) resulting in transplant allograft vasculopathy (TAV) is the major obstacle for long-term survival of solid organ transplants. AMR is caused by donor-specific antibodies to HLA, which contribute to TAV by initiating outside-in signaling transduction pathways that elicit monocyte recruitment to activated endothelium. Mechanistic target of rapamycin (mTOR) inhibitors can attenuate TAV; therefore, we sought to understand the mechanistic underpinnings of mTOR signaling in HLA class I Ab-mediated endothelial cell activation and monocyte recruitment. We used an in vitro model to assess monocyte binding to HLA I Ab-activated endothelial cells and found mTOR inhibition reduced ezrin/radixin/moesin (ERM) phosphorylation, intercellular adhesion molecule 1 (ICAM-1) clustering, and monocyte firm adhesion to HLA I Ab-activated endothelium. Further, in a mouse model of AMR, in which C57BL/6. RAG1 -/- recipients of BALB/c cardiac allografts were passively transferred with donor-specific MHC I antibodies, mTOR inhibition significantly reduced vascular injury, ERM phosphorylation, and macrophage infiltration of the allograft. Taken together, these studies indicate mTOR inhibition suppresses ERM phosphorylation in endothelial cells, which impedes ICAM-1 clustering in response to HLA class I Ab and prevents macrophage infiltration into cardiac allografts. These findings indicate a novel therapeutic application for mTOR inhibitors to disrupt endothelial cell-monocyte interactions during AMR. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

  9. Myocardin-related transcription factors are required for cardiac development and function

    Science.gov (United States)

    Mokalled, Mayssa H.; Carroll, Kelli J.; Cenik, Bercin K.; Chen, Beibei; Liu, Ning; Olson, Eric N.; Bassel-Duby, Rhonda

    2016-01-01

    Myocardin-Related Transcription Factors A and B (MRTF-A and MRTF-B) are highly homologous proteins that function as powerful coactivators of serum response factor (SRF), a ubiquitously expressed transcription factor essential for cardiac development. The SRF/MRTF complex binds to CArG boxes found in the control regions of genes that regulate cytoskeletal dynamics and muscle contraction, among other processes. While SRF is required for heart development and function, the role of MRTFs in the developing or adult heart has not been explored. Through cardiac-specific deletion of MRTF alleles in mice, we show that either MRTF-A or MRTF-B is dispensable for cardiac development and function, whereas deletion of both MRTF-A and MRTF-B causes a spectrum of structural and functional cardiac abnormalities. Defects observed in MRTF-A/B null mice ranged from reduced cardiac contractility and adult onset heart failure to neonatal lethality accompanied by sarcomere disarray. RNA-seq analysis on neonatal hearts identified the most altered pathways in MRTF double knockout hearts as being involved in cytoskeletal organization. Together, these findings demonstrate redundant but essential roles of the MRTFs in maintenance of cardiac structure and function and as indispensible links in cardiac cytoskeletal gene regulatory networks. PMID:26386146

  10. MicroRNA-155 attenuates late sepsis-induced cardiac dysfunction through JNK and β-arrestin 2.

    Science.gov (United States)

    Zhou, Yu; Song, Yan; Shaikh, Zahir; Li, Hui; Zhang, Haiju; Caudle, Yi; Zheng, Shouhua; Yan, Hui; Hu, Dan; Stuart, Charles; Yin, Deling

    2017-07-18

    Cardiac dysfunction is correlated with detrimental prognosis of sepsis and contributes to a high risk of mortality. After an initial hyperinflammatory reaction, most patients enter a protracted state of immunosuppression (late sepsis) that alters both innate and adaptive immunity. The changes of cardiac function in late sepsis are not yet known. MicroRNA-155 (miR-155) is previously found to play important roles in both regulations of immune activation and cardiac function. In this study, C57BL/6 mice were operated to develop into early and late sepsis phases, and miR-155 mimic was injected through the tail vein 48 h after cecal ligation and puncture (CLP). The effect of miR-155 on CLP-induced cardiac dysfunction was explored in late sepsis. We found that increased expression of miR-155 in the myocardium protected against cardiac dysfunction in late sepsis evidenced by attenuating sepsis-reduced cardiac output and enhancing left ventricular systolic function. We also observed that miR-155 markedly reduced the infiltration of macrophages and neutrophils into the myocardium and attenuated the inflammatory response via suppression of JNK signaling pathway. Moreover, overexpression of β-arrestin 2 (Arrb2) exacerbated the mice mortality and immunosuppression in late sepsis. Furthermore, transfection of miR-155 mimic reduced Arrb2 expression, and then restored immunocompetence and improved survival in late septic mice. We conclude that increased miR-155 expression through systemic administration of miR-155 mimic attenuates cardiac dysfunction and improves late sepsis survival by targeting JNK associated inflammatory signaling and Arrb2 mediated immunosuppression.

  11. Smooth muscle myosin light chain kinase efficiently phosphorylates serine 15 of cardiac myosin regulatory light chain

    International Nuclear Information System (INIS)

    Josephson, Matthew P.; Sikkink, Laura A.; Penheiter, Alan R.; Burghardt, Thomas P.; Ajtai, Katalin

    2011-01-01

    Highlights: ► Cardiac myosin regulatory light chain (MYL2) is phosphorylated at S15. ► Smooth muscle myosin light chain kinase (smMLCK) is a ubiquitous kinase. ► It is a widely believed that MYL2 is a poor substrate for smMLCK. ► In fact, smMLCK efficiently and rapidly phosphorylates S15 in MYL2. ► Phosphorylation kinetics measured by novel fluorescence method without radioactivity. -- Abstract: Specific phosphorylation of the human ventricular cardiac myosin regulatory light chain (MYL2) modifies the protein at S15. This modification affects MYL2 secondary structure and modulates the Ca 2+ sensitivity of contraction in cardiac tissue. Smooth muscle myosin light chain kinase (smMLCK) is a ubiquitous kinase prevalent in uterus and present in other contracting tissues including cardiac muscle. The recombinant 130 kDa (short) smMLCK phosphorylated S15 in MYL2 in vitro. Specific modification of S15 was verified using the direct detection of the phospho group on S15 with mass spectrometry. SmMLCK also specifically phosphorylated myosin regulatory light chain S15 in porcine ventricular myosin and chicken gizzard smooth muscle myosin (S20 in smooth muscle) but failed to phosphorylate the myosin regulatory light chain in rabbit skeletal myosin. Phosphorylation kinetics, measured using a novel fluorescence method eliminating the use of radioactive isotopes, indicates similar Michaelis–Menten V max and K M for regulatory light chain S15 phosphorylation rates in MYL2, porcine ventricular myosin, and chicken gizzard myosin. These data demonstrate that smMLCK is a specific and efficient kinase for the in vitro phosphorylation of MYL2, cardiac, and smooth muscle myosin. Whether smMLCK plays a role in cardiac muscle regulation or response to a disease causing stimulus is unclear but it should be considered a potentially significant kinase in cardiac tissue on the basis of its specificity, kinetics, and tissue expression.

  12. Smooth muscle myosin light chain kinase efficiently phosphorylates serine 15 of cardiac myosin regulatory light chain

    Energy Technology Data Exchange (ETDEWEB)

    Josephson, Matthew P.; Sikkink, Laura A. [Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905 (United States); Penheiter, Alan R. [Molecular Medicine Program, Mayo Clinic, Rochester, MN 55905 (United States); Burghardt, Thomas P., E-mail: burghardt@mayo.edu [Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905 (United States); Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905 (United States); Ajtai, Katalin [Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905 (United States)

    2011-12-16

    Highlights: Black-Right-Pointing-Pointer Cardiac myosin regulatory light chain (MYL2) is phosphorylated at S15. Black-Right-Pointing-Pointer Smooth muscle myosin light chain kinase (smMLCK) is a ubiquitous kinase. Black-Right-Pointing-Pointer It is a widely believed that MYL2 is a poor substrate for smMLCK. Black-Right-Pointing-Pointer In fact, smMLCK efficiently and rapidly phosphorylates S15 in MYL2. Black-Right-Pointing-Pointer Phosphorylation kinetics measured by novel fluorescence method without radioactivity. -- Abstract: Specific phosphorylation of the human ventricular cardiac myosin regulatory light chain (MYL2) modifies the protein at S15. This modification affects MYL2 secondary structure and modulates the Ca{sup 2+} sensitivity of contraction in cardiac tissue. Smooth muscle myosin light chain kinase (smMLCK) is a ubiquitous kinase prevalent in uterus and present in other contracting tissues including cardiac muscle. The recombinant 130 kDa (short) smMLCK phosphorylated S15 in MYL2 in vitro. Specific modification of S15 was verified using the direct detection of the phospho group on S15 with mass spectrometry. SmMLCK also specifically phosphorylated myosin regulatory light chain S15 in porcine ventricular myosin and chicken gizzard smooth muscle myosin (S20 in smooth muscle) but failed to phosphorylate the myosin regulatory light chain in rabbit skeletal myosin. Phosphorylation kinetics, measured using a novel fluorescence method eliminating the use of radioactive isotopes, indicates similar Michaelis-Menten V{sub max} and K{sub M} for regulatory light chain S15 phosphorylation rates in MYL2, porcine ventricular myosin, and chicken gizzard myosin. These data demonstrate that smMLCK is a specific and efficient kinase for the in vitro phosphorylation of MYL2, cardiac, and smooth muscle myosin. Whether smMLCK plays a role in cardiac muscle regulation or response to a disease causing stimulus is unclear but it should be considered a potentially significant

  13. Fluorescent Reporters in Human Pluripotent Stem Cells: Contributions to Cardiac Differentiation and Their Applications in Cardiac Disease and Toxicity

    NARCIS (Netherlands)

    den Hartogh, Sabine C.; Passier, Petrus Christianus Johannes Josephus

    2016-01-01

    In the last decade, since the first report of induced pluripotent stem cells, the stem cell field has made remarkable progress in the differentiation to specialized cell-types of various tissues and organs, including the heart. Cardiac lineage- and tissue-specific human pluripotent stem cell (hPSC)

  14. Mathematical cardiac electrophysiology

    CERN Document Server

    Colli Franzone, Piero; Scacchi, Simone

    2014-01-01

    This book covers the main mathematical and numerical models in computational electrocardiology, ranging from microscopic membrane models of cardiac ionic channels to macroscopic bidomain, monodomain, eikonal models and cardiac source representations. These advanced multiscale and nonlinear models describe the cardiac bioelectrical activity from the cell level to the body surface and are employed in both the direct and inverse problems of electrocardiology. The book also covers advanced numerical techniques needed to efficiently carry out large-scale cardiac simulations, including time and space discretizations, decoupling and operator splitting techniques, parallel finite element solvers. These techniques are employed in 3D cardiac simulations illustrating the excitation mechanisms, the anisotropic effects on excitation and repolarization wavefronts, the morphology of electrograms in normal and pathological tissue and some reentry phenomena. The overall aim of the book is to present rigorously the mathematica...

  15. Cardiac-specific ablation of the E3 ubiquitin ligase Mdm2 leads to oxidative stress, broad mitochondrial deficiency and early death.

    Directory of Open Access Journals (Sweden)

    Ludger Hauck

    Full Text Available The maintenance of normal heart function requires proper control of protein turnover. The ubiquitin-proteasome system is a principal regulator of protein degradation. Mdm2 is the main E3 ubiquitin ligase for p53 in mitotic cells thereby regulating cellular growth, DNA repair, oxidative stress and apoptosis. However, which of these Mdm2-related activities are preserved in differentiated cardiomyocytes has yet to be determined. We sought to elucidate the role of Mdm2 in the control of normal heart function. We observed markedly reduced Mdm2 mRNA levels accompanied by highly elevated p53 protein expression in the hearts of wild type mice subjected to myocardial infarction or trans-aortic banding. Accordingly, we generated conditional cardiac-specific Mdm2 gene knockout (Mdm2f/f;mcm mice. In adulthood, Mdm2f/f;mcm mice developed spontaneous cardiac hypertrophy, left ventricular dysfunction with early mortality post-tamoxifen. A decreased polyubiquitination of myocardial p53 was observed, leading to its stabilization and activation, in the absence of acute stress. In addition, transcriptomic analysis of Mdm2-deficient hearts revealed that there is an induction of E2f1 and c-Myc mRNA levels with reduced expression of the Pgc-1a/Ppara/Esrrb/g axis and Pink1. This was associated with a significant degree of cardiomyocyte apoptosis, and an inhibition of redox homeostasis and mitochondrial bioenergetics. All these processes are early, Mdm2-associated events and contribute to the development of pathological hypertrophy. Our genetic and biochemical data support a role for Mdm2 in cardiac growth control through the regulation of p53, the Pgc-1 family of transcriptional coactivators and the pivotal antioxidant Pink1.

  16. Biphasic role of chondroitin sulfate in cardiac differentiation of embryonic stem cells through inhibition of Wnt/β-catenin signaling.

    Directory of Open Access Journals (Sweden)

    Robert D Prinz

    Full Text Available The glycosaminoglycan chondroitin sulfate is a critical component of proteoglycans on the cell surface and in the extracellular matrix. As such, chondroitin sulfate side chains and the sulfation balance of chondroitin play important roles in the control of signaling pathways, and have a functional importance in human disease. In contrast, very little is known about the roles of chondroitin sulfate molecules and sulfation patterns during mammalian development and cell lineage specification. Here, we report a novel biphasic role of chondroitin sulfate in the specification of the cardiac cell lineage during embryonic stem cell differentiation through modulation of Wnt/beta-catenin signaling. Lineage marker analysis demonstrates that enzymatic elimination of endogenous chondroitin sulfates leads to defects specifically in cardiac differentiation. This is accompanied by a reduction in the number of beating cardiac foci. Mechanistically, we show that endogenous chondroitin sulfate controls cardiac differentiation in a temporal biphasic manner through inhibition of the Wnt/beta-catenin pathway, a known regulatory pathway for the cardiac lineage. Treatment with a specific exogenous chondroitin sulfate, CS-E, could mimic these biphasic effects on cardiac differentiation and Wnt/beta-catenin signaling. These results establish chondroitin sulfate and its sulfation balance as important regulators of cardiac cell lineage decisions through control of the Wnt/beta-catenin pathway. Our work suggests that targeting the chondroitin biosynthesis and sulfation machinery is a novel promising avenue in regenerative strategies after heart injury.

  17. Biphasic role of chondroitin sulfate in cardiac differentiation of embryonic stem cells through inhibition of Wnt/β-catenin signaling.

    Science.gov (United States)

    Prinz, Robert D; Willis, Catherine M; van Kuppevelt, Toin H; Klüppel, Michael

    2014-01-01

    The glycosaminoglycan chondroitin sulfate is a critical component of proteoglycans on the cell surface and in the extracellular matrix. As such, chondroitin sulfate side chains and the sulfation balance of chondroitin play important roles in the control of signaling pathways, and have a functional importance in human disease. In contrast, very little is known about the roles of chondroitin sulfate molecules and sulfation patterns during mammalian development and cell lineage specification. Here, we report a novel biphasic role of chondroitin sulfate in the specification of the cardiac cell lineage during embryonic stem cell differentiation through modulation of Wnt/beta-catenin signaling. Lineage marker analysis demonstrates that enzymatic elimination of endogenous chondroitin sulfates leads to defects specifically in cardiac differentiation. This is accompanied by a reduction in the number of beating cardiac foci. Mechanistically, we show that endogenous chondroitin sulfate controls cardiac differentiation in a temporal biphasic manner through inhibition of the Wnt/beta-catenin pathway, a known regulatory pathway for the cardiac lineage. Treatment with a specific exogenous chondroitin sulfate, CS-E, could mimic these biphasic effects on cardiac differentiation and Wnt/beta-catenin signaling. These results establish chondroitin sulfate and its sulfation balance as important regulators of cardiac cell lineage decisions through control of the Wnt/beta-catenin pathway. Our work suggests that targeting the chondroitin biosynthesis and sulfation machinery is a novel promising avenue in regenerative strategies after heart injury.

  18. Detection of cardiac transplant rejection with radiolabeled lymphocytes

    International Nuclear Information System (INIS)

    Bergmann, S.R.; Lerch, R.A.; Carlson, E.M.; Saffitz, J.E.; Sobel, B.E.

    1982-01-01

    To determine whether rejections of cardiac transplants could be detected specifically and non-invasively by lymphocytes labeled with indium-111 (111In), we studied 36 allogeneic and 14 isogeneic heterotopic cardiac transplants in rats. Allogeneic grafts accumulated autologous 111In-lymphocytes, detectable scintigraphically 24 hours after i.v. injection of the labeled cells. At the time of peak histologic rejection, the allogeneic grafts accumulated 92. +/- 4.8 times more activity than the native hearts (determined by well counting). The tissue-to-blood ratio in the rejecting transplants was 3.7 +/- 2.2; total uptake by the graft was 2.9 +/- 2.1% of the injected dose. Autoradiography confirmed that graft radioactivity was associated with labeled lymphocytes. In contrast, isogeneic grafts showed no signs of rejection and did not accumulate radioactivity. Because conventionally isolated and labeled lymphocytes are often contaminated with platelets, we prepared both 111In-platelets and purified 111In-lymphocytes for use in additional experiments. Allogeneic grafts accumulated platelets and purified lymphocytes independently. Thus, deposition of immunologically active cells in the rejecting graft representing specific pathophysiologic events can be detected. The results suggest that rejection of cardiac transplants can be detected noninvasively, potentially facilitating objective early clinical detection of rejection and titration of antirejection therapy

  19. Cardiac telomere length in heart development, function, and disease.

    Science.gov (United States)

    Booth, S A; Charchar, F J

    2017-07-01

    Telomeres are repetitive nucleoprotein structures at chromosome ends, and a decrease in the number of these repeats, known as a reduction in telomere length (TL), triggers cellular senescence and apoptosis. Heart disease, the worldwide leading cause of death, often results from the loss of cardiac cells, which could be explained by decreases in TL. Due to the cell-specific regulation of TL, this review focuses on studies that have measured telomeres in heart cells and critically assesses the relationship between cardiac TL and heart function. There are several lines of evidence that have identified rapid changes in cardiac TL during the onset and progression of heart disease as well as at critical stages of development. There are also many factors, such as the loss of telomeric proteins, oxidative stress, and hypoxia, that decrease cardiac TL and heart function. In contrast, antioxidants, calorie restriction, and exercise can prevent both cardiac telomere attrition and the progression of heart disease. TL in the heart is also indicative of proliferative potential and could facilitate the identification of cells suitable for cardiac rejuvenation. Although these findings highlight the involvement of TL in heart function, there are important questions regarding the validity of animal models, as well as several confounding factors, that need to be considered when interpreting results and planning future research. With these in mind, elucidating the telomeric mechanisms involved in heart development and the transition to disease holds promise to prevent cardiac dysfunction and potentiate regeneration after injury. Copyright © 2017 the American Physiological Society.

  20. Use of human stem cell derived cardiomyocytes to examine sunitinib mediated cardiotoxicity and electrophysiological alterations

    International Nuclear Information System (INIS)

    Cohen, J.D.; Babiarz, J.E.; Abrams, R.M.; Guo, L.; Kameoka, S.; Chiao, E.; Taunton, J.; Kolaja, K.L.

    2011-01-01

    Sunitinib, an oral tyrosine kinase inhibitor approved to treat advanced renal cell carcinoma and gastrointestinal stroma tumor, is associated with clinical cardiac toxicity. Although the precise mechanism of sunitinib cardiotoxicity is not known, both the key metabolic energy regulator, AMP-activated protein kinase (AMPK), and ribosomal S 6 kinase (RSK) have been hypothesized as causative, albeit based on rodent models. To study the mechanism of sunitinib-mediated cardiotoxicity in a human model, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) having electrophysiological and contractile properties of native cardiac tissue were investigated. Sunitinib was cardiotoxic in a dose-dependent manner with an IC 50 in the low micromolar range, observed by a loss of cellular ATP, an increase in oxidized glutathione, and induction of apoptosis in iPSC-CMs. Pretreatment of iPSC-CMs with AMPK activators AICAR or metformin, increased the phosphorylation of pAMPK-T172 and pACC-S79, but only marginally attenuated sunitinib mediated cell death. Furthermore, additional inhibitors of AMPK were not directly cytotoxic to iPSC-CMs up to 250 μM concentrations. Inhibition of RSK with a highly specific, irreversible, small molecule inhibitor (RSK-FMK-MEA) did not induce cytotoxicity in iPSC-CMs below 250 μM. Extensive electrophysiological analysis of sunitinib and RSK-FMK-MEA mediated conduction effects were performed. Taken together, these findings suggest that inhibition of AMPK and RSK are not a major component of sunitinib-induced cardiotoxicity. Although the exact mechanism of cardiotoxicity of sunitinib is not known, it is likely due to inhibition of multiple kinases simultaneously. These data highlight the utility of human iPSC-CMs in investigating the potential molecular mechanisms underlying drug-induced cardiotoxicity. -- Highlights: ► Cytoxic effect of sunitinib on human stem cell derived cardiomyocytes ► Sunitinib causes ATP depletion, LDH release, GSH

  1. Regional evidence of modulation of cardiac adiponectin level in dilated cardiomyopathy: pilot study in a porcine animal model

    Directory of Open Access Journals (Sweden)

    Caselli Chiara

    2012-11-01

    Full Text Available Abstract Background The role of systemic and myocardial adiponectin (ADN in dilated cardiomyopathy is still debated. We tested the regulation of both systemic and myocardial ADN and the relationship with AMP-activated protein kinase (AMPK activity in a swine model of non-ischemic dilated cardiomyopathy. Methods and results Cardiac tissue was collected from seven instrumented adult male minipigs by pacing the left ventricular (LV free wall (180 beats/min, 3 weeks, both from pacing (PS and opposite sites (OS, and from five controls. Circulating ADN levels were inversely related to global and regional cardiac function. Myocardial ADN in PS was down-regulated compared to control (p Conclusions Paradoxically, circulating ADN did not show any cardioprotective effect, confirming its role as negative prognostic biomarker of heart failure. Myocardial ADN was reduced in PS compared to control in an AMPK-independent fashion, suggesting the occurrence of novel mechanisms by which reduced cardiac ADN levels may regionally mediate the decline of cardiac function.

  2. Serum cardiac troponin I in canine syncope and seizures.

    Science.gov (United States)

    Dutton, E; Dukes-McEwan, J; Cripps, P J

    2017-02-01

    To determine if serum cardiac troponin I (cTnI) concentration distinguishes between cardiogenic syncope and collapsing dogs presenting with either generalized epileptic seizures (both with and without cardiac disease) or vasovagal syncope. Seventy-nine prospectively recruited dogs, grouped according to aetiology of collapse: generalized epileptic seizures (group E), cardiogenic syncope (group C), dogs with both epileptic seizures and cardiac disease (group B), vasovagal syncope (group V) or unclassified (group U). Most patients had ECG (n = 78), echocardiography (n = 78) and BP measurement (n = 74) performed. Dogs with a history of intoxications, trauma, evidence of metabolic disorders or renal insufficiency (based on serum creatinine concentrations >150 μmol/L and urine specific gravity disease) or vasovagal syncope. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. School Processes Mediate School Compositional Effects: Model Specification and Estimation

    Science.gov (United States)

    Liu, Hongqiang; Van Damme, Jan; Gielen, Sarah; Van Den Noortgate, Wim

    2015-01-01

    School composition effects have been consistently verified, but few studies ever attempted to study how school composition affects school achievement. Based on prior research findings, we employed multilevel mediation modeling to examine whether school processes mediate the effect of school composition upon school outcomes based on the data of 28…

  4. Causal Mediation Analysis of Survival Outcome with Multiple Mediators.

    Science.gov (United States)

    Huang, Yen-Tsung; Yang, Hwai-I

    2017-05-01

    Mediation analyses have been a popular approach to investigate the effect of an exposure on an outcome through a mediator. Mediation models with multiple mediators have been proposed for continuous and dichotomous outcomes. However, development of multimediator models for survival outcomes is still limited. We present methods for multimediator analyses using three survival models: Aalen additive hazard models, Cox proportional hazard models, and semiparametric probit models. Effects through mediators can be characterized by path-specific effects, for which definitions and identifiability assumptions are provided. We derive closed-form expressions for path-specific effects for the three models, which are intuitively interpreted using a causal diagram. Mediation analyses using Cox models under the rare-outcome assumption and Aalen additive hazard models consider effects on log hazard ratio and hazard difference, respectively; analyses using semiparametric probit models consider effects on difference in transformed survival time and survival probability. The three models were applied to a hepatitis study where we investigated effects of hepatitis C on liver cancer incidence mediated through baseline and/or follow-up hepatitis B viral load. The three methods show consistent results on respective effect scales, which suggest an adverse estimated effect of hepatitis C on liver cancer not mediated through hepatitis B, and a protective estimated effect mediated through the baseline (and possibly follow-up) of hepatitis B viral load. Causal mediation analyses of survival outcome with multiple mediators are developed for additive hazard and proportional hazard and probit models with utility demonstrated in a hepatitis study.

  5. Satisfactory rate of postprocessing visualization of standard fetal cardiac views from 4-dimensional cardiac volumes acquired during routine ultrasound practice by experienced sonographers in peripheral centers.

    Science.gov (United States)

    Rizzo, Giuseppe; Capponi, Alessandra; Pietrolucci, Maria Elena; Capece, Giuseppe; Cimmino, Ernesto; Colosi, Enrico; Ferrentino, Salvatore; Sica, Carmine; Di Meglio, Aniello; Arduini, Domenico

    2011-01-01

    The aim of this study was to evaluate the feasibility of visualizing standard cardiac views from 4-dimensional (4D) cardiac volumes obtained at ultrasound facilities with no specific experience in fetal echocardiography. Five sonographers prospectively recorded 4D cardiac volumes starting from the 4-chamber view on 500 consecutive pregnancies at 19 to 24 weeks' gestation undergoing routine ultrasound examinations (100 pregnancies for each sonographer). Volumes were sent to the referral center, and 2 independent reviewers with experience in 4D fetal echocardiography assessed their quality in the display of the abdominal view, 4-chamber view, left and right ventricular outflow tracts, and 3-vessel and trachea view. Cardiac volumes were acquired in 474 of 500 pregnancies (94.8%). The 2 reviewers respectively acknowledged the presence of satisfactory images in 92.4% and 93.6% of abdominal views, 91.5% and 93.0% of 4-chamber views, in 85.0% and 86.2% of left ventricular outflow tracts, 83.9% and 84.5% of right ventricular outflow tracts, and 85.2% and 84.5% of 3-vessel and trachea views. The presence of a maternal body mass index of greater than 30 altered the probability of achieving satisfactory cardiac views, whereas previous maternal lower abdominal surgery did not affect the quality of reconstructed cardiac views. In conclusion, cardiac volumes acquired by 4D sonography in peripheral centers showed high enough quality to allow satisfactory diagnostic cardiac views.

  6. Association between dental caries and out-of-hospital cardiac arrests of cardiac origin in Japan.

    Science.gov (United States)

    Suematsu, Yasunori; Miura, Shin-Ichiro; Zhang, Bo; Uehara, Yoshinari; Ogawa, Masahiro; Yonemoto, Naohiro; Nonogi, Hiroshi; Nagao, Ken; Kimura, Takeshi; Saku, Keijiro

    2016-04-01

    Oral infection contributes to atherosclerosis and coronary heart disease. We hypothesized that dental caries may be associated with out-of-hospital cardiac arrests (OHCA) of cardiac origin, but not non-cardiac origin. We compared the age-adjusted incidence of OHCA (785,591 cases of OHCA: 55.4% of cardiac origin and 44.6% of non-cardiac origin) to the age-adjusted prevalence of dental caries between 2005 and 2011 in the 47 prefectures of Japan. In both the total population and males over 65 years, the number of cases of dental caries was significantly associated with the number of OHCA of total and cardiac origin from 2005 to 2011, but not those of non-cardiac origin. In the total population, the age-adjusted prevalence of dental caries was not significantly associated with the age-adjusted incidence of OHCA (total OHCA: r correlation coefficient=0.22, p=0.14; OHCA of cardiac origin: r=0.25, p=0.09; OHCA of non-cardiac origin: r=-0.002, p=0.99). Among male patients over 65 years, the age-adjusted prevalence of dental caries was significantly associated with OHCA of total and cardiac origin, but not non-cardiac origin (total OHCA: r=0.47, p<0.001; OHCA of cardiac origin: r=0.37, p=0.01; OHCA of non-cardiac origin: r=0.28, p=0.054). While oral hygiene is important in all age groups, it may be particularly associated with OHCAs of cardiac origin in males over 65 years. Copyright © 2015. Published by Elsevier Ltd.

  7. Overexpression of Catalase Diminishes Oxidative Cysteine Modifications of Cardiac Proteins.

    Directory of Open Access Journals (Sweden)

    Chunxiang Yao

    Full Text Available Reactive protein cysteine thiolates are instrumental in redox regulation. Oxidants, such as hydrogen peroxide (H2O2, react with thiolates to form oxidative post-translational modifications, enabling physiological redox signaling. Cardiac disease and aging are associated with oxidative stress which can impair redox signaling by altering essential cysteine thiolates. We previously found that cardiac-specific overexpression of catalase (Cat, an enzyme that detoxifies excess H2O2, protected from oxidative stress and delayed cardiac aging in mice. Using redox proteomics and systems biology, we sought to identify the cysteines that could play a key role in cardiac disease and aging. With a 'Tandem Mass Tag' (TMT labeling strategy and mass spectrometry, we investigated differential reversible cysteine oxidation in the cardiac proteome of wild type and Cat transgenic (Tg mice. Reversible cysteine oxidation was measured as thiol occupancy, the ratio of total available versus reversibly oxidized cysteine thiols. Catalase overexpression globally decreased thiol occupancy by ≥1.3 fold in 82 proteins, including numerous mitochondrial and contractile proteins. Systems biology analysis assigned the majority of proteins with differentially modified thiols in Cat Tg mice to pathways of aging and cardiac disease, including cellular stress response, proteostasis, and apoptosis. In addition, Cat Tg mice exhibited diminished protein glutathione adducts and decreased H2O2 production from mitochondrial complex I and II, suggesting improved function of cardiac mitochondria. In conclusion, our data suggest that catalase may alleviate cardiac disease and aging by moderating global protein cysteine thiol oxidation.

  8. Exercise-related cardiac arrest in cardiac rehabilitation - The ...

    African Journals Online (AJOL)

    Prescribed physical activity plays a major role in the rehabilitation of patients with coronary artery disease, and as with any other form of treatment its benefits must be weighed against its possible risks. This study attempted to establish the safety of cardiac rehabilitation as a medical intervention at the Johannesburg Cardiac ...

  9. Low heart rate variability in unemployed men: The possible mediating effects of life satisfaction.

    Science.gov (United States)

    Jandackova, V K; Jackowska, M

    2015-01-01

    Unemployment has consistently been associated with increased risk of cardiovascular disease and premature mortality, and impaired autonomic modulation of the heart might be one mechanism partly explaining this. This study examined whether the possible effect of unemployment on cardiac autonomic modulation is in part mediated by lower psychological well-being. The sample comprised of 15 job-seeking men aged 30-49 years matched with 15 employed men on age, type of job, smoking habits, alcohol intake, frequency of physical activity, and body mass index. Heart rate variability (HRV) during a modified orthostatic test was the measure of cardiac autonomic modulation, and life satisfaction was the measure of psychological well-being. Unemployed men had significantly lower overall HRV (p = .040) than controls. This association was partially mediated through lower general life satisfaction, and in particular, by low financial satisfaction, independently of demographic and/or behavioral factors that influence HRV. These findings suggest that seeking a job is a potential stressor that may reduce overall HRV and contribute towards disturbance of cardiac autonomic modulation in men. Financial difficulties could be one mechanism through which the effects of unemployment are translated into impaired autonomic modulation.

  10. Development of new anatomy reconstruction software to localize cardiac isochrones to the cardiac surface from the 12 lead ECG.

    Science.gov (United States)

    van Dam, Peter M; Gordon, Jeffrey P; Laks, Michael M; Boyle, Noel G

    2015-01-01

    Non-invasive electrocardiographic imaging (ECGI) of the cardiac muscle can help the pre-procedure planning of the ablation of ventricular arrhythmias by reducing the time to localize the origin. Our non-invasive ECGI system, the cardiac isochrone positioning system (CIPS), requires non-intersecting meshes of the heart, lungs and torso. However, software to reconstruct the meshes of the heart, lungs and torso with the capability to check and prevent these intersections is currently lacking. Consequently the reconstruction of a patient specific model with realistic atrial and ventricular wall thickness and incorporating blood cavities, lungs and torso usually requires additional several days of manual work. Therefore new software was developed that checks and prevents any intersections, and thus enables the use of accurate reconstructed anatomical models within CIPS. In this preliminary study we investigated the accuracy of the created patient specific anatomical models from MRI or CT. During the manual segmentation of the MRI data the boundaries of the relevant tissues are determined. The resulting contour lines are used to automatically morph reference meshes of the heart, lungs or torso to match the boundaries of the morphed tissue. Five patients were included in the study; models of the heart, lungs and torso were reconstructed from standard cardiac MRI images. The accuracy was determined by computing the distance between the segmentation contours and the morphed meshes. The average accuracy of the reconstructed cardiac geometry was within 2mm with respect to the manual segmentation contours on the MRI images. Derived wall volumes and left ventricular wall thickness were within the range reported in literature. For each reconstructed heart model the anatomical heart axis was computed using the automatically determined anatomical landmarks of the left apex and the mitral valve. The accuracy of the reconstructed heart models was well within the accuracy of the used

  11. Unhealthy weight control behaviors mediate the association between weight status and weight-specific health-related quality of life in treatment-seeking youth who are obese.

    Science.gov (United States)

    Lim, Crystal S; Gowey, Marissa A; Cohen, Megan J; Silverstein, Janet; Janicke, David M

    2017-03-01

    Examine whether unhealthy and extreme weight control behaviors (WCBs) mediate the relationship between youth weight status and disease-specific health-related quality of life (HRQOL) in treatment-seeking youth who are overweight and obese (OV/OB). 82 youth 10-17 years of age who were OV/OB and attending an outpatient obesity-related medical appointment completed measures assessing unhealthy and extreme WCBs and disease-specific HRQOL. Parents completed a demographic questionnaire and medical staff measured youth height and weight. Regression analyses revealed that unhealthy WCBs mediated the associations between youth weight status and emotional and social avoidance disease-specific HRQOL, such that higher body mass index (BMI) predicted unhealthy WCBs, which were ultimately associated with poorer emotional and social HRQOL. Mediation analyses were not significant for total, physical, teasing/marginalization, and positive attributes disease-specific HRQOL. In addition, extreme WCBs did not mediate the association between youth weight status and any subscales of the disease-specific HRQOL measure. Weight status is an important predictor of disease-specific HRQOL in OV/OB youth; however, the association with emotional and social HRQOL is partially accounted for by youth engagement in unhealthy WCBs. Clinicians and researchers should assess WCBs and further research should explore and evaluate appropriate intervention strategies to address unhealthy WCBs in pediatric weight management prevention and treatment efforts.

  12. MR first pass perfusion of benign and malignant cardiac tumours - significant differences and diagnostic accuracy

    International Nuclear Information System (INIS)

    Bauner, K.U.; Picciolo, M.; Theisen, D.; Sandner, T.A.; Reiser, M.F.; Huber, A.M.; Sourbron, S.; Schmitz, C.

    2012-01-01

    To determine the diagnostic value of magnetic resonance (MR) first pass perfusion in the differentiation of benign and malignant cardiac tumours. 24 patients with cardiac tumours (11 malignant, histopathological correlation present in all cases) were examined using MRI. In addition to morphological sequences a saturation-recovery T1w-GRE technique was implemented for tumour perfusion. The maximum relative signal enhancement (RSE[%]) and the slope of the RSE t -curve (slopeRSE[%/s]) of tumour tissue were assessed. A t-test was used to identify significant differences between benign and malignant tumours. Sensitivities and specificities were calculated for detection of malignant lesions and were compared with the sensitivity and specificity based on solely morphological image assessment. The RSE and slopeRSE of malignant cardiac tumours were significantly higher compared with benign lesions (p < 0.001 and p < 0.001). The calculated sensitivities and specificities of RSE and slopeRSE for identification of malignant lesions were 100% and 84.6% and 100% and 92.3%, respectively with cut-off values of 80% and 6%/s. The sensitivity and specificity for identification of malignant lesions on the basis of morphological imaging alone were 90.9% and 69.2%. With first pass perfusion, malignant cardiac masses can be identified with higher sensitivity and specificity compared with morphological image assessment alone. (orig.)

  13. [Structure and functional organization of integrated cardiac intensive care].

    Science.gov (United States)

    Scherillo, Marino; Miceli, Domenico; Tubaro, Marco; Guiducci, Umberto

    2007-05-01

    The early invasive strategy for the treatment of acute coronary syndromes and the increasing number of older and sicker patients requiring prolonged and more complex intensive care have induced many changes in the function of the intensive care units. These changes include the statement that specially trained cardiologists and cardiac nurses who can manage patients with acute cardiac conditions should staff the intensive care units. This document indicates the structure of the units and specific recommendations for the number of beds, monitoring system, respirators, pacemaker/defibrillators and additional equipment.

  14. Sudden cardiac death

    Directory of Open Access Journals (Sweden)

    Neeraj Parakh

    2015-01-01

    Full Text Available Sudden cardiac death is one of the most common cause of mortality worldwide. Despite significant advances in the medical science, there is little improvement in the sudden cardiac death related mortality. Coronary artery disease is the most common etiology behind sudden cardiac death, in the above 40 years population. Even in the apparently healthy population, there is a small percentage of patients dying from sudden cardiac death. Given the large denominator, this small percentage contributes to the largest burden of sudden cardiac death. Identification of this at risk group among the apparently healthy individual is a great challenge for the medical fraternity. This article looks into the causes and methods of preventing SCD and at some of the Indian data. Details of Brugada syndrome, Long QT syndrome, Genetics of SCD are discussed. Recent guidelines on many of these causes are summarised.

  15. Noninvasive detection of cardiac repair after acute myocardial infarction in rats by 111In fab fragment of monoclonal antibody specific for tenascin-C

    International Nuclear Information System (INIS)

    Okada, Kenichi; Uehara, Tomoya; Arano, Yasushi

    2008-01-01

    Left ventricular (LV) remodeling after acute myocardial infarction (MI) causes heart failure, and thus it is important to evaluate cardiac repair as the early stage of LV remodeling. Tenascin-C (TNC), an extracellular matrix glycoprotein, is transiently and abundantly expressed in the heart during the early stage of tissue remodeling after MI. However, it is not expressed in healthy adult heart. This study was undertaken to develop a new noninvasive diagnostic technique to detect cardiac repair after acute MI using 111 In Fab fragment of a monoclonal antibody specific for TNC. 111 In-anti-TNC-Fab was injected intravenously in 13 rats at 1 (D1, n=3), 3 (D3, n=5), and 5 (D5, n=5) days after producing MI and in 5 sham-operated rats (S). We performed autoradiography and dual-isotope single-photon emission computed tomography imaging (SPECT) of 111 In-anti-TNC-Fab and 99m Tc methoxyisobutyl isonitrile (MIBI). The radioactivity in the heart was significantly higher in D (D1, 0.45±0.06% injected-dose/g; D3, 0.64±0.12; D5, 0.38±0.07) than S (0.27±0.06, P 111 In-anti-TNC-Fab, which was complementary to the perfusion image. The results of the present study indicated that we can localize the infarcted region in the heart by ex vivo and in vivo imaging methods using 111 In-anti-TNC-Fab, and suggested the potential usefulness of noninvasive detection of cardiac repair. (author)

  16. Cardiac glycosides induce cell death in human cells by inhibiting general protein synthesis.

    Directory of Open Access Journals (Sweden)

    Andrea Perne

    2009-12-01

    Full Text Available Cardiac glycosides are Na(+/K(+-pump inhibitors widely used to treat heart failure. They are also highly cytotoxic, and studies have suggested specific anti-tumor activity leading to current clinical trials in cancer patients. However, a definitive demonstration of this putative anti-cancer activity and the underlying molecular mechanism has remained elusive.Using an unbiased transcriptomics approach, we found that cardiac glycosides inhibit general protein synthesis. Protein synthesis inhibition and cytotoxicity were not specific for cancer cells as they were observed in both primary and cancer cell lines. These effects were dependent on the Na(+/K(+-pump as they were rescued by expression of a cardiac glycoside-resistant Na(+/K(+-pump. Unlike human cells, rodent cells are largely resistant to cardiac glycosides in vitro and mice were found to tolerate extremely high levels.The physiological difference between human and mouse explains the previously observed sensitivity of human cancer cells in mouse xenograft experiments. Thus, published mouse xenograft models used to support anti-tumor activity for these drugs require reevaluation. Our finding that cardiac glycosides inhibit protein synthesis provides a mechanism for the cytotoxicity of CGs and raises concerns about ongoing clinical trials to test CGs as anti-cancer agents in humans.

  17. Causal mediation analysis with multiple mediators.

    Science.gov (United States)

    Daniel, R M; De Stavola, B L; Cousens, S N; Vansteelandt, S

    2015-03-01

    In diverse fields of empirical research-including many in the biological sciences-attempts are made to decompose the effect of an exposure on an outcome into its effects via a number of different pathways. For example, we may wish to separate the effect of heavy alcohol consumption on systolic blood pressure (SBP) into effects via body mass index (BMI), via gamma-glutamyl transpeptidase (GGT), and via other pathways. Much progress has been made, mainly due to contributions from the field of causal inference, in understanding the precise nature of statistical estimands that capture such intuitive effects, the assumptions under which they can be identified, and statistical methods for doing so. These contributions have focused almost entirely on settings with a single mediator, or a set of mediators considered en bloc; in many applications, however, researchers attempt a much more ambitious decomposition into numerous path-specific effects through many mediators. In this article, we give counterfactual definitions of such path-specific estimands in settings with multiple mediators, when earlier mediators may affect later ones, showing that there are many ways in which decomposition can be done. We discuss the strong assumptions under which the effects are identified, suggesting a sensitivity analysis approach when a particular subset of the assumptions cannot be justified. These ideas are illustrated using data on alcohol consumption, SBP, BMI, and GGT from the Izhevsk Family Study. We aim to bridge the gap from "single mediator theory" to "multiple mediator practice," highlighting the ambitious nature of this endeavor and giving practical suggestions on how to proceed. © 2014 The Authors Biometrics published by Wiley Periodicals, Inc. on behalf of International Biometric Society.

  18. Cardiac Auscultation Using Smartphones: Pilot Study.

    Science.gov (United States)

    Kang, Si-Hyuck; Joe, Byunggill; Yoon, Yeonyee; Cho, Goo-Yeong; Shin, Insik; Suh, Jung-Won

    2018-02-28

    Cardiac auscultation is a cost-effective, noninvasive screening tool that can provide information about cardiovascular hemodynamics and disease. However, with advances in imaging and laboratory tests, the importance of cardiac auscultation is less appreciated in clinical practice. The widespread use of smartphones provides opportunities for nonmedical expert users to perform self-examination before hospital visits. The objective of our study was to assess the feasibility of cardiac auscultation using smartphones with no add-on devices for use at the prehospital stage. We performed a pilot study of patients with normal and pathologic heart sounds. Heart sounds were recorded on the skin of the chest wall using 3 smartphones: the Samsung Galaxy S5 and Galaxy S6, and the LG G3. Recorded heart sounds were processed and classified by a diagnostic algorithm using convolutional neural networks. We assessed diagnostic accuracy, as well as sensitivity, specificity, and predictive values. A total of 46 participants underwent heart sound recording. After audio file processing, 30 of 46 (65%) heart sounds were proven interpretable. Atrial fibrillation and diastolic murmur were significantly associated with failure to acquire interpretable heart sounds. The diagnostic algorithm classified the heart sounds into the correct category with high accuracy: Galaxy S5, 90% (95% CI 73%-98%); Galaxy S6, 87% (95% CI 69%-96%); and LG G3, 90% (95% CI 73%-98%). Sensitivity, specificity, positive predictive value, and negative predictive value were also acceptable for the 3 devices. Cardiac auscultation using smartphones was feasible. Discrimination using convolutional neural networks yielded high diagnostic accuracy. However, using the built-in microphones alone, the acquisition of reproducible and interpretable heart sounds was still a major challenge. ClinicalTrials.gov NCT03273803; https://clinicaltrials.gov/ct2/show/NCT03273803 (Archived by WebCite at http://www.webcitation.org/6x6g1f

  19. Cold stress accentuates pressure overload-induced cardiac hypertrophy and contractile dysfunction: role of TRPV1/AMPK-mediated autophagy.

    Science.gov (United States)

    Lu, Songhe; Xu, Dezhong

    2013-12-06

    Severe cold exposure and pressure overload are both known to prompt oxidative stress and pathological alterations in the heart although the interplay between the two remains elusive. Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel activated in response to a variety of exogenous and endogenous physical and chemical stimuli including heat and capsaicin. The aim of this study was to examine the impact of cold exposure on pressure overload-induced cardiac pathological changes and the mechanism involved. Adult male C57 mice were subjected to abdominal aortic constriction (AAC) prior to exposure to cold temperature (4 °C) for 4 weeks. Cardiac geometry and function, levels of TRPV1, mitochondrial, and autophagy-associated proteins including AMPK, mTOR, LC3B, and P62 were evaluated. Sustained cold stress triggered cardiac hypertrophy, compromised depressed myocardial contractile capacity including lessened fractional shortening, peak shortening, and maximal velocity of shortening/relengthening, enhanced ROS production, and mitochondrial injury, the effects of which were negated by the TRPV1 antagonist SB366791. Western blot analysis revealed upregulated TRPV1 level and AMPK phosphorylation, enhanced ratio of LC3II/LC3I, and downregulated P62 following cold exposure. Cold exposure significantly augmented AAC-induced changes in TRPV1, phosphorylation of AMPK, LC3 isoform switch, and p62, the effects of which were negated by SB366791. In summary, these data suggest that cold exposure accentuates pressure overload-induced cardiac hypertrophy and contractile defect possibly through a TRPV1 and autophagy-dependent mechanism. Copyright © 2013. Published by Elsevier Inc.

  20. Human muscle-specific A-kinase anchoring protein (mAKAP) polymorphisms modulate the susceptibility to cardiovascular diseases by altering cAMP/ PKA signaling.

    Science.gov (United States)

    Suryavanshi, Santosh V; Jadhav, Shweta M; Anderson, Kody L; Katsonis, Panagiotis; Lichtarge, Olivier; McConnell, Bradley K

    2018-03-30

    One of the crucial cardiac signaling pathways is cAMP-mediated PKA signal transduction which is regulated by a family of scaffolding proteins, A-kinase anchoring proteins (AKAPs). Muscle-specific AKAP (mAKAP) partly regulates cardiac cAMP/PKA signaling by binding to PKA and phosphodiesterase4D3 (PDE4D3) among other proteins and plays a central role in modulating cardiac remodeling. Moreover, genetics plays an incomparable role in modifying the risk of cardiovascular diseases (CVDs). Especially, single nucleotide polymorphisms (SNPs) in various proteins have been shown to predispose individuals to CVDs. Hence, we hypothesized that human mAKAP polymorphisms found in humans with CVDs alter cAMP/PKA pathway influencing the susceptibility of individuals to CVDs. Our computational analyses revealed two mAKAP SNPs found in cardiac disease related patients with highest predicted deleterious effects, Ser(S) 1653 Arg(R) and Glu(E) 2124 Gly(G). Co-immunoprecipitation data in HEK293T cells showed that S1653R SNP, present in the PDE4D3 binding domain of mAKAP, changed the binding of PDE4D3 to mAKAP and E2124G SNP, flanking the 3'-PKA binding domain, changed the binding of PKA before and after stimulation with isoproterenol. These SNPs significantly altered intracellular cAMP levels, global PKA activity and cytosolic PDE activity when compared with the wild-type (WT) before and after isoproterenol stimulation. PKA-mediated phosphorylation of pathological markers was found to be up-regulated after cell stimulation in both mutants. In conclusion, human mAKAP polymorphisms may influence the propensity of developing CVDs by affecting cAMP/PKA signaling supporting the clinical significance of PKA-mAKAP-PDE4D3 interactions.

  1. Zebrafish chemical screening reveals the impairment of dopaminergic neuronal survival by cardiac glycosides.

    Directory of Open Access Journals (Sweden)

    Yaping Sun

    Full Text Available Parkinson's disease is a neurodegenerative disorder characterized by the prominent degeneration of dopaminergic (DA neurons among other cell types. Here we report a first chemical screen of over 5,000 compounds in zebrafish, aimed at identifying small molecule modulators of DA neuron development or survival. We find that Neriifolin, a member of the cardiac glycoside family of compounds, impairs survival but not differentiation of both zebrafish and mammalian DA neurons. Cardiac glycosides are inhibitors of Na(+/K(+ ATPase activity and widely used for treating heart disorders. Our data suggest that Neriifolin impairs DA neuronal survival by targeting the neuronal enriched Na(+/K(+ ATPase α3 subunit (ATP1A3. Modulation of ionic homeostasis, knockdown of p53, or treatment with antioxidants protects DA neurons from Neriifolin-induced death. These results reveal a previously unknown effect of cardiac glycosides on DA neuronal survival and suggest that it is mediated through ATP1A3 inhibition, oxidative stress, and p53. They also elucidate potential approaches for counteracting the neurotoxicity of this valuable class of medications.

  2. Perspectives on stem cell therapy for cardiac regeneration. Advances and challenges.

    Science.gov (United States)

    Choi, Sung Hyun; Jung, Seok Yun; Kwon, Sang-Mo; Baek, Sang Hong

    2012-01-01

    Ischemic heart disease (IHD) accelerates cardiomyocyte loss, but the developing stem cell research could be useful for regenerating a variety of tissue cells, including cardiomyocytes. Diverse sources of stem cells for IHD have been reported, including embryonic stem cells, induced pluripotent stem cells, skeletal myoblasts, bone marrow-derived stem cells, mesenchymal stem cells, and cardiac stem cells. However, stem cells have unique advantages and disadvantages for cardiac tissue regeneration, which are important considerations in determining the specific cells for improving cell survival and long-term engraftment after transplantation. Additionally, the dosage and administration method of stem cells need to be standardized to increase stability and efficacy for clinical applications. Accordingly, this review presents a summary of the stem cell therapies that have been studied for cardiac regeneration thus far, and discusses the direction of future cardiac regeneration research for stem cells.

  3. Mechanism of arctigenin-mediated specific cytotoxicity against human lung adenocarcinoma cell lines.

    Science.gov (United States)

    Susanti, Siti; Iwasaki, Hironori; Inafuku, Masashi; Taira, Naoyuki; Oku, Hirosuke

    2013-12-15

    The lignan arctigenin (ARG) from the herb Arctium lappa L. possesses anti-cancer activity, however the mechanism of action of ARG has been found to vary among tissues and types of cancer cells. The current study aims to gain insight into the ARG mediated mechanism of action involved in inhibiting proliferation and inducing apoptosis in lung adenocarcinoma cells. This study also delineates the cancer cell specificity of ARG by comparison with its effects on various normal cell lines. ARG selectively arrested the proliferation of cancer cells at the G0/G1 phase through the down-regulation of NPAT protein expression. This down-regulation occurred via the suppression of either cyclin E/CDK2 or cyclin H/CDK7, while apoptosis was induced through the modulation of the Akt-1-related signaling pathway. Furthermore, a GSH synthase inhibitor specifically enhanced the cytotoxicity of ARG against cancer cells, suggesting that the intracellular GSH content was another factor influencing the susceptibility of cancer cells to ARG. These findings suggest that specific cytotoxicity of ARG against lung cancer cells was explained by its selective modulation of the expression of NPAT, which is involved in histone biosynthesis. The cytotoxicity of ARG appeared to be dependent on the intracellular GSH level. Copyright © 2013 Elsevier GmbH. All rights reserved.

  4. Establishment of colloid gold immunity chromatography assay for cardiac troponin I (cTnI)

    International Nuclear Information System (INIS)

    Wang Dezhi; Chen Jiying; Qin Lili; Zhao Baojian; Zhang Chunming

    2006-01-01

    Objective: To establish the colloid gold Immunity chromatography assay for cardiac troponin I. Methods: To purify cTnI from human cardiac muscle and immunize rabbit with it. cTnI antibody of rabbit anti-human cardiac muscle has been prepared and colloid gold immunity chromatography assay was established by using immunity chromatography technology. Results: Anti-serum titles of cTnI were 1:100000, Ka=2.38 x 10 9 L/mol; Methodological index: Sensitivity: 5 ng/ml; Specificity: cTnI is no cross-reaction with cTnT, cTnC and CK-MB. conclusion: The assay is highly specific, quick and simple. It can be widely used for the early diagnosis of AMI and scientific research. (authors)

  5. Clinical Utility of Iopamidol (Pamiray 370) for Cardiac CT

    International Nuclear Information System (INIS)

    Kim, Mok Hee; Seon, Hyun Ju; Choi, Song; Kim, Yun Hyeon; Kim, Jae Kyu; Park, Jin Gyoon; Kang, Heong Keun

    2011-01-01

    We evaluated the utility of iopamidol-based nonionic contrast media (Pamiray 370) for cardiac CT, with assessment of its image quality and safety. The study included 100 patients who underwent cardiac CT with Pamiray 370 (experimental group), and 100 patients who underwent cardiac CT with Ultravist 370 (control group). A comparison of the image qualities and degree of vascular contrast enhancement was made between the two groups and evaluated statistically by an independent t-test. Changes in vital signs and adverse events during cardiac CT were evaluated in the experimental group. There were no statistically significant differences in the image quality (image quality score in experimental group vs. control group: 4.26 ± 0.63 vs. 4.24 ± 0.62), and mean attenuation values at the coronary arteries(p > 0.05) between two groups. For the experimental group, 12% experienced adverse events, including mild and transient reactions such as dizziness (7%), nausea (4%), and fatigue (1%). Further, 94% of patients complained of mild to moderate febrile sense just after contrast agent administration, which spontaneously disappeared within 3 minutes without any specific management. For cardiac CT, Pamiray 370 was comparable to the widely-used contrast agent (Ultravist 370) in terms of image quality and safety without any severe adverse reaction.

  6. Modern Perspectives on Numerical Modeling of Cardiac Pacemaker Cell

    Science.gov (United States)

    Maltsev, Victor A.; Yaniv, Yael; Maltsev, Anna V.; Stern, Michael D.; Lakatta, Edward G.

    2015-01-01

    Cardiac pacemaking is a complex phenomenon that is still not completely understood. Together with experimental studies, numerical modeling has been traditionally used to acquire mechanistic insights in this research area. This review summarizes the present state of numerical modeling of the cardiac pacemaker, including approaches to resolve present paradoxes and controversies. Specifically we discuss the requirement for realistic modeling to consider symmetrical importance of both intracellular and cell membrane processes (within a recent “coupled-clock” theory). Promising future developments of the complex pacemaker system models include the introduction of local calcium control, mitochondria function, and biochemical regulation of protein phosphorylation and cAMP production. Modern numerical and theoretical methods such as multi-parameter sensitivity analyses within extended populations of models and bifurcation analyses are also important for the definition of the most realistic parameters that describe a robust, yet simultaneously flexible operation of the coupled-clock pacemaker cell system. The systems approach to exploring cardiac pacemaker function will guide development of new therapies, such as biological pacemakers for treating insufficient cardiac pacemaker function that becomes especially prevalent with advancing age. PMID:24748434

  7. Cardiac-specific expression of the tetracycline transactivator confers increased heart function and survival following ischemia reperfusion injury.

    Directory of Open Access Journals (Sweden)

    Laila Elsherif

    Full Text Available Mice expressing the tetracycline transactivator (tTA transcription factor driven by the rat α-myosin heavy chain promoter (α-MHC-tTA are widely used to dissect the molecular mechanisms involved in cardiac development and disease. However, these α-MHC-tTA mice exhibit a gain-of-function phenotype consisting of robust protection against ischemia/reperfusion injury in both in vitro and in vivo models in the absence of associated cardiac hypertrophy or remodeling. Cardiac function, as assessed by echocardiography, did not differ between α-MHC-tTA and control animals, and there were no noticeable differences observed between the two groups in HW/TL ratio or LV end-diastolic and end-systolic dimensions. Protection against ischemia/reperfusion injury was assessed using isolated perfused hearts where α-MHC-tTA mice had robust protection against ischemia/reperfusion injury which was not blocked by pharmacological inhibition of PI3Ks with LY294002. Furthermore, α-MHC-tTA mice subjected to coronary artery ligation exhibited significantly reduced infarct size compared to control animals. Our findings reveal that α-MHC-tTA transgenic mice exhibit a gain-of-function phenotype consisting of robust protection against ischemia/reperfusion injury similar to cardiac pre- and post-conditioning effects. However, in contrast to classical pre- and post-conditioning, the α-MHC-tTA phenotype is not inhibited by the classic preconditioning inhibitor LY294002 suggesting involvement of a non-PI3K-AKT signaling pathway in this phenotype. Thus, further study of the α-MHC-tTA model may reveal novel molecular targets for therapeutic intervention during ischemic injury.

  8. The heartbreak of depression: 'Psycho-cardiac' coupling in myocardial infarction.

    Science.gov (United States)

    Headrick, John P; Peart, Jason N; Budiono, Boris P; Shum, David H K; Neumann, David L; Stapelberg, Nicolas J C

    2017-05-01

    Ample evidence identifies strong links between major depressive disorder (MDD) and both risk of ischemic or coronary heart disease (CHD) and resultant morbidity and mortality. The molecular mechanistic bases of these linkages are poorly defined. Systemic factors linked to MDD, including vascular dysfunction, atherosclerosis, obesity and diabetes, together with associated behavioral changes, all elevate CHD risk. Nonetheless, experimental evidence indicates the myocardium is also directly modified in depression, independently of these factors, impairing infarct tolerance and cardioprotection. It may be that MDD effectively breaks the heart's intrinsic defense mechanisms. Four extrinsic processes are implicated in this psycho-cardiac coupling, presenting potential targets for therapeutic intervention if causally involved: sympathetic over-activity vs. vagal under-activity, together with hypothalamic-pituitary-adrenal (HPA) axis and immuno-inflammatory dysfunctions. However, direct evidence of their involvement remains limited, and whether targeting these upstream mediators is effective (or practical) in limiting the cardiac consequences of MDD is unknown. Detailing myocardial phenotype in MDD can also inform approaches to cardioprotection, yet cardiac molecular changes are similarly ill defined. Studies support myocardial sensitization to ischemic insult in models of MDD, including worsened oxidative and nitrosative damage, apoptosis (with altered Bcl-2 family expression) and infarction. Moreover, depression may de-sensitize hearts to protective conditioning stimuli. The mechanistic underpinnings of these changes await delineation. Such information not only advances our fundamental understanding of psychological determinants of health, but also better informs management of the cardiac consequences of MDD and implementing cardioprotection in this cohort. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Alternans promotion in cardiac electrophysiology models by delay differential equations.

    Science.gov (United States)

    Gomes, Johnny M; Dos Santos, Rodrigo Weber; Cherry, Elizabeth M

    2017-09-01

    Cardiac electrical alternans is a state of alternation between long and short action potentials and is frequently associated with harmful cardiac conditions. Different dynamic mechanisms can give rise to alternans; however, many cardiac models based on ordinary differential equations are not able to reproduce this phenomenon. A previous study showed that alternans can be induced by the introduction of delay differential equations (DDEs) in the formulations of the ion channel gating variables of a canine myocyte model. The present work demonstrates that this technique is not model-specific by successfully promoting alternans using DDEs for five cardiac electrophysiology models that describe different types of myocytes, with varying degrees of complexity. By analyzing results across the different models, we observe two potential requirements for alternans promotion via DDEs for ionic gates: (i) the gate must have a significant influence on the action potential duration and (ii) a delay must significantly impair the gate's recovery between consecutive action potentials.

  10. Alternans promotion in cardiac electrophysiology models by delay differential equations

    Science.gov (United States)

    Gomes, Johnny M.; dos Santos, Rodrigo Weber; Cherry, Elizabeth M.

    2017-09-01

    Cardiac electrical alternans is a state of alternation between long and short action potentials and is frequently associated with harmful cardiac conditions. Different dynamic mechanisms can give rise to alternans; however, many cardiac models based on ordinary differential equations are not able to reproduce this phenomenon. A previous study showed that alternans can be induced by the introduction of delay differential equations (DDEs) in the formulations of the ion channel gating variables of a canine myocyte model. The present work demonstrates that this technique is not model-specific by successfully promoting alternans using DDEs for five cardiac electrophysiology models that describe different types of myocytes, with varying degrees of complexity. By analyzing results across the different models, we observe two potential requirements for alternans promotion via DDEs for ionic gates: (i) the gate must have a significant influence on the action potential duration and (ii) a delay must significantly impair the gate's recovery between consecutive action potentials.

  11. Maternal Diet-Induced Obesity Programmes Cardiac Dysfunction in Male Mice Independently of Post-Weaning Diet.

    Science.gov (United States)

    Loche, Elena; Blackmore, Heather L; Carpenter, Asha A M; Beeson, Jessica H; Pinnock, Adele; Ashmore, Thomas J; Aiken, Catherine E; de Almeida-Faria, Juliana; Schoonejans, Josca; Giussani, Dino A; Fernandez-Twinn, Denise S; Ozanne, Susan E

    2018-04-04

    Obesity during pregnancy increases risk of cardiovascular disease (CVD) in the offspring and individuals exposed to over-nutrition during fetal life are likely to be exposed to a calorie-rich environment postnatally. Here, we established the consequences of combined exposure to a maternal and post-weaning obesogenic diet on offspring cardiac structure and function using an established mouse model of maternal diet-induced obesity. The impact of the maternal and postnatal environment on the offspring metabolic profile, arterial blood pressure, cardiac structure and function was assessed in 8-week old C57BL/6 male mice. Measurement of cardiomyocyte cell area, the transcriptional re-activation of cardiac fetal genes as well as genes involved in the regulation of contractile function and matrix remodelling in the adult heart were determined as potential mediators of effects on cardiac function. In the adult offspring: a post-weaning obesogenic diet coupled with exposure to maternal obesity increased serum insulin (P<0.0001) and leptin levels (P<0.0001); maternal obesity (P=0.001) and a post-weaning obesogenic diet (P=0.002) increased absolute heart weight; maternal obesity (P=0.01) and offspring obesity (P=0.01) caused cardiac dysfunction but effects were not additive; cardiac dysfunction resulting from maternal obesity was associated with re-expression of cardiac fetal genes (Myh7:Myh6 ratio; P=0.0004), however these genes were not affected by offspring diet; maternal obesity (P=0.02) and offspring obesity (P=0.05) caused hypertension and effects were additive. Maternal diet-induced obesity and offspring obesity independently promote cardiac dysfunction and hypertension in adult male progeny. Exposure to maternal obesity alone programmed cardiac dysfunction, associated with hallmarks of pathological left ventricular hypertrophy, including increased cardiomyocyte area, upregulation of fetal genes and remodelling of cardiac structure. These data highlight that the

  12. Antibody-mediated platelet phagocytosis by human macrophages is inhibited by siRNA specific for sequences in the SH2 tyrosine kinase, Syk.

    Science.gov (United States)

    Lu, Ying; Wang, Weiming; Mao, Huiming; Hu, Hai; Wu, Yanling; Chen, Bing-Guan; Liu, Zhongmin

    2011-01-01

    Immune thrombocytopenia depends upon Fc receptor-mediated phagocytosis that involves signaling through the SH2 tyrosine kinase, Syk. We designed small interfering (siRNA) sequences complementary to Syk coding regions to decrease the expression of Syk in the human macrophage cell line, THP-1. To evaluate the functional effect of siRNA on phagocytosis, we developed a new in vitro assay for antibody-mediated platelet ingestion by THP-1 cells. Incubation of THP-1 cells at 37°C with fluorescence-labeled platelets and anti-platelet antibody promoted ingestion of platelets that could be quantitated by flow cytometry. Transfection of THP-1 cells with Syk-specific siRNA resulted in a reduction in the amount of FcγRII-associated Syk protein. Coincident with decreased Syk expression, we observed inhibition of antibody-mediated platelet ingestion. These results confirm a key role for Syk in antibody-mediated phagocytosis and suggest Syk-specific siRNA as a possible therapeutic candidate for immune thrombocytopenia. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Guidelines for the Use of Echocardiography in the Evaluation of a Cardiac Source of Embolism.

    Science.gov (United States)

    Saric, Muhamed; Armour, Alicia C; Arnaout, M Samir; Chaudhry, Farooq A; Grimm, Richard A; Kronzon, Itzhak; Landeck, Bruce F; Maganti, Kameswari; Michelena, Hector I; Tolstrup, Kirsten

    2016-01-01

    Embolism from the heart or the thoracic aorta often leads to clinically significant morbidity and mortality due to transient ischemic attack, stroke or occlusion of peripheral arteries. Transthoracic and transesophageal echocardiography are the key diagnostic modalities for evaluation, diagnosis, and management of stroke, systemic and pulmonary embolism. This document provides comprehensive American Society of Echocardiography guidelines on the use of echocardiography for evaluation of cardiac sources of embolism. It describes general mechanisms of stroke and systemic embolism; the specific role of cardiac and aortic sources in stroke, and systemic and pulmonary embolism; the role of echocardiography in evaluation, diagnosis, and management of cardiac and aortic sources of emboli including the incremental value of contrast and 3D echocardiography; and a brief description of alternative imaging techniques and their role in the evaluation of cardiac sources of emboli. Specific guidelines are provided for each category of embolic sources including the left atrium and left atrial appendage, left ventricle, heart valves, cardiac tumors, and thoracic aorta. In addition, there are recommendation regarding pulmonary embolism, and embolism related to cardiovascular surgery and percutaneous procedures. The guidelines also include a dedicated section on cardiac sources of embolism in pediatric populations. Copyright © 2016 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

  14. Measuring cardiac efficiency using PET/MRI

    International Nuclear Information System (INIS)

    Gullberg, Grand; Aparici, Carina Mari; Brooks, Gabriel; Liu, Jing; Guccione, Julius; Saloner, David; Seo, Adam Youngho; Ordovas, Karen Gomes

    2015-01-01

    Heart failure (HF) is a complex syndrome that is projected by the American Heart Association to cost $160 billion by 2030. In HF, significant metabolic changes and structural remodeling lead to reduced cardiac efficiency. A normal heart is approximately 20-25% efficient measured by the ratio of work to oxygen utilization (1 ml oxygen = 21 joules). The heart requires rapid production of ATP where there is complete turnover of ATP every 10 seconds with 90% of ATP produced by mitochondrial oxidative metabolism requiring substrates of approximately 30% glucose and 65% fatty acids. In our preclinical PET/MRI studies in normal rats, we showed a negative correlation between work and the influx rate constant for 18FDG, confirming that glucose is not the preferred substrate at rest. However, even though fatty acid provides 9 kcal/gram compared to 4 kcal/gram for glucose, in HF the preferred energy source is glucose. PET/MRI offers the potential to study this maladapted mechanism of metabolism by measuring work in a region of myocardial tissue simultaneously with the measure of oxygen utilization, glucose, and fatty acid metabolism and to study cardiac efficiency in the etiology of and therapies for HF. MRI is used to measure strain and a finite element mechanical model using pressure measurements is used to estimate myofiber stress. The integral of strain times stress provides a measure of work which divided by energy utilization, estimated by the production of 11CO2 from intravenous injection of 11C-acetate, provides a measure of cardiac efficiency. Our project involves translating our preclinical research to the clinical application of measuring cardiac efficiency in patients. Using PET/MRI to develop technologies for studying myocardial efficiency in patients, provides an opportunity to relate cardiac work of specific tissue regions to metabolic substrates, and measure the heterogeneity of LV efficiency.

  15. Measuring cardiac efficiency using PET/MRI

    Energy Technology Data Exchange (ETDEWEB)

    Gullberg, Grand [Lawrence Berkeley National Laboratory (United States); Aparici, Carina Mari; Brooks, Gabriel [University of California San Francisco (United States); Liu, Jing; Guccione, Julius; Saloner, David; Seo, Adam Youngho; Ordovas, Karen Gomes [Lawrence Berkeley National Laboratory (United States)

    2015-05-18

    Heart failure (HF) is a complex syndrome that is projected by the American Heart Association to cost $160 billion by 2030. In HF, significant metabolic changes and structural remodeling lead to reduced cardiac efficiency. A normal heart is approximately 20-25% efficient measured by the ratio of work to oxygen utilization (1 ml oxygen = 21 joules). The heart requires rapid production of ATP where there is complete turnover of ATP every 10 seconds with 90% of ATP produced by mitochondrial oxidative metabolism requiring substrates of approximately 30% glucose and 65% fatty acids. In our preclinical PET/MRI studies in normal rats, we showed a negative correlation between work and the influx rate constant for 18FDG, confirming that glucose is not the preferred substrate at rest. However, even though fatty acid provides 9 kcal/gram compared to 4 kcal/gram for glucose, in HF the preferred energy source is glucose. PET/MRI offers the potential to study this maladapted mechanism of metabolism by measuring work in a region of myocardial tissue