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Cardiac Ion Channels (cardiac + ion_channel)
Selected AbstractsSingle Nucleotide Polymorphisms and Haplotype of Four Genes Encoding Cardiac Ion Channels in Chinese and their Association with ArrhythmiaANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 2 2008Yu Zhang Ph.D. Background: Many studies revealed that variations in cardiac ion channels would cause cardiac arrhythmias or act as genetic risk factors. We hypothesized that specific single nucleotide polymorphisms in cardiac ion channels were associated with cardiac rhythm disturbance in the Chinese population. Method: We analyzed 160 nonfamilial cardiac arrhythmia patients and 176 healthy individuals from which 81 individuals were selected for association study, and a total of 19 previously reported SNPs in four cardiac ion channel genes (KCNQ1, KCNH2, SCN5A, KCNE1) were genotyped. Results: The frequency of KCNQ1 1638G>A, as well as the haplotype harboring KCNQ1 1638A, KCNQ1 1685 + 23G and 1732 + 43T (haplotype AGT) was significantly higher in healthy controls than in arrhythmia patients. This finding implicated that this haplotype (AGT) might be a protective factor against arrhythmias. Conclusions: Our study provided important information to elucidate the effect of SNPs of cardiac ion channel genes on channel function and susceptibility to cardiac arrhythmias in Chinese population. [source] Zebrafish as a model for long QT syndrome: the evidence and the means of manipulating zebrafish gene expressionACTA PHYSIOLOGICA, Issue 3 2010I. U. S. Leong Abstract Congenital long QT syndrome (LQT) is a group of cardiac disorders associated with the dysfunction of cardiac ion channels. It is characterized by prolongation of the QT-interval, episodes of syncope and even sudden death. Individuals may remain asymptomatic for most of their lives while others present with severe symptoms. This heterogeneity in phenotype makes diagnosis difficult with a greater emphasis on more targeted therapy. As a means of understanding the molecular mechanisms underlying LQT syndrome, evaluating the effect of modifier genes on disease severity as well as to test new therapies, the development of model systems remains an important research tool. Mice have predominantly been the animal model of choice for cardiac arrhythmia research, but there have been varying degrees of success in recapitulating the human symptoms; the mouse cardiac action potential (AP) and surface electrocardiograms exhibit major differences from those of the human heart. Against this background, the zebrafish is an emerging vertebrate disease modelling species that offers advantages in analysing LQT syndrome, not least because its cardiac AP much more closely resembles that of the human. This article highlights the use and potential of this species in LQT syndrome modelling, and as a platform for the in vivo assessment of putative disease-causing mutations in LQT genes, and of therapeutic interventions. [source] Computational physiology and the physiome projectEXPERIMENTAL PHYSIOLOGY, Issue 1 2004Edmund J. Crampin Bioengineering analyses of physiological systems use the computational solution of physical conservation laws on anatomically detailed geometric models to understand the physiological function of intact organs in terms of the properties and behaviour of the cells and tissues within the organ. By linking behaviour in a quantitative, mathematically defined sense across multiple scales of biological organization , from proteins to cells, tissues, organs and organ systems , these methods have the potential to link patient-specific knowledge at the two ends of these spatial scales. A genetic profile linked to cardiac ion channel mutations, for example, can be interpreted in relation to body surface ECG measurements via a mathematical model of the heart and torso, which includes the spatial distribution of cardiac ion channels throughout the myocardium and the individual kinetics for each of the approximately 50 types of ion channel, exchanger or pump known to be present in the heart. Similarly, linking molecular defects such as mutations of chloride ion channels in lung epithelial cells to the integrated function of the intact lung requires models that include the detailed anatomy of the lungs, the physics of air flow, blood flow and gas exchange, together with the large deformation mechanics of breathing. Organizing this large body of knowledge into a coherent framework for modelling requires the development of ontologies, markup languages for encoding models, and web-accessible distributed databases. In this article we review the state of the field at all the relevant levels, and the tools that are being developed to tackle such complexity. Integrative physiology is central to the interpretation of genomic and proteomic data, and is becoming a highly quantitative, computer-intensive discipline. [source] Evidence for a Single Nucleotide Polymorphism in the KCNQ1 Potassium Channel that Underlies Susceptibility to Life-Threatening ArrhythmiasJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 11 2001TOMOYUKI KUBOTA M.D. Ion Channel Polymorphism and Cardiac Arrhythmia. Introduction: Congenital long QT syndrome (LQTS) is a genetically heterogeneous arrhythmogenic disorder caused by mutations in at least five different genes encoding cardiac ion channels. It was suggested recently that common polymorphisms of LQTS-associated genes might modify arrhythmia susceptibility in potential gene carriers. Methods and Results: We examined the known LQTS genes in 95 patients with definitive or suspected LQTS. Exon-specific polymerase chain reaction single-strand conformation polymorphism and direct sequence analyses identified six patients who carried only a single nucleotide polymorphism in KCNQ1 that is found in , 11% of the Japanese population. This 1727G> A substitution that changes the sense of its coding sequence from glycine to serine at position 643 (G643S) was mostly associated with a milder phenotype, often precipitated by hypokalemia and bradyarrhythmias. When heterologously examined by voltage-clamp experiments, the in vitro cellular phenotype caused by the single nucleotide polymorphism revealed that G643S- KCNQ1 forms functional homomultimeric channels, producing a significantly smaller current than that of the wild-type (WT) channels. Coexpression of WT- KCNQ1 and G643S- KCNQ1 with KCNE1 resulted in , 30% reduction in the slow delayed rectifier K+ current IKs without much alteration in the kinetic properties except its deactivation process, suggesting that the G643S substitution had a weaker dominant-negative effect on the heteromultimeric channel complexes. Conclusion: We demonstrate that a common polymorphism in the KCNQ1 potassium channel could be a molecular basis for mild IKs dysfunction that, in the presence of appropriate precipitating factors, might predispose potential gene carriers to life-threatening arrhythmias in a specific population. [source] Single Nucleotide Polymorphisms and Haplotype of Four Genes Encoding Cardiac Ion Channels in Chinese and their Association with ArrhythmiaANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 2 2008Yu Zhang Ph.D. Background: Many studies revealed that variations in cardiac ion channels would cause cardiac arrhythmias or act as genetic risk factors. We hypothesized that specific single nucleotide polymorphisms in cardiac ion channels were associated with cardiac rhythm disturbance in the Chinese population. Method: We analyzed 160 nonfamilial cardiac arrhythmia patients and 176 healthy individuals from which 81 individuals were selected for association study, and a total of 19 previously reported SNPs in four cardiac ion channel genes (KCNQ1, KCNH2, SCN5A, KCNE1) were genotyped. Results: The frequency of KCNQ1 1638G>A, as well as the haplotype harboring KCNQ1 1638A, KCNQ1 1685 + 23G and 1732 + 43T (haplotype AGT) was significantly higher in healthy controls than in arrhythmia patients. This finding implicated that this haplotype (AGT) might be a protective factor against arrhythmias. Conclusions: Our study provided important information to elucidate the effect of SNPs of cardiac ion channel genes on channel function and susceptibility to cardiac arrhythmias in Chinese population. [source] Myocardium distribution of sertindole and its metabolite dehydrosertindole in guinea-pigsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2006Mireille Canal-Raffin Abstract Sertindole, like other atypical antipsychotics, has been shown to increase the action potential duration and QT interval in a concentration dependent manner, in in vitro electrophysiological studies. However, this does not always translate into increased duration of the QT interval, increased risk of torsade de pointes or sudden death in clinical practice. The reasons for these apparent discrepancies are unclear and many studies have underscored the importance of the interpretation of in vitro electrophysiological data in the context of other pharmacodynamic (e.g. cardiac ion channels target, receptor affinity) and pharmacokinetic parameters (total plasma drug concentration and drug distribution). To address the possible relevance of the concentrations used in experimental studies, the myocardium distribution of sertindole and its metabolite was determined after single and repeated intraperitoneal administration to guinea-pigs. The data suggest that the plasma concentration appears to predict the concentration in the myocardium and that the myocardium concentrations of sertindole are 3.1 times higher than plasma concentrations. Using these data, the relevance of in vitro electrophysiological studies to clinical plasma concentrations has been appraised. Copyright © 2006 John Wiley & Sons, Ltd. [source] | |||||||||||||