Moleculaire basis van aritmieën gebaseerd op natriumkanaal dysfunctie
01 / 2001 - onbekend
It is unknown why some patients and members of particular families exhibit ventricular tachycardia (VT) or fibrillation (VF) during myocardial infarction (primary VT/VF), while others do not. The role of reduced sodium current in causing VT/VF is increasingly appreciated. For instance, VT/VF may be caused by class I antiarrhythmic drugs (sodium channel blockers), particularly during ischemia. Also, VT/VF in the inherited Brugada syndrome probably results from reduced sodium current generated by the responsible mutant sodium channel. During ischemia and infarction, sodium channel availability is reduced. We propose that primary VT/VF is, at least partly, caused by reduced sodium current and that those patients who exhibit primary VT/VF have a subclinical sodium channel mutation or polymorphism (single nucleotide polymorphism, SNP) which becomes manifest only when other conditions which reduce sodium current further, e.g., ischemia and infarction, are present. By recruiting patients who suffered primary VT/VF at several hospitals, we aim to identify sodium channel gene (SCN5A) SNPs linked to an increased risk of primary VT/VF and to functionally characterize the encoded sodium channels by heterologously expressing them in mammalian cells and conducting patch-clamp studies. In substudies, patients who developed VT/VF after sodium channel blockers and those with inherited arrhythmia syndromes based on SCN5A mutations will be studied in the same fashion. This study will help to further define the pathophysiological basis of life-threatening arrhythmias in acute myocardial ischemia/infarction and may identify patients/families at risk for sudden cardiac death. It is hoped that this will ultimately result in better treatment and prevention strategies in the clinical management of these patients. Thus, this project will be fully integrated within the strategic aims ofthe Department of Clinical and Experimental Cardiology of the Academic Medical Centre (AMC) and serve as an extension of ongoing research projects. DNA samples of patients exhibiting primary VT/VF, those with VT/VF after taking sodium channel blockers and those with inherited arrhythmia syndromes based on SCN5A mutations will be collected and subsequent electrophysiological characterization of the resulting mutant sodium channels will be performed throughout the project. All required techniques are readily available and routinely operative in the AMC, i.e., molecular genetics for analyzing the possible mutations and/or SNPs; molecular biology to engineer the mutant sodium (hH1) channels, and patch-clamp techniques for their functional characterization. Development of new techniques is not expected to be required, with the possible exception of methods to unmask the different electrophysiological characteristics of the mutant hH1 channels, since their characteristics may be only marginally different from normal hH1 channels under normal experimental conditions. In general, identification of SCN5A mutations or SNPs will be performed throughout the project. In the first year we will start functional studies of the mutant hH1 channels resulting from the SCN5A SNPs which have already been identified and which are most likely to have the greatest functional impact. Functional characterization of newly identified mutations or SNPs will mostly occur during the 2nd and 3rd years. Thus, all constituent parts of this study may be conducted throughout the course of this project.