Genetics of cardiac arrhythmias and sudden cardiac death

Abstract

This presentation deals with the molecular substrates of the inherited diseases leading to genetically determined cardiac arrhythmias and sudden death. In the first part of this article the current knowledge concerning the molecular basis of cardiac arrhythmias will be summarized. Second, we will discuss the most recent evidence showing that the picture of the molecular bases of cardiac arrhythmias is becoming progressively more complex. Thanks to the contribution of molecular genetics, the genetic bases, pathogenesis, and genotype-phenotype correlation of diseases--such as the long QT syndrome, the Brugada syndrome, progressive cardiac conduction defect (Lenegre disease), catecholaminergic polymorphic ventricular tachycardia, and Andersen syndrome--have been progressively unveiled and shown to have an extremely high degree of genetic heterogeneity. The evidence supporting this concept is outlined, with particular emphasis on the growing complexity of the molecular pathways that may lead to arrhythmias and sudden death, in terms of the relationships between genetic defect(s) and genotype(s), as well as gene-to-gene interactions. The current knowledge is reviewed, focusing on the evidence that a single clinical phenotype may be caused by different genetic substrates and, conversely, a single gene may cause very different phenotypes acting through different pathways.