Sudden Cardiac Death Sudden Cardiac Death and Genetic Ion Channelopathies Long QT, Brugada, Short QT, Catecholaminergic Polymorphic Ventricular Tachycardia, and Idiopathic Ventricular Fibrillation

Sudden cardiac death is a common outcome of several cardiac disorders such as acute myocardial ischemia, myocardial infarction, and heart failure. However, 5% to 15% of cardiac arrest victims fail to show evidence of structural abnormalities at autopsy.1–3 In 1997, a panel of experts defined sudden death in the absence of an identifiable cause as idiopathic ventricular fibrillation (IVF): “IVF is the terminology that best acknowledges our current inability to identify a causal relationship between the clinical circumstance and the arrhythmia.”4 In the same article, the requirements for the diagnosis of IVF were identified on the basis of the clinical tools available at the time. In 1992, using the phenotypes observed in the IVF registry, we advanced the hypothesis that IVF could be the manifestation of concealed forms of arrhythmogenic disorders5 exacerbated by appropriate triggers. A few years later, the discovery of the genes of long-QT syndrome (LQTS)6–8 and the detection of incomplete penetrance9 supported this early hypothesis. Incomplete penetrance and variable expressivity in inherited arrhythmogenic disorders imply that the distinctive ECG patterns that characterize these disorders may be concealed.10 Interestingly, however, the absence of the ECG markers of the disease is not an indicator of favorable outcome, as demonstrated by the evidence that the incidence of cardiac arrest in LQTS patients with normal QTc during the first 40 years of life is 4%, ie, 0.1%/y.11,12 In the last 15 years, the results of mutation screening in sudden unexplained death syndrome or sudden infant death syndrome, the so-called molecular autopsy, have been reported in several studies (Table 1).13–20 Although the yield of molecular autopsy reported by different studies is highly variable, ranging from 4% to 30%, it is sufficient to prove the concept that ion channel mutations may underlie IVF and that a positive genetic test may allow the extension of genotyping to family members of those affected to reduce additional deaths in the family.