BACKGROUND-Brugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype.

Substantial progress has been made recently in understanding the genetic basis of cardiomyopathy. Cardiomyopathies with known genetic cause include hypertrophic (HCM), dilated (DCM), restrictive (RCM), arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and left ventricular noncompaction (LVNC). HCM, DCM, and RCM have been recognized as distinct clinical entities for decades, whereas ARVD/C and LVNC are relative newcomers to the field. Hence the clinical and genetic knowledge for each cardiomyopathy varies, as do the recommendations and strength of evidence.

Abstract-The Brugada syndrome is a major cause of sudden death, particularly among young men of Southeast Asian and Japanese origin. The syndrome is characterized electrocardiographically by an ST-segment elevation in V1 through V3 and a rapid polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation. Our group recently linked the disease to mutations in SCN5A, the gene encoding for the ␣ subunit of the cardiac sodium channel. When heterologously expressed in frog oocytes, electrophysiological data recorded from the Thr1620Met missense mutant failed to adequately explain the electrocardiographic phenotype. Therefore, we sought to further characterize the electrophysiology of this mutant. We hypothesized that at more physiological temperatures, the missense mutation may change the gating of the sodium channel such that the net outward current is dramatically augmented during the early phases of the right ventricular action potential. In the present study, we test this hypothesis by expressing Thr1620Met in a mammalian cell line, using the patch-clamp technique to study the currents at 32°C. Our results indicate that Thr1620Met current decay kinetics are faster when compared with the wild type at 32°C. Recovery from inactivation was slower for Thr1620Met at 32°C, and steady-state activation was significantly shifted. Our findings explain the features of the ECG of Brugada patients, illustrate for the first time a cardiac sodium channel mutation of which the arrhythmogenicity is revealed only at temperatures approaching the physiological range, and suggest that some patients may be more at risk during febrile states. (Circ Res. 1999;85:803-809.)Key Words: Brugada syndrome Ⅲ Na ϩ channel Ⅲ temperature P olymorphic ventricular tachycardia (VT) and ventricular fibrillation (VF) developing in patients with structurally normal hearts accounts for 5% to 12% of the Ͼ300 000 sudden deaths of Americans each year. 1,2 Approximately half of these are attributed to the Brugada syndrome, a familial disease electrocardiographically characterized by a downsloping ST-segment elevation terminating in a negative T wave in the right precordial leads, an apparent right bundle branch block, 3,4 and rapid polymorphic VT capable of degenerating to VF. 5,6 Slightly prolonged H-V intervals are observed in 60% of patients 7 with Brugada syndrome.Chen et al 8 recently uncovered the first gene defects linked to the Brugada syndrome, identifying different mutations in SCN5A, the cardiac sodium channel gene, in each of the 3 families studied. A frameshift mutation resulted in an inframe stop codon in the pore region of domain III in one family. Because the syndrome has an autosomal dominant pattern of inheritance, the frameshift mutation is likely to result in a decrease in the number of functional channels, which can explain the clinical manifestation of the syndrome. 3,4 Missense mutations involving a double substitution of arginine at position 1232 by a tryptophan (Arg1232Trp) and the threonine at position 1620 by...