Ionic Mechanisms Responsible for the Electrocardiographic Phenotype of the Brugada Syndrome Are Temperature Dependent

TLDR

Brugada syndrome is a leading cause of sudden death in young Southeast Asian and Japanese men, marked by ST‑segment elevation in leads V1–V3 and polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation. The study aimed to characterize the electrophysiology of the Thr1620Met SCN5A mutation at physiological temperatures. The authors expressed the mutant in mammalian cells and recorded sodium currents at 32 °C using patch‑clamp techniques. At 32 °C the Thr1620Met mutant exhibits faster current decay, slower recovery from inactivation, and a shifted activation curve, explaining the Brugada ECG phenotype and indicating heightened arrhythmic risk during febrile states.

Abstract

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 α 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.