Ionic mechanisms responsible for the electrocardiographic phenotype of theBrugada syndrome are temperature dependent

The Brugada syndrome is a major cause of sudden death, particularly among y oung men of Southeast Asian and Japanese origin. The syndrome is characteri zed electrocardiographically by an ST-segment elevation in V1 through V3 an d a rapid polymorphic ventricular tachycardia that can degenerate into vent ricular fibrillation. Our group recently linked the disease to mutations in SCN5A, the gene encoding for the cu subunit of the cardiac sodium channel. When heterologously expressed in frog oocytes, electrophysiological data r ecorded from the Thr1620Met missense mutant failed to adequately explain th e electrocardiographic phenotype. Therefore, we sought to further character ize the electrophysiology of this mutant. We hypothesized that at more phys iological 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 p resent study, we test this hypothesis by expressing Thr1620Met in a mammali an cell line, using the patch-clamp technique to study the currents at 32 d egrees C. Our results indicate that Thr1620Met current decay kinetics are f aster when compared with the wild type at 32 degrees C. Recovery from inact ivation was slower for Thr1620Met at 32 degrees C, and steady-state activat ion was significantly shifted. Our findings explain the features of the ECG of Brugada patients, illustrate for the first time a cardiac sodium channe l 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.