Abstract
Genetic defects in cardiac Na channel gene (SCN5A) result in multiple distinct arrhythmic syndromes such as long QT syndrome (LQTS) and Brugada syndrome. Brugada syndrome is a subgroup of idiopathic ventricular fibrillation characterized by the ST elevation in the right precordial leads. Mutant Na channels responsible for Brugada syndrome heterologously expressed in tsA-201 cells have shown several distinct biophysical abnormalities including 1) non-functional channels, 2) reduced Na current due to gating modulation and 3) defect of channel protein trafficking to the plasma membrane. Loss-of-function of Na current of the cardiac action potential leaves transient outward K current (Ito) unopposed in the phase 1, and results in the transmural voltage gradient predominantly observed in the right ventricle. Genetic variations and subclinical mutations in LQTS-related K channel genes have been suggested as risk factors for drug-induced LQTS. We have identified a silent SCN5A mutation (L1825P) in a case with cisapride-induced acquired LQTS. The L1825P channel showed a prominent persistent component most commonly observed for LQT3, and the loss-of-function features characteristic of Brugada syndrome. Despite severe channel dysfunctions, the patient exhibited normal QT-interval until exposure to the potent IKr blocker cisapride. Our study suggests that SCN5A mutations may underlie some cases of acquired LQTS and potentially predispose apparently stable individuals to life-threatening arrhythmias when treated with agents that inhibit cardiac K channels. [Jpn J Physiol 55 Suppl:S7 (2005)]
