Hydroxyzine, a first generation H(1)-receptor antagonist, inhibits human ether-a-go-go-related gene (HERG) current and causes syncope in a patient with the HERG mutation.

QT prolongation, a risk factor for arrhythmias, can result from genetic variants in one (or more) of the genes governing cardiac repolarization as well as intake of drugs known to affect a cardiac K(+) channel encoded by human ether-a-go-go-related gene (HERG). In this paper, we will report a case of drug-induced long QT syndrome associated with an H(1)-receptor antagonist, hydroxyzine, in which a mutation was identified in the HERG gene. After taking 75 mg of hydroxyzine for several days, a 34-year-old female began to experience repetitive syncope. The deleterious effect of hydroxyzine was suspected because QTc interval shortened from 630 to 464 ms after cessation of the drug. Later on, the patient was found to harbor an A614V-HERG mutation. By using the patch-clamp technique in the heterologous expression system, we examined the functional outcome of the A614V mutation and confirmed a dominant-negative effect on HERG expression. Hydroxyzine concentration-dependently inhibited both wild-type (WT) and WT/A614V-HERG K(+) currents. Half-maximum block concentrations of WT and WT/A614V-HERG K(+) currents were 0.62 and 0.52 microM, respectively. Thus, accidental combination of genetic mutation and intake of hydroxyzine appeared to have led to a severe phenotype, probably, syncope due to torsade de pointes.

Tumor necrosis factor-alpha downregulates the voltage gated outward K+ current in cultured neonatal rat cardiomyocytes: a possible cause of electrical remodeling in diseased hearts.

BACKGROUND: Inflammatory cytokines have been reported to contribute to the progression of cardiac remodeling in various heart diseases and a remarkable prolongation of the monophasic action potential duration and reductions in the expression of Kv4.2 and K+ channel-interacting protein-2 (KChIP-2) in a rat autoimmune myocarditis model have been documented. In this study, the effect of tumor necrosis factor-alpha (TNF-alpha) on cultured cardiomyocytes was evaluated, focusing on the change in the voltage-gated outward K+ current and expression of related molecules. METHODS AND RESULTS: Cardiomyocytes isolated from 1-day-old Lewis rats were cultured for 72 h and treated with TNF-alpha (50 ng/ml) for an additional 48 h. The myocytes treated with TNF-alpha showed a 22% reduction in the peak K+ current, which consisted of a transient outward K+ current (Ito) and 1.4-fold enhancement of the cell-capacitance in comparison with the control. Among the cardiac ion channel related molecules evaluated in this study, Kv4.2 and KChIP-2 mRNA exhibited remarkable reductions (p < 0.05). CONCLUSIONS: Treatment with TNF-alpha induced reductions in Ito as well as cellular hypertrophy in neonatal cultured myocytes, which indicates that TNF-alpha might play a role in promoting electrical remodeling of cardiomyocytes under inflammatory conditions.