Sex, age, and regional differences in L-type calcium current are important determinants of arrhythmia phenotype in rabbit hearts with drug-induced long QT type 2.
Sims C, Reisenweber S, Viswanathan PC, Choi B-R, Walker WH, Salama G
Circ Res 2008 May 9 102(9):e86-100.
Sex differences in cardiac electrical and mechanical properties have been the subject of intense clinical and basic science studies and have been shown to underlie sex differences in responses to pharmacological agents and arrhythmia susceptibility. More precisely, women have longer QT intervals than men as recorded by cardiac electrograms (EKG) and have a higher risk of polymorphic ventricular arrhythmias, called Torsade de Pointes (TdP) in both drug-acquired and hereditary forms of the long QT syndrome type 2 (LQT2). Congenital forms of LQT2 are due to mutations of HERG, resulting in a loss of function of the K+ current, IKr (which inhibits cardiac repolarization) and to a greater susceptibility to TdP. In the acquired form of LQT2, TdP results from the administration of a drug that inhibits IKr resulting in prolonged action potential durations (APDs) and the firing of premature depolarizing spikes during the plateau phase of the AP, or early afterdepolarizations (EADs). The current consensus is that women have a reduced ‘repolarization reserve’ caused by lower levels of K+ channel expression and reduced IKr compared to men.
Sims et al., discovered that in adult rabbits, the L-type Ca2+ current is larger in females than males at the base of the heart whereas these differences are reversed in adolescent animals. Based on experimental and mathematical modeling, they showed that the higher levels of Ca2+ current promoted early afterdepolarizations and TdP. Moreover, in adolescents (men and rabbits) before the surge of sex hormones the vulnerability to TdP is reversed with males being more susceptible to lethal arrhythmias than females, even though the young female heart has longer QT and APD. Optical mapping of electrical activity revealed that arrhythmias are initiated at the base of the heart where the Ca2+ current is elevated. The work strongly suggests that differences in K+ channel function alone do not explain sex differences in arrhythmia risk and that sex differences in Ca2+ current influence the action potential duration, cellular Ca2+ overload, the incidence of EADs and the onset of arrhythmias.