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.
An evaluation of this paper by Dr. Kenneth MacLeod of Imperial College, UK reads:
This paper reports the fascinating finding that, in adult rabbits, L-type Ca current is larger in females than in males, whereas these differences are reversed in immature (prepubertal) animals. Using Luo-Rudy computer simulations, the work suggests that the increased L-type Ca current promotes the formation of early afterdepolarizations (EADs) and is an important determinant of arrhythmias in type 2 long QT syndrome. In congenital and acquired type 2 long QT syndromes, women are more vulnerable than men to arrhythmias, particularly torsade de pointes, and this is thought to arise from prolonged action potential duration. The work strongly suggests that, rather than differences in K channel function being of sole importance in the generation of arrhythmias, sex differences in the L-type Ca current can determine action potential duration, cellular Ca overload and the onset of EADs. Kenneth MacLeod: Faculty of 1000 Biology, 28 May 2008.
