WITHDRAWN: Sex-differences in sodium/calcium exchange expression is a determinant of the arrhythmia phenotype in pre-pubertal rabbit hearts with Long QT type 2

Abstract

Background Adult females are more prone to Torsade de Pointes (TdP) than males in long QT type 2 (LQT2) elicited by inhibiting the K+ current, IKr. Sex-differences in the propensity to early afterdepolarizations (EADs) and TdP are reversed in adolescence and correlate with higher levels of L-type Ca2+ channels and current, ICa,L at the base of the epicardium in adolescent male rabbit hearts, even though female hearts have longer action potential (AP) durations. Higher Ca2+-influx via ICa,L should be balanced by higher Ca2+-efflux. Objectives Sex-differences in Na+-Ca2+ exchanger and its current, INCX are investigated in adolescent rabbit hearts to determine if they parallel sex-differences in ICa,L. Methods and Results Optical APs and intracellular Ca2+ (Cai) were mapped in pre-pubertal Langendorff rabbit hearts. E4031 (0.5μM) blocked IKr, elicited EADs and TdP in male (n=10) but not female (n=18) hearts. KB-R4379 (INCX inhibitor, 1μM) reversed (n=5/5) or protected from EADs if perfused before E4031 (n=6/6). INCX density was 20–30% greater in base compared to apex myocytes of pre-pubertal male (p<0.02) or to apex and base myocytes of female hearts (p<0.02). In Western blots, NCX was 22% higher at the base of male versus female hearts and 25% higher than the apex (n=4, each gender). Immuno-histochemistry of ventricular sections revealed higher NCX levels in male versus female hearts. Conclusions Sex and regional differences in NCX correlate with L-type Ca2+ channels and NCX inhibition suppresses EADs and TdP in LQT2. These data provide compelling evidence that sex-differences in Ca2+ handling determine the arrhythmia phenotype.