Estradiol promotes sudden cardiac death in transgenic long QT type 2 rabbits while progesterone is protective

Background

Postpubertal women with inherited long QT syndrome type 2 (LQT2) are at increased risk for polymorphic ventricular tachycardia (pVT) and sudden cardiac death (SCD), particularly during the postpartum period.

Objective

To investigate whether sex hormones directly modulate the arrhythmogenic risk in LQTS.

Methods

Prepubertal ovariectomized transgenic LQT2 rabbits were treated with estradiol (EST), progesterone (PROG), dihydrotestosterone (DHT), or placebo (OVX).

Results

During 8 weeks of treatment, major cardiac events—spontaneous pVT or SCD—occurred in 5 of the 7 EST rabbits and in 2 of the 9 OVX rabbits (P <.05); in contrast, no events occurred in 9 PROG rabbits and 6 DHT rabbits (P <.01 vs PROG; P <.05 vs DHT). Moreover, EST increased the incidence of pVT (P <.05 vs OVX), while PROG reduced premature ventricular contractions, bigeminy, couplets, triplets, and pVT (P <.01 vs OVX; P <.001 vs EST). In vivo electrocardiographic monitoring, in vivo electrophysiological studies, and ex vivo optical mapping studies revealed that EST promoted SCD by steepening the QT/RR slope (P <.05), by prolonging cardiac refractoriness (P <.05), and by altering the spatial pattern of action potential duration dispersion. Isoproterenol-induced Ca²⁺ oscillations resulted in early afterdepolarizations in EST-treated hearts (4 of 4), while PROG prevented SCD by eliminating this early afterdepolarization formation in 4 of the 7 hearts (P = .058 vs EST; P <.05 vs OVX). Analyses of ion currents demonstrated that EST increased the density of I_Ca,L as compared with OVX (P <.05) while PROG decreased it (P <.05).

Conclusion

This study reveals the proarrhythmic effect of EST and the antiarrhythmic effect of PROG in LQT2 in vivo, outlining a new potential antiarrhythmic therapy for LQTS.

Keywords:  Long QT syndrome , Sex hormones , Arrhythmogenesis , Sudden cardiac death , Transgenic LQT2 rabbit model , Cardiac ion currents , Early afterdepolarization , In vivo electrophysiological study

Abbreviations:  APD, action potential duration, AV, atrioventricular, DHT, dihydrotestosterone, EAD, early afterdepolarization, ECG, electrocardiography, EPS, electrophysiological study, EST, estradiol, ISO, isoproterenol, LQT2, long QT syndrome type 2, LQTS, long QT syndrome, LV, left ventricular, NCX, sodium-calcium exchanger, OVX, ovariectomy and placebo-treatment, PLN, phospholamban, PROG, progesterone, PVC, premature ventricular contraction, pVT, polymorphic ventricular tachycardia, RV, right ventricular, SCD, sudden cardiac death, SERCA2a, sarcoplasmic reticulum calcium ATPase2a, SF, sham-operated female, SM, sham-operated male, VERP, ventricular effective refractory period, VF, ventricular fibrillation, VT, ventricular tachycardia