Abstract 15600: Mechanisms of Anti-Arrhythmic Effects of Progesterone and Pro-Arrhythmic Effects of Estradiol in Transgenic Long QT Type 2 Rabbits
Introduction: Women with inherited long QT syndrome types 1 and 2 (LQT1, LQT2) are at increased risk for polymorphic ventricular tachycardia (pVT) and sudden cardiac death (SCD). We hypothesize that sex hormones modulate arrhythmogenesis in LQT2 in vivo.
Methods: Prepubertal ovariectomized transgenic LQT2 rabbits were implanted with 90 day pellets containing estradiol (EST), progesterone (PROG), dihydrotestosterone (DHT), or placebo (OVX). All groups underwent telemetric ECG monitoring, in vivo electrophysiological studies, and dual voltage-calcium epicardial optical mapping. Changes in ion channels were assessed by patch clamp analysis and western blots.
Results: During 8 weeks of hormone-treatment, SCD occurred in 4/6 EST and 2/6 OVX rabbits, contrasting with no SCD and no pVT in 6 PROG and 6 DHT rabbits (p<0.05). Hormones altered cardiac refractoriness and spatial pattern of action potential duration (APD) dispersion: EST steepened the QT/RR slope and prolonged ventricular refractory periods compared to OVX, PROG, and DHT rabbits (p<0.05 each), particularly in the RV apex. Moreover, in EST rabbits the APD was longer in the LV apex contrasting with longer APD in the mid-septal region of the LV in OVX, PROG, and DHT. VF was inducible in 4/4 EST hearts, with activation waves propagating around the apical region of prolonged APD, contrasting with 0/4 DHT (p<0.05) and 1/4 OVX and PROG (p=0.07 each). Hormones also differentially altered the susceptibility to sympathetic stimuli: In 4/4 EST and OVX hearts, isoproterenol initiated Ca2+ oscillations that triggered early afterdepolarisations (EADs), while in (2/4) PROG and DHT hearts, Ca2+ oscillations failed to initiate EADs. SERCA expression was higher in PROG than in EST hearts (n=3, p<0.05), while ICa,L density was greater in EST than in PROG cardiomyocytes (n=14, p<0.01).
Conclusions: PROG prevents SCD in LQT2 rabbits by eliminating EAD formation in response to Ca2+ oscillations, likely by increasing SERCA expression. EST promotes SCD by prolonging cardiac refractoriness, altering spatial pattern of APD dispersion, and increasing ICa,L. In conclusion, this study provides mechanistic insights for the anti-arrhythmic effect of PROG and the pro-arrhythmic effect of EST in LQT2 syndrome.
- © 2010 by American Heart Association, Inc.