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

Katja E. Odening, Bum Rak Choi, Gong Xin Liu, Kathryn Hartmann, Ohad Ziv, Leonard Chaves, Lorraine Schofield, Jason Centracchio, Manfred Zehender, Xuwen Peng, Michael Brunner, Gideon Koren

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Abstract

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 ICa,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.

Original languageEnglish (US)
Pages (from-to)823-832
Number of pages10
JournalHeart Rhythm
Volume9
Issue number5
DOIs
StatePublished - May 1 2012

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All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Odening, K. E., Choi, B. R., Liu, G. X., Hartmann, K., Ziv, O., Chaves, L., Schofield, L., Centracchio, J., Zehender, M., Peng, X., Brunner, M., & Koren, G. (2012). Estradiol promotes sudden cardiac death in transgenic long QT type 2 rabbits while progesterone is protective. Heart Rhythm, 9(5), 823-832. https://doi.org/10.1016/j.hrthm.2012.01.009