title: Estradiol promotes sudden cardiac death in transgenic long QT type 2 rabbits while progesterone is protective.
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 Ca(2+) 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Katja E
authors.initials: KE
authors.lastname: Odening
authors.forename: Bum-Rak
authors.initials: BR
authors.lastname: Choi
authors.forename: Gong Xin
authors.initials: GX
authors.lastname: Liu
authors.forename: Kathryn
authors.initials: K
authors.lastname: Hartmann
authors.forename: Ohad
authors.initials: O
authors.lastname: Ziv
authors.forename: Leonard
authors.initials: L
authors.lastname: Chaves
authors.forename: Lorraine
authors.initials: L
authors.lastname: Schofield
authors.forename: Jason
authors.initials: J
authors.lastname: Centracchio
authors.forename: Manfred
authors.initials: M
authors.lastname: Zehender
authors.forename: Xuwen
authors.initials: X
authors.lastname: Peng
authors.forename: Michael
authors.initials: M
authors.lastname: Brunner
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004958:Estradiol / Q000009:adverse effects*; D005260:Female; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology*; D011374:Progesterone / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits
chemical_list: D013196:Dihydrotestosterone; D011374:Progesterone; D004958:Estradiol