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

Research output: Contribution to journalArticle

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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

Fingerprint

Sudden Cardiac Death
Progesterone
Estradiol
Rabbits
Ventricular Tachycardia
Long QT Syndrome
Dihydrotestosterone
Ventricular Premature Complexes
Gonadal Steroid Hormones
Isoproterenol
Postpartum Period
Action Potentials
Placebos
Ions
Incidence
Therapeutics

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., ... 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
Odening, Katja E. ; Choi, Bum Rak ; Liu, Gong Xin ; Hartmann, Kathryn ; Ziv, Ohad ; Chaves, Leonard ; Schofield, Lorraine ; Centracchio, Jason ; Zehender, Manfred ; Peng, Xuwen ; Brunner, Michael ; Koren, Gideon. / Estradiol promotes sudden cardiac death in transgenic long QT type 2 rabbits while progesterone is protective. In: Heart Rhythm. 2012 ; Vol. 9, No. 5. pp. 823-832.
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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.",
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Odening, KE, Choi, BR, Liu, GX, 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, vol. 9, no. 5, pp. 823-832. https://doi.org/10.1016/j.hrthm.2012.01.009

Estradiol promotes sudden cardiac death in transgenic long QT type 2 rabbits while progesterone is protective. / Odening, Katja E.; Choi, Bum Rak; Liu, Gong Xin; Hartmann, Kathryn; Ziv, Ohad; Chaves, Leonard; Schofield, Lorraine; Centracchio, Jason; Zehender, Manfred; Peng, Xuwen; Brunner, Michael; Koren, Gideon.

In: Heart Rhythm, Vol. 9, No. 5, 01.05.2012, p. 823-832.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Estradiol promotes sudden cardiac death in transgenic long QT type 2 rabbits while progesterone is protective

AU - Odening, Katja E.

AU - Choi, Bum Rak

AU - Liu, Gong Xin

AU - Hartmann, Kathryn

AU - Ziv, Ohad

AU - Chaves, Leonard

AU - Schofield, Lorraine

AU - Centracchio, Jason

AU - Zehender, Manfred

AU - Peng, Xuwen

AU - Brunner, Michael

AU - Koren, Gideon

PY - 2012/5/1

Y1 - 2012/5/1

N2 - 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.

AB - 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.

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