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

ABSTRACT: 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.To investigate whether sex hormones directly modulate the arrhythmogenic risk in LQTS.Prepubertal ovariectomized transgenic LQT2 rabbits were treated with estradiol (EST), progesterone (PROG), dihydrotestosterone (DHT), or placebo (OVX).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).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.

SUBMITTER: Odening KE

PROVIDER: S-EPMC4397932 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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

Odening Katja E KE Choi Bum-Rak BR Liu Gong Xin GX Hartmann Kathryn K Ziv Ohad O Chaves Leonard L Schofield Lorraine L Centracchio Jason J Zehender Manfred M Peng Xuwen X Brunner Michael M Koren Gideon G

Heart rhythm 20120111 5

<h4>Background</h4>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.<h4>Objective</h4>To investigate whether sex hormones directly modulate the arrhythmogenic risk in LQTS.<h4>Methods</h4>Prepubertal ovariectomized transgenic LQT2 rabbits were treated with estradiol (EST), progesterone (PROG), dihydrotestosterone (DHT), or placebo (OVX).<h4 ...[more]

PMID: 22245795

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Project description:BackgroundSudden cardiac death (SCD) is a global public health issue, accounting for 10-20% of deaths in industrialized countries. Identification of modifiable risk factors may reduce SCD incidence.MethodsThis umbrella review systematically evaluates published meta-analyses of observational and randomized controlled trials (RCT) for the association of modifiable risk and protective factors of SCD.ResultsFifty-five meta-analyses were included in the final analysis, of which 31 analyzed observational studies and 24 analyzed RCTs. Five associations of meta-analyses of observational studies presented convincing evidence, including three risk factors [diabetes mellitus (DM), smoking, and early repolarization pattern (ERP)] and two protective factors [implanted cardiac defibrillator (ICD) and physical activity]. Meta-analyses of RCTs identified five protective factors with a high level of evidence: ICDs, mineralocorticoid receptor antagonist (MRA), beta-blockers, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors in patients with HF. On the contrary, other established, significant protective agents [i.e., amiodarone and statins along with angiotensin-converting enzyme (ACE) inhibitors in heart failure (HF)], did not show credibility. Likewise, risk factors as left ventricular ejection fraction in HF, and left ventricular hypertrophy, non-sustain ventricular tachycardia, history of syncope or aborted SCD in pediatric patients with hypertrophic cardiomyopathy, presented weak or no evidence.ConclusionsLifestyle risk factors (physical activity, smoking), comorbidities like DM, and electrocardiographic features like ERP constitute modifiable risk factors of SCD. Alternatively, the use of MRA, beta-blockers, SGLT-2 inhibitors, and ICD in patients with HF are credible protective factors. Further investigation targeted in specific populations will be important for reducing the burden of SCD.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020216363, PROSPERO CRD42020216363.

Dataset Information

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

Publications

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

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