Progesterone pretreatment reduces the incidence of drug‐induced torsades de pointes in atrioventricular node‐ablated isolated perfused rabbit hearts

Tisdale, James E.; Jaynes, Heather A.; Overholser, Brian R.; Sowinski, Kevin M.; Kovacs, Richard J.

doi:10.1111/jce.13942

Cited by 6 publications

(7 citation statements)

References 39 publications

(51 reference statements)

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“…Progesterone and estrogens are reported to exert opposing effects on the heart. Progesterone pretreatment is shown to reduce the incidence of drug-induced TdP in atrioventricular node-ablated isolated perfused rabbit hearts ( Tisdale et al, 2019 ) and to protect against prolongation of action potential duration – APD (90) and triangulation associated with potassium channel inhibition ( Tisdale et al, 2011 ). In isolated guinea pig ventricular myocytes, progesterone shortened action potential duration, probably due to enhancement of the slow delayed rectifier K + current (I Ks ) under basal conditions and inhibition of L-type Ca 2+ currents (I CaL ) under cAMP-stimulated conditions ( Nakamura et al, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

TdP Incidence in Methoxamine-Sensitized Rabbit Model Is Reduced With Age but Not Influenced by Hypercholesterolemia

et al. 2021

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Metabolic syndrome is associated with hypercholesterolemia, cardiac remodeling, and increased susceptibility to ventricular arrhythmias. Effects of diet-induced hypercholesterolemia on susceptibility to torsades de pointes arrhythmias (TdP) together with potential indicators of arrhythmic risk were investigated in three experimental groups of Carlsson’s rabbit model: (1) young rabbits (YC, young control, age 12–16 weeks), older rabbits (AC, adult control, age 20–24 weeks), and older age-matched cholesterol-fed rabbits (CH, cholesterol, age 20–24 weeks). TdP was induced by α-adrenergic stimulation by methoxamine and IKr block in 83% of YC rabbits, 18% of AC rabbits, and 21% of CH rabbits. High incidence of TdP was associated with high incidence of single (SEB) and multiple ectopic beats (MEB), but the QTc prolongation and short-term variability (STV) were similar in all three groups. In TdP-susceptible rabbits, STV was significantly higher compared with arrhythmia-free rabbits but not with rabbits with other than TdP arrhythmias (SEB, MEB). Amplitude-aware permutation entropy analysis of baseline ECG could identify arrhythmia-resistant animals with high sensitivity and specificity. The data indicate that the TdP susceptibility in methoxamine-sensitized rabbits is affected by the age of rabbits but probably not by hypercholesterolemia. Entropy analysis could potentially stratify the arrhythmic risk and identify the low-risk individuals.

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Section: Discussionmentioning

confidence: 99%

TdP Incidence in Methoxamine-Sensitized Rabbit Model Is Reduced With Age but Not Influenced by Hypercholesterolemia

et al. 2021

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“…Older age is a risk factor, 2,3 which, in men, may be attributable to declining serum testosterone concentrations 4 . Testosterone and the androgenic female sex hormone progesterone have been shown in preclinical studies to protect against drug‐induced prolongation of ventricular repolarization 5,6 and arrhythmias 7,8 . In a randomized, double‐blind, placebo‐controlled crossover‐design proof‐of‐concept study, we found that transdermal testosterone attenuates drug‐induced QT lengthening in men ≥ 65 years of age 9 .…”

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confidence: 82%

“…4 Testosterone and the androgenic female sex hormone progesterone have been shown in preclinical studies to protect against drug-induced prolongation of ventricular repolarization 5,6 and arrhythmias. 7,8 In a randomized, double-blind, placebo-controlled crossover-design proof-of-concept study, we found that transdermal testosterone attenuates drug-induced QT lengthening in men ≥ 65 years of age. 9 The influence of oral progesterone on drug-induced QT lengthening was minimal.…”

Section: How Might This Change Clinical Pharma-cology or Translational Science?mentioning

confidence: 94%

Transdermal Testosterone Attenuates Drug‐Induced Lengthening of Both Early and Late Ventricular Repolarization in Older Men

Muensterman

Jaynes

Sowinski

et al. 2020

Clin Pharma and Therapeutics

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We have previously reported that transdermal testosterone attenuates drug‐induced QT interval lengthening in older men. However, it is unknown whether this is due to modulation of early ventricular repolarization, late repolarization, or both. In a secondary analysis of a prospective, randomized, double‐blind, placebo‐controlled three‐way crossover study, we determined if transdermal testosterone and oral progesterone attenuate drug‐induced lengthening of early and late ventricular repolarization, represented by the electrocardiographic measurements J‐Tpeakc and Tpeak‐Tend, respectively, as well as Tpeak‐Tend/QT, a measure of transmural dispersion of repolarization. Male volunteers ≥ 65 years of age (n = 14) were randomized to receive transdermal testosterone 100 mg, oral progesterone 400 mg, or matching transdermal/oral placebo daily for 7 days. On the morning following the seventh day, subjects received intravenous ibutilide 0.003 mg/kg, after which electrocardiograms were performed serially. One subject was excluded due to difficulty in T‐wave interpretation. Pre‐ibutilide J‐Tpeakc was lower during the testosterone phase than during progesterone and placebo (216 ± 23 vs. 227 ± 28 vs. 227 ± 21 ms, P = 0.002). Maximum post‐ibutilide J‐Tpeakc was also lower during the testosterone phase (233 ± 22 vs. 246 ± 29 vs. 248 ± 23 ms, P < 0.0001). Pre‐ibutilide Tpeak‐Tend was not significantly different during the three phases, but maximum post‐ibutilide Tpeak‐Tend was lower during the testosterone phase (80 ± 12 vs. 89 ± 18 vs. 86 ± 15 ms, P = 0.002). Maximum Tpeak‐Tend/QT was also lower during the testosterone phase (0.199 ± 0.023 vs. 0.216 ± 0.035 vs. 0.209 ± 0.031, P = 0.005). Progesterone exerted minimal effect on drug‐induced lengthening of J‐Tpeakc, and no effect on Tpeak‐Tend or Tpeak‐Tend/QT. Transdermal testosterone attenuates drug‐induced lengthening of both early and late ventricular repolarization in older men.

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“…In addition, Tisdale et al have recently shown in a randomized, double-blind, placebo-controlled crossover study that oral progesterone attenuated ibutilide’s effect on QTc prolongation [ 52 ]. In castrated rabbits implanted with sustained release pellets of progesterone or placebo, a significant decrease in the incidence of dofetilide-induced TdP (27% vs. 61%, respectively, p = 0.049), bigeminy (36% vs. 74%, p = 0.03) and trigeminy (18% vs. 57%, p = 0.01) [ 53 ] was demonstrated in the progesterone-exposed group. Overall, estrogens therefore play a role in lengthening QTc, while progesterone appears to be protective by limiting QTc prolongation.…”

Section: Role Of Estrogen and Progesterone During The Menstrual Cymentioning

confidence: 99%

Sexual Dimorphisms, Anti-Hormonal Therapy and Cardiac Arrhythmias

Grouthier

Moey

Gandjbakhch

et al. 2021

IJMS

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Significant variations from the normal QT interval range of 350 to 450 milliseconds (ms) in men and 360 to 460 ms in women increase the risk for ventricular arrhythmias. This difference in the QT interval between men and women has led to the understanding of the influence of sex hormones on the role of gender-specific channelopathies and development of ventricular arrhythmias. The QT interval, which represents the duration of ventricular repolarization of the heart, can be affected by androgen levels, resulting in a sex-specific predilection for acquired and inherited channelopathies such as acquired long QT syndrome in women and Brugada syndrome and early repolarization syndrome in men. Manipulation of the homeostasis of these sex hormones as either hormonal therapy for certain cancers, recreational therapy or family planning and in transgender treatment has also been shown to affect QT interval duration and increase the risk for ventricular arrhythmias. In this review, we highlight the effects of endogenous and exogenous sex hormones in the physiological and pathological states on QTc variation and predisposition to gender-specific pro-arrhythmias.

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Progesterone pretreatment reduces the incidence of drug‐induced torsades de pointes in atrioventricular node‐ablated isolated perfused rabbit hearts

Cited by 6 publications

References 39 publications

TdP Incidence in Methoxamine-Sensitized Rabbit Model Is Reduced With Age but Not Influenced by Hypercholesterolemia

TdP Incidence in Methoxamine-Sensitized Rabbit Model Is Reduced With Age but Not Influenced by Hypercholesterolemia

Transdermal Testosterone Attenuates Drug‐Induced Lengthening of Both Early and Late Ventricular Repolarization in Older Men

Sexual Dimorphisms, Anti-Hormonal Therapy and Cardiac Arrhythmias

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