Acute effects of sex steroid hormones on susceptibility to cardiac arrhythmias: a simulation study.
Acute effects of sex steroid hormones on susceptibility to cardiac arrhythmias: a simulation study.
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DOI：
10.1371/journal.pcbi.1000658
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发表时间：
2010-01-29
影响因子：
4.3
通讯作者：
Clancy CE
中科院分区：
文献类型：
--
作者：
Yang PC;Kurokawa J;Furukawa T;Clancy CE
性类固醇激素的急性作用可能有助于观察到青春期后男性的QT间期比女性短。然而，激素在调节心脏电生理参数和心律失常易感性中的具体作用尚不清楚。在这里，我们使用计算建模的方法，结合实验测量睾酮，雌激素和孕酮的生理浓度对心脏离子通道目标的影响。然后，我们研究了激素对心室细胞和组织动力学的影响，包括Faber-Rudy计算模型。“女性”模型预测月经周期不同阶段动作电位持续时间（APD）的变化，与临床观察到的QT间期波动一致。“男性”模型预测在生理睾酮浓度下APD和QT间期缩短。该模型表明，当雌二醇水平高时，对药物性心律失常的易感性增加，而睾酮和孕酮显然具有保护作用。模拟预测性类固醇激素对临床观察QT间期的影响，揭示雌激素介导的QT间期延长易感性的机制。模拟还表明，雌激素的急性效应并不足以单独引起心律失常，并解释了女性患Torsades de Pointes的风险增加。我们的研究结果表明，性类固醇激素对心脏离子通道的急性作用足以解释长qt相关性心律失常的性别特异性易感性的某些方面。众所周知，女性是某些类型心律失常的独立危险因素。然而，由于心脏系统异常复杂，很难确定循环性类固醇激素的生理浓度在与性别相关的心律失常易感性中起多大作用。在这里，我们采用一种基于实验测量的计算策略，梳理出雌激素、黄体酮和睾酮对心脏电行为的个体贡献，然后对它们在组合和药物存在下的影响做出预测。计算模型令人信服地再现了观察到的QT间期波动（记录在心电图上，QT间期反映了心室兴奋和舒张之间的时间间隔），通过女性月经周期和睾酮对心电图参数的影响。我们的模拟还预测，睾酮和孕酮对药物性心律失常具有保护作用，而雌激素可能会在qt延长药物的存在下加剧正常心电活动的破坏。
Acute effects of sex steroid hormones likely contribute to the observation that post-pubescent males have shorter QT intervals than females. However, the specific role for hormones in modulating cardiac electrophysiological parameters and arrhythmia vulnerability is unclear. Here we use a computational modeling approach to incorporate experimentally measured effects of physiological concentrations of testosterone, estrogen and progesterone on cardiac ion channel targets. We then study the hormone effects on ventricular cell and tissue dynamics comprised of Faber-Rudy computational models. The “female” model predicts changes in action potential duration (APD) at different stages of the menstrual cycle that are consistent with clinically observed QT interval fluctuations. The “male” model predicts shortening of APD and QT interval at physiological testosterone concentrations. The model suggests increased susceptibility to drug-induced arrhythmia when estradiol levels are high, while testosterone and progesterone are apparently protective. Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval. The simulations also indicate that acute effects of estrogen are not alone sufficient to cause arrhythmia triggers and explain the increased risk of females to Torsades de Pointes. Our results suggest that acute effects of sex steroid hormones on cardiac ion channels are sufficient to account for some aspects of gender specific susceptibility to long-QT linked arrhythmias. It is well known that female gender is an independent risk factor for some types of cardiac arrhythmias. However, it has been difficult to determine how much of a role physiological concentrations of circulating sex steroid hormones play in gender linked arrhythmia susceptibility because the cardiac system is so extraordinarily complex. Here we employ a computational strategy, based on experimental measurements, to tease out the individual contributions of estrogen, progesterone and testosterone on cardiac electrical behavior and then make predictions about their effects in combination and in the presence of drugs. The computational models convincingly reproduce observed fluctuations of QT intervals (as recorded on the ECG (electrocardiogram), the QT interval reflects the time period between ventricular excitation and relaxation) through the menstrual cycle in females and effects of testosterone on ECG parameters. Our simulations also predict that testosterone and progesterone are protective against drug-induced arrhythmias, while estrogen likely exacerbates the breakdown of normal cardiac electrical activity in the presence of QT-prolonging drugs.
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