Sato Daisuke, Hegyi Bence, Ripplinger Crystal M, Bers Donald M
bioRxiv. 2025 Jun 17:2025.06.11.659221. doi: 10.1101/2025.06.11.659221.
Beat-to-beat variability of the QT interval (QTV) is a well-established marker of cardiac health, with increased QTV (> 5 ms) often associated with a higher risk of arrhythmias. However, the underlying mechanisms contributing to this phenomenon remain poorly understood. Recently, we showed that cardiac instability is a major cause of QTV. Early afterdepolarizations (EADs) are abnormal electrical oscillations that occur during the plateau phase of the cardiac action potential (AP), often arising when the membrane potential becomes unstable. In this study, we use a physiologically detailed computational model of rabbit ventricular myocytes with stochastic ion channel gating to investigate the relationship between QTV and EAD propensity. We found that increased AP duration (APD) variability, which serves as a surrogate for QTV on the ECG at the single-cell level, can arise even in the absence of apparent EADs, driven by intrinsic dynamical instability. As the cellular state approaches the threshold for EAD generation, small perturbations in membrane voltage are amplified, leading to increased APD variability. The phase-plane analysis in the voltage-calcium channel inactivation space demonstrates that proximity to the EAD-generating basin of attraction strongly influences repolarization variability, establishing a mechanistic link between QTV and EAD propensity. Furthermore, we observed that QTV increases at longer pacing cycle lengths (PCLs), distinguishing it from alternans-associated APD variability, which increases at shorter PCLs. These findings suggest that increased QTV may serve as an early indicator of arrhythmic risk before the manifestation of EADs, potentially offering a critical window for preventive intervention. Our results provide novel insights into the fundamental mechanisms underlying QTV and its potential role in arrhythmia prediction.
This study investigates the relationship between beat-to-beat variability of the QT interval (QTV) and the propensity for early afterdepolarizations (EADs), abnormal electrical oscillations linked to life-threatening arrhythmias. Using a computational model, we show that increased QTV can precede apparent EADs, driven by inherent dynamical instability of cardiac cells. As cells approach an arrhythmia-prone state, small membrane voltage fluctuations are amplified, increasing repolarization variability and thus QTV. Furthermore, QTV increases with slower heart rates, distinguishing it from alternans, another type of instability arising at faster rates. Thus, increased QTV may serve as an early warning signal for arrhythmia risk, potentially enabling preventative interventions. Our results provide novel insights into the fundamental mechanisms underlying QTV and its potential role in arrhythmia prediction.
QT间期（QTV）的逐搏变异性是心脏健康的一个公认指标，QTV增加（>5毫秒）通常与心律失常风险较高相关。然而，导致这种现象的潜在机制仍知之甚少。最近，我们表明心脏不稳定性是QTV的主要原因。早期后去极化（EADs）是在心脏动作电位（AP）平台期出现的异常电振荡，通常在膜电位变得不稳定时出现。在本研究中，我们使用具有随机离子通道门控的兔心室肌细胞生理详细计算模型来研究QTV与EAD倾向之间的关系。我们发现，即使在没有明显EADs的情况下，由内在动态不稳定性驱动，作为单细胞水平心电图上QTV替代指标的动作电位时程（APD）变异性也会增加。当细胞状态接近EAD产生阈值时，膜电压的小扰动会被放大，导致APD变异性增加。电压-钙通道失活空间中的相平面分析表明，接近EAD产生的吸引盆会强烈影响复极化变异性，建立了QTV与EAD倾向之间的机制联系。此外，我们观察到在较长的起搏周期长度（PCL）下QTV增加，这与在较短PCL下增加的与交替现象相关的APD变异性不同。这些发现表明，在EADs出现之前，QTV增加可能作为心律失常风险的早期指标，可能为预防性干预提供关键窗口。我们的结果为QTV的基本机制及其在心律失常预测中的潜在作用提供了新的见解。
本研究调查了QT间期（QTV）的逐搏变异性与早期后去极化（EADs）倾向之间的关系，EADs是与危及生命的心律失常相关的异常电振荡。使用计算模型，我们表明，由心脏细胞固有的动态不稳定性驱动，QTV增加可能先于明显的EADs出现。当细胞接近心律失常易患状态时，小的膜电压波动会被放大，增加复极化变异性，从而增加QTV。此外，QTV随着心率减慢而增加，这与在较快心率下出现的另一种不稳定性——交替现象不同。因此，QTV增加可能作为心律失常风险的早期预警信号，可能实现预防性干预。我们的结果为QTV的基本机制及其在心律失常预测中的潜在作用提供了新的见解。
