Role of dynamical instability in QT interval variability and early afterdepolarization propensity

作者：Daisuke Sato, Bence Hegyi, Crystal M. Ripplinger, Donald M. Bers · 发表于：Biophysical Journal · 年份：2025 · DOI：10.1016/j.bpj.2025.07.017 · 被引用次数：4 · 研究领域：Cardiac electrophysiology and arrhythmias

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 electrocardiogram 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 ...