Beat‐to‐beat QT interval variability as a tool to detect the underlying cellular mechanisms of arrhythmias

作者：Daisuke Sato, Bence Hegyi, Crystal M. Ripplinger, Donald M. Bers · 发表于：The Journal of Physiology · 年份：2025 · DOI：10.1113/jp289051 · 被引用次数：4 · 研究领域：Cardiac electrophysiology and arrhythmias

Abstract Increased beat‐to‐beat QT interval variability (QTV) on the electrocardiogram (ECG) has been associated with arrhythmia risk and sudden cardiac death. However, the underlying mechanisms driving increased QTV are not fully understood. Our previous work showed that membrane voltage instability is a major contributor to QTV. In this study, we investigated how intracellular calcium (Ca 2+ ) cycling instability is also a major contributor to QTV using a mathematical model of a ventricular myocyte that incorporates stochastic ion channel gating and detailed Ca 2+ cycling. By independently modulating membrane voltage instability (via the L‐type Ca 2+ channel recovery time constant, τ f ) and intracellular Ca 2+ cycling instability (via the steepness of the sarcoplasmic reticulum Ca 2+ release‐load relationship, u ), we show that both voltage and Ca 2+ instabilities significantly increase action potential duration (APD) variability, which contributes to QTV, even in the absence of overt arrhythmic patterns. Ca 2+ transient variability increases with intracellular Ca 2+ cycling instability, contributing to APD variability via Ca 2+ ‐sensitive currents, and consequently to QTV. Notably, APD variability/QTV significantly increases just before the onset of alternans, regardless of whether instability originates from voltage or Ca 2+ dynamics. Thus, QTV may serve as a precursor to both voltage‐driven and Ca 2+ ‐driven alternans. Furthermore, pharmacological interventions that sel...