Role of Dynamical Instability in QT Interval Variability and Early Afterdepolarization Propensity.

Unlabelled: 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.

Significance Statement: 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.