Dynamical instability is a major cause of cardiac action potential variability

Increased beat-to-beat QT interval variability (QTV) in the electrocardiogram is strongly associated with ventricular arrhythmias and sudden cardiac death, yet its origins remain poorly understood. While heart rate variability decreases with deteriorating cardiac health, QTV increases, suggesting distinct underlying mechanisms. The stochastic nature of ion channel gating is a potential source of cardiac variability. However, the law of large numbers suggests that, with billions of channels in the heart, this stochasticity should be minimized. In this study, we tested the hypothesis that dynamical instability amplifies stochastic ion channel fluctuations, leading to increased action potential (AP) variability. Using a mathematical model of ventricular myocytes, we investigated the relationship between AP variability and voltage instability. Our results demonstrate that stochastic gating alone cannot cause large AP variability, but dynamical instability significantly amplifies this variability. We found a positive correlation between voltage instability, indicated by the slope of the AP duration restitution curve, and AP duration variability. Notably, the largest variability occurred at the onset of alternans when considering every other beat. These findings provide a mechanistic explanation for increased QTV in pathological conditions and suggest that measuring QTV using every other beat may predict the onset of alternans and severity of alternans. Our study highlights the critical role of dynamical instability in cardiac electrical variability and offers new insights into the mechanisms underlying arrhythmogenesis.