The interplay between dynamic regulation of ion-channel gating and trafficking in cardiac arrhythmogenesis

Cardiac arrhythmias remain a major cause of morbidity and mortality worldwide, yet therapeutic efficacy is constrained by an incomplete understanding of their multifactorial and time-dependent mechanisms. Traditional cardiac electrophysiology has largely focused on the acute gating behaviour of ion channels as determinants of arrhythmogenesis, but growing evidence highlights the importance of slower dynamic processes such as channel trafficking and transcriptional regulation that occur over timescales from minutes to days. Acute and long-term modulators, including temperature, extracellular potassium concentration, heart rate and/or pacing frequency, altered ventricular activation, and pharmacological agents, influence the function of key cardiac ion channels (Na _v1.5, Ca _v1.2, K _v4.3, K _v1.5, K _v11.1, K _v7.1, K _ir2.1 and SK channels) across multiple temporal scales. Evidence indicates that identical modulatory factors can exert opposing effects on ion currents depending on the duration of exposure, emphasising the importance of temporal dynamics in the regulation of cardiac electrophysiology. Overall, cardiac excitability emerges from the interplay between rapid channel gating and slower regulatory mechanisms that dynamically reshape ion-channel expression and availability. Understanding and quantifying these time-dependent interactions are essential for improving risk prediction and developing more effective antiarrhythmic therapies. (Figure presented.).