Sequence‐Dependent Repolarization Is Modulated by Endogenous Action Potential Duration Gradients Rather Than Electrical Coupling in Ventricular Myocardium

Background Previous studies suggest the relationship between activation time (AT) and action potential duration (APD) in the heart is dependent on electrotonic coupling, but this has not been directly tested. This study assessed whether acute changes in electrical coupling, or other determinants of conduction or repolarization, modulate APD heterogeneity. Methods and Results Langendorff‐perfused guinea pig hearts were epicardially paced and optically mapped after treatment with the gap junction uncoupler carbenoxolone, ephaptic uncoupler mannitol, ephaptic enhancer dextran 2MDa, sodium channel inhibitor flecainide, or rapid component of the delayed rectifier potassium channel inhibitor E4031. SD of APD and the AT–APD slope and coefficient of determination were quantified as metrics of APD heterogeneity. SD of APD increased with carbenoxolone, mannitol, and altered activation sequence. The AT–APD slope was insensitive to carbenoxolone, mannitol, dextran, flecainide, or E4031 but changed in response to activation sequence. The coefficient of determination did not change with carbenoxolone; decreased with mannitol, E4031, and activation sequence; but increased with dextran and flecainide. APD heterogeneity changes were dependent on whether the estimation used SD of APD or the AT–APD relationship. The pacing stimulus increased APD at the site of stimulation, revealing a confounding stimulus effect on APD within the measurement area. Simulations predict that the stimulus artifact and endogenous APD gradients are stronger determinants of APD heterogeneity than AT. Conclusions APD dependence on conduction is relatively small. Furthermore, APD heterogeneity within a mapping field of view is dependent on endogenous gradients, the stimulus artifact, and the experimental approach, rather than electrical coupling.