Remodeling of early-phase repolarization: A mechanism of abnormal impulse conduction in heart failure

Background - The early phase of action potential (AP) repolarization is critical to impulse conduction in the heart because it provides current for charging electrically coupled cells. In the present study we tested the impact of heart failure-associated electrical remodeling on AP propagation. Methods and Results - Subepicardial, midmyocardial, and subendocardial myocytes were enzymatically dissociated from control and pressure-overload failing left ventricle (LV), and APs were recorded. A unique coupling-clamp technique was used to electrically couple 2 isolated myocytes with a controlled value of coupling conductance (G_c). In sham-operated mice, AP duration manifested a clear transmural gradient, with faster repolarization in subepicardial myocytes than in subendocardial myocytes. AP propagation from subendocardial to subepicardial myocytes required less G_c compared with conduction in the opposite direction. In failing heart, AP morphology was dramatically altered, with a significantly elevated plateau potential and prolonged AP duration. Spatially nonuniform alteration of AP duration in failing heart blunted the transmural gradient of repolarization. Furthermore, increased pacing rate prolonged AP duration exclusively in myocytes from failing heart, and the critical conductance required for successful AP propagation decreased significantly at high frequencies. Finally, in failing heart, asymmetry of transmural electrical propagation was abolished. Conclusions - In failing heart, preferential conduction from subendocardial to subepicardial myocytes is lost, and failing myocytes manifest facilitated AP propagation at fast rates. Together, these electrical remodeling responses may promote conduction of premature impulses and heighten the risk of malignant arrhythmia, a prominent feature of heart failure.