Increase in Late Sodium Current and Cellular Uncoupling Exacerbates Transmural Dispersion of Repolarization in Heart Failure

Failing hearts undergo electrical and structural remodeling, setting the stage for malignant arrhythmias. Specifically, failing hearts show enhanced late Na+ current (I-NaL) and cellular uncoupling. In the present study, the effects of these changes on transmural dispersion of repolarization (TDR), on action potential duration (APD) gradient and on the safety factor for conduction (SF) were simulated. The human ventricular action potential model formulated by O'Hara et al. was modified to simulate the electrical remodeling observed in human heart failure (HF). The electrical activity of 1D ventricular tissue was measured under several conditions, with enhanced and blocked I-NaL and homogeneous intercellular uncoupling. Computer simulations showed that homogeneous electrical remodeling of failing ventricular tissue increased TDR in 69% and APD gradient in 36%. A two-fold increase in I-NaL and in homogeneous uncoupling further increased TDR 174% and APD gradient 204% with respect to normal conditions (NC). 90% block of I-NaL reduced TDR and APD gradient values in all the conditions simulated. Finally, HF remodeling provoked a reduction of SF with respect to NC, indicating a less safe conduction under HF conditions.