Heterogeneous electrical remodeling of the failing heart modulates the arrhythmogenic substrate

摘要

Failing hearts undergo electrical and structural remodeling, setting the stage for malignant arrhythmias. Increased dispersion of repolarization has been suggested to underlie increased arrhythmogenesis in human heart failure (HF). Recent experimental studies have shown that transmural dispersion of repolarization (TDR) decreases in failing hearts, while others have observed an increase in similar conditions. In this simulation work, we try to elucidate different mechanism of modulation of the repolarization gradient in failing human hearts and its implication for arrhythmogenesis. The human ventricular action potential (AP) models formulated by O'Hara et al. (ORd) and Grandi et al. (GPB) were modified to simulate the electrical remodeling observed in human heart failure. Several biomarkers (APD90, triangulation (APD90-APD50), Ca⁺² decay, Ca⁺² dynamics, systolic Na⁺ and AP-Ca⁺² Delay) were measured and calculated from individual ventricular cells simulations under different conditions of heterogeneous remodeling, modulating the changes in INCX and ISERCA in endocardial, midmyocardial and epicardial cells. The results of this study uncover the importance of the existence of M cells and how heterogeneous remodeling can modulate the gradient of AP repolarization and Ca²⁺ handling in failing hearts.