Ionic bases for electrical remodeling of the canine cardiac ventricle

Abstract

Emerging evidence suggests that ventricular electrical remodeling (VER) is triggered by regional myocardial strain via mechanoelectrical feedback mechanisms; however, the ionic mechanisms underlying strain-induced VER are poorly understood. To determine its ionic basis, VER induced by altered electrical activation in dogs undergoing left ventricular pacing ( n = 6) were compared with unpaced controls ( n = 4). Action potential (AP) durations (APDs), ionic currents, and Ca2+ transients were measured from canine epicardial myocytes isolated from early-activated (low strain) and late-activated (high strain) left ventricular regions. VER in the early-activated region was characterized by minimal APD prolongation, but marked attenuation of the AP phase 1 notch attributed to reduced transient outward K+ current. In contrast, VER in the late-activated region was characterized by significant APD prolongation. Despite marked APD prolongation, there was surprisingly minimal change in ion channel densities but a twofold increase in diastolic Ca2+. Computer simulations demonstrated that changes in sarcolemmal ion channel density could only account for attenuation of the AP notch observed in the early-activated region but failed to account for APD remodeling in the late-activated region. Furthermore, these simulations identified that cytosolic Ca2+ accounted for APD prolongation in the late-activated region by enhancing forward-mode Na+/Ca2+ exchanger activity, corroborated by increased Na+/Ca2+ exchanger protein expression. Finally, assessment of skinned fibers after VER identified altered myofilament Ca2+ sensitivity in late-activated regions to be associated with increased diastolic levels of Ca2+. In conclusion, we identified two distinct ionic mechanisms that underlie VER: 1) strain-independent changes in early-activated regions due to remodeling of sarcolemmal ion channels with no changes in Ca2+ handling and 2) a novel and unexpected mechanism for strain-induced VER in late-activated regions in the canine arising from remodeling of sarcomeric Ca2+ handling rather than sarcolemmal ion channels.