Ionic bases for electrical remodeling of the canine cardiac ventricle

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 earlyactivated 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) strainindependent 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 lateactivated regions in the canine arising from remodeling of sarcomeric Ca²⁺ handling rather than sarcolemmal ion channels.