title: 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 Ca(2+) 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 Ca(2+). 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 Ca(2+) accounted for APD prolongation in the late-activated region by enhancing forward-mode Na(+)/Ca(2+) exchanger activity, corroborated by increased Na(+)/Ca(2+) exchanger protein expression. Finally, assessment of skinned fibers after VER identified altered myofilament Ca(2+) sensitivity in late-activated regions to be associated with increased diastolic levels of Ca(2+). 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 Ca(2+) handling and 2) a novel and unexpected mechanism for strain-induced VER in late-activated regions in the canine arising from remodeling of sarcomeric Ca(2+) handling rather than sarcolemmal ion channels.
authors.affiliation: The Heart and Vascular Research Center and Department of Biomedical Engineering, MetroHealth Campus, Case Western Reserve University, Cleveland, OH 44109, USA. darwinjeyaraj@gmail.com
authors.forename: Darwin
authors.initials: D
authors.lastname: Jeyaraj
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wan
authors.forename: Eckhard
authors.initials: E
authors.lastname: Ficker
authors.forename: Julian E
authors.initials: JE
authors.lastname: Stelzer
authors.forename: Isabelle
authors.initials: I
authors.lastname: Deschenes
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.forename: Lance D
authors.initials: LD
authors.lastname: Wilson
authors.forename: Keith F
authors.initials: KF
authors.lastname: Decker
authors.forename: Tamer H
authors.initials: TH
authors.lastname: Said
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
authors.forename: Yoram
authors.initials: Y
authors.lastname: Rudy
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenbaum
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D002304:Cardiac Pacing, Artificial; D003198:Computer Simulation; D004285:Dogs; D006329:Heart Conduction System / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008955:Models, Cardiovascular; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D015221:Potassium Channels; D019831:Sodium-Calcium Exchanger; D011188:Potassium; D002118:Calcium
keywords: T-wave memory; calcium cycling; electrical remodeling; ion channels; mechanical strain