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Am J Physiol Heart Circ Physiol. 2013 Aug 1;305(3):H410-9. doi: 10.1152/ajpheart.00213.2013. Epub 2013 May 24.

Ionic bases for electrical remodeling of the canine cardiac ventricle.

Author information

1
The Heart and Vascular Research Center and Department of Biomedical Engineering, MetroHealth Campus, Case Western Reserve University, Cleveland, OH 44109, USA. darwinjeyaraj@gmail.com

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.

KEYWORDS:

T-wave memory; calcium cycling; electrical remodeling; ion channels; mechanical strain

PMID:
23709598
PMCID:
PMC3742876
DOI:
10.1152/ajpheart.00213.2013
[Indexed for MEDLINE]
Free PMC Article

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