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Electrotonic load triggers remodeling of repolarizing current I_to in ventricle

The Heart and Vascular Research Center and Departments of Medicine and Biomedical Engineering, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio 44109-1998

Submitted 23 December 2003 ; accepted in final form 7 January 2004

A change in activation sequence electrically remodels ventricular myocardium, causing persistent changes in repolarizing currents (T-wave memory). However, the underlying mechanism for triggering activation sequence-dependent remodeling is unknown. Optical action potentials were mapped with high resolution from the epicardial surface of the arterially perfused canine wedge preparation (n = 23) during 30 min of baseline endocardial stimulation, followed by 40 min of epicardial stimulation, and, finally, restoration of endocardial stimulation. Immediately after the change from endocardial to epicardial stimulation, phase 1 notch amplitude of epicardial cells was attenuated by 74 ± 8% (P < 0.001) compared with baseline and continued to diminish during the period of epicardial pacing, suggesting progressive remodeling of the transient outward current (I_to). When endocardial pacing was restored, notch amplitude did not immediately recover but remained attenuated by 23 ± 10% (P < 0.001), also consistent with a remodeling effect. Peak I_to current measured from isolated epicardial myocytes changed by 12 ± 4% (P < 0.025), providing direct evidence for I_to remodeling occurring on a surprisingly short time scale. The mechanism for triggering remodeling of I_to was a significant reduction (by 14 ± 4%, P < 0.001) of upstroke amplitude in epicardial cells during epicardial stimulation. Reduction in upstroke amplitude during epicardial pacing was explained by electrotonic load on epicardial cells by fully repolarized downstream endocardial cells. These data suggest a novel mechanism for triggering electrical remodeling in the ventricle. Electrotonic load imposed by a change in activation sequence reduces upstroke amplitude, which, in turn, attenuates I_to according to its known voltage-dependent properties, triggering downregulation of current.

cardiac memory; electrical remodeling; optical mapping

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