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Original Articles

Function of Ca²⁺ Release Channels in Purkinje Cells That Survive in the Infarcted Canine Heart

A Mechanism for Triggered Purkinje Ectopy

Masanori Hirose, MD, PhD; Bruno D. Stuyvers, PhD; Wen Dun, PhD; Henk E.D.J. ter Keurs, MD, PhD and Penelope A. Boyden, PhD

From the Department of Pharmacology (M.H., W.D., P.A.B.), Center for Molecular Therapeutics, Columbia University, New York, NY; University of Calgary (H.E.D.J.K), Calgary, Alberta; and Department of Medicine/Biomedical Sciences (B.D.S.), Memorial University, St John’s, NL, Canada.

Correspondence to Dr Penelope A. Boyden, Department of Pharmacology Columbia College of Physicians and Surgeons, 630 West 168th St, New York, NY 10032. E-mail pab4{at}columbia.edu

Received December 4, 2007; accepted August 8, 2008.

Background— Triggered Purkinje ectopy can lead to the initiation of serious ventricular arrhythmias in post–myocardial infarction patients. In the canine model, Purkinje cells from the subendocardial border of the healing infarcted heart can initiate ventricular arrhythmias. Intracellular Ca²⁺ abnormalities underlie these arrhythmias, yet the subcellular reasons for these abnormalities remain unknown.

Methods and Results— Using 2D confocal microscopy, we directly quantify and compare typical spontaneous Ca²⁺ events in specific subcellular regions of normal Purkinje cells with those Purkinje cells from the subendocardium of the 48-hour infarcted canine heart (IZPCs). The Ca²⁺ event rate was higher in the subsarcolemmal region of IZPCs when compared with normal Purkinje cells; IZPC amplitudes were higher, yet the spatial extents of these events were similar. The amplitude of caffeine-releasable Ca²⁺ in either the subsarcolemmal or core regions of IZPCs did not differ from normal Purkinje cells, suggesting that Ca²⁺ overload was not related to the frequency change. In permeabilized Purkinje cells from both groups, the event rate was related to free [Ca²⁺] in both subsarcolemmal and core, but in IZPCs, this event rate was significantly increased at each free Ca²⁺, suggesting an enhanced sensitivity to Ca²⁺ release. Furthermore, decays of wide long lasting Ca²⁺ release events in IZPC’s core were significantly accelerated compared with those in normal Purkinje cells. JTV519 (K201) suppressed IZPC cell wide Ca²⁺ waves as well as normalized the enhanced event rate and its response to free Ca²⁺.

Conclusions— Increased spontaneous Ca²⁺ release events in IZPCs are due to uniform regionally increased Ca²⁺ release channel sensitivity to Ca²⁺ without a change in sarcoplasmic reticulum content. In addition, Ca²⁺ reuptake in IZPCs is accelerated. These properties would lower the threshold of Ca²⁺ release channels, setting the stage for the highly frequent arrhythmogenic cell wide Ca²⁺ waves observed in IZPCs.

Key Words: arrhythmias • calcium • myocardial infarction • Ca²⁺ waves • Purkinje cells

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Related Article

Function of Ca²⁺ Release Channels in Purkinje Cells That Survive in the Infarcted Canine Heart: A Mechanism for Triggered Purkinje Ectopy

Masanori Hirose, Bruno D. Stuyvers, Wen Dun, Henk E.D.J. ter Keurs, and Penelope A. Boyden
Circ Arrhythm Electrophysiol 2008 1: 387-395. [Abstract] [Full Text] [PDF]