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(Circulation. 2008;118:2330-2337.)
© 2008 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Electrophysiological Consequences of Acute Regional Ischemia/Reperfusion in Neonatal Rat Ventricular Myocyte Monolayers

Carlos de Diego, MD^*; Rakesh K. Pai, MD^*; Fuhua Chen, MD; Lai-Hua Xie, PhD; Jan De Leeuw, PhD; James N. Weiss, MD; Miguel Valderrábano, MD

From the University of California at Los Angeles Cardiovascular Research Laboratory, Department of Medicine, Division of Cardiology, David Geffen School of Medicine at University of California at Los Angeles (C.d.D., R.K.P., F.C., L.X., J.N.W., M.V.), and Department of Statistics, University of California at Los Angeles (J.D.L.).

Correspondence to James N. Weiss, MD, Division of Cardiology, 3645 MRL Building, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095. E-mail jweiss{at}mednet.ucla.edu

Received April 29, 2008; accepted September 19, 2008.

Background— Electrophysiological changes promoting arrhythmias during acute regional ischemia/reperfusion are challenging to study in intact cardiac tissue because of complex 3-dimensional myocardial and vascular geometry. We characterized electrophysiological alterations and arrhythmias during regional ischemia/reperfusion in a simpler 2-dimensional geometry of cultured neonatal rat ventricular myocyte monolayers.

Methods and Results— Optical mapping of intracellular Ca (Ca_i) and voltage was performed with the use of Rhod 2-AM and Rh-237, respectively. Regional ischemia was mimicked by covering the central portion of monolayer with a glass coverslip, and reperfusion was mimicked by removing the coverslip. Monolayers were stained with fluorescent antibodies to detect total and dephosphorylated connexin-43 at various time points. During coverslip ischemia, action potential duration shortened, Ca_i transient duration was prolonged, and local conduction velocity (CV) slowed progressively, with loss of excitability after 10.6±3.6 minutes. CV slowing was accompanied by connexin-43 dephosphorylation. During ischemia, spontaneous reentry occurred in 5 of 11 monolayers, initiated by extrasystoles arising from the border zone or unidirectional conduction block of paced beats. On reperfusion, excitability recovered within 1.0±0.8 minutes, but CV remained depressed for 9.0±3.0 minutes, promoting reentry in the reperfused zone. As connexin-43 phosphorylation recovered in the reperfused zone, CV normalized, and arrhythmias resolved.

Conclusions— Acute regional ischemia/reperfusion in neonatal rat ventricular myocyte monolayers recapitulates electrophysiological alterations and arrhythmias similar to those observed during acute coronary occlusion/reperfusion in intact hearts. During early reperfusion, slow recovery from connexin-43 dephosphorylation leads to persistent CV slowing, creating a highly arrhythmogenic substrate.

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CLINICAL PERSPECTIVE

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