Spatially discordant alternans in cardiomyocyte monolayers

Cardiovascular Research Laboratory, Departments of Medicine (Cardiology), Pediatrics (Cardiology), and Physiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California Submitted 23 October 2007 ; accepted in final form 21 January 2008 Repolarization alternans is a harbinger of sudden cardiac death, particularly when it becomes spatially discordant. Alternans, a beat-to-beat alternation in the action potential duration (APD) and intracellular Ca (Ca i ), can arise from either tissue heterogeneities or dynamic factors. Distinguishing between these mechanisms in normal cardiac tissue is difficult because of inherent complex three-dimensional tissue heterogeneities. To evaluate repolarization alternans in a simpler two-dimensional cardiac substrate, we optically recorded voltage and/or Ca i in monolayers of cultured neonatal rat ventricular myocytes during rapid pacing, before and after exposure to BAY K 8644 to enhance dynamic factors promoting alternans. Under control conditions ( n = 37), rapid pacing caused detectable APD alternans in 81% of monolayers, and Ca i transient alternans in all monolayers, becoming spatially discordant in 62%. After BAY K 8644 ( n = 28), conduction velocity restitution became more prominent, and APD and Ca i alternans developed and became spatially discordant in all monolayers, with an increased number of nodal lines separating out-of-phase alternating regions. Nodal lines moved closer to the pacing site with faster pacing rates and changed orientation when the pacing site was moved, as predicted for the dynamically generated, but not heterogeneity-based, alternans. Spatial APD gradients during spatially discordant alternans were sufficiently steep to induce conduction block and reentry. These findings indicate that spatially discordant alternans severe enough to initiate reentry can be readily induced by pacing in two-dimensional cardiac tissue and behaves according to predictions for a predominantly dynamically generated mechanism. calcium cycling; arrhythmias Address for reprint requests and other correspondence: J. N. Weiss, Division of Cardiology, 3645 MRL Bldg., David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (e-mail: jweiss{at}mednet.ucla.edu )