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Inferring the Cellular Origin of Voltage and Calcium Alternans from the Spatial Scales of Phase Reversal during Discordant Alternans

Daisuke Sato ^* , Yohannes Shiferaw , Zhilin Qu , Alan Garfinkel  ^¶, James N. Weiss   and Alain Karma ^*

^* Department of Physics and Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, Massachusetts; Department of Physics, California State University at Northridge; and Departments of Medicine (Cardiology), Physiology, and ^¶ Physiological Science, University of California at Los Angeles, Los Angeles, California

Correspondence: Address reprint requests to Y. Shiferaw, E-mail: yshifera{at}yahoo.com.

Beat-to-beat alternation of the action potential duration (APD) in paced cardiac cells has been linked to the onset of lethal arrhythmias. Both experimental and theoretical studies have shown that alternans at the single cell level can be caused by unstable membrane voltage (V_m) dynamics linked to steep APD-restitution, or unstable intracellular calcium (Ca) cycling linked to high sensitivity of Ca release from the sarcoplasmic reticulum on sarcoplasmic reticulum Ca load. Identifying which of these two mechanisms is the primary cause of cellular alternans, however, has remained difficult since Ca and V_m are bidirectionally coupled. Here, we use numerical simulations of a physiologically detailed ionic model to show that the origin of alternans can be inferred by measuring the length scales over which APD and Ca_i alternans reverse phase during spatially discordant alternans. The main conclusion is that these scales are comparable to a few millimeters and equal when alternans is driven by APD restitution, but differ markedly when alternans is driven predominantly by unstable Ca cycling. In the latter case, APD alternans still reverses phase on a millimeter tissue scale due to electrotonic coupling, while Ca alternans reverses phase on a submillimeter cellular scale. These results show that experimentally accessible measurements of Ca_i and V_m in cardiac tissue can be used to shed light on the cellular origin of alternans.

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