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(Circulation Research. 2006;99:520.)
© 2006 American Heart Association, Inc.

Cellular Biology

Spatially Discordant Alternans in Cardiac Tissue

Role of Calcium Cycling

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

From the Department of Physics and Center for Interdisciplinary Research on Complex Systems (D.S., A.K.), Northeastern University, Boston, Mass; and Departments of Medicine (Cardiology) (Y.S., A.G., J.N.W., Z.Q.) and Physiology (A.G., J.N.W.), David Geffen School of Medicine at the University of California, Los Angeles.

Correspondence to Dr Yohannes Shiferaw, Department of Cardiology, UCLA Cardiovascular Research Laboratory, 675 Charles E. Young Dr S, MRL 3645, Los Angeles, CA 90095. E-mail yshiferaw{at}mednet.ucla.edu

Spatially discordant alternans, where the action potential duration (APD) and intracellular calcium transient (Ca_i) alternate with opposite phase in different regions of tissue, is known to promote wave break and reentry. However, this phenomenon is not completely understood. It is known that alternans at the cellular level can be caused by dynamical instabilities arising from either membrane voltage (V_m) attributable to steep APD restitution or to calcium (Ca) cycling. Here, we used a mathematical model of intracellular Ca cycling, coupled with membrane ion currents, to investigate the dynamics of V_m and Ca_i transient alternans in an isolated cell, in two electrotonically coupled cells, and in 1D spatially homogeneous tissue. Our main finding is a novel instability mechanism in which the bidirectional coupling of V_m and Ca_i can drive the Ca_i transient of two neighboring cells to be out of phase. This instability is manifested in cardiac tissue by the dynamical formation of spatially discordant alternans. In this case, Ca_i transient alternans can reverse phase over a length scale of one cell, whereas APD alternans reverses phase over a much longer length scale set by the electrotonic coupling. We analyze this mechanism in detail and show that it is a robust consequence of experimentally established properties of the bidirectional coupling between Ca cycling and V_m dynamics. Finally, we address the experimental relevance of these findings and suggest physiological conditions under which these patterns can be observed.

Key Words: discordant alternans • calcium cycling

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