Feedback-control induced pattern formation in cardiac myocytes: A mathematical modeling study

Abstract

Cardiac alternans is a dangerous rhythm disturbance of the heart, in which rapid stimulation elicits a beat-to-beat alternation in the action potential duration (APD) and calcium (Ca) transient amplitude of individual myocytes. Recently, "subcellular alternans", in which the Ca transients of adjacent regions within individual myocytes alternate out-of-phase, has been observed. A previous theoretical study suggested that subcellular alternans may result during static pacing from a Turing-type symmetry breaking instability, but this was only predicted in a subset of cardiac myocytes (with negative Ca to voltage (Ca-->V(m)) coupling) and has never been directly verified experimentally. A recent experimental study, however, showed that subcellular alternans is dynamically induced in the remaining subset of myocytes during pacing with a simple feedback control algorithm ("alternans control"). Here we show that alternans control pacing changes the effective coupling between the APD and the Ca transient (V(m)-->Ca coupling), such that subcellular alternans is predicted to occur by a Turing instability in cells with positive Ca-->V(m) coupling. In addition to strengthening the understanding of the proposed mechanism for subcellular alternans formation, this work (in concert with previous theoretical and experimental results) illuminates subcellular alternans as a striking example of a biological Turing instability in which the diffusing morphogens can be clearly identified.