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Calcium Instabilities in Mammalian Cardiomyocyte Networks

Harold Bien ^*, Lihong Yin ^* and Emilia Entcheva ^* 

^* Department of Biomedical Engineering, and Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York

Correspondence: Address reprint requests to Dr. Emilia Entcheva, Dept. of Biomedical Engineering, Stony Brook University, HSC T18-030, Stony Brook, NY 11794-8181. Tel.: 631-444 2368; Fax: 631-444 6646; E-mail: emilia.entcheva{at}sunysb.edu.

The degeneration of a regular heart rhythm into fibrillation (a chaotic or chaos-like sequence) can proceed via several classical routes described by nonlinear dynamics: period-doubling, quasiperiodicity, or intermittency. In this study, we experimentally examine one aspect of cardiac excitation dynamics, the long-term evolution of intracellular calcium signals in cultured cardiomyocyte networks subjected to increasingly faster pacing rates via field stimulation. In this spatially extended system, we observed alternans and higher-order periodicities, extra beats, and skipped beats or blocks. Calcium instabilities evolved nonmonotonically with the prevalence of phase-locking or Wenckebach rhythm, low-frequency magnitude modulations (signature of quasiperiodicity), and switches between patterns with occasional bursts (signature of intermittency), but period-doubling bifurcations were rare. Six ventricular-fibrillation-resembling episodes were pace-induced, for which significantly higher complexity was confirmed by approximate entropy calculations. The progressive destabilization of the heart rhythm by coexistent frequencies, seen in this study, can be related to theoretically predicted competition of control variables (voltage and calcium) at the single-cell level, or to competition of excitation and recovery at the cell network level. Optical maps of the response revealed multiple local spatiotemporal patterns, and the emergence of longer-period global rhythms as a result of wavebreak-induced reentries.