Complex patterns of subcellular cardiac alternans

Abstract

Cardiac alternans, in which the membrane potential and the intracellular calcium concentration exhibit alternating durations and peak amplitudes at consecutive beats, constitute a precursor to fatal cardiac arrhythmia such as sudden cardiac death. A crucial question therefore concerns the onset of cardiac alternans. Typically, alternans are only reported when they are fully developed. Here, we present a modelling approach to explore recently discovered microscopic alternans, which represent one of the earliest manifestations of cardiac alternans. In this case, the regular periodic dynamics of the local intracellular calcium concentration is already unstable, while the whole-cell behaviour suggests a healthy cell state. In particular, we use our model to investigate the impact of calcium diffusion in both the cytosol and the sarcoplasmic reticulum on the formation of microscopic calcium alternans. We find that for dominant cytosolic coupling, calcium alternans emerge via the traditional period doubling bifurcation. In contrast, dominant luminal coupling leads to a novel route to calcium alternans through a saddle-node bifurcation at the network level. Combining semi-analytical and computational approaches, we compute areas of stability in parameter space and find that as we cross from stable to unstable regions, the emergent patterns of the intracellular calcium concentration change abruptly in a fashion that is highly dependent upon position along the stability boundary. Our results demonstrate that microscopic calcium alternans may possess a much richer dynamical repertoire than previously thought and further strengthen the role of luminal calcium in shaping cardiac calcium dynamics.