Emergent synchronous beating behavior in spontaneous beating cardiomyocyte clusters

We investigated the dominant rule determining synchronization of beating intervals of cardiomyocytes after the clustering of mouse primary and human embryonic-stem-cell (hES)-derived cardiomyocytes. Cardiomyocyte clusters were formed in concave agarose cultivation chambers and their beating intervals were compared with those of dispersed isolated single cells. Distribution analysis revealed that the clusters’ synchronized interbeat intervals (IBIs) were longer than the majority of those of isolated single cells, which is against the conventional faster firing regulation or “overdrive suppression.” IBI distribution of the isolated individual cardiomyocytes acquired from the beating clusters also confirmed that the clusters’ IBI was longer than those of the majority of constituent cardiomyocytes. In the complementary experiment in which cell clusters were connected together and then separated again, two cardiomyocyte clusters having different IBIs were attached and synchronized to the longer IBIs than those of the two clusters’ original IBIs, and recovered to shorter IBIs after their separation. This is not only against overdrive suppression but also mathematical synchronization models, such as the Kuramoto model, in which synchronized beating becomes intermediate between the two clusters’ IBIs. These results suggest that emergent slower synchronous beating occurred in homogeneous cardiomyocyte clusters as a community effect of spontaneously beating cells.

Bursting behavior during fixed-delay stimulation of spontaneously beating chick heart cell aggregates

Spontaneously beating embryonic chick atrial heart cell aggregates were stimulated with depolarizing current pulses delivered at a fixed delay after each action potential. This preparation is an experimental model of a reentrant tachycardia. During fixed-delay stimulation, bursting behavior was typically observed for a wide range of delays. Episodes of bursting at a rate faster (slower) than control were followed by overdrive suppression (underdrive acceleration). We use a simple nonlinear model, based on the interaction between excitability and overdrive suppression, to describe these dynamics. A modified version of the Shrier-Clay ionic model of electrical activity of the embryonic chick heart cell aggregates that includes a simplified Na+ pump term is also presented. We show that the complex patterns during fixed-delay stimulation arise as a result of delicate interactions between overdrive suppression and phase resetting, which can be described in terms of the underlying ionic mechanisms. This study may provide a basis for understanding incessant tachycardias in the intact heart, as well as an alternative mechanism for the emergence of bursting activity in other biologic tissue.