Abstract

Phase resetting of cardiac oscillators underlies some complex arrhythmias. Here we use optogenetic stimulation to construct phase response curves (PRC) for spheroids of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) and a computational cardiomyocyte model to identify ionic mechanisms shaping the PRC. The clinical utility of the human PRCs is demonstrated by adding a patient-based conduction delay to the same equations to explain complex multi-day Holter ECG dynamics and cardiac arrhythmias. Periodic stimulation of these patient-based models and the computational model of human iPSC-CM reveal similar bifurcation patterns and entrainment zones. Cell therapy by injecting iPSC-CM into diseased hearts can induce ectopic foci-based engraftment arrhythmias. The PRC analysis offers a potential strategy to entrain these foci in a parameter space that avoids such arrhythmias.

Author summary

Biological rhythms are responsible for key life functions such as the heartbeat, breathing, sleeping, and reproduction. In this work, we study the effects of stimuli on the heart’s rhythm. A single stimulus delivered to a spontaneously beating cluster of human cardiomyocytes, derived from stem cells, changes the timing of subsequent beats. Using experimental data, we have developed a mathematical model predicting the response of human heart cells to periodic stimuli. We then use these insights to analyze the mechanism of a type of cardiac arrhythmia (parasystole) that results from the interaction between the normal heart rhythm and a secondary abnormal pacemaker. By extending and personalizing the mathematical model, we can simulate the heart rhythms in human patients over extended periods of time. These results are also of interest in the context of a major complication that arises during an emerging therapy in which beating human cardiac cells are transplanted into damaged hearts. During early stages following the transplantation, there are often dangerous heart rhythms - engraftment arrhythmias. By combining our insights concerning resetting of cardiac oscillators with an ionic model of heart cells, we suggest possible strategies to control such arrhythmias.

LINK TO PUBLICATION

PLoS Comput Biol.