Modeling heart rhythm using human engineered heart tissues.

Abstract

Heart rate is both an indicator and modulator of cardiovascular health. Prolonged elevation in heart rate or irregular heart rhythm can trigger the onset of cardiac dysfunction, a condition termed 'tachycardia-induced cardiomyopathy'. While large animals have historically served as the primary model for studying this condition owing to their similar resting heart rates to humans, their use is limited by cost and throughput constraints. We recently developed the first engineered model of tachycardia-induced cardiomyopathy to overcome this technical bottleneck. Our model uses matured human engineered myocardium coupled with programmable electrical stimulation to emulate the pathophysiological changes in human heart rhythm. This in vitro model, capable of acutely and chronically modulating both beating rate and rhythm, recapitulated the clinical hallmarks of tachycardia-induced cardiomyopathy, and its utility was further validated via molecular comparisons against data from a canine model and human patients. Moreover, this model has improved the throughput and relevance to human genetics, enabling deep mechanistic explorations that were previously impossible. Here we present a comprehensive workflow detailing the fabrication and maturation of human engineered heart tissue, assembly of the electrical pacing system, functional analysis using open-source software and preparation for proteomic and transcriptomic analyses. This 5-week Protocol could be implemented by an experienced bench scientist with strong expertise in cell culture, ideally involving stem cell-derived cardiomyocytes. Given the broad implications of heart rhythm alterations in various cardiac conditions, this workflow can be employed with other biophysical and chemical cues to generate more complex and physiologically relevant cardiac models.