Establishment Of An In Vitro Method To Evaluate Chronic Cardiac Contractility Modulation Signals In 3d Human Engineered Cardiac Tissues

Background: Cardiac contractility modulation (CCM) is a medical device-based therapy delivering non-excitatory electrical simulations to the heart during the absolute refractory period to enhance cardiac function. We previously evaluated the acute effects of CCM in isolated rabbit-CM and 2D hiPSC-CM monolayers, on flexible substrate, and found enhanced calcium and contractility. In the present study, we sought to extend these results to chronic studies in 3D human engineered cardiac tissues (ECTs) to develop a robust model to evaluate the long-term effects of CCM stimulation in vitro on intact human cardiac tissues. Methods: HiPSC-CMs and cardiac fibroblasts in a fibrin-based gel were combined to form ECTs (Figure 1). Morphology and contractility were evaluated. We found ECTs displayed baseline peak contraction amplitude of 194.8±80.8 a.u., (n=5) and peak force and stress of 26.5±6.8 uN, (n=5) and 87.9±22.0.8 Pa, (n=5) respectively. ECT displayed robust baseline electrophysiological (AP) properties and calcium handling properties. Chronic CCM pulses (i.e., 30 minutes) were applied using a commercial pulse generator. Under these conditions ECTs displayed enhanced contractile kinetics 29.0±0.04 %, (P<0.01, n=4), relaxation kinetics 23.0±0.05 %, (P<0.05, n=4), and shorter duration 32.0±0.03 %, (P<0.01, n=4) relative to time matched control. Conclusion: This study provides a comprehensive characterization of chronic CCM effects on 3D ECTs. Future studies will investigate prolonged time points. These data provide an in vitro model to assess physiologically relevant mechanisms and evaluate safety and efficacy of future cardiac electrophysiology medical devices. Disclaimer: The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services.