Abstract 11951: Acute Cardiac Contractility Modulation Assessment in Conventional 2D Monolayers and 3D Engineered Cardiac Tissues Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Abstract

Introduction: Cardiac contractility modulation (CCM) is a medical device therapy whereby non-excitatory electrical simulations are delivered to the myocardium during the absolute refractory period. We previously evaluated the effects of the standard CCM pulse parameters in isolated rabbit ventricular cardiomyocytes and 2D human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) monolayers, on flexible substrate. Hypothesis: In the present study, we sought to extend these results to 3D microphysiological systems to develop a human-based model to evaluate various clinical CCM pulse parameters in vitro. Methods: HiPSC-CMs were studied in conventional 2D monolayer format, on stiff substrate (i.e., glass), and as 3D human engineered cardiac tissues (ECTs). Cardiac contractile properties were evaluated by video-based analysis and custom force analysis. CCM pulses were assessed at varying clinical ‘doses’ using a commercial pulse generator. Robust response was observed at physiological Ca concentrations [1.8 mM] for 3D ECTs. Results: Under standard acute CCM stimulation 3D ECTs displayed enhanced contractile properties including increased peak contraction amplitude (i.e., force), and faster contraction and relaxation kinetics. Moreover, 3D ECTs displayed enhanced contractility in a CCM pulse parameter dependent manner. The observed effects subsided when the acute CCM stimulation was stopped and gradually returned to baseline. Under comparable conditions, conventional 2D monolayer hiPSC-CMs, on stiff substrate, displayed neutral response. Conclusions: These data represent the first study of acute CCM stimulation in a 3D hiPSC-CM model and provides a preclinical model to assess various CCM signals in human cardiac tissues prior to in vivo animal studies.