B-PO03-019 CARDIAC CONTRACTILITY MODULATION STIMULATION DURING SYSTOLE ENHANCES CONTRACTION AND CALCIUM HANDLING PROPERTIES IN HUMAN-INDUCED PLURIPOTENT STEM CELL-DERIVED CARDIOMYOCYTES

Abstract

Cardiac contractility modulation (CCM) is a cardiac therapy whereby non-excitatory electrical simulations are delivered to the heart during the absolute refractory period. We previously evaluated effects of CCM and found adult rabbit cardiomyocytes display a transient increase in calcium and contractility. In the present study, we sought to extend these results to human stem-cell cardiomyocytes (hiPSC-CMs). hiPSC-CMs (iCell Cardiomyocytes2, Fujifilm Cellular Dynamic Inc) were studied in monolayer format on Matrigel mattress substrate. Contractility, calcium and electrophysiology were evaluated by image and fluorescence analysis (CellOPTIQ, Clyde Biosciences). Standard clinical CCM pulse parameters were applied with an A-M Systems 4100 pulse generator (Figure 1). Robust CCM response was observed at 11 V/cm (64 mA) for pacing and 22 V/cm (128 mA) for CCM. The first CCM beat displayed a 19.7±0.03 %, (**P<0.01, n=10) contraction amplitude increase that reached steady-state within 5 beats at 8.3±0.16 %. CCM stimulation resulted in faster contraction and relaxation kinetics of 25.9±0.07 % and 18.6±0.07 % respectively. Likewise, calcium amplitude increased by 59.3±0.03% (*P<0.05, n=3). This study provides a comprehensive characterization of the effects of CCM on hiPSC-CMs. These data suggest, CCM exerts its effects by, at a minimum, two calcium centric mechanisms including 1) modulation of L-type calcium channels and 2) increased myofilament calcium sensitivity. These data provide the first study of CCM in hiPSC-CMs and demonstrates the utility of hiPSC-CMs to evaluate safety and effectiveness of cardiac medical devices.