Abstract
Cardiac contractility modulation (CCM) is a cardiac therapy whereby non-excitatory electrical simulations are delivered during the absolute refractory period of the cardiac cycle. CCM is indicated for patients with heart failure (Class III/IV) and reduced ejection fraction. We previously evaluated the effects of CCM and found isolated adult rabbit cardiomyocytes (rabbit-CMs) display a transient increase in calcium and contractility. In the present study, we sought to extend these results to human cardiomyocytes using human stem-cell cardiomyocytes (hiPSC-CMs). hiPSC-CMs were studied in both monolayer and isolated cells and results compared to that of rabbit-CMs. Contractility, calcium handling and electrophysiology was evaluated by image and fluorescence analysis. CCM was applied with a custom device covering a range of pulse parameters including standard clinical parameters (Figure 1). Pacing threshold was determined and stimulation performed at twice the diastolic capture threshold. Robust contractile response was observed at 16 V/cm, 70 mA for pacing and 28 V/cm, 120 mA for CCM. Under these conditions hiPSC-CMs and rabbit-CMs displayed increased contraction amplitude of 30 % (1.79 a.u., CCM vs 1.38 a.u., Control) and 22 % (3.67 a.u., CCM vs 3.00 a.u., Control) respectively and faster kinetics that subsided when the CCM signal was eliminated. This study provides a comprehensive characterization of the effects of CCM on hiPSC-CMs and rabbit-CMs in parallel under identical experimental conditions. These data provide the first study of CCM in hiPSC-CMs and demonstrates the potential utility of hiPSC-CMs to evaluate safety and effectiveness of cardiac medical devices.
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