Nonclinical evaluation of chronic cardiac contractility modulation on 3D human engineered cardiac tissues

Abstract Introduction Cardiac contractility modulation (CCM) is a medical device‐based therapy delivering non‐excitatory electrical stimulations to the heart to enhance cardiac function in heart failure (HF) patients. The lack of human in vitro tools to assess CCM hinders our understanding of CCM mechanisms of action. Here, we introduce a novel chronic (i.e., 2‐day) in vitro CCM assay to evaluate the effects of CCM in a human 3D microphysiological system consisting of engineered cardiac tissues (ECTs). Methods Cryopreserved human induced pluripotent stem cell‐derived cardiomyocytes were used to generate 3D ECTs. The ECTs were cultured, incorporating human primary ventricular cardiac fibroblasts and a fibrin‐based gel. Electrical stimulation was applied using two separate pulse generators for the CCM group and control group. Contractile properties and intracellular calcium were measured, and a cardiac gene quantitative PCR screen was conducted. Results Chronic CCM increased contraction amplitude and duration, enhanced intracellular calcium transient amplitude, and altered gene expression related to HF (i.e., natriuretic peptide B, NPPB ) and excitation‐contraction coupling (i.e., sodium‐calcium exchanger, SLC8 ). Conclusion These data represent the first study of chronic CCM in a 3D ECT model, providing a nonclinical tool to assess the effects of cardiac electrophysiology medical device signals complementing in vivo animal studies. The methodology established a standardized 3D ECT‐based in vitro testbed for chronic CCM, allowing evaluation of physiological and molecular effects on human cardiac tissues.