Commentary: Acute effects of cardiac contractility modulation stimulation in conventional 2D and 3D human induced pluripotent stem cell-derived cardiomyocyte models

With great interest we read the article by Feaster et al. (2022), in which they demonstrated cardiac contractility modulation (CCM) stimulation in 3D human engineered cardiac tissue (ECT).The authors showed that the contractile response of 3D ECT to CCM depends on the input parameters of the stimulation pulse, while this response in conventional 2D pluripotent stem-cell derived cardiomyocytes (hiPSC-CMs) remained unaffected.As such, the authors argue that 3D in-vitro models are better suited to evaluate safety and efficacy of novel cardiac devices, including CCM.We want to congratulate the authors, and applaud the initiative to introduce novel pre-clinical human models for medical device testing (Feaster et al., 2022).CCM stimulation has been investigated in different models and species, but these models were limited by poor in-vivo resemblance and lack of extensive experimentation on human tissue.Yet, the exact underlying mechanisms and direct effects of the therapy on human cardiomyocyte physiology remain poorly understood (Brunckhorst et al., 2006).The optimal CCM model should therefore be mechanically loaded, electrically stimulated and of high physiological resemblance.Feaster et al. (2022) greatly contributed to the development of better models to study CCM mechanisms with their 3D ECT.In light of the optimization of such a model, we want to propose human living myocardial slices (LMS) as an additional in-vitro platform for CCM testing.