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

Abstract

Cardiac contractility modulation (CCM) is a medical device therapy whereby non-excitatory electrical stimulations are delivered to the myocardium during the absolute refractory period to enhance cardiac function. 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. In the present study, we sought to extend these results to human 3D microphysiological systems to develop a robust model to evaluate various clinical CCM pulse parameters in vitro. 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 (i.e., pixel) and force-based analysis. CCM pulses were assessed at varying electrical ‘doses’ using a commercial pulse generator. A robust CCM contractile response was observed for 3D ECTs. Under comparable conditions, conventional 2D monolayer hiPSC-CMs, on stiff substrate, displayed no contractile response. 3D ECTs displayed enhanced contractile properties including increased contraction amplitude (i.e., force), and accelerated contraction and relaxation slopes under standard acute CCM stimulation. Moreover, 3D ECTs displayed enhanced contractility in a CCM pulse parameter-dependent manner by adjustment of CCM pulse delay, duration, amplitude, and number relative to baseline. The observed acute effects subsided when the CCM stimulation was stopped and gradually returned to baseline. These data represent the first study of CCM in 3D hiPSC-CM models and provide a nonclinical tool to assess various CCM device signals in 3D human cardiac tissues prior to in vivo animal studies. Moreover, this work provides a foundation to evaluate the effects of additional cardiac medical devices in 3D ECTs.

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

“…In conclusion, Feaster et al (2022) showed an important novel model for CCM studies supporting our belief that pre-clinical CCM testing in human tissue is necessary for better understanding of underlying CCM mechanisms. LMS form an additional, representative human in vitro platform and might accelerate this journey towards translational CCM and other cardiac devices research.…”

“…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 ).…”

“…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.…”

Human in vitro assay for irreversible electroporation cardiac ablation

“…These approach has been validated in multi-site studies ( Blinova et al, 2018 ) including chronic studies ( Narkar et al, 2022a ), and the best practice recommendations for use of these methods in drug safety assessment has been published ( Gintant et al, 2020 ). More recently, hiPSC-CMs have been proposed as a valid alternative to animal models in the evaluation of cardiac electrophysiology medical devices ( Casciola et al, 2020 ; Feaster et al, 2021 ; Casciola et al, 2022 ; Feaster et al, 2022 ; Narkar et al, 2022b ). Here, we establish a novel, species-relevant, standard laboratory protocol to evaluate and optimize PEF cardiac ablation parameters using hiPSC-CMs in a high-throughput monolayer format.…”