Mark F. A. Bierhuizen
Jorik H. Amesz
Natasja M. S. De Groot
Yannick J. H. J. Taverne- 1Translational Electrophysiology Lab, Lowlands Institute of Bioelectric Medicine, Department of Cardiology, Erasmus University Medical Center, Rotterdam, Netherlands
- 2Translational Cardiothoracic Surgery Research Lab, Lowlands Institute of Bioelectric Medicine, Department of Cardiothoracic Surgery, Erasmus University Medical Center, Rotterdam, Netherlands
by Bierhuizen MFA, Amesz JH, De Groot NMS. and Taverne YJHJ (2022). Front. Physiol. 13:1023563. doi: 10.3389/fphys.2022.1023563
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.
LMS are ultra-thin (300 µm) sections of intact cardiac tissue that maintain structural integrity with intact cellular connections, extracellular matrix proteins and heterocellularity, as they are directly prepared from patient biopsies with a high-precision vibratome (Schneider-Warme et al., 2018; Amesz et al., 2023). LMS are cultured in custom-made biomimetic cultivation chambers at 37°C with near-physiological preload of 1 mN, corresponding to a mean diastolic wall stress of 0.66 kN/m2 (Fischer et al., 2019; Amesz et al., 2023). Electrical stimulation is established with graphite field electrodes, leading to cardiac contraction of the LMS (Fischer et al., 2019; Amesz et al., 2023). In comparison to 3D-ECT, LMS represent more accurate in-vivo mimicry, because the complex microarchitecture of the cardiac system including all cell types and extracellular matrix proteins is difficult to mimic in-vitro, and hiPSC-CMs often fail to show complete cardiac maturity (Qu et al., 2020). Moreover, LMS can be produced from patients with end-stage HF, enabling the possibility to study CCM in the tissue of the population it was intended for.
Programmed CCM stimulation can be established via the electrodes of biomimetic cultivation chambers as a second pulse during the refractory period and dedicated force transducers continuously measure differences in contractility of the LMS. In addition, LMS of patients with HF remain beating for several months enabling studies on the chronic effects of CCM on cardiac contractility (Fischer et al., 2019). Furthermore, the LMS platform also contains ample opportunities for additional analyses to unravel the mechanisms of action of CCM, including culture medium biochemistry, histology of LMS and electrophysiology (Figure 1).
FIGURE 1. Living myocardial slices form a representative human in vitro translational cardiac device research platform.
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.
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
Amesz, J. H., Zhang, L., Everts, B. R., De Groot, N., and Taverne, Y. J. H. J. (2023). Living myocardial slices: Advancing arrhythmia research. Front. Physiology 14, 17. doi:10.3389/fphys.2023.1076261
Brunckhorst, C. B., Shemer, I., Mika, Y., Ben-Haim, S. A., and Burkhoff, D. (2006). Cardiac contractility modulation by non-excitatory currents: Studies in isolated cardiac muscle. Eur. J. Heart Fail 8, 7–15. doi:10.1016/j.ejheart.2005.05.011
Feaster, T. K., Feric, N., Pallotta, I., Narkar, A., Casciola, M., Graziano, M. P., et al. (2022). Acute effects of cardiac contractility modulation stimulation in conventional 2D and 3D human induced pluripotent stem cell-derived cardiomyocyte models. Front. Physiol. 13, 1023563. doi:10.3389/fphys.2022.1023563
Fischer, C., Milting, H., Fein, E., Reiser, E., Lu, K., Seidel, T., et al. (2019). Long-term functional and structural preservation of precision-cut human myocardium under continuous electromechanical stimulation in vitro. Nat. Commun. 10, 117. doi:10.1038/s41467-018-08003-1
Qu, Y., Feric, N., Pallotta, I., Singh, R., Sobbi, R., and Vargas, H. M. (2020). Inotropic assessment in engineered 3D cardiac tissues using human induced pluripotent stem cell-derived cardiomyocytes in the Biowire(TM) II platform. J. Pharmacol. Toxicol. Methods 105, 106886. doi:10.1016/j.vascn.2020.106886
Keywords: living myocardial slices, cardiac contractility modulation (CCM), heart failure, device therapy, engineered cardiac tissue, 3D microphysiological system
Citation: Bierhuizen MFA, Amesz JH, De Groot NMS and Taverne YJHJ (2023) Commentary: Acute effects of cardiac contractility modulation stimulation in conventional 2D and 3D human induced pluripotent stem cell-derived cardiomyocyte models. Front. Physiol. 14:1130674. doi: 10.3389/fphys.2023.1130674
Received: 23 December 2022; Accepted: 23 January 2023;
Published: 09 February 2023.
Edited by:
Josè Manuel Pioner, University of Florence, ItalyReviewed by:
Alec S. T. Smith, University of Washington, United StatesTamer M. Mohamed, University of Louisville, United States
Copyright © 2023 Bierhuizen, Amesz, De Groot and Taverne. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yannick J. H. J. Taverne, y.j.h.j.taverne@erasmusmc.nl