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Statins affect human iPSC-derived cardiomyocytes by interfering with mitochondrial function and intracellular acidification

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Abstract

Statins are effective drugs in reducing cardiovascular morbidity and mortality by inhibiting cholesterol synthesis. These effects are primarily beneficial for the patient’s vascular system. A significant number of statin users suffer from muscle complaints probably due to mitochondrial dysfunction, a mechanism that has recently been elucidated. This has raised our interest in exploring the effects of statins on cardiac muscle cells in an era where the elderly and patients with poorer functioning hearts and less metabolic spare capacity start dominating our patient population. Here, we investigated the effects of statins on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-derived CMs). hiPSC-derived CMs were exposed to simvastatin, atorvastatin, rosuvastatin, and cerivastatin at increasing concentrations. Metabolic assays and fluorescent microscopy were employed to evaluate cellular viability, metabolic capacity, respiration, intracellular acidity, and mitochondrial membrane potential and morphology. Over a concentration range of 0.3–100 µM, simvastatin lactone and atorvastatin acid showed a significant reduction in cellular viability by 42–64%. Simvastatin lactone was the most potent inhibitor of basal and maximal respiration by 56% and 73%, respectively, whereas simvastatin acid and cerivastatin acid only reduced maximal respiration by 50% and 42%, respectively. Simvastatin acid and lactone and atorvastatin acid significantly decreased mitochondrial membrane potential by 20%, 6% and 3%, respectively. The more hydrophilic atorvastatin acid did not seem to affect cardiomyocyte metabolism. This calls for further research on the translatability to the clinical setting, in which a more conscientious approach to statin prescribing might be considered, especially regarding the current shift in population toward older patients with poor cardiac function.

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Data availability statement

All data used in this study are available from the authors on reasonable request.

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Acknowledgements

The authors would like to thank Tjeu H Henst for his help in the data analysis of the microscopic TMRM images. The authors also would like to thank Radboudumc Technology Center Microscopy and Prof. Dr. Jan AM Smeitink and Dr. Svetlana Pecheritsyna from Khondrion BV for providing fluorescent microscopy facilities. Finally, the authors want to thank Christian Snijders Blok for performing the flow cytometry analyses.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

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Author notes

  1. Tim Somers, Sailay Siddiqi, Frans G. M. Russel, and Tom J. J. Schirris have contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiothoracic Surgery, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands

    Tim Somers, Sailay Siddiqi & Wim J. Morshuis

  2. Division of Pharmacology and Toxicology, Department of Pharmacy, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands

    Tim Somers, Petra H. H. van den Broek, Tanne J. Meuwissen, Frans G. M. Russel & Tom J. J. Schirris

  3. Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands

    Tim Somers, Sailay Siddiqi, Frans G. M. Russel & Tom J. J. Schirris

  4. Department of Cardiology, Experimental Cardiology Laboratory, Utrecht Regenerative Medicine Center, Circulatory Health Laboratory, University Utrecht, University Medical Center Utrecht, 3508 GA, Utrecht, The Netherlands

    Renee G. C. Maas & Joost P. G. Sluijter

  5. Department of Physiology, Amsterdam Cardiovascular Sciences, VU University, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands

    Jan W. Buikema

  6. Department of Cardiology, Amsterdam Heart Center, Amsterdam University Medical Center, De Boelelaan 1117, 1081 HZ, Amsterdam, The Netherlands

    Jan W. Buikema

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Contributions

TS: data curation, formal analysis, investigation, project administration, software, validation, visualization, writing—original draft, writing—reviewing and editing; SS: conceptualization, funding acquisition, supervision, writing—reviewing and editing; RM: methodology, investigation, resources, writing—reviewing and editing; JS: resources, writing—reviewing and editing; JB: resources, writing—reviewing and editing; PB: investigation, writing—reviewing and editing; TM: investigation, writing—reviewing and editing; WM supervision, writing—reviewing and editing; FR: resources, supervision, writing—reviewing and editing; T:S conceptualization, formal analysis, funding acquisition, methodology, resources, software, supervision, writing—reviewing and editing. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Frans G. M. Russel.

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Somers, T., Siddiqi, S., Maas, R.G.C. et al. Statins affect human iPSC-derived cardiomyocytes by interfering with mitochondrial function and intracellular acidification. Basic Res Cardiol 119, 309–327 (2024). https://doi.org/10.1007/s00395-023-01025-x

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