
Tsao, C. W. et al. Heart disease and stroke statistics—2023 update: a report from the American Heart Association. Circulation 147, e93–e621 (2023).
Gwathmey, J. K., Tsaioun, K. & Hajjar, R. J. Cardionomics: a new integrative approach for screening cardiotoxicity of drug candidates. Expert Opin. Drug Metab. Toxicol. 5, 647–660 (2009).
Weaver, R. J. & Valentin, J. P. Today’s challenges to de-risk and predict drug safety in human ‘Mind-the-Gap’. Toxicol. Sci. 167, 307–321 (2019).
Vunjak-Novakovic, G., Ronaldson-Bouchard, K. & Radisic, M. Organs-on-a-chip models for biological research. Cell 184, 4597–4611 (2021).
Baran, S. W. et al. Perspectives on the evaluation and adoption of complex in vitro models in drug development: workshop with the FDA and the pharmaceutical industry (IQ MPS Affiliate). ALTEX https://doi.org/10.14573/altex.2112203 (2022).
Huebsch, N. et al. Metabolically driven maturation of human-induced-pluripotent-stem-cell-derived cardiac microtissues on microfluidic chips. Nat. Biomed. Eng. 6, 372–388 (2022).
Charrez, B. et al. Heart muscle microphysiological system for cardiac liability prediction of repurposed COVID-19 therapeutics. Front. Pharmacol. 12, 684252 (2021).
Mathur, A. et al. Human iPSC-based cardiac microphysiological system for drug screening applications. Sci. Rep. 5, 8883 (2015).
Miller, J. M. et al. Heart slice culture system reliably demonstrates clinical drug-related cardiotoxicity. Toxicol. Appl. Pharmacol. 406, 115213 (2020).
Miller, J. M. et al. Biomimetic cardiac tissue culture model (CTCM) to emulate cardiac physiology and pathophysiology ex vivo. Commun. Biol. 5, 934 (2022).
Wu, P. et al. Maturation strategies and limitations of induced pluripotent stem cell-derived cardiomyocytes. Biosci. Rep. https://doi.org/10.1042/BSR20200833 (2021).
Schroer, A., Pardon, G., Castillo, E., Blair, C. & Pruitt, B. Engineering hiPSC cardiomyocyte in vitro model systems for functional and structural assessment. Prog. Biophys. Mol. Biol. 144, 3–15 (2019).
Ronaldson-Bouchard, K. et al. Advanced maturation of human cardiac tissue grown from pluripotent stem cells. Nature 556, 239–243 (2018).
Ribeiro, A. J. S. et al. Considerations for an in vitro, cell-based testing platform for detection of drug-induced inotropic effects in early drug development. Part 2: designing and fabricating microsystems for assaying cardiac contractility with physiological relevance using human iPSC-cardiomyocytes. Front. Pharmacol. 10, 934 (2019).
Wang, G. et al. Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat. Med. 20, 616–623 (2014).
Guo, J. et al. Substrate mechanics unveil early structural and functional pathology in iPSC micro-tissue models of hypertrophic cardiomyopathy. iScience 27, 109954 (2024).
Mozneb, M. et al. Multi-lineage heart-chip models drug cardiotoxicity and enhances maturation of human stem cell-derived cardiovascular cells. Lab Chip 24, 869–881 (2024).
Ribeiro, A. J. S. et al. Multi-imaging method to assay the contractile mechanical output of micropatterned human iPSC-derived cardiac myocytes. Circ. Res. 120, 1572–1583 (2017).
Maddah, M. et al. A non-invasive platform for functional characterization of stem-cell-derived cardiomyocytes with applications in cardiotoxicity testing. Stem Cell Rep. 4, 621–631 (2015).
Chen, T. W. et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295–300 (2013).
Huang, Y. L., Walker, A. S. & Miller, E. W. A photostable silicon rhodamine platform for optical voltage sensing. J. Am. Chem. Soc. 137, 10767–10776 (2015).
McCain, M. L., Sheehy, S. P., Grosberg, A., Goss, J. A. & Parker, K. K. Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip. Proc. Natl Acad. Sci. USA 110, 9770–9775 (2013).
Charrez, B. et al. In vitro safety ‘clinical trial’ of the cardiac liability of drug polytherapy. Clin. Transl. Sci. 14, 1155–1165 (2021).
Charwat, V. et al. Validating the arrhythmogenic potential of high-, intermediate-, and low-risk drugs in a human-induced pluripotent stem cell-derived cardiac microphysiological system. ACS Pharmacol. Transl. Sci. 5, 652–667 (2022).
Ferdinandy, P. et al. Definition of hidden drug cardiotoxicity: paradigm change in cardiac safety testing and its clinical implications. Eur. Heart J. 40, 1771–1777 (2019).
Yang, X., Ribeiro, A. J. S., Pang, L. & Strauss, D. G. Use of human iPSC-CMs in nonclinical regulatory studies for cardiac safety assessment. Toxicol. Sci. 190, 117–126 (2022).
Mamoshina, P., Rodriguez, B. & Bueno-Orovio, A. Toward a broader view of mechanisms of drug cardiotoxicity. Cell Rep. Med. 2, 100216 (2021).
Luo, M. & Anderson, M. E. Mechanisms of altered Ca2+ handling in heart failure. Circ. Res. 113, 690–708 (2013).
Leung, C. M. A guide to the organ-on-a-chip. Nat. Rev. Methods Primers 2, 33 (2022).
Huebsch, N. et al. Automated video-based analysis of contractility and calcium flux in human-induced pluripotent stem cell-derived cardiomyocytes cultured over different spatial scales. Tissue Eng. Part C Methods 21, 467–479 (2015).
Dame, K. & Ribeiro, A. J. S. Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects. Exp. Biol. Med. 246, 317–331 (2021).
Arefin, A. et al. Reproducibility of drug-induced effects on the contractility of an engineered heart tissue derived from human pluripotent stem cells. Front. Pharmacol. 14, 1212092 (2023).
Lian, X. et al. Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc. Natl Acad. Sci. USA 109, E1848–E1857 (2012).
Pointon, A. et al. Cardiovascular microphysiological systems (CVMPS) for safety studies—a pharma perspective. Lab Chip 21, 458–472 (2021).
Liu, S., Fang, C., Zhong, C., Li, J. & Xiao, Q. Recent advances in pluripotent stem cell-derived cardiac organoids and heart-on-chip applications for studying anti-cancer drug-induced cardiotoxicity. Cell Biol. Toxicol. 39, 2527–2549 (2023).
Arslan, U., Orlova, V. V. & Mummery, C. L. Perspectives for future use of cardiac microtissues from human pluripotent stem cells. ACS Biomater. Sci. Eng. 8, 4605–4609 (2022).
Wauchop, M. et al. Maturation of iPSC-derived cardiomyocytes in a heart-on-a-chip device enables modeling of dilated cardiomyopathy caused by R222Q-SCN5A mutation. Biomaterials 301, 122255 (2023).
Mastikhina, O. et al. Human cardiac fibrosis-on-a-chip model recapitulates disease hallmarks and can serve as a platform for drug testing. Biomaterials 233, 119741 (2020).
Mourad, O., Yee, R., Li, M. & Nunes, S. S. Modeling heart diseases on a chip: advantages and future opportunities. Circ. Res. 132, 483–497 (2023).
Ergir, E. et al. Generation and maturation of human iPSC-derived 3D organotypic cardiac microtissues in long-term culture. Sci. Rep. 12, 17409 (2022).
Volmert, B. et al. A patterned human primitive heart organoid model generated by pluripotent stem cell self-organization. Nat. Commun. 14, 8245 (2023).
Varzideh, F. et al. Human cardiomyocytes undergo enhanced maturation in embryonic stem cell-derived organoid transplants. Biomaterials 192, 537–550 (2019).
Lewis-Israeli, Y. R. et al. Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease. Nat. Commun. 12, 5142 (2021).
Ma, Z. et al. Contractile deficits in engineered cardiac microtissues as a result of MYBPC3 deficiency and mechanical overload. Nat. Biomed. Eng. 2, 955–967 (2018).
Caspi, O. et al. Modeling of arrhythmogenic right ventricular cardiomyopathy with human induced pluripotent stem cells. Circ. Cardiovasc. Genet. 6, 557–568 (2013).
Yazawa, M. et al. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 471, 230–234 (2011).
Huebsch, N. et al. Miniaturized iPS-cell-derived cardiac muscles for physiologically relevant drug response analyses. Sci. Rep. 6, 24726 (2016).
Lee-Montiel, F. T. et al. Integrated isogenic human induced pluripotent stem cell-based liver and heart microphysiological systems predict unsafe drug-drug interaction. Front. Pharmacol. 12, 667010 (2021).
Veldhuizen, J., Cutts, J., Brafman, D. A., Migrino, R. Q. & Nikkhah, M. Engineering anisotropic human stem cell-derived three-dimensional cardiac tissue on-a-chip. Biomaterials 256, 120195 (2020).
Liu, Y. et al. Human heart-on-a-chip microphysiological system comprising endothelial cells, fibroblasts, and iPSC-derived cardiomyocytes. Sci. Rep. 14, 18063 (2024).
Ang, Y. S. et al. Disease model of GATA4 mutation reveals transcription factor cooperativity in human cardiogenesis. Cell 167, 1734–1749 e1722 (2016).
Judge, L. M. et al. A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress. JCI Insight 2, e94623 (2017).
Yang, X., Pabon, L. & Murry, C. E. Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ. Res. 114, 511–523 (2014).
Biendarra-Tiegs, S. M., Secreto, F. J. & Nelson, T. J. Addressing variability and heterogeneity of induced pluripotent stem cell-derived cardiomyocytes. Adv. Exp. Med. Biol. 1212, 1–29 (2020).
Lyra-Leite, D. M. et al. A review of protocols for human iPSC culture, cardiac differentiation, subtype-specification, maturation, and direct reprogramming. STAR Protoc. 3, 101560 (2022).
Tagle, D. A. The NIH microphysiological systems program: developing in vitro tools for safety and efficacy in drug development. Curr. Opin. Pharmacol. 48, 146–154 (2019).
Tomlinson, L. et al. Considerations from an international regulatory and pharmaceutical industry (IQ MPS Affiliate) workshop on the standardization of complex in vitro models in drug development. Adv. Biol. https://doi.org/10.1002/adbi.202300131 (2023).
Kuo, H. H. et al. Negligible-cost and weekend-free chemically defined human iPSC culture. Stem Cell Rep. 14, 256–270 (2020).
Ohnuki, M., Takahashi, K. & Yamanaka, S. Generation and characterization of human induced pluripotent stem cells. Curr. Protoc. Stem Cell Biol. https://doi.org/10.1002/9780470151808.sc04a02s9 (2009).
Pantazis, C. B. et al. A reference human induced pluripotent stem cell line for large-scale collaborative studies. Cell Stem Cell 29, 1685–1702 e1622 (2022).
Viana, M. P. et al. Integrated intracellular organization and its variations in human iPS cells. Nature 613, 345–354 (2023).
Rivera, T., Zhao, Y., Ni, Y. & Wang, J. Human-induced pluripotent stem cell culture methods under cGMP conditions. Curr. Protoc. Stem Cell Biol. 54, e117 (2020).
Richards, C., Sarkar, S., Kandell, J., Snyder, R. & Lakshmipathy, U. Assessing the suitability of cell counting methods during different stages of a cell processing workflow using an ISO 20391-2 guided study design and analysis. Front. Bioeng. Biotechnol. 11, 1223227 (2023).
Warnecke, N. et al. Generation of bi-allelic MYBPC3 truncating mutant and isogenic control from an iPSC line of a patient with hypertrophic cardiomyopathy. Stem Cell Res. 55, 102489 (2021).
Marty, I. & Faure, J. Excitation-contraction coupling alterations in myopathies. J. Neuromuscul. Dis. 3, 443–453 (2016).
Butler, L. et al. Enhanced characterization of contractility in cardiomyocytes during early drug safety assessment. Toxicol. Sci. 145, 396––406 (2015).
Chung, J. H., Biesiadecki, B. J., Ziolo, M. T., Davis, J. P. & Janssen, P. M. Myofilament calcium sensitivity: role in regulation of in vivo cardiac contraction and relaxation. Front. Physiol. 7, 562 (2016).
Tandon, N. et al. Electrical stimulation systems for cardiac tissue engineering. Nat. Protoc. 4, 155–173 (2009).
Drubin, D. G. & Hyman, A. A. Stem cells: the new ‘model organism’. Mol. Biol. Cell 28, 1409–1411 (2017).
Fonoudi, H., Lyra-Leite, D. M., Javed, H. A. & Burridge, P. W. Generating a cost-effective, weekend-free chemically defined human induced pluripotent stem cell (hiPSC) culture medium. Curr. Protoc. Stem Cell Biol. 53, e110 (2020).
Wakabayashi, S. et al. Overexpression of Na+/H+ exchanger 1 specifically induces cell death in human iPS cells via sustained activation of the Rho kinase ROCK. J. Biol. Chem. 294, 19577–19588 (2019).
Anderson, P. A., Malouf, N. N., Oakeley, A. E., Pagani, E. D. & Allen, P. D. Troponin T isoform expression in humans. A comparison among normal and failing adult heart, fetal heart, and adult and fetal skeletal muscle. Circ. Res. 69, 1226–1233 (1991).
Garcia, M. I., Chen, J. J. & Boehning, D. Genetically encoded calcium indicators for studying long-term calcium dynamics during apoptosis. Cell Calcium 61, 44–49 (2017).
Garcia, M. I. & Boehning, D. Cardiac inositol 1,4,5-trisphosphate receptors. Biochim. Biophys. Acta Mol. Cell Res. 1864, 907–914 (2017).
Marks, A. R. Cardiac intracellular calcium release channels: role in heart failure. Circ. Res. 87, 8–11 (2000).
Marks, A. R. Calcium and the heart: a question of life and death. J. Clin. Invest. 111, 597–600 (2003).
He, J. Q., Ma, Y., Lee, Y., Thomson, J. A. & Kamp, T. J. Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization. Circ. Res. 93, 32–39 (2003).
Endoh, M. Force-frequency relationship in intact mammalian ventricular myocardium: physiological and pathophysiological relevance. Eur. J. Pharmacol. 500, 73–86 (2004).
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