Jordan Newman

Background: Heart failure (HF) is the world’s leading cause of death¹ and the most common diagnosis for hospital admissions over the age of 65 in developed countries.² The permanent nature of cardiomyocytes renders cell death from HF a permanent cellular outcome with no cure. As a result, efforts to improve regenerative capabilities of the mature cardiomyocyte are growing in proportion to the advances in the field of stem cell therapy but suffer from similar complications: host tissue integration, proliferation, functional maturity and growth delays, and graft uptake.³ In the heart, these engraftment complications manifest primarily as a severe arrhythmia that must be addressed before the promising advances in cardiomyocyte remuscularization can be implemented.^{3, 4}

Objective: In this narrative review, we explored cardiomyocyte remuscularization by stem cell grafts and strategies combating the resultant arrhythmia.

Search Methods: PubMed searches for articles between 2017-2023 were performed utilizing MeSH headings “Pluripotent Stem Cells*,” “Stem Cell Transplantation/adverse effects*,” “Human Embryonic Stem Cells/transplantation*,” and “Myocytes, Cardiac/transplantation*.”

Results: Studies have indicated that a 3-dimensional graft, appropriately sized for human-sized myocardial infarcts, can be cultured and matured in vitro to show improvements in contractile function/synchronicity, intercellular ion communication, angiogenesis, and reduced apoptotic rates.⁵ In vivo, high levels of graft acceptance and electrophysiological integration were found after a lethal two-week period of arrhythmia.⁵ Replicating the pliable and dynamic environment of the myocardium during in vitro graft maturation improved histological metrics of functionality, maturity, and electrophysiological integration, likely due to greater gaseous and nutrient diffusion with reduced contractility stress, with similar results in vivo.⁶ In addition to high rates of stem cell proliferation and integration, macaque monkeys monitored with continuous EKG, echocardiography, and MRI imaging showed significantly improved cardiac functionality at 12 weeks when compared to results found at week four, implying a paracrine influence proportional to graft maturity.⁷ The engraftment arrhythmia, arising from and related to the maturity of the grafted cardiomyocytes, was shown to operate as an ectopic focus and resulting from retained automaticity of immature grafted cells.⁷ Overexpression of the cell-cycle marker CyclinD2 has paracrine effects on host cardiomyocytes, reintroducing them to the cell-cycle and reducing the fibrotic, infarct, and hypertrophic size.⁸ The paracrine effects “concentrated” the graft, allowing for a 10-factor dose reduction and reducing the arrhythmia incidence.⁸ Common pharmacologic strategies for arrhythmia prevention and reduction – such as amiodarone and ivabradine – are effective in managing the engraftment arrhythmia until the graft has matured, with successful weaning of the pharmacologic treatment after three weeks.⁹

Conclusion: Stem cell-derived cardiomyocyte grafts can integrate and induce mitotic division of host cardiomyocytes, improving several metrics of functionality while reducing infarct and fibrotic tissues. The graft, before maturing completely, retains its automaticity and serves as an ectopic pacemaker, inducing arrhythmia. Increasing in vitro maturation periods and pharmacological treatment have been successful in mitigating the electrical dysfunction during the three-week window of instability. Further studies are indicated to ensure replication of the findings discussed in this literary review can be combined or achieved, but heart failure has a definitive cure looming.

Works Cited:

1. Garbern JC, Lee RT. Heart regeneration: 20 years of progress and renewed optimism. Dev Cell. 2022;57(4):424-439. doi: 10.1016/j.devcel.2022.01.012
2. Roth GA, Mensah GA, Johnson CO, et al. Global burden of cardiovascular diseases and risk factors, 1990–2019: Update from the GBD 2019 study. Am. Coll. Cardiol. 2020;76(25):2982–3021. doi:10.1016/j.jacc.2020.11.010
3. Heallen TR, Kadow ZA, Kim JH, Wang J, Martin JF. Stimulating Cardiogenesis as a Treatment for Heart Failure. Circulation Research 2019;124:1647-1657. doi: 10.1161/CIRCRESAHA.118.313573C
4. Romagnuolo R, Masoudpour H, Porta-Sánchez A, et al. Human embryonic stem cell-derived cardiomyocytes regenerate the infarcted pig heart but induce ventricular tachyarrhythmias. Stem Cell Rep. 2019;12(5):967-981. Doi: 10.1016/j.stemcr.2019.04.005
5. Gao L, Gregorich ZR, Zhu W, et al. Large cardiac muscle patches engineered from human-induced pluripotent stem cell-derived cardiac cells improve recovery from myocardial infarction in swine. Circulation. 2017;137(16):1712-1730. doi: 10.1161/CIRCULATIONAHA.117.030785
6. Dhahri W, Valdman TS, Wilkinson D, et al. In vitro matured human pluripotent stem cell-derived cardiomyocytes form grafts with enhanced structure and function in injured hearts. Circulation. 2022;145(18):1412-1426. doi: 10.1161/CIRCULATIONAHA.121.053563
7. Liu YW, Chen B, Yang X, et al. Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates. Biotechnol. 2018;36(7):597-605. doi: 10.1038/nbt.4162
8. Zhao M, Nakada Y, Wei Y, et al. Cyclin D2 overexpression enhances the efficacy of human induced pluripotent stem-cell derived cardiomyocytes for myocardial repair in a swine model of myocardial infarcation. Circulation. 2021;144(3):210-228. doi: 10.1161/CIRCULATIONAHA.120.049497
9. Nakamura K, Neidig LE, Yang X, et al. Pharmacologic therapy for engraftment arrhythmia induced by transplantation of human cardiomyocytes. Stem Cell Rep. 2021;16(10):2473–2487. doi: 10.1016/j.stemcr.2021.08.005