Esha Maknojia

Background: Cardiovascular disease is the leading cause of death worldwide, with myocardial infarction (MI) as one of its most deadly forms.^1,2 Drug-induced heart damage adds to this problem, by making up 31% of all harmful drug reactions.² Traditional two-dimensional cell cultures cannot capture the full interactions between heart muscle cells, support cells, and blood vessel cells that drive tissue damage, scarring, and irregular rhythms. Also, animal models often fail to predict how humans respond to drugs due to biological differences between species.^2,3 Human iPSC-derived multi-lineage cardiac organoids provide a three-dimensional platform to trace the step-by-step progression from cell death to clinical heart failure.^1,2,3

Objective: This review examines how human multicellular cardiac organoids can trace the transition from ischemia-driven cell death to functional heart failure, and whether these findings match outcomes seen in patients, such as a drop in ejection fraction, scarring, and irregular rhythms.

Search Methods: A literature search was conducted using the PubMed database from 2019 to 2026 with the following search terms: “cardiac organoids”, “myocardial infarction”, “cardiomyocyte apoptosis”, and “cardiotoxicity”.

Results: Studies indicated that low oxygen conditions in multicellular organoids turned on the FoxO signaling pathway, triggered mitochondrial permeability transition pore (mPTP) opening through calcium buildup inside cells, and caused a fast heart rate above 100 BPM along with significant scarring.⁴ When blood flow was restored, organoids released CCL2/CCL4 signals that drew in THP-1 immune cells and set off a self-amplifying Type I Interferon cycle involving STAT1 and IRF9. However, blocking IFNAR1 with Anifrolumab lowered oxidative stress and stopped immune cells from turning into the harmful M1 type.⁵ Oxygen gradients and two-photon light sheet microscopy was used to model distinct heart attack zones and to illustrate the scar tissue that broke apart the synchronized calcium signals in heart cells. This caused irregular rhythms that were reversed by the drug JQ1.⁶ Doxorubicin was also shown to cause cell death, collagen buildup, and disruption in the timing of heartbeats in cardiac organoids more effectively than flat cell cultures.⁷ It was also confirmed that Trametinib, a MEK1 blocker, caused IL-6-driven muscle wasting and misplacement of connexin-43 in both mouse and human organoids, which matched the drop in ejection fraction seen in 11% of melanoma patients. However, stopping the drug allowed for partial recovery.⁸

Conclusion: Together, these studies show that human cardiac organoids are a reliable tool for connecting cell death to heart failure.^4-8 Key treatment targets include the IFNAR1 receptor, the IL-6/JAK/STAT pathway, and regulators such as BRD4.^5,6,8 Future work should use patient-specific iPSC organoids to predict who is at risk for drug-related heart damage before it occurs, moving care from monitoring harm to stopping it early.^4,7,8

Works Cited

1. Lewis-Israeli YR, Wasserman AH, Aguirre A. Heart organoids and engineered heart tissues: novel tools for modeling human cardiac biology and disease. Biomolecules. 2021;11(9):1277. doi:10.3390/biom11091277
2. Zhu L, Liu K, Feng Q, Liao Y. Cardiac organoids: a 3D technology for modeling heart development and disease. Stem Cell Rev Rep. 2022;18(8):2593-2605. doi:10.1007/s12015-022-10385-1
3. Kim H, Kamm RD, Vunjak-Novakovic G, Wu JC. Progress in multicellular human cardiac organoids for clinical applications. Cell Stem Cell. 2022;29(4):503-514. doi:10.1016/j.stem.2022.03.012
4. Song M, Choi DB, Im JS, et al. Modeling acute myocardial infarction and cardiac fibrosis using human induced pluripotent stem cell-derived multi-cellular heart organoids. Cell Death Dis. 2024;15(5):308. doi:10.1038/s41419-024-06703-9
5. Zhang L, Jiang Y, Jia W, et al. Modelling myocardial ischemia/reperfusion injury with inflammatory response in human ventricular cardiac organoids. Cell Prolif. 2025;58(3):e13762. doi:10.1111/cpr.13762
6. Richards DJ, Li Y, Kerr CM, et al. Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity. Nat Biomed Eng. 2020;4(4):446-462. doi:10.1038/s41551-020-0539-4
7. Wu X, Williams S, Robidoux J, Sriramula S, Abdel-Rahman A. Advanced cardiac organoid model for studying doxorubicin-induced cardiotoxicity. Toxicol Sci. 2025;208(1):95-103. doi:10.1093/toxsci/kfaf115
8. Beck TC, Arhontoulis DC, Morningstar JE, et al. Cellular and molecular mechanisms of MEK1 inhibitor-induced cardiotoxicity. JACC CardioOncol. 2022;4(4):535-548. doi:10.1016/j.jaccao.2022.07.009