Amaan Merchant

Background: Ischemic Cardiovascular Diseases (ICDs) such as Atherosclerotic Coronary Artery Disease (CAD) and generalized Ischemic Heart Disease (IHD) are complex, multifactorial illnesses that continue to affect patients of incredibly diverse backgrounds despite many medical advancements in recent years¹. Many procedures have been developed in the last few decades to correct coronary vessel pathologies such as Coronary Artery Bypass Graft (CABG) and now, even catheterization based approaches such as Percutaneous Coronary Intervention² present a far less invasive approach to correct vascular flow issues in and around the heart. Despite such advances, little has been done for the treatment and healing of cardiovascular tissue following severe obstructive and ischemic pathologies, especially those that lead to Myocardial Infarctions (MI)³. This is an area that desperately needs further research as the heart possesses limited regenerative capacity, making Stem Cell based therapies ideal for restarting the healing of injured cardiomyocytes.

Objective: In this literature review, we explored various evidence based considerations for how to implement Stem Cell therapies in patients recovering from Ischemic Cardiovascular Diseases.

Search Methods: A PubMed search was conducted for articles published between 2017 and 2024 for the following phrases: “Coronary Artery Disease”, “Stem Cells”, “Myocardial Infarction”, “Stem Cell Mechanisms”.

Results: All of the studies showed Stem Cells were effective in promoting favorable conditions for tissue regeneration particularly via promoting angiogenesis in ischemic myocardium, increasing capillary and arteriole density in treated areas⁴,⁵. These therapies are especially effective when combined with means to augment their delivery/incorporation into the organism such as Extracellular Vesicles (EVs), Hydrogels, Biological Scaffolds, and Dual Cell therapies combining Stem Cells with other growth promoting complexes. EVs carry bioactive molecules like microRNAs (e.g., miR-221-3p) and long non-coding RNAs (e.g., MALAT1), which regulate cell survival, angiogenesis, and inflammation in injured cardiac tissue^6,7. Studies show that EV-treated animals experience similar or enhanced recovery compared to those receiving whole-cell transplants, highlighting the potential for EVs to act as safe, cell-free therapeutic agents^5-7. Another study found that Hydrogels modified with peptides like SDKP or RGD improve the retention, localization, and sustained release of both stem cells and EVs at the infarct site, leading to stronger and longer-lasting reparative effects⁵,⁶. We also found that Dual-cell strategies, such as co-delivering human iPSC-derived cardiovascular progenitor cells (hCVPCs) and cardiomyocytes (hCMs), result in greater improvements in cardiac function, scar reduction, and vascular density than single-cell approaches⁴.

Conclusion: The methods discussed provide important context for future clinicians in treating ICDs. Combination therapies especially show improved outcomes across the board and should be prioritised as such. Emphasis should be placed on optimizing EV cargo composition, cell-source selection, and delivery modalities like including hydrogel and ECM-based systems to facilitate reliable clinical translation and regulatory approval. These factors, when considered together, have the potential to provide drastically improved outcomes for who would otherwise have poor prognoses with current treatment guidelines.

Work Cited:

1. Stougiannou TM, Christodoulou KC, Dimarakis I, Mikroulis D, Karangelis D. To Repair a Broken Heart: Stem Cells in Ischemic Heart Disease. Curr Issues Mol Biol. 2024;46(3):2181-2208. Published 2024 Mar 8. doi:10.3390/cimb46030141
2. Saravanan S, Palaniappan NA, Panneerselvam A, et al. Emerging therapeutic and diagnostic strategies for coronary artery disease: Current trends and future perspectives. Curr Probl Cardiol. 2024;49(12):102863. doi:10.1016/j.cpcardiol.2024.102863
3. Bakinowska E, Kiełbowski K, Boboryko D, et al. The Role of Stem Cells in the Treatment of Cardiovascular Diseases. Int J Mol Sci. 2024;25(7):3901. Published 2024 Mar 31. doi:10.3390/ijms25073901
4. Jiang Y, Zhang LL, Zhang F, et al. Dual human iPSC-derived cardiac lineage cell-seeding extracellular matrix patches promote regeneration and long-term repair of infarcted hearts. Bioact Mater. 2023;28:206-226. Published 2023 May 27. doi:10.1016/j.bioactmat.2023.05.015
5. Choudhury T, Mozid A, Hamshere S, et al. An exploratory randomized control study of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with ischaemic cardiomyopathy: the REGENERATE-IHD clinical trial. Eur J Heart Fail. 2017;19(1):138-147. doi:10.1002/ejhf.676
6. Firoozi S, Pahlavan S, Ghanian MH, et al. Mesenchymal stem cell-derived extracellular vesicles alone or in conjunction with a SDKP-conjugated self-assembling peptide improve a rat model of myocardial infarction. Biochem Biophys Res Commun. 2020;524(4):903-909. doi:10.1016/j.bbrc.2020.02.009
7. Wu Q, Wang J, Tan WLW, et al. Extracellular vesicles from human embryonic stem cell-derived cardiovascular progenitor cells promote cardiac infarct healing through reducing cardiomyocyte death and promoting angiogenesis. Cell Death Dis. 2020;11(5):354. Published 2020 May 11. doi:10.1038/s41419-020-2508-y