Barna Veli

Background

In the United States, cardiovascular disease including myocardial infarction (MI) accounts for 40% of total deaths. MI accounts for 16.5% of all deaths from cardiovascular disease.¹ After hospital discharge for MI, 13% of patients are diagnosed with heart failure within 30 days and 20-30% of patients are diagnosed with heart failure within 1 year.² Cardiac lymphangiogenesis, the remodeling of lymphatic vessels, occurs in cardiovascular diseases that involve inflammation and edema.³ After cardiac ischemia, the lymphatic system responds by recruiting immune cells to the location of injury which help remove dead cardiomyocytes, stabilize scar formation, and resolve inflammation. Inefficient resolution of this inflammatory response can lead to the development of chronic heart failure.³ Though there are treatments for MI, preventing its progression to heart failure remains an issue. Fine tuning the inflammatory and anti-inflammatory responses to myocardial injury may help prevent negative disease progression after myocardial infarction.⁴

Objectives

In this narrative review, we investigate lymphangiogenesis post-MI and its impact on MI progressing to heart failure.

Search Methods

An online search in the PubMed database was conducted from 2016 to 2020 using the following keywords: “myocardial infarction”, “lymphangiogenesis”, “lymphatic system”, “heart failure”.

Results

Studies found that VEGF-C is upregulated in mice post-MI. In 2 groups of mice demonstrating chronic myocardial ischemia and myocardial ischemia followed by reperfusion therapy, there was an increase in the expression of both VEGF-C and VEGFR3 1 day following myocardial injury.⁵ In turn, VEGF-C was found to upregulate lymphangiogenesis, the creation of new lymphatic vessels. 4 weeks after implantation of lymphatic endothelial progenitor cells (LEPCs) and VEGF-C loaded with self assembling peptides (SAP) hydrogel in mice post-MI, there was an increase in cardiac lymphangiogenesis and induced differentiation of other cells.⁶ Sustained VEGF-C therapy in mice which stimulated lymphangiogenesis, led to reduced cardiac inflammation 3 weeks post-MI.³ Clearing immune cells post myocardial infarction via an expanded lymphatic network prevents the escalation of repair to chronic inflammation and favors better tissue repair.⁷ When lymphangiogenesis was inhibited after myocardial injury in mice, increased edema, cardiac dysfunction, and inflammation was found. Additionally, inhibiting lymphangiogenesis stopped the increase in lymphatic vessel density and lymphatic transport.⁵  Cardiac lymphangiogenesis is suppressed by both CD4+ and CD8+ T-cells via interferon gamma. Targeting T cells or interferon gamma can help enhance the lymphangiogenesis response that mediates cardiac repair.³

Conclusions

Due to the close relationship between lymphangiogenesis and reduced cardiac inflammation, gene therapy to induce lymphangiogenesis could be novel in management of cardiovascular diseases. Therapies that target lymphangiogenesis could help prevent heart failure as a result of acute ischemic myocardial infarction.³

Works Cited

1. Caldwell M, Martinez L, Foster JG, Sherling D, Hennekens CH. Prospects for the Primary Prevention of Myocardial Infarction and Stroke. Journal of Cardiovascular Pharmacology and Therapeutics. 2019;24(3):207-214. doi:10.1177/1074248418817344
2. Jenča, D., Melenovský, V., Stehlik, J., Staněk, V., Kettner, J., Kautzner, J., Adámková, V., and Wohlfahrt, P. Heart failure after myocardial infarction: incidence and predictors. ESC Heart Failure.2021;8:222– 237. https://doi.org/10.1002/ehf2.13144.
3. Houssari M, Dumesnil A, Tardif V, et al. Lymphatic and immune cell cross-talk regulates cardiac recovery after experimental myocardial infarction. Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40(7):1722-1737. doi:10.1161/atvbaha.120.314370
4. Chalise U, Becirovic-Agic M, Lindsey ML. The cardiac wound healing response to myocardial infarction. WIREs Mech Dis. 2023;15(1):e1584. doi:10.1002/wsbm.1584
5. Shimizu Y, Polavarapu R, Eskla KL, et al. Impact of lymphangiogenesis on cardiac remodeling after ischemia and reperfusion injury. Journal of the American Heart Association. 2018;7(19). doi:10.1161/jaha.118.009565
6. Zhang H-feng, Wang Y-li, Tan Y-zhen, Wang H-jie, Tao P, Zhou P. Enhancement of cardiac lymphangiogenesis by transplantation of CD34+VEGFR-3+ endothelial progenitor cells and sustained release of VEGF-C. Basic Research in Cardiology. 2019;114(6). doi:10.1007/s00395-019-0752-z
7. Vieira JM, Norman S, Villa del Campo C, et al. The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction. Journal of Clinical Investigation. 2018;128(8):3402-3412. doi:10.1172/jci97192