Encouragement of Lymphatic Vascular Growth after Myocardial Injury Improves Cardiac Function
In the past 10 years, the death rate due to heart failure has increased, proving that current therapeutic methods for heart failure are not adequate.1 Understanding the complex process and progression into heart failure is therefore crucial to developing novel therapeutics. A recent emerging area of interest is in cardiac lymphatics, where after cardiac injury, their underperformance leads to an inability to maintain fluid homeostasis, leading to residual buildup of edema and inflammation.2,3 The buildup of edema and inflammation proves to be deleterious to cardiac function, and therefore targeting the cardiac lymphatics might be beneficial, as it may halt the progression into heart failure.2 A literature review was performed to explore cardiac lymphatics and their function regarding the cardiovascular system. Papers that were focused on specifically looked at how increasing the overall amount of cardiac lymphatic vessels helps cardiac function after disease. In all studies, cardiac injury was mimicked using a left anterior descending artery ligation and compared to controls, except for a clinical trial.5-9 Specific regulators of cardiac lymphangiogenesis, VEGF-C and VEGF-D were commonly used as a method to increase lymphatic vessel growth after injury. After treatment, overall density and branching of lymphatic vessels was significantly increased in treatment groups compared to controls.6,7,9 Another study looked at the resolution of inflammation after cardiac damage, and showed that by encouraging lymphatic growth they could stimulate the resolution of inflammation.9 In one study cardiac function was examined and, end systolic volume was significantly decreased in treated groups vs control, indicative of improved cardiac function.6 Additionally, within this study, ejection fraction was also significantly higher in treatment groups compared to controls post injury.6 A phase I/II clinical trial looked at the injection of VEGF-D into patients with refractory angina, and found that patients quality of life and symptoms had improved, as well as cardiac perfusion when compared to the start of the study and those who did not receive treatment.5 The data presented not only shows that promotion of lymphangiogenesis increases the number of lymphatic vessels present, but that there are also functional benefits such as faster inflammatory resolution, and improvement in cardiac function. The improvement of cardiac function not only shows the importance of the cardiac lymphatic system on disease resolution, but that this treatment may also be one day used therapeutically to help halt myocardial progression into heart failure.
- Kurmani S, Squire I. Acute Heart Failure: Definition, Classification and Epidemiology. Curr Heart Fail Rep. 2017;14(5):385-392.
- Brakenhielm E, Alitalo K. Cardiac lymphatics in health and disease. Nature Reviews Cardiology. 2019;16(1):56-68.
- Klaourakis K, Vieira JM, Riley PR. The evolving cardiac lymphatic vasculature in development, repair and regeneration. Nat Rev Cardiol. 2021:1-12.
- Mazurek JA, Jessup M. Understanding Heart Failure. Heart Failure Clinics. 2017;13(1):1-19.
- Hartikainen J, Hassinen I, Hedman A, et al. Adenoviral intramyocardial VEGF-DΔNΔC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up. Eur Heart J. 2017;38(33):2547-2555.
- Klotz L, Norman S, Vieira JM, et al. Cardiac lymphatics are heterogeneous in origin and respond to injury. Nature. 2015;522(7554):62-67.
- Vivien CJ, Pichol-Thievend C, Sim CB, et al. Vegfc/d-dependent regulation of the lymphatic vasculature during cardiac regeneration is influenced by injury context. NPJ Regen Med. 2019;4:18.
- Trincot Claire E, Xu W, Zhang H, et al. Adrenomedullin Induces Cardiac Lymphangiogenesis After Myocardial Infarction and Regulates Cardiac Edema Via Connexin 43. Circulation Research. 2019;124(1):101-113.
- Vieira JM, Norman S, Villa Del Campo C, et al. The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction. J Clin Invest. 2018;128(8):3402-3412.