Cardiac lymphatics in health and disease

Abstract

The lymphatic vasculature, which accompanies the blood vasculature in most organs, is indispensable in the maintenance of tissue fluid homeostasis, immune cell trafficking, and nutritional lipid uptake and transport, as well as in reverse cholesterol transport. In this Review, we discuss the physiological role of the lymphatic system in the heart in the maintenance of cardiac health and describe alterations in lymphatic structure and function that occur in cardiovascular pathology, including atherosclerosis and myocardial infarction. We also briefly discuss the role that immune cells might have in the regulation of lymphatic growth (lymphangiogenesis) and function. Finally, we provide examples of how the cardiac lymphatics can be targeted therapeutically to restore lymphatic drainage in the heart to limit myocardial oedema and chronic inflammation.

Key points

  • Cardiac lymphatics show a dynamic range of fluid uptake and transport that is linked to cardiac contractility and heart rate.

  • Cardiac lymphatics undergo substantial remodelling in several cardiovascular diseases, which can alter the lymphatic drainage capacity in the heart.

  • Insufficient lymphangiogenesis might contribute to the build-up of atherosclerotic lesions in large arteries owing to accumulation of both lipids and activated immune cells.

  • Immune cells contribute to the process of lymphatic remodelling by stimulating or inhibiting lymphangiogenesis.

  • Therapeutic stimulation of cardiac lymphangiogenesis after myocardial infarction leads to accelerated resolution of myocardial oedema and inflammation, promoting cardiac recovery.

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Fig. 1: Structure of the lymphatic vessel drainage pathway.
Fig. 2: Lymphatic vasculature in the heart.
Fig. 3: Lymphatic function versus oedema in the heart.
Fig. 4: Perivascular lymphatics in atherosclerosis.

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Acknowledgements

The authors thank A. Ratajska (Warsaw Medical University, Poland) for critical reading of the manuscript, and they acknowledge the work of colleagues and collaborators in providing the background research for this Review. Special thanks goes to D. Godefroy (INSERM UMR1239-DC2N Laboratory, Rouen, France) and D. Schapmann (PRIMACEN, Rouen, France) for expert assistance with cardiac light sheet and confocal microscopy, respectively. E.B. is supported by the European Research Area Network (ERA-NET) on Cardiovascular Diseases (ERA-CVD) (LYMIT-DIS project, a transnational research and development programme jointly funded by national funding organizations within the framework of the ERA-NET ERA-CVD), FHU REMOD-VHF (INSERM U1096 laboratory) and generalized institutional funds from the French INSERM and the Normandy Region together with the European Union: “Europe gets involved in Normandie” with European Regional Development Fund (ERDF): CPER/FEDER 2015 (DO-IT) and CPER/FEDER 2016 (PACT-CBS). K.A. is supported by the Academy of Finland (Centre of Excellence Program 2014–2019 (271845 and 307366)), the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement 743155), the Novo Nordisk Foundation, the Sigrid Juselius Foundation, the Helsinki Institute for Life Sciences (HiLife), and the Finnish Cancer Society.

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Nature Reviews Cardiology thanks M. Achen, D. Kerjaschki, M. L. Khan and the other, anonymous reviewer for their contribution to the peer review of this work.

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Both authors researched data for the article and discussed its content. E.B. wrote the manuscript, and K.A. reviewed and edited it before submission.

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Brakenhielm, E., Alitalo, K. Cardiac lymphatics in health and disease. Nat Rev Cardiol 16, 56–68 (2019). https://doi.org/10.1038/s41569-018-0087-8

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