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COVID-19: The endothelial disease that can be managed by increasing heart rate variability and the number and functions of endothelial progenitor cells

The virus injures the endothelial lining of the cardiovascular system and the pulmonary alveolar epithelial system because the ACE2 receptors are abundant on them and ACE2 is one of the most important receptors for COVID-19 (1)(2)(3) Naturally, the major risk groups have cardiovascular disease, diabetes, old age, hypertension, atherosclerosis, cancer. (4) Elevated d-dimer predicts mortality in patients with COVID-19. (5) Elevated D-dimer that predicts thrombosis and pulmonary embolism are in an inverse relationship with endothelial progenitor cells (EPC). Decreased EPC is also a marker of platelet activation and elevated thrombosis risk. (6) (7) EPC can also help not only in the prevention but also in the resolution of thrombosis. (8)(9) Enhancing the activity of the parasympathetic nervous system, the heart rate variability (HRV) may help to increase the number of EPCs in people living with sympathetic predominance and so it may help to save the lives of the risk groups because they have a decreased EPC number and function generally. (10)(11)(12) With the help of centrally administered proinsulin c-peptide this goal may be achieved. (13)(14)(15)(16)

Increasing the EPC number also improves the gas exchange capability and inflammation of the injured lung and may prevent ventilation-induced lung damage by improving local and systemic inflammation. It may also prevent cell death and improve epithelial permeability. (17)(18) Women have a favorable disease outcome compared to men that may be explained by the protective role of estrogen for the pulmonary gas exchange process. (20)(21)

The importance of increasing HRV for COVID-19 patients is also emphasized by other scientific evidences. Diabetes and atherosclerosis are characterized by platelet activation, endothelial dysfunction, and microcirculatory problems. (22) Vagal stimulation protects against peripheral vascular dysfunction through the cholinergic anti-inflammatory pathway. The cholinergic system, acetylcholine has antithrombotic effects. (23) (24) Reduced cardiac vagal activity is accompanied by impaired endothelial function. Vagal heart rate variability indices are related to flow-mediated dilation across healthy male subjects. (25) Chronic vagal nerve stimulation (VNS) prevents hypertension-induced endothelial dysfunction and aortic stiffening in an animal model of severe hypertension. (26) Chronic VNS attenuates vascular endothelial impairments and reduces the inflammatory profile in ovariectomized rats. (27) Proinsulin C-peptide administration can also improve blood flow and capillary diffusion capacity in patients with type 1 diabetes mellitus. (28) (29) Reduced pulmonary diffusion capacity – one of the hallmarks of the severe consequences of COVID-19 infection – is also associated with autonomic dysfunction in type 1 diabetes. (30)

One of the most important external risk factors for the poor outcome of COVID-19 infection is air pollution. (31) It causes the elevation of inflammation, Il-6, d-dimer that is a prognostic factor for the increased risk of thrombosis and it decreases HRV significantly and impairs the functions and number of EPCs. (32)(33)(34)(35)(36) Elevated Il-6 is also an increased risk factor for the fatality of the infection. (37)(38) Inflammation marked by Il-6 is related to hypercoagulability and might particularly contribute to atherothrombotic events in settings of decreased HRV. (39)

COPD and cardiovascular disease are among the most important risk factors of COVID-19 infection. (40) For COPD patients impaired lung diffusion capacity was related to an altered parasympathetic response and impaired autonomic adjustment was related to the severity of pulmonary disease. (41)

Because the virus is targeting the endothelium it is important to decrease inflammation and other risk factors harming the vascular system. (42) In a cohort of individuals at increased cardiovascular risk, carotid intima media-thickness IMT as a marker of subclinical atherosclerosis was inversely associated with alterations of HRV indicating an impaired cardiac autonomic control (43) Autonomic dysfunction is associated with inflammation and atherosclerosis. (44)(45)

Taken together, improving autonomic functions by centrally administered proinsulin C-peptide may be related to better disease outcome for most of the risk groups affected by COVID-19 infection.


1. https://pubmed.ncbi.nlm.nih.gov/15141377/
2. https://pubmed.ncbi.nlm.nih.gov/32228252/
3. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30937-5/fulltext
4. https://www.bmj.com/content/368/bmj.m1198
5. https://pubmed.ncbi.nlm.nih.gov/32306492/
6. https://ashpublications.org/blood/article/128/22/3805/97010/Lower-Levels-of-Circulating-Endothelial-Progenitor
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215485/
8. https://pubmed.ncbi.nlm.nih.gov/26187355/
9. https://www.sciencedirect.com/science/article/abs/pii/S1465324919300118
10. https://pubmed.ncbi.nlm.nih.gov/24858852/
11. https://pubmed.ncbi.nlm.nih.gov/22488933/
12. https://www.hindawi.com/journals/sci/2016/8043792/
13. https://link.springer.com/article/10.1007/BF00418540
14. https://www.researchgate.net/publication/7738090_Proinsulin_C-peptide_activates_vagus_efferent_output_in_rats
15. https://pubmed.ncbi.nlm.nih.gov/11151760/
16. https://pubmed.ncbi.nlm.nih.gov/31346872/
17. https://pubmed.ncbi.nlm.nih.gov/21233499/
18. https://www.researchgate.net/publication/335869498_Endothelial_Progenitor_Cells_Attenuate_Ventilator-Induced_Lung_Injury_with_Large-Volume_Ventilation
19. https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC3038173&blobtype=pdf
20. https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/31069/21559
21. https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/31069/21559
22. https://pubmed.ncbi.nlm.nih.gov/18220940/
23. https://pubmed.ncbi.nlm.nih.gov/23519622/
24. https://pubmed.ncbi.nlm.nih.gov/30765424/
25. https://pubmed.ncbi.nlm.nih.gov/22749462/
26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967207/
27. https://pubmed.ncbi.nlm.nih.gov/26692419/
28. https://link.springer.com/article/10.1007/BF00401369
29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC508791/
30. https://pubmed.ncbi.nlm.nih.gov/19046231/
31. https://www.hsph.harvard.edu/news/hsph-in-the-news/air-pollution-linked-with-higher-covid-19-death-rates/
32. https://pubmed.ncbi.nlm.nih.gov/29191925/
33. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943671/
34. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753450/
35. https://www.researchgate.net/publication/278281210_Urban_air_pollution_associated_with_plasma_d-dimer_and_decreased_heart_rate_variability
36. https://pubmed.ncbi.nlm.nih.gov/32306492/
37. https://www.medrxiv.org/content/10.1101/2020.04.01.20047381v2
38. https://www.researchgate.net/publication/340266188_Interleukin-6_Use_in_COVID-19_Pneumonia_Related_Macrophage_Activation_Syndrome
39. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373608/
40. https://pubmed.ncbi.nlm.nih.gov/32267833/
41. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544724/
42. https://www.researchgate.net/publication/340538838_Is_COVID-19_an_endothelial_disease_Clinical_and_basic_evidence
43. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405141/
44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380339/
45. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412503/

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