Long Covid and the Vascular Endothelium

Infection with SARS-CoV2 infection often involves the vascular endothelium, resulting in a variety of deleterious effects. Among these is endothelial dysfunction, distinct from endothelial injury, in which the vascular endothelium loses elasticity and the ability to vasodilate and vasoconstrict. It constitutes a type of non-obstructive coronary artery disease and is generally associated with impaired production of nitric oxide (NO).

Damage to the endothelium is an important component in acute Covid, manifested as various pathologies including hypertension, kidney disease, diabetes, thrombosis, and neurologic problems(1). The extent to which these effects vary among different SARS-CoV2 variants is not well understood. The deleterious effects of Covid on the endothelium appear to be indirect, due to inflammation and dysregulated immune activities. There is also some evidence of direct infection as judged by particles and proteins of SARS-CoV2 within endothelial cells(2), but infection seems to be inefficient and non-productive of progeny virus(3). Any direct contribution from direct viral infection may thus be minimal, although circulating viral proteins could play a role. The S1 unit of the spike protein has been reported(4) to cause decreased microvascular trans-endothelial resistance and endothelial barrier function in vitro. Nucleocapsid protein from SARS-CoV2 (but not from other betacoronaviruses) activate human endothelial cells in vitro through TLR2 signaling; this is inhibited by simvastatin, a drug normally used to lower cholesterol(5). Endothelial cell circulation, another marker of endothelial pathology, is correlated with elevated pro-inflammatory cytokine expression including IL-6, IL-1β, TNFα, and INFγ, and these are likely important contributory factors.

The effects on the endothelium are multiple(6). Vasculitis can affect skin, lungs, heart, liver, kidney, and intestines. Mechanisms (other than endothelial dysfunction, defined as loss of vascular elasticity) can include microclots, circulation of endothelial cells (released from injured vasculature), vascular leakage, and tissue damage including ischemic stroke.

If endothelial dysfunction plays a substantial role in acute Covid, why is it of specific interest for long Covid? The reasons are that it has been found to persist in long Covid and seems to be present in only some long Covid, perhaps distinguishing different subtypes. In addition, it may suggest therapeutic options, at least for some cases of long Covid.

One measure of endothelial function that depends on endothelial elasticity is myocardial flow reserve (MFR), the ratio of blood flow during maximum coronary vasodilation to that during resting blood flow. MFR is typically assessed by cardiac PET scanning. As judged by PET scanning, patients with PCR-confirmed Covid at a median post-Covid time of 4.6 months had about a four-fold (44% vs 11.7%) incidence of reduced MFR compared to controls matched for cardiac risk factors(7), suggesting a contribution of endothelial dysfunction some people with long Covid. Half the people in this group had baseline cardiac risk factors such as obesity, but the same was true for the control group. This suggests that people with cardiac risk factors may be predisposed to this type of long Covid. Another study showed basically concordant results(8). A different report used endothelial quality index, as measured by finger thermal monitoring, to reach essentially the same conclusions.

As mentioned above, endothelial dysfunction doesn’t appear likely to be due to direct infection of endothelial cells, but rather to immune dysregulation, with inflammation or autoimmunity as possible specific factors. As noted above, simvastatin inhibits activation of TLR2 by nucleocapsid protein; statins, with their anti-inflammatory activity, might be useful options. Other anti-inflammatory treatments might also be useful. However, long Covid is probably not simply one thing, and what works for one group of patients might not work for another. In addition, if endothelial dysfunction leads to organ damage (due to clots, leakage, etc.), the only alternatives would by supportive/rehabilitative. We need a better understanding of the range of variables that contribute to what we call long Covid.

References:

1. Sardu, C., et al., Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence. J Clin Med, 2020. 9(5).

2. Liu, F., et al., SARS-CoV-2 Infects Endothelial Cells In Vivo and In Vitro. Front Cell Infect Microbiol, 2021. 11: p. 701278.

3. Schimmel, L., et al., Endothelial cells are not productively infected by SARS-CoV-2. Clin Transl Immunology, 2021. 10(10): p. e1350.

4. Colunga Biancatelli, R.M.L., et al., The SARS-CoV-2 spike protein subunit S1 induces COVID-19-like acute lung injury in Kappa18-hACE2 transgenic mice and barrier dysfunction in human endothelial cells. Am J Physiol Lung Cell Mol Physiol, 2021. 321(2): p. L477-L484.

5. Qian, Y., et al., Direct Activation of Endothelial Cells by SARS-CoV-2 Nucleocapsid Protein Is Blocked by Simvastatin. J Virol, 2021. 95(23): p. e0139621.

6. Ma, Z., et al., Endothelial contribution to COVID-19: an update on mechanisms and therapeutic implications. J Mol Cell Cardiol, 2022. 164: p. 69-82.

7. Weber, B., et al., Prior SARS-CoV-2 Infection Is Associated With Coronary Vasomotor Dysfunction as Assessed by Coronary Flow Reserve From Cardiac Positron Emission Tomography. J Am Heart Assoc, 2022. 11(20): p. e025844.

8. Verma, A., et al., Post COVID-19 syndrome with impairment of flow-mediated epicardial vasodilation and flow reserve. Eur J Clin Invest, 2022. 52(12): p. e13871.