Persistent Endothelial Dysfunction in Post-Acute COVID-19 Syndrome: A Case-Control Study

Abstract

Background: Endothelial dysfunction has a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its disabling complications. We designed a case-control study to assess the alterations of endothelium-dependent flow-mediated dilation (FMD) among convalescent COVID-19 patients.

Methods: COVID-19 patients referred to a Pulmonary Rehabilitation Unit within 2 months from swab test negativization were consecutively evaluated for inclusion and compared to controls matched for age, gender, and cardiovascular risk factors.

Results: A total of 133 convalescent COVID-19 patients (81.2% males, mean age 61.6 years) and 133 matched controls (80.5% males, mean age 60.4 years) were included. A significantly lower FMD was documented in convalescent COVID-19 patients as compared to controls (3.2% ± 2.6 vs. 6.4% ± 4.1 p < 0.001), confirmed when stratifying the study population according to age and major clinical variables. Among cases, females exhibited significantly higher FMD values as compared to males (6.1% ± 2.9 vs. 2.5% ± 1.9, p < 0.001). Thus, no significant difference was observed between cases and controls in the subgroup analysis on females (6.1% ± 2.9 vs. 5.3% ± 3.4, p = 0.362). Among convalescent COVID-19 patients, FMD showed a direct correlation with arterial oxygen tension (rho = 0.247, p = 0.004), forced expiratory volume in 1 s (rho = 0.436, p < 0.001), forced vital capacity (rho = 0.406, p < 0.001), and diffusing capacity for carbon monoxide (rho = 0.280, p = 0.008). Overall, after adjusting for major confounders, a recent COVID-19 was a major and independent predictor of FMD values (β = -0.427, p < 0.001).

Conclusions: Post-acute COVID-19 syndrome is associated with a persistent and sex-biased endothelial dysfunction, directly correlated with the severity of pulmonary impairment.

Keywords: COVID-19; biomarkers; disability; endothelial function; exercise; outcomes; rehabilitation.

Figure 1

Difference in flow-mediated dilation (FMD) between convalescent coronavirus disease 2019 (COVID-19) patients and controls stratified according to demographic and clinical characteristics. CV: Cardiovascular.

Figure 2

Difference in flow-mediated dilation (FMD) between convalescent coronavirus disease 2019 (COVID-19) patients and controls stratified according to the number of vascular risk factors.

Figure 3

Scatter plot of Spearman’s correlations between flow-mediated dilation (FMD) and arterial oxygen tension (PaO₂), forced expiratory volume in 1 s (FEV₁%), forced vital capacity (FVC%), and diffusing capacity for carbon monoxide (DLCO%) in convalescent coronavirus disease 2019 (COVID-19) patients.

Figure 4

Physiopathology of endothelial dysfunction and gender differences in coronavirus disease 2019 (COVID-19). SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; TNFα: Tumor necrosis factor alfa; ADAM17: A disintegrin and metalloprotease 17; ACE2: Angiotensin converting enzyme 2; Ang II: Angiotensin II; Ang 1–7: Angiotensin_1–7; MAS: Proto-oncogene G-protein–coupled receptor; AT1: Angiotensin receptor type 1; AT2: Angiotensin receptor type 2; AT4: Angiotensin receptor type 4; Gα_12/13: Guanine nucleotide-binding protein alpha 12/13; RhoA: Ras homolog family member A; ROCK: Rho-associated protein kinase; p38 MAPK: p38 mitogen-activated protein kinase; NO: Nitric oxide.