PostCOVID effect on endothelial function in hypertensive patients: A new research opportunity

Abstract SARS‐CoV‐2 is causing devastation both in human lives and economic resources. When the world seems to start overcoming the pandemics scourge, the threat of long‐term complications of COVID‐19 is rising. Reports show that some of these long‐term effects may contribute to the main cause of morbimortality worldwide: the vascular diseases. Given the evidence of damage in the endothelial cells due to SARS‐CoV‐2 and that endothelial dysfunction precedes the development of arteriosclerosis, the authors propose to measure endothelial function around 6–12 months after acute disease in hypertensive patients, especially if they have other cardiovascular risk factors or overt vascular disease. The methods the authors propose are cost‐effective and can be made available to any hypertension unit. These methods could be the “in vivo” assessment of endothelial function by flow mediated vasodilatation after ischemia by Laser‐Doppler flowmetry and the measurement of plasma free circulating DNA and microparticles of endothelial origin.


INTRODUCTION
One of the most recent and innovative techniques to assess the magnitude of response is Laser-Doppler flowmetry, which mainly allows the determination of the microcirculation status. This is a noninvasive technique, but its measurements are probably more independent of the observer since the results are automatically obtained by software. This software assesses many parameters both in general and adjusted analysis of the response. Although some parameters measure the speed of the response, such as the slope or the time to maximum hyperemia, others are related to the duration of this response, such as the time to reach the half value after the maximum hyperemia.
A previous study of our group found that the area of hyperemia was the parameter with higher sensitivity and specificity for identification of patients with coronary artery disease, because the area depends on the speed as well as on the intensity and duration of the response. 4

Cell-free DNA measurement
Although initially related to neoplastic diseases cell-free DNA (c-fDNA) levels, has more recently been related to pathologies involving ischemia such as acute coronary syndrome, 5 ischemic heart failure, 6 stroke, 7 and mesenteric ischemia, 8 as well as in patients who have suffered cardiac arrest outside the hospital. 9 Similarly, increases in circulating c-fDNA have been documented in situations involving hypoxia, such as experimental acute pulmonary thromboembolism 10 or obstructive sleep apnea/ hypopnea syndrome. 11 Our group have also observed higher levels of c-fDNA in patients with preeclampsia (PCL, a disease related to placental ischemia) that also increases with the severity of disease, being higher in patients with HELLP syndrome, acronym Hemolysis, Elevated Liver enzymes and Low Platelet count. According to our data, we proposed a cutoff point of 950 ng/ml of c-fDNA as being suspicious of severe illness because these values had high sensitivity and specificity for detecting severe PCL and HELLP syndrome 12,13 ( Figure 2).

F I G U R E 2
Circulating c-fDNA in controls and patients with preeclampsia according to the severity of disease (taken from Am J Hypertens 2013; 26 (12): 1377-80) Finally, Alvarado Vasquez and coworkers 14 have described that circulating cell-free mitochondrial DNA might be the probable inducer of early endothelial dysfunction.

Circulating endothelial microparticles
Circulating microparticles (MPs) are small vesicles that are released in response to several injuries. The level of circulating MPs in peripheral blood has been reported to be increased in cerebrovascular disease, hypertension, diabetes, smoking, coronary disease, and obstructive sleep apnea (OSA) syndrome. There exists a positive correlation between circulating levels of MPs and nocturnal hypoxemia severity. 15 We have also previously reported that changes in MPs after continuous positive airway pressure in OSA patients were greater in those with a more severe disease, defined according to the oxygen desaturation and apnea-hypopnea indexes, suggesting that in more severe patients the benefit is greater. 16   As these research studies will be on human beings, local ethics committee approval must be obtained and patients should be informed of the possible adverse effects of these techniques which will include those derived from venipuncture and keeping the cuff inflated on the arm for 4 min.

THE NEW PROPOSAL
Practically all hypertension units are located in hospitals that have or could have the three techniques mentioned above. The finding by Sinning and coworkers that is reproduced in Figure 1 (with the author's permission) shows how, from practically the first 6-12 months, both curves (those that present events and those that do not) begin to differ.
Our proposal is very simple: all hypertensive patients who have suffered an episode of SARS-CoV-2 infection -and even more so if they have other associated vascular risk factors or already manifested vascular disease-should be evaluated from the point of view of their endothelial function at least once 6-12 months after the episode, by any of the three aforementioned methods.
We encourage all interested researchers.to design a comparative study, age-sex-risk factor matched study of hypertensive patients with and without history of SARS-CoV-2. Both groups should be compared to decide whether there are significant differences, and in such case, establish cut-off points from which to establish measures aimed at improving the future vascular prognosis in infected patients who have worsened their vascular risk due to deterioration of endothelial function.

CONFLICTS OF INTEREST
There is not any conflict of interest.