In the present study, we found that COVID-19 disease and increased BMI are independent predictors of ED assessed by FMD. Cardiovascular-based morbidity and mortality rates have been reporting to be increased after COVID-19 disease. The main underlying pathophysiology of cardiovascular adverse consequences was shown to be the ED. As far as we know, this is the first study in the literature that evaluating ED with FMD in patients recovered from COVID-19 disease.
After the first case report was reported in China in December 2019, the SARS-CoV-2 virus spread across the world and was described to be pandemic since March 2020 by WHO . The SARS-CoV-2 virus is in the same family with viruses that cause severe acute respiratory syndrome-coronavirus syndrome (SARS-CoV) in 2002 and Middle East respiratory-coronavirus (MERS-CoV) outbreaks in 2012. However, unlike other family members, owing to having a highly pathogenic property, the virus became a threat to the global health system . SARS-CoV-2 penetrates tissues through the angiotensin-converting enzyme 2 (ACE2) receptor with 10–20 times higher binding affinity. The main target of SARS-CoV-2 is the upper and lower respiratory system and manifests with a dry cough, fever, fatigue, and/or dyspnea. COVID-19 disease may progress to a severe form requiring intensive care unit in 10–20% of the patients [1, 16]. ACE2 receptor also vastly presents on vascular endothelial cells in the whole circulatory system including both small and large arteries and veins. And so, there is a potential for systemic impaired microcirculatory function in different vascular beds including cardiovascular, kidney, cerebral, and gastrointestinal systems. The kidney and gastrointestinal tract were shown to have highly expressed ACE2, and thus more likely to be infected by SARS-CoV-2 [4, 17]. In addition, ACE2 was shown to protect endothelial function and diminish the inflammatory response. Inhibition of ACE2 was associated with increased platelet activation and thrombus formation in experimental studies . Angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB) are suggested to be promising agents for preventing disease severity by declining virus-receptor interaction . Even though antiviral and antibacterial medications were used frequently, supportive care to maintain efficient oxygen supply and controlling inflammation are the main management strategies yet.
Despite SARS-CoV-2 targets the respiratory system primarily, myocardial injury is observed in almost 28% of the COVID-19 patients and associated with worsened outcomes. Although some mechanisms are proposed to explain myocardial involvement, etiology is still needing to be resolved. Cytokine-mediated injury, stress-related cardiomyopathy, and microvascular injury are postulated pathways, though these are not proven yet [20, 21]. In addition, pericytes but not cardiomyocytes were demonstrated to express the highest ACE2 levels. Thus, pericytes are being potential target cells upon SARS-CoV-2 infection which culminate in capillary endothelial dysfunction. On the other hand, preliminary studies demonstrated that endothelial cells can be infected by the SARS-CoV-2 virus. Direct inflammation of endothelium and/or COVID-related-perivascular inflammation may also result in ED and tissue edema. Furthermore, COVID-19 was found to be associated with endotheliitis in several organs including lung, kidney, and liver. Besides, endotheliitis was extensive in severe COVID-19 forms [7, 22].
The endothelium is well-established to have many functions including endocrine and paracrine effects as well as a semipermeable barrier for circulating molecules. It is estimated that there are approximately 1013 endothelial cells which consist of almost one kg of the total body weight. Putatively, the endothelial function is considered to have a deep effect on all the systems of the body . A large number of cell products are secreted from the endothelial cells regulating the function of platelets, leukocytes, and smooth muscle cells. Thus, intravascular homeostasis consisting of vascular tone, cell proliferation, inflammatory and immune responses, and permeability is maintained by endothelial cells . The endothelium is also mainly responsible for providing blood circulation within the normo-thrombotic status by several pathways. Antithrombotic factors such as heparin, nitric oxide (NO), and antithrombin are produced by endothelium. In addition, inflammatory markers including interleukins, leukotrienes, and angiogenic growth factors are ordinary secretions of the endothelium. These mediators regulate thrombosis, fibrinolysis, coagulation, and blood flow balances in the vasculature .
Endothelial dysfunction term describes impaired function and integrity of endothelial cells. ED is a common denominator of cardiovascular risk factors such as advanced age, obesity, arterial hypertension, diabetes mellitus, and male gender for being hospitalized due to the severe COVID-19 disease . On one hand, COVID-19 disease may exaggerate existing ED-related diseases, on the other hand, inflammation or direct infiltration of endothelial cells may lead to ED . Subsequently, hypercoagulative status, thrombotic tendency, vasoconstriction, and impaired vascular homeostasis and immunity can occur. Moreover, clinically apparent forms of the ED may include myocardial injury, renal failure, or thromboembolic events. In addition, BMI was found to be a risk factor for ED independent of other provocative factors. It was also reported that obesity increased mortality rate in COVID-19 patients . Increased BMI was associated with ED in the present study. We think that BMI-related ED could be an important cause of higher mortality rate in COVID-19. In addition, endothelial function is affected by the inflammatory response to SARS-CoV-2. And so, an impaired endothelial function might be reflecting the severity of COVID-19 disease. Besides, endothelial function is crucial in the development of subclinical atherosclerosis. Given the result of our study, patients may have atherosclerotic cardiovascular disease in future after the COVID-19 disease.
Endothelial function or dysfunction can be measured by circulating endothelial-based molecules such as NO, soluble thrombomodulin, and endothelin or evaluating functional effects of these products [8, 25]. Endothelium synthesis various molecules in response to chemical or physical stimulus to preserve intravascular homeostasis. Among them, NO is the main substance regulating vascular tone according to the blood flow alterations. FMD is a vasodilatation response, provided by NO, to increased intravascular blood flow causing shear stress. An inflated sphygmomanometer cuff placed around the forearm creates a vasodilator stimulus. Thereafter deflating the cuff leads to reactive hyperemia, increased blood flow and shear stress, and subsequent further dilatation in the brachial artery. Thereby, quantifying the amount of vasodilatation in the brachial artery identifies insufficient NO synthesis from dysfunctional endothelial cells . This non-invasive and cost-effective ultrasonic ED assessment method was firstly described by Celermajer et al in 1992. Later, coronary artery function was found to be correlated with FMD in Anderson et al study. Besides, ED was found to be related to aortic stiffness. Additionally, FMD was confirmed to be associated with ED by numerous trials [27, 28]. In the present study, FMD was found to be related to COVID-19 disease, which is confirming the deteriorated endothelial function after COVID-19 disease.