key: cord-0774175-xb7a4f6y
authors: Canale, Maria Paola; Menghini, Rossella; Martelli, Eugenio; Federici, Massimo
title: COVID-19 Associated Endothelial Dysfunction and Microvascular Injury: from Pathophysiology to Clinical Manifestations.
date: 2021-10-30
journal: Card Electrophysiol Clin
DOI: 10.1016/j.ccep.2021.10.003
sha: 688c28e15582676027715c7c789d8f9226dab33b
doc_id: 774175
cord_uid: xb7a4f6y

Coronavirus-19 disease (COVID-19) affects more people than previous coronavirus infections, namely Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) and has a higher mortality. Higher incidence and mortality can probably be explained by COVID -19 causative agent greater affinity (about 10-20 times) for angiotensin-converting enzyme-2 (ACE-2) receptor compared to other coronaviruses. Here, we first summarize clinical manifestations, then present symptoms of COVID-19 and the pathophysiological mechanisms underlying specific organ/system disease. Endothelial cells activated by a hyperinflammatory state induced by viral infection may promote localized inflammation, increase reactive oxidative species (ROS) production and alter dynamic interplay between the procoagulant and fibrinolytic factors in the vascular system, leading to thrombotic disease not only in the pulmonary circulation but also in peripheral veins and arteries. In this context, the worse clinical outcome observed in COVID-19 patients with diabetes may be in part related to the increased ADAM17 activity and its unbalanced interplay with ACE2. Therefore, strategies aimed to inhibit ADAM17 activity may be explored to develop new effective therapeutic approaches.

Coronavirus-19 disease (COVID-19) affects more people than previous coronavirus infections, namely Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) and has a higher mortality. Higher incidence and mortality can probably be explained by causative agent greater affinity (about 10-20 times) for angiotensin-converting enzyme-2 (ACE-2) receptor compared to other coronaviruses (1, 2) . According to the World Health Organization (WHO) recent data "there have been 199.466.211 confirmed cases of COVID-19, including 4.244.541 deaths" (source: WHO data, August 4, 2021) . In the same way to SARS and MERS, it affects the respiratory system. Nevertheless, due to the viral rapid diffusion and the increased numbers of infected people, many extra-respiratory system manifestations have been documented (3) (4) (5) .

Severe symptoms result from hyper-inflammatory response, which in turn causes systemic cytokine release and endothelial damage and several clinical and laboratory findings support the role of endothelial dysfunction in the pathophysiology of disease, suggesting that the endothelium may represent an attractive target for new treatments (6) .

In this review, we first summarize clinical manifestations, then present symptoms of COVID-19 and the pathophysiological mechanisms underlying specific organ/system disease. After, we review current understanding of key pathophysiological mechanisms with particular regard to the role of endothelial dysfunction, microvascular injury, and systemic inflammatory response in disease progression and severity. Finally, we illustrate possible novel mechanisms and treatments aimed at protecting the endothelium.

COVID-19 transmission mainly occurs directly via respiratory and saliva droplets from person to person. Indirect transmission, through fomites, may also occur. Airborne transmission only occurs J o u r n a l P r e -p r o o f when procedures generate aerosol. Incubation period is usually less than one week (about 5-6 days) but may last longer up to two weeks. Initial symptoms are non-specific and similarly to other virosis like influenza: fatigue, myalgias, dry cough and low-grade fever (7) . Symptoms improve in the majority of cases or progress to dyspnea in fewer ones (3) . Zeng et al. reviewed the symptomatology of COVID-19: the commonest signs/symptoms were fever (90%), cough (68%) followed by dyspnea (22%), headache (12%) and sore throat (14%). Diarrhea was present in only about 4% of patients.

Mean duration of fever in survivors is about 12 days, whereas cough mean duration is slightly longer (19 days) (8) . Although fever is a very common finding, its absence does not rule out the diagnosis (9) . Longer duration of fever is proportionate to disease's severity (31 days for patients admitted to the intensive care unit versus 9 days for those hospitalized in a different setting) (10). As above mentioned, in about one-fifth of patient disease progresses to dyspnea (3, 7) . Rapid progression to respiratory failure requiring non-invasive and invasive ventilation may occur. Viral respiratory invasion alone is insufficient to explain these findings. Endothelial dysfunction, subsequent inflammation, and lung injury with diffuse alveolar damage leading in some cases to acute distress respiratory syndrome is the underlying pathophysiological mechanism responsible for respiratory failure (7) . Patients may experience other clinical features strongly suggestive of endothelial dysfunction and microvascular thrombosis. Pain, warmth and localized limb swelling are consistent with deep venous thrombosis and acute onset tachycardia, dyspnea and chest pain strongly suggest pulmonary embolism (5) . COVID-19 is characterized by a wide spectrum of clinical severity. Asymptomatic persons experience no symptoms, have normal chest X-rays but play an important role in disease transmission to others.

Mild illness is characterized by general symptoms common to other virosis, gastrointestinal symptoms may be present too (abdominal pain, nausea, vomiting, and diarrhea). In moderate illness, symptoms of pneumonia are present with still normal blood gases, and interstitial groundglass opacities appear on high resolution CT scan. Severe illness is characterized by pneumonia with hypoxemia (peripheral oxygen saturation is less than 92% in ambient air). Finally, critical state is J o u r n a l P r e -p r o o f characterized by the presence of acute distress respiratory syndrome, coagulation disorders, cardiac failure, acute renal injury and shock (7, 9, (12) (13) (14) (15) (16) (17) . Patients with comorbidities have a worse disease course and prognosis compared to healthy ones, as observed in previous coronavirus infections (1).

Advanced age, male sex, diabetes, hypertension, ischemic heart disease, cancer, chronic obstructive pulmonary disease, and chronic renal insufficiency are risk factors for developing a severe form of COVID-19 (18) (19) (20) . These conditions affect negatively patient's immune system (1, 21) .

A full description of the COVID-19 treatment by organ/system involvement is beyond the scope of this review. Most suitable treatment should be prescribed depending on disease's severity and organ involvement. At the present time, treatment encompasses oxygen (when required), symptomatic, anti-inflammatory, antiviral, anticoagulant drugs (prophylactic or therapeutic, with low molecular weight heparin) and monoclonal antibodies. Moreover, in selected patients resistant to treatment, plasma exchange therapy and immunomodulatory medications may be required (7).

Updated COVID-19 treatment guidelines by disease's severity are provided by national and international institutions at their web sites. Finally, major concern has been raised about the use of renin-angiotensin blocking agents in COVID-19 patients. Routine discontinuation is not recommended by the guidelines of international cardiology societies (22, 23) .

The COVID-19 clinical manifestations by organ/system and the underlying pathophysiological mechanisms of disease are summarized in Tables 1, 2 reactive oxidative species (ROS) production and alter dynamic interplay between the procoagulant and fibrinolytic factors in the vascular system, leading to thrombotic disease not only in the pulmonary circulation but also in peripheral veins and arteries (29) . It was proposed that mitochondrial dysfunction and oxidative stress, induced by viral infection can initiate a feedback loop promoting a chronic state of inflammatory cytokine production and endothelial alteration even after the viral particles have been eliminated from the body (30) . Agents that limit endothelial dysfunction may mitigate the pro-inflammatory and prothrombotic state induced by COVID-19

infection, therefore targeted inhibition of cytokines, major effectors of endothelial activation, represents a more focused approach than generalized anti-inflammatory agents. Some clinical trials J o u r n a l P r e -p r o o f that use strategies aimed to have inhibit the inflammasome-IL-1-IL-6 pathway already yielded preliminary results; some, but not all, indicate signals of efficacy being a critical aspect the maintaining of the balance between the potential benefits versus the potential of lowering immunological defences (24) .

to a superfamily of Zn dependent metalloproteases. ADAM17 plays a key role in the regulation of the proteolytic release from cellular membranes of some cytokines, chemokines, growth factors and their receptors, affecting downstream signalling and cellular responses. Increased ADAM17mediated shedding has been described in a variety of diseases such as ischemia, heart failure, arthritis, atherosclerosis, diabetes, cancer, neurological and immune diseases. Tissue Inhibitor of Metalloproteinase 3 (TIMP3), a key endogenous inhibitor involved in regulation of the activity of Matrix Metalloproteinases (MMPs) and ADAMs, is the only known physiological inhibitor of ADAM17. Previous reports have implicated the ADAM17/TIMP3 dyad as a mediator between metabolic stimuli, inflammation and innate immunity (31) . The increased activity of ADAM17 has been correlated with increased insulin resistance and hyperglycemia. Furthermore, the upregulation of ADAM17 activity increased insulin receptor resistance in patients with type 2 diabetes (32) . Several data support the involvement of an increased activity of ADAM17 in both COVID-19`s comorbidities and SARS-CoV-2 infection. In fact, the ADAM17 up-regulation leads to the ACE2 ectodomain proteolytic cleavage, facilitating viral entry, and to the cleavage of TNF-a and IL6R and other pro-inflammatory molecules, contributing to the "cytokine storm" and reinforcing the inflammatory process during SARS-CoV-2 infection. This hyper-inflammatory state has deleterious effects on the vascular system with resulting EC dysfunction and not only affects local endothelial J o u r n a l P r e -p r o o f function but can also provoke a prothrombotic and antifibrinolytic imbalance in blood that favours thrombus accumulation (33) . Coagulation abnormalities and disruption of factors released by endothelial cells represent also the common pathophysiological link between SARS-CoV-2 infection and the cardiovascular events, including acute cardiac injury, stroke, heart failure, arrhythmias, and cardiomyopathies. In particular, the molecular interaction of SARS-CoV-2 with the ACE2 receptor located in the endothelial cell surface, either at the pulmonary and systemic level, leads to early impairment of endothelial function, which, in turn, is followed by vascular inflammation and thrombosis of peripheral blood vessels (34) .

In this context, the worse clinical outcome observed in COVID-19 patients with diabetes may be in part related to the increased ADAM17 activity and its unbalanced interplay with ACE2. Therefore, strategies aimed to inhibit ADAM17 activity may be explored to develop new effective therapeutic approaches.

In the last two years a great progress had been made to provide mechanisms explaining how Sars- 

Pulmonary and Extra-Pulmonary Clinical Manifestations of COVID-19

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The role of ADAM17 in metabolic inflammation

Decreased IRS2 and TIMP3 expression in monocytes from offspring of type 2 diabetic patients is correlated with insulin resistance and increased intima-media thickness

ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19

The Contribution of Endothelial Dysfunction in Systemic Injury Subsequent to SARS-Cov-2 Infection

J o u r n a l P r e -p r o o f TABLES Table 1 

Clinical manifestations (references [1] [2] [3] [4] [5] Pathophysiological mechanisms (references 1-5 Respiratory Pneumonia Acute respiratory distress syndrome Microvascular lung thrombosis Respiratory failure

Direct viral injury and inflammation Endothelial dysfunction -pro-inflammatory -pro-coagulant -pro-aggregating -capillary leakage -increased vascular permeability Systemic inflammatory response ("cytokine storm")

Myocarditis/pericarditis Arrhythmias Right or/and left heart failure Acute coronary syndrome Cardiogenic shock

Direct viral injury and inflammation Endothelial dysfunction -pro-inflammatory -pro-coagulant High ACE2 levels Systemic inflammatory response ("cytokine storm") Hypoxemia Oxygen supply mismatch Arterial Large vessel occlusion: clinical presentation depending on the affected artery (cerebral, cardiac, mesenteric, renal, limb) Central nervous system vasculitis

Direct viral injury Endothelial dysfunction -pro-inflammatory -pro-coagulant -pro-aggregating Hypoxia.J o u r n a l P r e -p r o o f