The endothelium plays an important role in the response to infection. Endothelial cells release soluble substances, chemokines, which attract leucocytes to the infected location and produce cytokines, in turn activating the inflammatory response. Patients with chronic endothelial dysfunction present important alterations in the glycocalyx, intercellular junctions, and endothelial cells, which results in greater leukocyte adhesion and extravasation, as well as leads to a state of hypercoagulability and reduction in the fibrinolytic action. Chronic endothelial dysfunction thus contributes to the development of severe COVID-19.^{8 , 9}

The endothelium is an active organ, which is essential for the regulation of the tonus and the maintenance of vascular homeostasis.¹ In COVID-19, the recruitment of immune cells, be it through direct or immune-mediated viral aggression, can result in a widespread endothelial dysfunction, associated with apoptosis.^{3 , 11 - 13} Post-mortem histological studies have demonstrated a medical picture of lymphocytic endothelialitis in the lungs, heart, kidneys, and liver, as well as cell necrosis and the presence of microthrombi, which aggravate respiratory insufficiency in the lungs.^{1 , 6 , 8 , 9 , 14 , 15}

The endothelium has already been studied in other viral diseases, such as in the human immunodeficiency virus (HIV) and influenza. Much like HIV, SARS-CoV-2 also appears to be directly impacted by endothelial agression.^{13 , 16} Autopsy studies have found evidence of direct viral aggression from SARS-CoV-2 against the endothelial cell, coupled with widespread inflammation.^{1 , 12} Ackermann et al.¹ demonstrated a quantity of microthrombi that is nine times greater in the lungs of COVID-19 patients than in those patients with influenza. In these same lungs, the neo-angiogenesis was also 2.7 times more prevalent in COVID-19 than in influenza.

The idea that subclinical chronic inflammatory states are responsible for the installation of diseases or for their worsening is well-defined in the literature. The association of inflammatory cells and their respective products is well-known in the physiopathology of atherosclerosis, a condition which has a great repercussion upon the endothelium and in the components of the metabolic syndrome (obesity, diabetes mellitus, and hypertension).^{11 , 17}

Although the cardiometabolic disease can begin during childhood, it is in the adult and senile stage that it is more expressively prevalent. In atherosclerosis, as well as in COVID-19, there is a predominance of the T_H1 response, involving the interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and tumor necrosis factor beta (TNF-β), which amplifies the inflammatory response. The IFN-γ is considered to be one of the main pro-atherogenic cytokines, as it activates the macrophages and favors the participation of these in the inflammatory response.^{11 , 12} It thus becomes evident that an amplification in the atherosclerotic process occurs as of a specific immune response, with the production of T_H1 cytokines, such as interleukin-12 (IL-12) and IFN-γ.^{11 , 12}

Since the imbalance in the immune system is present in the physiopathology of CVDs and the metabolic syndrome, people with these diseases, even younger people with incipient atherosclerosis, would be more susceptible to the most severe form of COVID-19, as they already have a hyperactive and uncontrolled immune “terrain”.^{5 , 11 , 18}

Another explanation for cadiometabolic diseases being risk factors for the severe form of COVID-19 involves the recognition receptors of the Toll-Like-4 (TLR4) pathogens, which are molecular members of innate immunity.^{5 , 18} It is well-known that the TLR4 participate in the pathogenesis of the CVDs and metabolic diseases, such as atherosclerosis, diabetes, and obesity. The TLR4 are expressed in different types of cells of the atherosclerotic plaque, and various pro-atherogenic ligands can activate them. The TLR4 are also involved in lipotoxicity and in pancreatic beta cell dysfunction. The hyperextension of the TLR4 can even be genetically codified.^{5 , 18}

Interleukin-6 (IL-6) and TNF-α tend to be higher in the immunopathology of COVID-19. These cytokines are products of the activation of TLR4. In a study conducted using computer simulations illustrated that the S protein of SARS-CoV-2 is recognized by the TLR4.⁵ Consequently, individuals with a greater expression of these receptors, once infected by SARS-CoV-2, would suffer greater activation and release of IL-6 and TNF-α, a condition observed in the severe form of COVID-19.

As mentioned above, another probable mechanism responsible for the poor evolution of COVID-19 involves the ACE 2 receptor.¹⁹ The reduction in the ACE 2 activity caused by SARS-CoV-2 direct influences CVDs, as they increase the potential for the deregulation of RAAS and the immune system.^{6 , 20} There is already evidence that the use of medications that block the RAAS, such as ACE 1 inhibitors (ACEI) and angiotensin receptor blockers (ARBs), are not related to the increase in mortality caused by COVID-19, and can even serve as protection factors.^{19 , 21}

Exacerbated inflammatory states culminate in blood stasis, platelet activation, and endothelial dysfunction, raising the probability of episodes of venous and arterial thrombosis. The coagulopathy in severe COVID-19 infection is similar to coagulopathy induced by sepsis, characterized by widespread intravascular coagulation and thrombotic microangiopathy. In addition, one can highlight hypoxemia, secondary to the pulmonary lesion caused by COVID-19, which is a risk factor for thrombosis.^{8 , 9 , 17}

SARS-CoV-2 provokes SARS. In this syndrome, insoluble fibrin accumulates in the alveolar space. It can be said that the fibrinogen flows out of the plasma due to an increase in the vascular permeability and the widespread alveolar damage, with its incomplete elimination due to a state of hypofibrinolysis. Chronically, this insoluble fibrin contributes to pulmonary fibrosis and its negative repercussions.^{8 , 9 , 15 , 17}

The main alterations in the coagulation present in COVID-19 are: rise in the D-dimer, fibrogen, and time of prothrombin, as well as a reduction in fibrinolysis. The platelet count can be reduced in the more advanced stages of the disease, and is a predictive factor of mortality.^{8 , 9 , 15 , 17} The increase in the risk of thrombosis also occurs in the arteries and different clinical manifestations can appear, including: cerebrovascular accident, mesenteric ischemia, acute infarction of the myocardium, and arterial occlusion of the lower limbs, depending on the affected arterial bed.²² Corroborating with the hypothesis of vascular aggression, some cases with features of toxic shock or pediatric multisystemic inflammatory syndrome similar to the Kawasaki disease have been described and related to COVID-19.²⁰

Considering that put forth above, it is possible to highlight the importance of the strict control of cardiometabolic risk factors.⁵ The aim is to render the endothelium less reactive and less vulnerable to COVID-19. The optimization of the medicinal treatment with the use of anti-diabetic, anti-hypertensive, hypolipidemic (mainly statins), and anti-platelet (such as acetyl salicylic acid) medications can stabilize the endothelium.^{5 , 20 , 23} Drugs, such as ACEI and ARB, seem to be essential in the reduction of the risk of severe outcomes caused by COVID-19, since it helps to balance the RAAS.¹⁹ Regarding to the SARS-CoV-2, to date, no specific treatment has been proven to be effective in the fight against the virus. The therapeutic strategy has been based on the early recognition of the complications in the optimized support to alleviate the symptoms ( Figure 2 ).

Figure 2

In the hyperinflammatory stage of COVID-19, the medications that inhibit or reduce the effects of the pro-inflammatory cytokines are quite pertinent and should be taken into consideration. The IL-6 inhibitors, as well as the glucocorticoids, can avoid or lessen the storm of cytokines.²³ New modulator medications of the inflammatory response are key in this stage to avoid excessive inflammation, which intensely attacks the endothelium and the diverse organs and can result in multiple organ failure and even death.

Regarding to venous thromboembolism, hospitalized patients should receive pharmacological thromboprophylaxis with heparin in a low molecular weight or fondaparinux (preferably unfractionated heparin), unless the risk of bleeding exceeds the risk of thrombosis, in which case, mechanical prophylaxis should be applied.^{8 , 9 , 15 , 17} The adjustment in the heparin dose according to the body mass index (BMI), together with the clearance of creatinine, is recommended.^{8 , 15} Full heparinization is recommended in cases in which there is a strong clinic suspicion or confirmation of venous thromboembolism.^{8 , 15}

Heparin is a medication that is widely used in medicine because of its anti-coagulant action and its anti-inflammatory effect. However, in COVID-19, in addition to these effects, studies have suggested the use of heparin as a way to hinder viral replication. SARS-CoV-2 connects to the ECA2 receptor in order to penetrate the human cell and multiply. It is believed that, to achieve this link, the virus also needs to connect to the heparan sulfate, among other sites, present in the endothelial membrane. The use of heparin has been suggested as a strategy of connection to heparan sulfate, hindering the connection of SARS-CoV-2 to the ECA2 receptor, thus diminishing viral replication.²⁴