Intensive cardiac care unit admission trends during the COVID-19 outbreak in Italy: a multi-center study.

A significant decline in the admission to intensive cardiac care unit (ICCU) has been noted in Italy during the COVID-19 outbreak. Previous studies have provided data on clinical features and outcome of these patients, but information is still incomplete. In this multicenter study conducted in six ICCUs, we enrolled consecutive adult patients admitted to ICCU in three specific time intervals: from February 8 to March 9, 2020 [before national lockdown (pre-LD)], from March 10 to April 9, 2020 [during the first period of national lockdown (in-LD)] and from May 18 to June 17, 2020 [soon after the end of all containment measures (after-LD)]. Compared to pre-LD, in-LD was associated with a significant drop in the admission to ICCU for all causes (- 35%) and acute coronary syndrome (ACS; - 49%), with a rebound soon after-LD. The in-LD reduction was greater for women (- 49%) and NSTEMI (- 61%) compared to men (- 28%) and STEMI (- 33%). Length-of-stay, and in-hospital mortality did not show any significant change from to pre-LD to in-LD in the whole population as well as in the ACS group. This study confirms a notable reduction in the admissions to ICCUs from pre-LD to in-LD followed by an increment in the admission rates after-LD. These data strongly suggest that people, particularly women and patients with NSTEMI, are reluctant to seek medical care during lockdown, possibly due to the fear of viral infection. Such a phenomenon, however, was not associated with a rise in mortality among patients who get hospitalization.

COVID-19: ACE2centric Infective Disease?

Diffuse pulmonary inflammation, endothelial inflammation, and enhanced thrombosis are cardinal features of coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2. These features are reminiscent of several adverse reactions triggered by angiotensin II and opposed by angiotensin1-7, in many experimental models. Severe acute respiratory syndrome coronavirus 2 binds to ACE2 (angiotensin-converting enzyme 2) receptors and entries into the cell through the fusion of its membrane with that of the cell. Hence, it downregulates these receptors. The loss of ACE2 receptor activity from the external site of the membrane will lead to less angiotensin II inactivation and less generation of antiotensin1-7. In various experimental models of lung injury, the imbalance between angiotensin II overactivity and of antiotensin1-7 deficiency triggered inflammation, thrombosis, and other adverse reactions. In COVID-19, such imbalance could play an important role in influencing the clinical picture and outcome of the disease. According to this line of thinking, some therapeutic approaches including recombinant ACE2, exogenous angiotensin1-7, and angiotensin receptor blockers seem particularly promising and are being actively tested.

[ACE-inhibitors, angiotensin receptor blockers and severe acute respiratory syndrome caused by coronavirus]. / ACE-inibitori, sartani e sindrome respiratoria acuta da coronavirus 2.

Some Authors recently suggested that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) should be discontinued, even temporarily, given the current pandemic of SARS-CoV-2 virus. The suggestion is based on the hypothesis that ACE-inhibitors and ARBs may favor the entry and diffusion of SARS-CoV-2 virus into the human cells. ACE-inhibitors and ARBs may increase the expression of ACE2 receptors, which are the sites of viral entry into the human organism. ACE2 receptors are ubiquitous, although they are extremely abundant on the cell surface of type 2 pneumocytes. Type 2 pneumocytes are small cylindrical alveolar cells located in close vicinity to pulmonary capillaries and responsible for the synthesis of alveolar surfactant, which is known to facilitate gas exchanges. The increased expression of ACE2 for effect of ACE-inhibitors and ARBs can be detected by increased production of angiotensin1-7 and mRNA related to ACE2. There is the fear that the increased expression of ACE2 induced by ACE-inhibitors and ARBs may ultimately facilitate the entry and diffusion of the SARS-CoV-2 virus. However, there is no clinical evidence to support this hypothesis. Furthermore, available data are conflicting and some counter-intuitive findings suggest that ARBs may be beneficial, not harmful. Indeed, studies conducted in different laboratories demonstrated that ACE2 receptors show a down-regulation (i.e. the opposite of what would happen with ACE-inhibitors and ARBs) for effect of their interaction with the virus. In animal studies, down-regulation of ACE2 has been found as prevalent in the pulmonary areas infected by virus, but not in the surrounding areas. In these studies, virus-induced ACE2 down-regulation would lead to a reduced formation of angiotensin1-7 (because ACE2 degrades angiotensin II into angiotensin1-7) with consequent accumulation of angiotensin II. The excess angiotensin II would favor pulmonary edema and inflammation, a phenomenon directly associated with angiotensin II levels, along with worsening in pulmonary function. Such detrimental effects have been blocked by ARBs in experimental models. In the light of the above considerations, it is reasonable to conclude that the suggestion to discontinue ACE-inhibitors or ARBs in all patients with the aim of preventing or limiting the diffusion of SARS-CoV-2 virus is not based on clinical evidence. Conversely, experimental studies suggest that ARBs might be useful in these patients to limit pulmonary damage through the inhibition of type 1 angiotensin II receptors. Controlled clinical studies in this area are eagerly awaited. This review discusses facts and theories on the potential impact of ACE-inhibitors and ARBs in the setting of the SARS-CoV-2 pandemic.

The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.

Angiotensin converting enzyme-2 (ACE2) receptors mediate the entry into the cell of three strains of coronavirus: SARS-CoV, NL63 and SARS-CoV-2. ACE2 receptors are ubiquitous and widely expressed in the heart, vessels, gut, lung (particularly in type 2 pneumocytes and macrophages), kidney, testis and brain. ACE2 is mostly bound to cell membranes and only scarcely present in the circulation in a soluble form. An important salutary function of membrane-bound and soluble ACE2 is the degradation of angiotensin II to angiotensin1-7. Consequently, ACE2 receptors limit several detrimental effects resulting from binding of angiotensin II to AT1 receptors, which include vasoconstriction, enhanced inflammation and thrombosis. The increased generation of angiotensin1-7 also triggers counter-regulatory protective effects through binding to G-protein coupled Mas receptors. Unfortunately, the entry of SARS-CoV2 into the cells through membrane fusion markedly down-regulates ACE2 receptors, with loss of the catalytic effect of these receptors at the external site of the membrane. Increased pulmonary inflammation and coagulation have been reported as unwanted effects of enhanced and unopposed angiotensin II effects via the ACE→Angiotensin II→AT1 receptor axis. Clinical reports of patients infected with SARS-CoV-2 show that several features associated with infection and severity of the disease (i.e., older age, hypertension, diabetes, cardiovascular disease) share a variable degree of ACE2 deficiency. We suggest that ACE2 down-regulation induced by viral invasion may be especially detrimental in people with baseline ACE2 deficiency associated with the above conditions. The additional ACE2 deficiency after viral invasion might amplify the dysregulation between the 'adverse' ACE→Angiotensin II→AT1 receptor axis and the 'protective' ACE2→Angiotensin1-7→Mas receptor axis. In the lungs, such dysregulation would favor the progression of inflammatory and thrombotic processes triggered by local angiotensin II hyperactivity unopposed by angiotensin1-7. In this setting, recombinant ACE2, angiotensin1-7 and angiotensin II type 1 receptor blockers could be promising therapeutic approaches in patients with SARS-CoV-2 infection.