ABC | Volume 114, Nº6, June 2020

Review Article Figueiredo Neto et al. Coronavirus and Myocardium Arq Bras Cardiol. 2020; 114(6):1051-1057 were not present in cardiomyocytes, but only insidemacrophages in the cardiac interstice. Another hypothetical mechanism behind direct viral myocardial injury is due to infection-mediated vasculitis. The ACE-2 receptor is highly expressed in arteries and endothelial veins. 47 There are pathological data on SARS-CoV-1, showing evidence of vasculitis with the infiltration of monocytes and lymphocytes, as well as endothelial cell injury in the heart. 48 Direct viral entry in endothelial cells of the myocardium can trigger vasculitis, or the presence of the virus can lead to an indirect immunological response and consequent reaction of hypersensitivity. 49,50 This injury would be associated with myocardial injury and perhaps also with the myocardial dysfunction that is evident in COVID-19. Even though ACE-2 is only slightly expressed in cardiomyocytes, it is highly expressed in pericytes. COVID-19 may attack pericytes, which are essential to endothelial stability, thus causing endotelial dysfunction, which leads to microcirculatory disorders. This explains why COVID-19 may cause cardiac injury, even though ACE-2 is only slightly expressed in cardiomyocytes. 51 Autopsies have shown inflammatory infiltrates composed of macrophages and, to a lesser extent, T and CD4 + cells. 52,53 These mononuclear infiltrates are associated with areas of cardiomyocyte necrosis, which, according to the Dallas criteria, define myocarditis. 54 Real-time PCR analyses of post-mortem cardiac tissue from the SARS-CoV-1 epidemic detected the viral genome in 35% of patients who died of SARS-CoV-1. It is important to note that these hearts also showed decreased levels of ACE-2 and increased hypertrophy. 44 Observing these data together, it is still not clear towhat extent cardiac injury is attributable to direct viral infection versus indirect toxicity due to systemic infection. Furthermore, it has yet to be defined which cell populations in the myocardium are most vulnerable to infections and/or systemic inflammation. Levels of expression of ACE-2 may be important, but the implications of such differences are still debatable. Inciardi et al. 55 described a patient with COVID-19 who presented with fatigue, increased troponin, increased BNP, electrocardiographic changes, changes in segmental contraction, pericardial effusion, and left ventricular dysfunction on echocardiogram, with normal coronary angiography approximately one week after having presented fever and dry cough; magnetic resonance demonstrated biventricular myocardial interstitial edema, and diffuse late gadolinium enhancement suggesting diagnosis of myocarditis. The patient required inotropic support, and she showed clinical and laboratorial improvement after one week after treatment. Hu et al. 56 described a patient with chest pain and dyspnea for three days, as well as increased troponin and BNP, electrocardiographic changes, changes in segmental contraction, pericardial effusion, and left ventricular dysfunction, with normal coronary angiography. Upon admission, he had hypotension with clinical picture suggestive of fulminant myocarditis. He was treated with hemodynamic support (vasopressor and inotropic drugs) andmethylprednisolone associatedwith human immunoglobulin. After three weeks of treatment, the patient evolved with complete recovery of ventricular function and normalized markers of myocardial injury. In short, it seems clear that there is an association between the presence of myocardial injury, identified by increased troponin, and worse prognosis in patients with COVID-19. In relation to diagnosis of myocarditis, as defined by elevated markers, associated with a suggestive clinical picture and compatible alterations on cardiac imaging exams, some case reports have been described in patients with COVID-19, but without biopsy data confirming the cause of myocarditis. In this manner, considering that SARS-CoV-1 and SARS- CoV-2 infect cells through ACE-2, a membrane protein present in myocardial cells, it is possible that this mechanism is also responsible formyocarditis in patients diagnosedwithCOVID-19. However, more evidence is needed to prove this association. Conclusion Myocardial and pericardial involvement (strokes/pericarditis) is common in severe phases of COVID-19. Acute myocardial involvement has been described as acute cardiac injury, induced by a possible “inflammatory cytokine storm,” which may or may not cause cardiomyocyte necrosis. Rare cases of mild inflammatory infiltrate and the presence of the virus in inflammatory cells of the cardiac interstice and the endothelial cells of coronarymicrocirculation have been precisely described, confirming the real histological presence of viral myocarditis, but, to date, the coronavirus has not been described inside the cardiomyocyte. The state of adrenergic response and myocardial inflammation may explain the occurrence of the phenotypic pattern of takotsubo syndrome. In summary, high degree of clinical suspicion, characterized by chest pain, hemodynamic changes and/or changes in ST/Te arrhythmias (ECG), associated with morphofunctional abnormalities in cardiac imaging methods, and increased cardiac troponin, represent the pillars of clinical reasoning for the presence of acute myocardial aggression in the current coronavirus pandemic. Furthermore, cardiac monitoring has become necessary for these patients, given that, in light of the current knowledge, we do not know whether or not they may progress with late myocardial dysfunction. Author contributions Conception and design of the research, Analysis and interpretation of the data, Writing of the manuscript and Critical revision of the manuscript for intellectual content: Figueiredo Neto JA, Marcondes F, Moura L, Rocha RM, Mesquita ET; Data acquisition: Figueiredo Neto JA, Marcondes F, Moura L, Figueiredo AMS, Figueiredo VMS, Rocha RM, Mesquita ET. Potential Conflict of Interest The authors report no conflict of interest concerning the materials andmethods used in this study or the findings specified in this paper. 1055