ABC | Volume 114, Nº6, June 2020

Review Article Figueiredo Neto et al. Coronavirus and Myocardium Arq Bras Cardiol. 2020; 114(6):1051-1057 inflammatory response. Initial reports demonstrate that extremely high levels of inflammatory biomarkers and cytokines, IL-6, C-reactive protein, TNF- α , interleukin-2R (IL-2R), and ferritin were associated with more severe manifestations of COVID-19 and worst outcomes. 20 Several studies have demonstrated that cardiomyopathy in sepsis is partially mediated by inflammatory cytokines such as TNF- α , IL-6, IL-1 β , INF- γ , and IL-2. 21,22 Cultivated rat cardiomyocytes demonstrated reduced contractility when exposed to IL-6. The mechanism may be through modulated calcium channel activity with resulting myocardial dysfunction. 23 It is furthermore believed that nitric oxide is a mediator of myocardial depression in states of intense inflammation, such as sepsis. 24 More recently, observation of the role of mitochondrial dysfunction in septic states raised questions concerning the role of this entity in cardiomyopathy associated with sepsis. 25 Patients with more severe forms of COVID-19 have multiple organ dysfunction with cytokine storms and immune dysregulation, which are likely mechanisms involved in the myocardial injury observed in these patients. 26 Stress cardiomyopathy The role of stress cardiomyopathy (takotsubo syndrome) in cardiac injury related to COVID-19 is still not well known, and there are few reports to date. 27-29 It is, however, believed that several of the proposed mechanisms for cardiac injury related to COVID-19 that are detailed in this review are implicated in the pathophysiology of stress cardiomyopathy, especially microvascular dysfunction, cytokine storm, and sympathetic increase. 30 The intense emotional stress and the respiratory infections caused by COVID-19 may represent potential triggers in this context. It is possible that stress cardiomyopathy may also play a significant role in the COVID-19 pandemic. Non-obstructive acute coronary syndrome Patients with COVID-19 may have more classical signs and symptoms of ACS, such as chest pain and electrocardiographic changes suggestive of myocardial ischemia or acute myocardial infarction, making this differential diagnosis difficult. 31 The data published to date do not explain the incidence of ACS due to epicardial plaque rupture, as a mechanism for the cardiac injury observed in COVID-19. Nonetheless, existing acquired knowledge demonstrates the association between infection and increased risk of ACS. Epidemiological studies have demonstrated that hospitalization due to pneumonia is associated with increased risk of atherosclerotic events. 32 Studies evaluating influenza infection have demonstrated a temporal association between cardiovascular complications and ACS, and annual vaccination against influenza was associated with a 36% decrease inmajor adverse cardiovascular events in a meta-analysis of clinical trials evaluating this question. 33,34 In this manner, viral infection is associated with an increased risk of coronary events, and prevention is associated with reduced risk. It is, therefore, plausible that ACS is also an important cause of acute cardiac injury in patients with COVID-19. There are several possible pathophysiological mechanisms whereby systemic viral infection (by influenza or SARS-CoV-2, for example) can lead to an increased risk of plaque destabilization and ACS. The role of inflammation in the development and progression of atherosclerosis is well established. 35-38  The immune response to acute viral infection and the concomitant increase in cytokines and inflammatory mediators present in COVID-19 can lead to localized arterial inflammation, which may be more pronounced in coronary plaque. 39 The entrance of viral products into systemic circulation, also known as pathogen-associated molecular patterns (PAMP), can lead to innate activation of the immune receptor, in turn leading to activation of immune cells residing in pre-existing atheroma, which may cause plaque rupture; furthermore, viral PAMP can activate the inflammasome, promoting conversion of pro-cytokines to biologically active cytokines. 40,41 Finally, endothelial dysfunction resulting from infection and inflammation may lead to vessel constriction, with decreased coronary flow. 42 All of these physiopathological alterations present in COVID-19 can lead to destabilization of pre-existing atherosclerotic plaque, thus triggering an acute coronary event. Direct viral myocardial injury Reports of cases of myocarditis in COVID-19 provide evidence of cardiac inflammation, but they do not determine the mechanism. One of the proposed mechanisms behind the myocardial injury observed in COVID-19 is direct viral infection of the heart, with resulting myocarditis. In fact, the human myocardium expresses the receptor used by COVID-19 to infect host cells, namely, ACE-2. Thus, without a doubt, in some cases, viral myocarditis may occur due to this agent. The increase in troponin, however, appears to be omnipresent in patients who require intensive care, an indication of cardiac involvement, which is a marker of poor prognosis in many cases, as in many other circumstances. 41 A murine model of lung infection, demonstrated with SARS- CoV-1, also precipitatedmyocardial infection dependent onACE- 2 42-43 . In human beings, during the SARS outbreak in Toronto, RNA of the SARS-CoV-1 virus was detected in 35% of autopsied hearts. 1 This increases the likelihood of direct viral damage to cardiomyocytes. 44 In view of the host cell input receptor shared by SARS-CoV-1 and SARS-CoV-2, direct viral myocardial entry and the resulting injury is also plausible with SARS-CoV-2. SARS-CoV-2may share the samemechanismwith SARS-CoV-1, given that the two viruses have highly homologous genomes. 45,46 To date, we have only one report of viral myocarditis due to SARS-CoV-2 confirmed by biopsy, with viral inclusions of viral DNA detected in myocardial tissue. 46 Viral particles, however, 1054