Pathogenesis of SARS-CoV-2 induced cardiac injury from the perspective of the virus.

The association between infection and cardiovascular disease has long been recognized in the form of Chagas Disease, Diptheria, tuberculous pericarditis, viral myocarditis, and others. Almost any infectious pathogen can cause myocarditis or heart disease [1]. Viral infection has been and is a predominant cause of myocarditis in the developed world, but viruses can also cause disease without the typical cellular inflammatory disease. During the influenza pandemic of 1918, a large number of patients had evidence of heart damage on autopsy [2]. Myocarditis was found in over 50% of patients who died of poliomyelitis infection during the years 1942–1951 [3,4]. Myocarditis has also been associated with outbreaks of mumps [5], measles [6], and enterovirus pleurodynia [7] before 1960. Association of Coxsackievirus with myocarditis has been recognized since at least the 1950s [8,9]. It has been demonstrated that viral infection can affect the heart by direct infection of cardiovascular organs and cells and is usually accompanied by a potent immune response. It is often challenging to determine the contribution of direct infection as compared to the immune response in viral-mediated cardiovascular disease since they frequently overlap. A world pandemic has now turned attention to a novel viral infection, SARS-CoV-2, that primarily causes severe acute respiratory disease. However, the disease can be complicated by multiple cardiovascular abnormalities that are markers of a poor prognosis and most likely contribute directly to the severity of the disease. A better understanding of interactions between the virus and the host will ultimately guide the diagnosis and treatment of both pulmonary and cardiovascular complications seen in patients and ultimately contribute to the design of vaccines and other preventive strategies. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). It was identified in Wuhan, China, as the cause of an outbreak of acute respiratory distress syndrome (ARDS). At the time of writing, worldwide, there have been over 19 million confirmed cases and over 720,000 deaths caused by the virus [10]. The predominant manifestation of COVID-19 is ARDS. However, infection with SARS-CoV-2 is associated with multiple cardiac manifestations. These include: cardiac injury of uncertain etiology [11], and a thrombotic disease that may manifest as deep-vein thrombosis, pulmonary embolism, stroke, and peripheral arterial disease [12]. There is also growing evidence of an endothelial dysfunction that affects small vessels [13,14]. Recently, a form of Kawasaki disease, termed Multisystem Inflammatory Syndrome in Children (MIS-C), has been described in younger patients infected with SARS-CoV-2 [15]. MIS-C appears to have a direct effect on the vasculature and can be associated with cardiac dysfunction. While the associations between SARS-CoV-2 and the cardiovascular manifestations are clear, there is limited data that addresses how infection with SARS-CoV-2 affects the cardiovascular system. By understanding the molecular pathways involved in virus replication, one can begin to understand how the virus may directly affect the host [1,[16], [17], [18]]. Activation of a potent immune response, both innate and adaptive, can actively inhibit viral infection, but can also damage the infected cell and adjacent cells [19]. It has been demonstrated in animal models of viral myocarditis that inhibition of innate immune mechanisms may be detrimental to the host by reducing the host antiviral immune response to virus infection and allowing unrestrained replication of the virus [20,21]. However, inhibition of the immune response has the potential to decrease immune mediated cytopathic effects. Maintaining the proper balance is crucial when using immunomodulators to treat viral infections. A study of the viral life-cycle provides insight into viral tropism by understanding viral receptors and entry mechanisms. Direct cardiotoxic effects may involve the expression of virally encoded proteins such as viral proteases. Viral RNA-dependent, RNA-polymerases are crucial in the replication of the viral genome and, thus, the extent of viral-induced damage. Inhibition of mechanisms required for efficient viral replication is the primary clinical strategy for treating viruses such as HIV, Hepatitis B and C, influenza, and others [22,23].