Section 4: Viral Toxicity and Myocardial Injury in COVID-2 (from DOI: 10.1007/s11886-020-01292-3)
From publication: "Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response" published as Curr Cardiol Rep; 2020 04 21 ; 22 (5) 32. DOI: https://doi.org/10.1007/s11886-020-01292-3
Section 4: Viral Toxicity and Myocardial Injury in COVID-2
Myocardial injury, manifesting as elevated serum troponin levels, has been described in many patients infected with COVID-19, and mortality has been associated with increase in troponin levels > 99th percentile of the upper limit of normal and with electrocardiographic and echocardiographic abnormalities . In addition, reports of the rarer manifestation of fulminant myocarditis with markedly elevated troponin levels have been reported .
There are several thoughts on the mechanism of injury, including direct myocardial injury by the virus through ACE2 entry, hypoxia-induced myocardial injury, microvascular damage and endothelial shedding, and cytokine/inflammation-mediated damage . Direct viral toxicity on cardiomyocytes has occurred in the setting of other viral infections such as coxsackievirus-induced myocarditis. In this case, the entry of the coxsackievirus is through the coxsackievirus and adenovirus receptor (CAR) and through release of protease 2A coded by coxsackievirus particles, disrupting the dystrophin cytoskeleton complex. In the case of coronavirus, as mentioned above, the spike (S) protein of coronaviruses facilitates viral entry into target cells. Entry depends on binding of the surface unit, S1, of the S protein to ACE2, allowing the virus to attach to the surface of the target cell. In addition, entry requires S protein priming by cellular proteases, which entails S protein cleavage at the S1/S2 and S2' site and allows fusion of viral and cellular membranes, a process driven by the S2 subunit. It was found that SARS-2-S shares 76% amino acid identity with SARS-S, and both engage ACE2 and employ the cellular serine protease TMPRSS2 for S protein priming for host cell entry. Interestingly, injection of SARS-CoV Spike protein into mice worsened acute lung failure in vivo, and was attenuated by blockade of the renin-angiotensin pathway. Also of note, TMPRSS2 is highly expressed in the lung and kidneys, but is present in only low to moderate levels in the heart and blood vessels, suggesting other mechanisms of injury for the latter organ systems. Lastly, the amount of viral load in SARS-CoV-2 infection correlates with disease severity, with higher viral loads on presentation correlating with worse disease outcomes. This study highlights the potential importance of direct viral toxicity in the pathogenesis of COVID-19 infections.
In addition to direct damage caused by the virus, there has also been speculation of an ischemic effect, either in the form of demand ischemia from lung pathology or direct toxicity by the virus on the macro- or microvascular level. It has been suggested that, because ACE2 is expressed on the endothelium, it may induce endothelial shedding and dysfunction contributing to vascular damage, local inflammation, and production of procoagulant factors predisposing to thrombosis, similar to the increase in myocardial infarctions observed after influenza infections. In addition to endothelial inflammation and dysfunction, an increased incidence of abnormal coagulation parameters and of disseminated intravascular coagulation (DIC) has been noted in patients with SARS-CoV-2 infection, contributing to risk of thrombosis and ischemic events that could damage the myocardium.
