COVID-19–Associated Myocardial Injury

Corresponding Author

A rapidly growing body of published data has documented acute myocardial injury as an uncommon but important sequela of COVID-19 infection and vaccination with COVID-19 messenger RNA (mRNA) vaccines. Increased troponin levels are reported in 15% to 20% of patients admitted to hospital with COVID-19 infection¹ and a strong association between outcome and the magnitude of the increase in troponin levels has been observed;² however, the same pattern may hold true for other patients who are critically unwell. Elevated cardiac injury biomarkers occurring early after COVID-19 mRNA vaccination are reported with an incidence of 1 to 2 per 100,000 and are variably associated with relevant symptoms and imaging abnormalities.³

Demonstration of the association between infection with SARS-CoV-2 or exposure to an mRNA-based vaccine and myocardial injury has stimulated intense interest into its pathophysiologic basis. In contemplating the cause for the cardiac injury, it is timely to consider the distinction between terminologies that are commonly applied in the reports of acute cardiac involvement in COVID-19. Myocardial injury simply refers to the presence of cardiomyocyte cell death, typically detected by a significant increase in troponin levels. Based on the recognition that certain viruses (eg, coxsackie viruses) have the potential to cause myocarditis,⁴ there has often been an assumption that the increase in troponin levels observed in the setting of COVID-19 reflects the presence of an acute inflammatory cardiomyopathy. A definitive diagnosis of myocarditis is based on the histological demonstration of an inflammatory infiltrate within the myocardium usually in association with cardiomyocyte damage and which is not typical of ischemic damage caused by coronary disease. However, it is well appreciated that the diagnosis of myocarditis by endomyocardial biopsy can be challenging both in terms of access to centers with experience in cardiac biopsy and because of the often patchy distribution of myocarditis. As a result, schema have been developed on which to make a diagnosis of myocarditis with varying degrees of likelihood based on imaging, biomarker, and symptomatic grounds. Other than myocarditis, potential causes for myocardial injury occurring in patients with COVID-19 infection include type I or II ischemic injury related to epicardial coronary artery pathology, microvascular obstruction, takotsubo stress cardiomyopathy, acute right heart strain, and a systemic inflammatory response syndrome.

Prior to the report by Altman et al⁵ in this issue of JACC: Basic to Translational Science, the underpinning mechanism(s) for the relationship between COVID-19 and myocardial injury have been largely speculative. The investigators sought to address several key questions in patients with myocardial injury in the setting of COVID infection or mRNA vaccination: 1) Do biomarker/imaging signals relate to the presence of myocarditis? 2) Is the SARS-CoV-2 virion present in the myocardium of patients with COVID-19 infection? and 3) What is the role of the ACE2 receptor in the disease process? Whereas histological evidence of myocarditis was observed in 1 patient, there was no evidence of viral infection in any of the cohort with COVID-19 infection. In patients with evidence of myocardial injury after vaccination, there was no evidence of myocarditis, but microthrombi were observed in 1 patient. Whereas positive histological findings were relatively uncommon in the study cohorts, evidence of myocardial injury was compelling, including major increases in cardiac injury biomarkers supported by extensive changes on cardiac magnetic resonance (CMR) in those who underwent scanning. This apparent disconnect might be explained in several ways. First, changes observed on CMR indicated relatively patchy involvement with reference made to a relative predominance of late gadolinium enhancement being observed in the lateral wall of the left ventricle rather than the interventricular septum or right ventricle. In this context, given that acute left ventricular endomyocardial biopsies were not performed and with inherent biopsy sampling error, it is necessary to concede that histological changes may be more common than was observed in this study. Second, there was some variability in the timing between clinical presentation, troponin peak, imaging, and the performance of cardiac biopsy. As such it is possible that dynamic pathologic changes were missed or alternately that the frequently observed CMR changes relate to residual altered vascular permeability rather than myocardial scarring.

In an effort to understand the molecular basis for the patterns of myocardial injury observed, the investigators studied changes in the expression of ACE2 given its role in the internalization of SARS-CoV-2 viral particle via the interaction between the spike protein and ACE2. Altman et al⁵ found a significant decrease in the expression of ACE2 mRNA and in its balance with angiotensin converting enzyme mRNA when compared to gene expression levels from nonfailing donor heart and end-stage cardiomyopathy samples. If these changes are truly reflected at the protein and enzymatic levels, this would be expected to lead to a potentially unfavorable balance in which heightened angiotensin II production could lead to an impact on cardiomyocytes, cardiac fibroblasts, and endothelial cells. Interestingly, Altman et al⁵ demonstrated a significant increase in the expression of tissue factor mRNA in patients infected with COVID-19 and vaccinated compared with in control subjects but not to samples from patients with heart failure. Whereas this finding might be related to the presence of a local procoagulant state, it could also be more generally a reflection of a profibrotic, tissue repair state.

Taken together, the work by Altman et al⁵ has advanced the field considerably and has important implications for therapy and for directing future research. As an overarching principle, the conventional management of patients presenting with acute cardiac manifestations such as chest pain, arrhythmias, heart failure, and cardiogenic shock apply equally in COVID-19–related situations. Whereas the absence of evidence for active viral infection within the myocardium of patients infected with COVID-19 would not support the use of antiviral therapy per se, clearly such treatments are typically given to patients who are hospitalized who present with evidence of active viral replication elsewhere. The infrequent histological evidence of myocarditis in patients with positive indirect signals for myocardial injury serves as a reminder of the importance for a comprehensive evaluation of all potential causes and for careful consideration prior to the potentially counterproductive use of immunosuppression. The potential role of molecular mimicry in which antibodies generated against the SARS-CoV-2 spike protein may cross-react with myocardial proteins is of interest and could perhaps benefit from similar strategies used to detect the presence of antibody-mediated rejection in recipients of heart transplants. The relative disconnect between histology despite strong signals of myocardial injury as identified by biomarkers and CMR requires further explanation from a cellular and molecular perspective so that targeted therapies can be developed. These investigations likely will require future studies in which paired tissue, biomarker, and injury studies are performed. Future interventions specifically based on evidence of myocardial involvement might also target the other putative mechanisms of injury, including microvascular thrombosis and complement activation.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.