SARS-CoV-2-Induced Myocarditis: A State-of-the-Art Review

Abstract

In this review, we investigated whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can directly cause myocarditis with severe myocardial damage induced by viral particles. A review of the major data published from 2020 to 2022 was performed by consulting the major databases alongside first-hand experiences that emerged from the cardiac biopsies and autopsy examinations of patients who died of SARS-CoV-2 infections. From this study, a significantly large amount of data suggests that the Dallas criteria were met in a residual percentage of patients, demonstrating that SARS-CoV-2 myocarditis was a rare clinical and pathological entity that occurred in a small percentage of subjects. All cases described here were highly selected and subjected to autopsies or endomyocardial biopsies (EMBs). The most important discovery, through the detection of the SARS-CoV-2 genome using the polymerase chain reaction, consisted in the presence of the viral genome in the lung tissue of most of the patients who died from COVID-19. However, the discovery of the SARS-CoV-2 viral genome was a rare event in cardiac tissue from autopsy findings of patients who died of myocarditis It is important to emphasize that myocardial inflammation alone, as promoted by macrophages and T cell infiltrations, can be observed in noninfectious deaths and COVID-19 cases, but the extent of each cause is varied, and in neither case have such findings been reported to support clinically relevant myocarditis. Therefore, in the different infected vs. non-infected samples examined, none of our findings provide a definitive histochemical assessment for the diagnosis of myocarditis in the majority of cases evaluated. We report evidence suggesting an extremely low frequency of viral myocarditis that has also been associated with unclear therapeutic implications. These two key factors strongly point towards the use of an endomyocardial biopsy to irrefutably reach a diagnosis of viral myocarditis in the context of COVID-19.

Keywords: COVID-19; SARS-CoV-2-induced myocarditis; autopsy; endomyocardial biopsy; myocarditis.

Figure 1

Image of patients with active myocarditis that is suggestive of a lymphocytic and histiocytic infiltrate and higher T lymphocytes in heart-tissue sections. Hematoxylin and eosin immunohistochemistry of heart tissue samples depicts characteristic lesions of acute myocarditis with widespread lymphocytic and histiocytic infiltrate (red arrow) and associated myocyte damage (black arrow).

Figure 2

Borderline myocarditis characterized by the infiltration of lymphocytic and histiocytic cells is depicted using CD3 immunostaining of T lymphocytes.

Figure 3

SARS Cov-2 has been shown to possess a marked tropism for cells expressing the ACE2 receptor on their surface. This tropism is mediated by the expression of specific proteases that act synergistically with ACE2. After binding of the spike glycoprotein (S) to the receptor, transmembrane serine protease 2 (TMPRSS2) and TMPRSS13 cleave the full-length spike protein (S0). This reaction promotes the conversion at its S2 site through a complex mechanism mediated by the selective function of the host’s furin. Neuropilin 1 (NRP1) binds the RRAR motif’s carboxyterminal sequence of the spike exposed after furin cleavage. Abbreviations: ACE, angiotensin-converting enzyme; CatB/L, cathepsin B/L; NRP1, neuropilin; S, spike; RAR, RaTG13 virus lacks the furin cleavage motif RRAR↓S; and TMPRS, transmembrane protease, serine.

Figure 4

This figure illustrates the immunological mechanisms underlying the pathogenesis of myocarditis. The knowledge we have for understanding the cellular and molecular pathogenesis of post-viral and autoimmune myocarditis is substantially based on animal models. From these models, it emerges that the progression from acute injury to chronic dilated cardiomyopathy can be restricted to a process that includes three phases. In the first stage, acute injury promotes cardiac injury sustained by exposure to intracellular antigens such as cardiac myosin. The activation of the innate immune system activates the subsequent acute inflammatory phase, which develops over the course of several weeks. In this phase, specific immunity mediated by T lymphocytes and antibodies directed against pathogens and similar endogenous cardiac epitopes is triggered, causing a strong inflammatory response. Although most patients succeed, with the available immune defense mechanisms, in eliminating the pathogen, a downregulation of the immune reaction follows with the development of minor sequelae. However, in other patients, virus clearance does not occur, leading to persistent myocyte damage. Heart-specific inflammation persists and tends toward chronicity, which is furthered by the misrecognition of endogenous cardiac antigens as pathogenic entities. Abbreviation: APC, denotes an antigen-presenting cell [62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82].

Figure 5

Only a residual proportion of patients with COVID-19 have a diagnosis of viral myocarditis documented by the presence of SARS-CoV-2 in myocardiocytes. The most frequent lesions are induced by the development of micro- and macrothrombi. In patients with COVID-19, micro- and macrothrombotic formations localized both in the microcirculation and in the epicardial vascular system of the heart have been observed. SARS-CoV-2 infections promote dysregulation in the coagulation system, and several mechanisms are implicated. The coagulopathy is supported by the DIC, the cytokine storm process, and the direct action of the virus, which proves the damage and activation of macrophages. Hyperactivation of the RAAS associated with platelet and complement hyperactivation (direct and indirect) leads to inhibition of fibrinolysis. Abbreviations: ACE2, angiotensin-converting enzyme 2; C, complement; DIC, disseminated intravascular coagulation; FDP, fibrinogen-derived peptides; IFN-γ, interferon gamma; IL, interleukin; MAS, macrophage activation syndrome; PAI, platelet activator inhibitor; TNF, tumor necrosis factor; RAAS, renin-angiotensin-aldosterone system. The arrows explain the increase or decrease of the related component. ↑, increases; ↓, decreases. When to do the endomyocardial biopsy [42,43,44,45,46,47,48].

Figure 6

Patients with COVID-19 have different clinical evolutions. Their treatment options depend on the diagnosis of the complications that occur. Clinical variability in the manifestation of COVID-19 has been observed in the population developing SARS-CoV-2 infections. Myocarditis occurs rarely compared to thrombosis; however, both are driven by inflammation. The inflammatory response increases with age and bed rest, which is more frequent in severe COVID-19, and may contribute to thrombosis and adverse events resulting from multiorgan involvement. The FDA’s timeline for the approval of antivirals and the EUA’s process timeline. Veklury^® EUA’s process was formalized in January 2020. Its final approval occurred in October 2020. Molnupinavir and Paxlovid^® EUA’s process followed in December 2021. Abbreviations: ATE, arterial thromboembolism; COVID-19, coronavirus disease 2019; DIC, disseminated intravascular coagulation; EUA, Emergency Use Authorization; FDA, Food and Drug Administration; NSAIDs, non-steroidal anti-inflammatory drugs; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; and VTE, venous thromboembolism.

Figure 7

The lack of an established antiviral therapy has tempered the use of an EMB. The figure shows the most commonly used antivirals in patients with COVID-19, with or without the development of viral myocarditis, as well as the different times that led to their approval. The FDA’s and EUA’s process timeline for antiviral approval. Remdesivir (Veklury^®) EUA’s process was definitively formalized in January 2020, and its definitive approval occurred in October 2020. Molnupinavir and Paxlovid^® EUA’s process followed in December 2021. In addition, gray-outlined boxes demonstrate the presented indications on the side of each authorized therapeutic agent. Abbreviations: FDA: Food and Drug Administration; EUA: Emergency Use Authorization [131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154].