COVID-19-Induced Myocarditis: Pathophysiological Roles of ACE2 and Toll-like Receptors

Abstract

The clinical manifestations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection responsible for coronavirus disease 2019 (COVID-19) commonly include dyspnoea and fatigue, and they primarily involve the lungs. However, extra-pulmonary organ dysfunctions, particularly affecting the cardiovascular system, have also been observed following COVID-19 infection. In this context, several cardiac complications have been reported, including hypertension, thromboembolism, arrythmia and heart failure, with myocardial injury and myocarditis being the most frequent. These secondary myocardial inflammatory responses appear to be associated with a poorer disease course and increased mortality in patients with severe COVID-19. In addition, numerous episodes of myocarditis have been reported as a complication of COVID-19 mRNA vaccinations, especially in young adult males. Changes in the cell surface expression of angiotensin-converting enzyme 2 (ACE2) and direct injury to cardiomyocytes resulting from exaggerated immune responses to COVID-19 are just some of the mechanisms that may explain the pathogenesis of COVID-19-induced myocarditis. Here, we review the pathophysiological mechanisms underlying myocarditis associated with COVID-19 infection, with a particular focus on the involvement of ACE2 and Toll-like receptors (TLRs).

Keywords: COVID-19; SARS-CoV-2; Toll-like receptors (TLRs); angiotensin-converting enzyme 2 (ACE2); cardiovascular system; myocarditis.

Figure 1

Effect of ACE2 on the metabolism of angiotensin II and the cytoprotective effects of the metabolite angiotensin (1-7) in the heart via activation of the G-protein-coupled receptor MasR. ACE2 = angiotensin-conversing enzyme 2; AT₁R = angiotensin II type 1 receptor; AT₂R = angiotensin II type 2 receptor; MasR = Mas receptor Figure created with Biorender.

Figure 2

Proposed involvement of ACE2 in SARS-CoV-2-induced myocarditis. SARS-CoV-2 spike protein, after proteolytic activation by TMPRSS2, binds ACE2 on cardiomyocytes, enabling SARS-CoV-2 entry. Stress granule formation is then inhibited by intracellular SARS-CoV-2, leading to an increased viral replication and consequent amplified myocardial injury. ACE2 = angiotensin-converting enzyme; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TMPRSS2 = transmembrane serine protease 2. Created with BioRender.

Figure 3

Proposed roles of TLR4 in SARS-CoV-2-induced myocarditis. Triggering a sustained immunoinflammatory response, this receptor may contribute to myocardial damage observed in COVID-19 patients via two different signalling pathways: (a) the interaction between SARS-CoV-2 and TLR4 determines the recruitment of TRIF and TRAM, resulting in the phosphorylation and consequent nuclear translocation of IRF3. This alternative pathway culminates in the production of type I interferons (IFNα and IFNβ), which might lead to an increased expression of surface ACE2 via ISGs, therefore, amplifying ACE2-induced myocardial damage; (b) the canonical pathway of TLR4, also known as MyD88-dependent pathway, promotes the recruitment and activation of IRAK 1/2/4, in turn, responsible for inducing the activation of TRAF6/TAB2/TAK1 cascade. The consequent phosphorylation-induced degradation of IκB and nuclear translocation of NF-kB results in the release of proinflammatory cytokines, which might have a role in SARS-CoV-2-induced myocarditis. As part of the TLR4 canonical pathway, the activation of MAPKK might also contribute to the increased transcription of proinflammatory cytokines via the phosphorylation of ERK, JNK and p38 and consequent nuclear translocation of AP-1. AP-1 = activator protein 1; ERK = extracellular signal-regulated kinase; IFNα = interferon alpha; IFNβ = interferon beta; IκB = inhibitor of nuclear factor kappa B; IRAK 1/2/4 = IL-1 receptor-associated kinases 1/2/4; IRF3 = interferon regulatory factor 3; ISGs = interferon-stimulated genes; JNK = c-Jun N-terminal kinase; MAPKK = mitogen-activated protein kinase kinase; NF-kB = nuclear factor kappa B; p38 = p38 mitogen-activated protein kinases; TAB2 = TGF-beta activated kinase 1 binding protein 2; TAK1 =transforming growth factor-β activated kinase 1; TRAM = TRIF-related adaptor molecule; TRAF6 = TNF receptor associated factor 6; TRIF = TIR-domain-containing adapter-inducing interferon β. Created with BioRender.