Cardiovascular consequences of viral infections: from COVID to other viral diseases

Abstract

Infection of the heart muscle with cardiotropic viruses is one of the major aetiologies of myocarditis and acute and chronic inflammatory cardiomyopathy (DCMi). However, viral myocarditis and subsequent dilated cardiomyopathy is still a challenging disease to diagnose and to treat and is therefore a significant public health issue globally. Advances in clinical examination and thorough molecular genetic analysis of intramyocardial viruses and their activation status have incrementally improved our understanding of molecular pathogenesis and pathophysiology of viral infections of the heart muscle. To date, several cardiotropic viruses have been implicated as causes of myocarditis and DCMi. These include, among others, classical cardiotropic enteroviruses (Coxsackieviruses B), the most commonly detected parvovirus B19, and human herpes virus 6. A newcomer is the respiratory virus that has triggered the worst pandemic in a century, SARS-CoV-2, whose involvement and impact in viral cardiovascular disease is under scrutiny. Despite extensive research into the pathomechanisms of viral infections of the cardiovascular system, our knowledge regarding their treatment and management is still incomplete. Accordingly, in this review, we aim to explore and summarize the current knowledge and available evidence on viral infections of the heart. We focus on diagnostics, clinical relevance and cardiovascular consequences, pathophysiology, and current and novel treatment strategies.

Keywords: Advanced diagnostics; Inflammatory cardiomyopathy; Myocarditis; Treatment strategies; Viral infections.

Figure 1

(Immuno-)Histological manifestations of myocarditis and inflammatory cardiomyopathy. (A) CVB3-positive patient, histological analysis of active myocarditis with massively infiltrating cells and myocytolysis. Azan staining. Scale bars: 50 µm. (B) Active myocarditis in a case of EBV infection with dense infiltration of inflammatory cells, necrosis, and dissolution of myocytes in the centre of the panel. Azan stain. Scale bars: 50 µm. (C) Detection of B19V in the endothelial layer of an intramyocardial vessel in the heart (radioactive in situ hybridization, original high-power magnification, haematoxylin, and eosin) obtained at autopsy from an infant who died from myocarditis. Reprinted with permission from Bock et al. (D) Enhanced fibrosis in a B19V positive patient with transcriptional activity. H&E stain. Scale bars: 50 µm. (E) Histological analysis in a patient with positive proof of SARS-CoV-2 genomes in EMB. In the periphery of a fibrosis (f) capillaries (white arrow) with sinus-like structure contain aggregated erythrocytes (blue arrows), unstructured protein, and lack endothelial cells. Adjacent some round cells (white triangle). Myocytes distended without signs of damage. Azan stain. Scale bars: 50 µm. (F) Enhanced focal post-infectious autoimmune inflammation, IH staining of focal infiltration of CD3-positive T-lymphocytes. Scale bars: 50 µm. (G) Post-infectious autoimmune inflammation, IH staining of diffuse infiltration of CD45R0-positive T-memory cells. Scale bars: 50 µm. (H) Post-infectious autoimmune inflammation, IH staining of increased HLA-DR isotype—expression. Scale bars: 100 µm. (I) Post-infectious autoimmune inflammation, IH staining of increased VCAM-1 expression. Scale bars: 25 µm. B19V, parvovirus B19; EBV, Epstein–Barr virus; HLA-DR, human leukocyte antigen-DR; IH, immunohistochemistry; VCAM-1, vascular cell adhesion protein 1.

Figure 2

Distribution of viral genomes in EMBs of n = 1132 consecutive patients in 2020 with suspicion of myocarditis or unexplained heart failure. B19V infection is divided into latent (lB19V) and transcriptional active (taB19V) infection. For SARS-CoV-2, n = 364 EMBs were analysed, of which n = 5 (1.4%) were positive for SARS-CoV-2 genomes. B19V, parvovirus B19; ciHHV6, chromosomal integrated human herpesvirus 6; CMV, cytomegalovirus; EBV, Epstein–Barr virus; EMB, endomyocardial biopsy; EV, enterovirus; HHV6, human herpesvirus 6.

Figure 3

Most abundant cardiotropic viruses and their target cells in the heart. CVB-3 and ADV enter cardiomyocytes via binding the transmembrane CAR. In addition, decay-accelerating factor serves as CVB-3 receptor. Integrins (αvβ3 and αvβ5) promote ADV internalization. B19V targets endothelial cells by binding to erythrocyte P antigen and integrin αvβ1 as co-receptor. EBV efficiently infects resting human B lymphocytes, whereas HHV6 primarily targets CD4+ T lymphocytes. Using CD46 as cellular receptor, HHV6 can directly infect endothelial cells and subsequently enter adjacent tissues. SARS-CoV-2 cellular entry involves specific binding to the ACE2 receptor as well as proteolytic cleavage by the host cell surface serine protease TMPRSS2. For SARS-CoV-2, several cardiac targets including vascular endothelial cells and cardiomyocytes are proposed. Moreover, pulmonary-derived macrophages are suggested carrying the virus into the myocardium. As a consequence of viral infection, TLR3, 4, 7, 8, and 9 signalling cascade is initiated, followed by infiltration of several inflammatory cells including T and B lymphocytes, natural killer cells and bone-marrow derived monocytes, which differentiate into M1 and M2 macrophages. B19V infection can be differentiated into latent infection without myocardial damage and active infection characterized by VP1 and/or NS1 mRNA detection. The later can result in severe endothelial dysfunction, followed by immune cell infiltration and development of DCMi. ds, double stranded; ss, single stranded.

Figure 4

Innovative antiviral strategies. The continuing need for the development of innovative antiviral strategies is strikingly illustrated by the catastrophic SARS-CoV-2 pandemic, which suddenly arose by transmission of an animal virus to man and is difficult to control, amongst other problems, due to sequential accumulation of mutations. The recent introduction of novel therapeutic approaches based on biological antiviral defence systems (RNA interference, CRISPR-Cas) or antisense drugs (ASOs) is most welcome in this context. Although technically demanding, RNAi and ASO drugs have entered cardiovascular clinical practice when the key problem of their liver-directed targeting was solved by ligand-coupling and nanoparticle encapsulation (to the left). Further development of ASO, RNAi 141, 142 and CRISPR-Cas 140, 163 antiviral drugs justifies major efforts since essentially any viral or cellular target (examples are given for Cosackieviruses and SARS-CoV-2) may be addressed by these highly flexible tools once efficient delivery to the affected tissue is enabled. In that regard, a recent pioneering study by Bailey et al. is of interest. Decades after similar work on CVB3 myocarditis in humans, this article dealing with SARS-CoV-2 finds similarly restricted cellular tropism (cardiomyocytes but not cardiac macrophages, fibroblasts, or endothelial cells) and mechanistic sequelae of SARS-CoV-2 infection (innate immune activation with cytokine induction, sarcomere disassembly, and cell death). Whereas recombinant AAV vectors (to the right) were successfully employed for RNAi and anti-miR therapy of myocardial disorders in animal models, this approach has not yet entered the clinical arena. Global efforts, significantly driven by the current pandemic, are currently being devoted to fully exploit the clinical potential of these new antiviral strategies.