Pathogenesis of SARS-CoV-2 induced cardiac injury from the perspective of the virus

Abstract

The association between infection and cardiovascular disease has long been recognized in the form of Chagas Disease, Diptheria, tuberculous pericarditis, viral myocarditis, and others. Almost any infectious pathogen can cause myocarditis or heart disease [[1]Knowlton K.U. Anderson J.L. Savoia M.C. Oxman M.N. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases.in: Bennett J.E. Dolin R. Blaser M.J. Practice of Infectious Disease. Elsevier, 2019: 1151-1164Google Scholar]. Viral infection has been and is a predominant cause of myocarditis in the developed world, but viruses can also cause disease without the typical cellular inflammatory disease. During the influenza pandemic of 1918, a large number of patients had evidence of heart damage on autopsy [[2]Lucke B. Wight T. Kime E. Pathologic anatomy and bacteriology of influenza: epidemic of autumn 1918.Arch. Intern. Med. 1919; 24: 154-237Crossref Scopus (29) Google Scholar]. Myocarditis was found in over 50% of patients who died of poliomyelitis infection during the years 1942–1951 [[3]Teloh H.A. Myocarditis in Poliomyelitis. A.M.A. Archives of Pathology.55. 1953: 408-411Google Scholar,[4]Saphir O. Wile S.A. Myocarditis in poliomyelitis.Am J Med Sci. 1942; 203Crossref Google Scholar]. Myocarditis has also been associated with outbreaks of mumps [[5]Bengtsson E. Orndahl G. Complications of mumps with special reference to the incidence of myocarditis.Acta Med. Scand. 1954; 149: 381-388Crossref PubMed Scopus (15) Google Scholar], measles [[6]Lucke B. Postmortem findings in measles bronchopneumonia and other acute infections.JAMA. 1918; 70: 2006-2011Crossref Scopus (5) Google Scholar], and enterovirus pleurodynia [[7]Kilbourne E.D. Wilson C.B. Perrier D. The induction of gross myocardial lesions by a Coxsackie (pleurodynia) virus and cortisone.J. Clin. Invest. 1956; 35: 362-370Crossref PubMed Scopus (59) Google Scholar] before 1960. Association of Coxsackievirus with myocarditis has been recognized since at least the 1950s [[8]Dalldorf G. The Coxsackie viruses.Annu. Rev. Microbiol. 1955; 9: 277-296Crossref PubMed Scopus (23) Google Scholar,[9]Benirschke K. Kibrick S. Acute aseptic myocarditis and meningoencephalitis in the newborn child infected with coxsackle virus group B, type 3.N. Engl. J. Med. 1956; 255: 883-889Crossref PubMed Google Scholar]. It has been demonstrated that viral infection can affect the heart by direct infection of cardiovascular organs and cells and is usually accompanied by a potent immune response. It is often challenging to determine the contribution of direct infection as compared to the immune response in viral-mediated cardiovascular disease since they frequently overlap. A world pandemic has now turned attention to a novel viral infection, SARS-CoV-2, that primarily causes severe acute respiratory disease. However, the disease can be complicated by multiple cardiovascular abnormalities that are markers of a poor prognosis and most likely contribute directly to the severity of the disease. A better understanding of interactions between the virus and the host will ultimately guide the diagnosis and treatment of both pulmonary and cardiovascular complications seen in patients and ultimately contribute to the design of vaccines and other preventive strategies. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). It was identified in Wuhan, China, as the cause of an outbreak of acute respiratory distress syndrome (ARDS). At the time of writing, worldwide, there have been over 19 million confirmed cases and over 720,000 deaths caused by the virus [[10]Dong E. Du H. Gardner L. An interactive web-based dashboard to track COVID-19 in real time.Lancet Infect. Dis. 2020; 20: 533-534Abstract Full Text Full Text PDF PubMed Scopus (5279) Google Scholar]. The predominant manifestation of COVID-19 is ARDS. However, infection with SARS-CoV-2 is associated with multiple cardiac manifestations. These include: cardiac injury of uncertain etiology [[11]Shi S. Qin M. Shen B. Cai Y. Liu T. Yang F. et al.Association of Cardiac Injury with Mortality in Hospitalized Patients with COVID-19 in Wuhan. China, JAMA Cardiol2020Crossref Scopus (2505) Google Scholar], and a thrombotic disease that may manifest as deep-vein thrombosis, pulmonary embolism, stroke, and peripheral arterial disease [[12]Connors J.M. Levy J.H. COVID-19 and its implications for thrombosis and anticoagulation.Blood. 2020; 135: 2033-2040Crossref PubMed Scopus (155) Google Scholar]. There is also growing evidence of an endothelial dysfunction that affects small vessels [[13]Bryce C. Grimes Z. Pujadas E. Ahuja S. Beasley M.B. Albrecht R. et al.Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.medRxiv. 2020; https://doi.org/10.1101/2020.05.18.20099960Crossref Scopus (0) Google Scholar,[14]Varga Z. Flammer A.J. Steiger P. Haberecker M. Andermatt R. Zinkernagel A.S. et al.Endothelial cell infection and endotheliitis in COVID-19.Lancet. 2020; 395: 1417-1418Abstract Full Text Full Text PDF PubMed Scopus (3670) Google Scholar]. Recently, a form of Kawasaki disease, termed Multisystem Inflammatory Syndrome in Children (MIS-C), has been described in younger patients infected with SARS-CoV-2 [[15]Verdoni L. Mazza A. Gervasoni A. Martelli L. Ruggeri M. Ciuffreda M. et al.An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.Lancet. 2020; 395: 1771-1778Abstract Full Text Full Text PDF PubMed Scopus (1422) Google Scholar]. MIS-C appears to have a direct effect on the vasculature and can be associated with cardiac dysfunction. While the associations between SARS-CoV-2 and the cardiovascular manifestations are clear, there is limited data that addresses how infection with SARS-CoV-2 affects the cardiovascular system. By understanding the molecular pathways involved in virus replication, one can begin to understand how the virus may directly affect the host [[1]Knowlton K.U. Anderson J.L. Savoia M.C. Oxman M.N. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases.in: Bennett J.E. Dolin R. Blaser M.J. Practice of Infectious Disease. Elsevier, 2019: 1151-1164Google Scholar,16Fung G. Luo H. Qiu Y. Yang D. McManus B. Myocarditis.Circ. Res. 2016; 118: 496-514Crossref PubMed Scopus (256) Google Scholar, 17Yajima T. Knowlton K.U. Viral myocarditis: from the perspective of the virus.Circulation. 2009; 119: 2615-2624Crossref PubMed Scopus (188) Google Scholar, 18Lim B.K. Peter A.K. Xiong D. Narezkina A. Yung A. Dalton N.D. et al.Inhibition of Coxsackievirus-associated dystrophin cleavage prevents cardiomyopathy.J. Clin. Invest. 2013; 123: 5146-5151Crossref PubMed Scopus (37) Google Scholar]. Activation of a potent immune response, both innate and adaptive, can actively inhibit viral infection, but can also damage the infected cell and adjacent cells [[19]Liu P.P. Blet A. Smyth D. Li H. The science underlying COVID-19: implications for the cardiovascular system.Circulation. 2020; 142: 68-78Crossref PubMed Scopus (491) Google Scholar]. It has been demonstrated in animal models of viral myocarditis that inhibition of innate immune mechanisms may be detrimental to the host by reducing the host antiviral immune response to virus infection and allowing unrestrained replication of the virus [[20]Yajima T. Murofushi Y. Zhou H. Park S. Housman J. Zhong Z.H. et al.Absence of SOCS3 in the cardiomyocyte increases mortality in a gp130-dependent manner accompanied by contractile dysfunction and ventricular arrhythmias.Circulation. 2011; 124: 2690-2701Crossref PubMed Scopus (28) Google Scholar,[21]Yasukawa H. Yajima T. Duplain H. Iwatate M. Kido M. Hoshijima M. et al.The suppressor of cytokine signaling-1 (SOCS1) is a novel therapeutic target for enterovirus-induced cardiac injury.J. Clin. Invest. 2003; 111: 469-478Crossref PubMed Scopus (98) Google Scholar]. However, inhibition of the immune response has the potential to decrease immune mediated cytopathic effects. Maintaining the proper balance is crucial when using immunomodulators to treat viral infections. A study of the viral life-cycle provides insight into viral tropism by understanding viral receptors and entry mechanisms. Direct cardiotoxic effects may involve the expression of virally encoded proteins such as viral proteases. Viral RNA-dependent, RNA-polymerases are crucial in the replication of the viral genome and, thus, the extent of viral-induced damage. Inhibition of mechanisms required for efficient viral replication is the primary clinical strategy for treating viruses such as HIV, Hepatitis B and C, influenza, and others [[22]Chaudhuri S. Symons J.A. Deval J. Innovation and trends in the development and approval of antiviral medicines: 1987-2017 and beyond.Antivir. Res. 2018; 155: 76-88Crossref PubMed Scopus (111) Google Scholar,[23]Mohammadi Pour P. Fakhri S. Asgary S. Farzaei M.H. Echeverria J. The signaling pathways, and therapeutic targets of antiviral agents: focusing on the antiviral approaches and clinical perspectives of anthocyanins in the management of viral diseases.Front. Pharmacol. 2019; 10: 1207Crossref PubMed Scopus (78) Google Scholar]. SARS-CoV-2 belongs to the genus Betacoronavirus [[24]V. Coronaviridae Study Group of the International Committee on Taxonomy of The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2.Nat. Microbiol. 2020; 5: 536-544Crossref PubMed Scopus (4073) Google Scholar]. The human beta-coronaviruses include the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV that will be referred to as SARS-CoV-1 throughout this document), and other coronaviruses that cause mild respiratory illnesses like the common cold. Coronaviruses are enveloped viruses in which the envelope glycoproteins reside in a lipid bilayer. These proteins include the spike (S)-protein, the membrane (M)-protein, the envelope (E) protein, and the nucleoprotein (N) as well as a few other accessory proteins. Enclosed in the viral envelope is a 30 kb positive-strand RNA [[25]Oberfeld B. Achanta A. Carpenter K. Chen P. Gilette N.M. Langat P. et al.SnapShot: COVID-19.Cell. 2020; 181 (954–954 e1)Abstract Full Text PDF PubMed Scopus (85) Google Scholar] (Fig. 1). The viral life cycle can be broken down into three significant steps: 1) virus binding and entry into the cell, 2) translation of the viral genome with associated viral polyprotein processing and replication of the positive-strand RNA via a negative-strand intermediate, and 3) assembly of the viral genome, and viral envelope with subsequent release from the host cell (For an overview, see Fig. 2). Virus binding and entry into the cell: SARS-CoV-2 begins the infection process by binding of the viral envelop S-protein to angiotensin-converting enzyme-2 (ACE2) on the host cell membrane. Considerable investigation with SARS-CoV-1 and SARS-CoV-2 has demonstrated that cleavage of the S protein is required for efficient infection of the host cell. The binding and entry process is facilitated by cleavage of the full-length S-protein into S1 and S2 polyproteins. The S1 domain interacts with the receptor. The S2 domain is involved in the fusion of the viral envelope with the cell membrane [[26]Walls A.C. Park Y.J. Tortorici M.A. Wall A. McGuire A.T. Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein.Cell. 2020; 181 (e6): 281-292Abstract Full Text Full Text PDF PubMed Scopus (4850) Google Scholar]. In SARS-CoV-2, furin, a nearly ubiquitously expressed host proprotein convertase, participates in this cleavage [[27]Jaimes J.A. Millet J.K. Whittaker G.R. Proteolytic cleavage of the SARS-CoV-2 spike protein and the role of the novel S1/S2 site.iScience. 2020; 23: 101212Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar]. Furin is typically involved in the processing of a cell's normal surface glycoproteins. Interestingly, the SARS-CoV-1 does not have a furin cleavage site. In both viruses, S1 and S2 polyproteins are cleaved by interaction with a host transmembrane protease serine 2 (TMPRSS2) and/or cathepsin L [[28]Hoffmann M. Kleine-Weber H. Schroeder S. Kruger N. Herrler T. Erichsen S. et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181 (e8): 271-280Abstract Full Text Full Text PDF PubMed Scopus (10847) Google Scholar]. Both proteases can cleave the S-protein. A TMPRSS2 inhibitor has been demonstrated to block the entry of the virus into the cell [[25]Oberfeld B. Achanta A. Carpenter K. Chen P. Gilette N.M. Langat P. et al.SnapShot: COVID-19.Cell. 2020; 181 (954–954 e1)Abstract Full Text PDF PubMed Scopus (85) Google Scholar]. It appears that coronaviruses have evolved to preserve redundant mechanisms by which the S protein can be processed into the S1 and S2 domains. This processing facilitates binding of S1 to the receptor (ACE2 for SARS-CoV-1 and SARS-CoV-2), and S2 mediates fusion of the virion envelope to the cell membrane. Receptor binding and S protein cleavage affects tropism and pathogenicity of coronaviruses [[29]Millet J.K. Whittaker G.R. Host cell proteases: critical determinants of coronavirus tropism and pathogenesis.Virus Res. 2015; 202: 120-134Crossref PubMed Scopus (564) Google Scholar]. Inhibition of this binding and entry process can inhibit viral replication. For example, monoclonal antibodies directed against the S-protein are expected to inhibit the virus from binding to ACE2. A protease inhibitor directed against TMPRSS2, Camostat Mesylate, is being tested in clinical trials [[30]ClinicalTrials.govGoogle Scholar]. Translation, processing, and replication of the viral genome: After binding, the virus enters into the cell through an endocytic process. The viral positive-strand RNA is released from the viral envelope into the cytoplasm and translated into polyproteins and structural proteins using host cell translational mechanisms. Importantly, the viral RNA encodes proteases that are involved in proteolytic cleavage of the viral polyproteins. One of the best characterized of these proteases in SARS-CoV-1 and SARS-CoV-2 is the main protease Mpro, also called 3CLpro. The x-ray structures of the SARS-CoV-2 Mpro without ligand and associated with an inhibitor was recently reported. Using the Mpro structure without ligand, the investigators developed a lead compound for a potent inhibitor of the SARS-CoV-2 Mpro [[31]Zhang L. Lin D. Sun X. Curth U. Drosten C. Sauerhering L. et al.Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors.Science. 2020; 368: 409-412Crossref PubMed Scopus (1782) Google Scholar]. Replication of the positive-strand viral genome requires the virally expressed RNA-dependent RNA polymerase that generates a negative-strand RNA using the positive-strand viral RNA as its template. The negative-strand serves as the template for replication of the positive-strand RNA genome that is assembled in the virion. Mpro proteolytic activity is required to process the viral RNA-dependent RNA polymerase into its mature, active protein. Remdesivir has been approved for COVID-19 therapy [[32]Beigel J.H. Tomashek K.M. Dodd L.E. Mehta A.K. Zingman B.S. Kalil A.C. et al.Remdesivir for the treatment of Covid-19 - preliminary report.N. Engl. J. Med. 2020; (ahead of print)Crossref Scopus (3896) Google Scholar]. Remdesivir's primary mechanism of action is through inhibition of viral RNA-dependent RNA polymerase. An inhibitor of Mpro would prevent the maturation of multiple structural and non-structural proteins, including the RNA-dependent RNA polymerase, thus affecting the function of more than one essential viral protein. Inhibitors of RNA polymerases and proteases are the backbone of many antiviral strategies [[22]Chaudhuri S. Symons J.A. Deval J. Innovation and trends in the development and approval of antiviral medicines: 1987-2017 and beyond.Antivir. Res. 2018; 155: 76-88Crossref PubMed Scopus (111) Google Scholar]. Assembly of the viral genome, envelope, and release from the host cell: Once the viral structural and non-structural proteins are expressed, and the viral genome has replicated, the structural proteins and viral genome migrate to the Golgi apparatus where assembly of the viral components and viral envelope begins. The immature virion migrates to the endoplasmic reticulum and fuses with the cell membrane for release from the cell. Hydroxychloroquine and chloroquine have been considered for the treatment of COVID-19. Though their use continues to be controversial [33Mahevas M. Tran V.T. Roumier M. Chabrol A. Paule R. Guillaud C. et al.Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data.BMJ. 2020; 369: m1844Crossref PubMed Scopus (278) Google Scholar, 34Geleris J. Sun Y. Platt J. Zucker J. Baldwin M. Hripcsak G. et al.Observational study of hydroxychloroquine in hospitalized patients with Covid-19.N. Engl. J. Med. 2020; 382: 2411-2418Crossref PubMed Scopus (504) Google Scholar, 35Mehra M.R. Ruschitzka F. Patel A.N. 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This includes the presumed inhibition of maturation and release of the virus in the endosomes and lysosomes of the cell by increasing the cellular pH and inhibiting endosomal maturation in the cell. Endosomes are also required for endocytosis of the virus; thus, there may also be an inhibitory effect on virus internalization [[38]Liu J. Cao R. Xu M. Wang X. Zhang H. Hu H. et al.Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro.Cell Discov. 2020; 6: 16Crossref PubMed Scopus (1335) Google Scholar]. While the precise determinants of SARS-CoV-2 tissue tropism are not fully understood, there are insights that can be gained by consideration of molecules involved in the entry of the virus into the host cell. Tissue tropism of the virus likely contributes significantly to the pathogenesis of SARS-CoV-2, including the cardiovascular manifestations of COVID-19. As has been previously mentioned, ACE2 is the predominant receptor for SARS-CoV-2. ACE2 is a transmembrane protein expressed in the lung and blood vessels. The expression of ACE2 is detected at high levels in alveolar, type II epithelial cells in the lung. There is also evidence that it is expressed in the heart, kidney, and intestines [39Hamming I. Timens W. Bulthuis M.L. Lely A.T. Navis G. van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.J. Pathol. 2004; 203: 631-637Crossref PubMed Scopus (3597) Google Scholar, 40Monteil V. Kwon H. Prado P. Hagelkruys A. Wimmer R.A. Stahl M. et al.Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2.Cell. 2020; 181 (e7): 905-913Abstract Full Text Full Text PDF PubMed Scopus (1347) Google Scholar, 41Guo J. Huang Z. Lin L. Lv J. Coronavirus disease 2019 (COVID-19) and cardiovascular disease: a viewpoint on the potential influence of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on onset and severity of severe acute respiratory syndrome coronavirus 2 infection.J. Am. Heart Assoc. 2020; 9e016219PubMed Google Scholar]. These are tissues that have been reported to be affected by SARS-CoV2 infection. Recent, single-cell RNA-seq analysis of ACE2 expression in healthy human tissues demonstrated that ACE2 mRNA was detected in lung epithelial cells, cardiac myocytes, kidney proximal tubular cells, esophageal epithelial cells, bowel, and bladder urothelial cells [[42]Zou X. Chen K. Zou J. Han P. Hao J. Han Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection.Front. Med. 2020; 14: 185-192Crossref PubMed Scopus (1335) Google Scholar]. Another single-cell RNA-seq analysis of the heart found high levels of ACE2 in pericytes and low levels in cardiac myocytes. They also found that ACE2 was upregulated in failing hearts [[43]Chen L. Li X. Chen M. Feng Y. Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2.Cardiovasc. Res. 2020; 116: 1097-1100Crossref PubMed Scopus (268) Google Scholar]. ACE2 has also been shown to be expressed in endothelial cells of many organs [[14]Varga Z. Flammer A.J. Steiger P. Haberecker M. Andermatt R. Zinkernagel A.S. et al.Endothelial cell infection and endotheliitis in COVID-19.Lancet. 2020; 395: 1417-1418Abstract Full Text Full Text PDF PubMed Scopus (3670) Google Scholar,[39]Hamming I. Timens W. Bulthuis M.L. Lely A.T. Navis G. van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.J. Pathol. 2004; 203: 631-637Crossref PubMed Scopus (3597) Google Scholar,[40]Monteil V. Kwon H. Prado P. Hagelkruys A. Wimmer R.A. Stahl M. et al.Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2.Cell. 2020; 181 (e7): 905-913Abstract Full Text Full Text PDF PubMed Scopus (1347) Google Scholar]. The infection of endothelial cells by SARS-CoV-2 could be important in vascular events that have been demonstrated in COVID-19 patients [[14]Varga Z. Flammer A.J. Steiger P. Haberecker M. Andermatt R. Zinkernagel A.S. et al.Endothelial cell infection and endotheliitis in COVID-19.Lancet. 2020; 395: 1417-1418Abstract Full Text Full Text PDF PubMed Scopus (3670) Google Scholar]. Also, in order to infect organs such as the heart or kidney, the virus may need to infect endothelial cells to reach other cells since the virion is moderately large at 80–100 nM in size. It has been recently shown that SARS-CoV-2 can directly infect engineered human blood vessel organoids derived from human induced pluripotent stem cells (iPSCs) [[40]Monteil V. Kwon H. Prado P. Hagelkruys A. Wimmer R.A. Stahl M. et al.Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2.Cell. 2020; 181 (e7): 905-913Abstract Full Text Full Text PDF PubMed Scopus (1347) Google Scholar]. Infection of the blood vessel organelle was inhibited using a previously developed, clinical grade, human soluble recombinant ACE2 (hrsACE2) [[40]Monteil V. Kwon H. Prado P. Hagelkruys A. Wimmer R.A. Stahl M. et al.Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2.Cell. 2020; 181 (e7): 905-913Abstract Full Text Full Text PDF PubMed Scopus (1347) Google Scholar]. Since ACE2 has been shown to be expressed in human cardiac myocytes, it is possible that SARS-CoV-2 could infect cardiac myocytes and induce a myocarditis phenotype or a cardiomyopathy without the traditional cellular inflammation of myocarditis. It is also possible that SARS-CoV-2 could infect endothelial cells, induce a cytopathic effect in the endothelial cells that could then contribute to vascular thrombosis formation, an entity that is being more commonly recognized in COVID-19 patients [[12]Connors J.M. Levy J.H. COVID-19 and its implications for thrombosis and anticoagulation.Blood. 2020; 135: 2033-2040Crossref PubMed Scopus (155) Google Scholar]. Finally, SARS-CoV-2 could infect pericytes cells in the heart, activating a virus-specific immune response. While the expression of ACE2 is likely a significant determinant of tissue tropism for viral infection, there are other molecules that have a role in the entry of the virus within the cell, as is described above, including TMPRSS2. These have been implicated in determining viral tissue tropism for coronaviruses [[28]Hoffmann M. Kleine-Weber H. Schroeder S. Kruger N. Herrler T. Erichsen S. et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181 (e8): 271-280Abstract Full Text Full Text PDF PubMed Scopus (10847) Google Scholar]. It was recognized early during the outbreak of COVID-19 that greater than 20% of patients with COVID-19 had elevations in cardiac troponin and other manifestations of cardiac injury, including impaired left ventricular ejection fraction and an elevation in type-B-natriuretic peptide [[11]Shi S. Qin M. Shen B. Cai Y. Liu T. Yang F. et al.Association of Cardiac Injury with Mortality in Hospitalized Patients with COVID-19 in Wuhan. China, JAMA Cardiol2020Crossref Scopus (2505) Google Scholar]. The clinical aspects of these manifestations have been extensively reviewed elsewhere [[44]Akhmerov A. Marban E. COVID-19 and the heart.Circ. Res. 2020; 126: 1443-1455Crossref PubMed Scopus (423) Google Scholar,[45]Hendren N.S. Drazner M.H. Bozkurt B. Cooper Jr., L.T. Description and proposed management of the acute COVID-19 cardiovascular syndrome.Circulation. 2020; 141: 1903-1914Crossref PubMed Scopus (321) Google Scholar], but importantly, the manifestation of cardiovascular disease is a marker of a poor prognosis in COVID-19 [[12]Connors J.M. Levy J.H. COVID-19 and its implications for thrombosis and anticoagulation.Blood. 2020; 135: 2033-2040Crossref PubMed Scopus (155) Google Scholar,[46]Guo T. Fan Y. Chen M. Wu X. Zhang L. He T. et al.Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; 5: 811-818Crossref PubMed Scopus (2367) Google Scholar]. A description of potential mechanisms by which these processes can occur following SARS-CoV-2 infection will be described with an emphasis on the role that the virus may have in the pathogenesis. Unfortunately, there is limited histologic information available about the pathologic changes that occur in the heart with SARS-CoV-2 infection. However, there are anecdotal reports that provide early insight and new observations are reported on a regular basis. At least four mechanisms have been proposed for the cardiac injury that has been described: 1) myocarditis, 2) cytokine storm, 3) coronary artery ischemia in the setting of underlying coronary artery disease, and 4) increased vascular thrombosis of small and large coronary arteries that could occur in the absence of coronary artery disease. It is also important to note that cardiac injury could also occur as a result of global ischemia related to multi-organ failure, respiratory distress, and associated hemodynamic and metabolic abnormalities. The major emphasis of this paper will focus on the current reports related to myocarditis or direct viral infection of the heart with variable evidence of cellular inflammation. Other reviews highlight the role of other mechanisms that will be briefly addressed herein [[14]Varga Z. Flammer A.J. Steiger P. Haberecker M. Andermatt R. Zinkernagel A.S. et al.Endothelial cell infection and endotheliitis in COVID-19.Lancet. 2020; 395: 1417-1418Abstract Full Text Full Text PDF PubMed Scopus (3670) Google Scholar,[19]Liu P.P. Blet A. Smyth D. Li H. The science underlying COVID-19: implications for the cardiovascular system.Circulation. 2020; 142: 68-78Crossref PubMed Scopus (491) Google Scholar,[45]Hendren N.S. Drazner M.H. Bozkurt B. Cooper Jr., L.T. Description and proposed management of the acute COVID-19 cardiovascular syndrome.Circulation. 2020; 141: 1903-1914Crossref PubMed Scopus (321) Google Scholar,[47]Ranucci M. Ballotta A. Di Dedda U. Bayshnikova E. Dei Poli M. Resta M. et al.The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome.J. Thromb. Haemost. 2020; 18: 1747-1751Crossref PubMed Scopus (574) Google Scholar]. Viral infection, in general, has been previously identified as a cause of myocarditis that is generally defined by evidence of inflammation in the heart. It has also been recognized that there are forms of infectious viral heart disease that may not be associated with the typical inflammatory infiltrate [[1]Knowlton K.U. Anderson J.L. Savoia M.C. Oxman M.N. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases.in: Bennett J.E. Dolin R. Blaser M.J. Practice of Infectious Disease. Elsevier, 2019: 1151-1164Google Scholar]. Both forms of viral heart disease are often referred to, broadly, as myocarditis. Extensive work has defined significant interactions between viruses and the host myocardial cell. Also, there is a plethora of evidence that describes the activation of the immune system that is associated with viral infection that causes myocarditis. Given the large number of viruses that can cause myocarditis [[1]Knowlton K.U. Anderson J.L. Savoia M.C. Oxman M.N. Mandell, Douglas, and Bennett’s principles and pra