The Enemy Within Sudden-Onset Reversible Cardiogenic Shock With Biopsy-Proven Cardiac Myocyte Infection By Severe Acute Respiratory Syndrome Coronavirus 2

HomeCirculationVol. 142, No. 19The Enemy Within Free AccessCase ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCase ReportPDF/EPUBThe Enemy WithinSudden-Onset Reversible Cardiogenic Shock With Biopsy-Proven Cardiac Myocyte Infection by Severe Acute Respiratory Syndrome Coronavirus 2 Chonyang L. Albert, Andres E. Carmona-Rubio, Aaron J. Weiss, Gary G. Procop, Randall C. Starling and E. Rene Rodriguez Chonyang L. AlbertChonyang L. Albert Chonyang L. Albert, MD, Cleveland Clinic, Department of Cardiovascular Medicine, 9500 Euclid Ave J3-4, Cleveland, OH 44195. Email E-mail Address: [email protected] https://orcid.org/0000-0002-1403-3554 Department of Cardiovascular Medicine (C.L.A., A.E.C.-R., R.C.S.), Cleveland Clinic, OH. Search for more papers by this author , Andres E. Carmona-RubioAndres E. Carmona-Rubio https://orcid.org/0000-0002-3576-3660 Department of Cardiovascular Medicine (C.L.A., A.E.C.-R., R.C.S.), Cleveland Clinic, OH. Search for more papers by this author , Aaron J. WeissAaron J. Weiss https://orcid.org/0000-0002-3531-4144 Department of Thoracic and Cardiovascular Surgery (A.J.W.), Cleveland Clinic, OH. Search for more papers by this author , Gary G. ProcopGary G. Procop Department of Pathology (G.G.P., E.R.R.), Cleveland Clinic, OH. Search for more papers by this author , Randall C. StarlingRandall C. Starling https://orcid.org/0000-0002-1254-4860 Department of Cardiovascular Medicine (C.L.A., A.E.C.-R., R.C.S.), Cleveland Clinic, OH. Search for more papers by this author and E. Rene RodriguezE. Rene Rodriguez Department of Pathology (G.G.P., E.R.R.), Cleveland Clinic, OH. Search for more papers by this author Originally published30 Sep 2020https://doi.org/10.1161/CIRCULATIONAHA.120.050097Circulation. 2020;142:1865–1870Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: September 30, 2020: Ahead of Print Information about a real patient is presented in stages (boldface type) to expert clinicians (Drs Albert, Weiss, Starling, Rodriguez, and Procop), who respond to the information and share their reasoning with the reader (regular type). A discussion by the authors follows.Patient presentation: A 49-year-old Black man with no known cardiovascular disease but with a history of tobacco and alcohol use and active incarceration developed anosmia and loss of taste 2 weeks before presentation. A few days before presentation, he developed fevers, myalgias, and dyspnea. The patient was transferred to our center for further care.On arrival, he was afebrile (37.2 °C), hypotensive (77/57 mm Hg), tachycardic (109 bpm), and tachypneic (52 bpm) with an oxygen saturation of 89% on 6 L of supplemental O2 through a nasal cannula. A nasopharyngeal swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was sent along with a respiratory viral panel polymerase chain reaction (PCR). His SARS-CoV-2 PCR returned positive, whereas all other viruses tested, including human immunodeficiency virus, were negative. His initial laboratory studies showed leukocytosis (30 020/μL), elevated lactate (11 mmol/L), with evidence of end-organ dysfunction (Figure 1A). Myocardial enzymes, N-terminal pro hormone B-type natriuretic peptide, and inflammatory markers were elevated. There was no evidence of pulmonary infection by chest x-ray film or computed tomography (Figure 1B–1E). A 12-lead ECG demonstrated sinus tachycardia without acute ST-T wave changes. Transthoracic 2-dimensional echocardiography revealed a globally depressed left ventricular ejection fraction of 20% with left ventricular end-diastolic dimension of 5.8 cm, and increased wall thickness of 1.7 cm and 1.4 cm measured in the interventricular septum and posterior walls, respectively. There was depressed right ventricle systolic function, moderately severe mitral regurgitation, and severe tricuspid regurgitation.Download figureDownload PowerPointFigure 1. Patient laboratory data and imaging. A, Inflammatory markers and end-organ indexes during admission. B, Admission chest x-ray film. C through E, Representative computed tomography scan images demonstrating relative lack of pulmonary involvement of severe acute respiratory syndrome coronavirus 2 infection. ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; IL-6, interleukin 6; NA, not available; NT Pro BNP, N-terminal prohormone of brain natriuretic peptide; and WBC, white blood count.Dr Albert: This patient presented with acute cardiogenic shock in the setting of SARS-CoV-2 infection. Although the left ventricular end-diastolic dimension of 5.8 cm may suggest a potential antecedent cardiomyopathy, the increased wall thickness is suspicious for myocardial edema. Furthermore, left ventricular end-diastolic dimension <6.0 cm in the setting of recent-onset cardiomyopathy was deemed as a favorable predictor of recovery in the IMAC2 trial (Intervention in Myocarditis and Acute Cardiomyopathy).1 In light of these clinical findings, coupled with rapidly deteriorating cardiogenic shock, strong consideration must be made for myocarditis. The global nature of myocardial depression with relatively low-grade troponin elevation argues against acute coronary syndrome.Dr Weiss: Because the patient was facing impending hemodynamic collapse, it was imperative to provide full mechanical circulatory support as a bridge to recovery or advanced heart failure options. The cardiogenic shock team convened, and the patient was urgently placed on venoarterial extracorporeal membrane oxygenation by femoral cannulation with a distal arterial reperfusion catheter. An Impella-CP (percutaneous left ventricular assist device) was placed to offload the left ventricle as determined by continuous hemodynamic monitoring with a pulmonary artery catheter.Patient presentation (continued): Once mechanical circulatory support was initiated, the patient’s hemodynamics stabilized and oxygen requirement was weaned to 1 L nasal cannula, avoiding the need for endotracheal intubation. The patient was treated with a dose of 400 mg of tocilizumab. Remdesivir was not available at our institution at this time.DrAlbert: Given the patient’s rapid cardiovascular decompensation with clinical suspicion of myocarditis, the decision was made to perform an endomyocardial biopsy (EMB).On hospital day 2, an echocardiogram-guided EMB of the right ventricle was performed, and the patient was empirically started on methylprednisolone 250 mg IV for 4 days. The patient had received his first dose of methylprednisolone before the EMB.DrStarling: Although the use of steroids with active fulminant myocarditis may attenuate viral clearance, in cases of cytokine storm without marked myocyte necrosis, a strategy of anti-inflammatory agents, antibody neutralization, and antivirals might be appropriate. The markedly elevated inflammatory markers in this case bore some semblance to the phenomenon of Multisystem Inflammatory Syndrome described in children and adolescents with SARS-CoV-2 infection; however, our patient developed an isolated cardiac manifestation of viral infection rather than multisystemic symptoms.Patient presentation (continued): On hospital day 3, the patient remained on mechanical circulatory support. Intravenous immunoglobulin (total dose of 2 g/kg) was given over 2 days. The patient’s end-organ function and inflammatory markers began to improve. Serial echocardiography revealed sequential improvement in his biventricular function. On hospital day 5, the patient was decannulated from both venoarterial extracorporeal membrane oxygenation and Impella during a formal weaning trial in the operating room. He remained on low-dose intravenous inotropic support. On hospital day 6, echocardiogram demonstrated normal biventricular function with left ventricular end-diastolic dimension of 5.5 cm and resolution of regurgitant valvular lesions. The patient was successfully weaned off of the intravenous inotrope and continued to demonstrate clinical stability. He was subsequently discharged in good condition on hospital day 18 on carvedilol.DrRodriguez: EMB showed mild infiltration of mononuclear cells in the endocardium and myocardium with >14 inflammatory cells per mm2 indicating myocarditis (Figure 2). There were more CD68+ macrophages than CD4+ T lymphocytes followed by few CD8+ T lymphocytes and rare neutrophils in the inflammatory infiltrate. Microvasculature showed endothelial swelling without evidence of microthrombi. Viral particles were found in cardiac myocytes by transmission electron microscopy (Figures 3 and 4). Viral particles were also present in interstitial macrophages and endothelial cells. The viral particles measure 100 nm in average diameter (range 60–120 nm), consistent with coronavirus viral particles previously reported by electron microscopy.2 The myocytes showed no degenerative or apoptotic changes.Download figureDownload PowerPointFigure 2. Endomyocardial biopsy, light microscopy. A, A small trabecula carnea is shown. There are cardiac myocytes in the core of the trabecula. Conspicuous inflammatory cells infiltrate both the endocardium and the myocardium (hematoxylin and eosin, ×100). B, Other areas of the biopsy show mild interstitial inflammatory infiltrates consisting predominantly of histiocytes with pale, slightly foamy cytoplasm. There is no evidence of necrosis or dropout of myocytes. There are no thrombi in the microvasculature or endocardial surface (hematoxylin and eosin, ×400). C, At higher magnification, the myocardium is infiltrated by histiocytes; some smaller mononuclear cells are occasional polymorphonuclear leukocytes. There is no evidence of necrosis or depolymerization of sarcomeres in the myocytes (hematoxylin and eosin, ×600).Download figureDownload PowerPointFigure 3. Transmission electron micrographs of myocardium. A, Distinct sarcomeres bound by electron dense Z-band material are shown. The architecture of the sarcomere shows no myofibrillar loss. A viral particle of coronavirus is shown in the center (scale bar, 500 nm, ×30 000). B, The area marked by the white rectangle in A demonstrates a higher magnification of the viral particle (scale bar, 200 nm, ×68 000).Download figureDownload PowerPointFigure 4. Transmission electron micrographs of myocardium showing viral particles forming in the myocyte sarcoplasm. A, Myocytes are shown in a boundary area adjacent to a capillary endothelial cell in the center-low part of the image. The frame shows the boundary of the myocyte sarcolemma and the endothelial cell (scale bar, 2000 nm, ×6800). B, Sarcomeres attaching to the sarcolemma, and abundant electron-dense α-particles of glycogen are noted. There is a distinct basement membrane (gray) lining the sarcolemma. Numerous pinocytic vesicles are noted in the sarcolemma. Some viral particles are present in closer proximity to the smooth sarcoplasmic reticulum next to the mitochondria in the white frame (scale bar, 1000 nm, ×18 500). C, At this magnification, viral particles are noted in the lower mid third of the image, nestled between smooth sarcoplasmic reticulum and between the mitochondria (scale bar, 500 nm, ×30 000). D, A viral particle is shown budding out from a membrane that contains a light electron-dense matrix consistent with a T tubule (scale bar, 200 nm, ×68 000).DrProcop: Reverse transcription (RT) PCR from a segment of the formalin-fixed, paraffin-embedded cardiac tissue following deparaffinization and nucleic acid extraction using the Centers for Disease Control and Prevention SARS-CoV-2 assay confirmed the presence of SARS-CoV-2 viral genome, an assay that has been used previously to report viral presence.3 The Centers for Disease Control and Prevention SARS-CoV-2 test consists of 3 independent RT-PCR assays targeting 3 different loci within the nucleocapsid gene, all of which must be positive for a specimen to be characterized as positive. All 3 targets were detected in the extract from the myocardial tissue. Taken together, our findings suggest the cause of myocarditis is from a virally mediated immune response rather than from an overt virally mediated myocyte destruction and necrosis. Nevertheless, we demonstrate direct myocyte infection by the SARS-CoV-2 virus.DiscussionTo our knowledge, this patient represents the first documented case of direct myocardial infection by SARS-CoV-2 leading to acute cardiogenic shock in the absence of pulmonary infection. Previous reports have shown the presence of virus in the myocardium via postmortem RT-PCR, but our case is the first to demonstrate active histological findings of myocarditis, electron microscopy revealing coronavirus in the myocytes, and RT-PCR of myocardial tissue positive for 3 known nucleocapsids for SARS-CoV-2. We have demonstrated evidence of myocarditis based on the presence of inflammatory infiltrates and with visualization of viral particles within the myocyte.Viral-Mediated InflammationThe histological findings in hearts from autopsies and EMBs published thus far from patients with SARS-CoV-2 have ranged from no evidence of myocardial inflammation to low-grade inflammation without myocyte necrosis to frank myocarditis. A case of biopsy-proven SARS-CoV-2–induced myocarditis resulting in cardiogenic shock has previously been published by Tavazzi et al,4 but this case did not find evidence of myocyte infection by SARS-CoV-2. Unique to our report is the pathological documentation of direct infection of cardiac myocytes by the virus in the setting of isolated cardiac involvement.Postmortem RT-PCR from heart tissue has shown detectable viral load as evidence of cardiac tropism of SARS-CoV-2 despite the absence or low incidence of myocarditis on histology.5 The positive RT-PCR result from paraffin-embedded tissue in our case further complements the histological and ultrastructural evidence of myocarditis secondary to SARS-CoV-2 cardiotropism. However, investigations to understand the mechanisms of myocardial injury in SARS-CoV-2 infection remain limited.Our EMB findings are notable for inflammation of the myocardium with predominance of macrophages and lack of overt myocyte necrosis, suggesting that the cause of cardiogenic shock is an inflammatory response rather than viral-mediated myocyte destruction. We acknowledge that coinfection with another virus is possible, although it is unlikely because we found no evidence of coinfection based on the respiratory viral PCR panel from a nasopharyngeal swab.Treatment ConsiderationsMany common forms of acute fulminant viral myocarditis can rapidly improve with supportive care. Our case supports the notion that patients with SARS-CoV-2–related cardiogenic shock can recover with aggressive supportive care. Rapid recognition of cardiogenic shock followed by deployment of mechanical circulatory support allowed for stabilization of our patient’s hemodynamics, minimizing additional secondary organ dysfunction. The utility of EMB to guide treatment in suspected SARS-CoV-2 myocardial suppression remains an important question. We believe that EMB with evidence of myocardial inflammation and viral cardiotropism aided our clinical decision making.ConclusionsWe report a case of rapid-onset, reversible, acute heart failure from SARS-CoV-2 infection presenting as isolated cardiogenic shock. The EMB demonstrated direct viral infection of the myocardium and myocardial inflammatory cells. Although these findings do not conclusively prove a cause-and-effect relationship between SARS-CoV-2 and cardiac dysfunction, this is the first demonstration of viral particles present in the myocytes in the context of isolated acute systolic dysfunction with subsequent recovery. Patients presenting with SARS-CoV-2 infection and hemodynamic collapse should be evaluated for cardiogenic shock and, when necessary, rapid escalation of care through mechanical circulatory support may successfully bridge patients to myocardial recovery.AcknowledgmentsThe authors thank Drs Stephens, Krishnaswamy, Howard, Unai, and Estep for their significant contributions to the clinical care of this patient. The authors also thank Dr Tan for her contributions to analysis of pathology, along with Dr Hitomi, J. Horn, and T. Junkovic for tissue processing and electron microscopy, and M. Tuohy and S. Vogel for performing the reverse transcription polymerase chain reaction of formalin-fixed tissue.DisclosuresNone.Footnoteshttps://www.ahajournals.org/journal/circChonyang L. Albert, MD, Cleveland Clinic, Department of Cardiovascular Medicine, 9500 Euclid Ave J3-4, Cleveland, OH 44195. Email Albertc2@ccf.orgReferences1. 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Tavazzi G, Pellegrini C, Maurelli M, Belliato M, Sciutti F, Bottazzi A, Sepe PA, Resasco T, Camporotondo R, Bruno R, et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock.Eur J Heart Fail. 2020; 22:911–915. doi: 10.1002/ejhf.1828CrossrefMedlineGoogle Scholar5. Tian S, Xiong Y, Liu H, Niu L, Guo J, Liao M, Xiao SY. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies.Mod Pathol. 2020; 33:1007–1014. doi: 10.1038/s41379-020-0536-xCrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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Jaiswal V, Sarfraz Z, Sarfraz A, Mukherjee D, Batra N, Hitawala G, Yaqoob S, Patel A, Agarwala P, Ruchika , Sarfraz M, Bano S, Azeem N, Naz S, Jaiswal A, Sharma P and Chaudhary G (2021) COVID-19 Infection and Myocarditis: A State-of-the-Art Systematic Review, Journal of Primary Care & Community Health, 10.1177/21501327211056800, 12, (215013272110568), Online publication date: 1-Jan-2021. Verma A and Vader J (2021) Building Experience and Evidence, Circulation: Cardiovascular Imaging, 14:1, Online publication date: 1-Jan-2021. November 10, 2020Vol 142, Issue 19 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.050097PMID: 32997947 Originally publishedSeptember 30, 2020 Keywordsmyocarditisinflammationshock, cardiogenicsevere acute respiratory syndrome coronavirus 2PDF download Advertisement SubjectsHeart FailureInflammatory Heart Disease