{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T23:39:42Z","timestamp":1788305982753,"version":"build-2803163510"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2020,7,8]],"date-time":"2020-07-08T00:00:00Z","timestamp":1594166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81830072"],"award-info":[{"award-number":["81830072"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly binds to ACE2 (angiotensin-converting enzyme 2) to facilitate cellular entry. Compared with the lung or respiratory tract, the human heart exhibits greater ACE2 expression. However, little substantial damage was found in the heart tissue, and no viral particles were observed in the cardiac myocytes. This study aims to analyse ACE2 and SARS-CoV-2 spike (S) protein proteases at the single-cell level, to explore the cardiac involvement in COVID-19 and improve our understanding of the potential cardiovascular implications of COVID-19.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and Results<\/jats:title>\n                  <jats:p>With meta-analysis, the prevalence of cardiac injury in COVID-19 patients varies from 2% [95% confidence interval (CI) 0\u20135%, I2 = 0%] in non-ICU patients to 59% (95% CI 48\u201371%, I2 = 85%) in non-survivors. With public single-cell sequence data analysis, ACE2 expression in the adult human heart is higher than that in the lung (adjusted P &amp;lt; 0.0001). Inversely, the most important S protein cleavage protease TMPRSS2 (transmembrane protease serine protease-2) in the heart exhibits an extremely lower expression than that in the lung (adjusted P &amp;lt; 0.0001), which may restrict entry of SARS-CoV-2 into cardiac cells. Furthermore, we discovered that other S protein proteases, CTSL (cathepsin L) and FURIN (furin, paired basic amino acid cleaving enzyme), were expressed in the adult heart at a similar level to that in the lung, which may compensate for TMPRSS2, mediating cardiac involvement in COVID-19.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Compared with the lung, ACE2 is relatively more highly expressed in the human heart, while the key S protein priming protease, TMPRSS2, is rarely expressed. The low percentage of ACE2+\/TMPRSS2+ cells reduced heart vulnerability to SARS-CoV-2 to some degree. CTSL and FURIN may compensate for S protein priming to mediate SARS-CoV-2 infection of the heart.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvaa191","type":"journal-article","created":{"date-parts":[[2020,7,1]],"date-time":"2020-07-01T03:20:00Z","timestamp":1593573600000},"page":"1733-1741","source":"Crossref","is-referenced-by-count":83,"title":["Single-cell analysis of SARS-CoV-2 receptor ACE2 and spike protein priming expression of proteases in the human heart"],"prefix":"10.1093","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9760-207X","authenticated-orcid":false,"given":"Hanning","family":"Liu","sequence":"first","affiliation":[{"name":"National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China"},{"name":"Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujie","family":"Gai","sequence":"additional","affiliation":[{"name":"National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China"},{"name":"Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Wang","sequence":"additional","affiliation":[{"name":"National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China"},{"name":"Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juntong","family":"Zeng","sequence":"additional","affiliation":[{"name":"National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China"},{"name":"Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6284-7635","authenticated-orcid":false,"given":"Cheng","family":"Sun","sequence":"additional","affiliation":[{"name":"National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China"},{"name":"Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhao","sequence":"additional","affiliation":[{"name":"National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9162-6492","authenticated-orcid":false,"given":"Zhe","family":"Zheng","sequence":"additional","affiliation":[{"name":"National Clinical Research Center of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China"},{"name":"Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China"},{"name":"National Health Commission Key Laboratory of Cardiovascular Regenerative Medicine, Zhengzhou, PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,7,8]]},"reference":[{"key":"2020072414270442000_cvaa191-B1","first-page":"465","article-title":"Spread of SARS-CoV-2","volume":"26","author":"Stower","year":"2020","journal-title":"Nat Med"},{"key":"2020072414270442000_cvaa191-B2","doi-asserted-by":"crossref","DOI":"10.1001\/jamacardio.2020.1286","article-title":"Potential effects of coronaviruses on the cardiovascular system","author":"Madjid","year":"2020","journal-title":"JAMA Cardiol"},{"key":"2020072414270442000_cvaa191-B3","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0140-6736(20)30566-3","article-title":"Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study","volume":"395","author":"Zhou","year":"2020","journal-title":"Lancet"},{"key":"2020072414270442000_cvaa191-B4","doi-asserted-by":"crossref","DOI":"10.1016\/j.jaci.2020.04.006","article-title":"Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan","author":"Li","year":"2020","journal-title":"J Allergy Clin Immunol"},{"key":"2020072414270442000_cvaa191-B5","doi-asserted-by":"crossref","DOI":"10.1001\/jamacardio.2020.0950","article-title":"Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan","author":"Shi","year":"2020","journal-title":"China. JAMA Cardiol"},{"key":"2020072414270442000_cvaa191-B6","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1007\/s00134-020-05985-9","article-title":"Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target","volume":"46","author":"Zhang","year":"2020","journal-title":"Intensive Care Med"},{"key":"2020072414270442000_cvaa191-B7","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"2020072414270442000_cvaa191-B8","doi-asserted-by":"crossref","first-page":"e105114","DOI":"10.15252\/embj.20105114","article-title":"SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells","volume":"39","author":"Lukassen","year":"2020","journal-title":"EMBO J"},{"key":"2020072414270442000_cvaa191-B9","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s11684-020-0754-0","article-title":"Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection","volume":"14","author":"Zou","year":"2020","journal-title":"Front Med"},{"key":"2020072414270442000_cvaa191-B10","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/S2213-2600(20)30076-X","article-title":"Pathological findings of COVID-19 associated with acute respiratory distress syndrome","volume":"8","author":"Xu","year":"2020","journal-title":"Lancet Respir Med"},{"key":"2020072414270442000_cvaa191-B11","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1002\/ejhf.1828","article-title":"Myocardial localization of coronavirus in COVID-19 cardiogenic shock","volume":"22","author":"Tavazzi","year":"2020","journal-title":"Eur J Heart Fail"},{"key":"2020072414270442000_cvaa191-B12","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1016\/j.celrep.2019.01.079","article-title":"Single-cell transcriptome analysis maps the developmental track of the human heart","volume":"26","author":"Cui","year":"2019","journal-title":"Cell Rep"},{"key":"2020072414270442000_cvaa191-B13","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1038\/s41591-019-0512-5","article-title":"Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis","volume":"25","author":"Wirka","year":"2019","journal-title":"Nat Med"},{"key":"2020072414270442000_cvaa191-B14","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/s41556-019-0446-7","article-title":"Single-cell reconstruction of the adult human heart during heart failure and recovery reveals the cellular landscape underlying cardiac function","volume":"22","author":"Wang","year":"2020","journal-title":"Nat Cell Biol"},{"key":"2020072414270442000_cvaa191-B15","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive integration of single-cell data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"2020072414270442000_cvaa191-B16","doi-asserted-by":"crossref","first-page":"D721","DOI":"10.1093\/nar\/gky900","article-title":"CellMarker: a manually curated resource of cell markers in human and mouse","volume":"47","author":"Zhang","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"2020072414270442000_cvaa191-B17","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"2020072414270442000_cvaa191-B18","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/S0006-3223(98)00043-2","article-title":"Multiple correlations and Bonferroni\u2019s correction","volume":"44","author":"Curtin","year":"1998","journal-title":"Biol Psychiatry"},{"key":"2020072414270442000_cvaa191-B19","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1080\/01621459.1952.10483441","article-title":"Use of ranks in one-criterion variance analysis","volume":"47","author":"Kruskal","year":"1952","journal-title":"J Am Stat Assoc"},{"key":"2020072414270442000_cvaa191-B20","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.cell.2020.04.035","article-title":"HCA Lung Biological Network. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues","volume":"181","author":"Ziegler","year":"2020","journal-title":"Cell"},{"key":"2020072414270442000_cvaa191-B21","doi-asserted-by":"crossref","first-page":"104742","DOI":"10.1016\/j.antiviral.2020.104742","article-title":"The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade","volume":"176","author":"Coutard","year":"2020","journal-title":"Antiviral Res"},{"key":"2020072414270442000_cvaa191-B22","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cell.2020.02.058","article-title":"Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein","volume":"181","author":"Walls","year":"2020","journal-title":"Cell"},{"key":"2020072414270442000_cvaa191-B23","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1056\/NEJMc2005073","article-title":"SARS-CoV-2 infection in children","volume":"382","author":"Lu","year":"2020","journal-title":"N Engl J Med"},{"key":"2020072414270442000_cvaa191-B24","author":"Bryce","year":"2005"},{"key":"2020072414270442000_cvaa191-B25","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/S0140-6736(20)30937-5","article-title":"Endothelial cell infection and endotheliitis in COVID-19","volume":"395","author":"Varga","year":"2020","journal-title":"Lancet"},{"key":"2020072414270442000_cvaa191-B26","doi-asserted-by":"crossref","DOI":"10.1201\/9780429281808","volume-title":"The Endothelium: Modulator of Cardiovascular Function","author":"Luscher","year":"2020"},{"key":"2020072414270442000_cvaa191-B27","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1016\/j.lfs.2005.09.038","article-title":"Age- and gender-related difference of ACE2 expression in rat lung","volume":"78","author":"Xie","year":"2006","journal-title":"Life Sci"},{"key":"2020072414270442000_cvaa191-B28","doi-asserted-by":"crossref","DOI":"10.1001\/jamacardio.2020.1329","article-title":"The dilemma of coronavirus disease 2019, aging, and cardiovascular disease: insights from cardiovascular aging science","author":"AlGhatrif","year":"2020","journal-title":"JAMA Cardiol"},{"key":"2020072414270442000_cvaa191-B29","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1093\/eurheartj\/ehaa231","article-title":"Coronaviruses and the cardiovascular system: acute and long-term implications","volume":"41","author":"Xiong","year":"2020","journal-title":"Eur Heart J"},{"key":"2020072414270442000_cvaa191-B30","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/s41569-020-0360-5","article-title":"COVID-19 and the cardiovascular system","volume":"17","author":"Zheng","year":"2020","journal-title":"Nat Rev Cardiol"},{"key":"2020072414270442000_cvaa191-B31","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.bbrc.2020.03.044","article-title":"Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses","volume":"526","author":"Qi","year":"2020","journal-title":"Biochem Biophys Res Commun"},{"key":"2020072414270442000_cvaa191-B32","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1136\/gutjnl-2020-320832","article-title":"Diarrhoea may be underestimated: a missing link in 2019 novel coronavirus","volume":"69","author":"Liang","year":"2020","journal-title":"Gut"},{"key":"2020072414270442000_cvaa191-B33","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1053\/j.gastro.2020.02.055","article-title":"Evidence for gastrointestinal infection of SARS-CoV-2","volume":"158","author":"Xiao","year":"2020","journal-title":"Gastroenterology"},{"key":"2020072414270442000_cvaa191-B34","article-title":"Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin","volume":"41","author":"Hu","year":"2020","journal-title":"Eur Heart J"},{"key":"2020072414270442000_cvaa191-B35","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.1093\/eurheartj\/ehaa253","article-title":"Life-threatening cardiac tamponade complicating myo-pericarditis in COVID-19","volume":"41","author":"Hua","year":"2020","journal-title":"Eur Heart J"},{"key":"2020072414270442000_cvaa191-B36","doi-asserted-by":"crossref","DOI":"10.1001\/jamacardio.2020.1096","article-title":"Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19)","author":"Inciardi","year":"2020","journal-title":"JAMA Cardiol"},{"key":"2020072414270442000_cvaa191-B37","doi-asserted-by":"crossref","DOI":"10.1093\/cvr\/cvaa093","article-title":"The role of angiotensin-converting enzyme 2 in coronaviruses\/influenza viruses and cardiovascular disease","author":"Chen","year":"2020","journal-title":"Cardiovasc Res"}],"container-title":["Cardiovascular Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/cardiovascres\/article-pdf\/116\/10\/1733\/33529799\/cvaa191.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/cardiovascres\/advance-article-pdf\/doi\/10.1093\/cvr\/cvaa191\/33515187\/cvaa191.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/cardiovascres\/article-pdf\/116\/10\/1733\/33529799\/cvaa191.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,24]],"date-time":"2020-07-24T18:30:07Z","timestamp":1595615407000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cardiovascres\/article\/116\/10\/1733\/5868565"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,8]]},"references-count":37,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,7,8]]},"published-print":{"date-parts":[[2020,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/cvr\/cvaa191","relation":{},"ISSN":["0008-6363","1755-3245"],"issn-type":[{"value":"0008-6363","type":"print"},{"value":"1755-3245","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,8,1]]},"published":{"date-parts":[[2020,7,8]]}}}