Pathophysiological Characteristics and Therapeutic Approaches for Pulmonary Injury and Cardiovascular Complications of Coronavirus Disease 2019
Identifieur interne : 001713 ( Pmc/Corpus ); précédent : 001712; suivant : 001714Pathophysiological Characteristics and Therapeutic Approaches for Pulmonary Injury and Cardiovascular Complications of Coronavirus Disease 2019
Auteurs : Yong-Jian Geng ; Zhi-Yao Wei ; Hai-Yan Qian ; Ji Huang ; Robert Lodato ; Richard J. CastriottaSource :
- Cardiovascular Pathology [ 1054-8807 ] ; 2020.
Abstract
The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a major health crisis, with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) having infected over a million people around the world within a few months of its identification as a human pathogen. Initially, SARS-CoV-2 infects cells in the respiratory system and causes inflammation and cell death. Subsequently, the virus spreads out and damages other vital organs and tissues, triggering a complicated spectrum of pathophysiological changes and symptoms, including cardiovascular complications. Acting as the receptor for SARS-CoV entering mammalian cells, angiotensin converting enzyme-2 (ACE2) plays a pivotal role in the regulation of cardiovascular cell function. Diverse clinical manifestations and laboratory abnormalities occur in patients with cardiovascular injury in COVID-19, characterizing the development of this complication, as well as providing clues to diagnosis and treatment. This review provides a summary of the rapidly appearing laboratory and clinical evidence for the pathophysiology and therapeutic approaches to COVID-19 pulmonary and cardiovascular complications.
Url:
DOI: 10.1016/j.carpath.2020.107228
PubMed: NONE
PubMed Central: 7162778
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Pathophysiological Characteristics and Therapeutic Approaches for Pulmonary Injury and Cardiovascular Complications of Coronavirus Disease 2019</title><author><name sortKey="Geng, Yong Jian" sort="Geng, Yong Jian" uniqKey="Geng Y" first="Yong-Jian" last="Geng">Yong-Jian Geng</name><affiliation><nlm:aff id="aff0001">Department of Internal Medicine, McGovern School of Medicine, University of Texas Health Science Center at Houston, Texas, USA</nlm:aff></affiliation></author><author><name sortKey="Wei, Zhi Yao" sort="Wei, Zhi Yao" uniqKey="Wei Z" first="Zhi-Yao" last="Wei">Zhi-Yao Wei</name><affiliation><nlm:aff id="aff0002">Center for Coronary Heart Disease, Department of Cardiology, Fu Wai Hospital, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Qian, Hai Yan" sort="Qian, Hai Yan" uniqKey="Qian H" first="Hai-Yan" last="Qian">Hai-Yan Qian</name><affiliation><nlm:aff id="aff0002">Center for Coronary Heart Disease, Department of Cardiology, Fu Wai Hospital, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Huang, Ji" sort="Huang, Ji" uniqKey="Huang J" first="Ji" last="Huang">Ji Huang</name><affiliation><nlm:aff id="aff0003">Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Lodato, Robert" sort="Lodato, Robert" uniqKey="Lodato R" first="Robert" last="Lodato">Robert Lodato</name><affiliation><nlm:aff id="aff0001">Department of Internal Medicine, McGovern School of Medicine, University of Texas Health Science Center at Houston, Texas, USA</nlm:aff></affiliation></author><author><name sortKey="Castriotta, Richard J" sort="Castriotta, Richard J" uniqKey="Castriotta R" first="Richard J." last="Castriotta">Richard J. Castriotta</name><affiliation><nlm:aff id="aff0001">Department of Internal Medicine, McGovern School of Medicine, University of Texas Health Science Center at Houston, Texas, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff0004">Division of Pulmonary, Critical and Sleep Medicine, University of South California Keck School of Medicine, Los Angeles, California, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmc">7162778</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162778</idno><idno type="RBID">PMC:7162778</idno><idno type="doi">10.1016/j.carpath.2020.107228</idno><idno type="pmid">NONE</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">001713</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001713</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Pathophysiological Characteristics and Therapeutic Approaches for Pulmonary Injury and Cardiovascular Complications of Coronavirus Disease 2019</title><author><name sortKey="Geng, Yong Jian" sort="Geng, Yong Jian" uniqKey="Geng Y" first="Yong-Jian" last="Geng">Yong-Jian Geng</name><affiliation><nlm:aff id="aff0001">Department of Internal Medicine, McGovern School of Medicine, University of Texas Health Science Center at Houston, Texas, USA</nlm:aff></affiliation></author><author><name sortKey="Wei, Zhi Yao" sort="Wei, Zhi Yao" uniqKey="Wei Z" first="Zhi-Yao" last="Wei">Zhi-Yao Wei</name><affiliation><nlm:aff id="aff0002">Center for Coronary Heart Disease, Department of Cardiology, Fu Wai Hospital, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Qian, Hai Yan" sort="Qian, Hai Yan" uniqKey="Qian H" first="Hai-Yan" last="Qian">Hai-Yan Qian</name><affiliation><nlm:aff id="aff0002">Center for Coronary Heart Disease, Department of Cardiology, Fu Wai Hospital, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Huang, Ji" sort="Huang, Ji" uniqKey="Huang J" first="Ji" last="Huang">Ji Huang</name><affiliation><nlm:aff id="aff0003">Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Lodato, Robert" sort="Lodato, Robert" uniqKey="Lodato R" first="Robert" last="Lodato">Robert Lodato</name><affiliation><nlm:aff id="aff0001">Department of Internal Medicine, McGovern School of Medicine, University of Texas Health Science Center at Houston, Texas, USA</nlm:aff></affiliation></author><author><name sortKey="Castriotta, Richard J" sort="Castriotta, Richard J" uniqKey="Castriotta R" first="Richard J." last="Castriotta">Richard J. Castriotta</name><affiliation><nlm:aff id="aff0001">Department of Internal Medicine, McGovern School of Medicine, University of Texas Health Science Center at Houston, Texas, USA</nlm:aff></affiliation><affiliation><nlm:aff id="aff0004">Division of Pulmonary, Critical and Sleep Medicine, University of South California Keck School of Medicine, Los Angeles, California, USA</nlm:aff></affiliation></author></analytic><series><title level="j">Cardiovascular Pathology</title><idno type="ISSN">1054-8807</idno><idno type="eISSN">1879-1336</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Highlights</title><p><list list-type="simple" id="celist0001"><list-item id="celistitem0001"><label>•</label><p id="para0001">The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a major health crisis, with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) having infected over a million people around the world within a few months of its identification as a human pathogen.</p></list-item><list-item id="celistitem0002"><label>•</label><p id="para0002">Initially, SARS-CoV-2 infects cells in the respiratory system and causes inflammation and cell death.</p></list-item><list-item id="celistitem0003"><label>•</label><p id="para0003">Subsequently, the virus spreads out and damages other vital organs and tissues, triggering a complicated spectrum of pathophysiological changes and symptoms, including cardiovascular complications.</p></list-item><list-item id="celistitem0004"><label>•</label><p id="para0004">Acting as the receptor for SARS-CoV entering mammalian cells, angiotensin converting enzyme-2 (ACE2) plays a pivotal role in the regulation of cardiovascular cell function.</p></list-item><list-item id="celistitem0005"><label>•</label><p id="para0005">Diverse clinical manifestations and laboratory abnormalities occur in patients with cardiovascular injury in COVID-19, characterizing the development of this complication, as well as providing clues to diagnosis and treatment.</p></list-item><list-item id="celistitem0006"><label>•</label><p id="para0006">This review provides a summary of the rapidly appearing laboratory and clinical evidence for the pathophysiology and therapeutic approaches to COVID-19 pulmonary and cardiovascular complications.</p></list-item></list></p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Sun, P" uniqKey="Sun P">P. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Cardiovasc Pathol</journal-id><journal-id journal-id-type="iso-abbrev">Cardiovasc. Pathol</journal-id><journal-title-group><journal-title>Cardiovascular Pathology</journal-title></journal-title-group><issn pub-type="ppub">1054-8807</issn><issn pub-type="epub">1879-1336</issn><publisher><publisher-name>Published by Elsevier Inc.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmc">7162778</article-id><article-id pub-id-type="publisher-id">S1054-8807(20)30032-6</article-id><article-id pub-id-type="doi">10.1016/j.carpath.2020.107228</article-id><article-id pub-id-type="publisher-id">107228</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Pathophysiological Characteristics and Therapeutic Approaches for Pulmonary Injury and Cardiovascular Complications of Coronavirus Disease 2019</article-title></title-group><contrib-group><contrib contrib-type="author" id="au0001"><name><surname>Geng</surname><given-names>Yong-Jian</given-names></name><email>yong-jian.geng@uth.tmc.edu</email><xref rid="aff0001" ref-type="aff">a</xref><xref rid="cor0001" ref-type="corresp">⁎</xref></contrib><contrib contrib-type="author" id="au0002"><name><surname>Wei</surname><given-names>Zhi-Yao</given-names></name><xref rid="aff0002" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au0003"><name><surname>Qian</surname><given-names>Hai-Yan</given-names></name><xref rid="aff0002" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au0004"><name><surname>Huang</surname><given-names>Ji</given-names></name><xref rid="aff0003" ref-type="aff">c</xref></contrib><contrib contrib-type="author" id="au0005"><name><surname>Lodato</surname><given-names>Robert</given-names></name><xref rid="aff0001" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au0006"><name><surname>Castriotta</surname><given-names>Richard J.</given-names></name><xref rid="aff0001" ref-type="aff">a</xref><xref rid="aff0004" ref-type="aff">d</xref></contrib></contrib-group><aff id="aff0001"><label>a</label>Department of Internal Medicine, McGovern School of Medicine, University of Texas Health Science Center at Houston, Texas, USA</aff><aff id="aff0002"><label>b</label>Center for Coronary Heart Disease, Department of Cardiology, Fu Wai Hospital, National Center for Cardiovascular Diseases of China, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China</aff><aff id="aff0003"><label>c</label>Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China</aff><aff id="aff0004"><label>d</label>Division of Pulmonary, Critical and Sleep Medicine, University of South California Keck School of Medicine, Los Angeles, California, USA</aff><author-notes><corresp id="cor0001"><label>⁎</label>Corresponding author: Yong-Jian Geng, MD, PhD, Professor and Director, The Center for Cardiovascular Biology and Atherosclerosis Research, McGovern Medical School University of Texas Health Science at Houston (UTHealth), Houston, Texas, USA, Telephone: 713-500-6590. <email>yong-jian.geng@uth.tmc.edu</email></corresp></author-notes><pub-date pub-type="pmc-release"><day>17</day><month>4</month><year>2020</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="epub"><day>17</day><month>4</month><year>2020</year></pub-date><elocation-id>107228</elocation-id><permissions><copyright-statement>© 2020 Published by Elsevier Inc.</copyright-statement><copyright-year>2020</copyright-year><copyright-holder></copyright-holder><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions><abstract abstract-type="author-highlights" id="abs0001"><title>Highlights</title><p><list list-type="simple" id="celist0001"><list-item id="celistitem0001"><label>•</label><p id="para0001">The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a major health crisis, with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) having infected over a million people around the world within a few months of its identification as a human pathogen.</p></list-item><list-item id="celistitem0002"><label>•</label><p id="para0002">Initially, SARS-CoV-2 infects cells in the respiratory system and causes inflammation and cell death.</p></list-item><list-item id="celistitem0003"><label>•</label><p id="para0003">Subsequently, the virus spreads out and damages other vital organs and tissues, triggering a complicated spectrum of pathophysiological changes and symptoms, including cardiovascular complications.</p></list-item><list-item id="celistitem0004"><label>•</label><p id="para0004">Acting as the receptor for SARS-CoV entering mammalian cells, angiotensin converting enzyme-2 (ACE2) plays a pivotal role in the regulation of cardiovascular cell function.</p></list-item><list-item id="celistitem0005"><label>•</label><p id="para0005">Diverse clinical manifestations and laboratory abnormalities occur in patients with cardiovascular injury in COVID-19, characterizing the development of this complication, as well as providing clues to diagnosis and treatment.</p></list-item><list-item id="celistitem0006"><label>•</label><p id="para0006">This review provides a summary of the rapidly appearing laboratory and clinical evidence for the pathophysiology and therapeutic approaches to COVID-19 pulmonary and cardiovascular complications.</p></list-item></list></p></abstract><abstract id="abs0002"><p>The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a major health crisis, with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) having infected over a million people around the world within a few months of its identification as a human pathogen. Initially, SARS-CoV-2 infects cells in the respiratory system and causes inflammation and cell death. Subsequently, the virus spreads out and damages other vital organs and tissues, triggering a complicated spectrum of pathophysiological changes and symptoms, including cardiovascular complications. Acting as the receptor for SARS-CoV entering mammalian cells, angiotensin converting enzyme-2 (ACE2) plays a pivotal role in the regulation of cardiovascular cell function. Diverse clinical manifestations and laboratory abnormalities occur in patients with cardiovascular injury in COVID-19, characterizing the development of this complication, as well as providing clues to diagnosis and treatment. This review provides a summary of the rapidly appearing laboratory and clinical evidence for the pathophysiology and therapeutic approaches to COVID-19 pulmonary and cardiovascular complications.</p></abstract><abstract abstract-type="graphical" id="abs0003"><title>Graphical abstract</title><p><fig id="fig0003" position="anchor"><alt-text id="alttx001">Image, graphical abstract</alt-text><graphic xlink:href="fx1_lrg"></graphic></fig></p></abstract><kwd-group id="keys0001"><title>Keywords</title><kwd>Coronavirus</kwd><kwd>Lung</kwd><kwd>Heart</kwd><kwd>Blood vessels</kwd><kwd>Infection</kwd><kwd>Injury</kwd></kwd-group></article-meta></front><body><p id="para9001"><def-list><def-item><term id="dt0001">α-HBDH</term><def><p id="para0007">α-hydroxybutyrate dehydrogenase</p></def></def-item><def-item><term id="dt0002">ARDS</term><def><p id="para0008">acute respiratory distress syndrome</p></def></def-item><def-item><term id="dt0003">CCL2</term><def><p id="para0009">C-C motif chemokine ligand 2</p></def></def-item><def-item><term id="dt0004">COVID-19</term><def><p id="para0010">Coronavirus disease 2019</p></def></def-item><def-item><term id="dt0005">EAT</term><def><p id="para0011">epicardial adipose tissue</p></def></def-item><def-item><term id="dt0006">MERS-CoV</term><def><p id="para0012">middle east respiratory syndrome coronavirus</p></def></def-item><def-item><term id="dt0007">RAS</term><def><p id="para0013">renin–angiotensin system</p></def></def-item><def-item><term id="dt0008">SARS-CoV-2</term><def><p id="para0014">severe acute respiratory syndrome coronavirus 2</p></def></def-item><def-item><term id="dt0009">SARS-CoV</term><def><p id="para0015">severe acute respiratory syndrome coronavirus</p></def></def-item><def-item><term id="dt0010">TACE</term><def><p id="para0016">Tumor Necrosis Factor-α-converting enzyme</p></def></def-item><def-item><term id="dt0011">TMPRSS2</term><def><p id="para0017">type II transmembrane serine proteases</p></def></def-item></def-list></p><sec id="sec0001"><label>1</label><title>Introduction</title><p id="para0018">Since December 2019, an acute severe viral infectionivolving primarily the respiratory system has emerged with rapid transmission around the world to over a million people within a few months. Named <italic>coronavirus disease 2019 (COVID-19)</italic> by the World health organization <xref rid="bib0001" ref-type="bibr">[1]</xref>, the disease pandemic has resulted in a major health crisis. The pathogen of COVID-19 has been attributed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel beta coronavirus closely related to severe acute respiratory syndrome coronavirus (SARS-CoV) <xref rid="bib0002" ref-type="bibr">[2]</xref>. COVID-19 has resulted in many infections and death throughout the world <xref rid="bib0003" ref-type="bibr">[3]</xref>. Unlike those seen in influenza, the morbidity and transmission modality of COVID-19 appear more severe and uncontrollable <xref rid="bib0004" ref-type="bibr">[4]</xref>. The primary pulmonary injury and subsequent cardiovascular complications constitute the key pathophysiology of this deadly disease. This review updates and summarizes the pathophysiological features, possible underlying mechanisms, and clinical characteristics of pulmonary and cardiovascular injury of COVID-19.</p></sec><sec id="sec0002"><label>2</label><title>Pathogen(s) of COVID-19</title><p id="para0019">The highly contagious virus, SARS-CoV-2, has been identified as the primary pathogen responsible for the development of COVID-19. It belongs to the Coronaviridae family <xref rid="bib0005" ref-type="bibr">[5]</xref>. Structurally and functionally similar to most members of the Betacoranavirus Subgroup B, SARS-CoV-2 (<xref rid="fig0001" ref-type="fig">Fig. 1</xref>) has thought to be descended from a bat gene pool as the seventh member of coronavirus family known to infect humans, and comprises a positive-sense single-stranded RNA with 50–200nm in size <xref rid="bib0006" ref-type="bibr">[6]</xref>. Among the other 6 coronaviruses capable of causing illnesses, only SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) reportedly cause severe disease and fatalities <xref rid="bib0007" ref-type="bibr">[7]</xref>. Infection by the other 4 coronaviruses remains asymptomatic or mildly symptomatic in normal people. According to the full-length genome sequencing, SARS-CoV-2 is 79.5% homologous with SARS-CoV. Like SARS-CoV, SARS‐CoV‐2 infects lung alveolar epithelial cells by receptor-mediated endocytosis in association with angiotensin converting enzyme II (ACE2) <xref rid="bib0008" ref-type="bibr">[8]</xref>. An epidemiological study enrolling 44672 confirmed cases in China has indicated that the overall case-fatality rate of SARS-CoV-2 was about 2.3% <xref rid="bib0009" ref-type="bibr">[9]</xref>, whereas it was 9.6% (774/8096) in the SARS-CoV epidemic <xref rid="bib0010" ref-type="bibr">[10]</xref> and 34.4% (858/2494) in the MERS-CoV outbreak <xref rid="bib0011" ref-type="bibr">[11]</xref>. Mortality in Italy, Spain and France may be higher and closer to that of SARS-CoV. This may be due to strain variation, yet to be determined. However, in consideration of rapidly increasing numbers of confirmed cases and evidence of human-to-human transmission [<xref rid="bib0012" ref-type="bibr">12</xref>,<xref rid="bib0013" ref-type="bibr">13</xref>], the SARS-CoV-2 infectivity seems to be stronger than SARS-CoV and MERS-CoV. Ultrastructural examination of SARS-CoV-2 by cryo-electron microscopy has demonstrated that the binding affinity of SARS-CoV-2 to ACE2 appears approximately 10- to 20-fold higher than SARS-CoV, structurally explaining why SARS-CoV-2 has a high contagiousness <xref rid="bib0014" ref-type="bibr">[14]</xref>.<fig id="fig0001"><label>Fig. 1</label><caption><p>Schematic representation of the COVID-19 pathogenic virus, SARS-CoV2, invasion and triggering organ injury and symptoms. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ACE2, angiotensin converting enzyme II.</p></caption><alt-text id="alt0001">Fig 1</alt-text><graphic xlink:href="gr1_lrg"></graphic></fig></p><p id="para0020">In spite of the fact that SARS-CoV-2 has infected more than a million individuals it is largely unknown how and when the virus has been evolving and interacts with other microorganisms (<xref rid="tbl0001" ref-type="table">Table 1</xref>) in the lung and other vital organs, such as heart and brain. Shen, et al. <xref rid="bib0015" ref-type="bibr">[15]</xref> has recently reported a genomic diversity of SARS-Cov-2 in patients with COVID-19. They observed, by meta-transcriptomal sequencing for the bronchoalveolar lavage fluid samples from of COVID-19, community-acquired pneumonia, and healthy individuals. They observed a limited polymorphism and diversity in the intra-host setting, and a substantial proportion of bacteria in several COVID-19 patients, similar to other patients with non-coronaviral pneumonia. As a common complication of viral infection, especially for respiratory viruses, secondary bacterial infection often results in a significant increase in morbidity or even mortality. Indeed, in the retrospective observational study of 85 fatal cases of COVID-19, Du, et al. <xref rid="bib0016" ref-type="bibr">[16]</xref> reported that in addition to SARS-Cov-2 infection, simultaneously or secondarily, other pathogens may participate in the COVID-19 development and complications, contributing to the severity and mortality of COVID-19. Thus, co-infection of other pathogens certainly complicates the pathogenesis and management of COVID-19.<table-wrap position="float" id="tbl0001"><label>Table 1</label><caption><p>Co-pathogens of COVID-19*.</p></caption><alt-text id="alt0003">Table 1</alt-text><table frame="hsides" rules="groups"><thead><tr><th valign="top"><italic>Virus</italic></th><th valign="top"><italic>% cases</italic></th></tr></thead><tbody><tr><td valign="top">Sars-CoV2</td><td valign="top">100%</td></tr><tr><td valign="top">Respiratory syncytial virus</td><td valign="top">33.3%</td></tr><tr><td valign="top">Influenza A virus</td><td valign="top">9.1%</td></tr><tr><td valign="top">Influenza B virus</td><td valign="top">5.3%</td></tr><tr><td valign="top"><bold><italic>Other microorganisms</italic></bold></td><td valign="top"></td></tr><tr><td valign="top">Mycoplasma</td><td valign="top">26.5%</td></tr><tr><td valign="top">Chlamydia</td><td valign="top">34.1%</td></tr><tr><td valign="top">Fungus</td><td valign="top">33.3%</td></tr></tbody></table><table-wrap-foot><fn><p>Note. *, Reference: Du, et al. Clinical Features of 85 Fatal Cases of COVID-19 from Wuhan: A Retrospective Observational Study. Am J Respir Crit Care Med, 2020</p></fn></table-wrap-foot></table-wrap></p></sec><sec id="sec0003"><label>3</label><title>Diagnosis of COVID-19</title><p id="para0021">As recommended by WHO, most countries, including the United States, have adapted similar diagnostic procedures for COVID-19 and harvest certain clinical and epidemiologic information for diagnosis (<xref rid="tbl0002" ref-type="table">Table 2</xref>). In the United States, criteria have been developed for persons under investigation (PUI) for COVID-19. People with confirmed COVID-19 usually develop fever and/or symptoms of acute respiratory illness (e.g., cough, difficulty breathing). For the PUI individuals, health care providers should immediately put him or her under infection control and prevention measures. Initially, testing for all other sources of respiratory infection is implemented while assessing epidemiologic factors to assist their diagnosis, including the information as to whether the person has had close contact with a patient with laboratory-confirmed COVID-19 within 14 days of symptom onset or a history of travel from affected geographic areas or epicenters within 14 days.<table-wrap position="float" id="tbl0002"><label>Table 2</label><caption><p>Criteria implemented for assessment and diagnosis of COVID-19.</p></caption><alt-text id="alt0004">Table 2</alt-text><table frame="hsides" rules="groups"><tbody><tr><td valign="top"><bold><italic>Epidemiological evidence</italic></bold></td></tr><tr><td valign="top">History of travel or residence in the epicenter city and surrounding areas, or other communities where COVID-19 cases had been reported in the last 14 days before symptom onset.</td></tr><tr><td valign="top">History of contact with SARS-CoV-2 infectious cases (with positive nucleic acid test).</td></tr><tr><td valign="top">History of contacting with patients with fever or respiratory symptoms from the COVID-19 epicenter of city and surrounding areas, or other communities where COVID-19 had been reported in the last 14 days before symptom onset.</td></tr><tr><td valign="top">History of contacting with a cluster of confirmed cases (≥ 2 cases with fever and/or respiratory symptoms occurred within 2 weeks in small areas, such as home, office, class of school, etc).</td></tr><tr><td valign="top"><bold><italic>Clinical Symptoms</italic></bold></td></tr><tr><td valign="top">General discomforts, typically fever, fatigue, headache, muscle ache, diarrhea, etc.</td></tr><tr><td valign="top">Signs and symptoms of lung and airway abnormalities, typically cough and dyspnea.</td></tr><tr><td valign="top"><bold><italic>Laboratory Evidence</italic></bold></td></tr><tr><td valign="top">Total white blood cell counts showing normal, decreased, or reduced lymphocyte count in the early onset stage, and increased neutrophils in more advanced cases.</td></tr><tr><td valign="top">Real-time PCR test positive for SARS-CoV-2.</td></tr><tr><td valign="top">Viral sequencing showing high homogeneity to SARS-CoV-2.</td></tr><tr><td valign="top">Serum test positive for SARS-CoV-2 specific IgM and IgG.</td></tr><tr><td valign="top"><bold><italic>Chest Imaging Evidence</italic></bold></td></tr><tr><td valign="top">Chest radiography or CT scan showing multiple mottling and ground-glass opacities with or without consolidation in the lung periphery.</td></tr></tbody></table></table-wrap></p><p id="para0022">Diagnosis of COVID-19 requires collecting specimens from both the upper respiratory tract (naso- and oropharyngeal samples) and lower respiratory tract, including the expectorated sputum, endotracheal aspirate, or bronchoalveolar lavage. The samples need to be processed quickly and stored at four degrees celsius. The reverse polymerase chain reaction (RT-PCR) assays are a standard procedure for viral genomic sequence identification, which involves the synthesis of a double-stranded DNA molecule from the RNA template. If patients are confirmed COVID-19 positively, their laboratory evaluation should be repeated to evaluate for viral clearance prior to being released from quarantine. Patients with the early stage of COVID-19 may have a normal or decreased total white blood cell count and a decreased lymphocyte count. Subsequently, neutrophils arise wit lymphopenia, and the increased ratio of neutriophils vs. lymphocytes is considered a negative prognostic factor. Patients may have increased values of LDH, muscle enzymes, and C-reactive protein. In critical patients, the thrombogenic biomarker D-dimer may increase, the counts of blood lymphocytes decline persistently, and laboratory alterations in biomarkers of multi-organ injury become prominent.</p><p id="para0023">The clinical profiles and diagnosis for COVID-19 have been well documented to date. However, new evidence is now emerging that this deadly disease is far more mystery than previously thought as many cases appeared atypical and easily misdiagnostic <xref rid="bib0017" ref-type="bibr">[17]</xref>. According to the seventh edition (3 March 2020) of COVID-19 guideline by the General Office of National Health Committee, and Office of State Administration of Traditional Chinese Medicine, China (The notice on the issuance of program for the diagnosis and treatment of COVID-19, Trial Version 7, 2020), diagnosis of suspected case needs to combine any one item of epidemiological history features with two items of clinical manifestations to make a comprehensive analysis, or needs to meet three items of clinical manifestations with or without clear epidemiological history (<xref rid="tbl0002" ref-type="table">Table 2</xref>). Wang et al. <xref rid="bib0018" ref-type="bibr">[18]</xref> suggest that diagnosing the confirmed case should base on suspected case with any one item of pathogenic or serological evidence as following: (1) real-time PCR test positive for SARS-CoV-2; (2) viral whole genome sequencing showing high homogeneity to the known novel coronaviruses; (3) positive for the specific IgM antibody and IgG antibody to SARS-CoV-2 in serum test; or a change of the SARS-CoV-2-specific IgG antibody from negative to positive, or titer rising ≥4 times in the recovery phase above that in the acute phase.</p></sec><sec id="sec0004"><label>4</label><title>Pulmonary and Cardiac Injury Caused by COVID-19</title><p id="para0024">SARS-CoV-2 mainly attacks the respiratory system, clinically characterized by the rapid development of pneumonia, and in severe cases, the acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome <xref rid="bib0019" ref-type="bibr">[19]</xref><italic>.</italic> The death rate remains high in those admitted to the intensive care and on ventilator due to complications of respiratory and cardiac failure <xref rid="bib0016" ref-type="bibr">[16]</xref>. Even though the lung is the primary organ damaged by the virus, COVID-19 is now regarded as a systemic disease, involving a broad range of other vital organs, such as heart, liver and kidney <xref rid="bib0020" ref-type="bibr">[20]</xref>. However, it remains largely unclear whether the organ and tissue injury in patients with COVID-19 is the direct or indirect consequence of the virus infection. ACE2, a known protein binding to SARS-CoV-2, is expressed widely in various organs and tissues, including the cardiovascular, digestive and urogenital systems beside the respiratory tract [<xref rid="bib0021" ref-type="bibr">21</xref>,<xref rid="bib0022" ref-type="bibr">22</xref>]. Theoretically the virus may target those organs and tissues with positive expression of ACE2. Cardiovascular cells are known to express ACE2 at high levels, which serves as a key regulator of blood pressure and cardiac contractility <xref rid="bib0023" ref-type="bibr">[23]</xref>. Moreover, the virus infection may trigger a drastic immune response which leads to production of large quantities of cytokines, i.e. “cytokine storm”, which may indiscriminately injure vital organs <xref rid="bib0024" ref-type="bibr">[24]</xref>. For instance, SARS-CoV-2 infection injures the myocardium, leading to elevated levels of myocardial biomarkers (eg, troponin I > 28 pg/mL) and certain abnormalities in electrocardiography and echocardiography <xref rid="bib0025" ref-type="bibr">[25]</xref>. Increasing clinical evidence indicates that virus infection-associated cardiac dysfunction worsen COVID-19 patient's clinical conditions usually in association with the poor prognosis [<xref rid="bib0026" ref-type="bibr">26</xref>,<xref rid="bib0027" ref-type="bibr">27</xref>]. In spite of the observation that myocardial injury occurs frequently in COVID-19 patients <xref rid="bib0028" ref-type="bibr">[28]</xref>, the underlying mechanisms remains largely unclear. Several lines of clinical evidence point to the possibility of viral infection directly occurring in the myocardium. Both direct and indirect pathogenic impacts of the virus infection may cause injury of the pulmonary and myocardial tissues (<xref rid="fig0002" ref-type="fig">Fig. 2</xref>).<fig id="fig0002"><label>Fig. 2</label><caption><p>Schematic demonstration of the viral injury to the lung and heart triggering the “Lung-Heart” syndromes with a combination of the respiratory and cardiovascular adverse events and conditions.</p></caption><alt-text id="alt0002">Fig 2</alt-text><graphic xlink:href="gr2_lrg"></graphic></fig></p><p id="para0025">In epidemiology, high prevalence of cardiovascular dysfunction has been recently reported in COVID-19 patients, especially those with critical medical conditions <xref rid="bib0029" ref-type="bibr">[29]</xref>. In a study of 138 COVID-19 patients, 10 patients (7.2%) were diagnosed as acute myocardial injury based on the elevation of high-sensitivity cardiac troponin I (hs-cTnI), and 8 of them admitted into the intensive care unit (ICU) <xref rid="bib0012" ref-type="bibr">[12]</xref>. In another retrospective study, cardiac troponin I (cTnI) was significantly elevated in 33.3% of severe and 100.0% of critical patients <xref rid="bib0030" ref-type="bibr">[30]</xref>. Huang et al. also revealed increased numbers of COVID-19 patients with acute myocardial injury and in the critical conditions leading to admission into ICU <xref rid="bib0019" ref-type="bibr">[19]</xref>.</p></sec><sec id="sec0005"><label>5</label><title>Pathological characteristics of Pulmonary and Cardiovascular Injury in COVID-19</title><p id="para0026">Recent autopsy reports have demonstrated several anatomical features of COVID-19-induced pulmonary and myocardial injury. The early lung of COVID-19 patients exhibited edema, proteinaceous exudate, focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, and multinucleated giant cells <xref rid="bib0031" ref-type="bibr">[31]</xref>. Liu et al. showed that the lung and cardiac tissues contain significant amounts of inflammatory infiltrates, indicating the inflammatory nature of tissue damage by SARS-CoV-2 infection <xref rid="bib0026" ref-type="bibr">[26]</xref>. Patients with a medical history of coronary heart disease are prone to the cardiac injury caused by COVID-19. Although there was no evidence that the acute episode of cardiac injury was caused by coronary events in this patient, one may not rule out the possibility that the underlying medical condition might have made the patient more vulnerable to the hypoxia- and cytokine storm-induced cardiac ischemia <xref rid="bib0032" ref-type="bibr">[32]</xref>. Moreover, post-mortem examinations showed moderate pericardial effusion with light yellow and clear liquid and mild epicardial edema indicative of myocardial inflammation, further suggesting that a peri-cardiac inflammatory response contributes to the myocardial dysfunction in COVID-19 patients. In a pilot study, Xu et al. <xref rid="bib0033" ref-type="bibr">[33]</xref> failed to find evidence of myocardial injury in a histopathologic case by autopsy, in which there were only a few interstitial mononuclear inflammatory infiltrates without other substantial damage in the cardiac tissue. This paradoxical result may be attributed to the small sample size and absent clinical evidence of myocardial injury in this case. Overall, future research is needed to enroll more cases with definite clinical evidence of myocardial injury to further investigate histopathologic characteristics of COVID-19-related myocardial injury. The viral infection induces an excessive immune reaction in the host, which in turn generates a 'cytokine storm', comprising released by proinflammatory cytokines known to act on cardiovascular cells [<xref rid="bib0034" ref-type="bibr">34</xref>,<xref rid="bib0035" ref-type="bibr">35</xref>]. One of the protagonists in the cytokine storm is interleukin 6 (IL-6), which is produced and released by activated leukocytes and acts on a large number of cells and tissues. IL-6 promotes the differentiation and activation of B lymphocytes, and stimulates the production of acute phase proteins.</p><p id="para0027">The severity and lethality of COVID-19 may be, at least in part, due to the viral injury to the myocardium and blood vessels. This serves as a major challenge for successful management and care of COVID-19 patients. In an observational study of 52 critical sick adult COVID-19 patients, 19 patients suffered from acute myocardial injury, and 9 of them (75%) died <xref rid="bib0029" ref-type="bibr">[29]</xref>, suggesting a higher mortality in COVID-19 patients with cardiovascular complications. Analysis of COVID-19 related death cases has confirmed that myocardial injury was one of the major causes of death. In a review of 25 death cases with COVID-19, Xun et al. found that the serum cTnI were significantly increased in 18 cases, and more COVID-19 cases with heart injury than other organ injuries except for the lung. Zhang et al. reported that 89% of 82 death cases were observed with myocardial injury, which was second only to death cases with pulmonary injury <xref rid="bib0036" ref-type="bibr">[36]</xref>. Moreover, in a study of 416 COVID-19 patients, myocardial injury was independently associated with higher risk of in-hospital mortality <xref rid="bib0027" ref-type="bibr">[27]</xref>. Hence, early myocardial injury in COVID-19 leads to a poor prognosis in COVID-19 patients.</p></sec><sec id="sec0006"><label>6</label><title>Laboratory Evidence for Inflammation and Organ Injury</title><p id="para0028">Changes of cardiac-specific biomarkers in the peripheral blood have been reported in patients with COVID-19. As stated above, hs-cTnI acts as one of the specific biomarkers of myocardial injury <xref rid="bib0037" ref-type="bibr">[37]</xref>. Other non- or less-specific myocardial biomarkers may elevate in COVID-19 cardiovascular complications as well, such as creatine kinase (CK), creatine kinase MB isoenzyme (CK-MB) and lactate dehydrogenase (LDH). However, the biomarkers may not always change in the same pattern. For instance, in a study of 99 COVID-19 patients, only 13 patients had elevation of CK while 75 patients showed LDH elevation <xref rid="bib0038" ref-type="bibr">[38]</xref>. The measurements of myocardial biomarkers are believed to possess prognostic values. In the first multi-center study <xref rid="bib0039" ref-type="bibr">[39]</xref> which enrolled 1,099 patients with laboratory-confirmed COVID-19 from 552 hospitals in China, 675 patients had measurements of serum LDH, and 277 of them showed elevated LDH levels, accounting for 58.1% of total severe cases. Moreover, increased LDH and CK were also observed in the blood of patients at the composite endpoints (the admission to ICU, mechanical ventilation, and death). The elevation of myocardial biomarkers in COVID-19 patients may offer the prognostic information useful for assessing the disease progression, and development of adverse events. Since some of the biomarkers are not specific to the myocardium, the increased nonspecific biomarkers during the development of adverse events of COVID-19 patients may reflect not only the injury to the myocardium but also other vital organs or tissues.</p><sec id="sec0007"><label>6.1</label><title>Invasion through ACE2</title><p id="para0029">SARS-CoV-2 may directly invade cardiomyocytes and subsequently result in viral myocarditis and corresponding injury. Structurally, the SARS-CoV-2 particle has an ACE2-binding domain <xref rid="bib0040" ref-type="bibr">[40]</xref>. The virus binds to human ACE2 with high affinity, and uses it as an entry receptor to invade target cells. Cryo-electron microscopy reveals the structure of the SARS-CoV-2 spike glycoprotein in two distinct conformations, along with inhibition of spike-mediated entry by SARS-CoV polyclonal antibodies, providing a blueprint for the design of vaccines and therapeutics. Although the main target is the epithelium of respiratory system, the virus may use the ACE2 path to invade cardiomyocytes directly as many cardiovascular cells express ACE2 (<xref rid="fig0002" ref-type="fig">Figure 2</xref>). SARS-CoV-2 may trigger ACE2 activation and upregulate ACE2 downstream signal transduction, including the activation of Ras-ERK–AP-1 pathway <xref rid="bib0041" ref-type="bibr">[41]</xref>. Consequently, this may induce myocardial inflammation and fibrosis and exacerbate cardiac dysfunction.</p><p id="para0030">As the cellular receptor for the entry of SARS-CoV-2, ACE2 is a monocarboxylase highly expressed in cardiac tissue <xref rid="bib0042" ref-type="bibr">[42]</xref>, and exhibits cardio-protective roles as a potent negative regulator of the renin–angiotensin system (RAS) by counterbalancing functions of ACE <xref rid="bib0043" ref-type="bibr">[43]</xref>. As a membrane protein, it can also initiate outside-in signaling <xref rid="bib0044" ref-type="bibr">[44]</xref>. SARS<bold>-</bold>CoV have been previously demonstrated to induce myocarditis in a ACE2-dependent manner <xref rid="bib0045" ref-type="bibr">[45]</xref>. The trimers of the SARS-CoV spike protein initially extends into a hydrophobic pocket of ACE2 catalytic domain <xref rid="bib0046" ref-type="bibr">[46]</xref>, which consequentially leads to the endocytosis of SARS-CoV particles and fusion of virus to cardiomyocytes with the help of type II transmembrane serine proteases (TMPRSS2) <xref rid="bib0047" ref-type="bibr">[47]</xref>, finally downregulating ACE2 expression in cardiomyocytes [<xref rid="bib0048" ref-type="bibr">48</xref>,<xref rid="bib0049" ref-type="bibr">49</xref>]. When RAS is over-activated further myocardial injury is a consequence in SARS patients. Moreover, downregulation of ACE2 may be, at least partly, caused by the shedding of ACE2 ectodomain, mediated by TNF-α-converting enzyme (TACE) in coupling with the production of TNF-α, a well-known pro-fibrotic and myocardial impairing factor <xref rid="bib0050" ref-type="bibr">[50]</xref>. The binding between SARS-CoV spike protein and ACE2 on the cardiomyocyte surface also triggers the Ras-ERK–AP-1 pathway and activates the C-C motif chemokine ligand 2 (CCL2, a pro-fibrosis factor) <xref rid="bib0041" ref-type="bibr">[41]</xref>. The above theories are supported by an autopsy report of heart samples from SARS patients, in which the presence of SARS-CoV in the heart was associated with marked down-regulation of ACE2 expression as well as a significant increase in macrophage infiltration and interstitial fibrosis, verifying ACE2 inhibition is involved in SARS-CoV-driven myocardial injury <xref rid="bib0049" ref-type="bibr">[49]</xref>.</p><p id="para0031">The specific cellular mechanism for SARS-CoV-2 invading and damaging cardiomyocytes has not been clearly demonstrated yet, but it is probable that SARS-CoV-2 shares the similar mechanism with its relative SARS-CoV. A recent study investigated ultrastructure of full-length human ACE2 with cryo-EM <xref rid="bib0051" ref-type="bibr">[51]</xref>, indicating that SARS-CoV-2 also invaded host cells via spike protein trimers binding to an ACE2 homodimer. In addition, the interface between the receptor binding domains of spike proteins on SARS-CoV-2 is quite similar to that between the SARS-CoV and ACE2. Furthermore, the serine protease TMPRSS2 is also indispensable for the entry of SARS-CoV-2 <xref rid="bib0052" ref-type="bibr">[52]</xref>. Given that the high similarity of cellular entry with that of SARS-CoV, it is reasonable to speculate that SARS-CoV-2 interferes in ACE2 expression in the same way. However, this needs to be verified in cardiomyocytes in the further study.</p></sec><sec id="sec0008"><label>6.2</label><title>Hypoxia and Ischemic Injury</title><p id="para0032">Myocardial oxygen supply is determined by coronary blood flow and its oxygen carrying capacity while myocardial oxygen demand is determined by systolic wall tension, contractility, and heart rate <xref rid="bib0053" ref-type="bibr">[53]</xref>. This physiological mechanism may be involved in SARS-CoV-2-induced myocardial injury. As is well-known, pulmonary dysfunction is the primary insult of SARS-CoV-2, which induces hypoxemia, hypotension and, in some cases, shock [<xref rid="bib0020" ref-type="bibr">20</xref>,<xref rid="bib0039" ref-type="bibr">39</xref>]. As a consequencet, an insufficient oxygen supply may occur in multiple organs including the heart. Concomitantly, myocardial oxygen demand is increased in virus-infection states, as high metabolic rate induces an augmented burden on the myocardium <xref rid="bib0054" ref-type="bibr">[54]</xref>, further causing the imbalance between myocardial oxygen supply and demand. Along with disease progression, this imbalance is increasingly aggravated, which may result in myocardial injury in COVID-2019 patients, especially for those with cardiovascular disorders who have already exhausted myocardial reserve capacity on the supply side. Other systemic contributors may include, in addition to hypoxia, respiratory and/or metabolic acidosis, fluid or electrolyte disorders and an activated neuro-humoral system following severe infection may also lead to myocardial stunning and injury, even inducing malignant arrhythmia and sudden death.</p></sec><sec id="sec0009"><label>6.3</label><title>Cytokine Storm and Inflammation</title><p id="para0033">Previous studies have confirmed that the immune abnormality is related to the pathogenesis of SARS-CoV infection <xref rid="bib0045" ref-type="bibr">[45]</xref>. Specifically, cytokine storm, an excessive and uncontrollable cytokines production in response to infection, is suggested to be the main contributor, as numerous studies have found that the expression levels of pro-inflammatory cytokines [eg, Interleukin-1β (IL-1β), IL-6, interferon-γ (IFN-γ), IFNγ inducible protein-10 (IP-10), monocyte chemoattractant protein-1(MCP-1), granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein-1α (MIP-1α), tumor necrosis factor-α (TNF-α)] are significantly increased in COVID-19 patients, associated with disease progression [<xref rid="bib0055" ref-type="bibr">55</xref>,<xref rid="bib0056" ref-type="bibr">56</xref>]. Among so many cytokines, IL-6 serves as the core of cytokine storm, given that IL-6 not only amplifies cytokine storm by stimulating production of other pro-inflammatory cytokines, but also results in vascular leakage, interstitial edema <xref rid="bib0057" ref-type="bibr">[57]</xref>. Moreover, IL-6 has also been shown to weaken papillary muscle contraction, which causes myocardial dysfunction <xref rid="bib0058" ref-type="bibr">[58]</xref>. In addition, IFNγ is also regarded as a marker of cytokine storm, causing cell apoptosis through regulating JAK/STAT1 axis and p38-MAPK1 <xref rid="bib0059" ref-type="bibr">[59]</xref>. However, anti-inflammatory cytokines such as IL-4 and IL-10 are also increased in COVID-19 patients, and their levels are also related to disease severity [<xref rid="bib0055" ref-type="bibr">55</xref>,<xref rid="bib0056" ref-type="bibr">56</xref>], demonstrating the close relation between pro- and anti-inflammation. Cytokine storm is a clear contributor to COVID-19-related myocardial injury, demonstrated by a study that revealed that increased levels of IL-6 were significantly associated with high hs-TnI levels <xref rid="bib0026" ref-type="bibr">[26]</xref>, a cardiac-selective biomarker of myocardial infarction and injury <xref rid="bib0037" ref-type="bibr">[37]</xref>. Further studies are needed to explore the cytokine expression in cardiomyocytes, which will promote a better understanding for SARS-CoV-2-induced inflammation in cardiac tissue.</p><p id="para0034">Overall, direct infection through ACE2, the imbalance between myocardial oxygen supply and demand, and the abnormal immune response constitute the most plausible explanations for myocardial injury associated with COVID-19. To be noted, however, the above speculation is mostly based on clinical observation of COVID-19. Therefore, more in-depth research is required to understand the pathophysiology of SARS-CoV-2-induced myocardial injury in order to contribute to the future development of effective treatment.</p></sec></sec><sec id="sec0010"><label>7</label><title>Clinical Symptoms and Profiles</title><p id="para0035">The general clinical symptoms found in COVID-19 patients with cardiac dysfunction are similar to those observed in influenza, such as fever (87.9%), cough (67.7%), fatigue (38.1%) , expectoration (33.4%) <xref rid="bib0039" ref-type="bibr">[39]</xref>. Additionally, confirmed cases of COVID-19 show several more-specific symptoms, such as anosmia, dysgeusia, chest pain [<xref rid="bib0026" ref-type="bibr">26</xref>,<xref rid="bib0038" ref-type="bibr">38</xref>] and palpitation <xref rid="bib0060" ref-type="bibr">[60]</xref>. Electro physiologically, COVID-19 patients are prone to the development of arrhythmia, especially tachycardia, indicative for myocardial injury. In a study of 138 COVID-19 patients, 23 patients (16.7%) presented with arrhythmia, and other evidence for myocardial injury <xref rid="bib0012" ref-type="bibr">[12]</xref>. Indeed, the COVID-19 patients with tachycardia were often in severe or critical situations. For a better understanding of the etiology of cardiac dysfunction in patients with COVID-19, researchers analyzed body temperature in different groups (mild, light, severe and critical groups), given the fact that high fever caused by the virus infection and inflammation can elevate the heart rate. The result showed that there was no significant difference in the body temperature correlation with arrhythmia between the mild and severe/critical groups. Many COVID-19 patients with tachycardia are severely ill and need critical care, as tachycardia represents a sign of a failing heart <xref rid="bib0030" ref-type="bibr">[30]</xref>.</p><p id="para0036">With regard to the imaging features of cardiac injury, the epicardial adipose tissue (EAT) density, a measurement for inflammation, between the bifurcation of pulmonary artery and diaphragm as determined by lung CT scan may serve as a specific indicator for COVID-19-induced myocardial injury. Hui et al. reported that the mean EAT density of critical/severe groups in chest CT scan were significantly lower than patients in the light/mild groups (-98.77 /-96.08 HU vs -69.37/-84.76 HU), suggesting that myocardial inflammation occurred in COVID-19 patients <xref rid="bib0030" ref-type="bibr">[30]</xref>. As the cytokine storm and consequent inflammatory response are suggested to be the mechanisms contributing to myocardial injury, low EAT density showed in chest CT scan appears to be a high-risk factor for myocardial injury. However, low EAT density is not the optimal imaging parameter of COVID-19-related myocardial injury since it is an indirect sign of inflammation and may be substantively influenced by subjective factors in clinical practice. Other imaging modalities with high sensitivity and specificity such as echocardiography and myocardial magnetic resonance imaging should be preferentially chosen if appropriate.</p></sec><sec id="sec0011"><label>8</label><title>Management and Treatment of COVID-19</title><sec id="sec0012"><label>8.1</label><title>Pre-exiting condition management</title><p id="para0037">Treatment of COVID-19 has been mostly restricted to supportive measures as there has been, to date, no specific therapy available to treat this disease. Pre-existing poor-health conditions increase the risk of cardiovascular comorbidity, with poorer prognosis. Patients at age above 60 years old and those with diabetes are more susceptible to COVID-19 induced myocardial injury. They should be prioritized for treatment. In terms of diagnostic criteria, the dynamic change of myocardial biomarkers especially hs-TnI is the main criteria to identify COVID-19 patients with myocardial injury. However, the levels of myocardial biomarkers may be affected by other factors such as the status of infection, hypoxemia, and renal insufficiency, which are commonly observed in COVID-19 patients. Thus comprehensive assessments combining electrocardiography, imaging and histopathology should be performed in clinical practice.</p></sec><sec id="sec0013"><label>8.2</label><title>Anti-virus therapy</title><p id="para0038">Since the outbreak of COVID-19 several anti-virus agents have been proposed and currently are under intensive clinical investigation. Remdesivir is a broad-spectrum investigational antiviral agent which decreased SARS-Cov-2 RNA transcription with <italic>in vitro</italic> experiments <xref rid="bib0061" ref-type="bibr">[61]</xref>. The agent was originally developed for treating Ebola virus infection but was not shown to have satisfactory efficacy in clinical trials <xref rid="bib0062" ref-type="bibr">[62]</xref>. A few COVID-19 patients recovered soon after administering remdesivir [<xref rid="bib0063" ref-type="bibr">63</xref>,<xref rid="bib0064" ref-type="bibr">64</xref>], though its safety and efficacy have not been demonstrated in randomized controlled trials (RCTs) <xref rid="bib0065" ref-type="bibr">[65]</xref>, <xref rid="bib0066" ref-type="bibr">[66]</xref>, <xref rid="bib0067" ref-type="bibr">[67]</xref>. Another antiviral treatment, lopinavir/ritonavir, the protease inhibitor combination used in HIV, was previously given great expectation for treating COVID-19 but failed to show significant benefit in the first RCT. Other antiviral agents are now in RCTs after showing some promise with small numbers of patients during the initial wave of COVID-19 infections in China.</p></sec><sec id="sec0014"><label>8.3</label><title>Anti-inflammatory and immunoregulatory agents</title><p id="para0039">Hydroxychloroquine and chloroquine are traditional anti-malarial and autoimmune disease drugs. They have been shown to control the SARS-Cov-2 infection <italic>in vitro</italic> [<xref rid="bib0061" ref-type="bibr">61</xref>,<xref rid="bib0068" ref-type="bibr">68</xref>]. The underlying mechanism may involve the increase in the endosomal pH required for virus/cell fusion, interference with the glycosylation of ACE2 <xref rid="bib0069" ref-type="bibr">[69]</xref> and inactivation of IL-6 and TNF-α <xref rid="bib0070" ref-type="bibr">[70]</xref>. A small sample size study showed that hydroxychloroquine treatment was significantly associated with viral load reduction/disappearance in COVID-19 patients <xref rid="bib0071" ref-type="bibr">[71]</xref>, but this conclusion still has not been verified by ongoing RCTs [<xref rid="bib0072" ref-type="bibr">72</xref>,<xref rid="bib0073" ref-type="bibr">73</xref>]. The cardiotoxicity of hydroxychloroquine and chloroquine should not be neglected. They may prolong QT interval and induce ventricular arrhythmia <xref rid="bib0074" ref-type="bibr">[74]</xref>. Thus, they should be used very cautiously (if at all) to treat COVID-19 patients with cardiovascular comorbidities or uncorrected electrolyte disorder. Given the pivotal role of immunologic overresponse in COVID-19, anti-inflammatory therapy is also promising for treating COVID-19. Corticosteroids were used during the SARV-Cov and MERS-Cov outbreaks and have also been used for patients with COVID-19. However, previous studies on whether corticosteroids exert protective [<xref rid="bib0075" ref-type="bibr">75</xref>,<xref rid="bib0076" ref-type="bibr">76</xref>] or adverse <xref rid="bib0077" ref-type="bibr">[77]</xref> effect in SARV-Cov and MERS-Cov infection came to conflicting conclusions, since it might induce in-hospital secondary infection and long-term complications while inhibiting inflammation-related organ injury. With lack of conclusive evidence, the use of corticosteroids may be prudently considered in critical COVID-19 patients with clear evidence of immune overreaction, but their use is not generally recommended by the World Health Organization (WHO) or Centers for Disease Control (CDC). Some have advocated against non-steroidal anti-inflammatory agents (NSAIDs), notably ibruprofen, which may be associated with worse outcome with COVID-19, based on anecdotal reports. Targeted agents such as tocilizumab are also regarded as potential therapy. Tocilizumab was shown to facilitate chimeric antigen receptor-T cell (CAR-T) therapy because it can inhibit IL-6, the core cytokine of cytokine storm syndrome <xref rid="bib0078" ref-type="bibr">[78]</xref>. Several clinical observations demonstrated a predominant increase of IL-6 in COVID-19 patients, which is associated with severe conditions [<xref rid="bib0038" ref-type="bibr">38</xref>,<xref rid="bib0079" ref-type="bibr">79</xref>], so inhibiting IL-6 activation may ease the overreacting immune system. Future well-designed RCTs are expected to clarify tocilizumab's efficiency and its applicable patients.</p></sec><sec id="sec0015"><label>8.4</label><title>ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB)</title><p id="para0040">The structural evidence of SARS-Cov-2 invasion of cells via ACE2 has led to the hypothesis that ACEI/ARB treatment potentially induces overexpression of ACE2, which subsequently increases the susceptibility of host cells to SARS-Cov-2 invasion and the risk of infection or worsening the severity of disease <xref rid="bib0080" ref-type="bibr">[80]</xref>. For cardiovascular patients under regular anti-hypertensive treatment, it has been suggested that they should discontinue ACE inhibitors (ACEI) or angiotensin receptor blocker (ARB) medications. However, ACEI/ARB play a protective role in COVID-19, given that ACE2 shedding caused by SARS-Cov-2 invasion may result in its downregulation, following the activation of RAS axis which is partly responsible for severe organ injury in COVID-19 <xref rid="bib0048" ref-type="bibr">[48]</xref>. Thus far, there have been no clinical data supporting the case for ACEI/ARB discontinuation in COVID-19 patients. According to WHO's guideline, changing the routine antihypertensive therapy under the COVID-19 pandemic to avoid potential harm or pursue potential benefits is not recommended before any compelling evidence published.</p></sec><sec id="sec0016"><label>8.5</label><title>Neutralizing anti-virus plasma, stem cell transplantation, traditional herbal remedies and anti-ischemic therapy</title><p id="para0041">Other therapies with less evidence-based foundation are also worth mentioning. Plasma treatment means transfusing convalescent plasma containing anti-virus polyclonal antibodies, and were proved to be effective in treating SARS patients and COVID-19 patients in observational studies [<xref rid="bib0081" ref-type="bibr">81</xref>,<xref rid="bib0082" ref-type="bibr">82</xref>]. Although the number of patients so treated is small, this does make scientific sense. Dilated horse anti-SARS-CoV-2 serum could cross-neutralize SARS-CoV-2 in an in vitro study <xref rid="bib0008" ref-type="bibr">[8]</xref>. Some traditional herbal therapies against coronavirus infection were found to be effective during SARS outbreak and are widely used in current practice in China <xref rid="bib0083" ref-type="bibr">[83]</xref>. Mesenchymal stem cell transplantation has shown both efficiency and safety in treating ARDS <xref rid="bib0084" ref-type="bibr">[84]</xref>. All the above therapies need more verification by RCTs <xref rid="bib0085" ref-type="bibr">[85]</xref>, <xref rid="bib0086" ref-type="bibr">[86]</xref>, <xref rid="bib0087" ref-type="bibr">[87]</xref>, <xref rid="bib0088" ref-type="bibr">[88]</xref>, <xref rid="bib0089" ref-type="bibr">[89]</xref>. Due to the widespread cardiac injury in COVID-19 patients, new or worsening heart failure is common especially in those with poor prognosis <xref rid="bib0079" ref-type="bibr">[79]</xref>. After recognizing the onset of heart failure, causes leading to decompensation should be evaluated first, especially those should which could be managed and corrected immediately such as acute coronary syndrome and severe rapid arrhythmias. Hypoxemia following pneumonia and ARDS is common in COVID-19 patients and will be worsened by heart failure. Thus oxygen therapy and mechanical ventilation should be more rigorously used in COVID-19 patients with heart failure than those without. Diuretics should be considered under the evidence of volume overload, as well as renal replacement therapy which can simultaneously eliminate excessive cytokines. Rehydration should be more prudently prescribed in shock patients with COVID-19 than normal shock counterparts, considering that pulmonary edema following rapid fluid resuscitation will further impair alveolar ventilation. Mechanical assist devices such as intra-aortic balloon pump and extracorporeal membrane oxygenation (ECMO) may help patients get through critical periods and should be considered when necessary.</p></sec></sec><sec id="sec0017"><label>9</label><title>Conclusion</title><p id="para0042">COVID-19 causes not only pulmonary injury but also severe cardiac complications, in particular in those with pre-existing medical conditions. Although the precise mechanism for the development of myocardial injury associated with COVID-19 is not fully understood, a combination of direct and indirect pathogenic factors, such as ACE2-mediated SARS-CoV-2 infection of cardiomyocytes, hypoxia and cytokine storm, may contribute to the development of myocardial injury and other adverse events which aggravate conditions and increase mortality (<xref rid="tbl0003" ref-type="table">Table 3</xref>). Close and careful monitoring of cardiac function should be emphasized in order to early identify COVID-19-related myocardial injury.<table-wrap position="float" id="tbl0003"><label>Table 3</label><caption><p>Major signs and biomarkers for pulmonary and myocardiac injury in COVID-19.</p></caption><alt-text id="alt0005">Table 3</alt-text><table frame="hsides" rules="groups"><tbody><tr><td valign="top"><bold><italic>Pulmonary Injury</italic></bold></td></tr><tr><td valign="top">Respiratory rate, > 24 breaths per min</td></tr><tr><td valign="top">Hypoxemia (PaO2 decline, PaO<sub>2</sub>:FiO<sub>2</sub> ratio < 100–150 mm Hg; SaO2 < 95%)</td></tr><tr><td valign="top">Hypercapnia and acidosis (P<sub>aCO2</sub> elevation, respiratory, metabolic or combined)</td></tr><tr><td valign="top">Pulmonary hypertension</td></tr><tr><td valign="top"><bold><italic>Myocardiac Injury</italic></bold></td></tr><tr><td valign="top">Lactate dehydrogenase, > 245 U/L</td></tr><tr><td valign="top">Creatinine, >133 μmol/L</td></tr><tr><td valign="top">Creatine kinase, >185 U/L</td></tr><tr><td valign="top">Creatine kinase–MB fraction, > 2 ng/mL</td></tr><tr><td valign="top">High-sensitivity cardiac troponin I, > 28 pg/mL</td></tr><tr><td valign="top">Myoblobin, >30 μg/L</td></tr><tr><td valign="top">N-terminal pro-brain natriuretic peptide (NT-proBNP), >300 pg/mL</td></tr><tr><td valign="top"><italic>Inflammation</italic></td></tr><tr><td valign="top">High-sensitivity C-reactive protein (hs-CRP), > 3.0 mg/L</td></tr><tr><td valign="top">Interleukin-6 (IL-6), > 1 pg/mL</td></tr><tr><td valign="top">Ratio of neutrophils vs. lymphocytes, > 5-10</td></tr></tbody></table></table-wrap></p></sec><sec sec-type="COI-statement"><title>Declaration of Competing Interest</title><p id="para0045">All the co-authors have no conflict of interest to be declared.</p></sec></body><back><ref-list id="cebibl1"><title>References</title><ref id="bib0001"><label>1</label><mixed-citation publication-type="other" id="othref0001">Organization WH. 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