key: cord-282043-cs1oyohu authors: Giustino, Gennaro; Pinney, Sean P.; Lala, Anuradha; Reddy, Vivek Y.; Johnston-Cox, Hillary A.; Mechanick, Jeffrey I.; Halperin, Jonathan L.; Fuster, Valentin title: Coronavirus and Cardiovascular Disease, Myocardial Injury, and Arrhythmia: JACC Focus Seminar date: 2020-10-27 journal: J Am Coll Cardiol DOI: 10.1016/j.jacc.2020.08.059 sha: doc_id: 282043 cord_uid: cs1oyohu The cardiovascular system is affected broadly by severe acute respiratory syndrome coronavirus 2 infection. Both direct viral infection and indirect injury resulting from inflammation, endothelial activation, and microvascular thrombosis occur in the context of coronavirus disease 2019. What determines the extent of cardiovascular injury is the amount of viral inoculum, the magnitude of the host immune response, and the presence of co-morbidities. Myocardial injury occurs in approximately one-quarter of hospitalized patients and is associated with a greater need for mechanical ventilator support and higher hospital mortality. The central pathophysiology underlying cardiovascular injury is the interplay between virus binding to the angiotensin-converting enzyme 2 receptor and the impact this action has on the renin-angiotensin system, the body’s innate immune response, and the vascular response to cytokine production. The purpose of this review was to describe the mechanisms underlying cardiovascular injury, including that of thromboembolic disease and arrhythmia, and to discuss their clinical sequelae. close to 500,000 have died of the disease. Although originally believed to be a syndrome characterized by acute lung injury, respiratory failure, and death, it is now apparent that severe coronavirus disease 2019 (COVID-19) is further characterized by exuberant cytokinemia, with resultant endothelial inflammation, microvascular thrombosis, and multiorgan failure (2) . Involvement of the cardiovascular system is common in COVID-19 (3) (4) (5) (6) (7) (8) . Somewhere between one-fifth and one-third of hospitalized patients will have evidence of myocardial injury, defined as the presence of elevated cardiac troponin levels at the time of admission (9) (10) (11) (12) . Such patients are generally older and have a higher prevalence of hypertension, diabetes mellitus, coronary artery disease, and heart failure than those with normal troponin levels. Myocardial injury is associated with a greater need for mechanical ventilatory support and higher in-hospital mortality. The purpose of the current review was to describe the mechanisms producing cardio- binds with high affinity to the angiotensin-converting enzyme 2 (ACE2) receptor (13) . ACE2 serves as a master regulator of the renin-angiotensin system by metabolizing the vasoconstricting and proinflammatory angiotensin II (Ang II) to the vasodilating peptide angiotensin 1-7. While binding to ACE2, SARS-CoV-2 uses a host protease, transmembrane protease serine 2 (TMPRSS2), to prime the S protein and facilitate cell entry (14) . Once inside the cell, the virus uses the host machinery to translate RNA into polypeptides, including an RNAdependent RNA polymerase that the virus uses to replicate its own RNA. After synthesis of structural proteins and particle assembly, new virus is released from the cell by exocytosis. Host cells may be disabled or destroyed in the process, potentially triggering an innate immune response (15) . ACE2 and TMPRSS2 are co-expressed in a number of tissues, including the heart, lung, gut smooth muscle, liver, kidney, and immune cells (15) . The cardiovascular system is affected in diverse ways by severe acute respiratory syndrome coronavirus 2 infection (COVID-19). Myocardial injury can be detected in w25% of hospitalized patients with COVID-19 and is associated with an increased risk of mortality. Described mechanisms of myocardial injury in patients with COVID-19 include oxygen supply-demand imbalance, direct viral myocardial invasion, inflammation, coronary plaque rupture with acute myocardial infarction, microvascular thrombosis, and adrenergic stress. Inflammatory cytokines and excessive Ang II activity lead to endothelial activation, which is associated with a prothrombotic phenotype and increased endothelial permeability. In addition, SARS-CoV-2 has been shown to directly invade endothelial cells and cause endotheliitis. Image created with BioRender.com. PAI ¼ plasminogen activator inhibitor; TF ¼ tissue factor; vWF ¼ von Willebrand factor; other abbreviations as in Figure 1 . In hospitalized patients with COVID-19, hematologic and coagulation parameters are commonly measured, although there are currently insufficient data to recommend for or against using these data to guide management decisions bsd.uchicago.edu. Twitter: @spinneymd. GBD 2017 Causes of Death Collaborators Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study Covid-19-navigating the uncharted Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19) Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Risk of myocardial infarction and stroke after acute infection or vaccination Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China Prevalence and impact of myocardial injury in patients hospitalized with COVID-19 infection Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area Acute myocardial injury in patients hospitalized with COVID-19 infection: a review Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2 Host cell proteases: critical determinants of coronavirus tropism and pathogenesis The science underlying COVID-19: implications for the cardiovascular system SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS COVID-19-related myocarditis in a 21-year-old female patient Typical takotsubo syndrome triggered by SARS-CoV-2 infection Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19) Myocardial localization of coronavirus in COVID-19 cardiogenic shock Detection of viral SARS-CoV-2 genomes and histopathological changes in endomyocardial biopsies. ESC Heart Fail Evidence of SARS-CoV-2 mRNA in endomyocardial biopsies of patients with clinically suspected myocarditis tested negative for COVID-19 in nasopharyngeal swab Association of cardiac infection with SARS-CoV-2 in confirmed COVID-19 autopsy cases. JAMA Cardiol activation in primary human monocytes Angiotensin II induced proteolytic cleavage of myocardial ACE2 is mediated by TACE/ADAM-17: a positive feedback mechanism in the RAS Renin-angiotensin-aldosterone system inhibitors and risk of Covid-19 Renin-angiotensin-aldosterone system blockers and the risk of Covid-19 Ramipril in high-risk patients with COVID-19 The emerging role of ACE2 in physiology and disease Endothelial dysfunction in sepsis Severe COVID-19 infection associated with endothelial activation Targeting raised von Willebrand factor levels and macrophage activation in severe COVID-19: consider low volume plasma exchange and low dose steroid Endothelial cell infection and endotheliitis in COVID-19 Fourth universal definition of myocardial infarction Inflammation, immunity, and infection in atherothrombosis: JACC Review Topic of the Week Pathogen recognition and inflammatory signaling in innate immune defenses Inflammasome activation and IL-1beta and IL-18 processing during infection Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link? Catheterization laboratory considerations during the coronavirus (COVID-19) pandemic: from the ACC's Interventional Council and SCAI Management of acute myocardial infarction during the COVID-19 pandemic Considerations for cardiac catheterization laboratory procedures during the COVID-19 pandemic perspectives from the Society for Cardiovascular Angiography and Interventions Emerging Leader Mentorship (SCAI ELM) Members and Graduates Elevated cardiac troponin measurements in critically ill patients Prognostic impact of myocardial injury related to various cardiac and noncardiac conditions Clinical characteristics and outcomes of patients with myocardial infarction, myocardial injury, and nonelevated troponins Targeting inflammation in coronary artery disease Acute myocardial infarction after laboratoryconfirmed influenza infection Declining admissions for acute cardiovascular illness: the Covid-19 paradox Decline of acute coronary syndrome admissions in Austria since the outbreak of COVID-19: the pandemic response causes cardiac collateral damage Reduction of hospitalizations for myocardial infarction in Italy in the COVID-19 era Admission of patients with STEMI since the outbreak of the COVID-19 pandemic. A survey by the European Society of Cardiology Fewer hospitalizations for acute cardiovascular conditions during the COVID-19 pandemic Dysregulation of immune response in patients with COVID-19 in Wuhan, China Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock Effects of TNFalpha on [Ca2þ]i and contractility in isolated adult rabbit ventricular myocytes Dysregulation of intracellular calcium transporters in animal models of sepsis-induced cardiomyopathy TNF alpha receptor expression in rat cardiac myocytes: TNF alpha inhibition of L-type Ca2þ current and Ca2þ transients Drug-induced mitochondrial dysfunction and cardiotoxicity Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019 Echocardiographic findings in patients with COVID-19 with significant myocardial injury Echocardiographic findings in patients with COVID-19 pneumonia Spectrum of cardiac manifestations in COVID-19: a systematic echocardiographic study STsegment elevation in patients with Covid-19-a case series ST-elevation myocardial infarction in patients with COVID-19: clinical and angiographic outcomes Takotsubo cardiomyopathy in males with Covid-19 The variety of cardiovascular presentations of COVID-19 Fulminant COVID-19-related myocarditis in an infant Acute myocarditis associated with COVID-19 infection Myocarditis detected after COVID-19 recovery Diffuse myocardial inflammation in COVID-19 associated myocarditis detected by multiparametric cardiac magnetic resonance imaging Fulminant myocarditis due to COVID-19 Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19) COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC State-of-the-Art Review Thromboembolic risk and anticoagulant therapy in COVID-19 patients: emerging evidence and call for action Hypoxia downregulates protein S expression Severe arterial thrombosis associated with Covid-19 infection Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Cardiovascular adverse events in patients with cancer treated with bevacizumab: a meta-analysis of more than 20 000 patients Multifaceted effects of hydroxychloroquine in human disease Acute pulmonary embolism and COVID-19 pneumonia: a random association? COVID-19 pneumonia with hemoptysis: acute segmental pulmonary emboli associated with novel coronavirus infection Incidence of thrombotic complications in critically ill ICU patients with COVID-19 Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China Large-vessel stroke as a presenting feature of covid-19 in the young Acute limb ischemia in patients with COVID-19 pneumonia COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines The anti-inflammatory effects of heparin and related compounds Characterization of the heparin-binding properties of IL-6 Murine coronavirus with an extended host range uses heparan sulfate as an entry receptor Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites Prevention of adult respiratory distress syndrome with plasminogen activator in pigs Tissue plasminogen activator (tPA) inhibits interleukin-1 induced acute lung leak Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): a case series COVID-19 critical illness pathophysiology driven by diffuse pulmonary thrombi and pulmonary endothelial dysfunction responsive to thrombolysis Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19 Risk factors associated with clinical outcomes in 323 COVID-19 hospitalized patients in Wuhan, China Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label nonrandomized clinical trial Cardioimmunology of arrhythmias: the role of autoimmune and inflammatory cardiac channelopathies COVID-19, arrhythmic risk and inflammation: mind the gap! Acute kidney injury in patients hospitalized with COVID-19 Acute kidney injury in COVID-19: emerging evidence of a distinct pathophysiology Imbalanced host response to SARS-CoV-2 drives development of COVID-19 COVID-19, myocardial injury, SARS-CoV-2, thrombosis