Severe Acute Respiratory Syndrome Coronavirus-2 Cardiovascular Complications: Implications for Cardiothoracic Anesthesiology

Abstract

CORONAVIRUSES, so named for the crownlike spikes on their surfaces under electron microscopy, are enveloped, single-stranded positive-sense RNA viruses that have high propensity for mutation and recombination.1Cheng VC Lau SK Woo PC et al.Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection.Clin Microbiol Rev. 2007; 20: 660-694Crossref PubMed Scopus (737) Google Scholar Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as the causative agent of coronavirus disease-2019 (COVID-19), which emerged rapidly—with catastrophic global consequences—as a pandemic since its initial appearance in Wuhan, China, in early December 2019.2Guan WJ Ni ZY Hu Y et al.Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; 382: 1708-1720Crossref PubMed Scopus (17729) Google Scholar As of the writing of this article, there were more than 4 million persons infected with COVID-19, and more than 280,000 deaths worldwide had been attributed to the disease.3COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University Available at: https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6. Accessed May 10, 2020.Google Scholar In many parts of the world, a rapid increase in patients with COVID-19 who require hospitalization has been noted. Anesthesiologists have been tasked with caring for patients with COVID-19 in preoperative, intraoperative, and postoperative states and for patients in critical care units. Because of the broad perioperative “footprint” of the cardiovascular anesthesiologist, it is imperative to have a robust familiarity with the manifestations, therapies, and relevant considerations of COVID-19. Much of the early contributions to the medical literature addressed the respiratory-related issues of COVID-19 and for understandable reasons. There now are concerns for cardiovascular manifestations in patients with COVID-19. Malignant arrhythmias, ST elevations, and myocarditis all have been diagnosed in COVID-19 patients, even in individuals without previous cardiovascular disease.4Inciardi RM Lupi L Zaccone G et al.Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020 Mar 27; ([E-pub ahead of print])Crossref PubMed Scopus (1144) Google Scholar Not surprisingly, patients with COVID-19 in whom cardiac injury occurs have been shown to have increased risk of mortality more than those who do not have this presentation.5Guo T Fan Y Chen M et al.Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020 Mar 27; ([E-pub ahead of print] Accessed May 2, 2020)https://doi.org/10.1001/jamacardio.2020.1017Crossref PubMed Scopus (2439) Google Scholar In addition, an unusual degree of coagulopathy (mainly favoring hypercoagulability) has been associated with COVID-19 infection, with implications for considerable morbidity and mortality. Moreover, although many elective surgeries have been deferred during the surge of SARS-CoV-2, anesthesiologists must be prepared to care for patients with COVID-19 who require intraoperative care on an emergency basis. The present review addresses cardiovascular-specific factors in COVID-19 and the implications of the disease that are relevant for cardiothoracic anesthesiologists caring for patients during the current pandemic. It is well- established in retrospective data that elderly patients with comorbid conditions are at the highest risk of severe COVID-19 infection, with associated complications of acute respiratory distress syndrome (ARDS), cardiogenic or distributive shock, or multiorgan failure.6Huang C Wang Y Li X et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (28236) Google Scholar,7Zhou F Yu T Du R et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (16267) Google Scholar In early studies, cardiac and metabolic comorbidities in particular were associated with higher rates of death.8Wu Z McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention.JAMA. 2020 Feb 24; ([E-pub ahead of print] Accessed May 2, 2020)https://doi.org/10.1001/jama.2020.2648Crossref Scopus (10931) Google Scholar Even though these data are difficult to interpret because of sampling bias, testing scarcity, and reporting variability, these comorbidities also are closely related to advancing age.9Driggin E Madhavan MV Bikdeli B et al.Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic.J Am Coll Cardiol. 2020; 75: 2352-2371Crossref PubMed Scopus (1262) Google Scholar,10Vaduganathan M Vardeny O Michel T et al.Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19.N Engl J Med. 2020; 382: 1653-1659Crossref PubMed Scopus (1438) Google Scholar One study of 8,910 patients from 169 hospitals in North America, Asia, and Europe revealed that independent risk factors that increased mortality were age greater than 65 years (mortality of 10.0%), coronary artery disease (10.2%), heart failure (15.3%), cardiac arrhythmia (11.5%), chronic obstructive pulmonary disease (14.2%), and current smoker (9.4%).11Mehra MR Desai SS Kuy S et al.Cardiovascular disease, drug therapy, and mortality in Covid-19 [retracted].N Engl J Med. 2020 May 1; ([E-pub ahead of print] Accessed June 23, 2020)https://doi.org/10.1056/NEJMc2021225Crossref Scopus (212) Google Scholar Unsurprisingly, patients with immune system dysfunction also are at high risk for severe COVID-19 infection, and it is likely that existing metabolic and cardiac diseases impair the ability to prevent either SARS-CoV-2 infiltration or the sequelae of an uncontrolled inflammatory response.9Driggin E Madhavan MV Bikdeli B et al.Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic.J Am Coll Cardiol. 2020; 75: 2352-2371Crossref PubMed Scopus (1262) Google Scholar SARS-CoV-2 gains entry to host cells via a spike protein with binding affinity for angiotensin-converting enzyme 2 (ACE2),12Hoffmann M Kleine-Weber H Schroeder S et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: e278Google Scholar,13Zhou P Yang XL Wang XG et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Crossref PubMed Scopus (12448) Google Scholar a transmembrane protein widely expressed in the lung, heart, vasculature, kidney, and intestine.14Kuba K Imai Y Rao S et al.A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.Nat Med. 2005; 11: 875-879Crossref PubMed Scopus (2391) Google Scholar, 15Donoghue M Hsieh F Baronas E et al.A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.Circ Res. 2000; 87: E1-E9Crossref PubMed Google Scholar, 16Hamming I Timens W Bulthuis ML et al.Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis..J Pathol. 2004; 203: 63137Crossref Scopus (3695) Google Scholar This spike protein is nearly identical to that of the SARS-CoV-1 responsible for the 2002–2003 outbreak, but has an even greater affinity for ACE2, likely promoting the higher transmission rate seen in SARS-CoV-2.17Li F Li W Farzan M et al.Structure of SARS coronavirus spike receptor-binding domain complexed with receptor.Science. 2005; 309: 1864-1868Crossref PubMed Scopus (1379) Google Scholar, 18Wan Y Shang J Graham R et al.Receptor recognition by the novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS coronavirus.J Virol. 2020; 94Crossref Scopus (2821) Google Scholar, 19Zhang H Penninger JM Li Y et al.Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: Molecular mechanisms and potential therapeutic target.Intensive Care Med. 2020; 46: 586-590Crossref PubMed Scopus (1616) Google Scholar, 20Rossi GP Sanga V Barton M Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients.Elife. 2020; : 9Google Scholar The likeliest route of viral inoculation follows the observation that ACE2 is highly expressed in enterocytes of the small intestine and type II alveolar epithelial cells of the apical lung, which also offer a reservoir for viral replication and local tissue damage.16Hamming I Timens W Bulthuis ML et al.Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis..J Pathol. 2004; 203: 63137Crossref Scopus (3695) Google Scholar The ACE2 expression within the cardiovascular system is concentrated on the surfaces of myocytes, coronary endothelial cells, and arterial smooth muscle, which explains the potential for direct organ damage, and SARS-CoV-2–induced attenuation of ACE2 supports evidence for indirect cardiovascular damage via an unregulated systemic inflammatory response.16Hamming I Timens W Bulthuis ML et al.Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis..J Pathol. 2004; 203: 63137Crossref Scopus (3695) Google Scholar,19Zhang H Penninger JM Li Y et al.Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: Molecular mechanisms and potential therapeutic target.Intensive Care Med. 2020; 46: 586-590Crossref PubMed Scopus (1616) Google Scholar,21Chen L Li X Chen M et al.The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2.Cardiovasc Res. 2020; 116: 1097-1100Crossref PubMed Scopus (268) Google Scholar, 22Guo J Huang Z Lin L et al.Coronavirus disease 2019 (COVID-19) and cardiovascular disease: A viewpoint on the potential influence of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on onset and severity of severe acute respiratory syndrome coronavirus 2 infection.J Am Heart Assoc. 2020; 9e016219PubMed Google Scholar, 23Akhmerov A Marban E. COVID-19 and the heart.Circ Res. 2020; 126: 1443-1455Crossref PubMed Scopus (440) Google Scholar In healthy physiology, ACE2 counterbalances the proinflammatory angiotensin-converting enzyme 1 pathway of the renin-angiotensin-aldosterone system (RAAS).15Donoghue M Hsieh F Baronas E et al.A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.Circ Res. 2000; 87: E1-E9Crossref PubMed Google Scholar It does this by cleaving proinflammatory angiotensin II to form angiotensin-(1-7), which suppresses inflammation, vasoconstriction, apoptosis, and thrombosis while imparting cardioprotective effects against heart failure, arrhythmia, and atherogenesis.22Guo J Huang Z Lin L et al.Coronavirus disease 2019 (COVID-19) and cardiovascular disease: A viewpoint on the potential influence of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on onset and severity of severe acute respiratory syndrome coronavirus 2 infection.J Am Heart Assoc. 2020; 9e016219PubMed Google Scholar The cardiopulmonary protective role of ACE2 has been demonstrated in several ACE2 knockout studies in which the absence of ACE2 worsened ARDS as a result of SARS-CoV-1, and genetically absent ACE2 study groups developed severe left ventricular dysfunction and showed impaired ventricular remodeling.14Kuba K Imai Y Rao S et al.A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.Nat Med. 2005; 11: 875-879Crossref PubMed Scopus (2391) Google Scholar,24Crackower MA Sarao R Oudit GY et al.Angiotensin-converting enzyme 2 is an essential regulator of heart function.Nature. 2002; 417: 822-828Crossref PubMed Scopus (1412) Google Scholar,25Kassiri Z Zhong J Guo D et al.Loss of angiotensin-converting enzyme 2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction.Circ Heart Fail. 2009; 2: 446-455Crossref PubMed Scopus (174) Google Scholar Infection with SARS-CoV downregulates ACE2 expression.14Kuba K Imai Y Rao S et al.A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.Nat Med. 2005; 11: 875-879Crossref PubMed Scopus (2391) Google Scholar,26Oudit GY Kassiri Z Jiang C et al.SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS.Eur J Clin Invest. 2009; 39: 618-625Crossref PubMed Scopus (587) Google Scholar This decrease in ACE2 and derangement of RAAS are likely important mechanisms for the inflammation and cardiac dysfunction seen in severe COVID-19 patients .10,19,22,23 The resultant proinflammatory state is caused by unopposed angiotensin II and RAAS activation, with associated vasoconstriction, bronchoconstriction, and increased vascular permeability.10Vaduganathan M Vardeny O Michel T et al.Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19.N Engl J Med. 2020; 382: 1653-1659Crossref PubMed Scopus (1438) Google Scholar,20Rossi GP Sanga V Barton M Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients.Elife. 2020; : 9Google Scholar In fact, angiotensin II levels are strongly correlated with the viral load and the degree of lung injury sustained by SARS-CoV-2 patients.27Liu Y Yang Y Zhang C et al.Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury.Sci China Life Sci. 2020; 63: 364-374Crossref PubMed Scopus (1312) Google Scholar This illustrates that ACE2 likely serves a dual purpose as both receptor and arbiter of immune response and is crucial to the determining of the virulence of SARS-CoV-2. It not only acts as an entry point for SARS-CoV-2 but, upon binding, SARS-CoV-2 decreases ACE2 expression and prevents its protective effect.10Vaduganathan M Vardeny O Michel T et al.Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19.N Engl J Med. 2020; 382: 1653-1659Crossref PubMed Scopus (1438) Google Scholar,23Akhmerov A Marban E. COVID-19 and the heart.Circ Res. 2020; 126: 1443-1455Crossref PubMed Scopus (440) Google Scholar Some in vivo and animal studies have suggested that higher ACE2 expression could place a patient at greater risk of SARS-CoV-2 infection, although whether this clinically results in a greater infection rate or increased morbidity and mortality is unknown and controversial.10Vaduganathan M Vardeny O Michel T et al.Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19.N Engl J Med. 2020; 382: 1653-1659Crossref PubMed Scopus (1438) Google Scholar,20Rossi GP Sanga V Barton M Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients.Elife. 2020; : 9Google Scholar,22Guo J Huang Z Lin L et al.Coronavirus disease 2019 (COVID-19) and cardiovascular disease: A viewpoint on the potential influence of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on onset and severity of severe acute respiratory syndrome coronavirus 2 infection.J Am Heart Assoc. 2020; 9e016219PubMed Google Scholar,28Hofmann H Geier M Marzi A et al.Susceptibility to SARS coronavirus S protein-driven infection correlates with expression of angiotensin converting enzyme 2 and infection can be blocked by soluble receptor.Biochem Biophys Res Commun. 2004; 319: 1216-1221Crossref PubMed Scopus (201) Google Scholar Several authors theorized that angiotensin-converting enzyme inhibitors (ACEi) and angiotensin- receptor blockers (ARB) hypothetically could increase susceptibility to SARS-CoV-2 by increasing ACE2 receptor sites for the virus.29Fang L Karakiulakis G Roth M Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?.Lancet Respir Med. 2020; 8: e21Abstract Full Text Full Text PDF PubMed Scopus (1870) Google Scholar,30Zheng YY Ma YT Zhang JY et al.COVID-19 and the cardiovascular system.Nat Rev Cardiol. 2020; 17 (pp. 259-20)Crossref Scopus (1968) Google Scholar Momentum to discontinue ACEi/ARB followed, which led to several publications reiterating the duality of ACE2 and the cardioprotective nature of ACEi/ARB; many medical societies issued statements supporting continuing ACEi/ARB in patients with and without COVID-19 until contrary evidence arises.10Vaduganathan M Vardeny O Michel T et al.Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19.N Engl J Med. 2020; 382: 1653-1659Crossref PubMed Scopus (1438) Google Scholar,11Mehra MR Desai SS Kuy S et al.Cardiovascular disease, drug therapy, and mortality in Covid-19 [retracted].N Engl J Med. 2020 May 1; ([E-pub ahead of print] Accessed June 23, 2020)https://doi.org/10.1056/NEJMc2021225Crossref Scopus (212) Google Scholar,20Rossi GP Sanga V Barton M Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients.Elife. 2020; : 9Google Scholar,22Guo J Huang Z Lin L et al.Coronavirus disease 2019 (COVID-19) and cardiovascular disease: A viewpoint on the potential influence of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on onset and severity of severe acute respiratory syndrome coronavirus 2 infection.J Am Heart Assoc. 2020; 9e016219PubMed Google Scholar Clinical manifestations of COVID-19 are varied; some patients test positive for the presence of SARS-CoV-2 but remain asymptomatic. However, the development of a severe infection has the following 3 phases of illness: an inoculation/incubation phase; a pulmonary phase; and an acute, exaggerated, systemic inflammatory phase.9Driggin E Madhavan MV Bikdeli B et al.Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic.J Am Coll Cardiol. 2020; 75: 2352-2371Crossref PubMed Scopus (1262) Google Scholar,23Akhmerov A Marban E. COVID-19 and the heart.Circ Res. 2020; 126: 1443-1455Crossref PubMed Scopus (440) Google Scholar The definitive cardiac pathophysiology of SARS-CoV-2 is unclear and currently is hypothesized to be a combination of 2 direct mechanisms and 2 indirect mechanisms. Viral entry via cellular ACE2 expression, with direct toxicity to cells, has some supporting evidence but is yet to be proven and was observed in the SARS-CoV-1 outbreak.23Akhmerov A Marban E. COVID-19 and the heart.Circ Res. 2020; 126: 1443-1455Crossref PubMed Scopus (440) Google Scholar,26Oudit GY Kassiri Z Jiang C et al.SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS.Eur J Clin Invest. 2009; 39: 618-625Crossref PubMed Scopus (587) Google Scholar Because of the high level of ACE2 surface expression in pericytes and endothelial cells, viral-induced vasculitis and microthrombosis may be other sources of direct cardiac injury.31Atri D Siddiqi HK Lang J et al.COVID-19 for the cardiologist: A current review of the virology, clinical epidemiology, cardiac and other clinical manifestations and potential therapeutic strategies.JACC Basic Transl Sci. 2020; 5: 518-536Crossref PubMed Scopus (182) Google Scholar Indirect cardiac tissue damage can result from stress demand or hypoxia and immune-mediated cytokine storm.9Driggin E Madhavan MV Bikdeli B et al.Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic.J Am Coll Cardiol. 2020; 75: 2352-2371Crossref PubMed Scopus (1262) Google Scholar,22Guo J Huang Z Lin L et al.Coronavirus disease 2019 (COVID-19) and cardiovascular disease: A viewpoint on the potential influence of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on onset and severity of severe acute respiratory syndrome coronavirus 2 infection.J Am Heart Assoc. 2020; 9e016219PubMed Google Scholar,23Akhmerov A Marban E. COVID-19 and the heart.Circ Res. 2020; 126: 1443-1455Crossref PubMed Scopus (440) Google Scholar Appreciating the cardiac sequelae of COVID-19 patients is paramount to triage and treatment of this highest-risk cohort who can experience myocardial injury or myocarditis, heart failure, and arrhythmia.9Driggin E Madhavan MV Bikdeli B et al.Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic.J Am Coll Cardiol. 2020; 75: 2352-2371Crossref PubMed Scopus (1262) Google Scholar,23Akhmerov A Marban E. COVID-19 and the heart.Circ Res. 2020; 126: 1443-1455Crossref PubMed Scopus (440) Google Scholar,32Augoustides JG. Cardiovascular consequences and considerations of coronavirus infection - perspectives for the cardiothoracic anesthesiologist and Intensivist during the coronavirus crisis.J Cardiothorac Vasc Anesth. 2020; 34: 1713-1716Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar,33Fried JA Ramasubbu K Bhatt R et al.The variety of cardiovascular presentations of COVID-19.Circulation. 2020; 141: 1930-1936Crossref PubMed Scopus (340) Google Scholar Elevated troponin levels are pathognomonic for myocardial injury and, despite a connotation of acute coronary syndrome (ACS), should reinforce ischemic and non-ischemic differentials in all patients, particularly those with SARS-CoV-2.34Chapman AR Bularga A Mills NL High-sensitivity cardiac troponin can be an ally in the fight against COVID-19.Circulation. 2020; 141: 1733-1735Crossref PubMed Scopus (119) Google Scholar Because of its sensitivity, the troponin level is the earliest and most accurate indication of end-organ damage.34Chapman AR Bularga A Mills NL High-sensitivity cardiac troponin can be an ally in the fight against COVID-19.Circulation. 2020; 141: 1733-1735Crossref PubMed Scopus (119) Google Scholar Interestingly, elevated troponin levels were more closely associated with COVID-19 mortality than age, diabetes, and chronic cardiopulmonary disease; however, this is confounded by the fact that troponin can remain elevated with the impaired renal function often seen in critical illness. In a study of 416 patients hospitalized with SARS-CoV-2, 1 in 5 patients were found to have elevated troponin levels upon admission.5Guo T Fan Y Chen M et al.Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020 Mar 27; ([E-pub ahead of print] Accessed May 2, 2020)https://doi.org/10.1001/jamacardio.2020.1017Crossref PubMed Scopus (2439) Google Scholar,35Shi S Qin M Shen B et al.Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China.JAMA Cardiol. 2020 Mar 25; ([E-pub ahead of print] Accessed April 25, 2020)https://doi.org/10.1001/jamacardio.2020.0950Crossref PubMed Scopus (2584) Google Scholar These patients were significantly more likely to develop ARDS and acute kidney injury, and they experienced a mortality rate 10 times higher than patients without evidence of myocardial injury (51% v 5%).35Shi S Qin M Shen B et al.Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China.JAMA Cardiol. 2020 Mar 25; ([E-pub ahead of print] Accessed April 25, 2020)https://doi.org/10.1001/jamacardio.2020.0950Crossref PubMed Scopus (2584) Google Scholar The incidence of ACS, or type I myocardial infarction (MI), in COVID-19 patients is unknown, perhaps in part because of overlap of symptomatology in both conditions and difficulty in obtaining an angiographic diagnosis in an unstable and highly infectious patient population.9Driggin E Madhavan MV Bikdeli B et al.Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic.J Am Coll Cardiol. 2020; 75: 2352-2371Crossref PubMed Scopus (1262) Google Scholar,23Akhmerov A Marban E. COVID-19 and the heart.Circ Res. 2020; 126: 1443-1455Crossref PubMed Scopus (440) Google Scholar,33Fried JA Ramasubbu K Bhatt R et al.The variety of cardiovascular presentations of COVID-19.Circulation. 2020; 141: 1930-1936Crossref PubMed Scopus (340) Google Scholar There are multiple case reports of COVID-19 patients with MI signs and symptoms absent of actual obstructive coronary disease.33Fried JA Ramasubbu K Bhatt R et al.The variety of cardiovascular presentations of COVID-19.Circulation. 2020; 141: 1930-1936Crossref PubMed Scopus (340) Google Scholar,36Loghin C Chauhan S Lawless SM Pseudo acute myocardial infarction in a young COVID-19 patient.JACC Case Rep. 2020 Apr 27; ([E-pub ahead ofprint] Accessed May 5, 2020)https://doi.org/10.1016/j.jaccas.2020.04.015Crossref PubMed Google Scholar The predilection for thrombosis and disseminated intravascular coagulation demonstrated by elevated D-dimer levels in COVID-19 nonsurvivors lends evidence to the role of microvascular thrombosis in myocardial ischemia.7Zhou F Yu T Du R et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (16267) Google Scholar,23Akhmerov A Marban E. COVID-19 and the heart.Circ Res. 2020; 126: 1443-1455Crossref PubMed Scopus (440) Google Scholar,36Loghin C Chauhan S Lawless SM Pseudo acute myocardial infarction in a young COVID-19 patient.JACC Case Rep. 2020 Apr 27; ([E-pub ahead ofprint] Accessed May 5, 2020)https://doi.org/10.1016/j.jaccas.2020.04.015Crossref PubMed Google Scholar Inflammation-induced macrophage and platelet activation also are likely to be significant in patients with unstable atheromatous plaque, particularly because a significant portion of patients with severe COVID-19 have comorbid risk factors for ACS.7Zhou F Yu T Du R et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (16267) Google Scholar Paradoxically, a study from China found that blood pressure was significantly greater in intensive care unit (ICU) patients than in non-ICU patients (mean systolic blood pressure 145 mmHg v 122 mmHg), although hypotension requiring vasopressors also is typical.6Huang C Wang Y Li X et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (28236) Google Scholar Type II MI is also an important consideration for myocardial injury in these patients because hypoxia, elevated pulmonary afterload, hypermetabolic state, and hemodynamic deregulation combine to unbalance myocardial oxygen consumption and supply.9Driggin E Madhavan MV Bikdeli B et al.Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic.J Am Coll Cardiol. 2020; 75: 2352-2371Crossref PubMed Scopus (1262) Google Scholar In addition, it should be noted that after recovery from viral illnesses, including coronaviruses, patients have been found to be at greater risk for acute MI, although it remains to be seen whether this will be true for SARS-CoV-2.37Kwong JC Schwartz KL Campitelli MA Acute myocardial infarction after laboratory-confirmed influenza infection.N Engl J Med. 2018; 378: 2540-2541Crossref PubMed Scopus (586) Google Scholar Myocarditis as a product of systemic inflammation in SARS-CoV-2 is supported by the deregulation of cytokine cascades and histopathologic findings. Lymphocytopenia is a hallmark of critical COVID-19 patients and is correlated to mortality.7Zhou F Yu T Du R et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (16267) Google Scholar Specifically, this lymphocytopenia is manifested as decreases in helper and regulatory T cells, which further impairs the regulation of the immune response in addition to the mechanism of ACE2, as already discussed.23Akhmerov A Marban E. COVID-19 and the heart.Circ Res. 2020; 126: 1443-1455Crossref PubMed Scopus (440) Google Scholar Inflammatory markers, such as interleukin-6 (IL-6) and C-reactive protein (CRP), have been shown to be correlated with increased SARS-CoV-2 mortality but also with troponin levels and electrocardiographic abnormalities.5Guo T Fan Y Chen M et al.Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020 Mar 27; ([E-pub ahead of print] Accessed May 2, 2020)https://doi.org/10.1001/jamacardio.2020.1017Crossref PubMed Scopus (2439) Google Scholar Autopsy studies of the heart have demonstrated both cell necrosis and acute right ventricular dilation and did not report direct viral infiltration, reiterating the hypothesis of microvascular dysfunction as a possible cause.21Chen L Li X Chen M et al.The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2.Cardiovasc Res. 2020; 116: 1097-1100Crossref PubMed Scopus (268) Google Scholar Acute fulminant myocarditis is described, with one patient presenting 1 week after resolution of pulmonary symptoms, suggesting a persistently elevated inflammatory state even upon convalescence.4Inciardi RM Lupi L Zaccone G et al.Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020 Mar 27; ([E-pub ahead of print])Crossref PubMed Scopus (1144) Google Scholar Myocardial injury can present as acute heart failure in COVID-19 patients (23% in one study), with both reduced and preserved left ventricular ej