key: cord-273602-cq276tj8
authors: Bavishi, Chirag; Bonow, Robert O.; Trivedi, Vrinda; Abbott, J. Dawn; Messerli, Franz H.; Bhatt, Deepak L.
title: Acute myocardial injury in patients hospitalized with COVID-19 infection: A review
date: 2020-06-06
journal: Prog Cardiovasc Dis
DOI: 10.1016/j.pcad.2020.05.013
sha: 
doc_id: 273602
cord_uid: cq276tj8

The Coronavirus Disease 2019 (COVID-19) is now a global pandemic with millions affected and millions more at risk for contracting the infection. The COVID-19 virus, SARS-CoV-2, affects multiple organ systems particularly the lungs and heart. Elevation of cardiac biomarkers, particularly high-sensitivity troponin and/or creatine kinase MB, is common in patients with COVID-19 infection. In our review of clinical studies, we found that in 26 studies including 11,685 patients, the weighted pooled prevalence of acute myocardial injury was 20% (ranged from 5% to 38% depending on the criteria used). The plausible mechanisms of myocardial injury include, 1) hyperinflammation and cytokine storm mediated through pathologic T-cells and monocytes leading to myocarditis, 2) respiratory failure and hypoxemia resulting in damage to cardiac myocytes, 3) down regulation of ACE2 expression and subsequent protective signaling pathways in cardiac myocytes, 4) hypercoagulability and development of coronary microvascular thrombosis, 5) diffuse endothelial injury and ‘endotheliitis’ in several organs including heart, and, 6) inflammation and/or stress causing coronary plaque rupture or supply-demand mismatch leading to myocardial ischemia/infarction. Cardiac biomarkers can be used to aid in diagnosis as well as risk stratification. In patients with elevated hs-troponin, clinical context is important and myocarditis as well as stress induced cardiomyopathy should be considered in the differential, along with type I and type II myocardial infarction. Irrespective of etiology, patients with acute myocardial injury should be prioritized for treatment. Clinical decisions including interventions should be individualized and carefully tailored after thorough review of risks/benefits. Given the complex interplay of SARS-CoV-2 with the cardiovascular system, further investigation into potential mechanisms is needed to guide effective therapies. Randomized trials are urgently needed to investigate treatment modalities to reduce the incidence and mortality associated with COVID-19 related acute myocardial injury.

particularly the lungs and heart. The cardiac manifestations of the infection place an overwhelmed health care system under considerable stress due to the substantial resources and potential intensive care support required for these patients. In this concise review, we will focus on acute myocardial injury in COVID-19 infection, its prevalence, plausible pathophysiologic mechanisms, guidance on the use of cardiac biomarkers, and general management strategies.

Elevation of cardiac biomarkers, particularly high-sensitivity cardiac troponin (hs-troponin) and/or creatinine kinase MB, is a marker of myocardial injury. Elevation of cardiac biomarkers is common in patients with COVID-19 infection. In our review of clinical studies with at least 100 COVID-19 patients (published until May 20 th , 2020), we found that in 26 studies(1-26) including 11,685 patients, the overall prevalence of acute myocardial injury ranged from 5% to 38% depending on the criteria used. (Table 1 ). The overall crude prevalence of acute myocardial injury was 21.4% (1,961/9164). Using meta-analytic approach (27) , the overall weighted pooled prevalence estimate of acute myocardial injury was found to be 20% (95% confidence interval J o u r n a l P r e -p r o o f 6 lactate dehydrogenase. In another seminal study of 182 COVID-19 patients by Li et al.(20) markers of cellular and immune dysregulation were found to be associated with myocardial injury. On multivariate adjusted analysis, age, WBC count, neutrophil percentage, lymphocyte percentage, CD3+ T cell counts, CD4+ T cell counts, CD8+ T cell counts, CD16+CD56+ NK cell counts, hs-C-reactive protein, and procalcitonin were independently associated with myocardial injury in patients with COVID-19.

It appears that the magnitude of elevation of cardiac troponin may be associated with severity of disease and prognosis (29) . Shi et al. (23) studied 671 patients with confirmed COVID-19, the prevalence of myocardial injury defined as hs-troponin I above the 99 th percentile was 15.8%.

Both, CK-MB >2.2 ng/mL (hazards ratio, 6.62, p<0.001) and cardiac troponin I >0.026 ng/mL (hazards ratio, 4.56, p=0.02) were found to be independently associated with increased inhospital mortality. In a prospective cohort study by Du et al(11) of 179 patients with COVID-19 pneumonia, troponin I ≥0.05 ng/mL was independently associated with mortality in addition to age ≥65 years, pre-existing cardiovascular (CV) or cerebrovascular diseases and CD3+CD8+ Tcells ≤75 cells/μL. Further large-scale prospective studies are needed to thoroughly investigate these findings.

J o u r n a l P r e -p r o o f 7 colleagues including 138 consecutive hospitalized patients with COVID-19, the incidence of arrythmia was found to be 17%. In a recent study by Goyal et al(30) , examining the clinical characteristics of first 393 consecutive patients with COVID-19 admitted in 2 hospitals in Manhattan, 7.4% of patients had a cardiac arrythmia during hospitalization. Although the type of arrythmia was not described in these reports, both tachy-and brady-arrythmias can occur. In another study(7) of 187 COVID-19 patients by Guo et al, the overall incidence of ventricular tachycardia/fibrillation was 5.9% and was notably more common in patients with myocardial injury compared with those without (17.3% vs 1.4%, p<0.001). In the study of 191 COVID-19 patients by Zhou et al,(3) HF was observed in 23.0% of patients, however, the etiology of heart failure was not reported. Acute myocardial injury, arrythmia, and HF can manifest either alone or can occur in combination based on the clinical course.

The COVID-19 virus (SARS-CoV-2), uses the angiotensin converting enzyme (ACE) 2 for entry into target cells. ACE2 is predominantly expressed by epithelial cells of the lung, intestine, kidney, heart, and blood vessels. While ACE cleaves angiotensin I to angiotensin II and leads to vasoconstrictive, pro-inflammatory, and pro-oxidative effects through the angiotensin II receptor type 1 (AT-1) receptor, ACE2 leads to anti-inflammatory, anti-oxidative and vasodilatory effects through the angiotensin 1-9-Mas receptor complex. The protective effect of ACE2 in lung is well defined, and therefore down regulation of ACE2 due to viral binding to this receptor plays a key role in acute lung injury and acute respiratory distress syndrome. Our understanding of the pathophysiology of COVID-19 and host immune responses is still evolving, however, immunemediated inflammation plays a key role in the pathogenesis of COVID-19 (31, 32) . On one hand, Table 2 . Treatment protocols on in-patient management of COVID-19 from several US hospitals have included hs-troponin as a part of the routine laboratory assessment (44, 45) . In patients with elevated hs-troponin, clinical context is important and myocarditis as well as stress induced cardiomyopathy should be considered in the differential, along with type I and type II MI. Evaluation of NT-proBNP should be considered if clinically indicated. COVID-19 induced myocarditis has been reported in case reports from China and elsewhere that usually requires aggressive management (46) (47) (48) (49) . New onset cardiomyopathy and arrythmias with elevated troponins should raise the suspicion of myocarditis. The initial diagnostic modality includes echocardiography and right and left cardiac catheterization with placement of a pulmonary artery catheter for continuous hemodynamic monitoring in critically ill shock patients. Cardiac MRI and endomyocardial biopsy are more definite tests. However, in the face of COVID-19 pandemic, when resources are limited and one of the primary goals is to minimize health care personnel's exposure, imaging modalities may not be readily available. Conceivably, cardiac biomarkers can be used to aid in diagnosis as well as risk stratification. Given the complex interplay of SARS-CoV-2 with the CV system, further investigation into potential mechanisms is needed to guide effective therapies. Epidemiological studies and randomized trials are urgently needed to investigate treatment modalities regulating immune function and inhibiting inflammatory responses to reduce the incidence and mortality associated with COVID-19 related acute myocardial injury. Figure shows prevalence estimates of acute myocardial injury (boxes) with 95% confidence limits (bars) for each study selected; pooled prevalence estimate is represented by diamond in this forest plot.

Clinical stages are based on National Institute of Health treatment guidelines (31) . Acute myocardial injury is typically seen in advanced stages of disease and is associated with worse prognosis. 

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