Journal Pre-proof J o u r n a l P r e -p r o o f Abstract Background: Evidence about COVID-19 on cardiac injury is inconsistent.Objectives: We aimed to summarize available data on severity differences in acute cardiac injury and acute cardiac injury with mortality during the COVID-19 outbreak. Methods:We performed a systematic literature search across Pubmed, Embase and pre-print from December 1, 2019 to March 27, 2020, to identify all observational studies that reported cardiac specific biomarkers (troponin, creatine kinase-MB fraction, myoglobin, or NT-proBNP) during COVID-19 infection. We extracted data on patient demographics, infection severity, comorbidity history, and biomarkers during COVID-19 infection. Where possible, data were pooled for meta-analysis with standard (SMD) or weighted (WMD) mean difference and corresponding 95% confidence intervals (CI). Results:We included 4189 confirmed COVID-19 infected patients from 28 studies. More severe COVID-19 infection is associated with higher mean troponin (SMD 0.53, 95% CI 0.30 to 0.75, p<0.001), with a similar trend for creatine kinase-MB, myoglobin, and NT-proBNP.Acute cardiac injury was more frequent in those with severe, compared to milder, disease (risk ratio 5.99, 3.04 to 11.80; p<0.001). Meta regression suggested that cardiac injury biomarker differences of severity are related to history of hypertension (p = 0.030). Also COVID19-related cardiac injury is associated with higher mortality (summary risk ratio 3.85, 2.13 to 6.96; p<0.001). hsTnI and NT-proBNP levels increased during the course of hospitalization only in non-survivors. Conclusion:The severity of COVID-19 is associated with acute cardiac injury, and acute cardiac injury is associated with death. Cardiac injury biomarkers mainly increase in Journal Pre-proof J o u r n a l P r e -p r o o f non-survivors. This highlights the need to effectively monitor heart health to prevent myocarditis in patients infected with COVID-19. Journal Pre-proof J o u r n a l P r e -p r o o f Alphabetical list of abbreviations ACE2= angiotensin converting enzyme 2 CI = confidence intervals CK-MB = creatine kinase-MB COVID-19 = coronavirus disease 2019 hsTnI = hypersensitive troponin I NT-proBNP = N-terminal pro-B-type natriuretic peptide RR = risk ratio SARS-CoV = severe acute respiratory syndrome coronavirus SMD = standard mean difference WMD = weighted mean difference Journal Pre-proof J o u r n a l P r e -p r o o f Central illustration Journal Pre-proof Epidemiology (MOOSE) guidelines. 5 No language restrictions were imposed on the search. We searched the electronic databases Pubmed, and Embase from

We thank all participants, investigators, and trial teams for their participation in the trial. The CREDENCE study was sponsored by Janssen Research & Development, LLC, and was conducted collaboratively by the sponsor, an academic-led Steering Committee, and an Academic Research Organization, George Clinical. Analyses were performed by George Clinical and independently confirmed by the sponsor. Technical editorial assistance was provided by Kimberly Dittmar, PhD, of MedErgy, and was funded by Janssen Global Services, LLC.