Myocardial injury characterized by elevated cardiac troponin and in‐hospital mortality of COVID‐19: An insight from a meta‐analysis

Abstract

Since December 2019, coronavirus disease 2019 (COVID-19) caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a public health emergency of international concern. As of 22 May 2020, the World Health Organization has declared that approximately 5 000 000 cases of COVID-19 have been confirmed globally with more than 320 000 deaths (https://covid19.who.int/). Patients with COVID-19 show diverse clinical manifestations that range from no symptoms to severe pneumonia and even death. We are now encountering the difficulties in how to identify patients at risk for severe disease early in the course of COVID-19. A number of potential risk factors predicting poor prognosis of COVID-19 have been demonstrated, including older age, the presence of cardiovascular disease, lymphopenia, elevated D-dimer levels, elevated interleukin-6 levels, and high sequential organ failure assessment (SOFA) scores.1 In recent studies, myocardial injury characterized by elevated high-sensitivity cardiac troponin (hs-cTn) levels has been reported as an independent risk factor for in-hospital mortality in patients with COVID-19.2, 3 Given the lack of a definitive marker for risk stratification of COVID-19, we performed a meta-analysis of currently available studies to clarify the association between myocardial injury assessed by hs-cTn levels and in-hospital mortality in patients with COVID-19. A systematic search of all existing studies on myocardial injury detected by hs-cTn in patients with COVID-19 was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (http://www.prisma-statement.org). We searched PubMed and Embase through 13 April 2020 using the following search terms: (“coronavirus 2019” OR “2019-nCoV” OR “SARS-CoV-2” OR “COVID-19” OR “COVID” OR “2019 novel coronavirus”) AND (“troponin” OR “troponins” OR “TnI” OR “cTnI” OR “TnT” OR “cTnT” OR “CK-MB” OR “creatine kinase MB” OR “cardiac biomarkers” OR “cardiac injury” OR “cardiac damage” OR “myocardial injury” OR “myocardial damage” OR “myocardial infarction” OR “myocarditis” OR “clinical characteristics” OR “clinical features” OR “clinical course” OR “predictors” OR “risk factors” OR “outcomes”). All articles were downloaded for consolidation, elimination of duplicates, and further analyses without language or time restrictions. Studies were selected based on the following criteria: (a) published in peer-reviewed journals; (b) included only patients with laboratory-confirmed COVID-19; (c) reported the in-hospital mortality and myocardial injury defined as elevated hs-cTn levels to avoid arbitrary interference from outcome definitions. In cases where overlap of the study population or enrollment period was found in articles published from the same hospitals, the article with the largest number of patients was only included in the analysis. The pooled odds ratio was calculated using inverse-variance weighted random-effects models. Statistical analyses were performed using Review Manager (RevMan) version 5.3.5 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, Copenhagen, Denmark; https://training.cochrane.org/online-learning/core-software-cochrane-reviews/revman) and ProMeta 3.0 (https://idostatistics.com/prometa3/). Our initial search identified 480 potentially relevant articles from PubMed and 243 articles from Embase. After title, abstract, and full-text evaluation, we identified 21 studies that reported information about hs-cTn levels (Table 1), 15 of which were excluded attributable to the lack of in-hospital mortality by hs-cTn status and suspected large overlapping of patients populations. Finally, six observational studies which included a total of 1231 patients met the search criteria.1, 3-6, 2 All studies used troponin I as hs-cTn, except for the study by Guo et al,3 which used troponin T. The percentage of patients with hs-cTn levels varied across the studies (13%-41%). The funnel plot for in-hospital mortality indicated an absence of publication bias (data not shown). Regarding the impact of hs-cTn levels on outcomes in evaluated studies (Figure 1), elevated hs-cTn levels were significantly associated with an increase in in-hospital mortality (pooled odds ratio, 22.7; 95% confidence interval, 13.6-38.1; P < .001) with a moderate heterogeneity (I2 = 28%). Our meta-analysis results support the previous finding that the levels of hs-cTn might help to identify patients at high risk for adverse clinical events associated with COVID-19. Elevation of hs-cTn is a surrogate of myocardial injury, which appears to be a common complication of COVID-19 with incidence rates ranging from 7% to 44% (Table 1). Although the mechanism of myocardial injury associated with COVID-19 is not completely understood, patients with cardiovascular disease are four times likely to have elevated hs-cTn levels than those without.3 Increased myocardial oxygen demand during acute infection might induce myocardial ischemia due to exacerbations of cardiovascular diseases, including coronary artery disease, atrial fibrillation, and congestive heart failure. In fact, Guo et al3 has shown a positive correlation between hs-cTn and high-sensitivity C-reactive protein, supporting the theory that patients with cardiovascular disease may be susceptible to myocardial injury associated with severe systemic inflammatory response to COVID-19.7 Other proposed mechanisms include upregulation of cytokines1, 4 that are toxic to the myocardium and abundance of angiotensin-converting enzyme 2 receptor in the heart, which is the main receptor for SARS-CoV-2 cell entry. Further research studies are needed to assess the continuous relationship between mortality and hs-cTn levels in the early phase of the disease and the role of these mechanisms in patients with and without pre-existing cardiovascular diseases. Larger patient data sets will allow us to adjust hs-cTn levels for other confounding factors and inflammatory biomarkers, which might be helpful to establish hs-cTn as an independent predictor of poor outcome in COVID-19. So far, five meta-analyses have reported the association between myocardial injury and disease severity or mortality of COVID-19.8-12 However, those meta-analyses included multiple publications from the same institutions at the overlapped study period, which may result in double counting of patients. We carefully avoided double counting of patients from the same institutions (Table 1). Although the present results are subject to potential bias related to the availability of confounding factors, the lack of the specific purpose and timing of hs-cTn tests, and large differences in the study populations, elevated hs-cTn levels might be used as a reliable marker of disease severity early in the course of COVID-19. TA was supported by fellowships from the Uehara Memorial Foundation, the Kanzawa Medical Research Foundation, the Suginome Memorial Foundation, and the Nakayama Foundation for Human Science.

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