key: cord-0846007-yhct4wh9
authors: An, Wen; Kang, Ju-seop; Wang, Qiuyang; Kim, Tae-Eun
title: Cardiac biomarkers and COVID-19: a systematic review and meta-analysis
date: 2021-07-29
journal: J Infect Public Health
DOI: 10.1016/j.jiph.2021.07.016
sha: f31267b521b7d451d435729f1dea2c6c8ea28a42
doc_id: 846007
cord_uid: yhct4wh9

OBJECTIVE: To systematically investigate the relationship between cardiac biomarkers and COVID-19 severity and mortality. METHODS: We performed a literature search using PubMed, Web of Science, and Google Scholar. The standardized mean difference (SMD) and 95% confidence interval (CI) were applied to estimate the combined results of 67 studies. A meta-analysis of cardiac biomarkers was used to evaluate disease mortality and severity in COVID-19 patients. RESULTS: A meta-analysis of 7,812 patients revealed that patients with high levels of cardiac troponin I (SMD = 0.81 U/L, 95% CI = 0.14–1.48, P = 0.017), cardiac troponin T (SMD = 0.78 U/L, 95% CI = 0.07–1.49, P = 0.032), high-sensitive cardiac troponin I (SMD = 0.66 pg/ml, 95% CI = 0.51–0.81, P < 0.001), high-sensitive cardiac troponin T (SMD = 0.93 U/L, 95% CI = 0.21-1.65, P = 0.012), creatine kinase-MB (SMD = 0.54 U/L, 95% CI = 0.39-0.69, P < 0.001), and myoglobin (SMD = 0.80 U/L, 95% CI = 0.57-1.03, P < 0.001) were associated with prominent disease severity in COVID-19 infection. Moreover, 9,532 patients with a higher serum level of cardiac troponin I (SMD = 0.51 U/L, 95% CI = 0.37–0.64, P < 0.001), high-sensitive cardiac troponin (SMD = 0.51 ng/l, 95% CI = 0.29–0.73, P < 0.001), high-sensitive cardiac troponin I (SMD = 0.51 pg/ml, 95% CI = 0.38–0.63, P < 0.001), high-sensitive cardiac troponin T (SMD = 0.85 U/L, 95% CI = 0.63–1.07, P < 0.001), creatine kinase-MB (SMD = 0.48 U/L, 95% CI = 0.32–0.65, P < 0.001), and myoglobin (SMD = 0.55 U/L, 95% CI = 0.45-0.65, P < 0.001) exhibited a prominent level of mortality from COVID-19 infection. CONCLUSION: Cardiac biomarkers (cardiac troponin I, cardiac troponin T, high-sensitive cardiac troponin, high-sensitive cardiac troponin I, high-sensitive cardiac troponin T, creatine kinase-MB, and myoglobin) should be more frequently applied in identifying high-risk COVID-19 patients so that timely treatment can be implemented to reduce severity and mortality in COVID-19 patients.

COVID-19, cardiac biomarkers, meta-analysis, severity, mortality Introduction:

In December 2019, a novel coronavirus pneumonia (coronavirus disease 2019, outbreak was reported in Wuhan, China, and developed into a global pandemic. SARS-CoV-2 infection is induced by a combination of the spike protein of the virus and an angiotensin-converting enzyme 2 (ACE2), which is strongly expressed in the heart and lungs (1) ; it primarily invades alveolar epithelial cells and causes respiratory symptoms. ACE2 is not only expressed in the lung, but also in the heart and blood vessels. Therefore, SARS-CoV-2 may cause acute myocardial injury and chronic cardiovascular injury (2) . Myocardial injury, as shown by increased cardiac biomarkers, was identified among the first 41 patients with COVID-19 in Wuhan (3) .

Increases in lactose dehydrogenase (LDH), creatine kinase (CK), and aspartate aminotransferase (AST) can serve as markers of myocardial damage, as well as damage to the lungs, liver, kidneys, or other organs. In contrast, myoglobin (Mb), an oxygen binding protein, is mainly distributed in the cytoplasm of skeletal muscle and in the myocardium. Mb is a marker that can be detected early after myocardial injury. Creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), and cardiac troponin T (cTnT) are also myocardial-specific isoenzymes and proteins.

Increases in CK-MB, cTnI, cTnT, and hs-cTnT have high specificity in the diagnosis of J o u r n a l P r e -p r o o f myocardial injury. High-sensitive cardiac troponin I (hs-cTnI) has high sensitivity as a marker of early myocardial injury (4) . Some studies in patients with COVID-19 reported that levels of specific myocardial biomarkers including CK-MB, Mb, and cTnI were higher in patients treated in an intensive care unit (ICU) than in patients who did not require ICU care (5, 6, 7) . In this regard, identification of cardiac-specific biomarkers may reflect the severity of COVID-19 and improve outcomes by assisting with the management of COVID-19 patients.

The purpose of the present research was to investigate the relationships between cardiac-specific biomarkers (cTnI, cTnT, hs-cTn, hs-cTnI, hs-cTnT, CK-MB, and Mb) and COVID-19 severity and mortality through a meta-analysis.

This meta-analysis and systematic review is reported in accordance with the Preferred Reporting Items and Meta-Analyses (PRISMA) guidelines. Two researchers (An, Wang) screened the literature and chose the relevant studies using the Web of Science, PubMed, and Google Scholar for publications as of May 9, 2021, published in either English or Chinese. The following terms were used for the study search: ("SARS-CoV-2" or "COVID-19" or "Novel coronavirus 2019" or "coronavirus disease 2019") and ("Cardiac injury" or "Cardiac biomarkers" or "Heart" or "Myoglobin" or "Cardiac troponin I" or "cTnI" or "Cardiac troponin T" or "cTnT" or "Creatine Kinase-MB" or "Ck-MB" or "High-sensitive cardiac troponin I" or "hs-cTnI" or "High-sensitive cardiac troponin T" or "hs-cTnT" or "High-sensitive cardiac troponin" or "hs-cTn"). Studies in the reference list of related papers were also included in the study. IRB approval was not required.

The inclusion criteria were as follows: (a) types of studies: observational, retrospective, prospective, case-control, or descriptive studies of cardiac biomarkers including cTnI, cTnT, hs-cTn, hs-cTnI, hs-cTnT, CK-MB, and Mb in COVID-19 patients at admission; (b) subjects: patients diagnosed with COVID-19; (c) exposure/intervention: including at least one outcome of ICU vs. non-ICU, severe vs. non-severe, or survived vs. deceased; and (d) outcome measurements: mean and standard deviation or IQR for each laboratory experiment and total sample size for events. Editorial materials, reviews, summaries of discussions, and conference abstracts were excluded.

Severity was determined in this study based on admittance to the ICU. The mortality rate was determined by death regardless of other causes.

Data were extracted using a pre-designed excel worksheet. Any differences were resolved by a third investigator. The following data were extracted from the studies: first author; sample size; study design; age of patients; serum levels of cTnI, cTnT, hs-cTn, hs-cTnI, hs-cTnT, CK-MB, and J o u r n a l P r e -p r o o f Mb at admission; mortality; and severity.

Standardized mean difference (SMD) and 95% confidence interval (CI) for serum levels of cTnI, cTnT, hs-cTn, hs-cTnI, hs-cTnT, CK-MB, and Mb at admission were used to estimate the pooled results. We used fixed effects to evaluate the studies. Publication bias was estimated using a funnel plot. Sensitivity analyses were conducted to assess the impact of each study on the pooled effect.

A P value < 0.05 was considered statistically significant. All statistical analyses were carried out using Stata version 15.1 (StataCorp, USA).

A total of 4,607 articles were retrieved based on the keywords. After screening the abstracts and titles of the studies, 96 were selected for full-text evaluation. Among them, 29 were excluded owing to the lack of sufficient data such as median (IQR) or mean (SD). The final 67 studies were included in the meta-analysis and comprised 28 articles comparing the performance of severe vs. non-severe patients, and forty-one studies conducted to compare the performance of survivors vs. non-survivors ( Figure 1 ). The characteristics of the included studies are listed in Table 1 . 

The results of the sensitivity analysis (I 2 >50%) and publication bias (n≥10) showed that overall estimates were not dependent on a single publication (Supplement Figures S1-S15) . The source of heterogeneity and publication bias were mainly due to the different measurement methods within the group.

Based on a comprehensive analysis of a large number of studies, this meta-analysis identified cardiac biomarkers at admission (cTnI, cTnT, hs-cTn, hs-cTnI, hs-cTnT, CK-MB, and Mb) related to COVID-19 and analyzed their impact on the disease. One study showed that elevated serum myoglobin was associated with increased hospitalization mortality in patients, while elevated creatine kinase-MB and cardiac troponin I were not (73) . However, this study suggests that an increase in serum cTnI, hs-cTn, hs-cTnI, hs-cTnT, CK-MB, and Mb except for cTnT is directly related to COVID-19 mortality , while a raise in serum cTnI, cTnT, hs-cTnI, hs-cTnT, CK-MB, or

Mb except for hs-cTn is directly related to the severity of COVID-19. Our meta-analysis of 16, 791 samples suggests that increased cardiac biomarkers at admission in patients with COVID-19

infection are related to increased risk of disease and death. The present study's findings of increase in mortality and severity risk among COVID-19 patients with cardiac abnormality biomarkers test are consistent with previous narrative reviews (9, 74, 75, 76) .

In COVID-19 infection patients, in addition to the typical clinical manifestations of the respiratory system, there is also a certain proportion of patients with cardiac involvement in whom J o u r n a l P r e -p r o o f myocardial injury is more common (77) . Published studies showed that 7.2-19.7% of COVID-19 patients (6, 9, 78, 32) had acute heart injury, defined as cardiac troponin I above the 99th percentile.

Studies also revealed that patients with heart injuries had a higher mortality rate (9, 79) .

There are several possible mechanisms of COVID-19-induced myocardial injury: 1. Myocardial injury that is caused by an imbalance of oxygen supply and demand. Severe clinical symptoms such as arrhythmia, severe tachycardia, anaemia, and respiratory failure in patients with COVID-19 are related to increased cTnI due to myocardial injury (80) ; 2. Myocardial injury that is directly caused by viral invasion. The SARS-CoV-2 virus enters human cells by binding with angiotensin-converting enzyme 2 (ACE2) receptors, which is expressed in the heart and lungs.

The binding of the SARS-CoV-2 virus to ACE2 receptors may be the cause of acute myocardial and lung injury (1) ; 3. Excessive immune response further damages the heart, leading to ischemia and hypoxia of the heart tissue, and this overload of the heart maintains a high output and low resistance state. This leads to further ischemic injury and changes in laboratory cardiac markers, such as CK-MB, troponin I, and N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) increases. (5) Myocardial injury resulting in an excessive immune response mechanism can increase the severity of the disease and mortality.

Evidence suggested that five (12%) of 41 COVID-19 cases had virus-related myocardial injury that mainly manifested as increased high-sensitive cardiac troponin I (hs-cTnI) (>28 pg/ml) (3) and changes in laboratory cardiac biomarkers, such as increased creatine kinase-MB and cardiac troponin I, which can reflect ischemic damage of the heart (5) . There can also be progressive the week before death (55) . Another study reported that, four days after the onset of symptoms, the high-sensitive cardiac troponin I (hs-cTnI) level was 8.8 pg/ml in non-survivors and 2.5 pg/ml in survivors (81) . An Elevated level of serum myoglobin (≥306.5 μg/L) was related to greater in-hospital mortality among non-survivors (73) . Elevated hs-cTnI is also associated with increased utilization of non-invasive and invasive mechanical ventilation as well as acute respiratory distress syndrome (ARDS) (82) . However, cardiac biomarker levels at admission are also related to the mortality of COVID-19 patients. High levels of high-sensitive cardiac troponin I (hs-cTnI) (≥ 6.126 pg/ml) and creatine kinase-MB at admission were associated with increased mortality (83) .

Furthermore, creatine kinase-MB and cardiac troponin I have prognostic value in the prognosis of COVID-19 (84) . Elevated cTnT levels are common in patients with ARDS without electrocardiographic evidence of myocardial ischemia. Therefore, potential myocardial injury can be detected earlier by observing these biomarker levels at admission and comparing them to those during hospitalization. Once abnormal changes in myocardial markers are detected in COVID-19 patients at admission, the attending doctor can administer timely treatment to reduce the risk of serious disease and improve the prognosis of patients. 

The authors have no conflicts of interest to declare.

The authors received no financial support for the research, authorship, and/or publication of this article. 

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This appendix has been provided by the authors to give readers additional information about this work.