key: cord-0960399-3i00rwef
authors: Ogungbe, Oluwabunmi; Kumbe, Baridosia; Fadodun, Oluwadamilola; Latha, T.; Meyer, Diane; Asala, Adetoun; Davidson, Patricia M.; Dennison Himmelfarb, Cheryl R.; Post, Wendy S.; Commodore-Mensah, Yvonne
title: Subclinical myocardial injury, coagulopathy, and inflammation in COVID-19: A meta-analysis of 41,013 hospitalized patients
date: 2022-01-04
journal: Int J Cardiol Heart Vasc
DOI: 10.1016/j.ijcha.2021.100950
sha: 06757919d3f60d4e91ca7038c8ef71356a4fa825
doc_id: 960399
cord_uid: 3i00rwef

BACKGROUND: Infection with the SARS-CoV-2 virus can lead to myocardial injury, evidenced by increases in specific biomarkers and imaging. OBJECTIVE: To quantify the association between biomarkers of myocardial injury, coagulation, and severe COVID-19 and death in hospitalized patients. METHODS: Studies were identified through a systematic search of indexed articles in PubMed, Embase, CINAHL, Cochrane, Web of Science, and Scopus, published between December 2019 to August 2021. Effect estimates from individual studies for association between markers of myocardial injury (Troponin), myocardial stretch (N-terminal-pro hormone BNP, NT-proBNP), and coagulopathy (D-Dimer) and death or severe/critical COVID-19 were pooled using inverse variance weighted random-effects model. Odds Ratios (OR), Hazard Ratios (HR), and 95% Confidence Intervals (CI) were pooled separately and reported by outcomes of critical/severe COVID-19 and death. A meta-analysis of proportions was also performed to summarize the pooled prevalence of co-morbidities in patients hospitalized with COVID-19. RESULTS: We included 62 articles, with a total of 41,013 patients. The pooled proportion of patients with history of hypertension was 39% (95% CI: 34-44%); diabetes, 21% (95% CI: 18%-24%); coronary artery disease, 13% (95% CI: 10-16%); chronic obstructive pulmonary disease, 7% (95% CI: 5-8%), and history of cancer, 5% (95% CI: 4-7%). Elevated troponin was associated with higher pooled odds of critical/severe COVID-19 and death [Odds Ratio (OR: 1.76, 95% CI: 1.42-2.16)]; and also separately for death (OR: 1.72, 95% CI: 1.32-2.25), and critical/severe COVID-1919 (OR: 1.93, 95% CI: 1.45-2.40). Elevations in NT-proBNP were also associated with higher severe COVID-19 and death (OR: 3.00, 95% CI: 1.58-5.70). Increases in D-dimer levels was also significantly associated with critical/severe COVID-19 and death (pooled OR: 1.38, 95% CI: 1.07-1.79). CONCLUSIONS: This meta-analysis synthesizes existing evidence showing that myocardial injury, and coagulopathy are complications of COVID-19. The durability of these complications and their contributions to long-term cardiac implications of the disease is still being investigated. Patients who have recovered from COVID-19 may benefit from minimally invasive assessment for markers of myocardial injury, stretch and coagulopathy for early risk stratification purposes.

While COVID-19 may begin as a respiratory disease, sometimes causing pneumonitis and severe acute respiratory distress syndrome (ARDS), other major organs may also be affected, particularly the cardiovascular system, kidneys, and brain. 1 COVID-19 is associated with a wide range of symptoms, and a spectrum of clinical illnesses characteristic of multisystem disease with cardiovascular consequences. 2, 3 The characteristic of immune system activation may result in cytokine storm with the release of massive amounts of cytokines, causing both local and systemic inflammatory response, which contributes to disarray in immune, cardiac and inflammatory biomarkers. 4, 5 Infection with SARS-CoV-2 virus can lead to elevations in cardiac biomarkers and electrocardiographic changes that are associated with poorer clinical outcomes, including ICU admission, mechanical ventilation and death. [6] [7] [8] These cardiac biomarkers include troponin (cTnI), nterminal pro-b-type natriuretic peptide (NT-proBNP), galectin-3, d-dimer, interleukin-6 (IL-6), and creactive protein (CRP). [9] [10] [11] In one study of 2,736 patients hospitalized for COVID-19 in New York City, small elevations in cTnI laboratory values were associated with increased mortality. NT-proBNP, a hormone that is predominantly produced by ventricular myocytes in response to increased ventricular wall stress, is an established biomarker for diagnosis and prognosis of heart failure. 12 Elevated NT-proBNP is associated with increased risk of cardiogenic shock, 13 acute heart failure, 14, 15 myocardial infarction, 14 right ventricular dysfunctions, left ventricular dysfunction, 16, 17 stress cardiomyopathy, 16, 17 arrhythmias, 13-15 and venous and arterial thrombosis 18, 19 among hospitalized COVID-19 patients 20 . According to the American College of Cardiology (ACC), based on case reports from China, US, and Europe, about 40% of hospitalized COVID-19 patients have cardiovascular or cerebrovascular disease, 16.7% of them developed arrhythmias, and 7.2% developed acute cardiac injury. [21] [22] [23] Understanding accumulating evidence on the cardiac consequences of infection with SARS-CoV-2 virus is critical to better understanding biomarkers that may indicate poorer clinical outcomes. Thus, we conducted a systematic review and meta-analysis to quantify the association between biomarkers of myocardial injury (troponin), myocardial stretch (NT-proBNP, Gal-3), coagulation (D-Dimer), inflammation (CRP, IL-6) and severe COVID-19 or death in hospitalized patients. We also calculated pooled proportions of underlying co-morbidities (hypertension, CAD, diabetes, COPD, and cancer) from the articles reviewed.

This systematic review and meta-analysis followed recommendations from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (eTable 1 in the Supplement). A detailed literature search was conducted in relevant scientific databases, including MEDLINE (PubMed), Embase, CINAHL, Cochrane, Web of Science, and Scopus. Search terms and strategy were developed with the help of an informationist to search for studies conducted between December 2019 and January 2021. An updated search was conducted for articles between January and August 2021. The complete search strategy for each database is available in eTable 2 in the Supplement. This review was registered in the PROSPERO database with registration number CRD42021229341.

All studies identified via databases searches were imported into Covidence. 24 Three reviewers (O.O., B.K., O.A) independently screened identified studies for title and abstract eligibility. Discrepancies and divergencies were discussed and adjudicated with the help of two independent reviewers (L.T and A.A). The following criteria full-text review inclusion were: 1) study type: retrospective, prospective, observational, or case-control studies, reporting on cardiac biomarkers (specifically Troponin I or T, NT-proBNP, CRP, IL-6, and Gal-3); 2) population: adult patients diagnosed with COVID-19; 3) exposure/intervention: confirmed COVID 19 infection; 4) outcome indicators: myocardial injury, severe or critical clinical status, and death. Studies excluded include case reports, editorials, letters to the editor and correspondence, and conference abstracts that did not contain primary data. Preprints and non-peer reviewed articles, other review articles, and articles not published in English were also excluded.

Following title/abstract screening, three reviewers (O.O., B.K., OA.,) worked in pairs to independently assess the studies for full-text eligibility. A third and fourth reviewer performed conflict resolution, one adjudicator per article, to reach a consensus (L.T., and A.A). After full-text eligibility screening, data were extracted independently by a total of five reviewers (O.O., B.K., O.A., L.T., and D.M); for each article, there were two primary independent reviewers and one adjudicator. Discrepancies for extracted data were resolved by consensus, results adjudicated where applicable and confirmation checks were done. A predesigned and piloted data template in Covidence was used for data extraction. Data extracted included author, publication year, study design, sample size, participant characteristics, proportion of comorbidities in the sampled population, median or mean levels of cardiac biomarkers and their cut-off points, outcomes of interest (COVID-19 severity, death, ICU admission, etc.), and reported measures of association.

For this review, data on severe COVID-19 was abstracted based on the definition and categories as reported in the reviewed articles. Studies conducted in China defined severity of COVID-19 according to the Chinese guideline for COVID-19 management; 25 severe cases were defined as the presence of at least one of the following: (i) respiratory rate >30 breaths per minute; (ii) oxygen saturation (SpO2) ≤93%; and (iii) PaO2/FiO2 ratio ≤300 mmHg. Critical cases were defined as those including at least one of the following: (i) respiratory failure requiring mechanical ventilation; (ii) shock; (iii) presence of other organ damage apart from respiratory; and (iv) admission to intensive care unit. Other studies used the World Health Organization definitions of severe pneumonia (Adolescent or adult: fever or suspected respiratory infection, plus one of respiratory rate >30 breaths/min, severe respiratory distress, or SpO2 <90% on room air) or ARDS (Onset: new or worsening respiratory symptoms within one week of known clinical insult; Chest imaging (radiograph, CT scan, or lung ultrasound): bilateral opacities, not fully explained by effusions, lobar or lung collapse, or nodules; Origin of edema: respiratory failure not fully explained by cardiac failure or fluid overload; o exclude hydrostatic cause of edema if no risk factor present; Oxygenation (adults): PaO2/FiO2 ≤ 100 mmHg with PEEP ≥5 cmH2O, or nonventilated). 26 Majority of the articles defined myocardial injury as hs-Troponin I (hs-TnI) ≥99th percentile of the upper reference limit, regardless of new abnormalities in electrocardiography and echocardiography. 27

Quality Assessment was conducted using the Newcastle Ottawa Quality Assessment Scale (NOS) 28 which assesses design quality of non-randomized, cohort and case-control studies. A maximum score of 9 was aggregated across three domains of the NOS scale: selection of study groups (4 possible points), comparability of groups (2 possible points), and ascertainment of outcomes (3 possible points). The overall risk of bias was classified as either "high", "some concern", or "low" based on the cumulative NOS scores. The risk-of-bias assessment summary table and plots were created using the robvis application. 29

Analysis was conducted using the meta commands in Stata/IC 16.1. 30 All reported medians or mean values for biomarkers: Troponin I or T, NT-proBNP, Gal-3, IL-6, D-Dimer, and CRP were summarized in the original unit measured in the studies. When studies did not report mean and standard deviations, reported sample sizes, median and interquartile ranges were abstracted. Measures of associations reported in relevant studies (odds or hazard ratios) and the primary outcomes were summarized. For the meta-analysis, unadjusted hazard ratios (HR) and odds ratios (OR) and their 95% confidence intervals (CI), reported from each study were natural log-transformed. 31 OR, HRs and 95% CIs were pooled separately and reported by outcomes of death or critical/severe COVID-19. Random effect models with the inverse variance method were used to derive pooled measures of association, and the 95% CI and p-values to quantify the associations between elevated biomarkers and cardiovascular complications, and COVID-19 severity and death.

The pooled effect sizes were represented as forest plots. Heterogeneity of study estimates was assessed by Hedge's I 2 statistic, which was interpreted as I 2 <25%, 25-50%, 50-75%, and >75%, which indicates no, low, moderate, and high between-study heterogeneity. 32 The risk of publication bias was assessed using funnel plots. Egger's meta-regression was performed to assess for small-study effects. We visually inspected the distribution of relevant studies for asymmetry or by p-value <0.1, indicating possible publication bias. 33 To calculate pooled proportions from the reported underlying co-morbidities (hypertension, CAD, diabetes, COPD, and cancer) from each article, we performed a meta-analysis of proportions of this binomial data, using the metaprop package in Stata. 34 Using a random-effects model, we calculated 95% exact confidence intervals for each study and the overall pooled estimate for each comorbidity. We reported the measure of heterogeneity (I 2 ) and displayed the outputs using forest plots. Figure 1 shows the PRISMA flow chart for study selection. A total of 3,106 records were identified through the databases on initial search, and 2,032 records from the updated search; 2,454 duplicates were removed, and 2,684 titles and abstracts were screened for inclusion. Following title and abstract screening, 2,274 articles were excluded leaving 410 articles for full-text retrieval, 58 of which full-text versions were unretrievable or conference abstracts. Upon screening, a total of 290 articles were further excluded, leaving 62 articles that met the inclusion criteria and were included in the review and metaanalysis for this study. The PRISMA flowchart was completed according to the updated 2020 guideline, 35 and generated using an available online Shiny App. 36

The characteristics of the 62 studies included are presented in Table 1 . Most studies were conducted in China (50%), Italy (14%), the United States (12%), Turkey (3%), Spain (3%), the United Kingdom (2%), France (2%), Iran (2%), Korea (2%), Mexico (2%), Morocco (2%), Brazil (2%), Pakistan (2%), and the Netherlands (2%). Total sample size from the studies was 41,013, ranging from 38 to 11,159 patients, and median age of participants ranged from 44.6 to 75 years. The pooled proportion of participants who had severe COVID-19 or died during hospitalization was 16.8% (1,978/11,764) .

For the papers included in the meta-analysis, 24 were rated to have a low risk of bias, while 16 were rated to have a high risk of bias. Four were rated as unclear (eFigure 1 in the Supplement). Those studies assessed to have a high risk of bias were primarily due to incomplete outcome reporting.

A majority of the studies reported history of comorbidities among patients included in the study. The pooled proportion of patients with hypertension was 39% (95% CI: 35-43%), ranging from 15-73% (Figure 2) . For history of diabetes, the pooled proportion was 21% (18%-23%), this ranged from 8%-44%. The pooled proportion for history of CAD was 13% (95% CI: 11-16%), and this ranged from 1-49%. In the total sample, the pooled proportion of patients who had COPD was 7% (95% CI: 6-9%), which ranged from 2-23%, for history of cancer, the pooled proportion was 6% (95% CI: 5-7%) which also ranged from 2-16% (eFigures 4-7 in the Supplement).

For studies that reported myocardial injury, the proportion of patients who developed myocardial injury was 18.5% (3,943/ 21,367) (eTable 3 in the Supplement). The overall pooled odds ratio for the association between elevated troponin levels and death and critical/severe disease was 1.76 (95% CI: 1.42, 2.16); for the outcome of death, the pooled odds was OR: 1.72 (95% CI: 1.32, 2.25); and for the outcome of critical/severe COVID-19, the pooled odds ratio was 1.93 (95% CI: 1.45, 2.40) (Figure 3) . Similarly, the overall hazards ratio for elevated troponin and death and critical/severe disease was 1.55 (95% CI: 1.36, 1.77). The hazards for elevated troponin and death was 1.51 (95% CI 1.31, 1.75), and for critical or severe COVID-19 was 1.75 (95%CI 1.48, 2.10).

Elevations in NT-proBNP were also associated with severe COVID-19 and death: OR: 3.00 (95% CI: 1.58-5.70). The hazards ratio associated with elevated NT-proBNP and death, or critical/severe COVID-19 was 1.65 (pooled HR: 1.65, 95%CI: 0.88-3.10) (Figure 3) . Increased D-dimer levels were also significantly associated with death and severe disease, pooled OR: 1.38 (95%CI: 1.07-1.79). While the pooled hazards ratio associated with either death, critical/severe disease, and elevated D-dimer levels was HR: 1.16 (95% CI: 0.9, 1.48) (Figure 3) .

Abnormal increases in CRP were also associated with higher severe COVID-19 and death: OR: 1.60 (95% CI: 1.13-2.25). The hazards ratio associated with increased CRP and death or critical/severe COVID-19 was 1.15 (pooled HR: 1.15, 95% CI: 0.94-1.42) (eFigure 2 in Supplement). Elevated IL-6 levels were also significantly associated with death and severe disease, pooled OR: 1.55 (95% CI: 1.14-2.14) (eFigure 3 in the Supplement).

In this meta-analysis, we aimed to assess the association between biomarkers of myocardial injury and stretch, coagulation, and severe COVID-19 and death. From 62 articles reviewed, hospitalized COVID-19 patients had a high prevalence of underlying comorbidities such as hypertension, diabetes, COPD, CAD, and malignancy. Furthermore, the pooled data demonstrated that elevated biomarkers of inflammation, subclinical myocardial injury, coagulation, were significantly associated with severe COVID-19 and death.

Our findings are consistent with previous findings, which have reported early in the COVID-19 pandemic that individuals who have an underlying or preexisting cardiovascular disease such as heart failure, coronary heart disease and risk factors such as being of older age, hypertension, diabetes are over-represented in COVID-19 hospitalization. 37 In similar meta-analyses examining the association between COVID-19 and poor COVID-19 outcomes, there is a strong association between biomarker evidence of cardiac injury and worse COVID-19 outcomes; they include elevation of cTn, NT-proBNP, d-dimer, which predict poor clinical outcomes. 38, 39 Cardiac involvement in COVID-19 is determined by the extent of the viral inoculum, and magnitude of host immune response, and the presence of underlying comorbidities. 10 Some of the mechanisms through which direct and indirect cardiac injury may occur in the context of COVID-19 are through inflammation, endothelial activation, and microvascular thrombosis (eFigure 8 in the Supplement). 10, 40 In direct viral myocardial invasion, the outer membrane spike of the SARS-CoV-2 virus has a high affinity for the ACE2 receptors and the protease transmembrane protease serine 2 (TMPRSS2), which are highly expressed in cardiac tissues. 41 Hence, direct viral myocardial invasion is highly plausible, and evidence of SARS-CoV-2 positivity in cardiac tissues has been documented in autopsy reports. 42 The activation of macrophages (major sources of cytokines and the inflammatory cytokine tumor necrosis factor (TNF)-α) is promulgated by metalloproteinase domain 17 (ADAM-17), which is also responsible for shedding of ACE2. Loss of ACE2 receptor density due to binding from the SARS-CoV-2 spike protein leads to accumulation of Angiotensin II (Ang II), and continued triggering of ADAM-17. 43 This creates vicious positive feedback of activated ADA-19, more ACE2 shedding, and increased Ang II-mediated inflammatory responses, which is partially responsible for the cytokine storm characteristic of the SARS-CoV-2 immune response. 10, 44 In the context of COVID-19, plaque destabilization and eruption can be facilitated by viral products from the systemic circulation, which could activate immune receptors on cells in already existing plaques in coronary vasculature. 45 The ongoing infection and inflammation could also lead to dysregulation of coronary vascular endothelial function leading to vasoconstriction and thrombosis. 46 Endothelial dysfunction is expressed through alteration in the vessel barrier, promotion of a coagulative state, induction of endothelial inflammation, and mediation of leukocyte infiltration. 47 Importantly, myocardial oxygen supply and demand may result from the following: endothelial dysfunction in coronary microcirculation; fixed coronary atherosclerosis limiting myocardial perfusion, high levels of circulating Ang II and arteriolar vasoconstriction resulting in systemic hypertension, and hypoxemia from ARDS or pulmonary thrombosis. 10 The immense physiologic demands that result from the SARS-CoV-2 infection response and the systemic inflammatory cascade, may be sufficient to trigger this supply-demand mismatch, even in the absence of an atherothrombotic plaque. 10 Another possible contributory mechanism associated with high fatality in COVID-19 and complications is disseminated intravascular coagulation (DIC), with the cross-talk between inflammation and coagulation mediated through protease-activated receptors (PARS); there have been recommendations for clinical use of direct oral anticoagulants to inhibit PARS in acute care of COVID-19 and in patients experiencing persisting symptoms of COVID-19. 48 Evidence is emerging on the long-term cardiac sequela of COVID-19-related myocardial injury, with evidence of myocardial fibrosis or myocarditis in 9-78% of patients who have had COVID-19. 37 Ongoing inflammation has been reported in 60%, and cardiac involvement in 78% of patients recovered from acute COVID-19. 49 Based on the results of our meta-analysis and other similar studies, and in light of post-acute sequelae of COVID-19, it is important to consider measurements of sustained expression of biomarkers signaling inflammation and myocardial damage in persons who have previously tested positive for COVID-19. Such sustained expression of certain inflammatory biomarkers are yet to be characterized in COVID-19; however, these may indicate long-term hyperinflammatory state with cardiac involvement from damage mediated by the virus during the acute phase, or even possibilities of host viral reservoir, which is not uncommon in other viruses, but yet to be established in COVID-19. 50 Considerations of the prognostic value of these biomarkers in persons previously hospitalized for COVID-19, and identification of subclinical myocardial injury can help with risk stratification, and downstream decisions about care.

This study has some limitations. First, we could not find a sound and acceptable method for pooling reported medians and interquartile ranges in the literature. This was challenging considering that biomarker values are not typically normally distributed, hence cannot be confidently pooled without introducing bias, particularly when using meta-analysis methods that are reliant on means and standard deviation as measures of central tendency and dispersion. Second, several of the biomarkers were reported in different units, some of which could not be confidently converted to a single unit for use in statistical analyses. This severely limited our inclusion of the biomarker values reported in the articles in the meta-analyses. Third, this review was limited to articles published in English; excluding non-English articles during screening may have introduced some bias.

Nevertheless, this study has major strengths. The meta-analytic approach combined both observational and comparative methods. This included a meta-analysis of proportions for estimating the pooled prevalence of underlying comorbidities, and a comparative meta-analysis of odds and hazards of the associations between elevated biomarker levels and severe COVID-19 and/or death. In addition, our study comprehensively examined biomarkers that are representative of the different pathways of immune response and cardiac injury associated with the COVID-19. This study also offers an updated summary of existing evidence on the relationship between biomarkers of inflammations, myocardial injury in COVID-19, and their value in prognosis. Our meta-analysis included 41,013 patients from diverse global regions and contexts. Findings from our study also corroborate with findings from other studies showing an over-representation of persons with pre-existing comorbidities in persons with poor COVID-19 outcomes.

Our systematic review and meta-analysis showed significant associations between markers of myocardial injury and stretch, and coagulopathy with poor COVID-19 outcomes. There is also evidence in the literature of persisting symptoms suggestive of complications in patients recovered from COVID-19. The durability of these complications and their contributions to long-term cardiac implications of the disease is still being investigated. Recovered patients, may benefit from minimally invasive assessment for markers of myocardial injury and stretch and coagulopathy for early risk stratification purposes. 

COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options

Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review

Post-acute COVID-19 syndrome

Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy

Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: Review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts

Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)

Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

The relationship between cardiac injury, inflammation and coagulation in predicting COVID-19 outcome

Coronavirus and Cardiovascular Disease, Myocardial Injury, and Arrhythmia: JACC Focus Seminar

Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China

N-Terminal&#x2013;Pro-Brain Natriuretic Peptide Predicts Outcome After Hospital Discharge in Heart Failure Patients

Clinical Characteristics of 138 Hospitalized Patients With

Novel Coronavirus-Infected Pneumonia in Wuhan, China

Characterization and clinical course of 1000

Patients with COVID-19 in New York: retrospective case series. medRxiv

Cardiac manifestations of COVID-19 in Shenzhen, China. Infection

Indications for and Findings on Transthoracic Echocardiography in COVID-19

Cardiovascular manifestations and treatment considerations in COVID-19. Heart

Coronavirus Disease 2019-Associated Coagulopathy

Prognostic value of NT-proBNP in patients with severe COVID-19

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

COVID-19 and Cardiovascular Disease. Circulation

The cardiovascular impact of COVID-19. Diagnostic and Interventional Cardiology (DAIC)

Covidence systematic review software. Veritas Health Innovation. Melbourne, Australia. 25. National Health Commission of the People's Republic of China. Chinese management guideline for COVID-19

Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected: interim guidance

Fourth universal definition of myocardial infarction

The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses

Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments

Meta-Analysis of Odds Ratios: Current Good Practices. Med Care

Quantifying heterogeneity in a meta-analysis

Quantifying publication bias in meta-analysis

Metaprop: a Stata command to perform meta-analysis of binomial data

PRISMA2020: R package and ShinyApp for producing PRISMA 2020 compliant flow diagrams

COVID-19 and Cardiovascular Disease: From Bench to Bedside

Role of Cardiac Biomarkers in COVID-19: What Recent Investigations Tell Us?

Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): Evidence from a meta-analysis. Progress in cardiovascular diseases

Cardiac Biomarkers and COVID-19: What Nurses Should Know About Cardiac and Inflammatory Biomarkers and COVID-19. PCNA (Preventive Cardiovascular Nurses Association)

The Science Underlying COVID-19: Implications for the Cardiovascular System

Association of Cardiac Infection With SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases

Response by Gheblawi et al to Letter Regarding Article

Reactive oxygen species and p38 mitogenactivated protein kinase mediate tumor necrosis factor α-converting enzyme (TACE/ADAM-17) activation in primary human monocytes

Pathogen recognition and inflammatory signaling in innate immune defenses

Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link?

Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches. Signal Transduction and Targeted Therapy

The Cross-Talk between Thrombosis and Inflammatory Storm in Acute and Long-COVID-19: Therapeutic Targets and Clinical Cases

Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease

A Proposed Framework and Timeline of the Spectrum of Disease Due to SARS-CoV-2 Infection: Illness Beyond Acute Infection and Public Health Implications

Analysis of cardiac injury biomarkers in COVID-19 patients. Archives of Clinical Infectious Diseases

Myocardial injury and COVID-19: Serum hs-cTnl level in risk stratification and the prediction of 30-day fatality in COVID-19 patients with no prior cardiovascular disease

Myocardium injury biomarkers predict prognosis of critically ill coronavirus disease 2019 (Covid-19) patients

Prognostic implications of myocardial injury in patients with and without COVID-19 infection treated in a university hospital

The diagnostic and prognostic role of myocardial injury biomarkers in hospitalized patients with COVID-19

Suspected myocardial injury in patients with COVID-19: Evidence from front-line clinical observation in Wuhan, China

Reduced cardiac function is associated with cardiac injury and mortality risk in hospitalized COVID-19 Patients

Cardiovascular manifestations in severe and critical patients with COVID-19

Characteristics of cardiac injury in critically ill patients with COVID-19

Cardiac injuries in patients with coronavirus disease 2019: Not to be ignored

Risk factors for myocardial injury in patients with coronavirus disease 2019 in China

Risk factors for myocardial injury and death in patients with COVID-19: insights from a cohort study with chest computed tomography

Prognostic value of NT-proBNP in patients with severe COVID-19

Cardiac involvement at presentation in patients hospitalized with COVID-19 and their outcome in a tertiary referral hospital in Northern Italy. Internal and emergency medicine

Characterization of Myocardial Injury in Patients With COVID-19

Myocardial injury in severe and critical coronavirus disease 2019 patients

Cardiovascular Implications of Fatal Outcomes of Patients with Coronavirus Disease 2019 (COVID-19)

The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health: The latest 2019 novel coronavirus outbreak in Wuhan

Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection

Analysis of heart injury laboratory parameters in 273 COVID-19 patients in one hospital in Wuhan

Factors associated with acute cardiac injury and their effects on mortality in patients with COVID-19

Implications of myocardial injury in Mexican hospitalized patients with coronavirus disease 2019 (COVID-19)

Acute cardiac injury in adult hospitalized COVID-19 patients in Zhuhai

Prognostic Value of Troponin-T and B-Type Natriuretic Peptide in Patients Hospitalized for COVID-19

Cardiac Injury and Outcomes of Patients with COVID-19 in

Usefulness of Elevated Troponin to Predict Death in Patients With COVID-19 and Myocardial Injury

The Implication of Cardiac Injury Score on In-hospital Mortality of Coronavirus Disease

Longitudinal correlation of biomarkers of cardiac injury, inflammation, and coagulation to outcome in hospitalized COVID-19 patients

Cardiac damage in patients with the severe type of coronavirus disease 2019 (COVID-19)

Association of Troponin Levels with Mortality in Italian Patients Hospitalized with Coronavirus Disease

Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan

Myocardial Injury in Severe COVID-19 Compared to Non-COVID Acute Respiratory Distress Syndrome

Risk factors for COVID-19 patients with cardiac injury: pulmonary ventilation dysfunction and oxygen inhalation insufficiency are not the direct causes

The association between cardiac injury and outcomes in hospitalized patients with COVID-19

Association between cardiac troponin I and mortality in patients with COVID-19

Redefining the Prognostic Value of High-Sensitivity Troponin in COVID-19 Patients: The Importance of Concomitant Coronary Artery Disease

Myocardial Injury on Admission as a Risk in Critically Ill COVID-19 Patients: A Retrospective in-ICU Study

Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19. Hypertension (0194911X)

Cardiac function in relation to myocardial injury in hospitalised patients with COVID-19

Cardiac Injury and Clinical Course of Patients With Coronavirus Disease

Acute myocardial injury is common in patients with COVID-19 and impairs their prognosis

Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019

Association of Cardiac Injury with Mortality in Hospitalized Patients with COVID-19 in Wuhan, China

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan

Cardiac injury is associated with inflammation in geriatric COVID-19 patients

Myocardial injury and risk factors for mortality in patients with COVID-19 pneumonia

Elevated cardiac biomarkers may be effective prognostic predictors for patients with COVID-19: A multicenter, observational study

Cardiac troponin I in SARS-CoV-2-patients: The additional prognostic value of serial monitoring

Analysis of influencing factors related to elevated serum troponin I level for COVID-19 patients in Yichang

Cardiac injury prediction and lymphocyte immunity and inflammation analysis in hospitalized patients with coronavirus disease 2019 (COVID-19)

Prognostic significance of cardiac injury in COVID-19 patients with and without coronary artery disease. Coron Artery Dis

Cardiac Troponin I association with critical illness and death risk in 726 seriously ill COVID-19 patients: A retrospective cohort study

Prevalence and prognostic value of cardiac troponin in elderly patients hospitalized for COVID-19

Impact and Determinants of High-Sensitivity Cardiac Troponin-T Concentration in Patients With COVID-19 Admitted to Critical Care

Characteristics and laboratory findings on admission to the emergency department among 2873 hospitalized patients with COVID-19: the impact of adjusted laboratory tests in multicenter studies. A multicenter study in Spain (BIOCOVID-Spain study)

The prognostic value of myocardial injury in COVID-19 patients and associated characteristics

Evaluation of myocardial injury patterns and ST changes among critical and non-critical patients with coronavirus-19 disease

Clinical characteristics and predictors of mortality in young adults with severe COVID-19: a retrospective observational study

Cardiac Injury and Outcomes of Patients With COVID-19 in

The relationship between cardiac injury, inflammation and coagulation in predicting COVID-19 outcome

Assessment of COVID-19 deaths from cardiological perspective

Prognostic significance of N-Terminal Pro-BNP in patients with COVID-19 pneumonia without previous history of heart failure

The peak levels of highly sensitive troponin I predicts inhospital mortality in COVID-19 patients with cardiac injury: a retrospective study

Myoglobin and troponin as prognostic factors in patients with COVID-19 pneumonia

We would like to acknowledge the information specialist, Stella Seal; Williams H. Welch Medical Library, Johns Hopkins Medicine, who curated the search strategy and performed the initial literature search. We would also like to acknowledge Dr. Chakra Budthrodaki, Johns Hopkins University, who reviewed the biostatistics and analytical methods used in this meta-analysis.

The authors report no relationships that could be construed as a conflict of interest.

There was no funding for the study. The authors have full access to the data and have final responsibility.

Guo II 2020 67 China 187 -91 ( 

Notes: Hazard ratios and odds ratios with 95% confidence intervals on a logarithmic scale for individual or pooled study data for pair-wise comparison of odds associated with elevated biomarker levels. Logarithmic OR and HR exponentiated for interpretation, for instance, pooled odds ratio for association between troponin elevation and death/severe disease