Archives of Academic Emergency Medicine. 2021; 9(1): e18 https://doi.org/10.22037/aaem.v9i1.1071 REV I EW ART I C L E Cardiac Complications and Pertaining Mortality Rate in COVID-19 Patients; a Systematic Review and Meta- Analysis Amirmohammad Toloui1, Donya Moshrefiaraghi1, Arian Madani Neishaboori1, Mahmoud Yousefifard1∗, Mohammad Haji Aghajani2 † 1. Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran. 2. Prevention of Cardiovascular Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Received: December 2020; Accepted: January 2021; Published online: 13 February 2021 Abstract: Introduction: Raising knowledge over cardiac complications and managing them can play a key role in their recovery. In this study, we aim to investigate the evidence regarding the prevalence of cardiac complications and the resulting mortality rate in COVID-19 patients. Methods: Search was conducted in electronic databases of Medline (using PubMed), Embase, Scopus, and Web of Science, in addition to the manual search in preprint databases, and Google and Google scholar search engines, for articles published from 2019 until April 30th, 2020. Inclusion criterion was reviewing and reporting cardiac complications in patients with confirmed COVID- 19. Results: The initial search resulted in 853 records, out of which 40 articles were included. Overall analysis showed that the prevalence of acute cardiac injury, heart failure and cardiac arrest were 19.46% (95% CI: 18.23- 20.72), 19.07% (95% CI: 15.38-23.04) and 3.44% (95% CI: 3.08-3.82), respectively. Moreover, abnormal serum troponin level was observed in 22.86% (95% CI: 21.19-24.56) of the COVID-19 patients. Further analysis revealed that the overall odds of mortality is 14.24 (95% CI: 8.67-23.38) times higher when patients develop acute car- diac injury. The pooled odds ratio of mortality when the analysis was limited to abnormal serum troponin level was 19.03 (95% CI: 11.85-30.56). Conclusion: Acute cardiac injury and abnormal serum troponin level were the most prevalent cardiac complications/abnormalities in COVID-19 patients. The importance of cardiac compli- cations is emphasized due to the higher mortality rate among patients with these complications. Thus, troponin screenings and cardiac evaluations are recommended to be performed in routine patient assessments. Keywords: COVID-19; Cardiovascular System; Heart Injuries; Hospital Mortality Cite this article as: Toloui A, Moshrefiaraghi D, Madani Neishaboori A, Yousefifard M, Haji Aghajani M. Cardiac Complications and Pertaining Mortality Rate in COVID-19 Patients; a Systematic Review and Meta-Analysis. Arch Acad Emerg Med. 2021; 9(1): e18. 1. Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) is a novel coronavirus, which emerged in Wuhan, China in December 2019 and has spread to over 200 countries in the world, ever since (1). Coronavirus disease 2019 (COVID- 19) mostly causes lower respiratory tract infection symptoms such as fever, which is its most prevalent symptom, cough, ∗Corresponding Author: Mahmoud Yousefifard; Physiology Research Center, Iran University of Medical Sciences, Hemmat Highway, P.O Box: 14665-354, Tehran, Iran; Phone/Fax: +982186704771; E-mail: yousefifard.m@iums.ac.ir † Corresponding Author: Mohammad Haji Aghajani; Imam Hossein Hospi- tal, Madani St., Tehran, Iran; Phone/Fax: +982173432383/77582733; E-mail: dr.aghajani@yahoo.com and dyspnea (2). Although people with severe type of the disease form the minority of the patients, it is illustrated that mortality rate is the highest among patients who have comor- bidities such as cardiovascular diseases (3). Angiotensin converting enzyme 2 (ACE2) has been shown to be the receptor of the virus in human cells. Since this en- zyme is expressed in many organs such as lungs, heart, kid- neys and brain, extrapulmonary manifestations and compli- cations are being studied rigorously, all around the world (4). Cardiac involvement is one of the most common causes of death in COVID-19 patients (5). Cardiovascular compli- cations, whether being chronic or acute, can lead to criti- cally imbalanced homeostasis and could be a serious strike to patient’s recovery from the disease (6). Therefore, raising awareness over cardiac complications caused by the disease This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem A. Toloui et al. 2 and managing them as early as possible can play a key role in recovery of the patients. However, there is no comprehen- sive evaluation of this issue. Therefore, in this study, we aim to investigate the evidence regarding the prevalence of car- diac complications in COVID-19 patients. Moreover, the risk of mortality after COVID-19 related cardiac involvement has also been assessed. 2. Methods 2.1. Study design The present systematic review and meta-analysis aims to in- vestigate the evidence regarding cardiac complications in pa- tients, confirmed with COVID-19, and to see whether there is any potential association between the prevalence of car- diac complications and their mortality rate. As a result, PECO in the current study is defined as: P (patients): Patients with confirmed COVID-19 disease, E (exposure): SARS-CoV-2 in- fection, O (outcome): prevalence of cardiac complications and mortality after COVID-19 related cardiac involvement. As for comparison (C in PECO), mortality rate was compared between COVID-19 patients with cardiac complications and patients without any cardiac involvements. 2.2. Search strategy The searching process was initiated by selecting keywords with the help of experts in the field and screening titles of similar articles. Then, using MeSH and Emtree, equivalent and related synonyms were identified. As a result, a search strategy was constructed based on the instructions of elec- tronic databases of Medline, Embase, Scopus, and Web of Science, and an extensive search was performed in each of the mentioned databases for articles published from the February 1st of 2019 until April 30th, 2020. The search strat- egy in Medline database through PubMed search engine is presented in Appendix 1. In addition, a search was per- formed in preprint databases, Google, and Google scholar to obtain preprinted and possibly missed manuscripts (gray lit- terateur search). Moreover, references of the obtained review articles were screened to find additional articles. 2.3. Selection criteria The inclusion criteria in the present meta-analysis was re- porting cardiac complications and cardiac related mortality rate in patients with confirmed COVID-19. Original observa- tional studies were included. Since most COVID-19 studies had a retrospective nature, both retrospective and prospec- tive studies were included. Prevalence of cardiac complica- tions following COVID-19 and its pertaining mortality rate were extracted from cohort and cross-sectional studies. In addition, we added an extra aim to provide evidence on the relationship between cardiac complication occurrence in COVID-19 patients and their mortality. In this section, in addition to cohort and cross-sectional studies, case-control studies were also included. Furthermore, the exclusion cri- teria were case report studies, review articles, studies that did not report cardiac involvement and studies whose entire target population was patients with cardiac comorbidities as underlying disease. 2.4. Data collection Two independent reviewers screened titles and abstracts of the gathered articles. Then, full texts of the related articles were obtained and included articles were selected and en- tered the present systematic review and meta-analysis. Fi- nally, a summary of the included studies was recorded us- ing a checklist, consisting of following variables: first au- thor’s name, publication year, country in which the study was conducted in, number of patients, study design, number of patients in which the cardiac complication was assessed in, mean/median age of the patients, number of males among the patients, type of cardiac complication along with its di- agnostic method, number of the deceased in patients pre- senting with cardiac complication (if reported), and number of the deceased among patients without the cardiac com- plication of the included articles. If several types of cardiac complications were reported in the studies, the number of each cardiac involvement was recorded separately. Any dis- agreements within the process were resolved using a third re- viewer’s opinion. 2.5. Outcome The primary outcome of the present meta-analysis was the prevalence of cardiac complications in COVID-19 pa- tients. Secondary outcome was the risk of mortality af- ter COVID-19 related cardiac involvement. Our screening showed that most studies reported abnormal serum troponin level and acute cardiac injury, separately, as cardiac assess- ments/complications. Other reported cardiac complications were heart failure, cardiomyopathy, cardiac arrest, myocardi- tis, pericardial effusion, cardiac insufficiency, and myocar- dial infarction. 2.6. Quality assessment Two independent reviewers scored the quality of the stud- ies according to National Heart, Lung, and Blood Institute (NHLBI) quality assessment tool (7). This tool contains 14 items on study design, patient selection, sample size justifi- cation, analysis, timeframe between exposure and outcome, assessment of different level of exposure, validity and relia- bility of exposure and outcome assessment, blinding status, missing data management, and considering potential con- founders in the analysis. Each reviewer independently as- sessed the articles and categorized each item as low risk, high This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2021; 9(1): e18 risk, unclear risk of bias, cannot determine, or not applicable. Any disagreement was resolved by discussion with a third re- viewer. 2.7. Statistical analysis All analyses were performed using STATA 14.0 statistical pro- gram. Analyses were performed in two parts. Initially, the cardiac complications reported in the articles were cate- gorized into 9 subgroups: acute cardiac injury, abnormal serum troponin level, heart failure, cardiac arrest, myocardi- tis, cardiac insufficiency, pericardial effusion, myocardial in- farction, and cardiomyopathy. The prevalence of each car- diac complication among the COVID-19 patients was cal- culated with a 95% confidence interval (95% CI) using the “metaprop_one” command performed on the total sample size and the number of patients presenting each complica- tion in the included articles. In the second part of the analysis, the association between the manifestation of cardiac complications/abnormalities and mortality rate was calculated and presented as an overall odds ratio (OR) with a 95% CI using the “metan” command performed on four groups of data: number of the deceased in patients with a cardiac complication, number of the alive in patients with the cardiac complication, number of the de- ceased in patients without the cardiac complication, number of the alive in patients without the cardiac complication. I2 test was performed to assess heterogeneity, and if the hetero- geneity among data was considerable, random effect model was used to calculate 95% CI. Egger’s test was used to eval- uate publication bias. Finally, a sensitivity analysis was per- formed to determine whether the results can be considered robust or not. Therefore, in the sensitivity analyses we ex- cluded possible outlier studies. 3. Results 3.1. Study characteristics The systematic search resulted in 853 records, and after elim- inating duplicates, 557 articles remained. Then, after screen- ing titles and abstracts of the remaining articles, 181 studies were deemed potentially eligible. Afterwards, based on the mentioned exclusion and inclusion criteria, 40 articles were included in the present systematic review and meta-analysis (Figure 1) (5, 8-46). These 40 articles were treated as 60 dif- ferent experiments, as some studies reported more than one cardiac complication/abnormality. Two studies had taken place in the United States (41, 45), one study was conducted in Spain (9), one study was carried out in Italy (42) and the rest of the included studies were conducted in China. Re- garding the study design of the included articles, one study was ambispective (22), four studies were conducted prospec- tively (9, 14, 19, 39) and the other 35 studies were retrospec- tive. Overall, 15616 patients with confirmed COVID-19 were enrolled in the included studies, with 2985 males among them [patients’ gender was not reported in two of the stud- ies (42, 46)]; however, not all of the patients were assessed for each cardiac complication, so the total number of patients tested for each manifestation is presented for each compli- cation in Table 1. In general, 9 different cardiac complica- tions/abnormalities were reported in the studies including acute cardiac injury, which was reported in 26 studies (5, 8, 11, 13, 16, 18-20, 22-24, 26-30, 32, 33, 35, 37-41, 43, 46), ab- normal serum troponin level, reported in 19 studies (8, 10-12, 14, 15, 17, 19, 25, 30, 32, 36-38, 40, 41, 43-45), heart failure, re- ported in four studies (8, 11, 32, 41), cardiac arrest, reported in three studies (5, 34, 42), myocarditis, reported in two stud- ies (9, 44), cardiac insufficiency, reported in two studies (29, 30), pericardial effusion, reported in two studies (21, 31) and cardiomyopathy (45) and myocardial infarction (32), each re- ported in one study. Mortality rate was reported in 18 stud- ies (8, 11, 13, 14, 16-18, 20, 26, 29, 30, 33, 34, 37, 39, 40, 44, 46). These numbers were further used to evaluate the odds ratio (OR) between the manifestation of each cardiac com- plication and the mortality rate in COVID-19 patients. Table 1 demonstrates a summary of the characteristics of the in- cluded studies. 3.2. Risk of bias assessment No study had provided a sample size justification, power de- scription, or variance and effect estimates. In addition, 39 studies were not measured to have key potential confounders in their assessment of outcomes. 10 studies did not report the details of their inclusion and exclusion criteria. Moreover, the participation rate of eligible persons was not reported in 6 studies (Table 2). 3.3. Publication bias There were evidences of publication bias in the assessment of the prevalence of acute cardiac injury (Coefficient= -3.97; p=0.004) and abnormal serum troponin level (Coefficient = -8.65; p < 0.001) among the included studies. However, no evidence of publication bias was observed in the assessment of cardiac related mortality and the prevalence of other car- diac complications (Figure 2). 3.4. Meta-analysis In the beginning, the prevalence of cardiac complications fol- lowing SARS-CoV-2 infection was evaluated, and the results are depicted in figures 3, 4, 5 and 6, and table 3. Abnor- mal serum level of troponin was observed in 22.86% (95% CI: 21.19 to 24.56) of the patients (Figure 4). Moreover, the preva- lence of acute cardiac injury, heart failure and cardiac arrest was 19.46% (95% CI: 18.23 to 20.72), 19.07% (95% CI: 15.38 to 23.04) and 3.44% (95% CI: 3.08 to 3.82), respectively (Figure This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem A. Toloui et al. 4 3 and Table 3). Furthermore, the I2 test revealed no hetero- geneity regarding the prevalence of abnormal troponin lev- els and acute cardiac injury. The prevalence of other cardiac complications including myocarditis, cardiac insufficiency, pericardial effusion, myocardial infarction, and cardiomy- opathy are depicted in Table 3. Sensitivity analysis showed that after excluding the studies with a high prevalence rate, the prevalence of abnormal serum level of troponin (20.16%; 95% CI: 18.54 to 21.82; cut off for high prevalence rate=50%) and acute cardiac injury (17.17%; 95% CI: 15.94 to 18.43; cut off for high prevalence rate=30) decreased slightly. Further analysis revealed that the odds of mortality in COVID-19 patients with acute cardiac injury is 14.24 (OR = 14.24, 95% CI: 8.67 to 23.38) times higher than the COVID- 19 patients without acute cardiac injury. However, I2 test showed some degrees of heterogeneity regarding the rela- tionship of cardiac complication and mortality of COVID- 19 patients (Figure 5). There is a possible outlier study in acute cardiac injury section. After excluding this study, the odds of mortality in COVID-19 patients with acute cardiac in- jury is increased slightly (OR=15.77; 95% CI: 10.49 to 23.69). In the sensitivity analysis the heterogeneity was decreased (I2=45.5%). Moreover, the odds of mortality in a COVID-19 patient pre- senting with abnormal serum troponin level in his/her blood sample was 19.03 (OR=19.03; 95% CI: 11.85 to 30.56) times higher than the patients not having this manifestation. In- terestingly, no heterogeneity was observed when calculating the OR for the mortality in COVID-19 patients with abnormal serum troponin level (Figure 6). There are two possible out- lier studies in abnormal troponin level section. After exclud- ing these studies, the odds of mortality in COVID-19 patients with acute cardiac injury is increased slightly (OR=17.07; 95% CI: 10.41 to 27.99). The odds of mortality of patients having other cardiac complications are presented in Table 3. 4. Discussion In this systematic review and meta-analysis, we investigated the prevalence of 9 cardiac complications in COVID-19 pa- tients and their subsequent mortality rates. Abnormal serum level of troponin with 22.86% prevalence, detected by lab- oratory tests, and acute cardiac injury with 19.46% preva- lence, diagnosed with laboratory test results and other di- agnostic techniques, were among the most prevalent com- plications/abnormalities observed in COVID-19 patients. Al- though a large number of studies reported the prevalence of the two mentioned cardiac complications, no heterogeneity was observed in this section. To contemplate even more on the matter, the prevalence of abnormal troponin level and acute cardiac injury are rather close numbers, which might mean that by close observation of troponin changes in a COVID-19 patient, we could possibly anticipate acute cardiac injuries in them and take appropriate measures. However, serum troponin levels also increase due to damage to other tissues, such as the kidneys, which may make it impossible to use troponin level alone to detect cardiac damage. Other car- diac complications such as heart failure and cardiomyopa- thy were also prevalent among the patients. However, with the small number of the studies observing them, more data is needed on the matter. Regarding the limitations, each individual article used a dif- ferent reference range for troponin or other injury indicators to be classified as abnormal, and each one used different di- agnostic and laboratory test results to define acute cardiac injury, which could cause slight differences in the reported prevalence of acute cardiac injury and abnormal serum level of troponin. For example, Huang et al. defined acute car- diac injury as cardiac troponin rising to 3 or more times than normal or appearance of new abnormalities in echocardio- graphy or ECG (19); While many others defined it only with the appearance of abnormal troponin levels in blood sam- ples. Moreover, some articles’ study population only con- sisted of critically ill patients or deceased ones, which could shift prevalence statistics, causing inevitable heterogeneity in reported numbers (5, 15, 32). Additionally, it is worth men- tioning that the mechanism of myocardial injury, whether being done by direct viral invasion to the host tissue or due to imbalanced homeostasis, was of no concern for the writ- ers at the time. Although more research should be conducted to identify the exact causes of this damage, the effects it car- ries are the most important subject that should be studied at these critical times. Even though limitations were present in data reporting the prevalence of cardiac outcomes, it is important to pay enough attention to these complications, since many of them are directly related to patients’ general situation and illness severity. On the other hand, our study shows intriguing data regard- ing mortality rate in patients presenting with cardiac compli- cations, especially acute cardiac injury and abnormal serum level of troponin. Abnormal troponin levels are associated with about 19 times higher mortality risk in COVID-19 pa- tients, which is of great importance in disease management for health care providers around the world. Considering the fact that no heterogeneity was observed regarding the risk of mortality in patients with abnormal troponin level, labo- ratory screening during routine patient assessments can be critical in early detection of cardiac injury and intervening accordingly. In addition, we suggest that blood levels of tro- ponin should be evaluated as a prognostic factor in patients with cardiac involvement. Furthermore, our data indicated that acute cardiac injury could raise the mortality to about 14 times more in COVID- 19 patients. However, this number was associated with an This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2021; 9(1): e18 overall heterogeneity, which could be attributed to differ- ent definitions of cardiac injury in studies, discussed above. Nonetheless, although one can conclude that there is a re- lationship between acute cardiac injury following COVID- 19 and increased risk of mortality, the threat that acute car- diac injury poses to patients’ health status in the future is undeniable and demands careful monitoring and manage- ments when confronting this situation. Moreover, it is note- worthy that articles reporting mortality rates of cardiac com- plications were mostly focused on abnormal troponin level and myocardial injury and the number of the articles report- ing correlations between other cardiac complications such as heart failure, and mortality rate was very few; so, we cannot present an exact estimation of the contribution of other car- diac outcomes such as heart failure and myocarditis to pa- tients’ fatality. In addition, inability to blind the outcome as- sessors in the studies and some articles not explicitly present- ing inclusion and exclusion criteria were further limitations detected in the studies. Finally, we performed a sensitivity analysis and excluded possible outlier studies. The overall effect size slightly changed and therefore, the results seem to be robust. To conclude, our findings thoroughly approve of other pub- lished articles investigating associations between COVID-19 cardiac outcomes and related mortalities (47, 48), confirm- ing that cardiac injury, regardless of the mechanism of estab- lishment, is a factor determining disease severity and patient prognosis reliably in large scale and should be considered and monitored from early stages of disease. 5. Conclusion Cardiac complications/abnormalities can be prevalent in COVID-19 patients in the forms of acute cardiac injury, serum troponin levels abnormalities, heart failure, cardiac arrest, and other types. The importance of cardiac involve- ments is further highlighted when observing the higher mor- tality rate among COVID-19 patients presenting with cardiac involvements. Thus, careful monitoring of heart involve- ments should be performed in COVID-19 patients. 6. Abbreviations SARS-CoV-2: Severe Acute Respiratory Syndrome Coron- avirus 2 COVID-19: Coronavirus disease 2019 ACE2: Angiotensin Converting Enzyme 2 PECO: Problem, Exposure, Comparison, Outcome NHLBI: National Heart, Lung, and Blood Institute CI: Confidence Interval OR: Odds Ratio ECG: Electrocardiography 7. Declarations 7.1. Ethics approval and consent to participate This study received ethics approval from Ethics committee of Iran University of medical Sciences. 7.2. Consent for publication Not applicable. 7.3. Availability of data and materials All data generated or analyzed during this study are included in this published article [and its supplementary information files]. 7.4. Conflict of Interest There is no conflict of interest. 7.5. Funding This study was supported by Prevention of Cardiovascular Disease Research Center, Shahid Beheshti University of Med- ical Sciences, Tehran, Iran. 7.6. Authors’ contribution Study design: MY, MHA; Data gathering: AT, DM, AMN, MY; Analysis: MY; Interpreting the results: MY, MHA; Drafting: AT, DM, AMN; Critically revised the paper: All authors. 7.7. Acknowledgments None. References 1. Organization WH. Coronavirus disease 2019 ( COVID- 19): situation report, 121. 2020. 2. Guan W-j, Ni Z-y, Hu Y, Liang W-h, Ou C-q, He J- x, et al. Clinical characteristics of coronavirus dis- ease 2019 in China. New England journal of medicine. 2020;382(18):1708-20. 3. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hos- pitalized with COVID-19 in the New York City area. Jama. 2020. 4. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. 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Critical Care. 2020;24:1-9. 41. Aggarwal S, Garcia-Telles N, Aggarwal G, Lavie C, Lippi G, Henry BM. Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): Early report from the United States. Diagnosis. 2020;7(2):91-6. 42. Baldi E, Sechi GM, Mare C, Canevari F, Brancaglione A, Primi R, et al. Out-of-hospital cardiac arrest during the Covid-19 outbreak in Italy. New England Journal of Medicine. 2020. 43. Zhao X-Y, Xu X-X, Yin H-S, Hu Q-M, Xiong T, Tang Y-Y, et al. Clinical characteristics of patients with 2019 coron- avirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study. BMC Infectious Diseases. 2020;20:1-8. 44. Ma K-L, Liu Z-H, Cao C-f, Liu M-K, Liao J, Zou J-B, et al. COVID-19 myocarditis and severity factors: an adult co- hort study. medRxiv. 2020. 45. Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX, Chong M, et al. Characteristics and outcomes of 21 crit- ically ill patients with COVID-19 in Washington State. Jama. 2020;323(16):1612-4. 46. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predic- tors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive care medicine. 2020;46(5):846-8. 47. Zhu H, Rhee J-W, Cheng P, Waliany S, Chang A, Witteles RM, et al. Cardiovascular complications in patients with COVID-19: consequences of viral toxicities and host im- mune response. Current cardiology reports. 2020;22:1-9. 48. Santoso A, Pranata R, Wibowo A, Al-Farabi MJ, Huang I, Antariksa B. Cardiac injury is associated with mortal- ity and critically ill pneumonia in COVID-19: a meta- analysis. The American Journal of Emergency Medicine. 2020. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem A. Toloui et al. 8 Appendix 1: Medline search query Search terms 1.“COVID-19 “[Supplementary Concept] OR ”severe acute respiratory syndrome coronavirus 2”[Supplementary Concept] OR ”COVID-19 vaccine”[Supplementary Concept] OR ”COVID-19 diagnostic testing”[Supplementary Concept] OR ”COVID-19 drug treat- ment”[Supplementary Concept] OR “Betacoronavirus”[mh] OR “Coronavirus Infections”[mh] OR COVID-19[tiab] OR 2019 novel coro- navirus disease[tiab] OR COVID19[tiab] OR COVID-19 pandemic[tiab] OR SARS-CoV-2 infection[tiab] OR COVID-19 virus disease[tiab] OR 2019 novel coronavirus infection[tiab] OR 2019-nCoV infection[tiab] OR coronavirus disease 2019[tiab] OR coronavirus disease- 19[tiab] OR 2019-nCoV disease[tiab] OR COVID-19 virus infection[tiab] OR Severe Acute Respiratory Syndrom Coronavirus 2[tiab] OR Coronavirus[tiab] OR Coronaviruses[tiab] OR severe acute respiratory syndrome coronavirus 2[tiab] OR 2019-nCoV[tiab] OR Wuhan coronavirus[tiab] OR SARS-CoV-2[tiab] OR 2019 novel coronavirus[tiab] OR COVID-19 virus[tiab] OR coronavirus disease 2019 virus[tiab] OR COVID19 virus[tiab] OR Wuhan seafood market pneumonia virus[tiab] OR Betacoronavirus[tiab] OR Betacoro- naviruses[tiab] OR Coronavirus Infections[tiab] OR Coronavirus Infection[tiab] OR Infection, Coronavirus[tiab] OR Infections, Coro- navirus[tiab] OR COVID-19 vaccine[tiab] OR COVID-19 diagnostic testing[tiab] OR COVID-19 drug treatment[tiab] OR coronavirus disease 2019 drug treatment[tiab] OR Covid-19 treatment[tiab] OR treatment of Covid-19 virus infection[tiab] OR coronavirus disease- 19 drug treatment[tiab] 2.“Troponin”[mh] OR “Heart Injuries”[mh] OR “Myocarditis”[mh] OR “Cardiomyopathies”[mh] OR “Heart Diseases”[mh] OR “Peri- carditis”[mh] OR “Cardiovascular Abnormalities”[mh] OR “Cardiovascular Infections”[mh] OR “Cardiovascular Diseases”[mh] OR “Heart Arrest”[mh] OR “Ventricular Dysfunction”[mh] OR “Heart Failure”[mh] OR “Heart Failure, Diastolic”[mh] OR “Heart Failure, Systolic”[mh] OR Heart Injuries[tiab] OR [tiab] OR Injuries, Heart[tiab] OR Heart Injury[tiab] OR Injury, Heart[tiab] OR Myocardi- tis[tiab] OR Myocarditides[tiab] OR Carditis[tiab] OR Cardiomyopathies[tiab] OR Cardiomyopathy[tiab] OR Myocardial Diseases[tiab] OR Disease, Myocardial[tiab] OR Diseases, Myocardial[tiab] OR Myocardial Disease[tiab] OR Myocardiopathies[tiab] OR Myocardiopa- thy[tiab] OR Cardiomyopathies, Secondary[tiab] OR Cardiomyopathy, Secondary[tiab] OR Secondary Cardiomyopathies[tiab] OR Sec- ondary Cardiomyopathy[tiab] OR Secondary Myocardial Diseases[tiab] OR Disease, Secondary Myocardial[tiab] OR Diseases, Sec- ondary Myocardial[tiab] OR Myocardial Disease, Secondary[tiab] OR Secondary Myocardial Disease[tiab] OR Myocardial Diseases, Secondary[tiab] OR Heart Diseases[tiab] OR Heart Disease[tiab] OR Cardiac Diseases[tiab] OR Cardiac Disease[tiab] OR Cardiac Dis- orders[tiab] OR Cardiac Disorder[tiab] OR Heart Disorders[tiab] OR Heart Disorder[tiab] OR Pericarditis[tiab] OR Pleuropericardi- tis[tiab] OR Endocarditis[tiab] OR Endocarditides[tiab] OR Infective Endocarditis[tiab] OR Endocarditides, Infective[tiab] OR Endo- carditis, Infective[tiab] OR Infective Endocarditides[tiab] OR Heart damage[tiab] OR Cardiac injury[tiab] OR Acute cardiac injury[tiab] OR Cardiovascular Abnormalities[tiab] OR Abnormalities, Cardiovascular[tiab] OR Abnormality, Cardiovascular[tiab] OR Cardiovascu- lar Abnormality[tiab] OR Cardiovascular Infections[tiab] OR Cardiovascular Infection[tiab] OR Infection, Cardiovascular[tiab] OR In- fections, Cardiovascular[tiab] OR Cardiovascular Diseases[tiab] OR Cardiovascular Disease[tiab] OR Disease, Cardiovascular[tiab] OR Diseases, Cardiovascular[tiab] OR Heart Arrest[tiab] OR Arrest, Heart[tiab] OR Cardiac Arrest[tiab] OR Arrest, Cardiac[tiab] OR Asys- tole[tiab] OR Asystoles[tiab] OR Cardiopulmonary Arrest[tiab] OR Arrest, Cardiopulmonary[tiab] OR Ventricular Dysfunction[tiab] OR Dysfunction, Ventricular[tiab] OR Dysfunctions, Ventricular[tiab] OR Ventricular Dysfunctions[tiab] OR Heart Failure[tiab] OR Dias- tolic Heart Failures[tiab] OR Heart Failures, Diastolic[tiab] OR Diastolic Heart Failure[tiab] OR Heart Failure, Diastolic[tiab] OR Cardiac Failure[tiab] OR Heart Decompensation[tiab] OR Decompensation, Heart[tiab] OR Heart Failure, Right-Sided[tiab] OR Heart Failure, Right Sided[tiab] OR Right-Sided Heart Failure[tiab] OR Right Sided Heart Failure[tiab] OR Myocardial Failure[tiab] OR Congestive Heart Failure[tiab] OR Heart Failure, Congestive[tiab] OR Heart Failure, Left-Sided[tiab] OR Heart Failure, Left Sided[tiab] OR Left- Sided Heart Failure[tiab] OR Left Sided Heart Failure[tiab] OR Heart Failure, Systolic[tiab] OR Heart Failures, Systolic[tiab] OR Systolic Heart Failures[tiab] OR Systolic Heart Failure[tiab] OR Troponin[tiab] OR Troponins[tiab] OR Troponin Complex[tiab] 3. #1 AND #2 This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 9 Archives of Academic Emergency Medicine. 2021; 9(1): e18 Table 1: Summary of the included studies Author; Year; Country Study design Total study popula- tion Mean age Number of males Diagnostic methods Type of cardiac complication No. of patients tested for the compli- cation No. of patients with the compli- cation No. of deceased in patients with the complica- tion No. of deceased in patients without the complica- tion Aggarwal S; 2020; USA Retrospective 16 67 12 Blood Sample, Echo Acute cardiac injury 16 3 NR NR NR Heart failure 16 2 NR NR Blood Sample Abnormal Troponin 16 10 NR NR Arentz M; 2020; USA Retrospective 21 70 11 Blood Sample, Echo, Clinical Cardiomyopathy 21 7 NR NR Blood Sample Abnormal Troponin 21 3 NR NR Baldi E; 2020; Italy Retrospective 9806 NR NR Hospital report Cardiac arrest 9806 362 NR NR Barrasa H; 2020; Spain Prospective 48 63.2 27 NR Myocarditis 48 1 NR NR Chen C; 2020; China Retrospective 150 59 84 Blood Sample Abnormal Troponin 150 22 NR NR Chen T; 2020; China Retrospective 274 62 171 NR Acute cardiac injury 203 89 72 22 NR Heart failure 176 43 41 42 Blood Sample Abnormal Troponin 203 83 68 26 Deng Q; 2020; China Retrospective 112 65 57 Blood Sample Abnormal Troponin 112 42 NR NR Deng Y; 2020; China Retrospective 225 54 124 Blood Sample Acute cardiac injury 225 66 65 44 Du Ra; 2020; China Prospective 179 57.6 97 Blood Sample Abnormal Troponin 179 31 13 8 Du Rb; 2020; China Retrospective 109 70.7 75 Blood Sample Abnormal Troponin 109 52 NR NR Du Y; 2020; China Retrospective 85 65.8 62 Blood Sample Acute cardiac injury 85 38 NR NR Clinical Cardiac arrest 85 7 NR NR Guo T; 2020; China Retrospective 187 58.5 91 Blood Sample Acute cardiac injury 187 52 31 12 Han H; 2020; China Retrospective 273 NR 97 Blood Sample Abnormal Troponin 273 27 13 8 He X; 2020; China Retrospective 54 68 34 Blood Sample Acute cardiac injury 54 24 18 8 Hu L; 2020; China Retrospective 323 61 166 Blood Sample Acute cardiac injury 323 24 NR NR Blood Sample Abnormal Troponin 323 68 NR NR Huang C; 2020; China Prospective 41 49 30 Blood Sample Abnormal Troponin 41 5 NR NR Acute cardiac injury 41 5 NR NR Lei S; 2020; China Retrospective 34 55 14 Blood Sample Acute cardiac injury 34 5 4 3 Li K; 2020; China Retrospective 83 45.5 44 CT Pericardial effusion 83 4 NR NR Li X; 2020; China Ambispective 548 60 279 Blood Sample Acute cardiac injury 548 119 NR NR Li Y; 2020; China Retrospective 54 61.8 34 Blood Sample Acute cardiac injury 41 23 NR NR Liu M; 2020; China Retrospective 30 35 10 Blood Sample Acute cardiac injury 30 5 NR NR CT: Computed tomography scan; Echo: Echocardiography; ECG: Electrocardiography; NR: Not reported. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem A. Toloui et al. 10 Table 1: Summary of the included studies Author; Year; Country Study design Total study popula- tion Mean age Number of males Diagnostic methods Type of cardiac complication No. of patients tested for the compli- cation No. of patients with the compli- cation No. of deceased in patients with the complica- tion No. of deceased in patients without the complica- tion Liu Y; 2020; China Retrospective 76 45 49 Blood Sample Abnormal Troponin 76 14 NR NR Ma K; 2020; China Retrospective 84 48 48 Blood Sample Abnormal Troponin 84 36 0 0 Blood Sample, Clinical Symptom Myocarditis 84 4 0 0 Ruan Q; 2020; China Retrospective 150 NR NR NR Acute cardiac injury 68 5 5 63 Shi S; 2020; China Retrospective 416 64 205 Blood Sample Acute cardiac injury 416 82 42 15 Wan S; 2020; China Retrospective 135 47 72 Blood Sample Acute cardiac injury 135 10 NR NR Wang Da; 2020; China Retrospective 138 56 75 Blood Sample, ECG, Echo Acute cardiac injury 138 10 NR NR Wang Db; 2020; China Retrospective 107 51 57 Blood Sample Abnormal Troponin 107 6 5 14 Blood Sample, ECG, Echo Acute cardiac injury 12 8 19 Wang La; 2020; China Retrospective 339 69 166 Blood Sample Acute cardiac injury 339 70 39 26 Blood Sample, Clinical Symptom Cardiac insufficiency 339 58 25 52 Wang Lb; 2020; China Retrospective 202 63 88 Blood Sample Acute cardiac injury 202 27 17 14 Blood Sample, ECG, Echo Cardiac insufficiency 202 24 14 19 Blood Sample Abnormal Troponin 202 27 NR NR Wei J; 2020; China Prospective 101 49 54 Blood Sample Acute cardiac injury 101 16 3 0 Xu X; 2020; China Retrospective 90 50 39 CT Pericardial effusion 90 1 NR NR Yang F; 2020; China Retrospective 92 69.8 49 Blood Sample Acute cardiac injury 92 31 NR NR NR Myocardial infarction 92 6 NR NR NR Heart failure 92 2 NR NR Blood Sample Abnormal Troponin 92 31 NR NR Yang X; 2020; China Retrospective 52 59.7 35 Blood Sample Acute cardiac injury 52 12 9 23 Yao W; 2020; China Retrospective 202 63.4 136 Clinical Cardiac arrest 202 4 0 21 Zhang G; 2020; China Retrospective 221 55 108 NR Acute cardiac injury 221 17 NR NR Zhao X; 2020; China Retrospective 91 46 49 Blood Sample Acute cardiac injury 91 14 NR NR Blood Sample Abnormal Troponin 88 3 NR NR Zheng Y; 2020; China Retrospective 99 49.4 51 Blood Sample Abnormal Troponin 99 88 NR NR CT: Computed tomography scan; Echo: Echocardiography; ECG: Electrocardiography; NR: Not reported. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 11 Archives of Academic Emergency Medicine. 2021; 9(1): e18 Table 1: Summary of the included studies Author; Year; Country Study design Total study popula- tion Mean age Number of males Diagnostic methods Type of cardiac complication No. of patients tested for the compli- cation No. of patients with the compli- cation No. of deceased in patients with the complica- tion No. of deceased in patients without the complica- tion Zhou F; 2020; China Retrospective 191 56 119 Blood Sample Abnormal Troponin 145 24 23 31 Heart failure 145 44 28 26 Acute cardiac injury 145 33 32 22 Zou X; 2020; China Retrospective 178 60.68 67 Blood Sample, ECG, Echo Acute cardiac injury 154 45 34 18 Blood Sample Abnormal Troponin 154 33 28 24 CT: Computed tomography scan; Echo: Echocardiography; ECG: Electrocardiography; NR: Not reported. Figure 1: Flow diagram of the present meta-analysis; CVD: Cardiovascular disease. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem A. Toloui et al. 12 Table 2: Risk of bias assessment of included studies Author; Year Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7 Item 8 Item 9 Item 10 Item 11 Item 12 Item 13 Item 14 Aggarwal S; 2020 Yes Yes No Yes No Yes Yes NA Yes NA Yes NA Yes No Arentz M; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Baldi E; 2020 Yes Yes Yes No No Yes Yes NA Yes NA Yes NA Yes No Barrasa H; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Chen C; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Chen T; 2020 Yes Yes No Yes No Yes Yes NA Yes NA Yes NA Yes No Deng Q; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Deng Y; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Du Ra; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Du Rb; 2020 Yes Yes No Yes No Yes Yes NA Yes NA Yes NA Yes No Du Y; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Guo T; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Han H; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No He X; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Huang C; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Hu L; 2020 Yes Yes Yes Yes No Yes Yes NA No NA Yes NA Yes No Lei S; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Li K; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Liu M; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Liu Y; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Li X; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Li Y; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Ma K; 2020 Yes Yes Yes No No Yes Yes NA Yes NA Yes NA Yes No Ruan Q; 2020 Yes Yes Yes No No Yes Yes NA Yes NA Yes NA Yes No Shi S; 2020 Yes Yes No Yes No Yes Yes NA Yes NA Yes NA Yes No Wang Da; 2020 Yes Yes Yes No No Yes Yes NA Yes NA Yes NA Yes No Wang Db; 2020 Yes Yes No No No Yes Yes NA Yes NA Yes NA Yes No Wang La; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Wang Lb; 2020 Yes Yes Yes Yes No Yes No NA Yes NA Yes NA Yes No Wan S; 2020 Yes Yes Yes Yes No Yes No NA Yes NA Yes NA Yes No Wei J; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Xu X; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Yang F; 2020 Yes Yes Yes No No Yes Yes NA Yes NA Yes NA Yes Yes Yang X; 2020 Yes Yes No Yes No Yes Yes NA Yes NA Yes NA Yes No Yao W; 2020 Yes Yes Yes No No Yes Yes NA Yes NA Yes NA Yes No Zhang G; 2020 Yes Yes Yes No No Yes Yes NA Yes NA Yes NA Yes No Zhao X; 2020 Yes Yes Yes No No Yes Yes NA Yes NA Yes NA Yes No Zheng Y; 2020 Yes Yes Yes No No Yes Yes NA Yes NA Yes NA Yes No Zhou F; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No Zou X; 2020 Yes Yes Yes Yes No Yes Yes NA Yes NA Yes NA Yes No NA: Not applicable. Items: 1. Was the research question or objective in this paper clearly stated? 2. Was the study population clearly specified and defined? 3. Was the participation rate of eligible persons at least 50%? 4. Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? 5. Was a sample size justification, power description, or variance and effect estimates provided? 6. For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured? 7. Was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed? 8. For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., categories of exposure, or exposure measured as continuous variable)? 9. Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? 10. Was the exposure(s) assessed more than once over time? 11. Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? 12. Were the outcome assessors blinded to the exposure status of participants? 13. Was loss to follow-up after baseline 20% or less? 14. Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)? This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 13 Archives of Academic Emergency Medicine. 2021; 9(1): e18 Table 3: Summary of findings regarding cardiac complications in COVID-19 Complication Number of studies Prevalence 95% CI Number of studies Odds ratio 95% CI P Acute cardiac injury 26 19.46 18.23, 20.72 14 14.24 8.67, 23.38 <0.001 Abnormal troponin 19 22.86 21.19, 24.56 6 19.03 11.85, 30.56 <0.001 Heart failure 4 19.07 15.38, 23.04 2 10.66 5.69, 19.97 <0.001 Cardiac arrest 3 3.44 3.08, 3.82 1 0.04 0.00, >999.0 0.651 Myocarditis 2 3.66 0.88, 7.82 1 1.00 0.00, >999.0 >0.99 Pericardial effusion 2 2.62 0.58, 5.73 — — — — Cardiac insufficiency 2 15.06 12.15, 18.22 2 4.65 2.82, 7.66 <0.001 Cardiomyopathy 1 33.33 17.19, 54.63 — — — — Myocardial infarction 1 6.52 3.02, 13.51 — — — — —: No data; CI: Confidence interval This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem A. Toloui et al. 14 Figure 2: Funnel plot for publication bias in prevalence of cardiac complications in COVID-19 patients and mortality rate after incidence of cardiac manifestation. There are evidences of publication bias among the studies, which reported prevalence of cardiac complications. While, no publication bias was observed regarding the relationship of cardiac complication and mortality in COVID-19 patients. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 15 Archives of Academic Emergency Medicine. 2021; 9(1): e18 Figure 3: Forest plot for the assessment of the prevalence of acute cardiac injury in COVID-19 patients; CI: confidence interval. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem A. Toloui et al. 16 Figure 4: Forest plot for the assessment of the prevalence of abnormal troponin levels in COVID-19 patients; CI: confidence interval. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 17 Archives of Academic Emergency Medicine. 2021; 9(1): e18 Figure 5: Forrest plot for the assessment of risk of mortality in COVID-19 patients with acute cardiac injury; OR: odds ratio; CI: confidence interval. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem A. Toloui et al. 18 Figure 6: Forrest plot for the assessment of risk of mortality in COVID-19 patients with abnormal troponin level; OR: odds ratio; CI: confidence interval. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Conclusion Abbreviations Declarations References