key: cord-0775751-o74l0tyg
authors: Zhao, Guo-Jun; Huang, Pan; Du, Binbin; Kong, Lingyao; Zhang, Wenyuan; Zhang, Yanzhou; Dong, Jianzeng
title: Prevalence and Clinical Outcomes of Cardiac Injury in Patients with COVID-19: A Systematic Review and Meta-analysis
date: 2020-09-11
journal: Nutr Metab Cardiovasc Dis
DOI: 10.1016/j.numecd.2020.09.004
sha: 1463a3b016bb5177deb74739330508926093f5b4
doc_id: 775751
cord_uid: o74l0tyg

Background and aims Emerging data have linked the presence of cardiac injury with a worse prognosis in COVID-19 patients. However, available data cannot clearly characterize the correlation between cardiac injury and COVID-19. Thus, we conducted a meta-analysis of recent studies to 1) explore the prevalence of cardiac injury in different types of COVID-19 patients and 2) evaluate the association between cardiac injury and worse prognosis (severe disease, admission to ICU, and mortality) in patients with COVID-19. Methods and results Literature searched was conducted through PubMed, the Cochrane Library, Embase, and MedRxiv databases. Meta-analysis was performed with Stata 14.0. Fixed-effects model was used if the I 2 values ≤50%, otherwise the random-effects model was performed.Prevalence of cardiac injury was 19% (95%CI:0.15-0.22, p<0.001) in total COVID-19 patients, 36% (95%CI:0.25-0.47, p<0.001) in severe COVID-19 patients, and 48% (95%CI:0.30-0.66, p<0.001) in non-survivors. Furthermore, cardiac injury was found to be associated with a significant increase in risk of poor outcomes with pooled effect size(ES) of 8.46(95%CI:3.76-19.06, p=0.062), severe disease with ES of 3.54(95% CI:2.25-5.58, p<0.001), admission to ICU with ES of 5.03(95% CI:2.69-9.39,p<0.001), and mortality with ES of 4.99(95% CI:3.38-7.37, p<0.001). Conclusions Prevalence of cardiac injury was greatly increased in COVID-19 patients, particularly in patients with severe disease and non-survivors. COVID-19 patients with cardiac injury are more likely to be associated with poor outcomes, severity of disease, admission to ICU, and mortality.

The recent outbreak of novel coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to spread worldwide [1] . Up to now, 13 July,2020, at least 12,768,307 people have confirmed diagnosis and more than 566,654 infected cases have died across the global (https://www.who.int). As there are no effective treatments, the COVID-19 has now become one of the deadliest pandemics in modern history [2] .

On the basis of recent researches, SARS-CoV-2 enters cells via direct binding of the virus's spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor [3] . ACE2 has been identified expressed predominantly in the lungs but also throughout the cardiovascular system [3] . Thus, though the most common consequence of COVID-19 are pulmonary manifestations, causing severe pneumonia and respiratory distress syndrome, accumulating evidence suggests the increased frequency of a variety of cardiovascular complications in patients infected with this virus [4] [5] [6] [7] .

Cardiac injury, defined as an increase in troponin level above the 99th percentile upper reference limit, is the most reported cardiac abnormality in COVID-19 patients [8, 9] . Furthermore, there was evidence that COVID-19 patients with cardiac injury may face a greater risk of fatal outcomes. Therefore, we need to pay more attention to such patients and give them comprehensive management [4, 9] .

As a novel disease, the shortage of clinical data has greatly limited our understanding of the linkage between the cardiac injury and clinical outcome in COVID-19 patients. Moreover, data available provide wide variations of results and may have resulted in relatively poor conclusions. Therefore, we conducted a systemic review and meta-analysis to explore cardiac injury's prevalence and its connection with prognosis in patients with COVID-19.

The systematic review and meta-analysis were accomplished based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We performed a comprehensive systematic literature search from the following medical electronic database: Medline, Embase, PubMed, Medrvix, and Cochrane Central Databases with the search terms: ("COVID- 19" OR "SARS-CoV-2") AND ("heart injury" OR "cardiac injury" OR "myocardial injury").The studies retrieved from inception to June 5, 2020. In addition, we also manually reviewed the reference lists J o u r n a l P r e -p r o o f 4 of relevant articles for potential studies. After initial search, the duplicate results were then removed.

The remaining articles were screened for relevance by their titles and abstracts by two authors independently (Guojun Zhao and Pan Huang). All selected potential articles were then comprehensively reviewed by the remaining investigators to ensure their eligibility for inclusion in this review. Disagreements about eligibility of the literature were resolved by consensus based on the agreements of all investigators.

We include all research studies that meet the following criteria: (1) cross-sectional studies or cohort studies; (2) investigating the prevalence and outcomes of cardiac injury among patients with COVID-19. Exclusion criteria were as follows: (1)children or pregnant, (2)review, (3) language of studies with non-English.

Data extraction was performed by two independent authors via the standardized form. The following information was extracted: region, sample number, percentage of male, age, study design, definition of cardiac injury, clinical outcome. Any disagreements were resolved through discussions or referral to a third author.

For quality assessment, Newcastle-Ottawa Scale (NOS) was applied to evaluate the quality and risk of bias of all the selected studies. The studies with 7 points or more were considered of high quality.

The statistical analysis was carried out using Stata 14.0 (Stata Corp, College Station, TX). The heterogeneity in included studies was assessed by using the Cochran's Q chi-square and I 2 statistic analysis. Fixed-effects model was used when the I 2 values ≤50%, otherwise the random-effects model was used. In order to investigate the association between disease severity and cardiac injury, we evaluated the pool prevalence in the severe patients and non-survivors. For clinical outcomes, we calculated the pooled effect size (ES) for the association of cardiac injury with all-cause mortality, admission to ICU, and disease severity. Publication bias were evaluated by Egger test and Begger test.

J o u r n a l P r e -p r o o f

A total of 413 articles were found in the initial database search. 227 studies were remained after removing of duplicate publications and then screened through title and abstract. Among those, we identified forty-three articles for full-text review. Ultimately, all the forty-three studies were included for review [2, 4, 9, . All of these eligible studies were enrolled for analyzing the prevalence of cardiac injury in patients with COVID-19, and thirty-two of them were selected for analyzing the outcomes of COVID-19 patients who have cardiac injury, respectively. The workflow of the process of study selection is demonstrated in Figure 1 .

Essential characteristics of the included studies are outlined in Table 1 . A total of forty-three studies involving 9,475 patients were included in this meta-analysis. Among those studies, forty were carried out in China, one in Korea, and two in the USA. The sample size of studies varied from 21 to 2737 patients, whilst the clinical outcome was defined as poor outcomes in three studies, severity of disease in eight studies, ICU admission in seven studies, and death in twenty studies. Of all forty-three studies, twenty-seven were retrospective cohort study and the remaining sixteen were cross-sectional study. Most of the included studies defined cardiac injury as TnI elevation above 99 th percentile. There are studies that did not specify their definition of cardiac injury, however, these studies may presumably use definition similar to the existing studies.

Since cardiac injury is commonly recorded in patients with COVID-19, it is of particularly important to estimate the prevalence of cardiac injury in COVID-19 patients. Thus, we first analysed the overall prevalence of cardiac injury in COVID-19 patients. Forty-three studies reporting of cardiac injury in patients with COVID-19 were included in this analysis [2, 4, 9, . Our pooled analysis revealed the prevalence of cardiac injury in total COVID-19 patients was 19% (95%CI:0.15-0.22, p<0.001) (Figure 2) .

Furthermore, it appears that the COVID-19 patients with cardiac injury have higher risk of severe disease and mortality according to some retrospective studies. We next conducted the subgroup J o u r n a l P r e -p r o o f 6 analysis to evaluate the prevalence of cardiac injury in the severe COVID-19 patients or non-survivors. Fifteen studies reported data on cardiac injury in severe COVID-19 patients [12, 14, 16-19, 22, 25, 26, 28, 36, 37, 40, 45] . Pooled analysis result showed prevalence of cardiac injury was 36% (95%CI:0.25-0.47, p<0.001) in severe COVID-19 patients (Figure 3) .

Twelve studies were included for the analysis of prevalence of cardiac injury in non-survivors[13, 20, 21, 23, 24, 33, 35, 46-48, 50, 51] . According to the pooled analysis result, the prevalence of cardiac injury was 48% (95%CI:0.30-0.66, p<0.001) in the non-survivors (Figure 4) . Obviously, prevalence of cardiac injury was greatly increased in patients with COVID-19, particularly in patients with severe disease and non-survivors.

Subgroup analysis according to the quality of includes studies indicated the prevalence of cardiac injuries was 19% (95%CI:0.14-0.23, p<0.001) in both high quality group and 19% (95%CI:0.13-0.24, p<0.001) in low quality group (Supplementary Table 1 ).

Since there was a high prevalence of cardiac injury in patients with COVID-19, we conducted a systematic analysis of association between cardiac injury and the common adverse outcomes (poor outcomes, severity of disease, need for ICU care, and mortality) in such patients.

We first analysed the relationship between cardiac injury and poor outcome. A total of three studies reported data on the association between cardiac injury and poor outcome in patients with 37, 40] . In pooled analysis, cardiac injury was found to be associated with a significantly increased risk of poor outcomes in COVID-19 patients (ES= 8.46, 95% CI:3.76-19.06, 7 studies found patients with cardiac injury were five-times more liable to require ICU admission (ES= 5.03, 95% CI:2.69-9.39, I 2 =87.2%, p<0.001), (Supplementary Figure 3) .

Finally, twenty studies were enrolled in the pooled analysis to explore the association between cardiac injury and mortality in COVID-19 patients [2, 4, 9, 11, 12, 15, 20, 21, 23, 24, 31, 33-35, 39, 46-48, 50, 51] . Pooled analysis results showed patients with cardiac injury had an approximately five-fold higher risk of mortality (ES= 4.99, 95% CI:3.38-7.37, I 2 =91.4%, p<0.001), (Figure 5 ).

Subgroup analysis according to unadjusted or adjusted for covariates indicated cardiac injuries were significantly associated with increased all-cause mortality with 3.06 (95% CI:1.52-6.16, I 2 =93.1%, p=0.002) for adjusting covariates and 5.83 (95% CI:3.74-9.08, I 2 =86.4%, p<0.001) for unadjusting covariates.

The COVID-19 has resulted in 12,768,307 confirmed infections and 566,654 deaths worldwide over the past few months according to the World Health Organization (WHO) (https://www.who.int).

Although the main clinical characteristics of COVID-19 were dry cough, fever and shortness of breath, cardiac injury has been reported to be highly prevalent in patients affected by this virus [4, 52] . Our study evaluated the prevalence of cardiac injury in patients with COVID-19 and investigated the association between cardiac injury and prognosis in these patients. Findings from this meta-analysis indicated that the prevalence of cardiac injury was increased in patients with COVID-19, particularly correlated with the severity of the disease. Furthermore, we found that cardiac injury is significantly connected with poor outcomes and mortality in patients with COVID-19. Together, our meta-analysis results indicated that COVID-19 patients with cardiac injury are more likely to develop severe disease, and more prone to require ICU care or death.

Cardiac injury, usually defined as an elevation of troponin above the 99th percentile of the upper reference, is commonly recorded in hospitalized patients with COVID-19 [8, 53] . The earliest retrospective study, involving a number of 41 patients with COVID-19, detected cardiac injury in 5 patients (12%) [52] . Since then, several retrospective studies have reported an increased prevalence of cardiac injury in patients with COVID-19 , with the rate ranging from 5% to 28% [4, 9, 12, 51, 52, 54] . Additionally, patients with previous or underlying cardiovascular diseases (CVD) showed a J o u r n a l P r e -p r o o f 8 higher risk of cardiac injury during COVID-19. Studies have demonstrated that the prevalence of coronary artery disease and hypertension among patients with cardiac injury is to be up to 20%-30%, and 45%-65% separately [ 4, 9] .

Our meta-analysis, enrolling 34 studies, showed the prevalence of cardiac injury was 19% (95% CI:15%-22%) among patients with COVID-19, which might represent the average incidence of cardiac injury in patients with COVID-19. Numerous studies have indicated that cardiac TnI increased significantly in severe cases than in mild cases [55] [56] [57] [58] . Furthermore, there was also an significant increase of TnI in the end-stage group compared with the severe group, which indicates the prevalence of cardiac injury might increase with the severity of the disease[56, 58]. Based on these retrospective studies, our meta-analysis revealed that the prevalence of cardiac injury is 36% (95% CI:25%-47%) among the severe patients with COVID-19. Severe patients usually have worse outcomes and higher death rate, then the investigators sought to evaluate the association of myocardial injury with mortality. Zhou et al. found that there was a rapid rise of troponin in non-survivors starting from day 10, which was not observed in survivors [51] . Besides, Ruan et al.

showed that the top causes of death in the non-survivors are respiratory failure, combination of heart and respiratory failure, heart failure, which account for 53%,33%,7% of all the death respectively[59]. Furthermore, the occurrence of acute cardiac injury in hospitalized patients was associated with an increased risk of mortality (ES= 4.99, 95% CI:3.38-7.37, p<0.001) [9] . It's plausible to explain why there was up to 44% incidence of cardiac injury in non-survivors with COVID-19 according to our meta-analysis results. Thus, our results support the notion that cardiac injury is very common in patients with COVID-19 and the prevalence of cardiac injury increased with the severity of the disease.

Although the association between cardiac injury and prognosis in patients with COVID-19 has been consistently described, data on its independent prognostic role remain largely unexplored.

Therefore, we conducted a systematically meta-analysis to evaluate the outcome (poor outcomes, severe disease, ICU admission, and mortality) in consecutive patients with COVID-19 with and without troponin elevation. In our meta-analysis, a pooled analysis of the association between cardiac injury and poor outcomes revealed that cardiac injury was associated with poor outcomes in COVID-19 patients (ES=8.46, 95%CI:3.76-19.06, p=0.062). Our result was in accordance with a J o u r n a l P r e -p r o o f previous brief meta-analysis which showing that troponin levels were significantly higher in severe patients compared to those with mild forms of disease [53] . Therefore, it is reasonable to hypothesize that testing of cardiac troponin immediately after admission may help to evaluate the severity of the illness and the extent of injury in the heart. In a single-center case series study performed by Huang et al, four out of five patients with cardiac injury required ICU admission [28] . Similarly, in another single-center case series study of 138 patients, 36 of them were reported to had a higher level of TnT and CK-MB and required ICU admission [54] . Thus, it appears (COVID-19) patients with cardiac injury are more likely to be admitted to ICU. Then, we analyzed the association between cardiac injury and ICU admission and found ICU admission is truly associated with cardiac injury (ES= 5.03, 95% CI:2.69-9.39, I 2 =87.2%, p<0.001). Studies have shown that myocardial injury is associated with a higher risk of mortality and over all fatal outcome of COVID-19. Enrolled 416 COVID-19

patients, a case series study revealed that patients with cardiac injury had a much higher risk of death than those without cardiac injury during the time from admission to study endpoint (HR: 3.41; 95% CI: 1.62-7.16) [9] . Similarly, a retrospective cohort study including 188 patients found patients with high levels of hs-TnI had remarkable higher death rate (50%) than that with low or moderated levels of hs-TnI (9.1% or 10%). Further, hs-TnI levels were negatively correlated with the patients' Accordingly, our meta-analysis results are of prognostic importance, since patients with cardiac injury have higher risk of severe disease and mortality and are more prone to require ICU care. Thus, they deserve more clinical attention.

Up to now, the precise etiology of cardiac injury in patients with COVID-19 remains under investigation, the following potential mechanisms have been suggested. One potential mechanism is that SARS-CoV-2 uses ACE2 as a receptor to enter target cells and causes direct damage to heart[60, 61]. According to a previous research, SARS-CoV genome was detected in 35% of autopsied hearts [67] . Furthermore, another research further identified that SARS-CoV-2 uses ACE2 as their receptor for entry into the targeted cell [68] .

All of these data further suggested the SARS-CoV-2 can have a direct invasion and damage role to the myocardium. Viral infections could trigger the activation of the immune-mediated host antiviral response, including activation of macrophages, natural killer cells, and virus-related T lymphocytes, which has been recognized as one of the most frequent causes of cardiac injury [69] . Several studies have highlighted that there exists a severe systemic inflammatory response, including elevated interleukin levels, C-reactive protein, neutrophil and leukocyte counts, and globulin [4, 9] . Systemic inflammatory response after infection may further cause overexpression of tissue-resident macrophages and leukocyte adhesion molecule, causing reduction in coronary blood flow, decreases in oxygen supply, and destabilization of coronary artery [70, 71] . Similarly, Guo et al. revealed that in patients with COVID-19, the hs-CRP levels were significantly positively correlated with plasma TnT levels, which indicated that cardiac injury may be closely associated with inflammatory response [9] . Huang et al. have found that in patients with COVID-19, the plasma levels of cytokines, including MCP-1 (monocyte chemoattractant protein-1), interleukins (IL-2, IL-7, IL-10), MIP-1α (macrophage inflammatory protein 1-alpha), and TNF-α (tumor necrosis factor α) were higher in patients that admitted to the ICU [52] . Elevated plasma cytokines can further activate the proliferation of lymphocytes and macrophages, provoking the dysfunction of the coronary microvasculature, activating the microvascular endothelium, and consequent cardiac injury [4, 72] .

Another suggested mechanism is imbalance between myocardial oxygen supply and demand. Severe hypoxia due to acute lung injury and potential subsequent systemic complications can result in mismatch between myocardial oxygen supply and demand and hence cause myocardial injury [73, 74] . Further, hypoxia may also contribute to the development of systematic inflammatory response, which can be transformed into myocardial ischemia and injury [75] . Additionally, the current data based on up-to-date evidence suggests that patients with previous or underlying CVD were susceptible to suffer from cardiac injury. Patients with coronary artery disease had a high potential risk of coronary plaque rupture secondary to virus infection induced by systemic inflammation [76] .

J o u r n a l P r e -p r o o f mechanism is poorly understood77, 78]. Furthermore, volume evidence has indicated the presence of both pre-existing CVD and cardiac injury was associated with the highest death rate, while patients with CVD but without elevated troponin levels had a relatively favorable prognosis [9, 79] .

To the best of our knowledge, this systematic review is a comprehensive analysis of existing literature to explore the prevalence of cardiac injury in patients with COVID- 19 

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Overall (I-squared = 91.4%, p = 0.000)