key: cord-0777102-wvi6d89o authors: Changal, Khalid; Veria, Spiro; Mack, Sean; Paternite, David; Sheikh, Shoaib Altaf; Patel, Mitra; Mir, Tanveer; Sheikh, Mujeeb; Ramanathan, P. Kasi title: Myocardial injury in hospitalized COVID-19 patients: a retrospective study, systematic review, and meta-analysis date: 2021-12-31 journal: BMC Cardiovasc Disord DOI: 10.1186/s12872-021-02450-3 sha: 7fc74ccde82bc06db487ed5e69f976ea57b432cf doc_id: 777102 cord_uid: wvi6d89o INTRODUCTION: The majority of studies evaluating the effect of myocardial injury on the survival of COVID-19 patients have been performed outside of the United States (U.S.). These studies have often utilized definitions of myocardial injury that are not guideline-based and thus, not applicable to the U.S. patient population. METHODS: The current study is a two-part investigation of the effect of myocardial injury on the clinical outcome of patients hospitalized with COVID-19. The first part is a retrospective analysis of 268 patients admitted to our healthcare system in Toledo, Ohio, U.S.; the second part is a systematic review and meta-analysis of all similar studies performed within the U.S. RESULTS: In our retrospective analysis, patients with myocardial injury were older (mean age 73 vs. 59 years, P 0.001), more likely to have hypertension (86% vs. 67%, P 0.005), underlying cardiovascular disease (57% vs. 24%, P 0.001), and chronic kidney disease (26% vs. 10%, P 0.004). Myocardial injury was also associated with a lower likelihood of discharge to home (35% vs. 69%, P 0.001), and a higher likelihood of death (33% vs. 10%, P 0.001), acute kidney injury (74% vs. 30%, P 0.001), and circulatory shock (33% vs. 12%, P 0.001). Our meta-analysis included 12,577 patients from 8 U.S. states and 55 hospitals who were hospitalized with COVID-19, with the finding that myocardial injury was significantly associated with increased mortality (HR 2.43, CI 2.28–3.6, P 0.0005). The prevalence of myocardial injury ranged from 9.2 to 51%, with a mean prevalence of 27.2%. CONCLUSION: Hospitalized COVID-19 patients in the U.S. have a high prevalence of myocardial injury, which was associated with poorer survival and outcomes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12872-021-02450-3. The COVID-19 pandemic continues to affect millions of people in the United States (U.S.) and across the world [1] . Myocardial injury, as reflected by an increase in the serum troponin level above the 99th percentile, has been found to be relatively common in hospitalized COVID-19 patients and may predict a poor prognosis. However, most of these studies have been performed outside of the U.S. [2] [3] [4] and utilize definitions of myocardial injury that are not guideline-based, thus making it difficult to apply such findings to the hospitalized COVID-19 population within the U.S. [5] [6] [7] . The goal of the present study is to determine the prevalence of myocardial injury in the hospitalized COVID-19 patient population in the U.S., compare outcomes with hospitalized patients who have COVID-19 without myocardial injury, and to determine the risk factors for the development of myocardial injury and possible differences in clinical outcome between the two groups. In addition, we carry out a systematic review of current U.S. studies, summarize their findings, and perform a meta-analysis. This study has two parts: one is a retrospective analysis of patients admitted to our health system; the second is a systematic review and meta-analysis of all similar studies performed in the U.S. We conducted a retrospective study of a hospitalized patient population at two tertiary care hospitals in Toledo, Ohio, U.S. Adult (> 18 years) patients who were hospitalized with the diagnosis of COVID-19 from 1 January 2020 through 1 May 2020 were included. Patients with type 1, 3, 4, and 5 myocardial infarctions were excluded from the study. Real-Time RT-PCR (cobas ® SARS-CoV-2 Test) was used to establish COVID-19 diagnosis via nasopharyngeal and oropharyngeal swab samples obtained from our patients. Myocardial injury was defined using the fourth universal definition of myocardial infarction as below: Detection of a rise and/or fall of cTn with at least one value above the 99th percentile (in our laboratory this a troponin I > 0.04 ng/ml) and myocardial oxygen supply and demand mismatch not related to coronary thrombosis, with a minimum of one of the following: clinical symptoms related to cardiac ischemia; electrocardiographic changes suggestive of ischemia; new and pathological Q waves; imaging suggestive of acute loss of viable myocardium, or incident regional wall motion abnormalities consistent with ischemia [8] . All hospitalized COVID-19 patients received an EKG on admission. The present study only included patients who had serum troponin levels checked, which was based on clinical suspicion and/or EKG or imaging abnormalities. Eleven patients were excluded from the study as serum troponin was not measured in their cases. Data were collected by review of individual electronic medical records from the hospital database. Data were collected on demographics, baseline comorbidities, hospital course, clinical and laboratory variables, cost, and outcomes. The underlying cardiovascular disease (CVD) status was identified by review of patient charts. To qualify for the CVD group, patients needed to have at least one of the following diagnoses: ischemic heart disease, congestive heart failure, and/or atrial fibrillation. The statistics were performed using Statistical Package for the Social Sciences (SPSS), Version 20.0. We used mean, standard deviation/standard error of mean, and percentage when appropriate for the patient's characteristic description. Group differences were compared using the Pearson χ 2 or Fisher's exact test for categorical variables, or the Student t test for continuous variables. P values < 0.05 were regarded as significant. We conducted univariate and multivariate regression analysis for factors contributing to myocardial injury, and for the effect of myocardial injury on different outcomes. The variables with statistical significance on univariate analysis were analyzed with multivariate analysis. Multivariate analysis was performed separately for clinical factors (4 variables) and for hospital course/clinical outcomes (4 variables). The Institutional Review Board of Promedica Health System in Toledo, Ohio, U.S. approved the current study. Review and meta-analysis were performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The study methodology is described in the Additional file 1. We exclusively included studies performed in the U.S. We searched multiple databases using keywords such as "myocardial injury", "troponin", and "COVID-19". A systematic review was performed. Quantitative meta-analysis was performed only on studies that had clear outcomes defined. One study was excluded as it included only pregnant patients. We used hazard ratio (HR) and corresponding 95% confidence interval (CI) for measuring mortality outcomes. Metaanalysis was performed using Review Manager Version 5.3 (The Nordic Cochrane Center, The Cochrane Collaboration, 2014), R version 3.6.2. A total of 268 patients were included in this study at our health system in Toledo, Ohio, U.S. Fifty-eight (22.4%) patients met the inclusion criteria of myocardial injury, and 210 patients were included in the no myocardial injury group. Baseline characteristics are described in Table 1 . Patients with myocardial injury were older (mean age 73 vs. 59 years, P 0.001), more likely to have hypertension (86% vs. 67%, P 0.005), underlying cardiovascular disease (57% vs. 24%, P 0.001), ischemic heart disease (35% vs. 16%, P 0.003), heart failure with reduced ejection fraction (12% vs. 3%, P 0.009), heart failure with preserved ejection fraction (19% vs. 7%, P 0.012), atrial fibrillation (21% vs. 7%, P 0.005), history of stroke (28% vs. 8%, P 0.001), chronic kidney disease (26% vs. 10%, P 0.004), and end-stage renal disease (12% vs. 2%, P 0.003). No significant statistical difference was noticed for sex, race, history of diabetes mellitus, active cancer, chronic liver disease, or home ACE inhibitor or Angiotensin II receptor blocker therapy. Patients in the myocardial injury group were less likely to initially present with fever (40% vs. 58%, P 0.022), dry cough (47% vs. 68%, P 0.005), or myalgias (9% vs. 27%, P 0.006). Serum troponins were measured in 97% of patients hospitalized for COVID-19. Table 2 describes the effect of myocardial injury on hospital course and clinical outcomes. Patients with HFpEF congestive heart failure with preserved ejection fraction, EF < 40%, HFrEF congestive heart failure with reduced ejection fraction, EF > 50%. There were 3 patients with HfmrEF (EF 40-50%) and were included in HfrEF group. ESRD on HD = End stage renal disease on hemodialysis. Immunosuppressive state anyone on chronic immunomodulatory drugs or with immunodeficiencies such as HIV, ARNI angiotensin receptor-neprilysin inhibitor, EKG electrocardiogram Including the current study, a total of 7 studies were included in the review (Table 4 ) [8] [9] [10] [11] [12] [13] . Six studies were included in quantitative analysis. All studies were retrospective in design and included only hospitalized COVID-19 patients within the U.S. The study by Pachtman et al. [13] was excluded as it included only pregnant patients. The quantitative analysis included data from 8 states or 55 hospitals. 12,577 patients were included in the quantitative analysis. The prevalence of myocardial injury ranged from 9.2 to 51%. The overall mean prevalence of myocardial injury was 27.2%. All studies included hospitalized patients. In the meta-analysis, we found the presence of myocardial injury was significantly associated with mortality (HR 2.43, CI 2.28-3.6, P 0.0005, Fig. 1 ). Each study found an increased risk of mortality with myocardial injury. This study and review show myocardial injury is common (9-52%) in hospitalized COVID-19 patients in the U.S. [9] [10] [11] [12] [13] [14] . This is in contrast to studies from China, which show relatively lower (7-28%) rates of myocardial injury in hospitalized COVID-19 patients [15] [16] [17] [18] . We also found that development of myocardial injury in COVID-19 U.S. patients is associated with increased mortality, change of code status to "do not resuscitate", discharge to skilled nursing facilities instead of home, development of acute kidney injury, circulatory shock, and arrhythmias. We have, for the first time, shown in a meta-analysis on studies performed in the U.S. that myocardial injury significantly increases the mortality among hospitalized COVID-19 patients. This provides a high level of evidence. Similar to our results, a report of 416 patients from Wuhan, China demonstrated an HR of 3.41 (95% CI 1.62-7.16) for death in patients with myocardial injury compared with patients without myocardial injury [15] . Of note, Nuzzi V et al. found that in-hospital troponin elevation in Caucasian patients without myocardial injury at admission has a strong correlation with mortality [19] . We recommend that all patients admitted with COVID-19 should have troponin levels checked during their hospitalization. This, along with other clinical and laboratory variables, can provide further guidance on management and prognosis. The association of troponin elevation with increased mortality likely has two AMA against medical advice, ARNI angiotensin receptor-neprilysin inhibitor, VT ventricular tachycardia, ARDS acuterespiratory distress syndrome, PE pulmonary embolism, HD hemodialysis, CVVD continuous venovenous hemodialysis, SNF skilled nursing facility, LOS length of stay main reasons. Firstly, troponin elevation in COVID-19 is more likely to occur in patients with underlying cardiac and non-cardiac comorbidities, placing them at an increased risk of poor outcomes. Secondly, cardiac injury in the setting of COVID-19 is a marker of tissue hypoxia, myocardial cytotoxicity, systemic cytokine upregulation, demand-supply mismatch, thrombosis, and plaque vulnerability [20] [21] [22] . All of these processes suggest advanced disease and poor prognosis. The underlying factors that predispose to the development of myocardial injury are age, hypertension, underlying CVDs, and chronic kidney disease. The CVDs associated with the development of myocardial injury are ischemic heart disease, heart failure (both preserved and reduced EF), and atrial fibrillation. Our review of other U.S. studies suggests similar risk factors for developing myocardial injury [9] [10] [11] [12] [13] [14] . While some studies performed outside of the U.S. have investigated the association of myocardial injury with COVID-19, such studies have often used nonguideline definitions that utilize imaging and electrocardiographic abnormalities for establishing diagnosis. This increases the margin of error in diagnosing the patients with true myocardial injury, making such studies less reliable. We utilized a uniform and validated definition for Type 2 MI in an attempt to avoid this error. Although the patients with myocardial injury had poor outcomes, there was no significant difference in the healthcare costs. This is because many patients in the myocardial injury group were discharged to skilled nursing facilities rather than home, and likely would result in a higher overall cost. No other study in the review has studied the healthcare costs outcome. There are some limitations to our study. All findings are retrospective in design and are thus limited by this. Another limitation is that only patients who had troponin levels checked during their hospitalization were included. However, only a small number of patients were excluded for lack of serum troponin testing (n = 11). All of the studies included patients prior to when vaccination against COVID-19 was available. Additionally, none of the included studies have provided data on coronary angiography in the included patients. Nevertheless, on this final point, diagnosis of myocardial injury is based on clinical, EKG, laboratory, and imaging data and coronary angiography is often not required to make this diagnosis. While some authors [23] have suggested a racial predisposition to adverse outcomes from COVID-19, the present study could not study the effect of race on mortality outcomes due to sample size limitations. Such data was also not available for meta-analysis. To conclude, myocardial injury is a common phenomenon in hospitalized COVID-19 patients in the U.S. Elevated troponin in this population predicts a poor outcome and higher risk of mortality. 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ACEi: ACE inhibitor; ARBs: Angiotensin II receptor blocker; ARNI: Angiotensin receptor-neprilysin inhibitor; BBB: Bundle branch block (complete left or right); BNP: Brain natriuretic peptide; CVD: Cardiovascular disease; CVVHD: Continuous venovenous hemodialysis; ESRD: End stage renal disease; HD: Hemodialysis; HFpEF: Heart failure with preserved ejection fraction; HFrEF: Heart failure with reduced ejection fraction; hs-cTnT: High sensitivity cardiac troponin-t; LOS: Length of stay; SNF: Skilled nursing facility; SPSS: Statistical package for the social sciences; U.S.: United States; VT: Ventricular tachycardia. The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s12872-021-02450-3. None. Will be provided upon reasonable request. Please email Mujeeb A. Sheikh MD (smujeeb73@gmail.com) for requests. Ready to submit your research Ready to submit your research ? Choose BMC and benefit from:? Choose BMC and benefit from: Institutional Review Board of Promedica Health System in Toledo, Ohio, USA approved the study. Individual consents from patients were not required as hospital registry was used, and data was de-identified. The study protocol was carried out in accordance with the Declaration of Helsinki. Not applicable. The authors declared that they have no competing interest.