key: cord-1032180-s2x3mhic authors: Lala, A.; Johnson, K. W.; Russak, A. J.; Paranjpe, I.; Zhao, S.; Manna, S.; Solani, S.; Vaid, A.; Chaudhry, F.; De Freitas, J. K.; Fayad, Z. A.; Pinney, S. P.; Levin, M.; Charney, A.; Bagiella, E.; Narula, J.; Glicksberg, B. S.; Nadkarni, G.; Januzzi, J.; Mancini, D. M.; Fuster, V. title: Prevalence and Impact of Myocardial Injury in Patients Hospitalized with COVID-19 Infection date: 2020-04-24 journal: medRxiv : the preprint server for health sciences DOI: 10.1101/2020.04.20.20072702 sha: 571be5f91c730715cbdf1fdef19d9a0c16f86fd2 doc_id: 1032180 cord_uid: s2x3mhic ABSTRACT Importance: It is postulated that myocardial injury may be common in Coronavirus Disease (COVID-19) reflected by troponin elevation. The nature, degree and mechanism of myocardial injury in affected patients in the United States are unknown. Objective: To describe the severity and trends of myocardial injury in a large cohort of hospitalized patients with confirmed COVID-19. Design: Retrospective cohort study of data captured between February 27th and April 12th, 2020. Setting: Patients were admitted to one of five hospitals in the Mount Sinai Health System (MSHS) in New York City. Data was collected from the electronic health record (EHR) databases within the hospital system. Participants: We included all patients with confirmed COVID-19 admitted to the aforementioned hospitals during the study period who had at least one troponin-I measured within 24 hours of admission. Exposure(s) (for observational studies): SARS-CoV-2 infection as confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay of nasal and pharyngeal swabs. Main Outcome(s) and Measure(s): During the study period, 2736 patients met the inclusion criteria. Demographics, medical history, admission labs, and all troponin-I measurements during hospitalization were recorded for each patient. Admission troponin levels were characterized as mildly elevated (between one and three times the upper limit of normal) and elevated (above three times the upper limit of normal). Results: The median age was 66.4 years, with 59.6% men and 40.7% over age 70. In those patients with elevated troponins, cardiovascular disease (CVD) including coronary artery disease, atrial fibrillation, and heart failure, were more prevalent as were conditions of chronic kidney disease, hypertension and diabetes. Inflammatory markers were higher among patients with more substantial troponin elevations as well. Patients who had lower hemoglobin, hypo- or hypertension, or tachycardia generally presented with higher troponins. Conclusions and Relevance: Myocardial injury, manifesting as troponin elevation appears to be common among patients hospitalized with COVID-19 but present at generally low levels. Patients with a history of CVD are more likely to have myocardial injury than patients without CVD or risk factors for CVD. Troponin elevation among patients hospitalized with COVID-19 likely represents non-ischemic or secondary myocardial injury. Coronavirus Disease (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is now one of the deadliest pandemics in modern history. The mode of infection is caused by the SARS-CoV-2 virus entering cells via the human angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed predominantly in the lungs but also throughout the cardiovascular system. 1 Thus, while its most virulent manifestation is acute respiratory distress syndrome (ARDS), select reports from Europe and China have demonstrated cardiac injury reflected by elevated troponin concentrations among infected patients. [2] [3] [4] [5] Troponin elevation in these limited case series was associated with worse outcomes in patients hospitalized with COVID-19. 6 However, major gaps exist in our current understanding of the underlying mechanisms by which SARS-CoV-2 affects the cardiovascular system and how such involvement impacts clinical outcomes. First, the range of troponin elevation across different subpopulations based on history of cardiovascular disease (CVD) compared to those without history of CVD is unknown in patients in the United States (US). Second, whether these troponin elevations represent primary myocardial infarction, supply-demand inequity, or nonischemic myocardial injury remains unclear. We sought to explore these two aims amongst a large cohort of patients hospitalized with Covid-19 in New York City. Patients in this study were drawn from five New York City hospitals in the Mount Sinai Health System (MSHS). We included all patients with a laboratory confirmed SARS-CoV-2 infection who were at least 18 years old and were admitted to a MSHS hospital site between February All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 24, 2020. . https://doi.org/10.1101/2020.04.20.20072702 doi: medRxiv preprint 27th and April 12th, 2020. The Mount Sinai Institutional Review Board (IRB) approved this research under a regulatory protocol allowing for analysis of patient-level COVID-19 data. Data was collected from electronic health records (EHR) from the five hospitals. Variables collected included demographics, laboratory measurements, disease diagnoses, comorbidities, procedures, and outcomes (death or hospital discharge). Comorbidities were extracted using International Classification of Disease (ICD) 9/10 billing codes for atrial fibrillation (AF), asthma, coronary artery disease (CAD), cancer, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), diabetes (DM), heart failure (HF), and hypertension (HTN). Troponin I concentrations were assessed via the Abbott Architect method (Abbott, Abbott Park, Illinois) wherein the 99th percentile for a normal population is 0.028 ng/mL. The reference level for normal in MSHS is less than 0.03 ng/mL. Descriptive analyses were performed by troponin levels stratified into normal (0.00-0.03 ng/mL), mildly elevated (between one and three times the upper limit of normal, or >0.03-0.09 ng/mL), and elevated (more than three times the upper limit of normal, or >0.09 ng/mL). Categorical variables were reported as total count and percentage of patients. Continuous non-troponin laboratory values were reported as median and interquartile range. To assess the effects of troponin levels on outcomes, we conducted a survival analysis for mortality. We fit Cox proportional hazards regression models with mortality as the dependent variable, adjusting for gender, age, race, ethnicity, history of CAD, history of AF, history of HF, history of HTN, history of CKD, history of DM, and in-hospital intubation. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 24, 2020. During the study period, 3,047 COVID-19 positive patients were hospitalized at one of five MSHS New York City hospitals. Of these, 2,736 (89.8%) had at least one troponin-I measurement within 24 hours of admission. The median age was 66.4 years, with 59.6% men and 40.7% over age 70. Admission troponin-I concentrations are presented in Figure 1 Table 1 . Troponin elevations were categorized as mildly elevated and elevated as previously defined. In those patients with significant myocardial injury, CVD including CAD, AF, and HF, were more prevalent (34.9%, 13.0%, and 25.3% respectively) compared to patients with mildly elevated troponins (21.3%, 10.1% and 14.7% respectively) as well as those with normal troponins (9.8%, 5.2%, and 4.3% respectively). The same trends were seen for CKD, HTN, and DM. Inflammatory markers were higher among patients with more substantial troponin elevations as well. Patients who had lower hemoglobin, hypo-or hypertension, or tachycardia generally presented with higher troponins. Table 1 . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 24, 2020. . https://doi.org/10.1101/2020.04.20.20072702 doi: medRxiv preprint Patients with mildly elevated troponin levels (0.03-0.09 ng/dL) experienced less frequent discharge and were at higher risk for death than patients with troponin levels in the reference range after adjustment for covariates (HR: 1.77, 95% CI 1.39-2.26) (Figure 2 Patients with troponin elevations over 0.09 ng/dL had higher risk of death overall (HR 3.23, 95% CI 2.59-4.02) after adjustment for covariates. This risk was consistent across patients stratified by history of CVD, risk factors but no CVD, and neither CVD nor risk factors. (Figure 2 panel C). Although pulmonary manifestations are the most common consequences of COVID-19, the disease causes systemic inflammation with varying presentations of cardiac involvement as well. 7 In this multihospital retrospective cohort study of nearly 3000 patients, we demonstrate the following observations: 1) Myocardial injury is common among patients hospitalized with COVID -19 and though most often relatively minor, when significant may be associated with more than a tripling in risk of mortality and 2) COVID-19 patients with history of CVD are more likely to suffer myocardial injury than patients without CVD but without obvious corroborating evidence for acute myocardial infarction. Troponin elevation above the 99th percentile URL is considered the central marker of "myocardial injury" according to the Fourth Universal Definition of Myocardial Infarction. 8 Several non-ischemic mediated mechanisms, which include apoptosis, myocardial strain, myocyte necrosis, and increased cell membrane permeability mediated exocytotic release of troponin, All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 24, 2020. . https://doi.org/10.1101/2020.04.20.20072702 doi: medRxiv preprint may contribute to such injury. 9 ,10 Despite reports of COVID-19 associated myocarditis, no case has demonstrated detection of SARS-CoV-2 viral genome in cardiac tissue on biopsy or autopsy to date accompanied by troponin elevation. 3, 11, 12 Possible mechanisms by which COVID-19 leads to cardiovascular morbidity include direct myocardial injury as a result of the inflammatory cascade or cytokine release, acute coronary syndrome from acute inflammationtriggered destabilization of atheromas, microvascular damage due to disseminated intravascular coagulation and thrombosis, direct entry of SARS-CoV-2 into myocardial cells by binding to ACE2 receptors, and hypoxemia combined with increased metabolic demands of acute illness leading to myocardial injury akin to Type 2 Myocardial Infarction. 13 In the present report, we demonstrate that myocardial injury was prevalent, occurring in approximately 40% of hospitalized patients. Evidence for myocardial injury was more frequent in our patients compared to two recent reports from China, one with 416 patients and the other with 187 patients, which noted prevalence of 20% and 28%, respectively. 2,14 Similar to these smaller reports, we also noted that patients with myocardial injury tended to be older, have a history of CVD, lower hemoglobin values, higher inflammatory markers, and more frequent rates of tachycardia or hypo/hypertension. This observation tends to support a theory that troponin elevation associated with COVID-19 is more likely to be consistent with non-ischemic myocardial injury as opposed to dramatic acute coronary syndrome or myocarditis. There are limitations of this analysis that are notable and inherent to the use of EHR for patient level data. Some patients included had not completed their hospital course at the time of data freeze. Use of EHR despite these limitations enabled timely analysis of a large patient cohort at the epicenter of the pandemic. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 24, 2020. In conclusion, myocardial injury is prevalent among patients with acute COVID-19 and is associated with worse outcomes. Those with prior CVD are more likely to suffer myocardial injury related to COVID-19 infection. These results suggest abnormal troponin concentrations might be helpful with regard to triage decision-making. However, whether treatment strategies based on troponin concentrations would be expected to improve outcomes remains a testable hypothesis. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 24, 2020. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 24, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 24, 2020. Cumulative Outcome Incidence + + + ++ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +++ + + + + + + + + + + + + + + + + + + + + + + + + + + + + ++ + + + + + + + + + + + + + + + ++ + + ++ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + ++ + + + + + ++ + + + + + + + ++ + + + + + + + + + + + + + + + ++ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + ++ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + ++ + + + + + + + + ++ + + + + + + + + + + + + + + + + + + ++ + + + + + + + + + + + + + + + + + + + + + + + ++ + + + + + + + ++ + + + + + + + + + + + + + ++ + + + + ++ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + ++ + + + + + + + + + + + + + ++ + + ++ + + + + + ++ + + + + + + + + + + + + + + + + ++ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + ++ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + ++ + + + + + + + + + + + + + + + + + ++ + + + + + + ++ + + + + + + + + + ++ + + + + + + + + + + + + + + + + ++ + + + + + + ++ + + + + + + + + + + + + + + ++ + + + + + + + ++ + + + + + + ++ + + + + + + + + ++ + + + + + + + + + ++ + + + + + ++ + + +++ + Atrial fibrillation (N (%)) 206 Stratified by Troponin Levels, N = 2736 All Patients All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 24, 2020. . https://doi.org/10.1101/2020.04.20.20072702 doi: medRxiv preprint COVID-19, ACE2, and the cardiovascular consequences Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19) First case of COVID-19 complicated with fulminant myocarditis: a case report and insights Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin Sanchis-Gomar F. Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19): Evidence from a meta-analysis The Variety of Cardiovascular Presentations of COVID-19 Cardiac troponins: from myocardial infarction to chronic disease Lymphocyte (%) (median D-dimer above 1 mcg/mL (N (%) Creatine kinase (median Ferritin (median (IQR))