key: cord-0763349-u14zm1wb
authors: Weber, Brittany; Siddiqi, Hasan; Zhou, Guohai; Vieira, Jefferson; Kim, Andy; Rutherford, Henry; Mitre, Xhoi; Feeley, Monica; Oganezova, Karina; Varshney, Anubodh S.; Bhatt, Ankeet S.; Nauffal, Victor; Atri, Deepak S.; Blankstein, Ron; Karlson, Elizabeth W.; Di Carli, Marcelo; Baden, Lindsey R.; Bhatt, Deepak L.; Woolley, Ann E.
title: Relationship Between Myocardial Injury During Index Hospitalization for SARS‐CoV‐2 Infection and Longer‐Term Outcomes
date: 2021-12-31
journal: J Am Heart Assoc
DOI: 10.1161/jaha.121.022010
sha: 8e9895f02bb708eecf2ff0c7f1ee466adfd5f695
doc_id: 763349
cord_uid: u14zm1wb

BACKGROUND: Myocardial injury in patients with COVID‐19 is associated with increased mortality during index hospitalization; however, the relationship to long‐term sequelae of SARS‐CoV‐2 is unknown. This study assessed the relationship between myocardial injury (high‐sensitivity cardiac troponin T level) during index hospitalization for COVID‐19 and longer‐term outcomes. METHODS AND RESULTS: This is a prospective cohort of patients who were hospitalized at a single center between March and May 2020 with SARS‐CoV‐2. Cardiac biomarkers were systematically collected. Outcomes were adjudicated and stratified on the basis of myocardial injury. The study cohort includes 483 patients who had high‐sensitivity cardiac troponin T data during their index hospitalization. During index hospitalization, 91 (18.8%) died, 70 (14.4%) had thrombotic complications, and 126 (25.6%) had cardiovascular complications. By 12 months, 107 (22.2%) died. During index hospitalization, 301 (62.3%) had cardiac injury (high‐sensitivity cardiac troponin T≧14 ng/L); these patients had 28.6%, 32.2%, and 33.2% mortality during index hospitalization, at 6 months, and at 12 months, respectively, compared with 4.1%, 4.9%, and 4.9% mortality for those with low‐level positive troponin and 0%, 0%, and 0% for those with undetectable troponin. Of 392 (81.2%) patients who survived the index hospitalization, 94 (24%) had at least 1 readmission within 12 months, of whom 61 (65%) had myocardial injury during the index hospitalization. Of 377 (96%) patients who were alive and had follow‐up after the index hospitalization, 211 (56%) patients had a documented, detailed clinical assessment at 6 months. A total of 78 of 211 (37.0%) had ongoing COVID‐19–related symptoms; 34 of 211 (16.1%) had neurocognitive decline, 8 of 211 (3.8%) had increased supplemental oxygen requirements, and 42 of 211 (19.9%) had worsening functional status. CONCLUSIONS: Myocardial injury during index hospitalization for COVID‐19 was associated with increased mortality and may predict who are more likely to have postacute sequelae of COVID‐19. Among patients who survived their index hospitalization, the incremental mortality through 12 months was low, even among troponin‐positive patients.

is incompletely understood, but inflammation-induced as well as direct injury of the vascular endothelium and the myocardium are likely to play a central role. [4] [5] [6] [7] [8] Myocardial injury has been associated with increased morbidity and mortality during the index hospitalization for patients with COVID-19. 3, 9 However, the impact of myocardial injury on longer-term outcomes in these patients is unknown. The purpose of this study was to assess the relationship between cardiac injury during the index hospitalization and longer-term outcomes, including the incidence of postacute sequelae of COVID-19 at 6 months, readmission rate at 6 and 12 months, and mortality at 6 and 12 months.

The authors declare that all supporting data are available within the article and its online supplementary files.

The Brigham and Women's Hospital COVID-19 registry is a prospective cohort study of consecutive patients who were admitted with documented evidence of SARS-CoV-2 infection since March 2020. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology reporting guideline for cohort studies. 10 The study was approved by the Massachusetts General Brigham institutional review board, and informed consent was waived.

Patients were included if they tested positive for SARS-CoV-2 on a nasopharyngeal swab polymerase chain reaction test, received inpatient care at Brigham and Women's Hospital for COVID-19 from March to May 2020, and had troponin levels measured. Patients had follow-up through March 31, 2021.

For the study cohort, baseline demographics, clinical characteristics, laboratory measurements, readmission data, mortality, and outpatient clinical follow-up assessments were obtained from the electronic medical health record (EHR) (Epic Systems, Verona, WI) by a combination of automated queries using the National Death Index, Research Patient Data Registry, and confirmation through physician medical record review. In addition, deaths were confirmed through online obituaries. 11 Hospital readmissions, 6-month clinical followup assessments, and loss to follow-up were assessed by examining the EHR shared by the Mass General Brigham healthcare system, which includes 11 institutions in Massachusetts that provide both inpatient and ambulatory services. Median follow-up time and mortality data were assessed from March 2020 to May 2021.

As part of the Brigham and Women's Hospital COVID-19 inpatient protocols, high-sensitivity cardiac troponin T (hs-cTnT) was measured in all COVID-19 inpatients every other day until at least hospital day 8. 12 Hs-cTnT was systematically collected and analyzed as a surrogate for myocardial injury using the Elecsys 2010 system (Roche Diagnostics GmbH, Mannheim, Germany). The assay has a 6 ng/L lower limit of detection, with a 99th percentile cutoff at 14 ng/L. 13 For each patient, the maximum hs-cTnT level during his/her hospitalization was used for analyses. Levels of hs-cTnT were categorized as follows: undetectable (<6 ng/L), low-level positive (6-14 ng/L), and myocardial injury (≥14 ng/L). 14 Clinical outcomes during the index hospitalization and readmissions were ascertained on the basis of laboratory results, imaging, medications, and documentation of clinical assessment in the EHR and then were independently reviewed by a panel of physicians, including cardiologists and infectious disease physicians; and any discrepancies were adjudicated by at least 2 physicians. Cardiovascular outcomes

What Is New?

• SARS-CoV-2 infection is associated with a high prevalence of cardiac injury, defined as circulating high-sensitivity cardiac troponin T, and has been previously shown to associate with allcause and cardiovascular mortality. • This study provides insights into the relationship between myocardial injury during the index hospitalization and longer-term outcomes up to 12 months.

What Are the Clinical Implications?

• The relationship between myocardial injury in patients hospitalized with COVID-19 and longerterm outcomes suggests that assessment of myocardial injury may serve as an additional tool for clinical practice. • Future larger-scale prospective studies are needed to address the spectrum of myocardial injury across clinical severities of COVID-19 and the underlying mechanisms by which myocardial damage associates with longer-term outcomes. The clinical symptom assessments for postacute sequelae of COVID-19 at 6 months were ascertained through documentation in the shared EHR and adjudicated by at least 2 physicians. This assessment at 6 months included whether the patient had ongoing symptoms since his/her COVID-19 infection, including dyspnea, chest pain, palpitations, fatigue, anosmia, ageusia, headaches, neurocognitive decline, increased supplemental oxygen requirement, or decline in functional status, as documented by a decrease in the activities of daily living from his/her pre-COVID-19 baseline. [15] [16] [17] 

Categorical variables are reported as frequencies with percentages. Continuous variables are expressed as median (interquartile range [IQR] ). To test for the presence of a significant trend across the troponin categories, the Jonckheere-Terpstra test was used for continuous variables, and the Cochran-Armitage test was used for binary variables. For race/ethnicity and prodrome categories, the Fisher exact test was used. P values represent the comparison between cardiac injury (≥14 ng/L) versus noncardiac injury (low-level positive and undetectable). For in-hospital and 6-month outcomes stratified by myocardial injury, a binomial proportion test was used. Troponin was evaluated by both a continuous linear regression and using categories of cardiac injury, low-level positive, and undetectable. Multivariable logistic regression was then performed to determine the association between high-sensitivity troponin and all-cause mortality, readmissions, and postacute sequelae of COVID-19 while adjusting for clinically significant covariates (age, sex, history of coronary artery disease [CAD], hypertension, hyperlipidemia, heart failure, and type 2 diabetes). Adjusted P values with logistic regression were not calculated with categories with <7 events to avoid overfitting. For all statistical analyses, 2-sided and false discovery rate corrected P<0.05 was considered statistically significant. 18 Data analysis was conducted in R version 4.0.2 (R Project for Statistical Computing).

A total of 500 consecutive patients were hospitalized with COVID-19 from March to May 2020, of whom 483 had hs-cTnT measured systematically during the index admission ( Figure 1 ). Among these 483 patients who were included in the study cohort, 50.5% were women and had a median age of 63 years (IQR, 51-75 years), 24.6% were Hispanic, and 28.8% were Black non-Hispanic race/ethnicity. Median body mass index was 29 kg/m 2 (IQR, 25-33 kg/m 2 ), 64.6% had hypertension, 48% had hyperlipidemia, 34.2% had diabetes, 29.6% had CAD, and 14.9% had heart failure ( 

During the index hospitalization, 91 (18.8%) patients died ( Table 2 ). An additional 12 patients (103/483 [21.3%]) died by 6 months and 4 more died between 6 and 12 months after their index hospitalization (107/483

Overall, 301 (62.3%) patients had cardiac injury (hs-cTnT ≥14 ng/L) during the index hospitalization, 123 (25.5%) had low-level positive hs-cTnT, and 59 (12.2%) had an undetectable hs-cTnT level. Patients with evidence of cardiac injury were older and more likely to have diabetes, hypertension, dyslipidemia, and CAD ( Table 1 ). The patients with cardiac injury had a 28.6%, 32.2%, and 33.2% mortality during index hospitalization, at 6 months, and at 12 months, respectively, compared with 4.1%, 4.9%, and 4.9% mortality for those who had low-level positive hs-cTnT, and 0%, 0%, and 0% for those who had undetectable troponin (P<0.001 for index hospitalization, 6-month mortality, and 12month mortality) ( Figure 2 ). Adjusting for age, sex, CAD, hypertension, hyperlipidemia, heart failure, and diabetes, cardiac injury (hs-cTnT ≥14 ng/L) compared with undetectable hs-cTnT was associated with an increased risk of mortality (hazard ratio [HR], 13.76; 95% CI, 1.85-102.3; P=0.01), whereas low-level positive hs-cTnT compared with undetectable was not statistically significant (HR, 2.31; 95% CI, 0.27-19.48; P=0.44) ( Table 3 ). There was no relationship between cardiac injury and duration of symptoms before hospitalization (Table 1) .

Patients with evidence of cardiac injury were more likely to have infectious, thrombotic, and cardiac complications during index hospitalization, which remained significant after adjustment for age, sex, CAD, hypertension, hyperlipidemia, and diabetes ( Table 2 ). Among the cardiac complications, there were a total of 50 cases of type II myocardial infarction and 5 cases of acute coronary syndrome.

To further ascertain cardiac injury, we also examined cardiovascular imaging. Among the 483 patients, 122 had transthoracic echocardiograms during the index admission. Among the 122 patients, a total of 81 (66.4%) had left ventricular ejection fraction ≥40% and 16 (13.1%) had left ventricular ejection fraction <40%. Among the patients with left ventricular ejection fraction <40%, 16 of 17 (99%) had evidence of myocardial injury, defined as the highest category of troponin (Table S1 ). Additional cardiovascular imaging modalities were limited: 5 patients underwent coronary computed tomographic angiogram, and 3 patients had coronary angiograms.

Of the 392 (81.2%) patients who survived the index hospitalization, 377 (96%) had documented follow-up, with a median follow-up time of 170 days (IQR, 3-352 days). A total of 15 (3.8%) patients were lost to followup. A detailed flow chart of the study cohort is provided in Figure 1 . A total of 83 of 392 (21.2%) patients had ≥1 readmission within 6 months and 94 of 392 (24%) patients had ≥1 readmission within 12 months. Of the 6-month readmissions, 8 of 83 (9.6%) involved thrombotic complications and 20 of 83 (24.1%) had cardiac complications. Of the 12-month readmissions, 9 of 94 (9.6%) involved thrombotic complications and 28 of 94 (29.8%) had cardiac complications. Patients with myocardial injury were more likely to have a readmission than patients without myocardial injury (64.9% compared with 21.3% and 13.8% in low-level positive and undetectable troponin, respectively; P=0.01). However, this was not statistically significant after multivariable adjustment (HR, 1.5; 95% CI, 0.8-2.5; P=0.23; Table 2 ).

Of the 377 (96%) patients who had follow-up after the index hospitalization through May 2021, 211 (56%) had clinical follow-up with detailed symptom Figure 3 ). Patients with myocardial injury accounted for 58.2% of those with postacute sequelae of COVID-19. There was overall a gradation of risk for patients with undetectable troponin during the index hospitalization who were least likely to require readmissions, have postacute sequelae of COVID-19, or experience mortality at 6 months. Furthermore, older age (>65 years) was associated with higher degrees of cardiac injury and mortality ( Figure 3 ).

Limited data exist on long-term outcomes, [19] [20] [21] and to our knowledge, this is the first longitudinal study to assess the relationship with myocardial injury. Although our findings further support other US center studies on postacute sequelae of COVID-19, 22 our mortality rate after index hospitalization was much lower than a recent analysis of a large registry cohort in the United Kingdom. 23 In that study, they assessed rates of multiorgan dysfunction after discharge through September 2020 (mean of 140 days of follow-up) rather than ongoing COVID-19 symptoms or neurocognitive decline stratified by myocardial injury. Their findings suggest a greater severity of disease in their cohort, leading to a higher rate of mortality and multiorgan dysfunction, which is consistent with the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial analyses from the United Kingdom, which showed higher mortality rates compared with other US or European trial sites. 23, 24 The exact mechanism by which mortality and adverse outcomes are increased in patients with COVID-19 who have elevated circulating hs-cTnT is not known. However, this association has previously been seen in patients with other infections, such as influenza, and other noncardiovascular disease states. 14, [24] [25] [26] [27] Hs-cTnT likely serves as a subclinical marker of cardiac damage in response to these conditions, with higher levels associated with a greater degree of damage. Close to half of the cardiac events observed in our cohort were attributable to either type II myocardial infarction or acute coronary syndrome. Underreporting of these events is certainly possible, given the limited diagnostic interventions used in the beginning of the pandemic because of infection control concerns. More in-depth diagnostic evaluation with cardiac imaging and further biomarker analysis across the wide range of disease states associated with elevated hs-cTnT could provide further understanding of the myocardial function and structural changes that lead to the adverse outcomes and increased mortality.

Limitations of this single-center, observational study include its sample size, assessment of hospital readmissions being constrained to the 11 medical facilities Data are given as number (percentage) or number/total (percentage). Univariate P values (after false discovery rate correction) represent the comparison between cardiac injury (≥14 ng/L) vs noncardiac injury (low-level positive and undetectable) based on a binomial proportion test for whether patients with cardiac injury had an unadjusted proportion of 50% (ie, shared equal proportions with patients without cardiac injury) in each outcome group. Adjusted P value and odds ratios (95% CIs) are based on multivariable logistic regression, adjusting for clinical covariates that included age, sex, history of coronary artery disease, hypertension, hyperlipidemia, and diabetes and further adjusted using false discovery rate correction. Adjusted P values were not calculated for categories with <7 events because of overfitting. NA indicates not applicable. in our integrated healthcare system, and 6-month assessment of postacute sequalae of COVID-19 being limited to what was documented in the EHR. Although the overall loss to follow-up at 1 year of those who survived the index hospitalization was low at 3.8%, which increases our confidence in the reported mortality data, we only had enough detailed, documented assessments in 53.8% of the follow-up cohort to assess postacute sequelae of COVID-19 given the observational nature of this study. Therefore, there may have been a deselection bias at the 6-month clinical assessment attributable to a healthy effect. However, it is reassuring that the demographic and clinical characteristics were similar among the patients who were able to be assessed for postacute sequelae of COVID-19 compared with the total cohort. The highest troponin value obtained during the index hospitalization was used to categorize patients, but further delineation of the trajectory of troponin over time in a larger sample size could provide further insights. In addition, we did not have routine data for all patients on echocardiography or cardiac magnetic resonance imaging to evaluate how often patients with myocardial injury had underlying cardiac abnormalities. 28 The definition of postacute sequelae of COVID-19 will continue to evolve as we better understand its pathophysiological features, which may impact the clinical characteristics we used to ascertain postacute sequelae of COVID-19 in our cohort. Last, symptoms that were not reported by patients or documented in their medical record would have been missed by our data capture.

Although the exact mechanisms of cardiac injury during COVID-19 are not clearly understood, these findings highlight the need for further mechanistic studies to explore the relationship between myocardial injury and postacute sequelae of COVID-19. Approximately 100 million people are estimated to have recovered from COVID-19. Given the substantial public health consequences, future work is needed to address the predictors, duration, and long-term impact of postacute sequelae of COVID-19.

In conclusion, this study provides unique insights into the relationship between cardiovascular injury during the index hospitalization for patients with COVID-19 and longer-term outcomes. Patients with evidence of myocardial injury during index hospitalization had an increased risk of cardiac, thrombotic, and infectious complications during the hospitalization and all-cause mortality. Furthermore, these Data are given as number/total (percentage). Univariate P values (after false discovery rate correction) represent the comparison between cardiac injury (≥14 ng/L) vs noncardiac injury (low-level positive and undetectable) based on a binomial proportion test for whether patients with cardiac injury had an unadjusted proportion of 50% (ie, shared equal proportions with patients without cardiac injury) in each outcome group. For ongoing COVID-19 symptoms, adjusted P value and odds ratios (95% CIs) are based on multivariable logistic regression, adjusting for clinical covariates that included age, sex, history of coronary artery disease, hypertension, hyperlipidemia, and diabetes. Adjusted P values were not calculated for categories with <7 events because of overfitting. NA indicates not applicable. Figure 3 . The relationship between myocardial injury during COVID-19 infection and long-term outcomes. Shown is the distribution of the number of individuals with a readmission at 12 months, postacute sequelae of COVID-19 at 6 months, and all-cause mortality at 6 to 12 months, stratified by high-sensitivity cardiac troponin T level into cardiac injury, low-level positive, or undetectable during index hospitalization. Each bar graph demonstrates the age distribution by >65 and ≤65 years. The mortality and readmission represent the number of patients of the total 483. The patients noted to have postacute sequelae of COVID-19 (composite of ongoing COVID-19 symptoms, supplemental oxygen requirement, neurocognitive decline, or worsening function status) are among the 211 patients with 6-month follow-up. patients had higher rates of hospital readmissions and postacute sequelae of COVID-19 at 6 months, although this was not statistically significant. An additional unique aspect of our cohort findings is that even among those patients with positive troponins during their index hospitalization, the incremental mortality at 6 months and 1 year among COVID-19 survivors was low. These data suggest that patients who are hospitalized with COVID-19, even if critically ill, but survive the index hospitalization are likely to survive up to 1 year. Whether this trend is observed longer-term is not known and will be an important question to investigate as we gather longer-term data. 

This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) T32HL094301 (Dr Weber) and NHLBI T32HL094301 (Dr A. S. Bhatt). 

American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO (Self-expanding intra-annular versus commercially available transcatheter heart valves in high and extreme risk patients with severe aortic stenosis) trial, funded by St

Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE [A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease] trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief

Bhatt has received honorarium from Sanofi Pasteur. Dr Di Carli reports grants from Gilead Sciences and Spectrum Dynamics; and personal consulting fees from Janssen and Bayer, outside the submitted work. Dr Blankstein reports grants from Amgen incorporation and Astellas, outside of the submitted work

Characteristics and outcomes of 21 critically Ill patients with COVID-19 in Washington State

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China

Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19)

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

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

Increased prevalence of myocardial injury in patients with SARS-CoV-2 viremia

Special article -acute myocardial injury in patients hospitalized with COVID-19 infection: a review

COVID-19 -a vascular disease

The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies

Comparison of national death index and world wide web death searches

Analytical validation of a high-sensitivity cardiac troponin T assay

Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults

Post-acute COVID-19 syndrome

Symptoms and functional impairment assessed 8 months after mild COVID-19 among health care workers

Toward understanding COVID-19 recovery: National Institutes of Health workshop on postacute COVID-19

Controlling the false discovery rate: a practical and powerful approach to multiple testing

Four-month clinical status of a cohort of patients after hospitalization for COVID-19

Sequelae in adults at 6 months after COVID-19 infection

6-Month consequences of COVID-19 in patients discharged from hospital: a cohort study

Mortality and readmission rates among patients with COVID-19 after discharge from acute care setting with supplemental oxygen

Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study

Dexamethasone in hospitalized patients with Covid-19

6-Year change in high sensitivity cardiac troponin-T and risk for subsequent coronary heart disease, heart failure, and death

High-sensitivity troponin I and incident coronary events, stroke, heart failure hospitalization, and mortality in the ARIC study

Network for the C-AP. Association between cardiac injury and mortality in hospitalized patients infected with avian influenza A (H7N9) virus

Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19)

Tables S1-S2