Clinical significance of coronavirus disease 2019 in hospitalized patients with myocardial injury

Abstract Background The clinical significance of Coronavirus disease 2019 (COVID‐19) as an associate of myocardial injury is controversial. Hypothesis Type 2 MI/Myocardial Injury are associated with worse outcomes if complicated by COVID‐19. Methods This longitudinal cohort study involved consecutive patients admitted to a large urban hospital. Myocardial injury was determined using laboratory records as ≥1 hs‐TnI result >99th percentile (male: >34 ng/L; female: >16 ng/L). Endotypes were defined according to the Fourth Universal Definition of Myocardial Infarction (MI) and COVID‐19 determined using PCR. Outcomes of patients with myocardial injury with and without COVID‐19 were assessed. Results Of 346 hospitalized patients with elevated hs‐TnI, 35 (10.1%) had laboratory‐confirmed COVID‐19 (median age [IQR]; 65 [59–74]; 64.8% male vs. COVID‐19 negative: 74 [63–83] years; 43.7% male). Cardiac endotypes by COVID‐19 status (yes vs. no) were: Type 1 MI (0 [0%] vs. 115 [100%]; p < .0005), Type 2 MI (13 [16.5%] vs. 66 [83.5%]; p = .045), and non‐ischemic myocardial injury (cardiac: 4 [5.8%] vs. 65 [94.2%]; p = .191, non‐cardiac:19 [22.9%] vs. 64 [77.%]; p < .0005). COVID‐19 patients had less comorbidity (median [IQR] Charlson Comorbidity Index: 3.0 [3.0] vs. 5.0 [4.0]; p = .001), similar hs‐TnI concentrations (median [IQR] initial: 46 [113] vs. 62 [138]; p = .199, peak: 122 [474] vs. 79 [220] ng/L; p = .564), longer admission (days) (median [IQR]: 14[19] vs. 6[12]; p = .001) and higher in‐hospital mortality (63.9% vs. 11.3%; OR = 13.2; 95%CI: 5.90, 29.7). Conclusions Cardiac sequelae of COVID‐19 typically manifest as Non‐cardiac myocardial injury/Type 2MI in younger patients with less co‐morbidity. Paradoxically, the admission duration and in‐hospital mortality are increased.

Conclusions: Cardiac sequelae of COVID-19 typically manifest as Non-cardiac myocardial injury/Type 2MI in younger patients with less co-morbidity. Paradoxically, the admission duration and in-hospital mortality are increased.

K E Y W O R D S
coronavirus, COVID-19, myocardial Injury, outcomes, troponin, Type 2 myocardial infarction

| INTRODUCTION
Coronavirus disease 2019 (COVID-19) is a novel cause of myocardial injury. 1 The importance of elevated cardiac troponin I (cTnI) in patients requiring intensive care has been extensively documented. 2,3 What is less well understood is the clinical significance of troponin elevation in COVID-19 including in comparison with other causes of myocardial injury.

Cardiovascular involvement is observed in approximately 25%
of patients with COVID-19. Myocardial injury may be due to primary viral infection, secondary hypoxia, inflammatory state, hypotension, thromboembolism, or a combination of these problems. 4 Mechanistic studies of the cardiac and multisystem effects of  infection are on-going (ClinicalTrials.gov identifier NCT04403607). 5 Non-ischemic myocardial injury (cardiac or non-cardiac) and Type 2 myocardial infarction (T2MI) generally portend an adverse prognosis, however, evidence-based treatment options are less well established than is the case for Type 1 MI. Troponin-I elevation is associated with fatal outcomes, however the etiology of this elevation is unclear.. 6 We prospectively investigated a population of consecutively admitted patients with myocardial injury in relation to COVID-19 status. We hypothesized that in patients with myocardial injury, COVID-19 would associate with Type 2 MI more so than with other endotypes, and this combination would be an adverse prognostic factor for in-hospital outcomes.

| Diagnosis of COVID-19
A diagnosis of COVID-19 was determined by either laboratory evidence of SARS-CoV-2 infection by PCR biospecimen testing and/or a radiological diagnosis (chest computed tomography, chest radiograph) consistent with COVID-19 but biospecimen negative with a clinical presentation in keeping with SARS-CoV-2 infection. The laboratory tests used were either the Roche Cobas 6800 or Seegene SARS-CoV-2 tests.

| Patient characteristics
The characteristics of patients with COVID-19 infection and Type 2 MI or myocardial injury compared with those without COVID-19 infection are described in Table 1 The ECG features are described in Table S3, including patients with a diagnosis of Type 1 MI from the initial cohort.
Patients with Type 2 MI or myocardial injury, less frequently underwent further coronary assessment with either CT coronary angiography (n = 5) or invasive catheter angiography (n = 6). Cardiac MRI was performed in patients with a diagnosis of myocarditis in addition to clinical and ECG assessment.

| Non-cardiac myocardial injury or Type 2 myocardial infarction in COVID-19
Within this cohort, hypoxia was the most likely  (Figure 3 and Table S2).

| Outcomes of patients with elevated cTnI in COVID-19
Vital status was determined in all patients by assessment of electronic patient records. The duration of follow-up was a median of 71 days (inter-

| DISCUSSION
We have provided novel information on the nature and clinical significance of COVID-19 in a hospitalized population with myocardial injury.
Our study involved prospective clinical evaluation of consecutive patients in real-time during the study period. Cases of myocardial injury were identified based on a high sensitivity troponin result >URL. This approach was intended to minimize missing data and selection bias. We found that the cardiac sequelae of COVID-19 Type 2 MI/myocardial injury is associated with increased illness severity as evidenced by significantly higher mortality and duration of hospital stay. 16 Though exact mechanisms of myocardial injury and modifiable outcome in patients with COVID-19 is yet to be demonstrated, protocolized high-sensitivity troponin testing and its utilization in stratification could be a useful tool for early recognition of adverse outcome and early decision making in this group. 17

| Conclusions
The occurrence of myocardial injury and COVID-19 is associated with a high in-hospital mortality. Type 2 MI or myocardial injury in COVID-19 infection has poorer in-hospital outcomes compared with other causes of Type 2 MI or myocardial injury.