key: cord-0884774-rqgm7yc8
authors: Maino, Alessandro; Di Stasio, Enrico; Grimaldi, Maria Chiara; Cappannoli, Luigi; Rocco, Erica; Vergallo, Rocco; Biscetti, Federico; Baroni, Silvia; Urbani, Andrea; Landolfi, Raffaele; Biasucci, Luigi Marzio
title: Prevalence and characteristics of myocardial injury during COVID-19 pandemic: A new role for high-sensitive troponin
date: 2021-06-19
journal: Int J Cardiol
DOI: 10.1016/j.ijcard.2021.06.028
sha: 6493d296a9eed1f36780463a64ccd882ebfa7329
doc_id: 884774
cord_uid: rqgm7yc8

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a pandemic disease that is causing a public health emergency. Characteristics and clinical significance of myocardial injury remain unclear. METHODS: This retrospective single-center study analyzed analyzed 189 patients who received a COVID-19 diagnosis out of all 758 subjects with a high sensitive troponin I (Hs-TnI) measurement within the first 24 h of admission at the Policlinico A.Gemelli (Rome, Italy) between February 20th 2020 to April 09th 2020. RESULTS: The prevalence of myocardial injury in our COVID-19 population is of 16%. The patients with cardiac injury were older, had a greater number of cardiovascular comorbidities and higher values of acute phase and inflammatory markers and leucocytes. They required more frequently hospitalization in Intensive Care Unit (10 [32.3%] vs 18 [11.4%]; p = .003) and the mortality rate was significantly higher (17 [54.8%] vs. 15 [9.5%], p < .001). Among patients in ICU, the subjects with myocardial injury showed an increase need of endotracheal intubation (8 out of 9 [88%] vs 7 out of 19[37%], p = .042). Multivariate analyses showed that hs-TnI can significantly predict the degree of COVID-19 disease, the intubation need and in-hospital mortality. CONCLUSIONS: In this study we demonstrate that hs-Tn can significantly predict disease severity, intubation need and in-hospital death. Therefore, it may be reasonable to use Hs-Tn as a clinical tool in COVID-19 population in order to triage them into different risk groups and can play a pivotal role in the detection of subjects at high risk of cardiac impairment during both the early and recovery stage.

This single-center, retrospective, observational study was performed at "Policlinico Universitario Agostino Gemelli -Università Cattolica del Sacro Cuore", Rome (Italy). We retrospectively analyzed patients with a troponin measurement within the first 24 hours of admission who received a COVID-19 diagnosis, according to the interim guidance of the World Health Organization 11 , between February 20th 2020 to April 09th 2020. Patients whose clinical documentation was not available at the time of the study or under 18 years of age were excluded from the report. This study complied with the edicts of the 1975 Declaration of Helsinki 12 and was approved by the institutional ethics board of Catholic University of Sacred Heart. Consent was obtained from patients or patients' next of kin.

Clinical information was collected on admission and during hospitalization by attending physicians.

Each patient was identified with a numerical code to guarantee respect for privacy and anonymity.

The data were collected from the medical and nursing diary, monitoring and administration form of drug therapy, and consisted of:

-personal data (gender, age, admission diagnosis); -epidemiological-clinical data (comorbidities such as history of ischemic heart disease, atrial fibrillation, chronic heart failure, significant valvular heart disease, supraventricular or ventricular arrhythmia and cardiomyopathy; cardiovascular risk factors such as history of hypertension, smoking habits, dislipidemia, ischemic heart disease, diabetes, chronic renal failure and malignant tumor; previous pharmacologic therapy such as use of loop diuretics, ACEi, ARBs, Betablockers, Patients were categorized according to the presence or absence of (myocardial) injury. Cardiac injury was defined as blood levels of cardiac biomarkers (hs-TNI) above the gender specific 99thpercentile upper reference limit, regardless of new abnormalities in electrocardiography and echocardiography.

Covid-19 was diagnosed on the basis of the WHO interim guidance. 11 A confirmed case of Covid-19 was defined as a positive result on highthroughput sequencing or real-time reverse-transcriptasepolymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. 5 Only laboratory-confirmed cases were included in the analysis.

We defined the degree of severity of Covid-19 (mild, severe and critical) using the Chinese CDC report. 13 The authors of the Chinese CDC report divided the clinical manifestations of the disease by their severity:

-Mild disease: non-pneumonia and mild pneumonia; -Severe disease: dyspnea, respiratory frequency ≥ 30/min, blood oxygen saturation (SpO2) ≤ 93%, PaO2/FiO2 ratio or P/F [the ratio between the blood pressure of the oxygen (partial pressure of oxygen, PaO2) and the percentage of oxygen supplied (fraction of inspired oxygen, FiO2)] < 300, and/or lung infiltrates > 50% within 24 to 48 hours; J o u r n a l P r e -p r o o f Journal Pre-proof -Critical disease: respiratory failure, septic shock, and/or multiple organ dysfunction (MOD) or failure (MOF).

Acute respiratory distress syndrome (ARDS) was defined according to the Berlin definition. 14 Acute kidney injury was diagnosed according to the KDIGO clinical practice guidelines. 15 Furthermore, Sepsis and septic shock were defined according to the 2016 Third International Consensus Definition for Sepsis and Septic Shock. 16

The statistical analysis of the data was carried out using the "Statistical Package for Social Science (SPSS)" program. Continuous variables were expressed as mean ± D.S. or median and range, as appropriate, and categorical variables represented as frequencies. Normal data distribution was verified using the Kolmogorov-Smirnov test. We log-transformed hs-Tn levels in order to reduce the positive skew of their distribution. The appropriate statistical, parametric and non-parametric test (Student t-test, Mann-Whytney U-test, Χ2-test, as detailed in tables) was used in the analysis of the results. Correlations between variables was calculated using Pearson or Spearman coefficient, as appropriate. Multiple linear regression with backward-stepwise method, with the P-value for a feature to leave the model set at 0.05, was also performed to study the relationship between COVID gravity and clinical / laboratory parameters. Finally, a multivariate binary logistic analysis was performed to evaluate the relationship between death during hospitalization and clinical/laboratory findings. Effect modification by each previously described covariate was evaluated by testing whether including the interaction term in the multivariate logistic model significantly changed the log likelihood of the model applying stepwise logistic regression. The coefficients obtained from the logistic regression were expressed in terms of odds ratio with 95% confidence intervals. All of the tests were two-sided and statistical significance was set at p < 0.05.

The sample was composed of 189 out of 758 patients in whom hs-TnI was determined at the Policlinico A.Gemelli (Rome, Italy) from February 20th to April 09th, 2020. We excluded 569 patients that were not confirmed by SARS-CoV-2 RNA detection and nine inpatients without available key information in their medical records.

Thirty-two patients died during hospitalisation and one hundred seventy-seven were discharged.

The median age of the 189 patients was 66 years old (SD 12), ranging from 18 years old to 95 years old; 128 patients were male (table 1) and 61 were female.

History of cardiovascular disease was found in nearly 26.8% of patients, with Ischemic heart disease (11.6%) being the most common comorbidity, followed by atrial fibrillation (5.3%), chronic heart failure(5.3%), significant valvular heart disease (1.6%), supraventricular or ventricular arrhythmia (1.6%) and cardiomyopathy (0.05%) (table 1) Cardiovascular risk factors were present in 55.3%: the most common of them was hypertension (42.3%), followed by dyslipidemia (17.5%), diabetes (14.8%), chronic renal disease (9.5%), smoking (7.9%) and cancer (2.1%).

The most frequent cardiovascular pharmacologic therapy was use of beta-blockers ( correlated positively with the concentration of hs-TnI (and inverse correlation with chronic kidney disease).

Compared with patients with normal hs-TnI levels ( 

On admission, most patients affected by SARS-CoV-2 presented abnormal laboratory results, such as D-Dimer, C-reactive protein and NT-proBNP. (Table 1) Patients with elevated Hs-TnI levels were characterized with significantly higher white blood cell in the multivariable logistic regression model. We found that hs-Tn at admission, older age and CRP levels were associated with increased odds of death (table 3 ).

In addition, a different multivariable logistic regression model was conducted to examine whether Hs-TnI could prognosticate the need of intubation in ICU patients. Table 4 describes that Hs-Tn at admission was associated with increased odds of intubation need.

On the basis of cut-off stratification, hs-troponin levels presented a sensibility of 30%, specificity of 

The SARS-CoV-2 is mainly a pulmonary disease, although there is multiple evidence of its multisystem involvement, in particular the cardiovascular one. 17 This study has highlighted a prevalence of myocardial injury of 16% in our COVID-19 population, in the absence of patients with acute coronary syndrome at the time of admission. This result is consistent with other published works with percentage between 7-36%. 5, [7] [8] [9] [10] The patients with myocardial injury were older, and had a greater number of cardiovascular comorbidities, in particular history of hypertension and ischemic heart disease, than those without cardiac injury. Furthermore, this group of patients was significantly associated with previous use of beta-blockers, Aspirin, Statin and loop diuretics. This finding could be a confounding phenomenon, because these drugs are commonly used in chronic therapy of cardiovascular disease, as reported in other studies. 8, 9, 18, 19 In addition, there is no significant correlation between the use of ACEi/ARBs J o u r n a l P r e -p r o o f and myocardial injury. This is in keeping with recent studies demonstrating no increased risk associated with use of these drugs. 20, 21 The patients with cardiac injury had higher values of acute phase and inflammatory markers and leucocytes, which were linear correlated with plasma hs-TnI levels. This difference suggests that myocardial injury may be closely related in his pathogenesis with sustained inflammatory response showed that hs-Tn was a significant independent variable, enlightening its positive predictive role.

The correlation between hs-Tn values and the outcome of death arose in our report, regardless of history of CVD or risk factors. The group of patients with myocardial injury showed a significantly higher event rate. Furthermore, multivariate analysis (age, sex, history of CVD and risk factor, CRP, WBC were the other variables) confirmed hs-Tn has an indipendent predictor of in-hospital death. This is in keeping with reports worldwide. 8, 9, 18 Our study suggests that hs-Tn can have a role also in SARS-CoV-2 as a marker with a high positive predictive value of serious illness and a high negative predictive value for death, already when measured at admission. It is therefore reasonable to hypothesize that the initial measurement of heart damage biomarkers immediately after hospitalization for COVID 19 infection, as well as longitudinal monitoring during hospitalization, may help to identify a subset of patients with J o u r n a l P r e -p r o o f possible heart damage and therefore predict the progress of SARS -CoV-2 towards a worse clinical picture.

In our cohort, among patients hospitalized in ICU emerged a significant increased probability of endotracheal intubation need in subjects with cardiac injury and the multivariate analysis validated Hs-Tn as a indipendent predictive marker. This data assume an important practical implication as troponin can play the role of an additional guiding tool for key clinical decisions in critically ill patients, supporting the identification of subjects who would benefit from prompt intubation and thus avoiding the delay that often causes the irreversible worsening of clinical outcomes.

A valuable large meta-analysis reported that pre-existing cardiovascular comorbidities or risk factors were significant predictors of cardiovascular complications in COVID-19 patients, in addition to age and gender. In the same meta-analysis, involving 77317 patients, pre-existing cardiovascular comorbidities or risk factors and the development of cardiovascular complications (among which cardiac injury) had a significant interaction with death at meta-regression analysis.

These findings are relevant as they suggest that presence of cardiovascular comorbidities/risk factors is tied to a higher prevalence of cardiac injury, that is a proxy for death. This should inform vaccination strategies, suggesting a significant benefit from prioritization of cardiovascular patients. 22 The probable causes of heart suffering in the context of COVID 19 infection are a debated topic.

The profound inflammatory response and hemodynamic changes associated with severe disease may confer risk for atherosclerotic plaque rupture in susceptible patients and may lead to type I myocardial infarction. 23 Coronary heart disease has also been found to be associated with acute cardiac events and poor outcomes in influenza and other respiratory viral infections. [24] [25] [26] J o u r n a l P r e -p r o o f Other mechanisms of myocardial damage could be involved, for example mismatch between oxygen supply and demand, increased ventricular strain, direct myocyte trauma and increased catecholamines.

A small number of autopsy cases suggest infiltration by interstitial mononuclear inflammatory cells, 27 suggesting myocardial inflammation as a further possible mechanism, and some severe cases of myocarditis have been reported. 28, 29 Tavazzi Traditionally, cardiac imaging would feature prominently in the distinction between acute myocardial infarction and injury. 34 

In a small study of recovered patients with ongoing cardiac symptoms, cardiovascular magnetic resonance (CMR) imaging during the acute phase revealed cardiac involvement in 58% of patients consisting of myocardial edema and scar by late gadolinium enhancement (LGE). 35 In patients who have convalesced from COVID-19, studies have shown that myocardial damage and inflammation may be evident in a majority of patients when assessed with cardiac magnetic resonance imaging. 34 The study of Puntmann et al. enrolled 100 unselected patients recently recovered from COVID-19 illness and recorded a Cardiac Magnetic Risonance (CMR) two month after the acute phase of the disease. A total of 78 patients (78%) had cardiovascular involvement as detected by standardized CMR and this occured independently of the severity of original presentation and persists beyond the period of acute presentation. The most prevalent abnormality was myocardial inflammation (60%), followed by regional scar and pericardial enhancement. Most imaging findings pointed toward ongoing perimyocarditis after COVID-19 infection. In this report, high-sensitivity troponin was significantly correlated with CMR mapping, irrespective of comorbidities or treatment received during the COVID-19 illness. 36 Another study of Knight et al. used cardiovascular magnetic resonance (CMR) during early convalescence to assess the presence, type, and extent of myocardial injury in troponin-positive (during the hospitalitation) patients with COVID-19. In this cohort, abnormalities on CMR are common despite overall normal cardiac function. The CMR frequently revealed ischemic heart disease-related (17%), high rates of myocarditis-like Late Gadolinium Enhancement (38%), and sometimes dual pathology (ischemic and non-ischemic, 14%). The lack of edema in these patients suggests that the myocarditis-like scar may be permanent. 37

Furthermore, if the findings about cardiac involvement during 29, 35, 38, 39 and months after 36 will not abate but will instead shift to a new de novo incidence of heart failure and other chronic cardiovascular complications. 40 In this clinical contest, the detection of abnormal elevation of hs-Tn during the early acute phase may help to select patients at high risk, that need stricter cardiac monitoring, and during the convalescence phase the subjects with late myocardial impairment.

Our study has several limitations. First, only 189 patients with confirmed COVID-19 were included, and a larger cohort study is needed to verify our conclusions. Second, this is a retrospective study and there is incomplete data concerning some other specific information of cardiovascular system and inflammation such as echocardiography and interleukin 6, owing to the conditions in the isolation ward. As a consequence, we were only able to define acute myocardial injury by troponin elevation without detailing myocardial tissue characteristics and haemodynamic function. Third, we assessed the hs-Tn value on admission and further data on the role of longitudinal assessment of troponin values are needed.

Myocardial injury is prevalent in patients affected by SARS-CoV-2 and the patients with hs-Tn value above the upper reference limit are older and had a greater number of cardiovascular comorbidities. In this study we demonstrate a high positive predictive value of hs-Tn for disease severity and a high negative predictive value for in-hospital death. Therefore, it may be reasonable to use high sensitivity troponin as a screening tool in COVID-19 population in order to triage them into high and low general risk groups. In addition, our report indicates that hs-Tn is an indipendent predictor of intubation need among patients hospitalized in ICU, emerging as a guiding tool in critically ill patients, supporting the identification of subjects who would benefit from prompt intubation. Finally, recent studies enlighten cardiac involvement in the recovery phase of COVID-J o u r n a l P r e -p r o o f 19 with evidence of active myocardial inflammation and regional scar; the prevalence is high in patient discharged with myocardial injury. In this constest, hs-Tn can play a pivotal role in the detection of subjects at high risk of cardiac impairment and heart failure during both the early and recovery stage. J o u r n a l P r e -p r o o f 

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