ECG markers of malignant arrhythmias and in‐hospital outcome of COVID‐19 pneumonia

Abstract Background ECG abnormalities associated with COVID‐19 pneumonia and adverse outcome are undefined and poorly described in prior studies. Objectives To assess the predictive role of baseline ECG markers of increased risk of malignant arrhythmias and cardiac death for adverse in‐hospital outcomes. Patients and methods A retrospective study included 93 patients of newly diagnosed COVID‐19 with features consistent with pneumonia who were admitted to the hospital from August 20 to September 20, 2020. The main outcomes were defined as receiving mechanical ventilation, in‐hospital cardiac arrest, length of ICU stay, and degree of lung damage according to computed tomography (CT) score. Results Increased QTc (QT corrected) interval, Tp‐e (T from peak to end) interval, and transmural dispersion of repolarization (TDR) were independent predictors of prolonged ICU stay (P < .0001) after adjustment for baseline clinical characteristics. Increasing age (P < .0001) followed by increased QTc interval (P = .02) and history of chronic lung disease (P = .04) were independent predictors of extensive lung damage. The independent predictors for in‐hospital cardiac arrest were increased QTc (P = .02) followed by increasing age (P = .04) and increased Tp‐e interval (P = .04). Conclusion Repolarization abnormalities on baseline ECG may be useful prognostic markers in patients with COVID‐19 pneumonia.

have suggested that ECG changes recorded during the early presentation or hospital stay can be used as a predictor for disease severity related to the clinical course of viral infection. 4 Over the past decade, some electrocardiographic markers, including transmural dispersion of repolarization (TDR) of left ventricle measured by T peak to end interval (Tp-e) and Tp-e/QTc and index of cardiac electrophysiological balance (iCEB) measured by QTc/QRS, have emerged as novel ECG markers correlated with myocardial fibrosis, repolarization and conduction abnormalities, arrhythmic events, and even sudden cardiac death in various cardiovascular diseases. 7,8 Moreover, these ECG markers have suggested being a prognostic marker of adverse short-and long-term outcomes in patients with coronary artery disease. 9,10 The main aim of the study was to assess the baseline ECG markers of repolarization and depolarization disturbances associated with increased risk of malignant arrhythmias and cardiac death, including QTc, Tp-e, TDR, and iCEB, with short-term clinical outcomes for patients with COVID-19 pneumonia.

| PATIENTS AND ME THODS
This observational retrospective study included patients with newly diagnosed COVID-19 pneumonia who were presented to the outpatient clinic and admitted to Al-Sader teaching hospital in Al-Najaf governorate from August 20 to September 20, 2020. All patients were presented with features consistent with COVID-19 pneumonia based on clinical symptoms and radiological findings. Diagnosis of COVID-19 infection was either by (1) positive nasopharyngeal swab by real-time polymerase chain reaction (PCR) or (2) negative swab for COVID-19 but the clinical symptoms suggestive of viral illness (cough, fever, and shortness of breath) plus radiological features of COVID-19 infection on lung imaging. 3 At hospital admission, the baseline clinical characteristics were recorded using medical records and collected by physicians at the study site-level. The baseline clinical characteristics were: age, sex, hypertension, diabetes mellitus, chronic lung disease, smoking, body mass index (BMI), and previous coronary artery disease. The severity of lung damage by COVID-19 pneumonia was assessed by computed tomography (CT) scan score according to a previously reported method for assessment of lung involvement and severity in COVID-19 infection. 3 The main outcomes for the study were defined as receiving mechanical ventilation, inhospital cardiac arrest, length of ICU stay, and degree of lung damage according to CT score. Approval of this study was provided by our medicine College Board and verbal consent was obtained from patients or relatives.

| ECG examination
The 12-lead ECGs were obtained for all patients within 24 hours of hospital admission with a paper speed of 25 mm/s and voltage of 10 mm/mV by using a standard ECG system (Marquette Electronics, WI, USA) while the patient was resting in the supine position. ECG markers were measured manually by two cardiologists blinded to the patient's status, using calipers and a magnifying glass. Any disagreement in ECG interpretations between cardiologists was resolved by consensus. QRS duration in milliseconds (ms) was measured from the initiation of the Q or R waves until the end of the R or S waves.
Tp-e interval in ms was measured from the peak of the T wave to the end of the T wave in the precordial leads. The mean value of the measurements was used in the analysis. The QT interval in ms was measured from the beginning of the QRS complex to the end of the T wave. Measured QT intervals were corrected by Bazett's formula (QT/(RR interval)1/2) and defined as corrected QT interval (QTc). The Tp-e/QTc ratio and QTc/QRS were calculated from these measurements. 7,8

| Statistical analysis
Statistical analysis was performed using SPSS ver. 23.0 (SPSS Inc, Chicago, IL, USA). P-value of < .05 was chosen for statistical significance. Baseline clinical data of the patients and ECG markers were expressed as mean ± standard deviation for continuous variables or as numbers with percentages for categorical data. Receiver operating characteristic (ROC) curve analysis was used to assess the most optimal cut-off values of ECG markers as predictors for in-hospital cardiac arrest. These results were reported as area under the curve (AUC) with sensitivity and specificity. Univariate and multivariate logistic regression analyses were used to calculate the odds ratio and confidence intervals [OR (CI)], and assess the association of ECG markers and baseline characteristics with short-term outcomes, including receiving mechanical ventilation, in-hospital cardiac arrest, length of ICU stay, and degree of lung damage according to CT score.
Baseline clinical characteristics, including age, sex, hypertension, diabetes mellitus, chronic lung disease, smoking, body mass index (BMI), and previous coronary artery disease, and all ECG markers underwent univariable logistic regression to the clinical outcome.
Those with a P value of < .05 were candidates for inclusion in the final multivariable logistic regression analysis.

| Multivariate analysis
Baseline clinical characteristics and ECG markers that showed significant association in univariate analysis were selected for final multivariate analysis. Increased QTc interval, Tp-e interval, and TDR were independent predictors of increased length of ICU stay (P < .0001).
Increasing age (P < .0001) followed by increased QTc interval (P = .02) and history of chronic lung disease (P = .04) were independent predictors of extensive degree of lung damage as assessed by CT score. The independent predictors of in-hospital cardiac arrest were increased QTc interval (P = .02) followed by increasing age (P = .04) and increased Tp-e interval (P = .04) ( Table 3).

| D ISCUSS I ON
Given the high rates of acute phase morbidity and mortality associated with rapidly spreading COVID-19 pneumonia, there is an urgent need to identify prognostic markers that can help the physician in the rapid triage of patients and optimized allocations of health-care resources. 11 In the literature, there is scant data as of yet that address The prevalence of ICU admission and requiring mechanical ventilation was controversial among prior studies. 16 Abbreviations: iCEB, index of cardiac electrophysiological balance; ICU, intensive care unit; OR (CI), Odds ratio (confidence interval); TDR, transmural dispersion of repolarization; Tp-e, T from peak to end interval. Regarding ECG markers of repolarization disturbances, QTc,

Variables
Tp-e interval, and TDR have a prognostic significance in the prediction of increased risk of malignant arrhythmia and morality in patients with certain cardiovascular diseases, such as coronary artery disease and myocarditis. 22 ECG changes, such as QTc prolongation, conduction and repolarization abnormalities, and ventricular arrhythmias, may reflect myocardial injury directly or indirectly associated with COVID-19 pneumonia. 23  The present study has several limitations. This is a retrospective study, and the data of patients were extracted from medical patient history or records, so findings may be not generalizable.
The majority of enrolled patients (85%) were found to be positive PCR for SARS-CoV-2 in the present study, while the reaming patients (15%) with negative PCR test had probable or strongly suspected COVID-19 pneumonia based on clinical features and history, radiological findings, and clear epidemiological history.
Currently, it has been found that the PCR testing for COVID-19 has limited sensitivity, whereas lung CT may reveal early pulmonary alterations consistent with COVID-19 infection in patients with an initial negative PCR exam. 26 We did not assess the possibility of myocarditis because of the absence of data on serum markers and echocardiographic examination for most of our enrolled patients because of logistical limitations. The specific rhythm type that occurred in those who died of COVID-19 was not reported in medical records because of a lack of telemetry information or serial ECGs.
Therefore, we cannot verify the specific type of cardiac rhythm or arrhythmic events that occurred during ICU stay or prior to death.
Data from larger populations are required to further confirm the role of ECG markers as a clinical predictor in the long-term follow-up studies.

| CON CLUS ION
COVID-19 pneumonia patients with baseline ECG repolarization changes, particularly increased QTc interval, were at increased risk for in-hospital cardiac arrest, prolonged length of ICU stay, and extensive lung injury. Repolarization abnormalities on baseline ECG may be useful prognostic markers in patients with COVID-19 pneumonia.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no conflict of interest.