Fatih Sivri,Mehtap Şencan,Banu Öztürk Ceyhan,Yahya Kemal Içen,Mukremin Coskun,Fatih Aksoy
Prognostic value of R wave peak time in COVID-19 pneumonia
Electrocardiography,R wavepeak time,COVID-19 mortality
Background R wave peak time (RWPT) is also known as intrinsicoid deflection time or ventricular activation time. It shows the conduction time from the endocardium in the ventricle to the epicardium. It provides diagnostic and prognostic information for many cardiovascular diseases, such as RWPT prolongation, left ventricular hypertrophy, volume overload, conduction system abnormalities, and myocardial ischemia. Objectives The aim of this study is to investigate the relationship between COVID-19 mortality and RWPT in superficial ECG. Methods This study retrospectively examined 640 patients diagnosed with COVID-19 and treated in an intensive care unit at a single center between January 2021 and June 2022. All patients included in the study had clinical and radiological characteristics and signs of COVID-19 pneumonia. Results 640 patients included in the study were divided into 2 groups: surviving and deceased. There were 510 patients in the surviving group and 130 patients in the deceased group. The deceased group was found to be significantly older. The number of patients with COPD was higher in the deceased group. Troponin, lactate dehydrogenase (LDH), C-reactive protein (CRP), D-dimer and T-peak to T-end interval(Tpe) and RWPT were found to be significantly increased in the deceased group. In binary logistic regression analysis; age, COPD, LDH, CRP, troponin, D-dimer, Tpe interval, RWPT were determined as independent risk factors for mortality. Conclusions Prolonged RWPT is useful in risk stratification for COVID-19 pneumonia mortality.
Prognostic value of R wave peak time in COVID-19 pneumonia

R wave peak time (RWPT) is also known as intrinsicoid deflection time or ventricular activation time. It shows the conduction time from the endocardium in the ventricle to the epicardium. It provides diagnostic and prognostic information for many cardiovascular diseases, such as RWPT prolongation, left ventricular hypertrophy, volume overload, conduction system abnormalities, and myocardial ischemia. Objectives The aim of this study is to investigate the relationship between COVID-19 mortality and RWPT in superficial ECG.

This study retrospectively examined 640 patients diagnosed with COVID-19 and treated in an intensive care unit at a single center between January 2021 and June 2022. All patients included in the study had clinical and radiological characteristics and signs of COVID-19 pneumonia.

640 patients included in the study were divided into 2 groups: surviving and deceased. There were 510 patients in the surviving group and 130 patients in the deceased group. The deceased group was found to be significantly older. The number of patients with COPD was higher in the deceased group. Troponin, lactate dehydrogenase (LDH), C-reactive protein (CRP), D-dimer and T-peak to T-end interval(Tpe) and RWPT were found to be significantly increased in the deceased group. In binary logistic regression analysis; age, COPD, LDH, CRP, troponin, D-dimer, Tpe interval, RWPT were determined as independent risk factors for mortality.

Prolonged RWPT is useful in risk stratification for COVID-19 pneumonia mortality.

Although COVID-19 infection primarily affects the lungs and causes death due to pneumonia, acute respiratory distress syndrome (ARDS), and multi-organ failure, cardiovascular complications are among the most important causes of death [1]. It has been observed that the prognosis is poor, and mortality is high in patients with cardiac involvement [2]. Cardiac involvement is observed between 22 and 44%, especially in patients with severe infection [3]. As a result of cardiac involvement, myocarditis [4], tamponade [5], acute heart failure [6] arrhythmia(bradycardia-tachycardia) [7], transient ST elevation [8], hypotension, shock and sudden cardiac death.occur [9]. One of the most common cardiac complications is arrhythmia. In a single-center study, arrhythmia was observed at a rate of 19% in COVID-19 patients and was associated with a poor prognosis [10]. R wave peak time (RWPT) is also known as the intrinsicoid deflection time or ventricular activation time. On surface electrocardiography (ECG), it expresses the time from the beginning of the QRS complex to the peak of the R wave and shows the conduction time from the endocardium in the ventricle to the epicardium [11,12]. R wave peak time provides diagnostic and prognostic information for many cardiovascular diseases, such as left ventricular hypertrophy, volume overload, conduction system anomalies, and myocardial ischemia [[13], [14], [15]].Although there are studies in the literature regarding the deterioration of myocardial repolarization related to COVID-19 infection, there is no clear information about mortality [16]. In our study, we investigated whether there is any relationship between COVID-19 mortality and RWPT in superficial ECG and mortality.

This study retrospectively included 640 patients diagnosed with COVID-19 and treated in the intensive care unit between January 2021 and January 2022 in a single center after the approval of the local ethics committee and the Ministry of Health of the Republic of Turkey. The study was conducted in accordance with the Declaration of Helsinki. All patients included in the study had clinical and radiological characteristics and signs of COVID-19 pneumonia. Patients who had previously undergone percutaneous coronary intervention after acute coronary syndrome, patients with coronary artery disease, left ventricular dysfunction, pacemaker implanted, left bundle branch block pattern on ECG, use of anti-arrhythmic drugs, connective tissue disease, atrial fibrillation, abnormal serum electrolyte values, and chronic kidney and liver failure were not included in the study. The COVID-19 diagnosis of all patients was confirmed by polymerase chain reaction (PCR) examined with oropharyngeal swab. Demographic and clinical characteristics of all patients were recorded. All patients were investigated in detail in terms of hypertension, diabetes mellitus (DM), tobacco smoking, previous myocardial infarction, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), and cerebrovascular events (CVE). The diagnostic criteria for chronic obstructive pulmonary disease were accepted as FEV1/FEVC<70% or FEV1 < 70% after inhaled bronchodilator. Chronic renal failure was defined as a glomerular filtration rate of <60 for >3 months. The diagnosis of hypertension was accepted as taking antihypertensive therapy or having at least three measurements above systolic 140 mmHg and diastolic 90 mmHg. The patients who used antidiabetic drugs or had at least two fasting blood glucose measurements above 126 mg/dl were accepted to have diabetes.

Echocardiographic examination of all patients included in the study was performed with the iE33 cardiac ultrasound system (Phillips Healthcare, Best, The Netherlands) and 2.5–5-MHz probes system. The ejection fraction was measured with the modified Simpson method; the modified Bernoulli equation calculated PASP: PASP ¼ 4 VTR2 þ RAP (VTR ¼ peak tricuspid regurgitant velocity acquired by peak systolic pressure gradient across the tricuspid valve; RAP ¼ right atrial pressure estimated according to the size and respiratory variation of the inferior vena cava diameter in the subcostal view).

Superficial 12‑lead ECGs of all patients (Nıhon Kohden Cardiofix V Model ECG-1550 K Device 25 mm/s and standard 1mv/10 mm) were recorded before the treatment of COVID-19 infection and were evaluated by two independent cardiologists who did not know the patient characteristics. Heart rate, P wave time, P-R interval, QT and QTc times, Tpe interval, QRS times, and R wave peak time were measured and recorded. P-R interval was calculated as the time from the beginning of the P wave to the beginning of the QRS complex. The QT interval was measured from the beginning of the QRS complex to the end of the T wave. QT correct distance was measured with the Bazett formula. The QRS interval was calculated from the beginning of the QRS complex to the J point. The Tpe interval was defined as the time interval from the peak of the T wave. R wave peak time was measured as the time from the beginning of the QRS complex to the peak of the R or R' wave. All times were calculated in milliseconds, and the mean values were calculated from 12 leads.

Research data were evaluated using SPSS 21.0 statistical program. The conformity of continuous variables to normal distribution was investigated using visual (histogram and probability graphs) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests). Continuous variables were shown with mean and standard deviation. Categorical variables were shown with numerical values and percentages; the chi-square test was used to show whether there was a difference between them. Student-t-Test was used to compare the continuous variables with parametric characteristics in independent groups, and the Mann-Whitney U Test was used to compare continuous variables with non-parametric characteristics in independent groups. The independent variables for mortality were detected by performing binominal logistic regression analysis with the data whose only change was significant in the analyzes. For statistical significance, the p-value was determined to be <0.05.

A total of 640 patients were included in this study. The patients were divided into two groups: surviving and deceased. There were 510 patients in the surviving group (mean age: 59.5 ± 18.04 58% male, 42% female) and 130 (mean age: 67.6 ± 14.1 57% male, 43% female) patients in the deceased group. While there was no difference between the groups in terms of gender, age was found to be statistically significant in the deceased group. (p:0.001) While there was no difference between the groups in terms of hypertension, diabetes mellitus, and cerebrovascular disease, COPD was found to be statistically higher in the deceased group (p:0.002). When the medical treatments were compared between the groups, no difference was found between the groups. The main clinical and medical treatment characteristics of the groups are shown in Table 1, Table 2 . When laboratory characteristics were compared, troponin (29.7 ± 69.7 vs. 163.03 ± 369.6 p:0.033), LDH (310.6 ± 151.09 vs. 529.7 ± 243.2 p:0.001), CRP (66.9 ± 64.4 vs. 126.06 ± 80.6 p:0.001), and D-dimer (1.11 ± 2.01 vs. 15.8 ± 27.4 p,0.01) was found to be high in the deceased group.(Table 3 ). Electrocardiographic and echocardiographic characteristics are shown in Table 4 . Heart rate (87.6 ± 17.6 vs. 92.2 ± 24.07 p: 0.052), P-R interval (103.83 ± 11.9 vs. 104.08 ± 10.7 p: 0.860), QRS interval (104.9 ± 11.8 vs. 102.6 ± 16.1 p: 0.076), P wave time (90.3 ± 6.8 vs. 89.1 ± 6.07 p: 0.055), QT (395.66 ± 42.85 vs. 383.33 ± 27.63 p:0.105) and QTc (440.80 ± 46.14vs 430.55 ± 43.69 p:0.355) times did not differ significantly between groups. There was no difference between the groups in terms of left ventricular ejection fraction and pulmonary artery pressure (p:0.05). Tpe interval (83.9 ± 18.1 vs. 93.2 ± 16.1 p:0.001) and RWPT (33.01 ± 14.0 vs. 56.9 ± 19.8 p:0.001) were found to be statistically high in the deceased group. Age (OR: 1.035 95%CI:1.001–1.071 p:0.030), COPD (OR: 1.290 95%CI: 1.115–1.355 p:0.004), LDH (OR 1.004 95%CI:1.001–1.025 p:0.001), CRP (OR: 1.018 95%CI:1.010–1.025 p:0.001), troponin (OR:1.010 95%CI:1.005–1.015 p:0.001), D-dimer (OR:1.186 95%CI:1.066–1.320 p:0.002), Tpe interval (OR:1.056 95%CI:1.029–1.083 p:0.001), and RWPT (OR:1.055 95%CI:1.028–1.084 p:0.001) have been shown to be independent risk factors for mortality in binary logistic regression analysis.(Table 5 ).

In our study, the effect of surface ECG findings on mortality in patients with COVID-19 infection was investigated, and several important results were found. The most important of these is that the prolongation of the R wave peak time in the surface ECG is an independent risk factor for mortality. In addition, age, COPD, LDH, CRP, troponin, D-dimer, Tpe interval were determined to be associated with mortality. R wave peak time is a parameter that can be easily measured in surface ECG and provides information about the diagnosis, treatment, and long-term prognosis of various cardiovascular and viral diseases [[12], [13], [14]]. Various mechanisms have been associated with prolonged RWPT. Prolongation of action potential as a result of impaired cellular calcium and potassium conduction, decrease in gap junction density, increased cardiac myocyte sizes, and interstitial fibrosis are accepted as basic pathophysiological mechanisms. In the study of Darouian et al., prolonged RWPT was associated with sudden cardiac death in the long term, independent of ejection fraction [17]. O'neal et al., in their 11-year follow-up study, found that prolonged RWPT showed a better probability of developing heart failure than QRS time, with a 1.4-fold increase in risk for every 10 ms prolongation. In particular, they showed that the prolongation of >45 ms significantly increased the risk [18]. Çekirdekçi et al. found a negative correlation between prolonged RWPT and CD4 count, which is an indicator of disease severity, in HIV-infected individuals. Additionally, prolonged RWPT was associated with subclinical global myocardial dysfunction in patients without overt cardiomyopathy or heart failure [19]. Bayam et al. showed a relationship between prolonged RWPT and the severity of coronary artery disease in non-STEMI patients [20]. Increased comorbidity with aging, impaired immune mechanism, inadequate anti-viral mechanisms, and increased oxidative stress facilitate the progression of COVID-19 pneumonia [21]. In the studies conducted by Wu et al. and Zhu et al., COVID-19 was found to be observed at a rate of 0.4% under the age of 40, 1.3% at the age of 50, 3.6% at the age of 60, 8% at the age of 70, and 14.8% at the age of 80 [22,23]. CRP, one of the most important markers of systemic inflammation, provides essential information about the severity and prognosis of many COVID-19 infections [24].Stinger et al., in their study, associated CRP > 40 mg/l with high mortality [25].Structural damage in the lung caused by COPD, deterioration of local and systemic inflammatory response, increased ACE-2 level, and inadequate anti-viral response facilitates the progression of COVID-19 infection [26].A meta-analysis showed that the risk of progression of COVID-19 infection increased 4.3 times and mortality 1.93 times in the presence of COPD [27]. The concentration and activity of lactate dehydrogenase (LDH), which plays a vital role in intracellular energy production, increase in the blood when cell damage occurs for various reasons. In the published meta-analysis, high LDH level was associated with 6 times increased disease severity and 16 times increased mortality in COVID-19 infection [28]. In many studies, the increase in troponin value, which is the most specific indicator of cardiac damage, has been shown to be associated with increased morbidity and mortality in COVID-19 infections [29]. In a study of 259 patients by Al Abbasi et al., the mortality rate was 52% in the group with high troponin and 10% in the group with negative troponin [30]. D-Dimer is a fundamental biomarker for coagulation and fibrinolysis in the blood, and an increase has been observed in many conditions such as pulmonary intravascular coagulopathy, pulmonary embolism, ARDS, deep vein thrombosis in COVID-19 infections [31]. In the study of Zhang L. et al., among the patients treated in the hospital, mortality was found to be higher in patients with D-dimer>2 ng/dl, and the sensitivity was 92%, and the specificity was 83.3% [32]. Tpe interval is an ECG marker that has recently received close attention. In many studies, transmural dispersion has been shown as an indicator of repolarization abnormality [33]. In the study of Koç M. et al., it was observed that the Tpe interval value prolonged proportionally with the increase in the severity of COVID-19 infection [16]. Although SARS-CoV-2 infection primarily affects the lungs and causes pneumonia and/or ARDS, a higher rate of arrhythmia is observed, especially as the severity of the disease increases. Acute myocarditis and ventricular arrhythmia may be the first clinical manifestation [7]. Arrhythmia develops multifactorial. It may occur as a result of acute myocarditis developing as a result of direct cardiotoxicity, as well as hypopotassemia resulting from widespread inflammation, hypoxia, hypotension, and disruption of the RAS system may cause arrhythmia [[7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]]. IL-6, which increases with cytokine storm due to SARS-CoV-2 infection, causes prolongation of ventricular activation potential by affecting myocardial Herg-K channels [35]. In addition, increasing IL-1 and TNF-alpha creates an arrhythmogenic environment by acting on K and Ca channels in cardiomyocytes. While arrhythmia was observed in 16.7% of all COVID-19 infected patients in a clinical study, arrhythmia was observed in 44% of patients followed up in the intensive care unit [9]. In a retrospective study by Guo T. et al., ventricular arrhythmia was found more frequently in patients with elevated troponin, an indicator of cardiac damage, than in patients with normal troponin [36]. (17.3% vs. 1.5%) In our study, although no difference was found between the groups in terms of ejection fraction, the troponin value was found to be high in the deceased group in the regression analysis. This situation makes us think of left ventricular global ischemia and damage. For this reason, we thought that prolonged RWPT occur in deceased groups.

This study demonstrated that prolonged RWPT was a significant and independent risk factor for mortality from COVID-19 infection. We recommend that a prolonged RWPT not be neglected when evaluating high-risk patients.Further prospective and large-sample studies are warranted to gain a better understanding of the pathogenesis of COVID-19 and the diagnostic and therapeutic value of RWPT in COVID-19 patients.

This study has several limitations. First, the sample size was small, and the study had a retrospective design. In addition, values such as CRP and troponin, associated with subclinical myocardial damage, were not followed up serially. The ECGs of the patients at initial diagnosis were examined, while RWPT changes on ECGs were not examined. The medical treatments of the patients were not questioned in detail and their post-treatment ECG changes were not investigated. A prospective study with a large number of patients is needed to validate the results of this study.

Fatih Sivri: Conceptualization, Methodology, Software, Writing – review & editing. Mehtap Şencan: Visualization, Investigation. Banu Öztürk Ceyhan: Visualization, Investigation. Yahya Kemal Içen: Data curation, Writing – original draft. Mukremin Coskun: Supervision. Fatih Aksoy: Software, Validation.