Effect of dialysis and transplantation on myocardial repolarization parameters and P‐wave dispersion in chronic kidney disease

Abstract Background Chronic kidney disease (CKD) patients are at higher risk for cardiac arrhythmias. The risk of arrhythmia may change with different treatment modalities. We proposed to compare the effects of varied therapy methods on myocardial repolarization parameters (Tp‐e, QT, QTc intervals, Tp‐e/QT, Tp‐e/QTc ratios) and P‐wave dispersion (PWD) in patients with CKD. Methods Three groups were formed from the patients aged between 18 and 65 years, as Group 1 consisting of CKD patients receiving hemodialysis (HD) three times a week, Group 2 consisting of predialysis CKD patients and Group 3 consisting of CKD patients who underwent successful transplantation. All patients’ basic demographic data, risk factors, and echocardiographic parameters were recorded, and electrocardiographic repolarization parameters and PWD were analyzed. Results The PR, QT, and QTc intervals were significantly shorter in the transplantation group compared to the other groups (P = .020, P < .001, P = .035; respectively). Tp‐e interval, Tp‐e/QT, and Tp‐e/QTc ratios were significantly higher in the predialysis group compared to the other groups (P < .001, P < .001, P = .001; respectively), while there was no significant variation between the HD and transplantation groups (P > .05). PWD was significantly increased in the predialysis group compared to other two groups (P < .001), while no significant variation between the HD and transplantation groups was observed. Conclusion We found that the Tp‐e interval, Tp‐e/QT, Tp‐e/QTc, and PWD were significantly higher in the predialysis CKD group, but the PR, QT, and QTc intervals were significantly shorter in the transplantation group compared to the other groups. The prognostic significance and prediction of these parameters in arrhythmic events in CKD patients requires further evaluation with long‐time follow‐up.


| INTRODUC TI ON
Chronic kidney disease (CKD) is characterized by decreased glomerular filtration rate (GFR) (60 mL/min/1.73 m 2 ) and/or the presence of renal damage, such as microalbuminuria, for more than 3 months. 1 Cardiovascular diseases (CVD) are the major cause of morbidity and mortality in patients with CKD. 1 Coronary artery disease, heart failure, pericarditis, atrial fibrillation (AF), and arrhythmias are the most common CVD causing death as a result of CKD. 1,2 Increased risk factors such as diabetes mellitus (DM), hypertension, hyperlipidemia, left ventricular hypertrophy, myocardial fibrosis, arterial stiffness, progression of atherosclerosis, and changes in the concentrations of serum electrolytes are the main contributing factors. 1,2 The risk of cardiovascular mortality and arrhythmias may be changed with different treatment modalities in patients with CKD. 2 Several studies have demonstrated that hemodialysis (HD) affects a variety of electrolyte, fluid, and acid-base parameters, as well as electrocardiography (ECG) results. 3 Some ECG changes are used as a predictive factor for arrhythmia. The peak to end interval of T wave (Tp-e) is a measure of trans-myocardial distribution of repolarization and may be related to dangerous rhythm irregularity and ventricular arrhythmias. 4,5 Again, raised Tp-e/QT ratio is related to reentry mechanism for underlying pathophysiology in arrhythmic events. [6][7][8] Myocardial repolarization parameters are evaluated with QT interval, corrected QT (QTc), Tp-e interval, Tp-e/QT, and Tp-e/QTc ratio. The increase in these parameters is related with malignant rhythm disorders and sudden cardiac death. 7,8 P-wave dispersion (PWD) defined as the prolongation of interatrial and intraatrial conduction duration as a result of irregular spread of sinus beats are well-known predictors of AF and raised in patients with paroxysmal AF. [9][10][11] In this study, we proposed to compare the effects of different treatment strategies on myocardial repolarization parameters and P-wave dispersion in patients with CKD who received HD, patients with CKD in the predialysis period, and patients with CKD who underwent renal transplantation.

| Study population and study protocol
This study was a cross-sectional and observational study. A total of 120 CKD patients followed-up at the Nephrology Outpatient Clinic were directed to our clinic. Three groups were created from patients aged between 18 and 65 years, as Group 1 (40 patients) including CKD patients receiving HD three times a week, Group 2 (40 patients) consisting of predialysis CKD patients (GFR < 30 mL/ min/1.73 m 2 ) and Group 3 (40 patients) including CKD patients who underwent a successful transplantation (GFR > 60 mL/min/1.73 m 2 ).
The exclusion parameters included a history of hypertrophic or restrictive cardiomyopathy, previous myocardial infarction, bypass operation history, low ejection fraction (EF < 50%), AF on ECG, QRS duration ≥120 msn, chronic pulmonary disease, severe liver disease, severe obesity (BMI ≥ 40 kg/m 2 ), significant valvular disease or a history of valvular surgery, poor-quality visualization on echocardiography, constrictive pericarditis, severe pericardial effusion, pregnancy, a history and/or findings of amyloidosis, electrolyte abnormalities (K, Na, Ca abnormalities) or receiving treatment because of the abnormality, and a history of kidney rejection. Again, patients with frequent palpitations or a detected paroxysmal AF attack were excluded. Informed consent was obtained from all patients.
All patients' basic demographic data, age, height, weight, systolic and diastolic blood pressure, risk factors such as DM, hypertension and smoking, and CKD duration were questioned and recorded. The duration of dialysis and duration of renal transplantation were determined. Body mass index (BMI) was measured by dividing body weight in kilograms by the square of the height in meters (kg/m 2 ).
Laboratory parameters were evaluated in blood taken after 12 hours of fasting. Patients were routinely followed-up by the department of nephrology, and no abnormalities were found in their electrolytes such as calcium, potassium, magnesium, and sodium. GFR was calculated using the Modification of Diet in Renal Disease (MDRD) formula. All data were collected on a day between dialysis days in the HD group.

| Electrocardiography
Electrocardiography papers were recorded in a quiet room after 5 minutes of rest, with 20 mm/mV amplitude and 50 mm/s rate from an ECG machine (Cardiovit AT-102 ECG, Schiller, Switzerland). All ECG papers were scanned and transferred to a computer. Adobe Photoshop software was used for 400% magnification of the parameters. Then all the parameters were analyzed by two blinded cardiologists. All twelve lead electrodes were analysed, but the V5 and DII leads were evaluated more detailed due to best reflects of apicalbasal and interventricular distribution of repolarization. 9 The Tp-e interval may be described as the distance from the highest amplitude of the T wave to its return to the isoelectric line.
The QT interval was defined as the interval from the first deviation of the QRS wave to the end of the T wave. The R-R interval was measured and used to compute the heart rate and to correct QT distance (QTc) with Bazett's formula (QT interval/√(RR interval)). The P-wave times (Pmax and Pmin) were defined as the time from the beginning of the P-wave to the end of the P-wave according to the isoelectric line. All twelve lead electrodes were analyzed, and the difference among Pmax and Pmin was calculated and described as P-wave dispersion (PWD = Pmax − Pmin). For each parameter, the ECG data was measured average three times.
Intraobserver and interobserver variability for myocardial repolarization parameters and P-wave dispersion were assessed by repeating the measurements of 10 randomly selected individuals from each group. These parameters were reevaluated by the same physician at least 1 month later for intraobserver variability and by another one blinded to the data of the subjects for interobserver variability. Intraobserver and interobserver variability was lower than 5.0% and nonsignificant (P > .05) for all myocardial repolarization parameters and P-wave dispersion.

| Echocardiography
The echocardiographic evaluation was done in the left side de-

| Statistical analysis
The data of patients were evaluated with IBM SPSS 20 (SPSS Inc, Chicago, IL, USA) program. In terms of variables suitability for normal distribution was analyzed using visual histograms and Abbreviations: BMI, body mass index; BP, blood pressure; CKD, chronic kidney disease.
Bold values indicate statistically significant. a,b In pairwise comparisons between groups, there is no difference between groups with the same character.

| RE SULTS
Demographic data for study in the three groups are summarized in Table 1. Patients in the transplantation group were younger, while there was no statistically important variation among the HD and predialysis groups. BMI values were lower in the HD group compared to the predialysis group, while no significant difference was found between the other groups. Blood pressure parameters were lower in the transplantation group compared to the predialysis group, while no significant variation was found compared to the HD group. Again, no statistically significant variation was found between the HD and predialysis groups. No statistically significant variation was found among the groups in terms of heart rate, DM, hypertension, and smoking risk factors (Table 1).
Of the patients in the transplantation group, 82.5% (n = 33) received dialysis. Among these patients, 80% (n = 32) had living donors and 20% (n = 8) cadaver donors. The mean duration of dialysis before transplantation was found as 3 ± 4.3 years, and the mean time after transplantation was 3 ± 2.2 years. In the HD group, the mean duration of dialysis was 4.9 ± 4.5 years. In the predialysis group, duration of the diagnosis was found as minimum 1 and maximum 21 years.
The median GFR value was calculated as 12 (6-  to the other groups (P < .001, P < .001, P = .001; respectively), no significant variation was observed among the HD and transplantation groups (P > .05) ( Table 3; Figure 1). The Pmax was significantly lower in the transplantation group compared to the predialysis group (P = .009), and no significant variation was observed between the other groups (P > .05). The Pmin was significantly lower in the predialysis group compared to the HD group (P = .001), and no significant variation was observed among the other groups (P > .05). PWD was significantly increased in the predialysis group compared to the other two groups (P < .001), while no significant variation was found between the HD and transplantation groups (Table 3; Figure 1).

| D ISCUSS I ON
In our study, we compared the Tp-e interval, Tp-e/QT ratio, Tp-e/QTc ratio, QT, QTc interval, and P-wave dispersion between the different treatment strategies in CKD patients. To our knowledge, there is no previous direct research compared among their three groups and we found that the PR, QT and QTc durations were significantly shorter in the transplantation group compared to the predialysis and HD groups. Furthermore, the Tp-e interval, Tp-e/QT, Tp-e/QTc ratio, and PWD were significantly higher in the predialysis CKD group compared to the transplantation and HD groups.
Chronic kidney disease patients are known to be at higher risk for CVD and also lethal arrhythmias and sudden cardiac death. 1,3,13 Furthermore, CVD are related to poor clinical endpoints in CKD pa-

| Study limitations
Our study did not have a large patient population. We measured the electrocardiographic parameters from computer with magnified images. But this measurement technique has been performed and accepted in many previous studies. We evaluated the different treatment approaches on predictors of arrhythmias, such as PWD, QTc, Tp-e, and Tp-e/QT in CKD patients, but we could not perform a long-term ambulatory cardiac rhythm analysis and follow the arrhythmic events. Also, possible effects of immunosuppressive drugs used by the patients in the transplantation group were not considered. Another limitation of our study is that ambulatory electrocardiographic monitoring cannot applied to detect paroxysmal AF attack and evaluate the dynamic change of repolarization parameters.

| CON CLUS ION
Myocardial repolarization parameters (Tp-e interval, Tp-e/QT and Tp-e/QTc ratio) and P-wave dispersion increased in predialysis CKD patients compared with transplantation and HD patients. However, the PR, QT, and QTc intervals were significantly shorter in the transplantation group compared to other groups. Our results may suggest that the predialysis group is at most increased risk for the ventricular arrhythmias and least increased risk for the transplant patients.
The prognostic significance and prediction of these parameters in arrhythmic events in CKD patients requires further evaluation with long-term follow-up and large-scale prospective studies.

ACK N OWLED G EM ENT
Thanks to all doctors and nurses of our department and Nephrology department.

CO N FLI C T O F I NTE R E S T
None declared.

S TATE M E NT O F E TH I C S
This study was approved by the Institutional Ethics Committee. The study was performed in accordance with the Declaration of Helsinki.