Index of cardio-electrophysiological balance and Parkinson disease

Abstract

Neurodegeneration of the autonomic nervous systems due to Parkinson disease (PD) may lead to increase in the QT duration. In recent years, a new parameter index of cardio-electrophysiological balance (ICEB) was found. ICEB is a significant parameter of medicine related dysrhythmia. The purpose of this research is to assess ICEB in PD. Twenty-eight PD cases and 26 controls participated in our investigation. First diagnosed PD patients were registered in the research. The symptom progression of PD was assessed Modified Hoehn and Yahr Scale. Analyzed ECG variables are QRS, PR, QT, corrected QT (QTc) interval, ICEB and corrected index of cardio-electrophysiological balance (ICEBc). All cases had sinus rhythm. ICEB was analyzed by the ratio of QT/QRS. ICEBc was analyzed by the ratio of QTc/QRS. Twenty-eight PD cases participated in this research. Among PD cases, 15 patients were female (53.5%). The mean age of PD patients are 59.03 ± 9.94 years. There was no important difference between groups with respect to the clinical variables. The Modified Hoehn and Yahr Scale was appreciably higher in the PD group than the Control group. The heart rate of the PD group was significantly lower than that of the control group. PR intervals and QRS duration were similar in both groups. QT and QTc duration were significantly longer in PD patients. Also, the ICEB and ICEBc variables were appreciably higher in PD cases. The findings of our investigation suggest that ICEB is related to PD. ICEB can help to evaluate arrhythmia risk in patients with PD.

1. Introduction

Parkinson disease (PD) is a chronic progressive neurodegenerative disease.^[1] PD occurs as a result of the destruction of nigrostriatal dopaminergic neurons. The prevalence of patients with PD increases with age. PD disease occurs in approximately 1% of the population over 60 years of age. PD is more frequent in male patients. PD can cause both autonomic nervous systems (ANS) and motor symptoms. Motor findings in PD patients are rigidity, tremor and bradykinesia. Symptoms related to ANS in patients with PD are common in the cardiovascular, genitourinary and gastrointestinal systems. Cardiovascular diseases are common in patients with PD. These diseases are ANS dysfunction, ischemic heart disease, sudden cardiac death and cardiomyopathy. ANS dysfunction is an important causes of cardiovascular complications in PD cases. The frequency of cardiovascular ANS dysfunction in patients with PD is 25% to 35%. The most frequent cardiovascular complication in PD patients are orthostatic hypotension. Neurodegenerative pathology in PD affects the sympathetic ganglia, cardiac parasympathetic and sympathetic and nerves. ANS dysfunction can be seen in both the early and late phases of PD.^[2] Both sympathetic and parasympathetic systems can be affected in PD. Both central and peripheral parts of the ANS can be affected. Cardiovascular symptoms due to ANS involvement are frequent in PD patients.^[3] Cardiovascular abnormalities were associated with age, duration of disease and degree of ANS involvement in patients with PD. Prior investigations have found that a increase in heart rate before the primary findings of PD develop.^[4,5] Sudden deaths due to autonomic dysfunction have been reported. Ventricular arrhythmias is a significant reason of sudden cardiac death. Early diagnosis of patients at high risk of sudden cardiac death is very important. It has been reported that the QT duration is prolonged in these patients. QT interval measures cardiac depolarization and repolarization. Neurodegeneration of ANS due to PD may lead to increase in the QT duration.^[6] Increasing in the QT duration can lead to fatal arrhythmias. In some studies, it has been shown that QT prolongation may occur in cases with PD. Prior studies have suggested that the reason for QT prolongation in patients with PD is due to neurodegeneration in cardioselective neurons. In several studies, it has been suggested that QT prolongation is associated with the Hoehn and Yahr scale (HYS) of patients with PD.^[7] Corrected QT (QTc) evaluation alone may not always be sufficient to determine the risk of developing non torsadogenic VT/VF. Therefore new biomarkers are needed. In recent years, a new parameter-index of cardio-electrophysiological balance (ICEB) between the action potential of cardiac repolarization and depolarization was found.^[8,9] ICEB is a significant parameter of medicine related dysrhythmia. ICEB is calculated as QT duration divided by QRS interval. ICEB describes the equilibrium between cardiac repolarization and depolarization. The purpose of this research is to assess of ICEB in PD.

2. Materials and methods

Our investigation is retrospective research. Twenty-eight PD cases and 26 healthy controls participated in our investigation (Table 1). Diagnosis of PD was performed in accordance with the definition criteria for PD of the United Kingdom Parkinson Disease Society Brain Bank.^[7] The symptom progression of PD was assessed by Modified HYS.^[10] First diagnosed PD patients were registered in the research. PD cases did not take any anti-Parkinson medicine before hospitalization. Patients did not use medicine that had cardiac side effects, such as atypical antipsychotic or anti-depressant medicines. Exclusion criteria: history of diabetes mellitus, ischemic heart disease, hypertension, kidney failure, liver disease, electrolyte abnormalities, drugs that prolong QT interval, bundle branch block pattern on ECG. Our investigation was performed retrospectively. Therefore, the patient consent form was not obtained. This research was accepted by the ethics committee of Health Sciences University of Turkey, Gazi Yaşargil Education and Research Hospital with the number 355-2023.

Table 1.

Baseline clinical and laboratory characteristics of the study groups.

Variables	Parkinson disease patients (n = 28)	Control group (n = 26)	P value
Age (yr)	59.03 ± 9.94	56.63 ± 8.95	.514
Gender (F/M)	15/ 13	16/ 10	.724
Modified Hoehn and Yahr Scale	1.67 ± 0.62	0	.000
Urea (mg/dL)	44.42 ± 18.43	38.50 ± 13.37	.211
Creatinine (mg/dL)	0.85 ± 0.22	0.78 ± 0.14	.720
eGFR (mL/min/1.73 m2)	79.1 ± 12.5	74.2 ± 9.4	.680
Glucose (mg/dL)	126.67 ± 37.23	109.25 ± 25.36	.062
Total protein (g/L)	71.5 ± 13.6	76.9 ± 12.5	.779
Albumin (g/L)	38.2 ± 7.4	41.3 ± 8.1	.581
Sodium (mmol/L)	141.2 ± 3.7	143.2 ± 3.4	.274
Potassium (mmol/L)	4.21 ± 0.68	4.36 ± 0.52	.324
Calcium (mg/dL)	9.23 ± 0.42	9.58 ± 0.51	.651
Hemoglobin (g/dL)	13.21 ± 1.50	14.32 ± 1.40	.273
Total cholesterol (mg/dL)	186.43 ± 31.63	168.27 ± 39.97	.097
LDL cholesterol (mg/dL)	109.73 ± 25.49	92.72 ± 32.23	.056
HDL cholesterol (mg/dL)	43.81 ± 11.96	41.71 ± 9.74	.335
Triglyceride (mg/dL)	164.56 ± 67.23	138.77 ± 54.23	.330

F = female, M = male, eGFR = estimated glomerular filtration rate.

2.1. Electrocardiographic variables

ECG (Schiller Cardiovit AT-102 G2, Feldkirchen, Germany) device was adjusted at a gain of 10 mm/mV and rate of 25 mm/second. ECGs were analyzed by a cardiolog who was unknowing of the clinical parameters. Analyzed ECG variables are QRS, PR, QT, QTc interval, ICEB and corrected index of cardio-electrophysiological balance (ICEBc). All cases had sinus rhythm. The QTc parameter was measured according to the Bazett formula: QTc = QT √ (R-R interval). ICEB was analyzed by the ratio of QT/QRS. ICEBc was analyzed by the ratio of QTc/QRS.

2.2. Statistical analysis

The SPSS 18.0 statistical program was used for data analysis. Power analysis and sample size were made with G*power 3.1.9.7 program. We calculated that a minimum of 24 patients were sufficient for the study at 0.05 of the alpha (α) error value and at 95% of the research power. All clinical and laboratory variables were analyzed. The Kolmogorov-Smirnow test was utilized for the distribution of variables. The continuous variables with normally distribution were analyzed with the Independent-Samples t test. The continuous variables with non-normally distribution were analyzed with the Mann–Whitney U test. Analyzes of categorical parameters were calculated with the chi-square test. The correlation analyses were performed with the Spearman test. Linear regression analyses were used. The receiver operating characteristic (ROC) analysis was performed to assess the ICEBc and QTc as estimating arrhythmic risk. A P value < .05 was considered statistically significant.

3. Results

Twenty-eight PD cases participated in this research. Among PD cases, 15 patients were female (53.57%). The mean age of PD cases are 59.03 ± 9.94 years. The duration of the PD was between 2 months and 15 months. The clinical variables of control groups and PD patients are shown in Table 1. There were no important differences between groups with respect to the clinical variables. The Modified HYS was appreciably higher in the PD group than the Control group. In terms of laboratory variables (urea, creatinine, eGFR glucose, total protein, albumin, sodium, potassium, calcium, hemoglobin and lipid parameters), there were no differences between the control groups and PD patients (P > .05).

3.1. ECG variables

Table 2 shows electrocardiographic findings. The heart rate of the PD group was significantly higher than that of the control group. PR intervals and QRS duration were similar in both groups. QT and QTc duration were significantly longer in PD patients. Also, the ICEBc and ICEB variables were significantly higher in PD cases. Heart rate, ICEB, QT, ICEBc and QTc variables were positively correlated with Modified HYS (Table 3). According to analyses of linear regression, the heart rate, ICEB, QT, ICEBc and QTc were related to the Modified HYS (Table 4). In accordance with the ROC curve of ICEBc to estimate arrhythmic risk in the PD patients, when 4.14 was set as the cutoff point. ICEBc demonstrated the best estimating arrhythmic risk with the ROC analysis (sensitivity: 74.1% and specificity: 71.8%, AUC: 0.756, P = .037). In accordance with the ROC curve of QTc to estimate arrhythmic risk in PD patients, when 432.6 was set as the cutoff point. QTc demonstrated the best estimating arrhythmic risk with the ROC analysis (sensitivity: 69.7% and specificity: 67.2%, AUC: 0.621, P = .043).

Table 2.

ECG parameters of the study groups.

Variables	Parkinson disease patients (n = 28)	Control group (n = 26)	P value
Heart rate (beats/min)	81.26 ± 16.93	71.13 ± 12.71	.041
PR interval (ms)	178.2 ± 28.5	175.4 ± 25.7	.526
QRS duration (ms)	97.1 ± 14.7	95.8 ± 13.2	.290
QT interval (ms)	397.8 ± 42.5	381.4 ± 35.8	.036
QTc interval (ms)	458.6 ± 37.6	414.0 ± 28.3	.023
ICEB (QT/QRS)	4.34 ± 0.26	3.95 ± 0.19	.014
ICEBc (QTc/QRS)	4.71 ± 0.46	4.27 ± 0.38	.019

ICEB = index of cardio-electrophysiological balance, ICEBc = corrected index of cardio-electrophysiological balance, QTc = corrected QT.

Table 3.

Correlation analysis between Modified Hoehn and Yahr Scale and ECG parameters in Parkinson patients.

Variables	R	P value
Heart rate (beats/min)	0.35	.032
QT interval (ms)	0.33	.019
QTc interval (ms)	0.39	.005
ICEB (QT/QRS)	0.42	.024
ICEBc (QTc/QRS)	0.48	.010

ICEB = index of cardio-electrophysiological balance, ICEBc = corrected index of cardio-electrophysiological balance, QTc = corrected QT.

Table 4.

Linear regression analysis between Modified Hoehn and Yahr Scale and ECG parameters in Parkinson patients.

Variables	Β	P value
Heart rate (beats/min)	0.317	.037
QT interval (ms)	0.298	.027
QTc interval (ms)	0.417	.042
ICEB (QT/QRS)	0.369	.015
ICEBc (QTc/QRS)	0.475	.032

ICEB = index of cardio-electrophysiological balance, ICEBc = corrected index of cardio-electrophysiological balance, QTc = corrected QT.

4. Discussion

Cardiovascular complications in PD cases are related with duration of PD disease, age and severity of ANS involvement. Degeneration of sympathetic ganglia and cardiac sympathetic nerves leads to changes in heart rate and QT parameters. Cardiac arrhythmias can be seen in patients with PD. The most common causes of cardiac arrhythmias are autonomic nervous system dysfunction.^[11] In the present study, according to the PR interval, there is no significant difference between the Control group and the PD group. Whereas, Mochizuki H et al found that PD patients have a prolonged PR interval.^[12] Zhong LL et al found that PR prolongation correlated with Hoehn–Yahr classification.^[13]

Mochizuki H et al found that the modified YHS was positively correlated with the QRS duration.^[12] In our investigation, according to the QRS duration, there is no significant difference between the Control group and the PD group. Alonso et al found that decreased heart rate variability was related to an increased risk of PD.^[5] In our investigation, we found that heart rate was significantly longer in the control group than in the PD group. We found that the Modified HYS was positively correlated with heart rate. Also, based on analyses of linear regression, the modified HYS was significantly related to the heart rate.

The QT parameter contains ventricular repolarization and depolarization time. The cause of QT prolongation is cardiac autonomic dysfunction.^[14] The QT interval prolongation leads to increased cardiac mortality.

Ishizaki et al found that PD cases had a high rate of long QTc.^[15] Also, Oka et al suggested that long QTc was appreciably higher in the PD cases than the Control group.^[16] A review of ECGs shows that QTC prolongation was significantly higher in non-survivor PD cases than in a control group.^[17] In this research, we found that QT and QTc parameters were appreciably prolonged in the PD group than in the control group. QT and QTc parameters were positively correlated with Modified YHS. We found that the QT and QTc parameters were independently related to the Modified YHS with respect to analyses of linear regression. Previous studies and our research found that PD is a risk parameter for long QT.^[18,19]

However, in our study, the QT interval was within normal limits in patients with PD. Therefore, a normal QT value can not rule out the arrhythmia risk of PD patients. QT interval calculates only the cardiac action potential repolarization phase. However, ICEB calculates both the action potential of cardiac repolarization and depolarization phases. Therefore, ICEB can better estimate the cardiac arrhythmic risk than the QT parameter.^[20] High ICEB values are related to lethal ventricular arrhythmia.^[21] This is the first research to our knowledge to evaluate the association between ICEB and PD. In our investigation, we found that ICEB and ICEBc variables were appreciably higher in the PD cases than in the control group. ICEB and ICEBc were positively correlated with the Modified HYS. In accordance with analyses of linear regression, the ICEB and ICEBc were found to be related to the Modified HYS. The causes of high ICEB levels in PD cases may be owing to to cardiac ANS dysfunction. The cardiac autonomic nervous system is a significant regulator of ventricular repolarization.^[22] Prior researches found that cardiac ANS are a significant causes of cardiac arrhythmia.^[23,24]

5. Study limitations

Our research is a retrospective and single-center research.

6. Conclusion

The findings of our investigation suggest that ICEB is related to PD. ICEB can estimate arrhythmia risk in PD patients. Cardiac ANS dysfunction should be evaluated in PD patients. High-risk patients for sudden death should be diagnosed and treated early. However, further researches are required to confirm our results.

Author contributions

Conceptualization: Unal Ozturk, Onder Ozturk.

Data curation: Unal Ozturk, Onder Ozturk.

Formal analysis: Unal Ozturk, Onder Ozturk.

Funding acquisition: Unal Ozturk, Onder Ozturk.

Investigation: Unal Ozturk, Onder Ozturk.

Methodology: Unal Ozturk, Onder Ozturk.

Project administration: Unal Ozturk, Onder Ozturk.

Resources: Unal Ozturk, Onder Ozturk.

Software: Unal Ozturk, Onder Ozturk.

Supervision: Unal Ozturk, Onder Ozturk.

Validation: Unal Ozturk, Onder Ozturk.

Visualization: Unal Ozturk, Onder Ozturk.

Writing – original draft: Unal Ozturk, Onder Ozturk.

Writing – review & editing: Unal Ozturk, Onder Ozturk.