Assessing Autonomic Nervous Function by Heart Rate Variability and Heart Rate Turbulence in Patients with Acute Ischemic Stroke.

BACKGROUND: Acute ischemic stroke (AIS) induces adverse effects on the cardiovascular system by affecting the autonomic nervous system (ANS).
OBJECTIVES: This study aimed to determine whether the parameters of heart rate variability (HRV) and heart rate turbulence (HRT) differed in patients with AIS as compared to that in the control group. Furthermore, we aimed to determine the differences in the involvement of the ANS between right and left hemisphere (LH) strokes.
METHODS: A total of 148 [74 right hemispheres (RH) and 74 left hemispheres] patients with AIS and 80 control subjects were included in the study. The Holter device was used to obtain elcctrocardiogram readings for over 20 h from all patients. Results of HRV and HRT parameters [Tonset (TO) and Tslope (TS)] were acquired through an automatic analysis of the program.
RESULTS: All HRV parameters were found to be low in patients with AIS (P < 0.05, for all parameters). TO and TS were disrupted in 99 patients with AIS (66.8%) and in 15 control subjects (18.7%) (HRT-1 and HRT-2 groups, P = <0.001). HRV parameters were detected to be similar in patients, irrespective of the left or right infarct. TO and TS were normal in 31 patients (41.9%) with left hemisphere localization and in only 18 patients (24.3%) with right hemisphere localization.
CONCLUSIONS: Combined evaluation of HRV and HRT parameters may provide important information regarding the alterations in the ANS in patients with AIS. The utility of HRT in the determination of ANS alterations in patients with AIS should be investigated in larger future prospective studies. Copyright:

INTRODUCTION

Ischemic stroke is one of the most common causes of death worldwide.[1] The autonomic nervous system (ANS) has been shown to be affected after a stroke. Classically, this effect is hypothesized to be due to an increase in the sympathetic tone and a decrease in the parasympathetic tonus due to catecholamine discharge.[2] However, another hypothesize that has been deliberated is that ANS dysfunction occurs due to the disruption of the physiological asymmetry between the right and left cerebral hemispheres in the modulation of ANS activity of the central nervous system.[3] Remarkably, Brunetti et al. investigated the changes of heart rate variability (HRV) during wakefulness in their recent study and suggested that ANS dysfunction observed in acute ischemic stroke (AIS) may be the result of the loss of circadian modification of sympatho-vagal balance.[4] Overall, although the exact mechanism is not fully understood, several studies remark that the autonomic dysfunction thus created, especially the one occurring in the acute phase of the stroke, increases cardiac mortality and morbidity.[5678]

HRV and heart rate turbulence (HRT) are reliable Holter parameters that indicate cardiac autonomic function. HRV (a measure of the variations of the interval between consecutive heartbeats) enables an independent measurement of parasympathetic and sympathetic components of the ANS. HRT is defined in two parts: i) decrease in blood pressure due to decreased cardiac filling after ventricular premature beats (VPBs) and increase in heart rate by means of baroreflex mechanism (turbulence onset-TO) and ii) initiation of baroreflex response by restoring blood pressure to a normal level and restoring normal heart rate through parasympathetic signals from the brain (turbulence slope-TS).[910]

HRV and HRT may provide information regarding tendencies of cardiac arrhythmias and increased mortality risk.[10111213] To the best of our knowledge, HRT parameters of patients with previous AIS have never been evaluated. Combined evaluation of HRV and HRT in Holter elcctrocardiogram (ECG), which is an easily accessible and a noninvasive examination, may provide strong data on the cardiac prognosis of these patients. This study, therefore, aimed to determine whether the HRV and HRT parameters differed in patients with AIS as compared to that in the control group. The study also intended to investigate if the hemisphere with ischemia has any impact on these parameters.

MATERIALS AND METHODS

This prospective and cross-sectional study included 148 patients (85 men and 63 women, mean age 66.72 ± 13.07) admitted to the neurology clinic between September 2018 and April 2019 with the diagnosis of AIS. The diagnosis was made by neurologists through clinical evaluation and findings of magnetic resonance imaging. In addition, 80 (40 men and 40 women, mean age 65.30 ± 10.71) control participants having similar demographic features as the stroke group were also included in the study. The control group consisted of patients who admitted to cardiology polyclinic due to complaints of palpitation.

Patients with a previous cerebrovascular event history, kidney failure, or renal malignancy, those diagnosed with atrial fibrillation (AF) or AF detected in Holter monitor, having coronary artery disease, ejection fraction <%50, severe heart valve disease, complete or incomplete branch block, resistant or uncontrolled hypertension, acute infections, and hypo- and hyperthyroidism were excluded from the study. Besides, none of the patients were using beta-blockers, Ca-channel blockers, or antiarrhythmic medications that may have affected the ANS.

Echocardiography was performed 2–5 days after the AIS patients were admitted to the hospital and the ECG records were evaluated together with laboratory and Holter results. The Holter monitors were performed within the first week of the event in all patients with AIS. A total of 89 participants were excluded from the study as they had less than five VPBs [Figure 1]. All results were obtained from hospital records. Standard echocardiographic evaluations in the parasternal and apical positions were also performed. The ejection fraction was calculated by using the modified Simpson method.

Figure 1

Patient selection

The local ethical committee reviewed and approved the study (approval no: 030.04.01) according to the ethical principles for human investigations, and a written consent form was obtained from all participants, as indicated in the Declaration of Helsinki.

Heart rate variability and heart rate turbulence analysis

All subjects underwent Holter ECG monitoring (GE medical systems information technologies, Inc., software version 8.0.3, Milwaukee, USA). Recordings lasting more than 20 h and of sufficient quality for evaluation were analyzed. None of the patients were on sedation or ventilation during the time of Holter monitoring. A physician completely blind to the study assessed the Holter ECG records. All recordings were transferred to the computer. They were firstly analysed by the Holter program and, thereafter, manually screened. The VPBs were evaluated one by one and the artifacts diagnosed as VPBs were deleted.

HRT and HRV parameters were measured by an automatic computer program. HRV parameters time-domain measures included the standard deviation of the normal-to-normal (NN) interval (SDNN), the standard deviation of the average NN interval (SDANN) calculated over 5 min periods, average standard deviation of the averages of all NN RR intervals in all 5-min segments of the entire recording (ASDNN), the square root of the mean squared differences of successive NN intervals (rMSSD), and the division of the number of interval differences of successive NN intervals of more than 50 ms by the total number of NN intervals (pNN50); and frequency-domain measures included very low frequency (VLF) at frequency between 0.0033 and 0.04 Hz, low frequency (LF) at frequency between 0.04 and 0.15 Hz, high frequency (HF) at frequency between 0.15 and 0.4 Hz, and low frequency/high-frequency ratio (LF/HF). Time-domain indices of HRV quantify the amount of variability in measurements of the interbeat interval, which is the time period between successive heartbeats. Frequency-domain measurements estimate the distribution of absolute or relative power into different frequency bands.

Two phases of HRT were quantified numerically as TO and TS. The patients were in sinus rhythm at least 70% of Holter recording and ectopic beats were <10%. TO defined as the percentage change RR intervals after VPBs compare to pre-VPB period. To represents the initial acceleration of heart rate (HR) following VPB. TS was defined as the maximum positive regression slope obtained over any five consecutive sinus RR intervals within the first 15 sinus RR intervals following the VPB. TS represents the late deceleration of HR after the VPB. TO <% 0 (negative TO) and TS >2.5 ms/RR (positive TS) were accepted as normal values.[12] The patients were divided into three groups as follows: i) patients with normal HRT (HRT-0), ii) patients with abnormal TO or TS (HRT-1), and iii) patients with abnormal TO and TS (HRT-2).

All analyses were made according to the standards determined by the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology.[9]

Statistical analyses

Data were analyzed by using SPSS 21.0 Statistical Package Program for Windows (SPSS Inc., Chicago, IL, USA). The variables were examined using analytical methods (the Kolmogorov–Simirnov test) to determine whether or not they were normally distributed. Descriptive analyses were presented using means and standard deviations for normally distributed variables (parametric) and medians (interquartile range) for the nonnormally (nonparametric) distributed variables. Categorical variables were presented using percentages. The independent t-test was used for comparisons between groups regarding the means of the numerical variables, whereas the Mann–Whitney U test was used for the comparison of medians. Pearson’s Chi-square analysis was used to compare categorical data. Pearson’s correlation test was used for the normally distributed data, and the Spearman’s correlation test was used for data not showing a normal distribution. All tests of significance were two-tailed. Statistical significance was defined as P < 0.05.

RESULTS

The basal characteristics of the participants are depicted in Table 1. Infarction area was observed to be on the left hemisphere in 50% (74) of the patients with AIS and there was no significant difference between basal characteristics of both the groups. In addition, the maximum, minimum, mean heartbeats, and VPBs counts were found to be similar in both groups [Table 2].

Table 1

Baseline characteristics and laboratory findings of the study participants

	Total (n=228)	PAIS (n=148) (65%)	Control (n=80) (35%)	P
Age	66.22±12.29	66.72±13.07	65.30±10.71	0.40
Sex (male), n (%)	125 (54.8)	85 (57.4)	40 (50)	0.28
Hypertension, n (%)	132 (57.9)	92 (62.2)	40 (50)	0.08
Diabetes mellitus, n (%)	72 (31.6)	48 (32.4)	24 (30)	0.71
Smoker, n (%)	53 (23.2)	31 (20.9)	22 (27.5)	0.26
Hyperlipidemia	44 (19.3)	27 (18.2)	17 (21.3)	0.58
EF %	60.00 (56.00 63.00)	60.00 (55.00 63.00)	61.00 (58.00 63.00)	0.13
Urea	37.00 (29.00 44.75)	38.00 (31.25 46.00)	34.00 (28.00 40.00)	0.002
Creatine	0.81 (0.70 1.00)	0.80 (0.70 0.96)	0.87 (0.72 1.00)	0.12
Sodium	138.00 (137.00 140.00)	138.00 (137.00 140.00)	138.00 (137.00 140.00)	0.83
Potassium	4.16±0.42	4.18±0.40	4.20±0.45	0.82
WBC (×103/ml)	7.85 (6.52 9.20)	7.80 (6.52 9.00)	8.20 (6.55 10.17)	0.25
Hemoglobin	13.45±1.87	13.44±1.81	13.47±2.00	0.91
PLT	225.35±75.50	201.50±79.46	241.00±66.77	0.12
Neutrophil	5.00 (3.80 6.40)	4.95 (3.52 6.40)	5.10 (4.40 6.30)	0.16
Lymphocyte	1.90 (1.50 2.50)	1.90 (1.50 2.50)	2.04 (1.42 2.60)	0.51
TSH	1.37±0.89	1.37±0.90	1.37±0.87	0.98
Sedimentation rate	14.00 (8.00 22.00)	16.00 (7.25 24.00)	12.50 (9.00 18.00)	0.03
C reactive protein	0.70 (0.40 1.20)	0.70 (0.31 1.38)	0.73 (0.40 1.08)	0.80

PAIS: Patients with acute ischemic stroke, EF: Ejection fraction, WBC: white blood cell, PLT: platelets, TSH: throid-stimulating hormone

Table 2

Holter parameters of the study population

	Total (n=228)	PAIS (n=148) (%65)	Control (n=80) (%35)	P
Minimum HR	46.28±9.23	45.83±9.74	47.11±8.20	0.32
Average HR	74.94±10.70	74.73±11.06	75.32±10.07	0.69
Maximum HR	130.32±23.14	129.46±22.44	131.91±24.46	0.45
Total QRS	101550.22±17625.03	100429.24±19178.07	103624.03±14195.42	0.16
VLF	24.87 (20.05 33.30)	23.19 (18.89 31.16)	29.03 (22.82)	<0.001
LF	18.87 (13.86 27.24)	16.62 (11.12 22.95)	23.20 (18.22 31.97)	<0.001
HF	13.94 (10.17 19.43)	11.57 (8.28 15.16)	18.67 (15.06 23.79)	<0.001
LF/HF ratio	1.44±0.51	1.50±0.58	1.32±0.32	0.002
SDNN	114.32±42.62	96.29±33.15	147.68±37.92	<0.001
SDANN	98.95±43.79	80.68±37.18	132.76±34.00	<0.001
ASDNN	51.00 (39.25 62.75)	46.00 (33.25 58.75)	58.00 (47.00 72.50)	<0.001
rMSSD	33.00 (27.00 42.00)	33.00 (24.00 41.75)	33.50 (30.00 43.75)	0.03
pNN50	11.70 (6.90 20.47)	11.30 (5.00 20.60)	12.70 (9.50 20.47)	0.02
Tonset	0.40 (1.55 to 0.61)	0.03 (0.84 1.00)	1.22 (2.58 0.67)	<0.001
Tslope	3.76 (2.25 6.60)	3.55 (1.60 6.46)	4.10 (2.98 6.76)	0.005
PVBs	15.00 (9.00 77.25)	14.00 (8.00 102.50)	17.00 (10.00 50.25)	0.83

PAIS: Patients with acute ischemic stroke, HR: heart rate, VLF: very low frequency, LF: low frequency power, HF: high frequency power, LF/HF ratio: ratio of power in low/high frequency, Mean NN: the mean of all normal RR intervals, SDNN: standard deviation of normal-to-normal R wave in the entire recording, SDANN: standard deviation of the averages of all normal-to-normal RR intervals in all 5 min segments of the entire recording, ASDNN: average standard deviation of the averages of all normal-to-normal RR intervals in all 5 min segments of the entire recording, RMSSD: root mean square of the mean of the squared difference of two consecutive R-R intervals, pNN50: Percent of the differences between the adjacent normal-to-normal intervals >50 ms, BB50: Total number of instances per hour in which two consecutive RR intervals differ by more than 50 msec, PVBs: Premature ventricular beats

According to the Trial of Org 10172 in Acute Stroke Treatment classification, 57 (38.5%) of them were evaluated as large-vessel atherosclerosis, 26 (17.5) cardioembolic, 48 (32.4%) small vessel occlusion, and 17 (11.5%) stroke of undetermined etiology.

The patients with acute ischemic infarction were found to have higher urea and sedimentation values (P = 0.002, P = 0.03, respectively). All HRV parameters (VLF, LF, HF, SDNN, SDANN, ASDNN, rMSSD, pNN50) were significantly lower in the stroke group (P < 0.05, for all parameters). LF/HF ratio was higher in the stroke group (P = 0.002). TO and TS values differed significantly in the control group and the stroke group (