Article Text
Abstract
Aims To define parameters of autonomic nervous system activity in patients with normal tension glaucoma (NTG).
Methods Ambulatory 24-h ECG (Lifecard CF) and 24-h blood pressure (BP) monitoring (SpaceLab 90207-30) were carried out in 54 patients with NTG (44 women, mean age 59.7) and 43 matched control subjects (34 women, mean age 57.0). Heart rate variability time and frequency domain parameters (low frequency (LF), high frequency (HF) and LF/HF ratio), BP variability (BPV), diurnal and nocturnal BP variables were compared between study groups.
Results Patients with NTG demonstrated higher LF, LF/HF and lower HF values than control subjects for the 24-h, daytime and night-time periods. The mean 24-h, daytime and night-time LF/HF ratios were statistically higher in patients with glaucoma as compared to control subjects ((3.2±1.5 vs 2.2±0.8, p=0.0009), (3.5±1.7 vs 2.7±1.0, p=0.0173) and (2.6±1.7 vs 1.4±0.6, p=0.0001), respectively). There were no statistical differences in the mean BP during the whole day, daytime and night-time, and in BPV (10.4±1.9 vs 10.5±2.1, p=0.790) between study groups. No difference was also found in the percentage decrease in night-time mean BP (12.3% vs 13.6%, p=0.720). ‘Dippers’, ‘non-dippers’ and ‘overdippers’ with NTG showed significantly higher LF/HF ratio as compared to the same subgroups of control subjects.
Conclusions The sympathovagal balance of autonomic nervous system in patients with NTG shifted towards sympathetic activity however with no change of 24-h pattern of BPV as compared to controls.
- Normal tension glaucoma
- autonomic nervous system
- holter electrocardiography
- ambulatory blood pressure monitoring
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- Normal tension glaucoma
- autonomic nervous system
- holter electrocardiography
- ambulatory blood pressure monitoring
Introduction
It is believed that general vascular dysfunction and defective cardiovascular neuroregulation may play a major pathogenetic role in patients with normal tension glaucoma (NTG). A higher incidence of cardiovascular disorders1 and ischaemic cerebral lesions2 has been reported in patients with NTG compared to patients with primary open angle glaucoma or ocular hypertension.3
Variables such as arterial blood pressure (BP) and heart rate (HR) depend on the autonomic nervous system (ANS). Sympathetic neural activity (SNA) causes an increase of HR, stroke volume and vasoconstriction. SNA regulates the circadian variation of BP and is closely linked to nocturnal dipping. Chronic increased SNA can lead to arterial and cardiac remodelling, endothelial dysfunction, increased tissue oxygen demand and subsequent decreasing of the ischaemia threshold in all organs, including the eye.4 It has been postulated that optic nerve head (ONH) circulation is not purely autoregulated but may also be affected by the systemic ANS and circulating vasoactive hormones.5 High sympathetic drive may constrict the microvasculature nourishing the ONH and lead to a decrease of the ocular blood flow.
There is evidence that nitric oxide (NO) is a major modulator of the autonomic control of HR and acts as a sympatholytic factor.6 Reduced levels or bioavailability of NO in patients with glaucoma7 may therefore shift an ANS balance to a sympathetic tension.
Heart rate variability (HRV) and BP variability (BPV) represent reliable and non-invasive tools to assess the ANS modulation under physiological conditions. HRV describes variation of HR and RR intervals whereas BPV is defined in terms of SD of the BP readings and is a clinical marker to describe the adaptation of the systemic vascular resistance to the fluctuation in cardiac output.
The purpose of the present study was to evaluate the activity of the central ANS by defining 24-h HR modulation, 24-h BPV and nocturnal dipping status in patients with NTG.
Materials and methods
Patients newly and previously diagnosed as having early and middle-stage NTG and control subjects of either sex were included in this prospective study. The study was performed according to the tenets of the Declaration of Helsinki and was approved by an institutional review board at the Military Institute of Medicine in Warsaw. The study is listed on http://www.clinicaltrials.gov (NCT01192061). Signed informed consent forms were obtained from all patients before study enrolment.
NTG was defined as glaucomatous optic nerve neuropathy characterised by an intraocular pressure level ≤21 mm Hg, cup-to-disc ratio (c/d) >0.6 or an interocular c/d asymmetry ≥0.2, and at least one of the following abnormalities: thinning of the rim, notching, nerve fibre layer defects, or peripapillary atrophy, with repeatable reliable glaucomatous visual field defects demonstrated in the central 24-2 program of Humphrey threshold perimetry. Early and middle-stage glaucoma were defined on the basis of the mean defect index of visual fields <−6 decibels (dB) and between −12 dB and −6 dB, respectively, and on the basis of a vertical c/d <0.8.
Exclusion criteria included ocular hypertension, types of glaucoma other than NTG, history of eye surgery, trauma and inflammation, myopia above −6.0 dioptres, corneal dystrophies, and any significant cardiovascular, pulmonary and metabolic conditions other than controlled systemic hypertension HT (BP<140/90 mm Hg). The control group comprised subjects without glaucoma and was recruited from the family members of patients and other volunteers. Patients previously diagnosed as having glaucoma were instructed to stop using antiglaucoma medications 4 weeks before examination. Systemic medications were not discontinued.
All subjects underwent an eye examination that included: medical history, best corrected visual acuity, slit lamp and stereo optic disc evaluation, Goldmann applanation tonometry, central corneal thickness measurement using ultrasonic pachymetry (OcuScan RxP, Alcon Laboratories, Forth Worth, USA), Humphrey central 24-2 threshold perimetry test and optical coherence tomography (OCT) of the ONH and retinal nerve fibre layer (RNFL) with the Stratus OCT 3 (Carl Zeiss Meditec, Dublin, California, USA) V.4.0.2. In the NTG group, an eye with more advanced damage was selected, and one randomly selected eye per subject in the control group entered into the analysis.
The 24-h ambulatory ECG and BP monitoring were performed simultaneously. ECG monitoring was performed using Lifecard CF recorder (Del Mar Reynolds Medical, Hertford, UK). After initial arrhythmia analysis and elimination of artefacts the frequency-domain and time-domain measures of HRV were calculated using Symphony Impresario Holter System Analyser (Del Mar Reynolds Medical, Hertford, UK). Frequency-domain analysis of the RR interval for the whole hour throughout the 24-h period was performed by a Fast Fourier Transform method after sampling using interpolation methods, ‘cubic spline’ and ‘window function’ (Blackman-Harris). From the total spectrum, the powers of high-frequency (HF) (0.15–0.35 Hz) and low-frequency (LF) (0.05–0.15 Hz) components were obtained and the LF/HF ratio determined. The HF component reflects the influence of parasympathetic drive, and the LF/HF ratio represents sympathovagal balance.
In time-domain analysis the average normal-to-normal (NN) heartbeats (mean NN interval) were used. The SD of normal to normal RR intervals (SDNN) and SD of the successive differences between RR intervals (SD SD) were used as indices of the total HRV variability. The root mean square of successive differences (RMS-SD) and percentage of normal to normal RR interval, greater than 50 ms (pNN50) were used to assess the parasympathetic effect.8
Arterial systolic and diastolic BP (SBP, DBP) were measured with automated ambulatory BP System Spacelab 90207-30 (SpaceLab Healthcare Ltd, Hertford, UK) in 20 min intervals during the day (5:00 to 22:00) and 30 min intervals at night (22:00 to 5:00). These data were used to define averages values of SBP, DBP and mean BP (MBP) during the 24 h period (SBP24, DBP24, MBP24) during the day (SBPd, DBPd, MBPd) and at night (SBPn, DBPn, MBPn). MBP was calculated using the formula: MBP=DBP + 1/3 (SBP−DBP). In addition, average values of the minimum and maximum of SBP, DBP, MBP were defined during the 24 h period, during the day and at night. BPV was determined by calculating the SD of the average BP during the 24-h period (SD SBP24, SD DBP24, SD MBP24) during the day (SD SBPd, SD DBPd, SD MBPd) and at night (SD SBPn, SD DBPn, SD MBPn). The SBP, DBP and MBP reductions during the night were calculated according to the formula: (day−night) per day.
Patients in both groups were then divided into three subgroups, according to the degree of nocturnal MBP reduction (ΔMBP) as follows: ‘non-dippers’, (ΔMBP <10%), ‘dippers’, (10% ≤ΔMBP <20%) and ‘overdippers’ (ΔMBP ≥20%). In both study groups, the mean value of SBP, DBP, MBP, during the 24-h period, during the day and during the night were defined for each circadian rhythm profile subgroup and were further compared within the study groups. Finally, circadian rhythm profile subgroups of patients with NTG and control subjects were compared to one another by analysing the average value of SBP, DBP and MBP, during the 24-h period, during the day and at night, and by analysing the mean, minimum and maximum value of nocturnal SBP, DBP and MBP reduction.
At least 90% of the programmed recordings were required to be considered in the present analysis.
The minimum sample size of 51 for the NTG group and 41 for the control group was calculated for a power of 95%, a probability of an α error of 5% and the effect size was determined on the basis of an earlier study.9 Statistical analysis was carried out using SAS V.9.2 software (SAS Inc., Cary, North Carolina, USA). The comparisons of the values between study groups were carried out using paired t test, repeated-measures analysis of variance (ANOVA) with the Bonferroni adjustment for multiple comparisons and Kruskal–Wallis test. The Mann–Whitney U test and χ2 test were used to demonstrate the differences in the distribution of variables between groups. Multiple regression analysis was used to examine the relation between HRV spectral parameters as the outcomes of interest and NTG, age, gender, hypertension and central corneal thickness (CCT) as covariates. p Values <0.05 were considered statistically significant.
Results
A total of 56 patients with NTG and 52 control subjects were initially recruited to the study. Due to artefacts, electrode loss or presence of unsuspected arrhythmias, ECGs and BP recordings could not be interpreted in 11 study subjects, leaving 54 patients with NTG and 43 matched control subjects for analysis. The characteristics of study groups are presented in table 1.
The HRV spectral analysis revealed significant differences in nearly all parameters in a 24-h monitoring, as well as for daily activities and nocturnal sleep between study groups. In patients with NTG, the mean HF values of the 24-h, daytime and night-time periods were significantly lower than those of the control group ((27.5±7.5 vs 33.6±6.5, p=0.0002), (24.8±7.7 vs 28.2±6.4, p=0.0486) and (32.3±9.2 vs 43.9±10.3, p=0.0000), respectively) (figure 1). In turn, the mean LF values were significantly higher in patients with NTG, as compared with control subjects ((62.6±10.7 vs 55.8±10.6, p=0.0048), (64.3±11.8 vs 59.9±11.5, p=0.0431) and (59.7±10.9 vs 47.6±11.2, p=0.0000), respectively).
The mean 24-h, daytime and night-time LF/HF ratios were statistically higher in patients with glaucoma as compared to controls ((3.2±1.5 vs 2.2±0.8, p=0.0009), (3.5±1.7 vs 2.7±1.0, p=0.0173) and (2.6±1.7 vs 1.4±0.6, p=0.0001), respectively) (figure 2).
The HRV time analysis for daily activities and nocturnal sleep showed no significant differences between study groups (table 2).
There were no significant differences in the mean, minimum, maximum values of MBP, SBP or DBP and in BPV during the whole 24-h period, day or night between the NTG and control groups (table 3).
No difference was found between study groups in the percentage decrease in night-time MBP (p=0.720). The percentage distributions of patients with NTG and control subjects in ‘dippers’ group were 57.4% and 51.2%, respectively; in ‘non-dippers’ group: 31.5% and 32.6% and in ‘overdippers’ group: 11.1% and 16.3%. The average reduction of MBP at night was 12.3% and 13.6%, respectively (p=0.312).
The HRV parameters of ‘dippers’, ‘non-dippers’ and ‘overdippers’ differed greatly between study groups. Within ‘dippers’, those with glaucoma showed significantly lower HF component (27.1±6.9 vs 34.5±7.2, p=0.001) and significantly higher LF/HF ratio (3.2±1.4 vs 2.3±0.8, p=0.000) than those in the control group. NTG ‘non-dippers’ and ‘overdippers’ also presented significantly higher LF/HF ratio as compared to the same subgroups of control subjects ((3.1±1.5 vs 1.9±0.7, p=0.000) and (3.3±1.9 vs 2.3±0.8, p=0.001), respectively). ‘Dippers’ with NTG showed nearly statistically higher LF component (p=0.059) as compared with the control ‘dippers’.
Multivariate analysis selected only NTG as an independent factor correlating with LF, HF and LF/HF.
Discussion
To the best of our knowledge this study represents the first simultaneous 24-h HRV and 24-h BPV analysis in evaluating the ANS activity in patients with NTG.
The study revealed that both groups differed in the spectrum of HRV changes during the whole day. In patients with NTG the day–night differences in power of HF and LF components were smaller, resulting in more flat circadian profile of HRV as compared to controls. Significantly lower values of HF component and higher values of LF component in evening and night hours represent an increased SNA. At the same time, a higher LF/HF ratio, which occurred throughout most of the 24-h period (15 h), indicates a shift of sympathetic–parasympathetic balance towards sympathetic activity.
Earlier studies demonstrated that glaucoma was associated with ANS dysfunction, by using baroreceptor reflex activation tests. Brown et al10 found a reduced modulation of both components of ANS whereas Riccadonna et al11 demonstrated the advantage of the sympathetic drive in patients with glaucoma. The authors have observed a significant reduction of HRV and DBPV at night in patients with glaucoma, moreover the range of reduced modality of ANS was correlated with the glaucoma damage. The results of our study are consistent with the results of Kashiwagi et al12 and Gherghel et al.9 Gherghel et al9 also noted that the ANS imbalance occurred in patients with glaucoma and coexisting silent ischaemic heart disease, as well as in patients with glaucoma without any ischaemic abnormalities on ECG.
An increased SNA results in increased vascular resistance and especially under circumstances of the endothelial dysfunction may have circulatory implications relevant to glaucoma pathogenesis. Altered ocular blood flow13 or reduced visual field sensitivity14 during sympathetic provocation tests has been demonstrated in patients with primary open angle glaucoma. However the range of ischaemia that is vulnerable in glaucomatous damage is not known. A positive correlation between choroidal blood flow and BP15 and lack of any correlation between them16 have both been reported.
In our study, the time-domain analysis of HRV did not show any significant differences between study groups. Na et al17 observed significantly decreased SDNN values in patients with NTG.
We did not find a different pattern of 24-h BP values in patients with NTG compared to control subjects, which was in agreement with Graham et al18 and Meyer et al19 findings. In turn, Kaiser et al20 noted that patients with glaucoma presented significantly lower SBP only. Others21 22 reported that patients with NTG exhibited higher MBP compared to controls.
In our study, both groups did not differ in the nocturnal MBP decline profile. The mean reduction of MBP at night was 12.3% in patients with NTG. Other authors observed similar21 22 or greater19 mean nocturnal dips. The distributions of nocturnal BP reduction profiles in study groups were similar. ‘Overdippers’ and ‘non-dippers’ accounted for 11% and 31% of the patients with NTG, respectively. Other authors found higher rates of ‘overdippers’ profile (41% to 50%) and similar percentage of ‘non-dippers’ among NTG population.23 24 However, not all authors use the same definition of nocturnal BP profiles.
In accordance with the previously published studies,19 20 24 patients with controlled HT were not excluded from our study as such exclusion could alter the actual characteristics of NTG subpopulation and lead to statistical bias to lower values of BP in patients with NTG.
We found that 46% of the patients with NTG also had HT. Our finding is in agreement with the Low-pressure Glaucoma Treatment Study.25 Recent studies suggest that SNA can influence also the long-term BP control and sympathetic overdrive, among other factors that underlie the pathogenesis of HT. Sharphedinsson et al26 demonstrated that normotensive individuals with high baseline sympathetic traffic tended to have higher levels of plasma nitrates. The authors suggested that the strong vasodilating effect of NO might counterbalance the sympathetic vasoconstriction and BP rise. We can speculate that this ‘intrinsic’ antihypertensive mechanism may be insufficient in patients with NTG who demonstrate the decreased level or bioavailability of NO. No relation between BP or HT and NTG was demonstrated in the Rotterdam study.27
We found that both study groups did not differ in BPV. Plange et al22 observed a significantly increased BPV at night in patients with NTG, which might lead to ocular perfusion pressure fluctuations and ischaemic episodes in the ONH. In turn, Riccadonna et al11 found a decreased variability of DBP during the night in patients with NTG.
In our study, ‘dippers’, ‘non-dippers’ and ‘overdippers’ of both study groups differed significantly in HRV parameters. In patients with NTG, the LF/HF ratio for the whole day was statistically higher compared with the control group, regardless of the profile of nocturnal BP reduction. The values of HF spectrum were lower in all three NTG subgroups (although significantly only in the NTG ‘dippers’) as compared to controls, which suggested a reduction of HR fluctuations, due to vagal activity in patients with glaucoma. We have not found any comparative data in an NTG population in the literature.
When interpreting our findings some aspects and limitations of the study design should be considered. First, HRV and BPV represent indirect methods of evaluating the ANS. Microneurography, the only direct method, is characterised by high interindividual variation in healthy population. Second, BPV could be determined during fixed periods, which made capturing short-term and transient changes of BP impossible. Finally, some subjects were on antihypertensive treatment and although both study groups did not differ in antihypertensive medications, the impact of these drugs on autonomic function should be considered. Most currently used antihypertensive drugs have been found to attenuate postsynaptic vascular sympathetic tone in patients who were hypertensive, whereas diuretics can increase sympathetic tone and HR.28
In summary, our data indicate that the sympathovagal balance of ANS in patients with NTG shifted towards sympathetic activity. However we did not find any change of 24-h pattern of BPV in patients with NTG. Further studies are needed to verify our findings as well as studies on any therapies that favourably influence ANS activity in patients with glaucoma.
Acknowledgments
The authors would like to gratefully acknowledge the help of Dr Janusz Sierdziński for his statistical analysis in this study.
References
Footnotes
Funding Grant of Polish Ministry of Science and Higher Education Nr N N402 165637.
Competing interests None.
Ethics approval Ethics approval was approved by the Institutional Review Board at the Military Institute of Medicine in Warsaw.
Provenance and peer review Not commissioned; externally peer reviewed.
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