Original article 1
Assessment of pupillary autonomic functions by dynamic pupillometry in different circadian arterial blood pressure patterns Sercan Okutucua, Mustafa Civeleklerb, Hakan Aksoya, Begum Yetis Sayina and Ali Otoa Objective The aim of the present cross-sectional study was to evaluate the autonomic nervous system by dynamic pupillometry (DP) in normotensive and hypertensive individuals with either a non-dipper-type or a dipper-type circadian rhythm of blood pressure (BP). Patients and methods A total of 80 patients were allocated into four groups: normotensive/dipper (n = 23), normotensive/nondipper (n = 19), hypertensive/dipper (n = 18), and hypertensive/nondipper (n = 20). Pupil diameters (R0, R1, R2, and R%): latency (Lc), amplitude (Ac), velocity (Vc), and duration (Tc) of pupil contraction: latency (Ld), velocity (Vd), and duration (Td) of pupil dilatation were measured by DP. Among the DP parameters, Vc and Ac were known parasympathetic indices and R% was the major sympathetic index. Results Vc and Ac were higher in the dipper normotensives with respect to nondipper normotensives (Vc = 5.19 ± 0.85 vs. 4.58 ± 0.71, P = 0.017; Ac = 1.66 ± 0.27 vs. 1.49 ± 0.28, P = 0.048). Vc and Ac were higher in dipper hypertensives with respect to the nondipper subgroup of hypertensive cases (Vc = 4.44 ± 0.81 vs. 3.94 ± 0.45, P = 0.024; Ac = 1.47 ± 0.26 vs. 1.27 ± 0.11, P = 0.004). R% was higher in the nondipper subgroup of hypertensives than the dipper
Introduction Arterial blood pressure (BP) follows a circadian-type biological rhythm [1–3]. Most individuals present a decline in arterial BP between 10 and 20% during nighttime intervals that is called a dipper pattern [4–6]. It has been reported that the lack of nocturnal BP fall, which is called nondipping, is associated with more severe end organ damage compared with hypertensives with a dipping pattern [5,6]. Although pathologic mechanisms responsible for blunted nocturnal fall in BP are still uncertain, it has been suggested that nondippers show impairment in the autonomic nervous system (ANS) that includes abnormal parasympathetic activity [2–4]. As a decrease in vagal activity has been known to be a powerful independent predictor of overall mortality, the decline in vagal tone might lead to the additional increase in the cardiovascular risk in nondipper patients besides the harmful effects of high BP [7,8]. 1359-5237 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
subgroup of hypertensive cases (36.7 ± 4.8 vs. 33.5 ± 3.8, P = 0.033). Correlation analyses showed moderate positive correlations of night-time decline in BP with Vc (r = 0.460, P = 0.001) and Ac (r = 0.420, P = 0.001). There was also a negative correlation between night-time decline in BP and R% (r = –0.259, P = 0.001). Conclusion Nondipping in BP is associated with lower parasympathetic activity both in normotensive and in hypertensives cases. Furthermore, in the nondipper subgroup of hypertensive cases, there is higher sympathetic activity than the dipper subgroup. Blood Press Monit 00:000–000 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. Blood Pressure Monitoring 2018, 00:000–000 Keywords: autonomic nervous system, blood pressure, circadian rhythm, dynamic pupillometry, hypertension a Department of Cardiology, Memorial Ankara Hospital and bDepartment of Ophthalmology, Etimesgut Sait Erturk State Hospital, Ankara, Turkey
Correspondence to Sercan Okutucu, MD, Department of Cardiology, Memorial Ankara Hospital, Cankaya, Ankara 06520, Turkey Tel: + 90 312 253 6666 x4207; fax: + 90 312 253 6623; e-mail:
[email protected] Received 8 February 2018 Revised 18 March 2018 Accepted 16 April 2018
Sympathetic and parasympathetic limbs of ANS modulate dynamic changes in pupil size [9–11]. Both sphincter and dilator muscles of the iris receive dual innervations from the two branches of the ANS [9,12]. Parasympathetic fibers supply the iris sphincter and cause a reduction in pupil size by contraction of the muscle. Meanwhile, the sphincter has sympathetic innervations that are capable of inhibiting pupil contraction by relaxation of sphincter muscle. This inhibition occurs primarily by β-adrenergic receptors. Pupil dilation by sympathetic inhibition of the sphincter is about one-third of the maximum physiological dilation. However, sympathetic innervation causes contraction of iris dilator muscle by α-adrenergic receptors, which results in an increase in pupil diameter [12,13]. Dynamic pupillometry (DP) is a novel, standardized, fully automated computerized system for the evaluation of the ANS [14,15]. The pupil is a convenient and DOI: 10.1097/MBP.0000000000000327
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2 Blood Pressure Monitoring 2018, Vol 00 No 00
accessible terminal station for studying ANS because the parasympathetic and sympathetic nervous systems innervate constrictor and dilator muscles of the iris [9,14,15]. Therefore, the infrared DP, which uses pupillary light reflex, enables an independent evaluation of both branches of ANS [10,11]. Infrared DP indices have been evaluated in patients with heart failure [9], obstructive sleep apnea [12], diabetes mellitus [16], and neurological diseases [17,18]. The aim of the present cross-sectional study was to evaluate ANS by computerized DP in normotensive and hypertensive individuals with either a non-dipper-type or a dipper-type circadian rhythm of BP.
Patients and methods Study population and data collection
The study population included 80 individuals (mean age: 45.8 ± 4.8 years, 32 women and 48 men). Patients were divided into four groups according to the presence of hypertension and circadian BP pattern as follows: (i) normotensive/dipper, n = 23; (ii) normotensive/nondipper, n = 19; (iii) hypertensive/dipper, n = 18; and (iv) hypertensive/nondipper, n = 20. Thus, dipper and nondipper cases were compared with their respective groups. All patients were enrolled and assessed during the initial evaluation of arterial hypertension. Therefore, none of the patients were on medication including antihypertensive drugs. All patients underwent 24-h ambulatory BP monitorization and DP analysis. These two studies were carried out by researchers blinded to the results of one another. In addition to DP analysis, all participants underwent a complete ocular examination consisting of slit-lamp biomicroscopy, fundus examination, and intraocular pressure evaluation. All participants’ best-corrected visual acuity was 20/20 with Snellen and ophthalmologic examination was normal. Patients with a history of cardiovascular, cerebrovascular, or other systemic diseases were excluded. All patients had no systemic and neurological conditions with known ocular involvement, use of medication, and topical eye treatment. During participation and data collection, five (5.9%) cases were excluded. Exclusion criteria were diabetes mellitus in two cases, coronary artery disease in two cases, and mitral valve prolapse in one case. Data collection was carried out by face-to-face interviews of the participants by two trained researchers. Demographic features, smoking habits, and use of medications were determined using a questionnaire. All patients underwent a complete physical examination, and their height and weight were recorded. BMI was calculated as weight divided by the square of height (kg/m2). All patients underwent transthoracic echocardiography. Echocardiographic examination was performed in the left lateral position from the parasternal long axis and short axis, and apical two-chamber
and four-chamber views. From the parasternal long axis, the left ventricle end-diastolic diameter and the left ventricle end-systolic diameter were measured using M-mode (at the mitral chordal level perpendicular to the long axis of the ventricle), and then the left ventricular ejection fraction (LVEF) was calculated. The measurements were performed on the basis of the criteria proposed by the American Society of Echocardiography [19]. The current study complies with the Declaration of Helsinki. Informed consent was obtained from all participants and the study was approved by the Research Ethics Committee. Ambulatory blood pressure monitoring and definition of hypertension
Ambulatory BP monitoring studies were carried out using a Tracker NIBP2 (Del Mar Reynolds Medical Ltd, Hertford, UK) monitoring device. The first hour was excluded from analysis. BP readings were obtained automatically at 15-min intervals during the daytime and at 30-min intervals during the night-time. Recordings were accepted only if more than 85% of the raw data were valid. The absolute decrease and the percentage of the decrease in night-time systolic BP versus daytime systolic BP were calculated in all participants. Time in bed was defined on the basis of the patient-kept diary that documented the exact time of getting into and arising from bed. The average BP for this time in bed was calculated from the ambulatory monitoring data (termed night-time BP). Daytime BP was defined as the average BP during the remainder of the 24-h period. The mean BP was calculated as the diastolic pressure plus one-third of the pulse pressure. The percentage decline in nighttime BP was calculated as follows: [(daytime mean BP − night-time mean BP)/(daytime mean BP) × 100]. Patients with a decline in night-time mean BP of less than 10% were considered nondippers. Patients were considered hypertensive if the following were present: (i) presence of resting systolic BP of 140 mmHg and/or diastolic BP of 90 mmHg or (ii) an average 24-h BP value above 130/80 mmHg [5,6]. Computerized dynamic pupillometry
Monocular DP analysis were carried out for each eye (darkness adaptation 300 s, duration of 90 s, sampling frequency = 30 Hz) using MonPack One Software (Metrovision, Perenchies, France), which is provided in the DP device and automatically outlines pupillary contour on the images, ensuring the accuracy of the measurements (accuracy of measurements of pupil diameter = 0.1 mm) under controlled illumination conditions. The DP device stimulator had near-infrared illumination (950 nm) and a high-resolution near-infrared image sensor that allows measurement of pupil diameter even in absolute darkness. From the DP analysis of response to visual stimulus: pupil diameters (initial, R0; maximum, R1; minimum, R2; R2/R0
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Dynamic pupillometry and circadian BP Okutucu et al. 3
Fig. 1
Computerized dynamic pupillometry (DP). DP curve (a), automatic pupil identification (b), pupillometry device (c), and DP indices (d). LE, left eye; OD, oculus dexter; OS, oculus sinister; RE, right eye
expressed as (R%): latency (Lc), amplitude (Ac), velocity (Vc), and duration (Tc) of pupil contraction: latency (Ld), velocity (Vd), and duration (Td) of pupil dilatation were measured [10,11]. Among the DP parameters, Vc and Ac are known parasympathetic indices, and R% is the major sympathetic index of autonomic functions (Fig. 1). Statistical analysis
Statistical analysis of the data was carried out using SPSS 15 (SPSS Inc., Chicago, Illinois, USA) and a two-tailed P value less than 0.05 was considered statistically significant. Distribution of data was assessed using a onesample Kolmogorov–Smirnov test. Data are shown as mean ± SD for normally distributed continuous variables, median (minimum–maximum) for skew-distributed continuous variables, and frequencies for categorical variables. For numerical variables, an independent-sample
t-test and the Mann–Whitney U-test were used for intergroup comparisons. A χ2-test and Fischer’s exact χ2-test were used for comparisons of categorical variables. In addition to a subgroup comparison in two BP categories, one-way analysis of variance was used to assess DP parameters among four subgroups. DP parameters of both eyes were averaged, and the mean values were used for statistical analysis. As a measure of internal consistency, the intraclass correlation coefficient (ICC) and Cronbach’s α coefficient were calculated from repeated same-day measurements of the first 20 patients included in our study. Pearson’s correlation analysis was used to (i) assess the relationship between the DP indices and the percentage of decline in night-time BP and (ii) evaluate the correlation between the DP indices of each eye. Spearman’s correlation analysis was used for skewdistributed continuous DP variables to evaluate the
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4 Blood Pressure Monitoring 2018, Vol 00 No 00
relationship with decline in night-time BP. A multivariate linear regression analysis was carried out to evaluate the effects of various variables, such as age, sex, basal heart rate (BHR), LVEF, average systolic BP (AvSBP), average diastolic BP (AvDBP), and decline in night-time BP values, on DP indices.
Results The demographic characteristics, ambulatory BP monitoring, DP analysis, and echocardiographic parameters of the groups are summarized in Tables 1 and 2. The dipper and nondipper subgroups of normotensive and hypertensive cases were similar with respect to age, sex distribution, smoking status, BHR, LVEF, left ventricle end-diastolic diameter, left ventricle end-systolic diameter, and AvSBP. Nevertheless, in the normotensive/ dipper and hypertensive/dipper group, the AvDBP values were significantly lower than those in the normotensive/nondipper group (P = 0.001) and the hypertensive/nondipper group (P = 0.023), respectively. In addition, in the normotensive/dipper group, the average mean 24-h ambulatory BP values were also significantly Table 1 Demographic characteristics and clinical parameters of the normotensive group
Variables Age (years) Sex (male) (n) Smoking (%) BHR (bpm) BMI (kg/m2) LVEDD (mm) LVESD (mm) LVEF (%) Av. systolic 24-h ABPM (mmHg) Av. diastolic 24-h ABPM (mmHg) Av. mean 24-h ABPM (mmHg) Decline in nighttime BP (%) R0 (mm) R1 (mm) R2 (mm) R% Lc (ms) Ld (ms) Dc (ms) Dd (ms) Ac (mm) Vc (mm/s) Vd (mm/s)
Normotensive/dipper (n = 23)
Normotensive/ nondipper (n = 19)
P value
45.1 ± 5.6 15 30.4 72.4 ± 7.9 22.4 ± 2.0 46.7 ± 3.6 29.1 ± 3.3 64.8 ± 3.8 119.1 ± 6.8
45.8 ± 4.7 11 36.8 75.4 ± 8.9 22.6 ± 1.9 45.5 ± 3.2 28.9 ± 2.1 63.5 ± 2.3 121.6 ± 4.9
0.687 0.753 0.748 0.251 0.719 0.318 0.864 0.235 0.174
70.8 ± 5.7
80.1 ± 3.9
0.001
86.6 ± 4.3
94.2 ± 3.0
0.001
15.2 ± 2.5
4 (1–9)
0.001
4.20 ± 0.91 4.78 ± 0.85 3.12 ± 0.72 32.1 (28–38) 297 (167–333) 817.5 ± 83.4 553.7 ± 97.9 1613.1 ± 118.4 1.66 ± 0.27 5.19 ± 0.85 2.01 ± 0.62
4.39 ± 0.92 4.75 ± 0.74 3.26 ± 0.77 32.7 (28–38) 267 (133–333) 812.3 ± 63.1 568 ± 96.4 1638.5 ± 94.5 1.49 ± 0.28 4.58 ± 0.71 1.77 ± 0.30
0.486 0.922 0.530 0.410 0.491 0.824 0.632 0.453 0.048 0.017 0.141
Data are shown as mean ± SD for normally distributed continuous variables, median (minimum–maximum) for skew-distributed continuous variables, and frequencies for categorical variables. DP indices: pupil diameters (initial, R0; maximum, R1; minimum, R2; R2/R0 expressed as R%); latency (Lc), amplitude (Ac), velocity (Vc) and duration (Tc) of pupil contraction; latency (Ld), velocity (Vd), and duration (Td) of pupil dilatation. Please refer to the text for a detailed description. ABPM, ambulatory blood pressure monitoring; Av., average; BHR, basal heart rate; BP, blood pressure; bpm, beats per minute; LVEDD, left ventricle end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricle end-systolic diameter.
Table 2 Demographic characteristics and clinical parameters of the hypertensive group
Variables Age (years) Sex (male) (n) Smoking (%) BHR (bpm) BMI (kg/m2) LVEDD (mm) LVESD (mm) LVEF (%) Av. systolic 24-h ABPM (mmHg) Av. diastolic 24-h ABPM (mmHg) Av. mean 24-h ABPM (mmHg) Decline in nighttime BP (%) R0 (mm) R1 (mm) R2 (mm) R% Lc (ms) Ld (ms) Dc (ms) Dd (ms) Ac (mm) Vc (mm/s) Vd (mm/s)
Hypertensive/dipper (n = 18)
Hypertensive/ nondipper (n = 20)
P value
45.7 ± 4.4 11 38.9 72.7 ± 10.5 23.0 ± 2.1 45.9 ± 2.2 29.2 ± 2.8 63.7 ± 2.1 136.3 ± 4.1
46.7 ± 4.5 11 35 74.1 ± 11.6 23.3 ± 2.1 45.5 ± 3.6 29.4 ± 2.2 64.7 ± 2.6 135.9 ± 4.2
0.481 0.752 0.535 0.704 0.665 0.789 0.863 0.265 0.782
85.5 ± 5.3
88.9 ± 3.6
0.023
103.5 ± 4.5
105.4 ± 3.5
0.139
12.7 ± 1.8 4.34 ± 0.92 4.71 ± 0.87 3.23 ± 0.77 33.5 ± 3.8 271 (127–344) 790.8 ± 61.4 540.7 ± 112.3 1621.2 ± 125.1 1.47 ± 0.26 4.44 ± 0.81 1.62 ± 0.29
3.6 (1–9) 4.83 ± 0.99 4.91 ± 0.78 3.64 ± 0.81 36.7 ± 4.8 270 (131–300) 806.6 ± 29.8 551 ± 78.9 1551.4 ± 152.4 1.27 ± 0.11 3.94 ± 0.45 1.59 ± 0.32
0.001 0.133 0.452 0.128 0.033 0.696 0.311 0.731 0.134 0.004 0.024 0.705
Data are shown as mean ± SD for normally distributed continuous variables, median (minimum–maximum) for skew-distributed continuous variables, and frequencies for categorical variables. DP indices: pupil diameters (initial, R0; maximum, R1; minimum, R2; R2/R0 expressed as R%); latency (Lc), amplitude (Ac), velocity (Vc) and duration (Tc) of pupil contraction; latency (Ld), velocity (Vd), and duration (Td) of pupil dilatation. Please refer to the text for a detailed description. ABPM, ambulatory blood pressure monitoring; Av., average; BHR, basal heart rate; BP, blood pressure; bpm, beats per minute; LVEDD, left ventricle end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricle end-systolic diameter.
lower than those of the normotensive/nondipper group (P = 0.001). Among the DP indices, Vc and Ac were higher in the dipper subgroup of normotensive cases with respect to the nondipper subgroup of normotensive cases (Vc = 5.19 ± 0.85 vs. 4.58 ± 0.71, P = 0.017; Ac = 1.66 ± 0.27 vs. 1.49 ± 0.28, P = 0.048) (Fig. 2). Similarly, Vc and Ac were higher in the dipper subgroup of hypertensive cases with respect to the nondipper subgroup of hypertensive cases (Vc = 4.44 ± 0.81 vs. 3.94 ± 0.45, P = 0.024; Ac = 1.47 ± 0.26 vs. 1.27 ± 0.11, P = 0.004). In addition, R% was higher in the nondipper subgroup of hypertensives than the dipper subgroup of hypertensive cases (36.7 ± 4.8 vs. 33.5 ± 3.8, P = 0.033) (Fig. 3). One-way analysis of variance is used to assess DP parameters among four subgroups. There was a significant difference among four subgroups with respect to Vc (F = 10.775, P = 0.001), Ac (F = 9.012, P = 0.001), and R% (F = 5.138, P = 0.003).
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Dynamic pupillometry and circadian BP Okutucu et al. 5
Fig. 2
Distribution of dynamic pupillometry indices among two subgroups of normotensive groups according to dipping status.
Fig. 3
Distribution of dynamic pupillometry indices among two subgroups of hypertensive groups according to dipping status.
Correlation analyses showed moderate positive correlations of night-time decline in BP with Vc (r = 0.460, P = 0.001) and Ac (r = 0.420, P = 0.001). There was also a negative correlation between night-time decline in BP and R% (r = –0.259, P = 0.02) (Fig. 4). The effects of age, BHR, AvSBP, AvDBP, decline in night-time BP, and LVEF on Vc were examined in a multivariate linear regression analysis, and it was determined that the degree of dipping and AvSBP were independent predictors of Vc (Table 3). In this model, the influence of night-time dipping (β = 0.425, P = 0.001) was more prominent than the other factors. The effects of age, BHR, AvSBP, AvDBP, decline in night-time BP, and LVEF on R% were also examined in a multivariate linear regression analysis and it was determined that the degree of dipping and AvSBP were independent predictors of R%, too. In this model, the influence of AvSBP (β = 0.285, P = 0.011) had a more prominent impact than the other factors.
When statistical power calculation was performed for our study population using mean values for Vc (5.19 ± 0.85 vs. 4.58 ± 0.71) in two different BP groups, the power of our study was 93.8% (α-error level or confidence level = 5%). In further correlation analysis of DP parameters for each eye, there were strong positive correlations for Vc of each eye (r = 0.937, P = 0.001), Ac of each eye (r = 0.964, P = 0.001), and R% of each eye (r = 0.914, P =0.001). Internal consistency indices were high during repeated measurements of Vc (ICC: 0.942 and Cronbach’s α: 0.970), Ac (ICC: 0.896 and Cronbach’s α: 0.945) and R% (ICC: 0.887 and Cronbach’s α: 0.940).
Discussion To the best of our knowledge, our study is the first to evaluate the relationship between circadian BP rhythm and DP indices. The results of current study suggest that (i) absence of dipping in night-time BP were associated with lower parasympathetic indices of DP both in
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6 Blood Pressure Monitoring 2018, Vol 00 No 00
Fig. 4
Correlations for dynamic pupillometry indices and decline in night-time blood pressure in the entire study population; r indicates the correlation coefficient.
Results of multivariate linear regression analysis for the independent predictors influencing Vc and R%
Table 3
Vc
R%
Variables
β value
P value
β value
P value
Age BHR Av. systolic 24-h ABPM Av. diastolic 24-h ABPM Decline in night-time BP LVEF
0.174 0.168 − 0.314 − 0.044 0.425 0.079
0.094 0.097 0.015 0.756 0.001 0.784
0.037 0.137 0.285 0.005 − 0.250 − 0.037
0.764 0.257 0.011 0.978 0.025 0.760
ABPM, ambulatory blood pressure monitoring; Av., average; BHR, basal heart rate; BP, blood pressure; LVEF, left ventricular ejection fraction.
normotensive and in hypertensive individuals; (ii) degree of night-time dipping correlated positively with Vc and Ac and correlated negatively with R% in the study population; (iii) R% was higher in nondipper hypertensive patients; and (iv) degree of dipping and AvSBP were independent predictors of Vc and R%. Circadian-type blood pressure rhythm refers to the daily variation in BP that is generally higher during the day than at night. Most individuals present a decline in arterial BP during night-time intervals, which is called the dipping pattern [1,20]. Blunted decline in night-time BP (nondipping pattern) is associated with end organ damage, cardiovascular morbidity and mortality [21–23], diabetes mellitus [24–26], and chronic kidney disease [27,28]. Furthermore, diminished nocturnal decline in BP is a predictor of cardiovascular events [2,27]. It has been suggested that nondippers show impairment in the autonomic system functions that include abnormal parasympathetic and sympathetic activities [2–4]. Computerized DP is a noninvasive, standardized, and fully automated system to assess the ANS activity of pupils. The characteristic V-shaped light response recorded during DP is divided into three parts: the first part reflects parasympathetic activation; the second part consists of both sympathetic and the parasympathetic
activity; and the third part signifies sympathetic activity alone [9–11] (Fig. 1). From the first part, Ac and Vc are indicators of parasympathetic activity [9–11]. However, R0, R%, and Lc are mainly under sympathetic control and can be used as an indicator of pupillary autonomic activity [9]. Pupillary autonomic functions assessed by DP are important because they correlate with cardiac autonomic functions [9–11]. Recently, we evaluated the utility of DP as a predictor of cardiac autonomic activity in two different studies [10,11]. In the first study [10], the utility of DP as a predictor of cardiac autonomic activity was assessed by heart rate recovery (HRR). In that analysis, we found that Ac and Vc have significant positive correlations with HRR at the first minute (HRR1). Because of sympathetic withdrawal and parasympathetic reactivation in the process of HRR, indicators of parasympathetic activity were found to be correlated positively. Importantly, Vc was found to independently predict cardiac autonomic activity assessed by HRR1. We also found that R% and Lc have negative correlations with cardiac autonomic activity assessed by HRR1. Furthermore, Lc was found to be an independent predictor of HRR1. In the latter study [11], Ac and Vc have significant positive correlations with parasympathetic heart rate variability (HRV) indicators. Importantly, Vc was found to independently predict parasympathetic HRV indicators of cardiac autonomic activity. In that analysis, we found that R% and Lc have positive correlations with sympathetic and negative correlations with parasympathetic HRV indicators. Furthermore, R% was found to be an independent predictor of sympathetic indices. On the basis of the results of the current study and the information presented above, nondippers might have altered autonomic functions that include abnormal pupillary parasympathetic and sympathetic activities. From the clinical point of view, patients with abnormal
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Dynamic pupillometry and circadian BP Okutucu et al. 7
DP indices should be followed more closely. In addition, these autonomic alterations might be modified with the treatment of underlying disease, pharmacological therapy, and exercise training. Conclusion
The current study suggests that blunting of the nocturnal fall in BP is associated with lower parasympathetic DP indices both in normotensive and in hypertensive cases. Although fluctuation in BP is predominantly related to endogenous circadian bio-clock, the parasympathetic branch of ANS activity seems to be an important pathway that mediates the circadian rhythm. Furthermore, sympathetic activity is higher in nondipper hypertensive cases with respect to the dipper hypertensive subgroup. This indicates that nondipper hypertensive individuals show impairment in the ANS that includes decreased parasympathetic and increased sympathetic nervous system activity. Further studies should be carried out for a better understanding of the interrelations between these two autonomic systems and application of DP indices in different clinical settings of cardiology.
Acknowledgements
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Conflicts of interest
There are no conflicts of interest.
References 1 Biaggioni I. Circadian clocks, autonomic rhythms, and blood pressure dipping. Hypertension 2008; 52:797–798. 2 Okutucu S, Karakulak UN, Kabakci G. Circadian blood pressure pattern and cardiac autonomic functions: different aspects of same pathophysiology. Anadolu Kardiyol Derg 2011; 11:168–173. 3 Dauphinot V, Gosse P, Kossovsky MP, Schott AM, Rouch I, Pichot V, et al. Autonomic nervous system activity is independently associated with the risk of shift in the non-dipper blood pressure pattern. Hypertens Res 2010; 33:1032–1037. 4 Ragot S, Herpin D, Siche JP, Ingrand P, Mallion JM. Autonomic nervous system activity in dipper and non-dipper essential hypertensive patients. What about sex differences? J Hypertens 1999; 17 (Pt 2):1805–1811. 5 Okutucu S, Karakulak UN, Sahiner L, Aytemir K, Demiri E, Evranos B, et al. The relationship between circadian blood pressure pattern and ventricular repolarization dynamics assessed by QT dynamicity. Blood Press Monit 2012; 17:14–19. 6 Okutucu S, Kabakci G, Deveci OS, Aksoy H, Kaya EB, Aytemir K, et al. Relationship between exercise heart rate recovery and circadian blood pressure pattern. J Clin Hypertens (Greenwich) 2010; 12:407–413. 7 Nakano Y, Oshima T, Ozono R, Higashi Y, Sasaki S, Matsumoto T, et al. Nondipper phenomenon in essential hypertension is related to blunted nocturnal rise and fall of sympatho-vagal nervous activity and progress in retinopathy. Auton Neurosci 2001; 88:181–186. 8 Sahiner L, Okutucu S, Karakulak UN, Aytemir K, Fatihoglu SG, Kaya EB, et al. Assessment of the relationship between non-dipping phenomenon and heart rate turbulence. Cardiol J 2012; 19:140–145. 9 Keivanidou A, Fotiou D, Arnaoutoglou C, Arnaoutoglou M, Fotiou F, Karlovasitou A. Evaluation of autonomic imbalance in patients with heart
20 21
22
23 24
25
26
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failure: a preliminary study of pupillomotor function. Cardiol J 2010; 17:65–72. Okutucu S, Civelekler M, Sabanoglu C, Aparci M, Dikmetas O, Uzun S, et al. Assessment of the relationship between dynamic pupillometry and exercise heart rate recovery among healthy subjects. Eur Rev Med Pharmacol Sci 2016; 20:1344–1349. Okutucu S, Civelekler M, Aparci M, Sabanoglu C, Dikmetas O, Aksoy H, et al. Computerized dynamic pupillometry indices mirrors the heart rate variability parameters. Eur Rev Med Pharmacol Sci 2016; 20:2099–2105. Monaco A, Cattaneo R, Mesin L, Fiorucci E, Pietropaoli D. Evaluation of autonomic nervous system in sleep apnea patients using pupillometry under occlusal stress: a pilot study. Cranio 2014; 32:139–147. Monaco A, Cattaneo R, Mesin L, Ciarrocchi I, Sgolastra F, Pietropaoli D. Dysregulation of the autonomous nervous system in patients with temporomandibular disorder: a pupillometric study. PLoS One 2012; 7: e45424. Martinez-Ricarte F, Castro A, Poca MA, Sahuquillo J, Exposito L, Arribas M, et al. Infrared pupillometry. Basic principles and their application in the noninvasive monitoring of neurocritical patients. Neurologia 2013; 28:41–51. Koike Y, Kawabe T, Nishihara K, Iwane N, Hano T. Cilnidipine but not amlodipine suppresses sympathetic activation elicited by isometric exercise in hypertensive patients. Clin Exp Hypertens 2015; 37:531–535. Piha SJ, Halonen JP. Infrared pupillometry in the assessment of autonomic function. Diabetes Res Clin Pract 1994; 26:61–66. Fotiou DF, Brozou CG, Haidich AB, Tsiptsios D, Nakou M, Kabitsi A, et al. Pupil reaction to light in Alzheimer’s disease: evaluation of pupil size changes and mobility. Aging Clin Exp Res 2007; 19:364–371. Tsiptsios D, Fotiou DF, Haidich AB, Brozou GC, Nakou M, Giantselidis C, et al. Evaluation of pupil mobility in patients with myasthenia gravis. Electromyogr Clin Neurophysiol 2008; 48:209–218. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015; 16:233–270. Izzedine H, Launay-Vacher V, Deray G. Abnormal blood pressure circadian rhythm: a target organ damage? Int J Cardiol 2006; 107:343–349. Ohkubo T, Hozawa A, Yamaguchi J, Kikuya M, Ohmori K, Michimata M, et al. Prognostic significance of the nocturnal decline in blood pressure in individuals with and without high 24-h blood pressure: the Ohasama study. J Hypertens 2002; 20:2183–2189. Cuspidi C, Sala C, Tadic M, Rescaldani M, Grassi G, Mancia G. Non-dipping pattern and subclinical cardiac damage in untreated hypertension: a systematic review and meta-analysis of echocardiographic studies. Am J Hypertens 2015; 28:1392–1402. Sarigianni M, Dimitrakopoulos K, Tsapas A. Non-dipping status in arterial hypertension: an overview. Curr Vasc Pharmacol 2014; 12:527–536. Hjortkaer H, Jensen T, Kofoed K, Mogensen U, Kober L, Hilsted KL, et al. Nocturnal antihypertensive treatment in patients with type 1 diabetes with autonomic neuropathy and non-dipping of blood pressure during night time: protocol for a randomised, placebo-controlled, double-blind, two-way crossover study. BMJ Open 2014; 4:e006142. Oh SW, Han SY, Han KH, Cha RH, Kim S, Yoon SA, et al. Morning hypertension and night non-dipping in patients with diabetes and chronic kidney disease. Hypertens Res 2015; 38:889–894. Stella P, Tabak AG, Zgibor JC, Orchard TJ. Late diabetes complications and non-dipping phenomenon in patients with Type 1 diabetes. Diabetes Res Clin Pract 2006; 71:14–20. Androulakis E, Papageorgiou N, Chatzistamatiou E, Kallikazaros I, Stefanadis C, Tousoulis D. Improving the detection of preclinical organ damage in newly diagnosed hypertension: nocturnal hypertension versus non-dipping pattern. J Hum Hypertens 2015; 29:689–695. Anusionwu OF. Non-dipping phenomenon in patients with essential hypertension with renal cysts. Int Urol Nephrol 2011; 43:245.
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