Hypertension is a chronic health problem for adults and children worldwide and appears to target all endothelial tissues, leading to multiple end-organ damage, particularly affecting the cardiovascular (CV) system. High blood pressure (BP) in childhood has been described as a risk for hypertension in early adulthood. Essential hypertension is identifiable in children and adolescents. The prevalence of high BP in children is close to 3%, and unfortunately, this figure is rising. The increasing prevalence of pediatric hypertension is particularly concerning due to the proven association between atherosclerosis and higher BP levels.1 Ambulatory blood pressure monitorization (ABPM) is more valuable than office BP for measuring BP accurately in children and adolescents, and also for evaluating pediatric cardiovascular mortality and morbidity.2 The use of ABPM has been on the rise since the publication of the first consensus recommendations for children and adolescents.3 Elevated BP is associated with various alterations in vascular structure and function. Endothelial function can be assessed by measuring aortic stiffness (AS) using a noninvasive method. Two basic measurements are used to assess AS; pulsed wave velocity (PWV) and the augmentation index (AIx).4 Aortic PWV appears to be of prognostic importance and is the gold standard for assessing central AS. The autonomic nervous system regulates heart rate and vascular tone and, thus, may contribute to increased AS in individuals with hypertension. We aimed to contribute to the literature by presenting some early indicators of hypertensive target organ damage and to detect hypertensive children who could be at greater risk of developing CV diseases.

Assessment of heart rate variability (HRV), obtained by 24-h Holter ECG monitoring, is the most frequently used noninvasive form of assessing autonomic nervous system activity. Multiple studies have demonstrated the association between HRV and CV diseases.5,6 However, while circadian rhythm disorders and changes in HRV parameters have been found in hypertensive adults, the link between childhood-onset hypertension and HRV has not yet been defined precisely.7

The major cardiac effect of hypertension is concentric hypertrophy of the left ventricle. In a hypertensive patient, pressure overload leads to an increase in wall thickness, relative wall thickness and consequently, remodeling myocardial contraction-relaxation arrangements may occur.

The primary hypothesis of this study is to demonstrate the relationship between left ventricular (LV) diastolic dysfunction, aortic elasticity impairment and reduced HRV parameters in children with hypertension compared with normotensive children. Our secondary hypothesis is to compare the HRV indices of dipper/non-dipper status, measured based on time domains.

A three-channel 24-h Holter monitor (Risingmed, Beijing, China) was used to assess hypertensive and control groups. HRV analyzes were performed using an ECGLAB premier Holter Analyzer system and calculated automatically by the device after the manual cleaning of the artifacts. Similar to other studies, the HRV parameters were calculated during the daytime and at nighttime over 24 hours.10 The time domain analysis of HRV consisted of the standard deviation of all RR intervals (SDNN), the root mean square of the successive differences (RMSSD), and pNN50, which is the percentage of consecutive RR intervals that differ by more than 50 milliseconds.7 The frequency domain analysis of HRV consisted of the power of high frequency (0.15–0.40 Hz); low frequency (0.04–0.15 Hz).7

A total of 60 children with newly diagnosed essential hypertension and their healthy controls aged 10-18 years were retrospectively enrolled in the study. The 24-hour ABPM revealed 15 patients with dipper and 15 patients with non-dipper patterns. Table 1 summarizes the sample characteristics of the subjects enrolled in this study. Among the children that had office BP measurements, <95th was classified as normotensive and this was confirmed by a 24-hour ABPM. Measurements >95th were regarded as hypertensive, and this was confirmed by a 24-hour ABPM.

The patients in this study were carefully screened and matched according to age, although weight and body mass index were appreciably higher in the hypertension group. There was no significant difference in LV ejection fraction in the groups. In the hypertension group, IVS diastolic diameter, LV end-diastolic diameter, LV posterior wall diastolic diameter, LV mass index values were considerably higher than the control group (Table 1). The 24-hour PWV parameters in patients with hypertension are shown in Table 1. There were statistically significant differences between the two groups relating to PWV, central systolic BP, peripheral systolic BP, peripheral diastolic BP, and peripheral mean BP, while central diastolic BP, AugP and AIx values were similar.

As Table 2 illustrates, mean ambulatory systolic BP, diastolic BP, mean BP and heart rate values were significantly higher in the newly diagnosed hypertension patients compared with the controls. Daytime and nighttime systolic BP, diastolic BP, mean BP and heart rate values in the hypertension patients differed compared with the normotensive group.

Of the time domain measures, only the daytime SDNN values were substantially lower in the hypertension subjects compared with the normotensive subjects. The hypertensive subjects had higher time domain measurements compared with the controls, but the differences were not statistically significant. The values analyzed from the frequency domain measures included the power of low frequency, high frequency, in ms2 and normalized units (nu), and the low frequency to high frequency ratio. Only the daytime low frequency power (ms2) was significantly lower in the hypertensive subjects, whereas high frequency power (ms2), high frequency (nu), low frequency (nu) and the low frequency to high frequency ratio were comparable between the groups.

Table 3 illustrates the clinical characteristics of the hypertensive children according to dipping patterns. In the dipper group, only LV end-diastolic diameter was markedly increased (Table 3). In comparison with the dipper group, only the nighttime heart rate values were notably higher in non-dipper patients, while the other parameters of the 24-hour ABPM were similar. Only the AIx values were significantly higher in the non-dipper patients while the other parameters of the pulse wave analysis were similar (Table 3). SDNN (total, day, night), Triangular index (night), total power (TP) (total, night), low frequency ms (night) values were lower in the non-dipper group (Table 4) compared with the dipper group.

Essential hypertension is one of the major predictors of atherosclerosis and a risk factor for CV disease in both children and adults. The present study aims to show some of the early changes in hypertensive CV indices to detect clinical significance. Body weight, lipid disorders, diet and life style all play an important role in hypertension. Cardiac hypertrophy, observed in adults with hypertension, have also been detected in children. LV posterior wall and septal hypertrophy, as well as diastolic LV enlargement, are thought to exist in children with hypertension. In our study, similar to previous reports, M-mode echocardiography in the hypertensive group revealed an increase in diastolic septal, posterior wall and LV internal diameters.16 LV hypertrophy is the most significant factor in target organ damage among hypertensive children and has a prevalence of 10% to 38%.17

Reduced arterial stiffness or arterial compliance is an important factor in high BP. Therefore, we investigated whether PWV was higher in our hypertensive children compared with the controls. PWV measurements were higher in the hypertensive group, demonstrating statistical significance. These results corroborate the findings of some published studies.4

This study was designed to demonstrate whether there was any variation in the cardiovascular autonomic function of children with newly diagnosed hypertension. Huikuri et al. were the first to demonstrate the circadian rhythm of HRV parameters in healthy subjects.18 A comparison between the hypertension and control group showed that the SDNN (total-day-night), RMSDD (total-day-night), PN50 (total-day-night) parameters were all reduced, however only the SDNN daytime value from the time domain variables was statistically lower in hypertensive children. From the time domain analysis, the strongest prognostic parameter for heart disease is reported to be SDNN.19 The findings in the time domain parameters can be explained due to healthy subjects having higher fluctuations in heart rate. Thus, the time domain analysis of HRV showed decreased parasympathetic activity in hypertension children.

Frequency domain measures revealed that low frequency power (ms2) (total-day-night) and high frequency power (ms2) (total-day-night) parameters were reduced, but only daytime low frequency power (ms2) values were considerably lower in hypertensive children. However, there was no statistical significance between high frequency (ms2), low frequency (nu), high frequency (nu) and low frequency/high frequency values between the groups. Our findings show the loss of parasympathetic tone in subjects with newly diagnosed essential hypertension, as demonstrated by previous reports on the matter.7,10,20

This study aims to evaluate the HRV parameters between the dipper and non-dipper groups. An insufficient lowering of nocturnal BP is related to CV mortality, and the existence of non-dipping patterns is associated with CV damage in most patients. In essential hypertension, as well as LV hypertrophy and early LV dysfunction, patients with non-dipper patterns are at a high risk of end-organ damage, which is relevant to adverse cardiac remodeling.21

The absolute power of the low frequency component (ms2) decreased slightly during the daytime in the hypertension group and according to dipper patterns, low frequency (night) decreased in the non-dipper group, while the normalized units of low frequency (nu) were similar. Normalization serves to attenuate the effect on the values of low frequency and high frequency component of the changes in TP.22 Low frequency appears to be affected by both the vagal and the sympathetic nerves. The low frequency/high frequency ratio is thought to indicate sympathovagal balance and functions as a marker of sympathetic nerve activity. Low frequency (nu) is also considered to be a sign of sympathetic nerve function.18 Concerning the frequency domain analysis, it has been observed that children with hypertension have decreased cardiac parasympathetic activity but not sympathetic activity. There is also some evidence in the literature of a decreasing low frequency trend in untreated non-dipper hypertensive subjects.23 A comparison of the dipping patterns seems relevant as its role in n the decrease in nighttime BP has been demonstrated. There are, however, few studies comparing the two groups.

A comparison of the daytime and nighttime low frequency, SDNN and TP values between dipping groups, reveals there is a significant difference in the dipper group, while this difference is absent in the non-dipper group. These important data show the deactivation of the parasympathetic system during the night period in the non-dipper group.

The differences between hypertensive and normotensive children are similar to previous reports on HRV.24 In our study, it appears that parasympathetic withdrawal is primarily responsible for these results, rather than sympathetic overdrive. As a supporting factor, the lack of significant alteration in the sympathetic system parameters is also an important finding. Although the non-significant results on the sympathetic system have previously been interpreted as being due to antihypertensive therapy, our subjects did not receive medical treatment.25 Although it is not routinely used to evaluate sympathovagal balance in clinical assessment, HRV may lead to an early autonomic assessment of the disorder at the time of diagnosis. However, we have no idea whether the ongoing period with higher BP and HRV parameters, which demonstrates alterations in the autonomic nervous system, may help to predict this period in newly diagnosed hypertension patients. Further studies are required to determine this prognosis in hypertension patients.

As CV disease is clinically silent in the early stages, essential hypertension is often asymptomatic. However, cardiovascular hypertrophy begins to develop in the early stages of hypertension. To reduce CV morbidity, early echocardiographic screening is required in hypertensive adolescents before the progression to CV disease. The circadian patterns of HRV could be useful in medical management and for assessing treatment response. Our study highlights the need for a more extensive model of central autonomic control.

This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

The author has no conflicts of interest to declare.