Background
High blood pressure (HBP) or hypertension is a serious public health problem worldwide [
1], especially in China that possesses the largest population [
2]. In recent decades, the incidence of HBP or hypertension is rising in children and adolescents [
3]. It is well acknowledged that the natural history of essential hypertension origins from childhood [
4]. Meanwhile, children and adolescents with high BP are more likely to develop cardiovascular disease (CVD) [
5], cognition impairment [
6], and eventually death [
7] later in life.
BP is one of the most dynamic physiologic variables [
8]. BP variability (BPV) can be accessed as variability of beat to beat (very short-term BPV), over 24 h (short-term BPV), day-to-day (midterm BPV), and from visit-to-visit (long-term BPV) [
8]. As a typical type of BPV, visit-to-visit BP variability (VVV) was demonstrated not to be random, but significantly reproducible over a long period of follow-up [
9].
In adults, ample evidence indicated that higher VVV was associated with the development, progression and severity of vascular, cardiac and renal target-organ damage, and with an increased risk of cardiovascular events and cardiovascular and all-cause mortality, independent of average BP values [
10‐
12]. In addition, higher VVV and impaired cognitive function was observed in the elderly [
13,
14]. Studies also suggested that, VVV was promising in facilitating risk classification for further cardiovascular disease [
15].
While BPV has been relatively clearly understood in the adult literature, the significance of BPV in children and adolescents is not well described. In different pediatric disease settings, 24 h BPV has been tied to hypertension [
16], left ventricular mass index [
17], and arterial stiffness [
18]. The 24-h BPV needs ambulatory BP monitoring, which is rather problematic to be interpreted in very young children [
19]; while VVV can be determined relatively conveniently in clinical setting [
20]. In children and young adults, increased VVV was shown to predict adult hypertension [
21]. Also, higher systolic VVV was independently related to impaired neurocognitive function [
22] in pediatric renal disease patients. What’s more, it has been reported that in children with primary proteinuric glomerulopathies, greater VVV was an independent predictor of poor clinical outcomes (e.g., end-stage renal disease or estimated glomerular filtration rate decline) [
23]. However, the literature with longitudinal studies linking VVV to future HBP among general childhood and adolescence is rather scarce.
Utilizing data of Suzhou Health Promotion Program for Children and Adolescents (HPPCA), the present study aimed to examine the associations between VVV and risk of HBP, and investigate whether any VVV indices was capable of improving risk discrimination for HBP in a large-scale Chinese pediatric population.
Discussion
In the current study, we found that SD or ARV of BP was significantly and independently associated with HBP in children and adolescents, beyond the average BP values. In addition, systolic VVV, especially SBP-SD, could potentially become a variable to aid in the discrimination of participants at high risk of HBP.
VVV was significantly higher in individuals with HBP than its counterparts in the current study, although another study revealed that VVV was not significantly different between four normotensive and 20 hypertensive children and adolescents with renal disease in Japan [
32]. Difference in sample size, ethnicity and disease setting may contribute to the discrepancy. The physiopathological mechanisms linking high VVV to HBP remains obscure. Under normal physiological conditions, BPV mainly represents a response to environmental stimulation and challenges of daily life, which aimed at maintaining the so-called BP “homeostasis” [
8]. Sustained elevations in BPV may also reflect alterations in the mechanisms responsible for cardiovascular homeostasis or underlying pathological conditions, and may therefore represent a source of damage to the cardiovascular system. For example, VVV was found to be associated with markers of cardiac, vascular, and cerebral diseases as well as albuminuria [
8]. Furthermore, VVV has been related with central sympathetic overactivity, variations in renin–angiotensin–aldosterone system stimulation, adverse alterations in cardiac structure or function (i.e., left ventricular dysfunction, atrial fibrillation), as well as vascular target organ damage (i.e., carotid atherosclerosis and stiffness) in adults [
12,
33] and the elderly [
34]. In pediatrics with renal disease, increased VVV was tied with reduced eGFR [
32]. Thus greater VVV may represent an inability to maintain hemodynamic homeostasis, and contribute to HBP in children and adolescents.
Interestingly, systolic VVV showed stronger associations with HBP than diastolic VVV in the current study. In adults, regarding prediction of cardiovascular endpoints, SBP was considered to be better than DBP [
35], and systolic VVV was superior to diastolic VVV [
36]. Meanwhile, it was reported that systolic BPV was higher than diastolic BPV in adolescents with essential hypertension [
37]. Stabouli et al
. also showed that increased SBP variability was closely associated with arterial stiffness (assessed by pulse wave velocity) in children and adolescents [
18]. One possible reason for this finding might be owing to different hemodynamic mechanisms of BP increase [
38]. Pediatric elevated SBP was associated with higher urinary noradrenaline levels, suggesting hyperactivity of the sympathetic nervous system (SNS) [
39], while no such phenomenon was found for elevated DBP [
40]. Moreover, in the conscious rats experiment, systolic BPV levels reflected α-adrenoceptor-mediated vasomotor function and β-adrenoceptor-mediated cardiac sympathetic function [
41]. The activation of the SNS and cardiac sympathetic function was closely associated with left ventricular systolic function [
42], therefore, hyperactivity of the sympathetic function could potentially induce a deeper impairment of systolic function, high SBP variability and subsequent HBP.
We also found that associations between VVV and HBP were enhanced when we restricted to boys. Boys are more susceptible to the impact of VVV than girls, which could possibly be explained by the varied timing and duration of sexual maturation between boys and girls [
43]. Differences in lifestyles (including diet habits, physical activities, etc.) may also account for the gender-difference in the associations of VVV with HBP, so the potential gender-specific associations need to be elucidated further.
The present study found stronger links between SD or ARV of BP and childhood HBP, instead of CV. It seemed that SD or ARV, as indicators of BP variability, were more widely assessed in the field of pediatrics [
16,
22,
23,
32,
44], as only a few studies have evaluated CV [
16,
44]. Our results also were in agreement with previous studies in adults. Chen et al. demonstrated that even after adjusting for mean childhood BP levels, adult hypertension was associated with increased BPV in terms of SD of serial BP measurements obtained during childhood [
44]. It was reported that both high BP-SD and BP-CV might increase the risk of chronic kidney disease, but the former association was more significant [
45]. One meta-analysis provided evidence that great SBP-SD may indicate an increased risk of stroke (RR 1.20, 95% CI 1.07–1.35); however, when CV was considered, the hazard for stroke was not stable (RR 1.12, 95% CI 1.00–1.26) [
46]. In addition, Mokadem et al. indicated that ARV was the only independent predictor of target organ damage in contrast to SD and CV [
47]. Further studies are warrant to determine the most appropriate index for the evaluation of BP variability.
The current study benefits from its large sample size and representativeness of the general pediatric population that referred for hypertension evaluation. Almost all children and adolescents of considered grades would be recruited to attend HPPCA, which may contribute to reduced selection bias of the current study. Besides, observational studies have suggested that VVV may be importantly influenced by seasonal changes in weather conditions [
48]. But in HPPCA [
24], all the participants were regularly measured at a settled time within a year. However, several limitations should be admitted. First, in this study, we just used the average of three separate BPs at single visit in 2018 to determine HBP or HNBP status. Ideally, hypertension is suggested to be assessed based on BP values from at least three separate office visits [
29]. Due to limited time and energy, BP was only measured at single time point among the hundreds of thousands of child/adolescent in HPPCA, and it was also difficult to track those with abnormal BP values during the HPPCA surveillance to further determine their status of hypertension. As a result, we used terms “high BP” and “high normal BP” instead of “hypertension” and “prehypertension”, and our findings may be subject to BP misclassification. Nevertheless, this systematic overestimation is unlikely to bias our trend results [
24]. Second, the participants were only recruited from Suzhou, a developed city in Eastern China. Besides, the vast majority of the included subjects were adolescents. Therefore, our findings may not be applicable to children with age < 10 years or generalizable to other racial/ethnic populations. Third, some potential confounding parameters that may influence the development of HBP, such as living environment, dietary pattern, and physical activity, were not available in the current study. Fourth, the relationship between VVV and HBP may not necessarily be causal, given the observational nature of the study. Last but not least, BP variability may be independently involved in the progression and severity of cardiac, cerebral and renal target-organ damage. For example, greater BPV appears to increase the risk of adverse alterations in cardiac structure in both adults and pediatrics independent of mean BP levels [
12,
16]. However, such information is not available for the current study, preventing us to effectively detect the independent prognostic value of VVV. Further studies focus on VVV and other target-organ damage are encouraged.
Our findings support the view that cardiovascular risk may depend not only on average BP levels but also on the degree of BPV in both children and adolescents. The clinical relevance of evaluating the dynamic patterns of several cardiovascular and metabolic variables, including BPV overtime, in addition to the assessment of magnitude and duration of average BP level elevation, has been emphasized in a large number of studies. VVV is a non-invasive, inexpensive and applicable method; therefore, the application of VVV for minoring childhood HBP should be considered, especially for similar kinds of school-based surveillance. Besides, the current study indicated that more attention should be paid for boys, who may be more vulnerable to higher VVV.
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