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The impact of decreased SIRT1 levels on pediatric primary hypertension and left ventricular hypertrophy: a case-control study

BMC Pediatrics volume 25, Article number: 340 (2025) Cite this article

Abstract

Background

Decreased SIRT1 exhibits a correlation with a range of cardiovascular diseases. However, the changes in serum SIRT1 levels in pediatric primary hypertension have not been reported. This study aimed to investigate serum SIRT1 levels in pediatric primary hypertension and explore its association with left ventricular hypertrophy in the context of hypertension.

Methods

126 participants were recruited and categorized into the hypertensive group and the control group. Serum SIRT1 levels were comparatively investigated. Spearman correlation was utilized to establish an association between SIRT1 and blood pressure. Additionally, SIRT1 levels were comparative analyzed between the patients with and without left ventricular hypertrophy.

Results

The case group had markedly decreased SIRT1 levels than the control group (p < 0.001), and a negative association between SIRT1 levels and blood pressure was revealed (p < 0.01). In subgroup analysis, patients with left ventricular hypertrophy exhibited notably reduced SIRT1 levels (p = 0.011). The multivariate logistic regression analysis showed that lower serum SIRT1 level was an independent risk factor for hypertension (OR = 0.447, 95% CI: 0.269–0.743, p = 0.002) and left ventricular hypertrophy (OR = 0.639, 95% CI: 0.486–0.840, p = 0.001).

Conclusions

Serum SIRT1 levels were significantly lower in pediatric primary hypertension patients and were negatively correlated with blood pressure. Patients with left ventricular hypertrophy had significantly lower serum SIRT1 levels, and decreased serum SIRT1 was an independent risk factor for left ventricular hypertrophy.

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Background

Hypertension is a chronic multifactorial cardiovascular disorder involving the vascular, kidney, endocrine, immune, and nervous systems [1, 2]. In recent years, with the prevalence of unhealthy lifestyle behaviors and obesity, the incidence of pediatric primary hypertension (PH) has increased gradually, and has been a clinical research hotspot. The assessment of childhood blood pressure (BP) levels hinges on age, sex, and height, while the definition of pediatric PH is based on the distribution of BP in healthy subjects according to the recent guidelines of Hypertension [3]. Untreated or poorly treated pediatric PH can last into adulthood [4] and cause various target organ damages, such as left ventricular hypertrophy (LVH) [5], reduction of cardiac function [6], hypertensive nephropathy [7], and brain functional lesions [8]. Research have shown that 14–26.7% of hypertensive children suffered from LVH, which increases the risk of developing cardiovascular disease during their adult years [6, 9, 10]. Fortunately, studies have shown that prompt treatment of PH could reduce the severity of LVH [11]. Therefore, it is important to investigate the risk factors of pediatric hypertension and LVH.

Sirtuin-1 (SIRT1), a member of the sirtuins family, is localized to the nucleus and is involved in a variety of cell functions through histone deacetylation. Previous studies have shown that SIRT1 is widely distributed in almost all body organs and has a marked effect on multifarious pathological and physiological processes, such as aging, obesity, stress resistance, and inflammation [12,13,14]. In addition, SIRT1 has been observed to exhibit a correlation with a range of cardiovascular diseases, involving cardiac fibrosis, cardiac hypertrophy, and heart failure [15,16,17]. However, the change in SIRT1 levels in pediatric PH and its relationship with LVH remain unclear.

Hence, the purpose of this study is to evaluate the serum SIRT1 levels of children with PH compared to those with normal BP and assess their association with LVH.

Materials and methods

Recruitment of patients

The research was carried out at the Children’s Hospital Capital Institute of Pediatrics. Patients first diagnosed with PH between January 2022 to June 2023 were recruited as the hypertensive case group. The inclusion criteria were as follows: (a) age between 6 and 17 years; (b) no BP medication used within one month prior to the start of the study; (c) diagnosis and grading of PH were on the basis of the diagnostic criteria on pediatric hypertension made by the 2018 Chinese Guidelines for Prevention and Treatment of Hypertension [3]. Specifically, hypertension was diagnosed when the average systolic and/or diastolic BP was in the ≥ 95th percentile from the auscultation measurement on at least 3 separate occasions adjusted for gender, age and height. Stage 1 hypertension was diagnosed if a child’s BP was greater than the 95th percentile but less than or equal to the 99th percentile plus 5 mm Hg; and stage 2 hypertension was diagnosed if a child’s BP was greater than the 99th percentile plus 5 mm Hg. The exclusion criteria were as follows: (a) with secondary hypertension; (b) with organic heart diseases, acute infectious diseases, genetic diseases, metabolic diseases, and immune diseases. The control group was formed with healthy children of similar sex and age range with normal BP.

Blood pressure and anthropometric measurements

The measurement of BP was taken using the auscultation method, and the selection of cuff size was according to the right arm circumference. Children were instructed to remove shoes and outer clothing before standing still for the measurement of weight using an electronic scale and height using a height board mounted at a right angle between a level floor and wall.

Blood samples collection and biochemical measurements

After overnight fasting, 4 ml venous blood was collected in a sterilized environment and divided into two equal anticoagulation tubes. Half of the sample was immediately centrifuged at 3,000 rpm for 15 min at 4 °C to obtain the serum, which was then stored at -80 °C for further SIRT1 measurement. Another 2 ml of blood sample was collected for biochemical measurement. Blood glucose was measured using the enzymatic method, while blood lipids such as triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured using the endpoint method. Renal functions including serum creatinine (Scr), urea, and uric acid (UA) levels were evaluated through the colorimetric method. An automatic biochemical analyzer (AU640, Olympius, Shizuoka, Japan) was utilized to analyze the above biochemical indicators.

Echocardiography

A Philips iE33 ultrasound system (Philips Healthcare, Bothell, WA, United States) was used to evaluate LVH by measuring echocardiographic indicators including left ventricular internal dimension (LVIDd), interventricular septal thickness (IVST), and left ventricular posterior wall thickness (LVPWT). To determine the left ventricular mass (LVM), the formula LVM = 1.04 × 0.8 ×((LVIDd + IVST + LVPWT)3–LVIDd3) + 0.6 was used. The LVM index (LVMI) was calculated by dividing the LVM by the height to the power of 2.7. The relative left ventricular wall thickness (RWT) was obtained by dividing the sum of the IVST and LVPWT by the LVIDd. The left ventricular mass-to-volume ratio (LVMTV) was calculated by dividing the LVM by the left ventricular end-diastolic endocardial volume calculated by the Teichholz formula [18]. Abnormal cardiac geometry was diagnosed if LVMI ≥ 37.08 g/m2.7 in males, LVMI ≥ 34.02 g/m2.7 in females, or RWT > 0.36 in either males or females [19]. The Z-score calculator was based on the Pediatric Heart Network website (www.pediatricheartnetwork.com) [20].

Serum SIRT1 measurement

Serum SIRT1 levels were evaluated using enzyme-linked immunosorbent assay (ELISA) kits (mlbio, Shanghai, China; ml060273). Diluted samples were mixed with biotinylated antibodies in each sample well and incubated at 37 °C for 60 min with airtight and light-free. Subsequently, the chromogenic solution A/B and stop solution were added for 10 min in sequence. According to the instructions provided by the manufacturer, the SIRT1 levels were expressed as relative ng/ml (Quidel Corporation, San Diego, USA).

Statistical analysis

After conducting a Shapiro-Wilk test to determine normality, parametric continuous data were analyzed using a two-tailed Student’s t-test and expressed as mean ± standard deviation (SD). Non-parametric data were analyzed by the Mann-Whitney U test and expressed as median (interquartile range). Categorical variables were verified using the chi-square test and presented as numbers and percentages. The correlation between SIRT1, body mass index (BMI), and various parameters was evaluated using a non-parametric Spearman correlation. Furthermore, multifactor logistic regression was used to analyze the association between significant factors and outcomes. The statistical analysis was carried out using SPSS software (version 23.0; IBM, Armonk, NY, USA) and Prism 8.3.1 (GraphPad Software, La Jolla, California, USA). p < 0.05 was considered statistically significant.

Results

Demographic data and biochemical parameters of the population

After excluding 6 patients with missing clinical information, 87 children aged 8-17 years (median age 13.0 years, 67 males) with PH were enrolled in the hypertension group. A group of 39 healthy children with normal BP were selected as the control group. The clinical characteristics and biochemical parameters of all the subjects are presented in Table 1. There were no significant differences in the average ages and sex between the two groups. The body mass index (BMI) Z-score was significantly higher in the hypertension group than in the control group. Both systolic BP and diastolic BP in the hypertension group were substantially higher than those in the control group, the p level was less than 0.001 (Table 1). The levels of Scr, UA, TC, and HDL-C were higher in the hypertension group than in the control group, the difference had striking significance.

Table 1 The demographic data, biochemical parameters and SIRT1 levels in HTN and control groups
Full size table

Serum SIRT1 levels between hypertension and control group

Serum SIRT1 levels of all subjects were presented in ng/ml. The mean SIRT1 level in the hypertension group decreased significantly compared to the control group (p < 0.001,Table 1). We further separately analyzed the serum SIRT1 levels in children of different genders. In males,the serum SIRT1 levels showed a decrease in the case group (5.44 ± 2.42 ng/ml) compared to the control group (7.79 ± 2.02 ng/ml), p < 0.001. And in females,hypertensive patients (6.26 ± 2.37 ng/ml) also have lower levels of serum SIRT1 than children with normal BP (7.97 ± 1.42 ng/ml),p = 0.012.

Correlation analysis of SIRT1 in all subjects

We conducted Spearman correlation analysis between SIRT1, BMI Z-score, and BP to investigate their correlation. The results demonstrated a negative correlation between serum SIRT1 levels and systolic BP (r = -0.308, p < 0.001), as well as SIRT1 levels and diastolic blood pressure (r = -0.250, p = 0.005). Furthermore, a negative correlation between SIRT1 and BMI Z-score was confirmed (r = -0.225, p = 0.011). We also examined the correlation between SIRT1 and blood pressure levels in different genders and discovered a significant negative correlation in male children (SBP,r = -0.364, p < 0.001; DBP,r = -0.312, p = 0.003) but not in female children (SBP,r = -0.202, p = 0.236; DBP,r = -0.047, p = 0.786).

Multifactor binary logistic regression for hypertension

Multifactor logistic regression was used to analyze the association between the significant factors and pediatric PH. After adjusting for sex, age and puberty, BMI Z-score (p < 0.001) and SIRT1 (p = 0.002) on hypertension were independent risk factors (Table 2).

Table 2 Multifactor binary logistic regression analysis for hypertension
Full size table

Demographic data, biochemical parameters and SIRT1 levels in the LVH and non-LVH group

We evaluated all hypertensive patients for LVH using echocardiography. Of all 87 cases, 29 (33.3%) had LVH. Demographic data and biochemical parameters were compared between subgroups of patients. Compared to the non-LVH group, the LVH group showed an elevation in BMI Z-score and a reduction in SIRT1, the p levels were both less than 0.05 (Table 3). No substantial difference was found in other parameters between hypertensive children with and without LVH.

Table 3 The demographic data, blood pressure, SIRT1 levels and echocardiography parameters in LVH and non-LVH group
Full size table

Correlation analysis in pediatric PH

In subgroup analysis, Spearman correlation analysis revealed that SIRT1 was negatively correlated with LVMTV Z-score (p < 0.001) and LVM Z-score (p = 0.002) (Fig. 1). BMI Z-score did not show any statistical correlation with SIRT1 (r = 0.077, p = 0.479), systolic BP (r = 0.022, p = 0.840), diastolic BP (r = 0.182, p = 0.092), LVMTV Z-score (r = 0.071, p = 0.516), or LVM Z-score (r = -0.056, p = 0.605) in PH patients.

Fig. 1
figure 1

Scatter plot of correlation between SIRT1 and the indexes of Echocardiogram. LVM Z-score (a), LVMTV Z-score (b). LVM, left ventricular mass; LVMTV, left ventricular mass-to-volume ratio. * p < 0.05 is considered for statistical analysis

Full size image
Table 4 Multifactor binary logistic regression analysis for LVH
Full size table

Multiple multifactor binary logistic regression for LVH

Based on the multivariate logistic regression analysis adjusted for sociodemographic factors, as shown in Table 4, serum SIRT1 levels in patients with PH might be independent contributing factors to the occurrence of LVH. Moreover, BMI Z-score was also found to be an independent risk factor associated with LVH related to PH.

Discussion

PH in children and adolescents can cause pathological changes in multiple target organs, including the heart, great vessels, retina, and kidney [21]. This study evaluated serum SIRT1 levels in pediatric PH and its relationship with LVH. In this study, we first reported that SIRT1 levels were significantly decreased in children with pediatric PH compared to those with normal BP, and the degree of this decrease was positively correlated with elevated BP. In subgroup analysis, hypertensive patients with LVH had remarkably decreased serum SIRT1 levels compared to those in the non-LVH group. Furthermore, in hypertensive patients, a notable inverse association was observed between serum SIRT1 concentration and echocardiographic indicators of LVH, including LVM Z-score and LVMTV Z-score. Additionally, a decrease in SIRT1 levels might serve as an independent risk factor for potential LVH in pediatric PH and could predict LVH associated with PH.

SIRT1 is widely distributed in cardiovascular and renal systems and plays a causal role in various cardiovascular disorders [15]. Although there have been some animal and cell studies investigating the correlation between SIRT1 and BP [22, 23], there remains a dearth of clinical evidence, especially in children. In this study, we conducted a comparative analysis of serum SIRT1 levels in hypertensive and normotensive children and found that there was a decreased expression of SIRT1 in patients with PH. Further Spearman correlation analysis showed that SIRT1 levels were inversely correlated with BP levels. PH is a multifactorial and multigenic disease influenced by both environmental and genetic factors and the exact mechanism of SIRT1 and PH remains poorly understood.

The renin-angiotensin-aldosterone system, triggered by angiotensin II (Ang II), has a vital function in regulating BP [24]. Mouse research discovered a notable decrease in the expression of SIRT1 in the aorta in the hypertension model induced by Ang II, and over-expression of SIRT1 decreased the expression of NF-κB and the production of reactive oxygen species, thereby reducing vascular inflammation and ultimately alleviating Ang II induced hypertension [25]. Additionally, endogenous SIRT1 in aortic smooth muscle could alleviate Ang II elevation and regulate BP by suppressing the activity of oxidant-induced matrix metalloproteinases [26]. According to the above literature, SIRT1 might affect BP through regulating the renin-angiotensin-aldosterone system.

LVH, a type of hypertensive myocardial remodeling, could be led by sustained BP load [27]. LVH was considered to be the most common target organ damage of pediatric PH and could further develop into coronary heart disease, atrial fibrillation, varied arrhythmias, heart failure, and stroke [28, 29]. Some children had complications of LVH when they were first diagnosed with PH, which indicated subclinical cardiac damage [30, 31]. In this study, we comparatively analyzed the SIRT1 levels in patients with and without LVH. The results indicated that patients with LVH had notably lower SIRT1 levels. Then the correlation among SIRT1 levels, LVM Z-score and LVMTV Z-score were evaluated, and the result revealed that serum SIRT1 levels were negatively correlated with these echocardiographic indicators related to LVH. Furthermore, after adjusting for sociodemographic factors, multifactorial binary logistic regression analysis for LVH in hypertensive children indicated that SIRT1 was an independent risk factor for LVH. The exact mechanism between SIRT1 and LVH remain unclear. It has been confirmed that enhancement of SIRT1 activity could improve cardiac hypertrophy by inhibiting acetylation of PKC-ζ and PKC-ζ phosphorylation in cardiac hypertrophy [32]. Research on animals reported that SIRT1 expression was decreased in the left ventricular tissue of obesity hypertension rats with LVH, while it recovered following therapy [33]. The deacetylation impact of SIRT1 on PGC-1α was relevant to this. Additionally, it has been revealed that promoting the deacetylase activity of SIRT1 could protect the heart from cardiac hypertrophy and dysfunction induced by angiotensin II [34]. Thus, the effect of SIRT1 on LVH might be attributed to its deacetylation effect.

Hypertension has been proven to be associated with excess body weight. Obesity rates are higher in hypertensive children than in normotensive children [35] and children with PH have a higher rate of obesity [36]. A previous investigation discovered that the prevalence of hypertension in children increased from 3% in nonobese children to 25% in obese children [37]. The relationship between serum SIRT1 levels and obesity has also been previously described. Compared with the normal weight population, obese patients presented with reduced vascular expression of SIRT1, regardless of whether they were children and adults [38]. In this study, the analysis of all subjects revealed that the BMI Z-score in hypertensive patients were remarkably higher than those in children with normal BP. Correlation analyses revealed that BMI Z-score was positively correlated with BP levels and negatively correlated with SIRT1. These results were consistent with literature reports. However, there was no relationship between BMI Z-score and SIRT1 level in the subgroup analysis. These discrepancies might be due to the majority of the children in the hypertension group being obese and the insufficient number of cases. A study of adipose stem cells found that SIRT1 could modulate the differentiation of adipose stem cells (ASCs), and overexpression of SIRT1 in visceral ASCs from obese subjects inhibited ASCs differentiation and alleviated obesity [39]. Moreover, SIRT1 regulates obesity through autophagy. Reduced SIRT1 levels in adipose tissue disrupt the process of autophagy, resulting in the buildup of lipid droplets and development of obesity [40].

The hearts of patients with obesity can develop into cardiomyocyte hypertrophy. A study involving 3922 healthy subjects concluded that BMI was closely related to LVM, left ventricular wall thickness, and left ventricular internal size [41]. And this type of change also emerges in the child population [42]. In the present study, subgroup analysis showed that patients with LVH had significantly higher BMI than those without LVH and there was a positive correlation between BMI and LVMI (r = 0.396, p < 0.001). The relationship may be explained by an increase in cardiac output and blood volume, which in turn exerts tension on the left ventricular wall, leading to its dilation in obese patients [43].

Considering that this was a small-scale single-center study, the generalizability of our data might be limited. Additionally, the statistical power could have been limited by the small patient population and low number of females. Moreover, the lack of long-term follow-up could not determine the impact of SIRT1 levels on the development of PH and complications of LVH.

Conclusions

In conclusion, our results revealed that serum SIRT1 levels were significantly lower in children and adolescents with PH and that serum SIRT1 levels were negatively correlated with BP. To date, there have been no reports on the measurement of circulating SIRT1 in children with PH. Subgroup analysis indicated that patients with LVH had significantly lower levels of serum SIRT1, and decreased serum SIRT1 was an independent risk factor for LVH.

Data availability

The original contributions presented in this study are included in the article material, and further inquiries can be directed to the corresponding author.

Abbreviations

Ang II:

Angiotensin II

ASC:

Adipose Stem Cell

BMI:

Body Mass Index

BP:

Blood Pressure

HDL-C:

High-Density Lipoprotein Cholesterol

IVST:

Interventricular Septal Thickness

LDL-C:

Low-Density Lipoprotein Cholesterol

LVH:

Left Ventricular Hypertrophy

LVIDd:

Left Ventricular Internal Dimension

LVM:

Left Ventricular Mass

LVMI:

Left Ventricular Mass Index

LVPWT:

Left Ventricular Posterior Wall Thickness

PH:

Primary Hypertension

RWT:

Relative Left Ventricular Wall Thickness

Scr:

Serum Creatinine

SIRT1:

Sirtuin-1

TC:

Total Cholesterol

TG:

Triglyceride

UA:

Uric Acid

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Acknowledgements

Not applicable.

Funding

This study was supported by The Special Fund of Beijing Municipal Science & Technology Commission (Z211100002921035), and Capital’s Funds for Health Improvement and Research (CFH2022-3-2105).

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Authors and Affiliations

  1. Department of Cardiology, Children’s Hospital of Capital Institute of Pediatrics, No. 2, Yabao Road, Chaoyang District, Beijing, China

    Yuting Wang, Yao Lin, Hui Wang, Yaqi Li, Chen Shen & Lin Shi

  2. Peking Union Medical College Graduate School, Beijing, China

    Yuting Wang & Hui Wang

Authors
  1. Yuting Wang
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  2. Yao Lin
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Contributions

[YTW] contributed to the design of the study, literature overview, data analysis, and creation of the first draft of the manuscript. [YL] contributed to the analysis of the data and correction of the manuscript. [HW], [YQL], and [CS] contributed to the clinical diagnosis and sample collection. [LS] contributed to the manuscript design, final review, and correction of the manuscript. All authors have checked and approved the final manuscript.

Corresponding author

Correspondence to Lin Shi.

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Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Capital Institute of Pediatrics (No: SHERLL2022017). Written consent was obtained from the participant’s parents or guardians.

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Not applicable.

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The authors declare no competing interests.

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Wang, Y., Lin, Y., Wang, H. et al. The impact of decreased SIRT1 levels on pediatric primary hypertension and left ventricular hypertrophy: a case-control study. BMC Pediatr 25, 340 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12887-025-05671-z

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Keywords

BMC Pediatrics

ISSN: 1471-2431

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