Systemic anti-oxidant capacity is inversely correlated with systolic blood pressure and pulse pressure in children with obesity

Journal Pre-proof Systemic Anti-Oxidant Capacity Is Inversely Correlated With Systolic Blood Pressure And Pulse Pressure In Children With Obesity Anita Morandi, Massimiliano Corradi, Claudia Piona, Elena Fornari, Rossella Puleo, Claudio Maffeis PII:

S0939-4753(19)30389-8

DOI:

https://doi.org/10.1016/j.numecd.2019.10.008

Reference:

NUMECD 2170

To appear in:

Nutrition, Metabolism and Cardiovascular Diseases

Received Date: 23 April 2019 Revised Date:

1 October 2019

Accepted Date: 10 October 2019

Please cite this article as: Morandi A, Corradi M, Piona C, Fornari E, Puleo R, Maffeis C, Systemic Anti-Oxidant Capacity Is Inversely Correlated With Systolic Blood Pressure And Pulse Pressure In Children With Obesity, Nutrition, Metabolism and Cardiovascular Diseases, https://doi.org/10.1016/ j.numecd.2019.10.008. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V. on behalf of The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University.

SYSTEMIC ANTI-OXIDANT CAPACITY IS INVERSELY CORRELATED WITH SYSTOLIC BLOOD PRESSURE AND PULSE PRESSURE IN CHILDREN WITH OBESITY Anita MORANDIa, Massimiliano CORRADIa, Claudia PIONAa, Elena FORNARIa, Rossella PULEOa, Claudio MAFFEISa a. Pediatric Diabetes and Metabolic Disorders Unit, Integrated University Hospital of Verona, Verona, Italy

Corresponding Author: Claudio Maffeis Pediatric Diabetes and Metabolic Disorders Unit University Hospital of Verona 1, Piazzale Stefani, 37121, Verona Phone: +39 045 8127664 E-mail: [email protected]

Abstract word count: 202 Text word count: 2105 Number of references: 37 Number of figures: 2 Number of tables: 1

ABSTRACT:

BACKGROUND AND AIMS: oxidative stress leading to endothelial dysfunction is a candidate driver of obesity-related hypertension. We aimed to assess whether the total anti-oxidant capacity (TAC) was associated with blood pressure in children/adolescents with obesity. METHODS AND RESULTS: one hundred and fifty-two children/adolescents with obesity (79 boys; age 11.9+/-2.5 years) underwent blood drawing for the assessment of TAC, lipids and HOMA-IR. Blood pressure was measured and classified according to the latest American Academy of Pediatrics Guidelines. Serum TAC was measured by a commercial kit (Sigma- Aldrich). The average TAC was 1.11+/-0.4 mMol/Trolox equivalents. Systolic blood pressure was predicted by TAC (B=-5.8, p=0.003), z-BMI (B=2.39, p=0.008),height[cm] (B=0.38, p<0.001) and diastolic blood pressure (B=0.56, p<0.001). Diastolic blood pressure was predicted by age[years] (B=0.58, p=0.001), log-HOMA-IR (B=3.0, p=0.002), and systolic blood pressure (B=0.26, p<0.001), but not by TAC. The pulse pressure was predicted only by TAC (B=- 6.6, p=0.002), and height[cm] (B=0.42, p<0.001). Overall “elevated blood pressure + hypertension” or hypertension alone were not associated with TAC. However, systolic “elevated blood pressure + hypertension” was associated with TAC (OR=0.4[0.1-0.9], p=0.037), and z-BMI (OR=2.1[1.3-3.6], p=0.004). CONCLUSION: the systemic anti-oxidant capacity is inversely associated with systolic blood pressure and pulse pressure in children and adolescents with obesity.

INTRODUCTION: Hypertension is a frequent complication of obesity from childhood onwards and is a strong causal predictor of long term cardiovascular morbidity and mortality [1].Therefore, understanding the mechanisms linking childhood obesity to increased blood pressure would be of great importance to guide research on potential options to prevent or treat hypertension in the child with obesity, beyond lifestyle changes and weight loss. Oxidative stress is a candidate driver of increased blood pressure in childhood obesity [2]. In fact, in people with obesity, reactive oxygen species (ROS) are largely produced by the NADPH oxidase expressed in the adipose tissue and muscle [3-5]. This favors mitochondrial damage and activation of the inflammatory NF-KB cascade, leading to insulin resistance (IR) and further ROS production, which in turn causes endothelial dysfunction , a wellknown cause of increased blood pressure in both adults and children (6-10) . ROS also directly impair the vascular function by reacting with the nitric oxide (NO), thus decreasing its availability [11-13]. Oxidative stress has been well documented in children and adolescents with obesity [2, 14-17]. However, evidence about the potential role of oxidative stress in increasing the blood pressure of children and adolescents with obesity is scarce and based on very small cohorts [16-18]. In particular, one study highlighted a positive correlation between plasma peroxy radicals and systolic blood pressure in twenty-four obese children [16], another one reported an association between oxidized-LDL (ox-LDL) and hypertension and a correlation between ox-LDL and systolic blood pressure in thirty-eight obese children [19], and a last one described a positive correlation between urine 8-isoprostane, a marker of oxidative stress, and systolic ambulatory blood pressure (ABP) in twenty-five obese children. Besides relying on small cohorts of children, all the above-mentioned studies focused on single markers of oxidative stress, thus failing to capture possible associations between blood pressure and global systemic red-ox status. The measures of global red-ox status are stronger indices of oxidative stress and are probably a more appropriate potential therapeutic target compared to single markers. The total anti-oxidant capacity (TAC) of serum, which is a measure of the net serum capacity to reduce the Cu2+ ion, results from the sum of serum anti-oxidant molecules and oxidant molecules neutralizing each other, thus representing a measure of global systemic red-ox status [19]. We aimed to assessing the association between serum TAC and blood pressure in a cohort of children and adolescents with obesity. METHODS: One hundred and fifty-two children/adolescents with obesity (79 boys; age 11.9+/-2.5 years) were consecutively recruited at the Obesity Out-Patient Clinic of the Pediatric Diabetes and Metabolic Disorders Unit of the University Hospital of Verona and underwent physical examination and blood drawing in the morning after overnight fasting. Inclusion criteria were: age above six years, presence of obesity defined as a BMI above the 97° percentile of the WHO reference charts, according to the Italian Society for Pediatric Endocrinology and Diabetes Consensus [20], no drug or supplement assumed in the past three months, no chronic disease apart from obesity. Blood pressure was measured and classified according to the latest American Academy of Pediatrics Guidelines [1]. In details, blood pressure was measured with an aneroid auscultatory device using the most appropriate cuff for the patient’s arm size [1]. If the first measure was elevated (≥ 90° percentile), two additional measures were taken in the same visit and averaged [1]. Blood pressure

was classified in the normal, elevated or hypertensive category according to the guidelines cut-offs [1]. Pulse pressure, i.e. the difference between systolic and diastolic blood pressure, was also taken into account as a predictor of vascular damage [21].The degree of adiposity was estimated as the zscore of the BMI according to the WHO reference charts [22]. Serum TAC was measured with a commercial kit (Sigma- Aldrich). Cu2+ ion is converted to Cu+ by both small molecules and proteins. The reduced Cu+ ion chelates with a colorimetric probe, giving a broad absorbance peak at ~570 nm, which is proportional to the total antioxidant capacity. The kit gives antioxidant capacity in Trolox equivalents (ranging from 4-20 nmole/well). Trolox, a water-soluble vitamin E analog, serves as an antioxidant standard. Besides TAC, traditional metabolic markers were measured to be used as potential confounders of the relationship between oxidative status and blood pressure. In details, triglycerides (TG), total cholesterol (TC), and high density lipoproteincholesterol (HDL-C) were measured using commercial enzyme-based assays (Siemens, Dimension Vista System, Newark, DE), fasting plasma glucose (FPG) was measured by the Trinder method (Sclavo Diagnostics International, Siena, Italy), and fasting serum insulin (FSI) was measured with a commercial ELISA kit (Mercodia, Upsala, Sweden). Homeostasis model assessment of IR (HOMA-IR) was defined as [FPG (mg/dL) * FSI (µU/mL)/405] and used as an estimate of insulin resistance. The distribution of continuous variables was checked by the Kolgomorov-Smirnov test and skewed variables were log-transformed to reach a normal distribution. Pearson bivariate correlations were run between TAC and blood pressure measures and the other continuous variables in order to detect potential confounders of the relationship between TAC and blood pressure. Continuous and dichotomous variables were compared across genders by Student t test and Chi Squared test respectively. Then, general linear models and backward binary logistic models were run to test whether TAC was associated with the blood pressure as continuous variable or dichotomous variable respectively. The potential confounders highlighted by bivariate correlations or Student t test or Chi squared test were entered in both the linear and the logistic models. Blood pressure was dichotomized both as hypertension versus all other values and as “hypertension + elevated blood pressure” versus normal blood pressure. All statistical analyses were performed by IBM SPSS 24. All the parents of the participants gave their written consent to the participation of their children in the study. The study was approved by the local Ethical Committee of the University Hospital of Verona.

RESULTS: The characteristics of the study participants altogether and separated by gender are displayed in table 1. The average TAC was 1.11+/-0.45 mMol/Trolox equivalents. TAC correlated inversely with BMI z-score (r = - 0.23, p = 0.002), log-HOMA-IR (r = -0.19, p = 0.01),systolic blood pressure (r = -0.29, p < 0.001) and pulse pressure (r = -0.30, p < 0.001). Besides TAC, systolic blood pressure correlated with diastolic blood pressure (R = 0.50, p < 0.001), pulse pressure (0.81, p < 0.001), age (r = 0.47, p < 0.001), height (r = 0.57, P < 0.001), BMI z-score (r = 0.46, p < 0.001), log-HOMA-IR (r = 0.36, p < 0.001), and HDL-C (r = -0.29, p < 0.001). Besides systolic blood pressure, diastolic blood pressure correlated with age (r = 0.28, p <

0.001), height (r = 0.24, p < 0.001), BMI z-score (0.36, p < 0.001), log-HOMA-IR (r = 0.42, p < 0.001), HDL-C (r = -0.21, p = 0.008) and TG (r = 0.34, p < 0.001). Besides TAC and systolic blood pressure, pulse pressure correlated with age (r = 0.35, p < 0.001), height (r = 0.49, p < 0.001), BMI z-score (r = 0.28, p < 0.001) and HDL-C (r = - 0.18, p = 0.023). In general linear models, systolic blood pressure was predicted by TAC (B=- 5.8, p=0.003), z-BMI (B = 2.39, p = 0.008), height[cm] (B = 0.38, p < 0.001) and diastolic blood pressure (B = 0.56, p < 0.001) (Figure 1). Diastolic blood pressure was predicted by age[years] (B=0.58, p=0.001), logHOMA-IR (B=3.0, p=0.002), and systolic blood pressure (B = 0.26, p < 0.001), but not by TAC. The pulse pressure was predicted only by TAC (B = - 6.6, p = 0.002), and height[cm] (B = 0.42, p < 0.001) (Figure 2). The prevalence of elevated blood pressure and hypertension was 23% and 25% respectively in the whole population and did not vary significantly by gender (Table 1). TAC was not associated with overall “elevated blood pressure + hypertension” or hypertension alone, but was negatively associated with systolic “elevated blood pressure + hypertension” (OR = 0.4[0.1-0.9], p = 0.037), independently of the other significant predictor: z-BMI (OR = 2.1[1.3-3.6], p = 0.004). TAC was not associated with diastolic “elevated blood pressure + hypertension” or diastolic hypertension alone.

DISCUSSION: The study highlights that the systemic anti-oxidant capacity of children and adolescents with obesity correlates inversely with their systolic blood pressure and pulse pressure and is negatively associated with their risk of hypertensive systolic blood pressure. In the studied cohort, characterized by an average TAC of 1.11 +/- 0.45 mMol/Trolox equivalents, a unitary increase of the TAC, i.e. about a two standard deviations increase, corresponded to a decrease in the systolic blood pressure around 6 mmHg, and a decrease in the pulse pressure around 7 mmHg. Moreover, it is associated with and a more than 50% decrease of the odds to present with elevated or hypertensive systolic blood pressure. This suggests a clinically relevant relationship between redox status and systolic blood pressure and pulse pressure in youth with obesity. To our knowledge, the study describes the largest cohort of children and adolescents with obesity ever studied as regards the relationship between oxidative stress and blood pressure in youth with obesity. Moreover, this is the first study assessing the relationship between redox status and blood pressure in children with obesity by means of a measure of total oxidative status rather than markers of oxidative stress. Previous studies in general or mainly normal weight pediatric populations did not find significant correlations between markers of oxidative stress and blood pressure [15, 23-24]. In contrast, all of the three studies previously performed in cohorts of children and adolescents with obesity are in accordance with ours [16-18]. It is very intriguing that both the present study and the three above-mentioned ones highlighted a relationship between oxidative stress and systolic blood pressure and not between oxidative stress and diastolic blood pressure. This could be explained hypothesizing that oxidative stress would increase the blood pressure by producing endothelial dysfunction. In fact, endothelial dysfunction correlates much more strongly with systolic blood

pressure than with diastolic blood pressure, as demonstrated by the Framingham study in more than three thousand adults who underwent the assessment of FMD and blood pressure [8]. This is the first study assessing the relationship between redox status and pulse pressure in children and adolescents. The role of pulse pressure in young adults is still debated and there is evidence that a high pulse pressure among young adults may just represent a high pulse pressure amplification from central to peripheral vessels and may even be a favorable cardiovascular predictor in young adults with first stage hypertension [25-28]. However, recent longitudinal data from a large pediatric cohort followed into adulthood have shown that in a general child population pulse pressure correlates positively with adult arterial stiffness and subclinical vascular damage [21]. The evidence of relationship between TAC and systolic blood pressure and pulse pressure in children/adolescents with obesity is very interesting from the clinical point of view. In particular, it suggests that clinical trials aiming to reduce the systolic blood pressure and/or the pulse pressure of children with obesity by improving their anti-oxidant capacity are warranted. In fact, nutritional counseling and dietary supplements could improve the blood pressure of children and adolescents with obesity in a safe and effective way, without implying weight loss or the use of drugs. Interestingly, diet is associated with the systemic oxidative status in humans [13, 29-30] and previous trials have shown that increasing the anti-oxidant capacity by vitamin E supplementation improves arterial compliance [31] and decreases the systolic blood pressure and, to a much lesser extent, the diastolic blood pressure in mildly hypertensive adults [32]. There is also evidence that the antioxidant capacity of green tea and cocoa is associated with a decrease in the blood pressure, making these plant-derived nutraceuticals interesting potential tools against hypertension [33-37]. The main strengths of the study are the relatively large size of the cohort of obese children/adolescents assessed and the use of a measure of global red-ox status to investigate the relationship between oxidation and blood pressure in obese children/adolescents. The main limitations is the lack of data on endothelial function of participants, which makes not possible to confirm the hypothesis that the red-ox status influences the blood pressure by modulating the endothelial function. Other limitations are the lack of data on sodium/potassium intake and excretion and on physical activity and the lack of prospective data. In conclusion, our study provides evidence that the systemic oxidative status may influence the systolic blood pressure and the pulse pressure of children and adolescents with obesity. Trials targeting the anti-oxidant capacity of children and adolescents with obesity to improve their blood pressure, are warranted.

Acknowledgements: Anita Morandi designed the study and analysed data, Massimiliano Corradi carried out experiments, Elena Fornari, Claudia Piona and Rossella Puleo recruited and examined patients and prepared the study database, Anita Morandi and Claudio Maffeis wrote the manuscript. All authors had final approval of the submitted version. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Table 1: characteristics of the studied cohort by gender. Girls (N=73)

Boys (N=79)

P

Age (years) Height(meters) Weight (kilograms) BMI z-BMI Total cholesterol (mg/dl) HDL-cholesterol (mg/dl) Triglycerides (mg/dl) Log-HOMA-IR Systolic Blood Pressure (mmHg) Diastolic Blood Pressure (mmHg) Pulse pressure (mmHg) TAC (mMol/Trolox equivalents) Hypertension [proportion(percentage]

11.6(2.7) 1.50(0.12) 68.2(22.9) 29.2(6.4) 2.69(0.88) 155.3(33.8) 46.7(12.5) 101.7(79.7) 1.31(0.67) 112.0(11.9) 67.2(8.3) 44.8(10.7) 1.18(0.39) 14/73 (19.2%)

12.2(2.3) 1.57(0.15) 75.5(26.9) 29.6(6.2) 2.87(0.74) 153.1(29.6) 49.0(12.6) 91.3(91.3) 1.30(0.67) 115.9(14.8) 67.6(7.9) 48.4(12.8) 1.06(0.40) 24/79 (30.3%)

0.14 0.02 0.16 0.80 0.22 0.63 0.63 0.09 0.67 0.06 0.95 0.06 0.53 0.13

Elevated Blood Pressure + Hypertension [proportion(percentage] Systolic hypertension [proportion(percentage] Systolic elevated blood pressure + hypertension [proportion(percentage] Diastolic Hypertension [proportion(percentage] Diastolic elevated blood pressure + hypertension [proportion(percentage]

32/73 (43.8%)

41/79 (51.8%)

0.33

12/73 (16.4%)

20/79 (25.3%)

0.23

27/73 (36.9%)

40/79 (50.6%)

0.10

7/73 (9.5%)

8/79 (10.1%)

1

12/73 (16.4%)

13/79 (16.4%)

1

Total (N=152) 11.9(2.5) 1.54(0.14) 72.2(24.7) 29.4(6.3) 2.83(0.74) 153.7(31.3) 47.7(12.5) 96.2(65.9) 1.31(0.67) 114.0(13.5) 67.4(8.0) 46.6(11.8) 1.11(0.40) 38/152 (25.0%) 73/152 (48.0%) 32/152 (21.0%) 67/152 (44.0%) 15/152 (9.8%) 25/152 (16.4%)

Figure Legends: Figure 1: Correlation between TAC and standardized systolic blood pressure (adjusted for height, Z-BMI and diastolic blood pressure). Figure 2: Correlation between TAC and standardized pulse pressure (adjusted for height).

HIGHLIGHTS:

The systemic anti-oxidant capacity is inversely associated with systolic blood pressure in children with obesity; The systemic anti-oxidant capacity is inversely associated with pulse pressure in children with obesity; The systemic anti-oxidant capacity is inversely associated with systolic “elevated blood pressure + hypertension” in children with obesity.