The mechanisms that regulate blood pressure are numerous and complex; one mechanism that plays an important role in this scenario is represented by the balance between the vasoconstrictor effect of endothelin-1 and the vasodilator effect of nitric oxide. While there is agreement on the fact that increased endothelin-1 activity and decreased nitric oxide bioavailability are present in hypertensive adults, the situation is less clear in children and adolescents. Not all studies agree on the finding of an increase in plasma endothelin-1 levels in hypertensive children and adolescents; in addition, the picture is often confused by the concomitant presence of obesity, a condition that stimulates the production of endothelin-1. Furthermore, there is recent evidence that, in younger obese and hypertensive subjects, there is an overproduction of nitric oxide, rather than a reduction. This condition may change over time, causing endothelial dysfunction due to a reduced availability of nitric oxide in hypertensive adolescents. The purpose of this review is to address the main biochemical and pathophysiological aspects of endothelin and nitric oxide involvement in hypertension and to summarize the available scientific evidence on their role in the onset and maintenance of high blood pressure in children and adolescents.

It has been argued that metabolically healthy obesity (MHO) does not increase the risk of cardiovascular disease. The aim of this study is to evaluate whether, in a population of obese children/adolescents, the metabolically unhealthy obesity (MUO) phenotype is associated with higher left ventricular mass index and/or higher prevalence of left ventricular hypertrophy than the MHO phenotype. We also tested whether the addition of an insulin resistance index (HOMA-index >90th percentile by sex and age) and the presence of hyperuricemia (serum uric acid >90th percentile by sex and age) to the definition of MUO better identified obese children with early cardiac damage. Left ventricular hypertrophy was defined as the presence of left ventricular mass index greater than or equal to the age- and sex-specific 95th percentile.The study population included 459 obese children (males 53.2%, mean age 10.6 [standard deviation, 2.6] years), of whom 268 (58.4%) were MUO. The left ventricular mass index was higher in MUO children than in MHO children (37.8 vs 36.3 g/m2.7, p=0.015), whereas the percentage of MUO children presenting left ventricular hypertrophy was only slightly higher in MUO children (31.1 vs 40%, p=0.06). Multiple linear regression analyses showed that the variables significantly associated with higher left ventricular mass index were male gender (p<0.01), Body Mass Index z-score (p<0.001) and Waist-to-Height-ratio (p<0.001). Multiple logistic regression analyses showed that the presence of left ventricular hypertrophy was only significantly associated with higher Body Mass Index z-score (p<0.05) and Waist-to-Height-ratio (p<0.05). In spite of the higher left ventricular mass index of MUO as compared to MHO children, the MUO phenotype was not a significant predictor of either higher left ventricular mass index or higher left ventricular hypertrophy prevalence. The MUO phenotype had a low predictive ability on the presence of left ventricular hypertrophy. The area under the receiver operating characteristic curve was 0.57 (sensitivity 0.64, 1-specificity 0.55). The addition of insulin resistance and hyperuricemia to the definition of MUO did not change the results observed with the standard definition of MUO at multivariable analysis.The MUO phenotype appears to be of little usefulness in identifying the early presence of cardiac damage in a large population of obese children and adolescents. Excess weight and abdominal obesity are confirmed as an important determinant of early organ damage in obese children.

Cardiometabolic risk factors are frequent in children and adolescents with excess weight. The aim of this study was to evaluate the effects of lifestyle modifications on alterations in lipid and glycemic profiles and uric acid values in a pediatric population at increased cardiovascular risk. The study involved 276 subjects with a mean age of 10.6 (2.3) years. Body mass index (BMI) z-score and biochemical parameters (serum low-density lipoprotein (LDL) cholesterol, triglycerides and uric acid and homeostasis model assessment to quantify insulin resistance (HOMA index)) were assessed at baseline and at the end of a median follow-up of 14.7 (12.4, 19.3) months. Throughout follow-up, all children received a non-pharmacological treatment based on increased physical activity, reduced sedentary activity and administration of a personalized, healthy and balanced diet. All children attended periodic quarterly control visits during follow-up. Multivariable statistical analyses showed that each BMI z-score point reduction at follow-up was associated with an 8.9 (95%CI −14.2; −3.6) mg/dL decrease in LDL cholesterol (p = 0.001), 20.4 (95%CI −30.0; −10.7) mg/dL in triglycerides (p < 0.001), 1.6 (95%CI −2.2; −1.0) in HOMA index (p < 0.001), and 0.42 (95%CI −0.66; −0.18) mg/dL in uric acid (p = 0.001) values. At each reduction of the BMI z-score by one point, the odds of presenting with insulin resistance and hyperuricemia at follow-up significantly decreased (OR 0.23, 95%CI 0.10–0.50, and OR 0.32, 95%CI 0.10–0.95, p < 0.001 and p < 0.05, respectively). Improvement of dietary habits and lifestyles may improve lipid and glycemic profiles and serum uric acid values in a pediatric population.

Arterial hypertension, dyslipidemia, alterations in glucose metabolism and fatty liver, either alone or in association, are frequently observed in obese children and may seriously jeopardize their health. For obesity to develop, an excessive intake of energy-bearing macronutrients is required; however, ample evidence suggests that fructose may promote the development of obesity and/or metabolic alterations, independently of its energy intake. Fructose consumption is particularly high among children, because they do not have the perception, and more importantly, neither do their parents, that high fructose intake is potentially dangerous. In fact, while this sugar is erroneously viewed favorably as a natural nutrient, its excessive intake can actually cause adverse cardio-metabolic alterations. Fructose induces the release of pro-inflammatory cytokines, and reduces the production of anti-atherosclerotic cytokines, such as adiponectin. Furthermore, by interacting with hunger and satiety control systems, particularly by inducing leptin resistance, it leads to increased caloric intake. Fructose, directly or through its metabolites, promotes the development of obesity, arterial hypertension, dyslipidemia, glucose intolerance and fatty liver. This review aims to highlight the mechanisms by which the early and excessive consumption of fructose may contribute to the development of a variety of cardiometabolic risk factors in children, thus representing a potential danger to their health. It will also describe the main clinical trials performed in children and adolescents that have evaluated the clinical effects of excessive intake of fructose-containing drinks and food, with particular attention to the effects on blood pressure. Finally, we will discuss the effectiveness of measures that can be taken to reduce the intake of this sugar.

Background: High blood pressure (BP) and excess weight can lead to early cardiovascular organ damage already in children. Carotid-femoral pulse wave velocity (cf-PWV) is the non-invasive gold standard method for assessing aortic stiffness, while carotid-radial PWV (cr-PWV) provides information on the distensibility of the upper limb arteries. The aim of this study was to evaluate the relationship of BP and BMI z-scores with arterial stiffness and left ventricular mass index (LVMI) in a pediatric population. Methods: In 343 children (57.7% males; age ± SD 11.7 ± 2.9 years), systolic (SBP) and diastolic (DBP) BP, BMI, cf-PWV, cr-PWV and LVMI were measured. A multiple linear regression model was used to assess the impact of BMI and SBP (or DBP) z-scores on cf-PWV, cr-PWV and LVMI. Results: About 21% of children were normal weight, 34% were overweight and 45% obese. Adjusted for possible confounders, SBP and DBP z-scores were significantly associated with cf-PWV (p < 0.001), while only DBP z-scores were related to cr-PWV (p < 0.01). BMI was neither associated with cf-PWV nor with cr-PWV values but was a strong predictor of LVMI (<0.001), whereas cardiac mass and BP z-scores were not related. Conclusions: Our study suggests that, in children, elevated BP values and excess weight may have different effects on the heart and the vessels in causing early cardiovascular alterations.