Cardiovascular health in children and adolescents with obesity : prevalence, prediction and supervised exercise

Sammanfattning: Background: Cardiovascular disease (CVD) is a major cause of death worldwide and is preceded by a long process in which several cardiovascular (CV) risk factors are present, sometimes already in childhood. Some of these risk factors such as non-dipping blood pressure and microvascular endothelial dysfunction and possible associated factors are little studied among children with obesity. In addition to these CV risk factors, obesity in childhood is also associated with adverse CV health in general populations adults. However, the clinical value of childhood CV risk factors for identifying children at increased risk of adverse end-organ function in young adulthood is unclear. Weight loss is effective for improving CV risk factors but is found to be hard to achieve especially among adolescents with obesity. As such, new approaches to diminish their CV risk must be evaluated. Aims: In Study I, acetylcholine-induced endothelium-dependent vasodilatation was compared between children with obesity and children with normal weight. Associations between vasodilatation and potential risk factors were also studied. In Study II, the prevalence of nocturnal blood pressure dipping among prepubertal and early pubertal children with obesity was studied. In addition, associations between dipping and measures of insulin-glucose metabolism or sleep-disordered breathing were evaluated. In Study III, the aim was to evaluate whether well-established cardiovascular risk factors could be used clinically for the early identification of children and adolescents with obesity at risk of a rapid deterioration in cardiovascular health in young adulthood. In Study IV, the aim was to evaluate whether regular supervised individualised aerobic exercise for a period of three months could increase cardiorespiratory fitness (CRF), lead to improved long-term CRF, and affect CV risk factors among adolescents in obesity treatment. Subjects and methods: In Study I, endothelium-dependent vasodilatation was compared between 54 children (14.3 years old, 41% girls) with obesity and 44 (13.7 years old, 82% girls) normal-weight children. Acetylcholine was administered via transdermal iontophoresis to induce vasodilatation in the dorsal hand skin, and the subsequent change in perfusion was measured with laser Doppler flowmetry. In a subgroup of children with obesity, associations between acetylcholine-induced vasodilatation and inflammation, 24-hour ambulatory blood pressure (ABP), CRF, blood lipids, glucose/insulin metabolism, and duration of obesity were evaluated. In Study II, non-dipping—measured via 24-hour ABP and defined as nocturnal blood pressure reduction lower than 10%—was studied among 76 (10.4 years old, 41% girls) prepubertal and early pubertal children with obesity. Frequently sampled intravenous lucose-tolerance tests, fasting blood samples, and polygraph recordings were performed to study associations between dipping, insulin/glucose metabolism and sleep-disordered breathing. As a measure of end-organ damage, left ventricular mass (LVM) was measured using echocardiography and associations with the above factors were evaluated. The longitudinal, prospective cohort of Study III included 49 young adults (23.4 years old, 25 females) who had been extensively examined before entering a childhood obesity treatment program at an age of 13.8 years. At inclusion, 24-hour ambulatory blood pressure, blood lipids, CRF, and metabolic syndrome score were determined. Five to fifteen years later, a comprehensive cardiovascular follow-up was performed in which left ventricular mass, carotid intima-media thickness, arterial stiffness and endothelial function were considered as main outcomes. In Study IV, eight adolescents (15.1 years old) undergoing obesity treatment performed regular individualised aerobic exercise, supervised by a personal coach, for 3 months. The exercise was performed at an intensity of ≥ 150 bpm, for ≥ 30 minutes, 3 times per week. The adolescent was responsible for performing the exercise over the following 9 months. Biochemical factors (blood lipids, glucose, insulin and markers of inflammation), ambulatory blood pressure, body composition, endothelial function, arterial stiffness, CRF, metabolic syndrome score, pediatric health-related quality of life and objectively measured physical activity) were assessed before and after the 3 months of supervised exercise, and 9 months after the end of the supervised exercise. Results: In Study I, endothelium-dependent vasodilatory response to acetylcholine was lower in children with obesity compared with normal-weight children (p < 0.001), and peak perfusion was 33% lower among children with obesity (p = 0.001). The lowest vasodilatation was found among children with the shortest duration of obesity (p = 0.03). Except for a trend in association between vasodilatation and triglycerides (p = 0.07) no associations were found with 24-hour ABP, CRF, inflammation, or insulin/glucose metabolism. Study II showed a prevalence of 42% systolic non-dippers and 17% diastolic non-dippers among prepubertal and early pubertal children with obesity. Systolic and diastolic dipping were not associated with measures of insulin/glucose metabolism (adjusted for BMI SDS, sex and pubertal status) or with measures of sleep-disordered breathing. No associations were found between LVM index as a measure of end-organ damage and measures of blood pressure (p = 0.2–0.9), insulin/glucose metabolism (p = 0.2–0.9) or measures of sleep-disordered breathing (p = 0.3–1.0) (adjusted for BMI SDS, sex, and pubertal status). In Study III, childhood total serum cholesterol, triglycerides and daytime systolic blood pressure were positively associated with carotid intima-media thickness independent of sex and change in BMI SDS at follow up (p < 0.05). High blood pressure or dyslipidaemia in childhood did not predict increased left ventricular mass index, arterial stiffness, or endothelial dysfunction in young adult life. The strongest tracking correlations were for daytime diastolic blood pressure (r = 0.56, p < 0.01) and total cholesterol (r = 0.75, p < 0.001). At follow-up, severe obesity was present in 74% of subjects, although one-third had decreased their BMI SDS > 0.25 BMI SDS from childhood. In Study IV, supervised exercise increased absolute and relative CRF (0.65 ± 0.41, p = 0.01 and 6.02 ± 3.69, p = 0.01, respectively), but did not improve the CV risk factor profile or long-term CRF. Arterial stiffness decreased 9 months after the supervised exercise (-16 ± 11 units, p = 0.03), whereas gynoid fat percentage (1 ± 1 %, p = 0.04) and apolipoprotein B (0.11 ± 0.08 g/L, p = 0.01) increased. Conclusions: Children with obesity without comorbidities have impaired microvascular endothelial function compared with normal-weight children. Children with a longer duration of obesity, however, seem less affected. In addition, nocturnal non-dipping was highly present among prepubertal and early pubertal children with obesity. Compared with previous reports on children in general, non-dipping was about two times higher among children with obesity. No associations between dipping and insulin/glucose metabolism or measures of sleep-disordered breathing were found. Few associations between childhood CV risk factors and end-organ function in young adults previously attending childhood obesity treatment were found. However, childhood serum cholesterol, triglycerides, and systolic blood pressure were associated with carotid intima- media thickness, but not with other intermediate markers of increased cardiovascular risk in young adult life. Clinicians should evaluate blood lipids and 24-hour ABP and perhaps treat these factors, if elevated, starting in childhood to reduce the future risk of CVD these subjects appear to be exposed to. In this small but comprehensive study of the effects of supervised aerobic exercise in adolescents with obesity, it was found that short-term CRF increased, but there were no other statistically significant effects on CV risk factor profile or weight. The improved CRF was not maintained long-term when the adolescents exercised on their own, and the effect on CV risk factors was still absent, except for improved arterial stiffness. This exercise regimen cannot therefore be recommended for clinical implementation as a complement to childhood obesity treatment to reduce CV risk factors without weight reduction.