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Endothelial dysfunction and cardiovascular disease in childhood obesity
Disfunção endotelial e doença cardiovascular na obesidade infantil
Michael Freemark
Duke University Medical Center, Pediatric Endocrinology and Diabetes, Durham, United States
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"michael.freemark@duke.edu" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Duke University Medical Center, Pediatric Endocrinology and Diabetes, Durham, United States" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Disfunção endotelial e doença cardiovascular na obesidade infantil" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">It is a popular misconception that myocardial infarction and stroke are acute events that strike suddenly and unexpectedly in middle aged and elderly adults. Yet the Bogalusa, Muscatine, Young Finns, and PDAY studies clearly demonstrate that atherosclerosis is a chronic, progressive disease that begins in childhood.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">1</span></a> Identification of high-risk children and institution of preventive measures at an early age are therefore imperative.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Critical determinants of atherosclerosis in adolescence and adulthood include obesity, hyperlipidemia, hypertension, glucose intolerance, smoking, sedentary activity, and a family history of early cardiovascular disease and stroke. The earliest structural lesions of atherosclerosis, fatty streaks, can be detected even in young children. Accumulation of lipid-laden macrophages, monocytes, and T cells is followed by platelet aggregation, vascular smooth muscle cell proliferation, and the formation of a lesion capped by smooth muscle and collagen known as a fibrous plaque. But prior to the emergence of fatty streaks and plaques there are changes in endothelial function manifest as heightened permeability to lipoproteins, up-regulation of leukocyte adhesion molecules, and translocation of leukocytes into the arterial wall.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">2</span></a> These are associated with functional changes in micro- and macro-vascular compliance and reactivity that are associated, at least in adults, with mortality from cardiovascular disease.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">As assessed by reductions in flow-mediated dilation of the brachial artery and flow-mediated hyperemia of peripheral vessels, endothelial dysfunction has been demonstrated in children and adolescents with obesity and insulin resistance.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> Poorly understood, however, are the roles of diet and physical activity in the control of vascular function in obese and lean young people.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The study by Penha et al.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">5</span></a> examined the relationship between physical activity in prepubertal children and vascular function as measured by venous occlusion plethysmography. This method assesses changes in limb volume following venous occlusion. An acute increase in limb volume during venous outflow obstruction reflects arterial blood inflow, which depends on the capacity of the major arterial conduit vessels to overcome resistance of small arterioles; an inadequate rise in limb volume during venous occlusion reflects higher resistance, or lower vasodilatory capacity, of small resistance vessels. Thus, the technique is an indirect measure of the vasoreactivity of the microcirculation.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The authors found a reduced hyperemic response to venous occlusion in overweight and obese children, in association with measures of adiposity (% body fat and hyperleptinemia). Interestingly, there was no relationship between arterial vascular reactivity and physical fitness or habitual physical activity, as assessed by questionnaire and a speed-shuttle endurance run. Run performance did correlate negatively with body fat and waist circumference; whether a decrease in physical fitness is a cause or consequence (or both) of adiposity is currently unclear.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">1</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The authors did not explore the mechanisms by which obesity reduces microvascular reactivity in prepubertal children. A defect in vascular relaxation may signify a deficit of nitrous oxide (NO) generation by vascular endothelial cells or an impaired response of vascular smooth muscle cells to NO or other endogenous vasodilatory substances.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">6,7</span></a> Endothelial synthesis of NO is controlled in part by insulin and various other hormones and cytokines. In lean subjects, insulin promotes vasodilatation by increasing the expression of NO synthase (eNOS) in endothelial cells; this action is mediated by <span class="elsevierStyleItalic">tyrosine</span> phosphorylation of insulin receptor substrates 1 and 2 and activation of phosphoinositide 3-kinase (PI-3 kinase) and Akt. In obesity and other states associated with insulin resistance, <span class="elsevierStyleItalic">serine</span> phosphorylation of insulin receptor substrates inhibits activation of PI-3 kinase and Akt and impedes NO generation; under these conditions, insulin promotes <span class="elsevierStyleItalic">vasoconstriction</span> through mitogen-activated protein kinase (MAPK)-mediated induction of endothelin-1.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">6,7</span></a> The overweight subjects in this study were insulin resistant, as determined by hypoadiponectinemia and increases in HOMA-IR and the ratio of triglycerides to HDL. Nevertheless, the hyperemic response did not correlate with measures of insulin sensitivity.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In parallel with its effects on insulin sensitivity, obesity can impair endothelial function through visceral and perivascular fat accretion and vascular inflammation: obesity-induced hypertrophy of visceral and perivascular white adipocytes is accompanied by free fatty acidemia, macrophage infiltration, and generation of inflammatory cytokines and reactive oxygen species. In concert, these promote tissue inflammation, reduce vascular NO availability, and inhibit the smooth muscle cell vasodilatory response to NO.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">6–8</span></a> Other factors contributing to loss of vascular compliance in obesity include activation of the sympathetic nervous system by hyperleptinemia,<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">6–8</span></a> induction of renin-angiotensin-aldosterone activity via heightened white adipocyte angiotensinogen production,<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">6–9</span></a> and loss of capillary perfusion associated with hypoadiponectinemia.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">6–10</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">What is the significance of endothelial dysfunction in overweight and obese children? Loss of endothelial vasodilatation likely contributes to hypertension, a common co-morbidity in obese subjects, and to the development of obesity-related glomerulosclerosis.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">7</span></a> Of equal or more concern, experimental evidence suggests that endothelial dysfunction might limit cerebral blood flow and predispose to cognitive dysfunction.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">7</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The relationship between endothelial dysfunction in prepubertal children and adult cardiovascular disease is less clear. No studies to date clearly demonstrate that prepubertal endothelial dysfunction predisposes to myocardial infarction or stroke. On the other hand, obesity during childhood and adolescence increases the risks for coronary artery disease if excess fat deposition persists into adulthood. A large (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2.3 million), longitudinal study<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">11</span></a> of Israeli adolescents found that obesity at mean age 17.3 years was associated with a 4.9-fold increase in the risk of coronary artery disease and a 4.1-fold increase in cardiovascular deaths by ages 47–57 years. Lower (but statistically significant) risks of future acute coronary events (10% increase for every 1-unit increase in BMIz) were noted in a study of 7–13-year-old Danish children.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">12</span></a> Finally, a meta-analysis<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">13</span></a> showed that a 1-SD increase in BMI in childhood and adolescence (ages 7–18 years) predicts a 14–30% increase in the risk of adult coronary heart disease.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Nevertheless, the association of carotid intimal thickening with childhood obesity was abolished after adjustment for adult obesity in the Bogalusa, Muscatine and Young Finns studies.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">1</span></a> Moreover, cardiovascular mortality was not increased in adult Swedes who were obese in childhood but not during adolescence or adult life.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">14</span></a> Thus, endothelial dysfunction in children and obesity-related risks for cardiovascular morbidity and mortality are potentially reversible.</p><p id="par0055" class="elsevierStylePara elsevierViewall">What measures might be taken to reverse the endothelial dysfunction in obese children? Weight loss is known to promote NO generation, and a combination of diet and aerobic exercise training improves <span class="elsevierStyleItalic">macro</span>-vascular endothelial function in obese children in as little as 6–8 weeks<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">15,16</span></a>; more prolonged interventions may be needed to improve <span class="elsevierStyleItalic">micro</span>-vascular endothelial function.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">17</span></a> It is thought that surges in limb blood flow during bouts of physical activity may facilitate a rise in endothelial NO production and/or activity. Both aerobic and resistance training are effective<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">18</span></a>; however, the benefits of exercise on vascular function appear to be lost if training ceases.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">15</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Dietary and exercise counseling may not suffice for subjects with more severe metabolic dysfunction; in such cases, the addition of a pharmacologic agent may prove salutary. For example, an emerging literature suggests that metformin can enhance endothelial function in adults with severe insulin resistance, type 2 diabetes mellitus, and the polycystic ovary syndrome.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">19</span></a> The drug may therefore provide cardiovascular as well as glycemic benefits to adolescents with prediabetes or overt glucose intolerance. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) improve endothelial-dependent vasodilation in adults with renal disease<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">9,20</span></a> and may be useful in obese children and adolescents with hypertension and/or microalbuminuria.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Critical gaps remain in our understanding of the development and pathogenesis of vascular dysfunction and atherogenesis in children. Long-term studies of dietary and exercise interventions in overweight and obese subjects will enhance our ability to prevent long-term vascular complications and increase quality of life.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0070" class="elsevierStylePara elsevierViewall">The author declares no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Freemark M. Endothelial dysfunction and cardiovascular disease in childhood obesity. J Pediatr (Rio J). 2019;95:503–5.</p>" ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">See paper by Penha et al. in pages 531–7.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0105" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Childhood obesity in the modern age: global trends, determinants, complications and costs" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "M. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 4 | 8 |
| 2024 October | 22 | 21 | 43 |
| 2024 September | 24 | 29 | 53 |
| 2024 August | 31 | 31 | 62 |
| 2024 July | 33 | 41 | 74 |
| 2024 June | 14 | 35 | 49 |
| 2024 May | 27 | 11 | 38 |
| 2024 April | 33 | 24 | 57 |
| 2024 March | 18 | 24 | 42 |
| 2024 February | 15 | 22 | 37 |
| 2024 January | 16 | 24 | 40 |
| 2023 December | 12 | 28 | 40 |
| 2023 November | 22 | 35 | 57 |
| 2023 October | 20 | 36 | 56 |
| 2023 September | 18 | 37 | 55 |
| 2023 August | 14 | 16 | 30 |
| 2023 July | 17 | 15 | 32 |
| 2023 June | 14 | 12 | 26 |
| 2023 May | 17 | 15 | 32 |
| 2023 April | 15 | 8 | 23 |
| 2023 March | 31 | 23 | 54 |
| 2023 February | 18 | 9 | 27 |
| 2023 January | 15 | 15 | 30 |
| 2022 December | 32 | 18 | 50 |
| 2022 November | 15 | 21 | 36 |
| 2022 October | 34 | 33 | 67 |
| 2022 September | 19 | 34 | 53 |
| 2022 August | 22 | 26 | 48 |
| 2022 July | 18 | 31 | 49 |
| 2022 June | 17 | 40 | 57 |
| 2022 May | 16 | 33 | 49 |
| 2022 April | 47 | 38 | 85 |
| 2022 March | 20 | 47 | 67 |
| 2022 February | 9 | 25 | 34 |
| 2022 January | 8 | 20 | 28 |
| 2021 December | 17 | 20 | 37 |
| 2021 November | 5 | 12 | 17 |
| 2021 October | 7 | 16 | 23 |
| 2021 September | 6 | 6 | 12 |
| 2021 August | 15 | 16 | 31 |
| 2021 July | 14 | 5 | 19 |
| 2021 June | 16 | 5 | 21 |
| 2021 May | 18 | 11 | 29 |
| 2021 April | 19 | 8 | 27 |
| 2021 March | 10 | 10 | 20 |
| 2021 February | 17 | 9 | 26 |
| 2021 January | 9 | 14 | 23 |
| 2020 December | 22 | 12 | 34 |
| 2020 November | 8 | 12 | 20 |
| 2020 October | 7 | 8 | 15 |
| 2020 September | 13 | 16 | 29 |
| 2020 August | 18 | 5 | 23 |
| 2020 July | 9 | 14 | 23 |
| 2020 June | 15 | 13 | 28 |
| 2020 May | 11 | 15 | 26 |
| 2020 April | 9 | 26 | 35 |
| 2020 March | 12 | 12 | 24 |
| 2020 February | 11 | 12 | 23 |
| 2020 January | 19 | 19 | 38 |
| 2019 December | 20 | 8 | 28 |
| 2019 November | 19 | 16 | 35 |
| 2019 October | 41 | 41 | 82 |
| 2019 September | 6 | 9 | 15 |
| 2019 August | 8 | 8 | 16 |
| 2019 July | 13 | 6 | 19 |
| 2019 June | 4 | 9 | 13 |
| 2019 May | 8 | 8 | 16 |
| 2019 April | 11 | 9 | 20 |
| 2019 March | 6 | 5 | 11 |
| 2019 February | 4 | 5 | 9 |
| 2019 January | 6 | 5 | 11 |
| 2018 December | 6 | 6 | 12 |
| 2018 November | 32 | 8 | 40 |
| 2018 October | 71 | 23 | 94 |
| 2018 September | 4 | 0 | 4 |
| 2018 August | 15 | 7 | 22 |
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