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Endothelial Dysfunction in Obese Children Biochemistry Section Namrata ChhaBra, SahiBa KuKreja, Sahil ChhaBra, Sarah ChhaBra, KaviSh rameSSur that link obesity to endothelial dysfunction. Endothelial The magnitude of lifetime risk of cardiovascular disease dysfunction is a reversible disorder, pharmacological (CVD) has radically increased along with the high and non pharmacological interventions can reverse the prevalence of obesity in children. The risk factors emerge changes. Weight loss leads to an attenuation of the pro- quite early in the clinical course of obesity, which might inflammatory state and the physical exercise increases have important consequences for the development the synthesis and release of nitric oxide, which leads of atherosclerosis later in life. Endothelial dysfunction to augmented flow-mediated dilation and improvement represents a key early step in the development of in endothelial function. These changes are consistent atherosclerosis and is also involved in plaque progression with a decreased risk of atherosclerotic progression and and the occurrence of atherosclerotic complications. reduced risk of cardiovascular disease in obese children.
Endothelial changes are known to commence in Obesity is associated with both endothelial dysfunction childhood and are present in severely obese children. In and increased risk of CVD. Measurement of endothelial endothelial dysfunction, there is a reduction in the bio- dysfunction in children can predict the onset of availability of vasodilators whereas endothelial derived atherosclerosis. Non pharmacological and pharmacological contracting factors are increased; aside from that there interventions targeting obesity can improve clinical is a state of ‘Endothelial activation' that favors all stages cardiovascular outcomes in obese children.
of atherogenesis. Insulin resistance and the presence of a proinflammatory state are two likely mechanisms Keywords: Atherosclerosis, Cardiovascular disease (CVD), Endothelial dysfunction, Endothelial activation, Insulin resistance, Nitric oxide, Obesity alone. Several factors contribute to the obesity epidemic. The increasing prevalence of medically significant childhood The sustained excess of energy-dense foods, an increasingly obesity raises great concern. Childhood obesity has more sedentary lifestyle—attributed in part to urbanization, which than doubled in children and tripled in adolescents in the past limits the opportunities for physical activity, are the major 30 years [1]. In 2010, more than one third of children and causes of energy imbalance leading to childhood obesity. adolescents were overweight or obese [1].
The metabolic programming can occur as a result of in utero Although body mass index (BMI) >25 indicates overweight environmental exposures [7]. Small-for-gestational age babies and >30 defines obesity in adults, the diagnosis of overweight have an increased incidence of adverse health outcomes in children relies on age-adjusted percentiles [2]. The World later in life associated with insulin resistance, including type Health Organization and U.S. Centers for Disease Control and 2 diabetes, obesity, and cardiovascular disease. Some Prevention, each have definitions of overweight and obesity in instances of severe, early-onset, morbid obesity may result children and adolescents [Table/Fig-1]. At different ages, these from defects in genes encoding adipose-derived hormones criteria give somewhat different estimates of overweight and such as leptin, neuropeptides such as proopiomelanocortin, obesity prevalence [3-6]. The increased incidence of childhood cocaine- and amphetamine-regulated transcript (CART), and obesity cannot be blamed on either environment or genetics melanocortin-4, or the receptors for these ligands [8].
National Journal of Laboratory Medicine. 2015 Apr, Vol 4(2): 17-24 Namrata Chhabra et al., Endothelial Dysfunction in Obese Children Definition of Childhood Obesity World Health Organization WHO Child Growth Standards (birth to age 5) [3]
• Obese: Body mass index (BMI) > 3 standard deviations above the WHO growth standard median
• Overweight: BMI > 2 standard deviations above the WHO growth standard median
• Underweight: BMI < 2 standard deviations below the WHO growth standard median
WHO Reference 2007 (ages 5 to 19) [4]
• Obese: Body mass index (BMI) > 2 standard deviations above the WHO growth standard median
• Overweight: BMI > 1 standard deviation above the WHO growth standard median
• Underweight: BMI < 2 standard deviations below the WHO growth standard median
U.S. Centers for Disease Control CDC Growth Charts [5]
In children ages 2 to 19, BMI is assessed by age- and sex-specific percentiles:• Obese: BMI ? 95th percentile• Overweight: BMI ? 85th and < 95th percentile• Normal weight: BMI ? 5th and < 85th percentile• Underweight: BMI < 5th percentileIn children from birth to age 2, the CDC uses a modified version of the WHO criteria [6] [Table/Fig-1]: Childhood obesity definition [3-6]
IMPLICATIONS OF CHILDHOOD
OBESITY
Obesity is associated with an increase in mortality, with a 50–
100% increased risk of death mostly due to cardiovascular c) Endothelial dysfunction causes. Although the data in childhood are less exhaustive, d) Ischemic heart disease about 60% of overweight 5 to10-year-old children are reported e) Left ventricular hypertrophy to have at least one associated cardiovascular risk factor, f) Increased Carotid artery stiffness and 25% have 2 or more [9]. The important implications of childhood obesity [10] have been highlighted in [Table/Fig-2]. g) Increased carotid artery intima media thickness It has been recognized that the risk factors emerge quite early in the clinical course of obesity, which might have important a) Impaired glucose tolerance consequences for development of atherosclerosis later in life. b) Insulin resistance Increase in body mass index (BMI), an indicator of general c) Diabetes mellitus obesity, is often an independent risk factor for the development d) Metabolic syndrome of elevated blood pressure, clustering of various cardiovascular risk factors in metabolic syndrome, abnormal vascular wall thickness, endothelial dysfunction and left ventricular f) Early menarche hypertrophy [11]. Baker et al., reported the association between BMI in childhood (7 to 13 years of age) and coronary b) Obesity hypoventilation syndrome heart disease in adulthood (25 years or older) in a huge c) Bronchial asthma cohort of men and women in whom childhood BMI data were available [12]. The results of various studies have indicated a) Non alcoholic fatty liver disease that a deleterious alteration of endothelial physiology, also b) Cholelithiasis referred to as endothelial dysfunction, represents a key early step in the development of atherosclerosis and is also involved in plaque progression and the occurrence of atherosclerotic a) Poor self esteem complications [13]. Endothelial changes are known to commence in childhood [14,15] and are present in severely b) Distorted peer relationships obese children [15]. Diabetes mellitus, hypercholesterolemia, and arterial hypertension have all been shown to promote atherosclerosis by their cumulative effects on the vascular endothelium.
[Table/Fig-2]: The clustering of obesity induced cardiovascular risk
factors in childhood can explain the increased risk of adult coronary
FUNCTION OF ENDOTHELIUM
heart disease [10] Endothelium is no more considered an inert lining of the blood vessels; it is actually a highly specialized, metabolically National Journal of Laboratory Medicine. 2015 Apr, Vol 4(2): 17-24 www.njlm.jcdr.net Namrata Chhabra et al., Endothelial Dysfunction in Obese Children examples of biomolecules ROLE OF NITRIC OXIDE
The most critical of the substances released by endothelium is nitric oxide (NO). Like other vasodilators, NO exerts its effect on the vascular smooth muscle by activating soluble guanylate cyclase to produce cyclic Guanosine monophosphate (cGMP), Endothelium-derived hyperpolarizing which is the intracellular second messenger of NO [17]. Shear stress and/or acetylcholine stimulate the release of NO from endothelial cells [18]. There is a well-established relationship between reactive oxygen species (ROS) and NO. NO has a direct effect on oxidative stress by scavenging ROS, and NO inactivation is enhanced in the presence of excess ROS [19].
Angiotensin II (AII) NO not only regulates vascular tone, it also has a key "antiatherogenic" role with the regulation of vascular permeability, the inhibition of platelet adhesion/aggregation, leukocyte/wall interaction, and smooth muscle proliferation [20]. These biologic actions of NO make it an important component in the endogenous defense against vascular Endothelin (ET-1) injury, inflammation, and thrombosis, which are all key events in the progression of atherosclerosis [21].
Platelet derived growth factor (PDGF) Basic fibroblast growth factor (PGF) Insulin-like growth factor – I (IGF-I) Endothelial dysfunction can be defined as, "the partial or complete loss of balance between vasoconstrictors and vasodilators, growth promoting and growth inhibiting factors, proatherogenic and anti-atherogenic factors" [22]. Growth Inhibitors Nitric oxide In endothelial dysfunction, there is reduction in the bio- Transforming growth factor I (TGFB) availability of vasodilators, in particular, nitric oxide (NO), whereas endothelial derived contracting factors are increased [23]. Endothelial dysfunction, aside from denoting impaired endothelium dependent vasodilatation, also comprises a specific state of ‘Endothelial activation' which is characterized Endothelial leukocyte adhesion molecule; by a pro-inflammatory, proliferative and procoagulatory milieu that favors all stages of atherogenesis [19]. It is thought that Intercellular adhesion molecule disruption of the functional integrity of the vascular endothelium Vascular cell adhesion molecule (VCAM) plays an integral role in all stages of atherogenesis ranging from lesion initiation to plaque rupture.
Tissue-type plasminogen activator Obesity is associated with both endothelial dysfunction and increased risk of CVD in adults; therefore it is hypothesized that Plasminogen activator inhibitor-1 (PAI-I) a similar relationship can be found between these variables in children. It is suggested that programming effects and the [Table/Fig-3]: The vascular homeostasis is maintained by
endothelium derived biomolecules [16]
classical cardiovascular risk factors such as obesity, impair the endothelial function from as early as the first decade of life [20]. Thus, measurement of endothelial dysfunction in children can predict the onset of atherosclerosis without the need to active interface between blood and the underlying tissues. follow to an age when clinical manifestations of CVD become The endothelium plays a vital role in vascular homeostasis, vascular tone regulation, vascular smooth cell proliferation, trans endothelial leukocyte migration, thrombosis and MECHANISM OF OBESITY INDUCED
thrombolytic balance. In response to various mechanical and chemical stimuli, endothelial cells synthesize and release a While the causes of endothelial dysfunction in obesity remain large number of vasoactive substances, growth modulators unclear and incompletely explored, insulin resistance and the and other factors that mediate these functions [16]. [Table/ presence of a proinflammatory state are two likely mechanisms Fig-3] depicts the details of the biomolecules release by linking obesity to endothelial dysfunction. Abnormalities in endothelium to maintain the vascular homeostasis [16].
LDL characteristics, increased activity of the renin–angiotensin system and elevated concentrations of non esterified fatty National Journal of Laboratory Medicine. 2015 Apr, Vol 4(2): 17-24 Namrata Chhabra et al., Endothelial Dysfunction in Obese Children acids (NEFA) have all been implicated. However, the most expression in vascular endothelial cells. In clinical studies in compelling evidences are for insulin resistance, an effect of adults, hypoadiponectinemia has been found to be directly inflammation and/or elevated leptin concentration on the correlated with endothelial function of the peripheral arteries endothelium [24].
Several factors including visceral adiposity, physical inactivity Leptin concentrations rise exponentially with increasing and genetic factors contribute to the development of insulin percentage body fat, and obese individuals have markedly resistance. Insulin resistance is associated with endothelial increased leptin production, probably as a consequence of dysfunction and insulin sensitivity is inversely proportional to resistance to its actions. However, the widespread distribution the development of atherosclerosis [25]. Petrie et al., showed of functioning leptin receptors on vascular cells and other cell a close positive relationship between insulin sensitivity and populations and on atherosclerotic lesions suggests that leptin basal endothelial NO production [26]. Winkler et al., showed also plays an important role in vascular physiology [28].
that increased levels of TNF-α may be one of the linking Taken together, the status of endothelial function represents factors in the insulin resistance and endothelial dysfunction an integrated index of both the overall cardiovascular risk relationship [27].
factor burden and the sum of all vasculoprotective factors As obesity is associated with features of acute-phase activation in any given individual [42]. The presence of endothelial and low-grade inflammation, elevated levels of inflammatory dysfunction can be regarded as a clinical syndrome that markers such as fibrinogen, C-reactive protein and IL-6 might per se is associated with and predicts an increased rate of also affect vascular dysfunction. Furthermore, adipose tissue adverse cardiovascular events [43].
produces cytokine-like molecules such as leptin and TNF-α, collectively termed adipokines that could affect vascular ASSESSMENT OF ENDOTHELIAL
function by their local and distant actions [28].
Various studies have shown that overweight children have A common approach to the evaluation of endothelial function higher CRP levels than normal weight children [29,30]. is the assessment of blood flow and vascular reactivity Fichtlscherer et al., showed that elevated CRP levels indicative since the first description of endothelial dysfunction in of a systemic inflammatory response reflected blunted atherosclerotic epicardial coronary arteries in 1986 by Ludmer et al., [44]. The consequences of an abnormal vasodilator systemic endothelial function and normalization of CRP levels response (i.e. impaired vasodilatation and even paradoxical over time were associated with a significant improvement in vasoconstriction of coronary arteries upon the administration endothelium-mediated blood flow responses [31].
of acetylcholine) have thereafter been extensively studied. IL-6 is a proinflammatory, endocrine cytokine that stimulates Epicardial and microvascular coronary endothelial dysfunction the production of acute-phase proteins, including CRP [29]. predicts CV events in patients with and without coronary Within adipose tissue, both adipocytes and macrophages artery disease [45]. Measurement of flow-mediated dilation secrete IL-6, with roughly 30 percent of total production (FMD) at the level of a large conduit artery, usually the brachial being initiated in the adipose tissue [32]. Production of IL-6 artery, has since then become the most applied technique by adipose tissue increases with increasing adiposity, and [46]. Typically, ischemia is induced in the forearm or hand circulating IL-6 concentrations are highly correlated with both using a tourniquet inflated to above systolic pressure. Release percent body fat [33] and insulin resistance [34].
of the tourniquet causes reactive hyperemia, an increase in TNF-α, a proinflammatory cytokine has been shown to induce blood flow through the brachial artery, and hence a release of NO. The resulting vasodilation is measured by continuous an impairment of endothelium-dependent vasodilatation in a high-resolution ultrasound and the maximum vasodilation is variety of vascular beds by increasing oxidative stress and expressed as a percentage of the baseline brachial arterial decreasing the release of NO [35]. TNF-α has a major role in diameter [47]. Peripheral arterial tonometry was developed adipose tissue and there is evidence of a three-fold increase in as a novel technique to overcome the disadvantages of TNF-α mRNA protein and circulating levels in obese individuals user dependence of FMD. Invasive assessment of coronary [36]. Within adipose tissue, macrophages account for nearly endothelial function by quantitative coronary angiography all TNF-α production [32] and increased TNF- α expression and coronary Doppler flow measurements, along with graded has also been linked to the development of insulin resistance intracoronary infusions of endothelium dependent vasodilators such as acetylcholine were considered the ‘Gold standard' for In an obese state, plasma concentrations of adiponectin endothelial function testing [47] but the invasive characters are decreased [37]. Adiponectin plays an important role in prohibit their use in healthy individuals and children.
the regulation of insulin action, and has been shown to be Another approach is to measure levels of the members of negatively correlated with insulin resistance [38]. In addition endothelial activation, such as soluble vascular cell adhesion to its effect on glucose metabolism, adiponectin appears to molecule (VCAM), soluble intracellular adhesion molecules modulate endothelial function. Adiponectin has been shown to (ICAM), Endothelin-I (ET-I) and other markers of coagulation stimulate production of NO and suppress adhesion molecule and fibrinolysis such as PAI-I, Tissue plasminogen activator National Journal of Laboratory Medicine. 2015 Apr, Vol 4(2): 17-24 www.njlm.jcdr.net Namrata Chhabra et al., Endothelial Dysfunction in Obese Children or Von-Willebrand factors (VWP) and markers of low grade The pathological vasoreactivity in obesity is a complex inflammation such as C-reactive proteins, IL-I, IL-6, and TNF- multifactorial phenomenon. Increased serum levels of vasoconstrictive prostaglandins, proinflammatory cytokines, The identification and quantification of circulating endothelial and adiponectin and changes in lipoproteins (elevated serum cells (CECs) has evolved as a novel marker of endothelial LDL and chylomicron remnants, lowered HDL) have all been function. CECs appear to be a different population of cells to implicated in its pathogenesis [2].
endothelial progenitor cells [48]. As a technique, it correlates Although the mechanisms by which diet alone improves with other markers of endothelial function such as flow- endothelial function remain far from being fully understood, mediated dilation, the measurement of von Willebrand factor, evidence is accumulating that a combined reduction of and tissue plasminogen activator. Quantification of CECs is LDL and other atherogenic lipoproteins, reduced rate of difficult due to low numbers, variable morphology, and a lack hyperglycemia, and lower oxidative stress are involved [59].
of standardization in current techniques used. A combination of diet and exercise leads to a better MANAGEMENT OF ENDOTHELIAL
improvement of endothelial function as contrast to diet alone [60]. Although results from several randomized controlled trials DYSFUNCTION IN OBESE CHILDREN
with dietary components are quite promising, effects need to Endothelial dysfunction is a reversible disorder, pharmacological be confirmed in larger population-based studies.
and non pharmacological interventions can reverse the Orlistat, a reversible blocker of lipase, is the only drug available Non pharmacological Interventions
to help weight loss. A meta-analysis of available data in children a) Weight management- Weight loss leads to an improvement
stated that the drug caused 5kg weight loss and 5cm reduction of CV risk factors associated with endothelial dysfunction in in waist circumference after at least 6 months of therapy childhood obesity [49]. Weight loss leads to a reduction in the compared with placebo, but failed to improve dyslipidemia and plasma levels of various adipocytokines, to an attenuation of insulin levels [61]. Rimonabant and sibutramine, the other two the pro-inflammatory state, and to improvement in endothelial drugs due the increased risk of psychiatric adverse events [62] function [50].
and increased CV risk [63], respectively, have been withdrawn b) Physical exercise- The increase in blood flow and shear from the international market. Metformin significantly improves stress that accompanies regular aerobic exercise elicits an both endothelial function and insulin resistance in adults with adaptive response that alters the intrinsic responsiveness of metabolic syndrome [64] but the results are less satisfactory the endothelium by increasing mRNA expression of eNOS. in children [65].
This in turn increases the synthesis and release of NO which Given that increased oxidative stress plays a pivotal role in leads to augmented flow-mediated dilation and ultimately the pathogenesis of endothelial dysfunction, administration of improves endothelial function [51].
antioxidants would be expected to be a reasonable strategy to On top of increasing NO synthesis, exercise decreases treat this disorder. Supplementation with antioxidants such as production of ROS by reducing Nicotinamide Adenine Glutathione, N-acetyl cysteine, and vitamin C has been shown Dinucleotide Phosphate (NAD (P) H) oxidase activity [52] and by to reverse endothelial dysfunction in coronary and peripheral enhancement of antioxidant capacity [53]. Other contributing arteries [66]. LDL reduction by either diet or statin therapy mechanisms might include improvements in insulin sensitivity, has been related to improved endothelial function in previous proinflammatory cytokines, and/or lipoprotein profiles [54].
intervention studies [59,67]. Although statin therapy has been Watts et al., [55] reported that FMD was impaired in obese effectively used to normalize endothelial dysfunction in children children, and the exercise was successful in improving with familial hypercholesterolemia,[68] the consensus is that the impairment. As little as eight weeks of exercise training pharmacological interventions should not be the first choice consisting of three 1-hour sessions of circuit training each to treat alimentary-induced hyperlipidemia and endothelial week led to a significant improvement in endothelial function, dysfunction in obesity [2].
even without weight loss in a randomized cross-over study The treatment of obesity remains difficult. Certain effective drug [55,56]. Two other studies, one involving endurance training therapies have been withdrawn from the market because of and another applying aerobic interval training, confirmed the dangerous cardiovascular effects, [69]. Nonpharmacological effect of exercise alone on endothelial function [56,57] interventions such as low- calorie diet and physical exercise c) Dietary Interventions- It is not obesity itself that causes
therefore represent the mainstays of obesity prevention and endothelial dysfunction but rather the hypercaloric high-fat diet that precedes the weight gain [2]. In obese adults (BMI 35±5), a low-calorie diet can significantly enhance flow-mediated brachial artery vasodilation by 60% and reduce body weight Endothelial dysfunction is significantly associated with obesity by 11% [58].
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5. Department of Biochemistry, S.S.R. Medical College, 1. Dr. Namrata Chhabra 2. Dr. Sahiba Kukreja 3. Dr. Sahil Chhabra Name, aDDreSS, e-mail iD OF the 4. Dr. Sarah Chhabra COrreSPONDiNG authOr: 5. Dr. Kavish Ramessur Dr. Namrata Chhabra, 5, Loretto Convent Street, Curepipe, Mauritius PartiCularS OF CONtriButOrS: E-mail : [email protected] 1. Professor and Head, Department of Biochemistry, S.S.R. Medical College, Mauritius FiNaNCial Or Other COmPetiNG iNtereStS: 2. Professor and Head, Department of Biochemistry, Sri Guru Ram Das Medical College and Research Institute, Amritsar, Punjab, India 3. Department of Perioperative Medicine and Anesthesiology, University of Louisville, Louisville, Kentucky, USA.
4. Department of Biochemistry, S.S.R. Medical College, Date of Publishing: apr 01, 2015 National Journal of Laboratory Medicine. 2015 Apr, Vol 4(2): 17-24

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