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Medicine » Cardiology and Cardiovascular Medicine » "Cardiovascular Risk Factors", book edited by Armen Yuri Gasparyan, ISBN 978-953-51-0240-3, Published: March 14, 2012 under CC BY 3.0 license. © The Author(s).

Chapter 3

Novel and Traditional Cardiovascular Risk Factors in Adolescents

By Alice P.S. Kong and Kai Chow Choi
DOI: 10.5772/34447

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Novel and Traditional CardiovascularRisk Factors in Adolescents

Alice P. S. Kong1 and Kai Chow Choi2

1. Introduction

Cardiovascular diseases are prevalent conditions which impose significant negative impacts on the healthcare system. According to World Health Organization (WHO), non-communicable diseases (NCD) including cardiovascular diseases account for more than 60% of all deaths globally. Overweight/obesity, diabetes, hypertension and dyslipidemia are all traditional cardiovascular risk factors in adults. Of particular concern, adolescence obesity and its associated cardiovascular risk and co-morbidities have substantial tracking into adulthood (1-4).

Advances in technology of agriculture have helped to increase food production resulting in easily available, excessive provision of food in many developed countries. Urbanization also leads to changes in leisure activities from doing sports to television viewing and computer games. As a consequence to increasing demand from school and leisure activities, sleep deprivation is another novel risk factor contributing to the escalation of cardiovascular risk in the youth populations. In addition, exposure to heavy metals is increasingly recognized as a consequence of urbanization and may contribute to premature atherosclerosis.

2. Traditional cardiovascular risk factors in adolescents

2.1. Overweight and obesity

Overweight/obesity is an important and well-known cardiovascular risk factor in children, adolescents and adults. Obesity is closely associated with clustering of cardiovascular risk factors with insulin resistance being the possible link(5). Obesity is also associated with increased risk of a number of co-morbidities and premature mortality in both adult and the youth populations (2, 6-11). In a British cohort followed up for 57 years, overweight in childhood was associated with 1.5 times increased risk of all-cause mortality and two-fold increased risk of ischemic heart disease (6). Co-morbidities of adolescence obesity include type 2 diabetes mellitus, micro-inflammation, atherogenic dyslipidemia, hypertension, left ventricular hypertrophy, premature atherosclerosis leading to cardiovascular diseases, obstructive sleep apnoea, gastroesophageal reflux disease, depression and other psychosocial abnormalities (2, 12-16). Clustering of traditional cardiovascular risk factors, namely metabolic syndrome, is noted to have ethnic disparities (17)and the prevalence also varies according to the different definitions of metabolic syndrome adopted(11, 18). Despite the controversies regarding the exact definitions of metabolic syndrome in both adults and children(19, 20), International Diabetes Federation (IDF) recently suggests abdominal obesity as the core criteria in making a diagnosis of metabolic syndrome(21), highlighting the pivotal role of obesity in linking these cardiometabolic abnormalities and cardiovascular diseases.

Childhood obesity can predict the cardiovascular risk in adulthood (22). With increasing childhood obesity, there is increasingly early onset of atherosclerosis(23). In a study involving Hong Kong Chinese overweight children aged 9-12 years (mean BMI 25 ± 3 kg/m2), BMI was independently associated with impaired arterial endothelial function and increased carotid intimal medial thickness, which are early markers of atherosclerosis (24). An important message from this study is that these obesity-related early vascular dysfunctions are partially reversible by lifestyle modifications (25).

Prevalence of childhood and adolescence overweight/obesity has marked variation among developed and developing countries. The prevalence of childhood and adolescence obesity has tripled between 1980 and 2000 in United States (US) and doubled between 1985 and 1995 in Australia(26). In a systemic review of published literatures examining data of prevalence of overweight/obesity among children living in developing countries, lowest prevalence was found in India and Sri Lanka whereas highest prevalence was found in Eastern Europe and the Middle East(27).When comparing epidemiological and clinical studies examining childhood and adolescence overweight/obesity, the diagnostic criterion used to define overweight/obesity should be interpreted with cautions. Despite the importance to identify overweight/obese individuals and screen for associated cardiovascular risk factors early, there is no consensus regarding the diagnostic criteria of childhood and adolescence obesity (28). Compared to adults, assessment of overweight and obesity in children and adolescents are different and not that straightforward. We need to take growth and puberty into consideration because BMI is anticipated to change with age and depends on gender. Gender difference is particularly important in the assessment of childhood and adolescence obesity as girls and boys enter puberty at different pace. In children and adolescents, there are ongoing debates regarding the optimal cutoff values of BMI and waist circumference (WC) to define childhood and adolescence overweight and obesity with various diagnostic criteria adopted by different countries and authorities (28-32).

From published pediatric literatures, at least four diagnostic criteria have been used for the definition of overweight and obesity in children and adolescents (11, 28):

  • 1. An international BMI-for-age reference curve for defining overweight and obesity in children 2 to 18 years of age by the US National Center for Health Statistics, Centers for Disease Control and Prevention (CDC) and the International Obesity Task Force (IOTF) in 2000 (IOTF criteria) (31).

These criteria were based on median BMI by age and gender in six nationally representative datasets from Brazil, Hong Kong, Netherlands, Singapore, United Kingdom (UK) and the US from an international growth survey in 2000. These surveys had over 10,000 subjects each and altogether covered 97,876 boys and 94,841 girls. Overweight and obesity were defined as BMI-for-age ≥25 and ≥30 kg/m2 respectively.

  • 2. A national BMI reference curve for Chinese children and adolescents reported by the Group of China Obesity Task Force (COTF) in 2004 (COTF criteria) (33).

These criteria were based on the Chinese National Survey on Students Constitution and Health in 2000 involving 244,200 primary and secondary Chinese students aged 7–18 years. Overweight and obesity were defined as BMI-for-age ≥24 and ≥28 kg/m2 respectively.

  • 3. CDC 2000 Growth Charts for the US (CDC criteria) (34).

These criteria were based on the US National data collected in a series of 5 surveys between 1963 and 1994 for children and adolescents aged 2–20 years. Overweight and obesity were defined as BMI-for-age ≥85th and ≥95th percentiles respectively.

  • 4. The Hong Kong Growth Survey (HKGS) conducted in 1993 with sex-specific reference charts of weight-for-height (HKGS criteria) (35).

This was a territory-wide cross-sectional growth survey which covered around 25,000 Hong Kong Chinese children from birth to 18 years of age. Childhood obesity in this survey was defined as weight > median weight for height × 120%. No definition for childhood overweight was set in this survey.

In recent years, increasing clinical attention has been drawn to central obesity because central body fat is a better predictor than overall body fat for cardiovascular risk factors in both adults (36, 37) and children (7, 38, 39). Central obesity reflects excess visceral adiposity which is a major culprit for insulin resistance and associated cardiovascular disease in both adults and children (7, 38, 40-43). WC and WC-derived indexes such as waist-to-hip ratio (WHR) and waist-to-height ratio (WHTR) are commonly employed anthropometric measurements as proxy measures of central obesity. In Caucasian adults, WC ≥102cm in men and ≥ 88cm in women are used to define central obesity (1,3). The corresponding cutoff values in Chinese and South Asian men and women are ≥ 90cm and ≥ 80cm respectively (5, 44). In adults, there are at least 14 different methods to quantify WC (19). In pediatric literatures, measurements of WC have been described at 5 different sites: 1) midway between the lowest rib and superior iliac crest (45-49); 2) at the umbilical level (50, 51); 3) at the narrowest point of the torso (52); 4) at the level of the right upper iliac crest (53); and 5) at the level of 2 cm above the umbilicus (54). Based on the 2005/2006 Hong Kong Growth Survey including 14,842 Hong Kong Chinese school children aged 6 to 18 years, reference values and percentile curves for WC and WHRT are established (49). These charts are based on WC measured midway between the lowest rib and superior iliac crest and provide reference values for estimation of central obesity in local Hong Kong Chinese youth populations.

In summary, adolescence obesity is a global concern because obesity associated cardiovascular risk factors and abnormalities are potentially reversible in early disease stage. Despite the epidemic of childhood and adolescence obesity worldwide, the most appropriate criterion to ascertain the diagnosis is still inconclusive. Given the high rates of adolescence obesity, adolescents are important population for monitoring and intervention.

2.2. Diabetes

Diabetes is a disorder of glucose metabolism with complex interplays between genetic, lifestyle and environmental factors. Historically, type 2 diabetes is much less common in children and adolescents compared to autoimmune type 1 diabetes and type 2 diabetes has once been thought to be non-existent in children (55). However, with increasing prevalence of obesity worldwide, type 2 diabetes in children and adolescents is increasing at an alarming pace (55). Atherosclerosis starts in young people with type 2 diabetes(56). The general awareness of type 2 diabetes in adolescents should be escalated, particularly in those with obesity and family history of type 2 diabetes. American Diabetes Association (ADA) (57)has recommended the testing for type 2 diabetes in asymptomatic children and adolescents who are: aged 10 years or at onset of puberty, overweight (BMI>85th percentile for age and sex, weight for height >85th percentile, or weight>120% of ideal for height), plus any two of the following risk factors:

  1. family history of type 2 diabetes in first- or second-degree relative;

  2. race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander);

  3. clinical evidence and/or association of insulin resistance, e.g. polycystic ovarian syndrome, metabolic syndrome, acanthosis nigricans, etc;

  4. maternal history of gestational diabetes during the child’s gestation.

ADA recommends a three yearly screening in these at-risk young individuals (57). In making the diagnosis of diabetes in adolescents, the possibility of “hybrid” disease with obesity and concomitant diseases with compromised insulin secretion such as maturity-onset diabetes of the young (MODY) or latent autoimmune diabetes in adult (LADA) should always be considered(58).

For adolescents with type 1 diabetes who present with acute decompensation and diabetic ketoacidosis (DKA), insulin therapy is the standard therapy. Insulin use is also advised in youth with type 2 diabetes who present with severe hyperglycemia (≥11.1 mmol/L), HbA1c>8.5% or severe manifestation of insulin deficiency such as DKA (59). Although oral antidiabetic agents are not recommended in treatment of type 1 diabetes traditionally, metformin use in conjunction with insulin in adolescents with poorly controlled diabetes has been reported to improve their glycemic control (60). Despite the escalating rate of type 2 diabetes in the youth, therapeutic modalities remain limited with metformin being the only U.S. Food and Drug Administration (FDA)-approved oral treatment for youth with type 2 diabetes (61). Similar recommendation has been adopted in other countries (62).

2.3. Hypertension

The global epidemic of obesity is leading to a shift in the diabetes, as well as hypertension distribution towards increasing levels in children and adolescent (63, 64). In addition, physical inactivity and high salt/sodium intake contribute to the rise in the prevalence of hypertension in the youth. Similar to childhood and adolescence obesity, there is also tracking of high blood pressure from childhood into adulthood(65, 66). Autopsy findings from Bogalusa Heart Study and the Pathobiologic Determinates of Atherosclerosis in Youth (PDAY) have shown that higher blood pressure in the youth populations is associated with increased atherosclerosis(67, 68).

Accurate measurement of blood pressure and correct diagnosis of hypertension or pre-hypertension in the youth populations are important to prevent end-organ damage in adults. The fourth report on the diagnosis, evaluation and treatment of high blood pressure in children and adolescents has suggested a diagnosis of hypertension as >95th percentile for gender, age and height on ≥ 3 occasions. Stage 1 hypertension is diagnosed if systolic or diastolic blood pressure reaches 95th to 99th percentile plus 5 mmHg on at least 3 separate occasions(69) whereas stage 2 hypertension is defined as >99th percentile plus 5mmHg. Various diagnostic cutoff values have been suggested for defining hypertension and pre-hypertension in the youth population (Table 1). Pre-hypertension is defined as >120/80 mmHg or ≥ 90th to <95th percentile (69). Blood pressure increases with age, yet there is limited information regarding the time course for children and adolescents with pre-hypertension to progress to hypertension. For early diagnosis of pre-hypertension and hypertension, reference blood pressure standards by sex-, age-, weight- and height are clinically important (70, 71).

The 4th report on the diagnosis, evaluation, and treatment of high BP in children and adolescents(69)Cool et al (76) , (77) and Kong et al (39, 78)Cruz et al (79) and de Ferranti et al (75)Weiss et al (80)Zimmet et al (21)
BP "/ 95th percentile for gender, age and height on "/3 occasionsBP ≥ 90th percentile for gender, age and heightBP "/ 90th percentile for gender, age and heightBP "/ 95th percentile for gender, age and heightBP≥ 130/85 mmHg

Table 1.

Diagnostic criteria used in pediatric literatures for definition of hypertension. Blood pressure: BP.

White coat hypertension is a well recognized phenomenon of transiently high blood pressure related to stress. Home-clinic blood pressure difference can vary substantially by age in children with the difference reduced with advancing age and substantially diminshed after 12 year-old(72). Therefore, ambulatory blood pressure (AMBP) is gaining popularity in both children and adults due to the stronger correlation between high AMBP with target organs damage observed in an emerging number of studies in both adults and paediatric populations (73).

For youth with pre-hypertension and hypertension, a search and thorough evaluation for secondary causes is recommended as secondary hypertension is more common in children than adults(69). If secondary hypertension is ruled out, children and adolescents with pre-hypertension should start lifestyle modifications(69). For stage 2 hypertension, drug therapy should be initiated but for those with stage 1 hypertension, pharmacological treatment is recommended if symptomatic, evidence of end-organ damage, concomitant diabetes or persistent high blood pressure despite non-pharmacological measures(69). A detailed elaboration of the dosage, dosing interval and precautions of different types of antihypertensive drugs for children with hypertension has been described in the fourth report on the diagnosis, evaluation and treatment of high blood pressure in children and adolescents(69).

2.4. Dyslipidemia

Dyslipidemia continue to track from childhood into adulthood(74). Similar to the controversies in diagnosis of obesity and hypertension, there is no consensus regarding the definition of dyslipidemia in children and adolescents. Typical dyslipidemia in children and adults with obesity and insulin resistance include increased triglyceride and decreased high-density lipoprotein (HDL) cholesterol levels. The definitions of high triglyceride level in the youth range from ≥ 1.1 mmol/l (ie ≥ 100 mg/dL) (75), ≥ 1.2 mmol/l (39, 76, 77) to ≥ 1.7 mmol/l (21, 39, 78). Some researchers adopt age-, sex- and/or race-specific percentile cutoff to diagnose hypertriglyceridemia with triglyceride ≥ 90th percentile (79)and >95th percentile (80) used. For defining low HDL cholesterol levels in the pediatric literatures, a cutoff value of ≤ 1.03 mmol/l (ie< 40mg/dL) for all ages/sexes (39, 76-78), < 1.03 mmol/l (21), <1.3 mmol/l (ie <50mg/dL)(75), or gender-specific cutoff ≤ 1.03 mmol/l for boys and ≤ 1.3 mmol/l for girls (81), or percentile specific cutoff <5th percentile (age-, sex- and race- specific)(80) and ≤ 10th percentile (age-, sex- and height-specific) (79, 82) have been reported.

Low density lipoprotein (LDL) cholesterol remains to be the primary target of lipid control to prevent cardiovascular events in adults (83). Hence, majority of randomized controlled trials carried out in pediatric populations have also focused on the use of statins in youth with elevated LDL cholesterol levels. There is general consensus that statin should be initiated, in combination with diet and lifestyle modification if LDL cholesterol level > 4.1 mmol/l (ie 160mg/dl) in at-risk youth (84, 85). Fibrates and niacin are lipid lowering drugs targeted to treat high triglyceride and low HDL cholesterol in adults, but neither drugs is approved for use by US FDA in the pediatric population.

3. Novel cardiovascular risk factors in adolescents

3.1. Sleep

Physiologically, average sleep duration decreases with progression from infancy, childhood to adolescence (86). With increasing demand from school and work, as well as changes in leisure activities such as television watching and computer games, the average sleep duration in the US adults has decreased from 9 hours per night a century ago to 6.9 hours per night in 2005 (87). In Sweden, the average sleep time has decreased from 9 hours per night in 1910 to 7.5 hours in 1990’s in adults aged 20-64 years (88).

Sleep deprivation is now increasingly recognized as a lifestyle factor contributing to the global epidemic of childhood obesity and a novel, potentially reversible cardiovascular risk factor. Both laboratory and epidemiological studies suggested associations of obesity, insulin resistance, diabetes and cardiovascular disease with sleep debt in children, adolescents and adults (89-91). Increasing number of epidemiological studies show close association between sleep duration and obesity, which is evident as early as during early childhood (92-96). Short duration of sleep at age of 3 years predict future risk of obesity in childhood (92). In a Japanese study of 8274 children aged 6-7 years, an inverse relationship between hours of sleep and risk of childhood obesity was observed (93). Cross-sectional studies from US, Canada, UK, France, Germany and Japan suggest increased risk for overweight or obesity in Caucasian, Hispanic, African-American and Japanese children who sleep long hours than those with short sleep duration (93, 97-101). Prospective studies also suggest a predictive role of short sleep duration for overweight and obesity in Caucasians children (92, 102). Similar data from Chinese children and adolescents are comparatively sparse. A recent survey in Taiwan involving 656 boys and girls aged 13-18 years showed that sleep deprivation (defined as sleep <6 hours on schooldays) was associated with poor health status as measured by health-related behaviors in self-reported questionnaires (103).

Although the exact underlying mechanism linking sleep and obesity is not fully understood, preliminary results suggest a possible neurohormonal basis. There is evidence showing that sleep curtailment can activate the hypothalamo-pituitary-adrenal (HPA) axis (104). Van Cauter et al have demonstrated a significant rise in plasma cortisol levels in the following evening amongst subjects after partial (0400-0800 hours) and total sleep deprivation (37% and 45% increases, p=0.03 and 0.003 respectively) compared to those with normal sleep duration (2300-0700 hours) (104). In another study by Van Cauter et al, sleep debt was associated with adverse effects on carbohydrate metabolism and endocrine function (105). Glucose tolerance and thyrotropin concentrations were reduced while evening cortisol concentrations and activity of sympathetic nervous system were increased in the sleep debt group (4 hours per night) (105). Interestingly, these hormonal and metabolic changes are very similar to that accompanying normal ageing. Based on rodent studies, positive relation between sleep curtailment and hyperphagia has been noted. Van Cauter et al further demonstrated an inverse relationship between sleep debt and leptin, an important anorexigenic hormone secreted by adipocytes mediating the signals between adipose tissues and the hypothalamic regulatory centers (106, 107). In concert with this phenomenon, elevated ghrelin levels, the orexigenic hormone, were observed with reduced sleep duration accompanied by increased hunger and appetite (106). Similar results have also been reported by other workers showing associations between high BMI, short sleep duration, decreased leptin and elevated ghrelin levels (95). In addition, lipid and energy metabolism are regulated by circadian rhythm (108). Sleep problems may result in dysregulation of lipid metabolism and metabolic syndrome. In a national study in Japan, sleep duration in adults was closely related with serum lipid and lipoprotein levels (109). Recently, an association between atherogenic dyslipidemia and reduced sleep duration is reported in both U.S. and Hong Kong Chinese adolescents(110, 111).

3.2. Inflammation

Atherosclerosis can be regarded as a state of chronic, low-grade inflammation of the arterial wall, resulting from the interactions between plasma lipoproteins, peripheral blood mononuclear cells (PBMC) and the endothelium (112). It has been increasing recognized the clinical utility and prognostic role of serum inflammatory markers levels, in addition to traditional cardiovascular risk factors, in estimating cardiovascular risk in both adults and the youth populations. Both high circulating white cell counts and high serum high sensitivity C-reactive protein (hsCRP) are associated with increased risk of diabetes and associated complications in adults (113, 114). Increasing clinical evidence also suggest a link between inflammation, insulin resistance and cardiovascular risk factors in children and adolescents (13, 115-117). In a school children study including over 2,000 Hong Kong Chinese adolescents (median age: 16 years), overweight/obesity was associated with two to six-fold increased risk of having high hsCRP tertiles(13). In another cross-sectional study including 326 obese children aged 6-12 years (mean age 8.9 years), white blood cell counts were associated with plasma lipid profile (triglyceride, total and LDL cholesterol) and obesity indices (body mass index and WC)(117).

3.3. Heavy metals and environmental pollutants

Apart from changes in habits and lifestyle, exposure to heavy metals is increasingly recognized as a consequence of urbanization. Most heavy metals cannot be metabolized by our body, and excessive accumulation in the body will disturb the normal functions of cells. Kidney is the key organ to eliminate heavy metals from the body. Heavy metals might lead to albuminuria through inducing oxidative stress to renal tubular cells(118, 119). Certain heavy metals have additive effect in inducing nephrotoxicity. For example, synergistic effect of arsenic (As) and cadmium (Cd) in causing renal damage has been demonstrated in Chinese general population(120). In addition, chronic exposure to toxic heavy metals may promote atherosclerosis and contribute to the development of chronic kidney disease and cardiovascular diseases (119, 121). Furthermore, air pollutants can provoke systemic pro-inflammatory and pro-thrombotic response and lead to increase in platelet counts and platelet activation(122). The significance of platelet activation and whether anti-platelet therapies can help reducing cardiovascular risk profiles in the youth populations is still a debatable subject(123). Further studies are required to examine the impact of heavy metals and environmental pollutants, as novel cardiovascular risk factors, in accelerating the development of cardiovascular disease in both adults and the youth populations(124).

4. Controversies and the unmet needs to be addressed

Lifestyle modification including regular exercise and diet are cornerstones of management of traditional cardiovascular risk factors including obesity, diabetes, dyslipidemia and hypertension. With recent evidence demonstrating the importance of adequate sleep duration in adolescents, education for a healthy sleep habit becomes one of the essential targets of lifestyle modification to prevent cardiovascular risk factors in the youth. Childhood and adolescence are vulnerable periods for habit formation due to substantial tracking of lifestyle habits and cardiovascular risk from this period into adulthood (125, 126). Thus, promoting healthy eating habit, regular exercise and healthy sleep habit in the youth are important strategies to curb the public health problem of obesity.

The optimal dietary approach to combat obesity and reduce cardiovascular risk factors is still a matter of controversies. Indeed, modern food-processing technology produces many food products with high glycemic index (GI). There is now emerging evidence showing that both the quality and quantity of dietary components can impact upon various physiological processes underlying energy metabolism and control of satiety which can provide the basis for dietary intervention in diabetes and obesity (127, 128). Epidemiological studies from US and China indicate that the risks of chronic diseases such as type 2 diabetes and coronary heart disease are strongly related to dietary GI (129, 130). High GI food, especially rice, the main carbohydrate-contributing food in Chinese, may increase risk of diabetes (130). WHO and Food and Agriculture Organization (FAO) recommend low-GI diet to prevent common chronic diseases of affluence, including obesity and type 2 diabetes (131). Recently, it has been suggested that low GI diet may have a role in the management of childhood obesity(132).

Promotion of regular exercise is another important aspect of lifestyle modifications in reducing cardiovascular risk in adolescents. Physical inactivity has been reported to be associated with obesity and other cardiovascular risk factors in adolescents(133). The role of exercise in weight management and control of cardiovascular risk factors is usually associated with its direct impact on energy expenditure and its potential to alter various components of appetite control and eating behavior. Low physical activity level predicts weight gain in different ethnic groups (134, 135). Regular physical activity maintains good health and prevents myocardial infarction, cardiovascular events and premature mortality (136, 137). Since early 1990s, many studies have demonstrated the beneficial effects of physical activity on promoting weight reduction and fat loss as well as reducing risk of diabetes and hypertension (138-141). Beneficial effects of exercise and diet are possibly beyond weight reduction. In a small scale study of obese Hong Kong Chinese children, combined intervention with diet and exercise reduced adiposity as well as improved lipid profiles and endothelial function compared to diet alone (25). In another study, a 6-week intervention with diet and strength training improved lipid profile in obese Chinese children (142).

WHO recommends regular and accumulated physical activities to prevent premature death and other adverse health outcomes (143). However, there are ongoing debates on the optimal frequency, duration and intensity of physical activity. Most international guidelines recommend moderate activity in adults, especially those who are older and less active (136). In a systematic review of over 850 published literatures, the authors recommended ≥ 60 minutes physical activity of moderate to vigorous level in school-age youth (144). In 1988, the American College of Sports Medicine first recommended children and adolescents to have 20-30 minutes of vigorous exercise daily (145). In 2007, the Regional Office for Europe of the WHO made similar recommendations (146). Other guidelines suggested physical activity of moderate intensity at least twice or more weekly to enhance and maintain muscular strength, flexibility and bone health (20) while others suggested high levels and long duration of regular exercise (e.g. daily physical activity lasting at least 90 minutes) in the youth population (147).

As previously discussed, despite the escalating rate of diabetes and dyslipidemia in the youth population, therapeutic modalities remain limited with metformin and statin being the only US FDA approved oral treatment for youth with type 2 diabetes (61, 62) and dyslipidemia respectively (84, 85). More clinical researches are required to demonstrate the efficacy and safety for more therapeutic options in managing adolescents with type 2 diabetes and dyslipidemia.

5. Conclusion

In conclusion, cardiovascular disease is an increasing world health problem. In view of the substantial tracking of cardiovascular risk factors from adolescents to adulthood, there is an urgent need to intervene early with efficacious strategies to identify and treat the youth with cardiovascular risk factors. The traditional cardiovascular risk factors, namely overweight/obesity, diabetes, hypertension and dyslipidemia do not account for all cardiovascular deaths and novel factors, including lifestyle (e.g. sleep deprivation) and environmental (e.g. heavy metal poisoning), as well as the consequences and interactions related to these traditional and novel risk factors (e.g. inflammation and platelet activation) appear to be important, accounting for the dramatic recent changes in prevalence and would be of public health concern. Moreover, more intensive program for lifestyle modification and aggressive approach of pharmacological treatment should be considered in the youth at-risk of cardiovascular events.


Figure 1.

Traditional and Novel Cardiovascular Risk Factors in Adolescents.


This book chapter and some of the cited studies were partially supported by funding from the Research Grants Council (RGC reference no.: CUHK 4055/01M, CUHK 4465/06M and CUHK 467410).


1 - A. S. Singh, C. Mulder, J. W. Twisk, W. van Mechelen, M. J. Chinapaw, 2008 Tracking of childhood overweight into adulthood: a systematic review of the literature. Obes Rev; 9 5 474 88 . Epub 2008 Mar 5.
2 - S. R. Daniels, D. K. Arnett, R. H. Eckel, S. S. Gidding, L. L. Hayman, S. Kumanyika, et al. 2005 Overweight in children and adolescents: pathophysiology, consequences, prevention, and treatment. Circulation; 111 15 1999 2012 .
3 - S. R. Srinivasan, W. Bao, W. A. Wattigney, G. S. Berenson, 1996 Adolescent overweight is associated with adult overweight and related multiple cardiovascular risk factors: the Bogalusa Heart Study. Metabolism; 45 2 235 40 .
4 - S. S. Guo, C. Huang, L. M. Maynard, E. Demerath, B. Towne, W. C. Chumlea, et al. 2000 Body mass index during childhood, adolescence and young adulthood in relation to adult overweight and adiposity: the Fels Longitudinal Study. Int J Obes Relat Metab Disord; 24 12 1628 35 .
5 - A. P. Kong, N. N. Chan, J. C. Chan, 2006 The Role of Adipocytokines and Neurohormonal Dysregulation in Metabolic Syndrome. Current Diabetes Reviews; 2 397 407 .
6 - D. J. Gunnell, S. J. Frankel, K. Nanchahal, T. J. Peters, G. Davey Smith, 1998 Childhood obesity and adult cardiovascular mortality: a 57-y follow-up study based on the Boyd Orr cohort. Am J Clin Nutr; 67 6 1111 8 .
7 - D. S. Freedman, W. H. Dietz, S. R. Srinivasan, G. S. Berenson, 1999 The relation of overweight to cardiovascular risk factors among children and adolescents: the Bogalusa Heart Study. Pediatrics; 103(6 Pt 1):1175-82.
8 - C. B. Ebbeling, D. B. Pawlak, D. S. Ludwig, G. S. Berenson, 2002 Childhood obesity: public-health crisis, common sense cure. Lancet; 360 9331 473 82 .
9 - D. A. Patel, S. R. Srinivasan, J. H. Xu, W. Chen, G. S. Berenson, 2007 Persistent elevation of liver function enzymes within the reference range is associated with increased cardiovascular risk in young adults: the Bogalusa Heart Study. Metabolism; 56 6 792 8 .
10 - A. Romero-Corral, V. M. Montori, V. K. Somers, J. Korinek, R. J. Thomas, T. G. Allison, et al. 2006 Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies. Lancet; 368 9536 666 78 .
11 - A. P. Kong, C. C. Chow, 2010 Medical consequences of childhood obesity: a Hong Kong perspective. Res Sports Med; 18 1 16 25 .
12 - G. S. Berenson, S. R. Srinivasan, W. Bao, W. Newman, 3 3rd, Tracy RE, Wattigney WA. (1998) Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med; 338 23 1650 6 .
13 - A. P. Kong, K. C. Choi, G. T. Ko, G. W. Wong, R. Ozaki, W. Y. So, et al. 2008 Associations of overweight with insulin resistance, beta-cell function and inflammatory markers in Chinese adolescents. Pediatr Diabetes; 9 5 488 95 .
14 - R. M. Lauer, J. Lee, W. R. Clarke, 1988 Factors affecting the relationship between childhood and adult cholesterol levels: the Muscatine Study. Pediatrics; 82 3 309 18 .
15 - R. M. Lauer, W. R. Clarke, 1989 Childhood risk factors for high adult blood pressure: the Muscatine Study. Pediatrics; 84 4 633 41 .
16 - J. C. Lumeng, K. Gannon, H. J. Cabral, D. A. Frank, B. Zuckerman, 2003 Association between clinically meaningful behavior problems and overweight in children. Pediatrics; 112 5 1138 45 .
17 - P. Schwandt, R. Kelishadi, G. M. Haas, 2010 Ethnic disparities of the metabolic syndrome in population-based samples of German and Iranian adolescents. Metab Syndr Relat Disord; 8 2 189 92 .
18 - A. P. Kong, G. T. Ko, R. Ozaki, G. W. Wong, P. C. Tong, J. C. Chan, 2008 Metabolic syndrome by the new IDF criteria in Hong Kong Chinese adolescents and its prediction by using body mass index. Acta Paediatr; 97 12 1738 42 . Epub 2008 Oct 6.
19 - G. M. Reaven, 2005 The metabolic syndrome: requiescat in pace. Clin Chem; 51 6 931 8 .
20 - E. Goodman, 2006 Pediatric metabolic syndrome: smoke and mirrors or true magic? J Pediatr; 148 2 149 51 .
21 - P. Zimmet, K. G. Alberti, F. Kaufman, N. Tajima, M. Silink, S. Arslanian, et al. 2007 The Metabolic Syndrome in Children and Adolescents- an IDF consensus report. Pediatr Diabetes; 8 5 299 306 .
22 - S. S. Sun, R. Liang, T. T. Huang, S. R. Daniels, S. Arslanian, K. Liu, et al. 2008 Childhood obesity predicts adult metabolic syndrome: the Fels Longitudinal Study. J Pediatr; 152 2 191 200 .
23 - H. C. McGill , Jr.C. A. McMahan, E. E. Herderick, G. T. Malcom, R. E. Tracy, J. P. Strong, 2000 Origin of atherosclerosis in childhood and adolescence. Am J Clin Nutr; 72(5 Suppl):1307S-1315S.
24 - K. S. Woo, P. Chook, C. W. Yu, R. Y. Sung, M. Qiao, S. S. Leung, et al. 2004 Overweight in children is associated with arterial endothelial dysfunction and intima-media thickening. Int J Obes Relat Metab Disord; 28 7 852 7 .
25 - K. S. Woo, P. Chook, C. W. Yu, R. Y. Sung, M. Qiao, S. S. Leung, et al. 2004 Effects of diet and exercise on obesity-related vascular dysfunction in children. Circulation; 109 16 1981 6 .
26 - C. L. Ogden, K. M. Flegal, M. D. Carroll, C. L. Johnson, 2002 Prevalence and trends in overweight among US children and adolescents, 1999-2000. JAMA; 288 14 1728 32 .
27 - R. Kelishadi, 2007 Childhood overweight, obesity, and the metabolic syndrome in developing countries. Epidemiol Rev; 29 62 76 .
28 - G. T. Ko, R. Ozaki, G. W. Wong, A. P. Kong, W. Y. So, P. C. Tong, et al. 2008 The problem of obesity among adolescents in Hong Kong: a comparison using various diagnostic criteria. BMC Pediatr; 8:10.
29 - C. Power, J. K. Lake, T. J. Cole, 1997 Measurement and long-term health risks of child and adolescent fatness. Int J Obes Relat Metab Disord; 21 7 507 26 .
30 - W. H. Dietz, T. N. Robinson, 1998 Use of the body mass index (BMI) as a measure of overweight in children and adolescents. J Pediatr; 132 2 191 3 .
31 - T. J. Cole, M. C. Bellizzi, K. M. Flegal, W. H. Dietz, 2000 Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ; 320 7244 1240 3 .
32 - J. J. Reilly, 2002 Assessment of childhood obesity: national reference data or international approach? Obes Res; 10 8 838 40 .
33 - Group of China Obesity Task Force. 2004 [Body mass index reference norm for screening overweight and obesity in Chinese children and adolescents]. Zhonghua Liu Xing Bing Xue Za Zhi; 25 2 97 102 .
34 - C. L. Ogden, R. J. Kuczmarski, K. M. Flegal, Z. Mei, S. Guo, R. Wei, et al. 2002 Centers for Disease Control and Prevention 2000 growth charts for the United States: improvements to the 1977 National Center for Health Statistics version. Pediatrics; 109 1 45 60 .
35 - S. S. F. Leung, J. T. F. Lau, L. Y. Tse, S. J. Oppenheimer, 1996 Weight-for-age and weight-for height references for Hong Kong children from birth to 18 years. Journal of Paediatrics and Child Health; 32 103 9 .
36 - J. P. Despres, S. Moorjani, P. J. Lupien, A. Tremblay, A. Nadeau, C. Bouchard, 1990 Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arteriosclerosis; 10 4 497 511 .
37 - H. S. Kahn, R. Valdez, 2003 Metabolic risks identified by the combination of enlarged waist and elevated triacylglycerol concentration. Am J Clin Nutr; 78 5 928 34 .
38 - R. Kelishadi, R. Gheiratmand, G. Ardalan, K. Adeli, Gouya M. Mehdi, Razaghi E. Mohammad, et al. 2007 Association of anthropometric indices with cardiovascular disease risk factors among children and adolescents: CASPIAN Study. Int J Cardiol; 117 3 340 8 . Epub 2006 Jul 21.
39 - V. W. Ng, A. P. Kong, K. C. Choi, R. Ozaki, G. W. Wong, W. Y. So, et al. 2007 BMI and waist circumference in predicting cardiovascular risk factor clustering in Chinese adolescents. Obesity (Silver Spring); 15 2 494 503 .
40 - W. B. Kannel, L. A. Cupples, R. Ramaswami, Stokes, 3 3rd, Kreger BE, Higgins M. (1991) Regional obesity and risk of cardiovascular disease; the Framingham Study. J Clin Epidemiol; 44 2 183 90 .
41 - P. Björntorp, 1991 Metabolic implications of body fat distribution. Diabetes Care; 14 1132 1143 .
42 - C. Maffeis, A. Pietrobelli, A. Grezzani, S. Provera, L. Tato, 2001 Waist circumference and cardiovascular risk factors in prepubertal children. Obes Res; 9 3 179 87 .
43 - J. C. Seidell, L. Perusse, J. P. Despres, C. Bouchard, 2001 Waist and hip circumferences have independent and opposite effects on cardiovascular disease risk factors: the Quebec Family Study. Am J Clin Nutr; 74 3 315 21 .
44 - K. G. Alberti, P. Zimmet, J. Shaw, 2005 The metabolic syndrome--a new worldwide definition. Lancet; 366 9491 1059 62 .
45 - L. A. Moreno, J. Fleta, L. Mur, G. Rodriquez, A. Sarria, M. Bueno, 1999 Waist circumference values in Spanish children--gender related differences. Eur J Clin Nutr; 53 6 429 33 .
46 - H. D. McCarthy, K. V. Jarrett, H. F. Crawley, 2001 The development of waist circumference percentiles in British children aged 5.0-16.9 y. Eur J Clin Nutr; 55 10 902 7 .
47 - A. M. Fredriks, S. van Buuren, M. Fekkes, S. P. Verloove-Vanhorick, J. M. Wit, 2005 Are age references for waist circumference, hip circumference and waist-hip ratio in Dutch children useful in clinical practice? Eur J Pediatr; 164 4 216 22 . Epub 2005 Jan 21.
48 - R. Kelishadi, M. M. Gouya, G. Ardalan, M. Hosseini, M. Motaghian, A. Delavari, et al. 2007 First reference curves of waist and hip circumferences in an Asian population of youths: CASPIAN study. J Trop Pediatr; 53 3 158 64 . Epub 2007 Feb 17.
49 - R. Y. Sung, H. K. So, K. C. Choi, E. A. Nelson, A. M. Li, J. A. Yin, et al. 2008 Waist circumference and waist-to-height ratio of Hong Kong Chinese children. BMC Public Health; 8:324.
50 - R. Zannolli, G. Morgese, 1996 Waist percentiles: a simple test for atherogenic disease? Acta Paediatr; 85 11 1368 9 .
51 - S. C. Savva, Y. Kourides, M. Tornaritis, M. Epiphaniou-Savva, P. Tafouna, A. Kafatos, 2001 Reference growth curves for cypriot children 6 to 17 years of age. Obes Res; 9 12 754 62 .
52 - P. T. Katzmarzyk, 2004 Waist circumference percentiles for Canadian youth 11-18y of age. Eur J Clin Nutr; 58 7 1011 5 .
53 - J. R. Fernandez, D. T. Redden, A. Pietrobelli, D. B. Allison, 2004 Waist circumference percentiles in nationally representative samples of African-American, European-American, and Mexican-American children and adolescents. J Pediatr; 145 4 439 44 .
54 - Y. Weili, B. He, H. Yao, J. Dai, J. Cui, D. Ge, et al. 2007 Waist-to-height ratio is an accurate and easier index for evaluating obesity in children and adolescents. Obesity (Silver Spring); 15 3 748 52 .
55 - K. L. Jones, 2008 Role of obesity in complicating and confusing the diagnosis and treatment of diabetes in children. Pediatrics; 121 2 361 8 .
56 - A. P. Kong, J. C. Chan, 2010 Atherosclerosis in young people with type 2 diabetes. International Diabetes Monitor; 22 5 223 224 .
57 - American Diabetes Association. 2010 Standards of Medical Care in Diabetes-2010. Diabetes Care; 33 (Suppl):S11 61 .
58 - A. P. Kong, J. C. Chan, 2010 Other Disorders with Type 1 Phenotype. Textbook of Diabetes (4th Edition):9.14 9 .21.
59 - A. Flint, S. Arslanian, 2011 Treatment of type 2 diabetes in youth. Diabetes; 34(Suppl 2):S177 83 .
60 - S. Sarnblad, M. Kroon, J. Aman, 2003 Metformin as additional therapy in adolescents with poorly controlled type 1 diabetes: randomised placebo-controlled trial with aspects on insulin sensitivity. Eur J Endocrinol; 149 4 323 9 .
61 - M. J. Weigensberg, M. I. Goran, 2009 Type 2 diabetes in children and adolescents. Lancet; 373 9677 1743 4 .
62 - A. L. Rosenbloom, J. H. Silverstein, S. Amemiya, P. Zeitler, G. J. Klingensmith, 2009 Type 2 diabetes in children and adolescents. Pediatr Diabetes; 10(Suppl 12):17-32.
63 - P. Muntner, J. He, J. A. Cutler, R. P. Wildman, P. K. Whelton, 2004 Trends in blood pressure among children and adolescents. JAMA; 291 17 2107 13 .
64 - L. C. Leung, R. Y. Sung, H. K. So, S. N. Wong, K. W. Lee, K. P. Lee, et al. 2011 Prevalence and risk factors for hypertension in Hong Kong Chinese adolescents: waist circumference predicts hypertension, exercise decreases risk. Arch Dis Child; 96 9 804 9 .
65 - O. T. Raitakari, K. V. Porkka, L. Rasanen, T. Ronnemaa, J. S. Viikari, 1994 Clustering and six year cluster-tracking of serum total cholesterol, HDL-cholesterol and diastolic blood pressure in children and young adults. The Cardiovascular Risk in Young Finns Study. J Clin Epidemiol; 47 10 1085 93 .
66 - W. Bao, S. A. Threefoot, S. R. Srinivasan, G. S. Berenson, 1995 Essential hypertension predicted by tracking of elevated blood pressure from childhood to adulthood: the Bogalusa Heart Study. Am J Hypertens; 8 7 657 65 .
67 - R. E. Tracy, W. P. Newman , 3rd.W. A. Wattigney, S. R. Srinivasan, J. P. Strong, G. S. Berenson, 1995 Histologic features of atherosclerosis and hypertension from autopsies of young individuals in a defined geographic population: the Bogalusa Heart Study. Atherosclerosis; 116 2 163 79 .
68 - S. Homma, T. Ishii, G. T. Malcom, A. W. Zieske, J. P. Strong, S. Tsugane, et al. 2001 Histopathological modifications of early atherosclerotic lesions by risk factors--findings in PDAY subjects. Atherosclerosis; 156 2 389 99 .
69 - National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. 2004 The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics; 114(2 Suppl 4th Report):555 76 .
70 - R. Y. Sung, K. C. Choi, H. K. So, E. A. Nelson, A. M. Li, C. W. Kwok, et al. 2008 Oscillometrically measured blood pressure in Hong Kong Chinese children and associations with anthropometric parameters. J Hypertens; 26 4 678 84 .
71 - B. Falkner, S. S. Gidding, R. Portman, B. Rosner, 2008 Blood pressure variability and classification of prehypertension and hypertension in adolescence. Pediatrics; 122 2 238 42 .
72 - G. S. Stergiou, V. C. Rarra, N. G. Yiannes, 2008 Changing relationship between home and office blood pressure with increasing age in children: the Arsakeion School study. Am J Hypertens; 21 1 41 6 .
73 - E. Urbina, B. Alpert, J. Flynn, L. Hayman, G. A. Harshfield, M. Jacobson, et al. 2008 Ambulatory blood pressure monitoring in children and adolescents: recommendations for standard assessment: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee of the council on cardiovascular disease in the young and the council for high blood pressure research. Hypertension; 52 3 433 51 .
74 - T. A. Nicklas, S. P. von Duvillard, G. S. Berenson, 2002 Tracking of serum lipids and lipoproteins from childhood to dyslipidemia in adults: the Bogalusa Heart Study. Int J Sports Med; 23(Suppl 1):S39 43 .
75 - S. D. de Ferranti, K. Gauvreau, D. S. Ludwig, E. J. Neufeld, J. W. Newburger, N. Rifai, 2004 Prevalence of the metabolic syndrome in American adolescents: findings from the Third National Health and Nutrition Examination Survey. Circulation; 110 16 2494 7 .
76 - S. Cook, M. Weitzman, P. Auinger, M. Nguyen, W. Dietz, 2003 Prevalence of a metabolic syndrome phenotype in adolescents. Findings from the Third National Health and Nutrition Examination Survey, 1988-1994. Arch Pediatr Adolesc Med; 157 821 827 .
77 - E. S. Ford, U. A. Ajani, A. H. Mokdad, 2005 The metabolic syndrome and concentrations of C-reactive protein among U.S. youth. Diabetes Care; 28 4 878 81 .
78 - A. P. Kong, K. C. Choi, C. S. Cockram, C. S. Ho, M. H. Chan, R. Ozaki, et al. 2008 Independent associations of alanine aminotransferase (ALT) levels with cardiovascular risk factor clustering in Chinese adolescents. J Hepatol; 49 1 115 122 .
79 - M. L. Cruz, M. J. Weigensberg, T. T. Huang, G. Ball, G. Q. Shaibi, M. I. Goran, 2004 The metabolic syndrome in overweight Hispanic youth and the role of insulin sensitivity. J Clin Endocrinol Metab; 89 1 108 13 .
80 - R. Weiss, J. Dziura, T. S. Burgert, W. V. Tamborlane, S. E. Taksali, C. W. Yeckel, et al. 2004 Obesity and the metabolic syndrome in children and adolescents. N Engl J Med; 350 23 2362 74 .
81 - S. M. Grundy, 2005 Metabolic syndrome scientific statement by the American Heart Association and the National Heart, Lung, and Blood Institute. Arterioscler Thromb Vasc Biol; 25 11 2243 4 .
82 - E. Goodman, S. R. Daniels, J. B. Meigs, L. M. Dolan, 2007 Instability in the diagnosis of metabolic syndrome in adolescents. Circulation; 115 17 2316 22 .
83 - Expert Panel on Detection Evaluation and Treatment of high blood cholesterol in adults. 2001 Executive summary of the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA; 285 2486 97 .
84 - B. W. Mc Crindle, E. M. Urbina, B. A. Dennison, M. S. Jacobson, J. Steinberger, A. P. Rocchini, et al. 2007 Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing. Circulation; 115 14 1948 67 .
85 - C. Mc Neal, D. P. Wilson, 2008 Metabolic syndrome and dyslipidemia in youth. J Clin Lipidol; 2 3 147 55 .
86 - I. Iglowstein, O. G. Jenni, L. Molinari, R. H. Largo, 2003 Sleep duration from infancy to adolescence: reference values and generational trends. Pediatrics; 111 2 302 7 .
87 - National Sleep Foundation. 2005 National Sleep Foundation 2005 Omnibus "Sleep in America" Poll. 2005:Available at: http://www/
88 - J. E. Broman, L. G. Lundh, J. Hetta, 1996 Insufficient sleep in the general population. Neurophysiol Clin; 26 1 30 9 .
89 - E. Van Cauter, K. Knutson, 2008 Sleep and the epidemic of obesity in children and adults. Eur J Endocrinol 2008:[Epub ahead of print].
90 - E. Van Cauter, K. Knutson, 2008 Sleep and the epidemic of obesity in children and adults. Eur J Endocrinol; 159(Suppl):S59 66 .
91 - E. Van Cauter, U. Holmback, K. Knutson, R. Leproult, A. Miller, A. Nedeltcheva, et al. 2007 Impact of sleep and sleep loss on neuroendocrine and metabolic function. Horm Res; 67(Suppl 1):2-9.
92 - S. Taheri, 2006 The link between short sleep duration and obesity: we should recommend more sleep to prevent obesity. Arch Dis Child; 91 11 881 4 .
93 - J. J. Reilly, J. Armstrong, A. R. Dorosty, P. M. Emmett, A. Ness, I. Rogers, et al. 2005 Early life risk factors for obesity in childhood: cohort study. BMJ; 330(7504):1357.
94 - M. Sekine, T. Yamagami, S. Hamanishi, K. Handa, T. Saito, S. Nanri, et al. 2002 Parental obesity, lifestyle factors and obesity in preschool children: results of the Toyama Birth Cohort study. J Epidemiol; 12 1 33 9 .
95 - H. Shigeta, M. Shigeta, A. Nakazawa, N. Nakamura, T. Yoshikawa, 2001 Lifestyle, obesity, and insulin resistance. Diabetes Care; 24(3):608.
96 - S. Taheri, L. Lin, D. Austin, T. Young, E. Mignot, 2004 Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med; 1(3):e62.
97 - R. D. Vorona, M. P. Winn, T. W. Babineau, B. P. Eng, H. R. Feldman, J. C. Ware, 2005 Overweight and obese patients in a primary care population report less sleep than patients with a normal body mass index. Arch Intern Med; 165 1 25 30 .
98 - J. P. Chaput, M. Brunet, A. Tremblay, 2006 Relationship between short sleeping hours and childhood overweight/obesity: results from the’Quebec en Forme’ Project. Int J Obes (Lond); 30 7 1080 5 .
99 - N. K. Gupta, W. H. Mueller, W. Chan, J. C. Meininger, 2002 Is obesity associated with poor sleep quality in adolescents? Am J Hum Biol; 14 6 762 8 .
100 - E. Locard, N. Mamelle, A. Billette, M. Miginiac, F. Munoz, S. Rey, 1992 Risk factors of obesity in a five year old population. Parental versus environmental factors. Int J Obes Relat Metab Disord; 16 10 721 9 .
101 - Kries. R. von, A. M. Toschke, H. Wurmser, T. Sauerwald, B. Koletzko, 2002 Reduced risk for overweight and obesity in 5- and 6-y-old children by duration of sleep--a cross-sectional study. Int J Obes Relat Metab Disord; 26 5 710 6 .
102 - K. L. Knutson, 2005 Sex differences in the association between sleep and body mass index in adolescents. J Pediatr; 147 6 830 4 .
103 - W. S. Agras, L. D. Hammer, F. Mc Nicholas, H. C. Kraemer, 2004 Risk factors for childhood overweight: a prospective study from birth to 9.5 years. J Pediatr; 145 1 20 5 .
104 - Chen MY, Wang EK, Jeng YJ. 2006 Adequate sleep among adolescents is positively associated with health status and health-related behaviors. BMC Public Health; 6:59.
105 - R. Leproult, G. Copinschi, O. Buxton, E. Van Cauter, 1997 Sleep loss results in an elevation of cortisol levels the next evening. Sleep; 20 10 865 70 .
106 - K. Spiegel, R. Leproult, E. Van Cauter, 1999 Impact of sleep debt on metabolic and endocrine function. Lancet; 354 9188 1435 9 .
107 - K. Spiegel, E. Tasali, P. Penev, E. Van Cauter, 2004 Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med; 141 11 846 50 .
108 - K. Spiegel, R. Leproult, M. L’Hermite-Baleriaux, G. Copinschi, P. D. Penev, E. Van Cauter, 2004 Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. J Clin Endocrinol Metab; 89 11 5762 71 .
109 - T. Kudo, K. Horikawa, S. Shibata, 2007 Circadian rhythms in the CNS and peripheral clock disorders: the circadian clock and hyperlipidemia. J Pharmacol Sci; 103 2 139 43 .
110 - Y. Kaneita, M. Uchiyama, N. Yoshiike, T. Ohida, 2008 Associations of usual sleep duration with serum lipid and lipoprotein levels. Sleep; 31 5 645 52 .
111 - J. E. Gangwisch, D. Malaspina, L. A. Babiss, M. G. Opler, K. Posner, S. Shen, et al. 2010 Short sleep duration as a risk factor for hypercholesterolemia: analyses of the National Longitudinal Study of Adolescent Health. Sleep; 33 7 956 61 .
112 - A. P. Kong, Y. K. Wing, K. C. Choi, A. M. Li, G. T. Ko, R. C. Ma, et al. 2011 Associations of sleep duration with obesity and serum lipid profile in children and adolescents. Sleep Medicine; 12 7 659 65 .
113 - R. Kelishadi, 2010 Inflammation-induced atherosclerosis as a target for prevention of cardiovascular diseases from early life. Open Cardiovasc Med J; 4 24 9 .
114 - M. I. Schmidt, B. B. Duncan, A. R. Sharrett, G. Lindberg, P. J. Savage, S. Offenbacher, et al. 1999 Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis risks in communities study): a cohort study. Lancet; 353 1649 52 .
115 - P. C. Y. Tong, K. F. Lee, W. Y. So, M. C. Y. Ng, W. B. Chan, M. K. W. Lo, et al. 2004 Association of white blood cell counts with macrovascular and microvascular complications in Chinese patients with type 2 diabetes. Diabetes Care; 27 216 222 .
116 - A. Misra, 2004 C-reactive protein in young individuals: problems and implications for Asian Indians. Nutrition; 20 5 478 81 .
117 - R. H. Eckel, S. M. Grundy, P. Z. Zimmet, 2005 The metabolic syndrome. Lancet; 365 9468 1415 28 .
118 - R. Kelishadi, M. Hashemipour, P. Ashtijou, P. Mirmoghtadaee, P. Poursafa, N. Khavarian, et al. 2010 Association of cell blood counts and cardiometabolic risk factors among young obese children. Saudi Med J; 31 4 406 12 .
119 - M. Huang, S. J. Choi, D. W. Kim, N. Y. Kim, C. H. Park, S. D. Yu, et al. 2009 Risk assessment of low-level cadmium and arsenic on the kidney. J Toxicol Environ Health A; 72(21-22):1493-8.
120 - M. C. Houston, 2007 The role of mercury and cadmium heavy metals in vascular disease, hypertension, coronary heart disease, and myocardial infarction. Altern Ther Health Med; 13(2): S128 33 .
121 - F. Hong, T. Jin, A. Zhang, 2004 Risk assessment on renal dysfunction caused by co-exposure to arsenic and cadmium using benchmark dose calculation in a Chinese population. Biometals; 17 5 573 80 .
122 - A. Navas-Acien, E. K. Silbergeld, R. Sharrett, E. Calderon-Aranda, E. Selvin, E. Guallar, 2005 Metals in urine and peripheral arterial disease. Environ Health Perspect; 113 2 164 9 .
123 - P. Poursafa, R. Kelishadi, A. Amini, A. Amini, M. M. Amin, M. Lahijanzadeh, et al. 2011 Association of air pollution and hematologic parameters in children and adolescents. J Pediatr (Rio J); 87 4 350 6 .
124 - P. Poursafa, R. Kelishadi, 2010 Air pollution, platelet activation and atherosclerosis. Inflamm Allergy Drug Targets; 9 5 387 92 .
125 - E. M. Alissa, G. A. Ferns, 2011 Heavy metal poisoning and cardiovascular disease. J Toxicol; 2011:870125.
126 - P. L. Kristensen, N. C. Moller, L. Korsholm, N. Wedderkopp, L. B. Andersen, K. Froberg, 2008 Tracking of objectively measured physical activity from childhood to adolescence: the European youth heart study. Scand J Med Sci Sports; 18 2 171 8 .
127 - J. L. Baker, L. W. Olsen, T. I. Sorensen, 2007 Childhood body-mass index and the risk of coronary heart disease in adulthood. N Engl J Med; 357 23 2329 37 .
128 - D. S. Ludwig, 2002 The glycemic index: physiological mechanisms relating to obesity, diabetes, and cardiovascular disease. JAMA; 287 18 2414 23 .
129 - J. Brand-Miller, J. Mc Millan-Price, K. Steinbeck, I. Caterson, 2008 Carbohydrates--the good, the bad and the whole grain. Asia Pac J Clin Nutr; 17(Suppl 1):16-9.
130 - S. Krishnan, L. Rosenberg, M. Singer, F. B. Hu, L. Djousse, L. A. Cupples, et al. 2007 Glycemic index, glycemic load, and cereal fiber intake and risk of type 2 diabetes in US black women. Arch Intern Med; 167 21 2304 9 .
131 - R. Villegas, S. Liu, Y. T. Gao, G. Yang, H. Li, W. Zheng, et al. 2007 Prospective study of dietary carbohydrates, glycemic index, glycemic load, and incidence of type 2 diabetes mellitus in middle-aged Chinese women. Arch Intern Med; 167 21 2310 6 .
132 - Obesity: preventing and managing the global epidemic. 2000 Report of a WHO consultation. World Health Organ Tech Rep Ser;2000;894:i-xii.
133 - Kong AP, Chan RS, Nelson EA, Chan JC. 2011 Role of low-glycemic index diet in management of childhood obesity. Obes Rev; 12 7 492 8 .
134 - A. P. Kong, K. C. Choi, A. M. Li, S. S. Hui, M. H. Chan, Y. K. Wing, et al. 2010 Association between physical activity and cardiovascular risk in Chinese youth independent of age and pubertal stage. BMC Public Health; 10:303.
135 - J. Esparza, C. Fox, I. T. Harper, P. H. Bennett, L. O. Schulz, M. E. Valencia, et al. 2000 Daily energy expenditure in Mexican and USA Pima indians: low physical activity as a possible cause of obesity. Int J Obes Relat Metab Disord; 24 1 55 9 .
136 - A. C. Bell, K. Ge, B. M. Popkin, 2001 Weight gain and its predictors in Chinese adults. Int J Obes Relat Metab Disord; 25 7 1079 86 .
137 - J. Erlichman, A. L. Kerbey, W. P. James, 2002 Physical activity and its impact on health outcomes. Paper 1: The impact of physical activity on cardiovascular disease and all-cause mortality: an historical perspective. Obes Rev; 3 4 257 71 .
138 - M. Inoue, H. Iso, S. Yamamoto, N. Kurahashi, M. Iwasaki, S. Sasazuki, et al. 2008 Daily total physical activity level and premature death in men and women: results from a large-scale population-based cohort study in Japan (JPHC study). Ann Epidemiol; 18 7 522 30 .
139 - D. L. Ballor, R. E. Keesey, 1991 A meta-analysis of the factors affecting exercise-induced changes in body mass, fat mass and fat-free mass in males and females. Int J Obes; 15 11 717 26 .
140 - R. Baba, M. Koketsu, M. Nagashima, H. Inasaka, 2009 Role of exercise in the prevention of obesity and hemodynamic abnormalities in adolescents. Pediatr Int; 51 3 359 63 .
141 - W. C. Knowler, E. Barrett-Connor, S. E. Fowler, R. F. Hamman, J. M. Lachin, E. A. Walker, et al. 2002 Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med; 346 393 403 .
142 - N. A. Khan, B. Hemmelgarn, R. J. Herman, C. M. Bell, J. L. Mahon, L. A. Leiter, et al. 2009 The 2009 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2--therapy. Can J Cardiol; 25 5 287 98 .
143 - R. Y. Sung, C. W. Yu, S. K. Chang, S. W. Mo, K. S. Woo, C. W. Lam, 2002 Effects of dietary intervention and strength training on blood lipid level in obese children. Arch Dis Child; 86 6 407 10 .
144 - World Health Organization 2004 Global strategy on diet, physical activity and health. Geneva 2004;World Health Organization.
145 - W. B. Strong, R. M. Malina, C. J. Blimkie, S. R. Daniels, R. K. Dishman, B. Gutin, et al. 2005 Evidence based physical activity for school-age youth. J Pediatr; 146 6 732 7 .
146 - American College of Sports Medicine 1998 Physical fitness in children and youth. Med Sci Sports Exerc 20 422 23 .
147 - World Health Organization 2007 Steps to Health: A European Framework to Promote Physical Activity for Health.
148 - L. B. Andersen, M. Harro, L. B. Sardinha, K. Froberg, U. Ekelund, S. Brage, et al. 2006 Physical activity and clustered cardiovascular risk in children: a cross-sectional study (The European Youth Heart Study). Lancet; 368 9532 299 304 .