1 1 1 Lifetime Cardiovascular Risk of Childhood Obesity 2 3 4 Geetha Raghuveer MD, MPH 5 6 Correspondence 7 Geetha Raghuveer 8 Cardiology 9 2401 Gillham Rd, Kansas City, MO 6410810 Phone: 816-234-325511 Fax: 816-234-370112 firstname.lastname@example.org Lifetime Cardiovascular Risk of Childhood Obesity1617 The author has no Conflict of Interest to disclose.18
2 219Abstract:2021As a result of the increased prevalence of childhood obesity there is a potential for an22increase in incidence and an earlier onset of coronary artery disease. Co morbidities of23obesity such as dyslipidemia, insulin resistance syndrome, hypertension, associated24nutritional deficiencies, sedentary lifestyle or associated lifestyle factors, such as tobacco25smoke exposure are likely to account for this increase as they can result in premature26atherosclerosis. As clinical atherosclerotic cardiovascular disease does not manifest in27obese children, assessment of subclinical markers of atherosclerosis may help in28evaluating the progression of atherosclerosis, in further stratifying risk, and in monitoring29the effects of intervention. Furthermore, as multiple risk factors with poorly understood30interplay may be frequently present in obese children, assessing the vasculature directly31and perhaps, assigning a “vascular age” may be a useful method of quantifying the “end32organ” effect of exposure to these various risks.3334Obese children may show favorable changes in their risk factor profile with clinic based35and behavior modification therapies but the vascular benefits of such interventions need36to be studied further. Broad social, cultural, legislative and policy changes which support37healthy lifestyles within families and communities need to be implemented in order to38decrease the prevalence of childhood obesity and its cardiovascular consequences. The39effect of risk factor modification on the vasculature will continue to be a resource for40directing evidence-based therapy as clinical end points of atherosclerosis are not manifest41in children.
4 444Introduction:4546A mismatch between the excessively processed, calorie dense but nutritionally deficient47diet we consume and the Paleolithic genome we possess is likely the cause for many48chronic illnesses such as atherosclerotic cardiovascular disease, hypertension, diabetes,49certain cancers, and obesity that are so prevalent in our sociey (1). Food, shelter, energy50and health care expenditures a family incurs have changed over decades and as food51prices have decreased, illness and health care expenditures have increased suggesting that52cheaper foods are not necessarily healthier or nutritious. Our current diet is significantly53deficient in fresh produce, fruits and vegetables, lean protein, other essential nutrients and54vitamins, good fats and omega 3 fatty acids (Table 1). We no longer drink water but rely55on calorie dense beverages to quench our thirst, we do not exercise or venture outdoors as56often; and all these are at odds with our genetic make up. Cardiovascular disease is the57leading cause of disease and along with childhood onset obesity constitutes a pressing58public health problem in the United States and many other countries including developing59countries with dire medical and economic implications. Between the years 2003-2006,60about a third of 2 to 19 year olds were diagnosed as overweight in the United States with61a body mass index (weight in kilograms/height in meters2 BMI) ≥ 85th percentile for age62and sex (2). There is a clustering of childhood obesity, childhood onset dyslipidemia,63hypertension, and insulin resistance and these comorbidities when manifest in childhood64track into and may worsen in adult life as obese children likely become obese adults (3,654). These effects of childhood onset obesity on the vasculature can result in premature66onset and accelerated progression of atherosclerosis (5, 6). This can potentially result in
5 567much higher rates of hospitalizations, interventions, disabilities, and premature deaths in68the coming decades (7, 8).6970Nature versus Nurture:71Are we genetically predisposed to obesity and cardiovascular disease or is it just the72result of the way we live and the way we eat? Historical and trend data for obesity and73cardiovascular disease suggest that it is likely the latter but there appears to be a complex74interplay between genetics and the environment in the causation of obesity and heart75disease. There is evidence to support that the alarming increase in the prevalence of76obesity in emerging and developing nations may be as a result of mal adaptation to the77rapidly changing nutritional and life style mileu. This influence of a changed life style on78a “thrifty genotype” (frugal utilization of fuel) that may favor survival and metabolic79adaptations of a malnourished fetus and the influence of social and cultural changes on80the “thrifty phenotype” (lean, fit and frugal lifestyle) may explain the increasing81incidence of metabolic syndrome and type 2 diabetes in developing countries (9).82Apolipoprotein E4 prevalence and its association with obesity, atherosclerosis and83coronary artery disease and mortality from coronary artery disease has also been84extensively studied (10, 11, 12, 13, 14). Apolipoprotein E4 is a genetic determinant of85coronary artery disease through its influence on cholesterol production and the resultant86gene-diet interactions could account for the individual variability in response to lifestyle87alterations. Furthermore, there is evidence that obese/diabetic individuals show variations88in apolipoprotein E4 levels based on ethnic backgrounds (11, 15). Polymorphisms of89multiple genes have been associated with differential effects on lipid metabolism and
6 6 90cardiovascular disease and some of these genetic markers may have prognostic value 91(16). However, most genetic studies have been conducted in the adult population and the 92implications of genetics in obese children needs to be explored further. 93 94Co morbidities of Childhood Obesity: 95 96 97Obese Children may have several coexisting risk factors that are detrimental to 98cardiovascular health. Though clinical effects of these cardiac risks may not be notable in 99childhood, their existence and tracking into adulthood are of concern. The commonly100noted cardiac disease promoting co morbidities in obese children include dyslipidemia101with a combination of high total and low density lipoprotein (LDL) cholesterol, high102triglycerides, low high density lipoprotein (HDL) cholesterol and high very low density103lipoprotein (VLDL) cholesterol levels. Several obese children are also hypertensive, have104associated insulin resistance and exposure to tobacco smoke may be prevalent in this105population. Recently there has accumulated a body of evidence linking sex, race, cardiac106disease, dyslipidemia, hypertension, insulin resistance, arterial calcifications, bone107turnover and obesity to low Vitamin D levels (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,10828). Vitamin D may have a potential anti atherosclerotic effect by promoting insulin109secretion and sensitivity, through immunomodulation, anti-inflammatory,110antihypertensive and anticoagulation effects (29). Further support to the cardioprotective111effects of vitamin D is the observation is the observation linking sub clinical112atherosclerosis (increased carotid artery intima-media thickness - CIMT) to low vitamin113D levels (30). Vitamin D has a negative regulatory effect on the rennin-angiotensin114system, and a favorable effect on the lipid profile, cardiac remodeling, inflammatory
7 7115markers and glycemic control (31). In a cross sectional study involving 3,577 adolescents116who had participated in the National Health and Nutrition Examination Survey, an117independent relationship existed between low vitamin D levels and hypertension,118hyperglycemia and insulin resistance (32). Vitamin D levels may be lower in obese119individuals due to several reasons including inadequate intake, inadequate exposure to120sunshine due to physical inactivity or due to excessive sequestering of vitamin D in fat121stores and consequent poor bioavailability (33, 34).122123 Evidence supporting increased morbidity and mortality in adults with history of124childhood obesity:125In a cohort of children born in Denmark and followed for over 5 million person-years, a126higher BMI during childhood was associated with increased risk of coronary artery127disease in adulthood (35). A 55 year follow up of the Harvard Growth Study of 1922 to1281935 showed that being overweight in adolescence resulted in over a two fold higher129relative risk of coronary artery disease mortality, independent of adult weight (36).130Furthermore, a British study involving a 57 year follow up of a cohort has also confirmed131that all-cause and cardiovascular mortality were increased when childhood BMI was even132>75th percentile (37). Thus it is likely that there is a linear relationship between BMI and133cardiovascular disease and adverse outcomes may manifest even at BMI percentiles that134do not qualify as overweight or obese. The current epidemic of childhood obesity has135been projected to further increase rates of coronary artery disease in young and middle136age adults and by 2035, it is estimated that the prevalence of coronary artery disease may137increase by a range of 5 to16% (38).
8 8138139Evidence supporting the long-term vascular impact of cardiovascular risk factors140noted in childhood:141Pediatric epidemiological studies have shown that high total cholesterol (39), a high BMI142and LDL cholesterol in childhood (40) are associated with an increased CIMT in143adulthood. The Bogalusa study that involves a long-term follow up of a racially diverse144population sample showed that the atherosclerotic lesions in the coronary arteries were145increased in youth with multiple atherosclerosis promoting risk factors (6). Figure 1146These investigators also found that childhood obesity that tracked into obesity in adult147life resulted in a further increase in CIMT suggesting the persisting vascular adverse148effects of childhood onset obesity (5). Figure 2149150Natural and unnatural evolution of atherosclerosis:151152Atherosclerosis is a degenerative disease process that is noted in all humans beginning in153childhood but its progression to clinically manifest disease spans over years. Figure 3154The disease evolution is accelerated in the presence of several mutable and immutable155atherosclerosis promoting risk factors such as advanced age, male sex, family history of156premature coronary artery disease/strokes and peripheral vascular disease, dyslipidemia,157hypertension, insulin resistance, obesity, tobacco smoke exposure and other risks (Table1582). Historical and autopsy data have attested to the childhood origins of this disease and159its long, pre-symptomatic, “silent” period. This provides the rationale for treatment160initiation in those affected with premature atherosclerosis at an early age, as there is161potential for halting the process with an earlier intervention. Thus the aim for162intervention in children is to prevent the premature onset of and to contain atherosclerosis
9 9163rather than prevention of clinical disease events. The vasculature in children serves as a164surrogate end point in the absence of clinical end points and thus, monitoring the165vasculature with a non invasive imaging modality over time may be of value.166167Amongst young, apparently healthy victims of the Korean and Vietnam wars who were168autopsied, there was a 45% to 77% prevalence of atherosclerosis of the coronary arteries169suggesting its childhood origins (41, 42). These observations were made over 50 years170ago when the prevalence of childhood obesity was lower than it is at present. In 1990s,171the investigators from the Pathobiological Determinants of Atherosclerosis in Youth172research group reported the link between atherosclerosis and risk factors such as173dyslipidemia, tobacco smoke exposure, hypertension, diabetes and age (43) and in a174follow up study suggested a link between obesity (especially abdominal obesity) and175coronary artery lesions in youth (44).176177The earliest manifestation of atherosclerosis is a fatty streak, an accumulation of lipid178filled macrophages within the arterial intima. Progressive lipid accumulation over time179results in macrophage and smooth muscle proliferation and development of a fibrous180plaque. These plaques increase in size over years, there may be bleeding within the181plaque or the plaque could rupture. Pro oxidative and pro inflammatory states facilitate182some of these changes in the vascular intima. Even if there is no bleeding or rupture, the183enlarging plaque could lead to progressive luminal narrowing. Consequences of these can184be a slow occlusion of the vessel or sudden occlusion of a distal vessel because of plaque185embolization (45, 46, 47). Figure 4
10 10186187188Assessment of subclinical markers of atherosclerosis by measuring carotid artery189intima-media thickness (CIMT) and the concept of “Vascular Age”:190191One method of examining coronary artery health is obtaining ultrasound of the carotid192arteries and measuring CIMT, a measure of carotid atherosclerosis. Assessment of CIMT193is non-invasive, technically easy to perform, relatively inexpensive, devoid of radiation or194side effects and so can be repeated to track changes over time. Changes in the CIMT and195carotid atherosclerosis are known to parallel atherosclerotic changes seen in the coronary196arteries (48, 49). Increased CIMT in adults has been associated with cardiovascular risk197factors (50), coronary artery disease, stroke (51, 52), and progression of coronary198atherosclerosis (49, 51, 53, 54, 55). As clinical cardiovascular events do not typically199occur in childhood, the effect of the risk factors on the CIMT may help in understanding200the progression of the structural disease processes in high risk children and in monitoring201the effectiveness of interventions. Obese children may also frequently have multiple202coexisting atherosclerosis promoting risk factors and their sum effects on the vasculature203may vary based on the length of exposure to the various risks, risk factor interactions,204genetic predisposition and perhaps the presence of other unknown and undocumented205risks. Thus CIMT measures can be considered the “end organ effect” of all the known206and unknown risk factors that may be prevalent in children. Pediatric epidemiological207studies have shown that high total cholesterol (39), a high BMI and LDL cholesterol in208childhood (40) are associated with an increased CIMT in adulthood. Furthermore,209several case control and observational studies in children have confirmed increased
11 11210CIMT in childhood in the presence of atherosclerosis promoting risk factors such as211hypertension, dyslipidemia, diabetes mellitus and obesity (56, 57, 58, 59).212213“Vascular age” estimation in comparison to chronological age:214“A man is as old as his arteries” – said Thomas Sydenham, a 16th century physician. An215assessment of “Vascular age” compared to chronological age may be a useful concept in216children with multiple risk factors. This may more accurately predict atherosclerotic217burden than risk factor assessments alone. “Vascular age” can be estimated by218performing a carotid artery ultrasound and measuring CIMT. Figure 5 In adults,219estimation of vascular age and reclassification of “Framingham 10 year cardiovascular220event probability risk” based on “Vascular age” has been found to be reliable (60).221However, the lack of normative data for CIMT in children at this time implies that these222children’s CIMT be compared against that of sex and race matched adult normative223CIMT data.224225Effects of lifestyle alteration and pharmacotherapy on vasculature in obese226children:227228Weight reduction, aerobic and strength training or gastric bypass surgery in obese229children are associated with a decrease in LDL-C, triglycerides, insulin levels, and blood230pressures and an improvement in HDL-C (61, 62, 63, 64, 65). The efficacy and relative231safety of statin therapy as a lipid-modifying drug in children with familial dyslipidemia232has also been established (66). The intriguing question would be if the premature aging of233the vasculature is reversible with lifestyle alterations or with pharmacologic therapy of234the risk factors. Improvements in CIMT have been reported with interventions in adults
12 12235(65). A few pediatric reports have also described short-term, favorable changes in236vascular function (66, 67, 68) and CIMT measures (58, 68) with life style alterations or237lipid-modifying therapy in obese children and children with familial dyslipidemia238respectively. However a long-term follow up in this regard is needed.239240Conclusions:241242Several risk factors that facilitate premature acceleration of atherosclerosis are present in243obese children and these risk factors frequently track into adulthood imposing an unusual244burden as these children become young adults. Obese children with multiple245atherosclerosis promoting risk factors may have accelerated progression of246atherosclerosis and hence should be screened for these associated risk factors. In addition247childhood obesity itself which tracks into adulthood creates a cumulative burden on248cardiovascular health. The use of carotid artery ultrasound and CIMT measurement may249help further stratify children who are at higher risk for developing premature coronary250artery disease. These children may need intensive management including251pharmacotherapy for risk factor modification in selected instances with the goal of252halting progression of atherosclerosis. Such interventions may alter the life time risk of253excess morbidity and mortality due to atherosclerosis.254255Broad social and cultural changes that support healthy lifestyles within families,256communities, work places need to be implemented in order to halt the epidemic of257childhood obesity and its cardiovascular consequences. Although these population-based
13 13258strategies are of utmost importance in curtailing the effects of childhood obesity on the259cardiovascular system, there may be a small number of obese children with the most260serious atherosclerosis promoting risk factor abnormalities who need pharmacological261therapies in addition to the lifestyle interventions.262263264265
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26 26534Table 1: The Fundamentals of the Hunter-Gatherer Diet and Lifestyle535(Reproduced with permission Mayo Clinic Proceedings. Online by James H O’Keefe.536Copyright 2004 by Dowden Heath Media. Reproduced with permission of Dowden537Health Media via Copyright Clearance)538539___________________________________________________________540Eat whole, natural, fresh foods; avoid highly processed and541 high-glycemic-load foods542543Consume a diet high in fruits, vegetables, nuts, and berries and low in544 refined grains and sugars. Nutrient-dense, low-glycemic-load fruits and545 vegetables such as berries, plums, citrus, apples, cantaloupe, spinach,546 tomatoes, broccoli, cauliflower, and avocados are best547548Increase consumption of omega-3 fatty acids from fish, fish oil, and plant549 sources550551Avoid trans-fats entirely, and limit intake of saturated fats. This means552 eliminating fried foods, hard margarine, commercial baked goods, and553 most packaged and processed snack foods. Substitute monounsaturated554 and polyunsaturated fats for saturated fats555556Increase consumption of lean protein, such as skinless poultry, fish, and557 game meats and lean cuts of red meat. Cuts with the words round or loin558 in the name usually are lean. Avoid high-fat dairy and fatty, salty559 processed meats such as bacon, sausage, and deli meats560561Incorporate olive oil and/or non–trans-fatty acid canola oil into the diet562563Drink water564565Participate in daily exercise from various activities (incorporating aerobic566 and strength training and stretching exercises). Outdoor activities are567 ideal 568______________________________________________________________________
27 27569Table 2: Immutable and Mutable Risk Factors for Atherosclerosis.570571572 Immutable Risks Age Male Sex Family History Genetic markers Mutable Risks Obesity especially abdominal adiposity Hypertension Exposure to tobacco smoke Insulin resistance High Total and LDL Cholesterol Low HDL Cholesterol High Triglycerides High VLDL Cholesterol Novel Risk Factors – C reactive protein, Vitamin D
28 28573Legend for Figures:574575Figure 1 Effect of multiple risk factors on the extent of atherosclerosis in the aorta and576coronary arteries in children and young adults. (Reproduced with permission from577Berenson GE, Srinivasan SR, Bao W, Newman WP III, Tracy RE, Wattigney WA. For the578Bogalusa Heart Study. Association between multiple cardiovascular risk factors and579atherosclerosis in children and young adults. N Engl J Med 1998;338:1650-6.)580581Figure 2 Relation of cumulative levels of the BMI Z-score during childhood to adult582CIMT as estimated in regression analyses (solid, black line) that controlled for race, sex583and age. The effects of further adjustment for adult BMI is shown by the dashed gray584lines. The estimated difference in CIMT by adult BMI (at a constant childhood BMI for585age) is represented by the vertical distance between the dashed lines. (Reprinted with586permission from Macmillan Publishers Ltd: International Journal of Obesity (Freedman587DS, Patel DA, Srinivasan SR, Chen W, Tang R, Bond Mg, Berenson GS. The contribution588of childhood obesity to aduly carotid intima-media thickness: the Bogalusa Heart Study.589International Journal of Obesity. 32:749-756.), copyright (2008)590591Figure 3 The natural history of atherosclerosis. (Reproduced with permission from the592author - Dr. Henry McGill)593594Figure 4 Slide depicting the evolution of atherosclerosis as seen in the cross section of the595artery. (Reproduced from Netter Illustration with permission of Elsevier Inc.)596
29 29597Figure 5 Ultrasound images of the right common carotid artery, the bifurcation, and the598external and internal carotid arteries. The 10 mm wide box contains the region of interest599where the CIMT is measured with the reading depicted on the right.600601