Obesity
Impact on Cardiovascular Disease
- Ronald M. Krauss, MD;
- Mary Winston, EdD;
- Barbara J. Fletcher, RN, MN, FAAN, (conference codirectors);
- Scott M. Grundy, MD, PhD (conference codirectors)
The American Heart Association conference entitled “Obesity: Impact on Cardiovascular Disease” was held May 22–24, 1998, in Amelia Island, Fla. It was cosponsored by Futura Media Services and the American Heart Association Councils on Cardiovascular Nursing; Arteriosclerosis, Thrombosis, and Vascular Biology; Cardiovascular Disease in the Young; Clinical Cardiology; Epidemiology and Prevention; and High Blood Pressure Research; the AHA Nutrition Committee; and the AHA Prevention Coordinating Committee. The proceedings are summarized briefly in this report. A monograph of the conference will be published by Futura Publishing Company, Inc.
Obesity is an important determinant of cardiovascular disease (CVD). Previous epidemiological studies of obesity have documented a modest association of obesity and risk of CVD, especially in younger age groups. The study of obesity and CVD should now focus on weight change over time, especially differences between childhood versus younger and older adult weight gains, and the distribution of body fat, especially visceral or intra-abdominal fat. Weight gain during young adult life may be one of the most important determinants of cardiovascular risk factors. Increased intra-abdominal fat, or waist circumference, is probably related to a constellation of risk factors, the so-called insulin resistance syndrome. It is also associated with higher levels of inflammatory markers such as C-reactive protein and fibrinogen.
Age and Sex as Determinants of Obesity
The increasing prevalence of obesity in children is cause for great concern. There is no definition of obesity in children that relates body mass index (BMI) to health outcomes. However, >20% of children aged 6 to 17 years are >20% overweight at the 85th percentile of BMI, and 10% of children aged 6 to 17 are overweight at the 95th percentile. It appears that 50% of children who are overweight are also overweight as adults, but it is not possible to identify any individual child who will become an overweight adult. CVD risk factors, such as elevated blood pressure, elevated total cholesterol and LDL cholesterol (LDL-C), and low levels of HDL cholesterol (HDL-C) track from childhood, although less strongly than BMI. Overweight children also tend to have a cluster of risk factors. Risk factors tend to occur in families and are especially evident in children when an adult relative is obese. Children with a family history of CVD are heavier than those without family history of disease. All of this suggests that the obese child has an elevated risk of developing CVD in adulthood. A few studies have linked childhood obesity with adult morbidity and mortality. One study showed a trend toward an increase in all-cause mortality; in another, very obese children (before and after puberty) were at greater risk for adult mortality from CVD. A BMI greater than the 70th percentile versus the 25th to 50th percentiles in childhood resulted in a greater relative risk of coronary heart disease (CHD) mortality in men but not in women. Increased relative risk for all-cause mortality was present in both men and women in this study population.
Weight gain occurs differently in men and women. The greatest weight gain in men occurs in those with the highest BMI and those in the older age groups. Compared with women, men live longer and are obese later in life. In women, the greatest weight gain is in the younger age groups. Recent epidemiological studies have shown that in women, weight loss is also accompanied by bone loss. Another difference in weight gain between men and women is that as women’s educational level rises, obesity decreases, for both white and black women, whereas in men, educational level appears not to be related to obesity.
Genetics
The causes of obesity are many, but there is little doubt that genetic factors play an important role in its etiology. Humans carry probably dozens of genes that are directly related to body size. One of the specific roles for genes is the determination of set points. Identification of such genes is important, and several types of studies must be performed to address this. Linkage analysis can be used to find physical locations of genes that are relevant to a phenotype. If a specific gene plays a role in the determination of a given phenotype, the gene and the phenotype will be transmitted together (cosegregate) across generations. The fact that the etiology of obesity is so complex underscores the need for better understanding of genetic determinants as a basis for more rational interventions to treat obesity.
Several approaches have been used to search for specific genes involved in obesity: identification of mutations responsible for obesity in rodent models, association or linkage of obesity measures with candidate genes in humans, and chromosomal localization of genes by linkage of polymorphic markers to obesity and related phenotypes in humans and mice. To date, causative genes have been found for 5 obese mouse models. Two, leptin and leptin receptor, have been linked with variation in body fat in some human studies, but, for leptin, causation has been shown only in 2 obese children with homozygous missense mutations in the leptin gene. Linkages or associations with body fat measures have been reported for >20 other candidate genes in humans, but relationships involving these genes were generally not strong and in some cases were inconsistent among studies. Chromosomal sites of genes responsible for several rare familial human obesity syndromes have been identified, but none to date have been linked to obesity in the general population. On the other hand, with genome-wide searches, quantitative trait linkages of body fat indexes have been reported for several genetic markers in both humans and mouse models. Although multiple genetic influences on obesity phenotypes are suggested by these studies, in most cases the responsible gene variants, their pathophysiological effects, and their interactions with other genes and environmental factors remain to be determined.
Environmental Factors
Environmental as well as genetic factors greatly affect the expression of obesity across the lifespan. The relative contribution of each of these factors to the phenotypic variance of obesity is not fully understood. Knowledge of the nongenetic determinants of obesity-CVD risk factor clustering is essential for planning effective multidisciplinary interventions focused on primary prevention of CVD. Data from a longitudinal twin-family study and co-twin control studies combined with population-based data on patterns of dietary intake and physical activity provide persuasive evidence for an environmental hypothesis. Collectively, these data point to the importance of primary prevention beginning early in life, emphasize the role of health behaviors including physical activity and dietary intake, and suggest the need for modification of health-related practices and policies focused on consumers, providers, schools, and communities.
Obesity and Cardiovascular Health
The effects of obesity on cardiovascular health and disease are many, one of the most profound of which is hypertension. Risk estimates from population studies suggest that ≥75% of hypertension can be directly attributed to obesity. However, the precise mechanisms of hypertension related to obesity are not fully understood. Contemporary thinking concerning the link between obesity and subsequent renal failure has evolved from repeated observations of the relationship between body weight and blood pressure. It is well documented that blood pressure increases with weight gain and decreases with weight loss. In addition, there is increasing evidence that obesity may provide the impetus for sympathetic nervous system activation as well as for changes in renal structure and function. There is considerable evidence that renal dysfunction, characterized by increased tubular sodium reabsorption and resetting of pressure natriuresis, plays a key role in increasing blood pressure in obese subjects. The increased tubular pressure reabsorption is closely related to the sympathetic nervous and renin-angiotensin systems, as are structural changes that cause compression of the renal medulla. Renal vasodilation, glomerular hyperfiltration, and increased arterial pressure are compensations that help overcome increased renal tubular reabsorption and maintain sodium balance in obesity. This also leads to increased glomerular capillary wall stress, which, along with activation of the neurohumoral systems, increased lipids, and glucose intolerance, eventually causes glomerulosclerosis and loss of nephron function in obese subjects. Further research is needed to identify the mechanisms involved in sympathetic nervous system activation and changes in renal structure and function that accompany obesity.
Obesity has a strong effect on lipoprotein metabolism, regardless of ethnic group. Increased weight is a determinant of higher levels of triglycerides, elevated LDL-C, and low HDL-C. Conversely, weight loss is associated with a healthier lipoprotein profile in both men and women: triglycerides decrease, HDL-C increases, and LDL-C decreases. Changes in HDL-C levels are more pronounced in women than in men. The association between obesity and LDL-C is more complex. LDL-C concentrations increase with BMI in men, but such increases are not as pronounced in women, the elderly, and some ethnic groups. Increasing BMI is associated with small, atherogenic LDL. Furthermore, central obesity in women is associated with elevated LDL-C concentrations. Research should be directed toward understanding the relative importance of obesity-related changes in lipoproteins in predicting actual and potential CVD.
There is a strong link between obesity and a generalized metabolic disorder of which insulin resistance is an indicator. It is difficult to define the precise contribution of obesity to insulin resistance, but most analyses suggest that it can account for ≥50% of the variance in insulin sensitivity in the general population. Insulin resistance is associated with a constellation of metabolic abnormalities, including obesity, diabetes, dyslipoproteinemia, hypertension, and atherosclerosis. It is also linked to a prothrombotic state. Because of the complex nature of insulin resistance, it is not known whether it is independently related to atherogenesis by an unknown mechanism. Future research should explore whether insulin resistance can promote atherosclerosis independently of other risk factors.
The response of various ethnic groups to insulin resistance is variable; eg, Asian Indians are more susceptible to insulin resistance than are other ethnic groups and are at very high risk of coronary disease. The role of body fat distribution in insulin resistance is important; the key may be abdominal fat, which is highly correlated with insulin resistance. It is also necessary to consider the role of aging, exercise, diet, and genetics in insulin resistance.
Biological Factors in Obesity
Currently, little is known about the basic causes of obesity, but a great deal is happening in the area of translational research that will lead to the therapeutics of tomorrow. An important focus of research is the biology of weight reduction. The role of proteins and receptors in the regulation of obesity is not yet fully understood. A good example is orphan receptors, the recent screening of which revealed orexin A and B. These receptors are found in the lateral hypothalamus of the brain, the area known to be associated with regulation of body weight. Orexin peptides A and B are neurotransmitters responsible for regulation of fasting and feeding. It is possible that other peptides and amines that regulate energy are present, but this remains to be demonstrated. The function of such peptides and amines and their relationship to obesity remains to be shown and is an area for future research.
The uncoupling proteins UCP-2 and -3 may be important in regulating metabolic rate and therefore in obesity. The relationships between these proteins, which act in the mitochondria, and obesity are not completely understood. Because UCP-3 is thought to regulate energy balance, research in this area would be valuable.
Sleep apnea is a major factor to consider in obesity. This dysfunction may be associated with the release of the cytokines tumor necrosis factor and interleukin-6. Sequelae associated with sleep apnea appear to play a role in mortality of severely obese patients.
Circulating estrogens increase with body weight. However, an association of weight gain with hormone replacement therapy (HRT) has not been supported by findings from scientific studies. The relation between HRT and incidence of CVD is similar at all levels of BMI. Breast cancer increases only in the group with the lowest BMI. HRT appears to protect against initial myocardial infarction and hip fracture in both obese and lean women.
Assessing the Obese Patient
In assessing the obese patient, it is critical to determine the relative contributions made by fat and fat-free mass to total body mass. Body composition assessment has improved over the century. Various measures are used to grossly estimate the degree of obesity in large-scale epidemiological settings, including body weight, BMI, waist circumference, and the waist-to-hip ratio. In smaller-scale studies and clinical settings, measurements of triceps and subscapular skinfolds are more practical and accurate methods. Bioelectrical impedance, total body electrical conductivity methods, and dual-energy x-ray absorptiometry are also used in clinical settings. Indirect methods such as hydrostatic weighing and measurement of total body potassium and deuterated and 18O2-labeled water are used in research settings.
It is essential that valid and reliable measures of dietary intake be used in studies aimed at determining the links between dietary intake and obesity. Various instruments are available, but a valid assessment requires clear identification of the primary objective of the assessment and the intended uses of the derived information. Other considerations include defining what components of the diet will be assessed, participant burden, and reporting bias. Understanding the strengths and weakness of food records, dietary recalls, and food frequency questionnaires is important for the selection of methods, the development of strategies to minimize problems, and the appropriate interpretation of the data.
A better understanding of why modest weight reduction benefits many of the comorbidities and why the elderly may be relatively protected from obesity-related consequences may better delineate who should be treated and how aggressively. For example, in hypertensives, nonpharmacological treatment combined with pharmacological treatment is the most effective, and the development of diabetes can be prevented by weight loss and exercise.
Another factor to consider is diet composition. The recommendations for dietary intake for the prevention of CVD may require modification. The following areas are being considered: increasing monounsaturated fatty acids to replace saturated fatty acids; the role of water in obesity; the role of high energy density in obesity; and the role of meal replacements, diet supplements, vitamin and mineral supplements, and macronutrients.
Altering the diet composition for short-term weight loss (12 to 20 weeks) adds little to the amount of weight loss achieved. However, diet composition is important for weight maintenance. Small changes, such as eating 50 fewer calories a day, exercising for 15 to 20 minutes a day, or expending 100 additional calories per day, can result in a 10-lb weight loss per year or can help maintain weight. Small changes are additive.
Obesity is the normal physiological response to an environment in which energy intake exceeds energy output. It is an adaptive mechanism. Major environmental changes that support this adaptive mechanism are the greater availability of foods and the increase in sedentary lifestyle. The social environment has moved from being obesity retardant to being obesity conducive. This has important implications for patients with certain genotypes. Metabolic rates differ between patients and may be important in determining who becomes obese.
Obesity can develop when an imbalance exists between energy intake and energy expenditure. Despite this seemingly simple statement, the relative contributions of energy intake and energy expenditure in obesity development are poorly understood. Total energy expenditure can be divided into the following components:
- Resting metabolic rate, the largest single component of energy expenditure. Approximately 60% to 80% of the variation in resting metabolic rate can be explained by fat-free body mass;
- The thermic effect of food, or the increase in energy expenditure that occurs after eating; and
- Energy expended in physical activity. This varies due to differences in body mass. The energy expended in physical activity is an important component in understanding both why obesity occurs and how it can be treated.
In the context of a 3000-calorie diet, typical energy expenditure can be anywhere from 450 to 1500 calories. There is little evidence that “defective” energy expenditure exists. Efforts to increase energy expenditure by increasing physical activity are considered an important treatment for obesity. Physical activity is beneficial to cardiovascular health in many ways. For example, HDL-C levels increase and triglyceride, glucose, and blood pressure levels decrease. These changes occur in connection with small changes in weight. Diet and exercise strategies provide relatively equal amounts of weight loss in premenopausal and postmenopausal women. In men, this combination is also a very effective means of achieving weight loss. Further research is needed to determine a “prescription” of exercise; that is, its intensity, frequency, duration, and total amount as well as the length of the training period. The most important factor in successful weight loss is likely to be adherence to whatever exercise regimen a person adopts.
Medical Treatment of Obesity
One group of medications currently available for treatment of obesity works primarily by reducing food intake. The central regulation of food intake involves both monoamine and peptide neurotransmitters. Sibutramine, a newly approved sympathomimetic drug, reduces food intake and increases thermogenesis in experimental animals. There is a dose-related reduction in body weight. Sibutramine is associated with a 1 to 3 mm Hg increase in blood pressure and a 4 to 5 bpm increase in heart rate. Another group of drugs works by altering metabolism; orlistat, a lipase inhibitor, is in this group. Five long-term trials lasting 1 to 2 years have been reported in which drug-treated patients lost significantly more weight than control subjects. Gastrointestinal symptoms were rather severe the first year but subsided the second year. Yet another way to increase energy expenditure is through thermogenic mechanisms; however, no drugs are currently available that work in this manner. The impact of drug treatment on cardiac mechanics was discussed at the conference. The most striking example, of course, was the recent withdrawal of the combination of fenfluramine and phentermine (fen/phen) from the market by the Food and Drug Administration (FDA). This was prompted by a report from the Mayo Clinic of 24 cases of valvular heart disease in women who were treated with fen/phen. In addition, unpublished data on the World Wide Web provided the basis for the withdrawal of the combination drug. The percentage of patients meeting the FDA criteria for valvulopathy was 31.7%; 68.3% of patients taking these drugs did not exhibit valvular changes. It will be necessary to determine whether obesity without pharmacological intervention is associated with valvular changes before cause can be attributed to any drug used to treat human obesity. There is clearly a need to first identify which heart valve changes occur as a direct result of obesity before deciding that pharmacological therapy is the cause of valvular disease. At present, little is known about the incidence of new, significant valvular disorders associated with fen/phen. Information will come from case-control studies and smaller retrospective studies with patients serving as their own control subjects. The risk factors for valvulopathy must be identified, as well as whether the valve abnormalities are reversible if the obesity drugs are discontinued.
Nondrug Treatment of Obesity
Lifestyle and psychosocial treatments have their roots in behavior modification and include techniques and approaches that focus on changing behaviors that are thought to contribute to or maintain obesity. Most of the various lifestyle approaches have several factors in common, including the following: the use of self-monitoring and goal setting; stimulus control; modification of eating style and habits; the use of reinforcement for healthy behaviors; nutrition education; moderate physical activity; and cognitive restructuring, including stress management, relaxation skills, meditation, and relapse-prevention training. These approaches produce moderate weight loss and have minimal side effects. They are most useful for individuals with mild obesity (BMI of 27 to 30). Individuals who follow such an approach to weight loss maintain on average about two thirds of their initial weight loss 12 months after treatment termination. In studies with extended follow-up, patients return gradually to baseline within a few years after treatment termination. Thus far, only a continuous-care model of lifestyle intervention that views obesity as a chronic disease requiring support or contact after the conclusion of formal treatment produces significant results in terms of long-term maintenance. Future research needs to address the barriers to this approach, such as insurance reimbursement for obesity-related treatments and the lack of data to support the cost-effectiveness and feasibility of continuous care. Research should also focus on methods of implementing lifestyle interventions at the lowest cost possible and evaluating which elements of multicomponent treatments are most effective for which individuals. Despite the lack of substantive evidence to support specific strategies to achieve weight maintenance, empirical evidence has provided some insight into this problem. Factors related to weight maintenance are different from those involved in initial weight loss. Regular exercise is crucial, as is social support. Effective strategies for maintaining weight loss include ongoing contact with a physician or counselor, provision of problem solving, and enhancement of interactions. These can be accomplished by telephone and/or mail contacts. Multicomponent and home-based strategies appear to be the most effective. Social support can be enhanced by looking beyond the usual sources. For example, program participants can be asked to bring in 3 friends. Intragroup activities and intergroup competition have been shown to be effective. In summary, weight maintenance requires ongoing contact with a physician or other weight-loss counselor, exercise, social support, and extended treatment. In the long term, the most effective approach to controlling obesity may be to view it as a chronic disease. Maintenance of quality of life (QOL) has recently emerged as a standard for the successful treatment of obesity. Investigators agree that QOL consists of the following domains: physical functioning, psychological functioning, social functioning, overall life satisfaction, and perceptions of health status. In one focus group of moderately obese individuals, an attempt to gain insight into patients’ perceptions of why obesity is problematic revealed that in the area of physical functioning, such things as lack of energy, esophageal reflux, and pain emerged. In the psychological arena, patients felt out of control and were entangled in a cycle of depression and weight gain. Socially, they were withdrawn, they avoided certain situations such as air travel because of the seating difficulties, and they felt embarrassed to take part in their children’s activities. Finally, the economic costs were significant with regard to food and clothing. The economic cost of obesity is enormous. The monetary burden on society of illness and premature death is measured in terms of direct and indirect costs. Direct costs represent the value of resources (personal health care, other professional services, and drugs) that could be allocated to other uses in the absence of disease. Indirect costs are the value of lost output because of the cessation or reduction of productive activity due to morbidity and mortality. The direct costs of CHD, non–insulin-dependent diabetes mellitus, and hypertension attributed to obesity have been shown in 1 study to amount to $42.62 billion. The indirect costs of non–insulin-dependent diabetes attributed to obesity were $30.74 billion. A 1998 article showed that 17% of the costs of CHD were related to obesity. The economic costs of weight-related disease become significant at a BMI >25. In 1995, 5.7% ($99.2 billion) of the US health expenditure was related to individuals with a BMI of 29. Using a BMI of 25, this cost would be even greater. It is important to recognize that obesity is not confined to the United States; it is an international problem. With regard to personal costs, >$16 million is spent on diet sodas, $9 million in health clubs, $600 million in medically supervised programs, $5 million on diet meals, $4 million on exercise equipment, and $2 million on commercial weight reduction programs. The cost and benefits of obesity to society represent a very important issue that needs to be thoroughly examined. The challenge is how to reduce the increasing prevalence of obesity and its sequelae in both children and adults. It is difficult to lose weight and maintain the loss; there are side effects; people tend to regain weight once pharmacological agents are withdrawn; and surgery is not without problems. These concepts clearly support a preventive approach to obesity beginning in early childhood, with a focus on eating and activity patterns and on health as opposed to cosmetics. A family approach should be adopted. Two strategies should be used, ie, the population approach and the individual approach. The population-based effort should focus on such areas as the media, community, and schools. The individual strategy will probably require a multidisciplinary approach consisting of physicians, dietitians, nurses, and physical therapists. To date, health professionals have focused most of their efforts on an individual approach, but serious consideration should be given to a population approach. The scientific community has not yet reached consensus on viable ways to approach the problems associated with obesity. However, several lines of attack are being investigated. Because of the complexity of the obesity problem, a multifactorial approach will undoubtedly be required. The pharmacological approach has yielded disappointing results, but promise is on the horizon regarding possible drugs to modify appetite and others that reduce absorption of foods or enhance energy expenditure. The public health approach requires a systematic education of the public about the dangers of obesity. Various health agencies could work together to promulgate such a message that would reach all population groups. There is a great need to address the social factors that contribute to obesity and to initiate efforts on a broad scale to modify these factors. Much skepticism exists regarding the possibility of achieving success in the treatment of obesity. It is important to note that many of the cardiovascular complications of obesity arise as a result of mild to moderate degrees of overweight. The availability of ancillary personnel, eg, dietitians and exercise therapists, will be required to assist physicians in the treatment of obesity in the clinical setting. Finally, management of associated risk factors (atherogenic dyslipidemia, hypertension, prothrombic state, and insulin resistance) will help prevent the cardiovascular complications of obesity.
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