- Email: [email protected]
Obesity as a risk factor in coronary artery disease
Obesity as a risk factor in coronary artery disease Sunil V. Rao, MD,a Mark Donahue, MD,a F. Xavier Pi-Sunyer, MD, MPH,b and Valentin Fuster, MD, PhDc Durham, NC, and New York, NY
In the United States and other developed countries, obesity is becoming an increasingly prevalent risk factor for cardiovascular disease. Data from the third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) show that approximately 33% of the US population in the early 1990s was obese, demonstrating an increase from the 25% figure recorded from the second NHANES study, NHANES II (1976-1980).1 Estimates for certain minority populations are even higher. There is a known association between body mass index (BMI) and the risk for mortality in adults ( Figure 1). Citing epidemiologic studies that implicate obesity as an important determinant of cardiovascular health, the American Heart Association has added obesity to its list of major modifiable risk factors for coronary artery disease.2 This review examines the evidence supporting the conclusion that obesity is an important risk factor for coronary heart disease (CHD).
Figure 1
Definition of overweight and obesity The definitions for the terms overweight and obesity were traditionally based on actuarial survival data provided by the Metropolitan Life Insurance Company.3 These definitions were limited by their reliance on data gathered exclusively from white populations, by their use of an arbitrary definition of frame size, and by their failure to take into account obesity-related comorbidities. BMI, calculated by dividing an individual’s weight in kilograms by height in meters squared, has been proposed as a better measure of obesity. The World Health Organization4 and National Institutes of Health5 have adopted this measure, and they define overweight as a BMI ≥25 but <30, obesity as a BMI ≥30 but <39.9, and extreme obesity as a BMI ≥40. Although this definition remedies some limitations of using weight alone, it does not account for body fat distribution, an independent predictor of health risk.6 Weight loss is often indicative of fat loss in younger populations, but weight loss in elderly individuals may be caused by the loss of fat mass, the loss of lean body mass, or both. In the case of From the aDivision of Cardiology, Duke University Medical Center, Durham, NC, and the bSt Lukes/Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, and cMt Sinai Hospital, New York, NY. Reprint requests: Sunil V. Rao, MD, Division of Cardiology, Duke University Medical Center, Box 31101, Durham, NC 27710. E-mail: [email protected] Am Heart J 2001;142:1102-7. Copyright © 2001 by Mosby, Inc. 0002-8703/2001/$35.00 + 0 4/1/119419 doi:10.1067/mhj.2001.119419
Multivariate relative risk of death from cardiovascular disease, cancer, and all other causes among men and women who had never smoked and who had no history of disease at enrollment, according to BMI. (Adapted with permission from Calle EE, Thun MJ, Petrelli JM, et al. Body-mass index and mortality in a prospective cohort of US adults. N Engl J Med 1999;341: 1097-110.)
elderly persons, assessing fat distribution by use of the waist-to-hip circumference ratio may be a better measure of obesity. Whatever the measurement used, however, the available evidence suggests that individuals
American Heart Journal Volume 142, Number 6
who are overweight or obese have an increased risk for cardiovascular morbidity and mortality.
Obesity and related conditions Any discussion of the impact of obesity on cardiovascular disease also requires a discussion of obesityrelated conditions such as diabetes mellitus and hypertension. Until recently the importance of obesity alone in predicting adverse cardiovascular outcomes has been a subject of debate because obesity influences the development of other established cardiovascular risk factors. Overweight, obesity, and abdominal distribution of fat are associated with type 2 diabetes mellitus, hypertension, and dyslipidemia. Additionally, newer putative risk factors for cardiovascular disease, such as levels of C-reactive protein (CRP) and lipoprotein(a) (Lp[a]), have also been shown to be elevated in obese individuals.
Glucose intolerance Several longitudinal population studies have demonstrated the association that exists between obesity and glucose intolerance.7,8 Data from NHANES III shows that 67% of individuals with type 2 diabetes mellitus have a BMI that meets the criteria for overweight and nearly half these persons have a BMI that meets the definition of obese.6 In the Iowa Women’s Health Study, women in the highest quintile of BMI and waist-to-hip ratio had a relative risk of 29 for development of diabetes mellitus over the 12-year follow-up period.7 Although the exact molecular mechanism by which obesity contributes to glucose intolerance remains elusive, it is likely that glucose intolerance results from a combination of genetic and molecular mechanisms in which the adipocyte is an active participant.9
Hypertension That a relationship exists between a person’s weight and blood pressure has been known for decades. A number of epidemiologic studies have established overweight and obesity as risk factors for hypertension.7,10,11 The precise mechanism by which increased weight contributes to higher blood pressure is not known, but evidence exists that the mechanism may be related to overactivity of the sympathoadrenal system.12 In animals, food intake produces the release of sympathetic hormones and insulin; insulin, in turn, further stimulates sympathetic outflow.13 Sympathetic activation and obesity both contribute to insulin resistance; as circulating insulin levels rise, a cycle of sympathetic overactivity and hyperinsulinemia develops that results in hypertension.14 Recently, the theory that hypertension contributes to obesity has been proposed.12
Rao et al 1103
According to this theory, the sympathetic overactivity seen in hypertension may lead to down-regulation of βreceptors, which influence the expenditure of calories. As these receptors are down-regulated, the hypertensive individual is less able to expend calories, which thereby results in weight gain.
Metabolic syndrome The strongest evidence for the association between obesity and dyslipidemia derives from the observation that obesity, dyslipidemia, glucose intolerance, and hypertension tend to cluster in certain individuals. In what has been termed the “metabolic syndrome” or “syndrome X,” the development of these powerful risk factors for CHD likely share a common pathophysiologic process. The hyperinsulinemia that results from obesity leads to increased production of very-low-density lipoprotein with subsequent hypertriglyceridemia and increased concentrations of intermediate and lowdensity lipoproteins (LDL).15 These LDL particles tend to be smaller, denser, and more atherogenic than other lipoproteins.16 Furthermore, there appears to be an inverse relationship between obesity and the serum concentration of high-density lipoprotein.17
Lipoprotein(a) Evidence has emerged that, in addition to being associated with abnormalities in the traditional lipid profile, obesity may be associated with elevated levels of Lp(a). Lp(a) resembles LDL but has the apoprotein B-100 attached to one end. It is structurally similar to plasminogen and may have some prothrombotic activity. Although far from conclusive, some studies have established a link between Lp(a) and CHD.18 The association between obesity and elevated levels of Lp(a) is suggested by a few small studies.19 The mechanism for the correlation between adiposity and Lp(a) has not been elucidated, but it has been observed that weight loss may result in reduced Lp(a) levels.20
C-reactive protein Another putative risk factor for cardiovascular disease in an individual is found in the level of CRP. The role of inflammation in atherogenesis is supported by population studies that demonstrate the association of CRP with coronary events.21,22 In NHANES III, obese individuals and individuals with high waist-tohip ratios had significantly higher levels of CRP; this relationship persisted after restricting the analysis to healthy, young, nonsmoking obese persons.23 Although high CRP levels are associated with features of the insulin resistance syndrome, most of this association is accounted for by an elevated BMI,24 thus
1104 Rao et al
suggesting that a state of low-grade inflammation may exist in overweight individuals. How the interaction between BMI and CRP contributes to cardiovascular disease remains unclear.
Evidence for obesity as an independent risk factor Despite the profound influence that obesity has on both traditional and newly discovered risk factors for CHD, many investigators and clinicians have viewed the impact of obesity on cardiovascular disease as being one that is indirect. Establishing the independence of obesity as a discrete risk factor for cardiovascular disease is difficult. Most studies have used mortality as an end point, but as Willett et al25 illustrate in a recent review on guidelines for healthy weight, this approach is rife with methodologic problems. These authors pinpoint 3 potential methodologic problems that can distort studies investigating the relationship between obesity and the risk for cardiovascular mortality. One such problem relates to what is called reverse causation, another relates to the issue of confounding variables, and a third problem arises from the process by which investigators make statistical adjustments for conditions related to obesity in the study population. Reverse causation has been cited as the reason for the U-shaped relationship between weight and the risk for mortality. Because patients tend to lose weight during chronic illnesses that are ultimately fatal, the appearance is created that persons with lower body weight have an increased mortality. Excluding patients from prospective studies who have lost significant weight in the recent past can often eliminate reverse causation. In addition, it can be helpful to adjust separately for weight loss and fat loss. For example, an analysis of 2 cohort studies found that, after adjustment for fat loss, weight loss was associated with an increased risk for mortality. Conversely, after adjustment for weight loss, fat loss was associated with a decreased risk for mortality.26 Like reverse causation, confounding variables may also lead investigators to draw false conclusions from study data. This is especially true when survival analyses do not adjust for smoking. As a group, smokers weigh less and have a higher mortality risk than do nonsmokers, which again produces the impression that persons with a lower weight have an increased mortality risk compared with persons with a higher weight. It is important to notice that when the Metropolitan Life Insurance Company conducted its studies to set standards for desirable weight in the US population, it did not include data about the smoking practices of their subjects.25 The third methodologic problem that can limit study conclusions involves the adjustments that investigators make for conditions related to obesity.
American Heart Journal December 2001
Willett et al25 point out that the practice of controlling for factors related to obesity serves to remove some of the adverse effects that result from the condition of overweight; it thereby produces the false impression that the effect of obesity on the risk for mortality is neutral. The danger in this premise is the implication that obesity without concomitant coronary risk factors is a benign condition. The available evidence indicates that this is not the case and that obesity itself independently increases a person’s risk for cardiovascular disease. One of the earliest epidemiologic studies to examine the influence of body weight on the development of cardiovascular disease was the Framingham Heart Study.27 This pioneering report was published soon after the Metropolitan Life Insurance Company had revised its standards for desirable weight. On the basis of survival data from its subscribers—data that suggested that a heavier weight was healthier than the weight that the company had previously prescribed— Metropolitan adjusted its table of desirable weights in an upward direction. For the Framingham trial, 5070 men and women with no cardiovascular disease at enrollment were followed up for 26 years; the objective was to investigate the development of cardiovascular disease in this population, defined as CHD, congestive heart failure, stroke, and claudication. It is interesting to note that the designers of the Framingham study used the Metropolitan Relative Weight (MRW), the percentage of desirable weight, to measure obesity in study subjects. By using MRW, the Framingham investigators found that, on average, the men and women in its study were 20% above their desirable weights. Women were heavier than men in the older age group. During the follow-up period, the majority of cardiovascular events that were observed were related to CHD (angina, unstable angina, myocardial infarction, and sudden death). The risk for cardiovascular disease increased with increasing MRW, and the most profound effect was seen in subjects younger than 50 years old. When the individual elements of the CHD end point were evaluated, a higher MRW was found to be related to an increased risk for development of each component. The risk for sudden death showed the steepest gradient. A higher risk for congestive heart failure and stroke, but not claudication, was also seen as MRW increased. The relationship between total cardiovascular disease and MRW persisted after adjustments for age, systolic blood pressure, serum cholesterol, cigarettes per day, glucose intolerance, and electrocardiographic left ventricular hypertrophy. The individual events of myocardial infarction, stroke, and cardiovascular death were associated with increasing MRW in the case of female subjects only, whereas MRW predicted sudden death in male subjects only. To further establish MRW as an
American Heart Journal Volume 142, Number 6
independent risk factor, it was decided that the subset of patients completely free of cardiovascular risk factors at enrollment should be analyzed separately. Again, the risk for cardiovascular disease increased with increasing MRW. In addition, an increase in MRW after the age of 25 years independently predicted the risk for cardiovascular disease. Despite their detailed methods, the authors of the Framingham study were criticized for using multivariate regression to control for the adverse physiologic effects of obesity such as glucose intolerance, hypertension, and dyslipidemia. After this potential limitation in method was taken into account, the Nurses’ Health Study28 examined the relationship between obesity and mortality by using BMI as a measure of obesity, as shown in Figure 2. In this study a cohort of 115,195 women, all without cardiovascular disease at study inception, was followed up for 16 years. The primary end point in the study was all-cause mortality. Secondary end points were death from CHD, cardiovascular disease, and cancer. Weight was selfreported but was highly correlated with measured weight in a small sample of the study cohort. After adjustment for age, there was a J-shaped relationship seen between BMI and the risk for mortality. When the subset of women who had never smoked was analyzed separately, the increase in mortality risk at a low BMI disappeared. In a multivariate analysis a BMI >29 was associated with a relative risk of 2.1 for allcause mortality and 4.6 for death from CHD. Women who had never smoked and had a BMI of ≥32 were found to be at highest risk, with a relative risk of 5.8 for death from cardiovascular disease. Although the primary analysis did not control for hypertension, diabetes mellitus, or hypercholesterolemia, these risk factors were controlled for in a separate multivariate analysis where the relationship between BMI and mortality persisted. Consistent with the findings of the Framingham study, weight gain in adulthood was associated with increased mortality risk. The Nurses’ Health Study also measured the waist-to-hip ratio to determine whether fat distribution influenced outcome measures. Among women who had never smoked, this ratio was a strong predictor of death from CHD, with a higher ratio conferring a higher risk. The association between abdominal fat distribution and mortality effects has been addressed in several epidemiologic studies.7,29,30 As noted previously, the waist-to-hip ratio, like obesity, is associated with an increased risk for development of other traditional
Rao et al 1105
Figure 2
Relative risk of death from cardiovascular disease, cancer, and other causes, according to BMI among women who never smoked. Deaths from cardiovascular disease include those resulting from coronary heart disease, stroke, and other cardiovascular causes. (Adapted with permission from Manson JE, Willett WC, Stampfer MJ, et al. Body weight and mortality among women. N Engl J Med 1995;333:677-85.)
1106 Rao et al
cardiac risk factors such as glucose intolerance, hypertension, and dyslipidemia. Some observational studies have adjusted for these obesity-related conditions,7 others have not.29 In an adjusted analysis, an increased waist-to-hip ratio was associated with an increased risk for total mortality and mortality from CHD, thus indicating that, when this measure of adiposity proves to be in the high range, it also constitutes an independent risk factor for cardiovascular disease.
Summary Obesity is becoming increasingly prevalent in developed countries. Measures of obesity such as BMI and waist-to-hip ratio are associated with the development of risk factors for CHD. Observational studies have consistently shown that increasing BMI or android distribution of body fat is correlated with hypertension, glucose intolerance, and dyslipidemia. Moreover, newer cardiac risk factors such as Lp(a) and CRP are also present in higher concentrations in persons who are overweight or obese. Despite the commonly held belief that obesity without concomitant coronary risk factors is a benign condition, available evidence indicates that both a high BMI and a high waist-to-hip ratio are independent risk factors for CHD and mortality. The mechanisms by which increased adipose and android fat distribution lead to the development of coronary risk factors and increased risk for mortality is unclear. It is imperative that strategies be developed to identify, treat, and ultimately prevent obesity. In the coming years new management and therapeutic strategies for obesity will likely emerge. Both existing strategies and those that are developed in the future will need to be studied in randomized clinical trials so that their impact on morbidity and mortality outcomes in the setting of obesity can be rationally assessed.
References 1. Eckel RH. Obesity and heart disease: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1997;96:3248-50. 2. Eckel RH, Krauss RM. American Heart Association call to action: obesity as a major risk factor for coronary heart disease. Circulation 1998;97:2099-100. 3. Metropolitan Life Insurance Company. Metropolitan height and weight tables. Stat Bull Met Life Ins Co 1983;64:2-9. 4. World Health Organization. Obesity: preventing and managing the global epidemic. Report of a WHO consultation on obesity. Geneva, Switzerland, June 3-5, 1997. Geneva: WHO; 2000. WHO Technical Report Series No.: 894. 5. National Institutes of Health. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report. Obes Res 1998;6(Suppl):51-209S.
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6. National Task Force on Obesity. Overweight, obesity, and health risk. Arch Intern Med 2000;160:898-904. 7. Folsom AR, Kushi LH, Anderson KE, et al. Associations of general and abdominal obesity with multiple health outcomes in older women: the Iowa Women’s Health Study. Arch Intern Med 2000; 160:2117-28. 8. Ohlson LO, Larsson B, Svardsudd K, et al. The influence of body fat distribution on the incidence of diabetes mellitus: 13.5 years of follow-up of the participants in the study of men born in 1913. Diabetes 1985;34:1055-8. 9. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest 2000;106:473-81. 10. Kannel WB, Brand N, Skinner JJ, et al. The relation of adiposity to blood pressure and the development of hypertension. Ann Intern Med 1967;67:48-59. 11. Stamler R, Stamler J, Riedlinger WF, et al. Weight and blood pressure: findings in hypertension screening of 1 million Americans. JAMA 1978;240:1607-10. 12. Julius S, Valentini M, Palatini P. Overweight and hypertension: a 2way street? Hypertension 2000;35:807-13. 13. Young JB, Landsberg L. Stimulation of the sympathetic nervous system during sucrose feeding. Nature 1977;269:615-7. 14. Reaven G, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities: the role of insulin resistance and the sympathoadrenal system. N Engl J Med 1996;334:374-81. 15. DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173-94. 16. Smith SC Jr, Greenland P, Grundy SM. Prevention conference V, beyond secondary prevention: identifying the high-risk patient for primary prevention: executive summary. Proceedings of an American Heart Association conference; 1998 Oct 26-28; San Francisco Calif. Circulation 2000;101:111-6. 17. Wood PD, Stefanick ML, Williams PT, et al. The effects on plasma lipoproteins of a prudent weight-reducing diet, with or without exercise, in overweight men and women. N Engl J Med 1991;325: 461-6. 18. Stein JH, Rosenson RS. Lipoprotein Lp(a) excess and coronary heart disease. Arch Intern Med 1997;157:1170-6. 19. Wassef N, Sidhom G, Zakareya E, et al. Lipoprotein(a) in android obesity and NIDDM. Diabetes Care 1997;20:1693-6. 20. Zamboni M, Facchinetti R, Armellini F, et al. Effects of visceral fat and weight loss on lipoprotein(a) concentration in subjects with obesity. Obesity Res 1997;5:332-7. 21. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:115-26. 22. Danesh J, Collins R, Appleby P, et al. Association of fibrinogen, Creactive protein, albumin, or leukocyte count with coronary heart disease. JAMA 1998;279:1477-82. 23. Visser M, Bouter LM, McQuillan GM, et al. Elevated C-reactive protein levels in overweight and obese adults. JAMA 1999;282:2131-5. 24. Hak AE, Stehouwer CD, Bots ML, et al. Associations of C-reactive protein with measures of obesity, insulin resistance, and subclinical atherosclerosis in healthy, middle-aged women. Arterioscler Thromb Vasc Biol 1999;19:1986-91. 25. Willett W, Dietz WH, Colditz GA. Primary care: guidelines for healthy weight. N Engl J Med 1999;341:427-34. 26. Allison DB, Zannolli R, Faith MS, et al. Weight loss increases and fat loss decreases all-cause mortality rate: results from two independent cohort studies. Int J Obes Relat Metab Disord 1999;23:603-11.
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27. Hubert HB, Feinleib M, McNamara PM, et al. Obesity as independent risk factor for cardiovascular disease: a 26-year follow-up of the participants in the Framingham Heart Study. Circulation 1983; 67:968-77. 28. Manson JE, Willett WC, Stampfer MJ, et al. Body weight and mortality among women. N Engl J Med 1995;333:677-85. 29. Rimm EB, Stampfer MJ, Giovannucci E, et al. Body size and fat
distribution as predictors of coronary heart disease among middle-aged and older US men. Am J Epidemiol 1995;141:111727. 30. Larsson B, Svardssudd K, Welin L, et al. Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: a 13 year follow-up of participants in the population study of men born in 1913. BMJ Clin Res Ed 1984;288:1401-4.
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In the United States and other developed countries, obesity is becoming an increasingly prevalent risk factor for cardiovascular disease. Data from the third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) show that approximately 33% of the US population in the early 1990s was obese, demonstrating an increase from the 25% figure recorded from the second NHANES study, NHANES II (1976-1980).1 Estimates for certain minority populations are even higher. There is a known association between body mass index (BMI) and the risk for mortality in adults ( Figure 1). Citing epidemiologic studies that implicate obesity as an important determinant of cardiovascular health, the American Heart Association has added obesity to its list of major modifiable risk factors for coronary artery disease.2 This review examines the evidence supporting the conclusion that obesity is an important risk factor for coronary heart disease (CHD).
Figure 1
Definition of overweight and obesity The definitions for the terms overweight and obesity were traditionally based on actuarial survival data provided by the Metropolitan Life Insurance Company.3 These definitions were limited by their reliance on data gathered exclusively from white populations, by their use of an arbitrary definition of frame size, and by their failure to take into account obesity-related comorbidities. BMI, calculated by dividing an individual’s weight in kilograms by height in meters squared, has been proposed as a better measure of obesity. The World Health Organization4 and National Institutes of Health5 have adopted this measure, and they define overweight as a BMI ≥25 but <30, obesity as a BMI ≥30 but <39.9, and extreme obesity as a BMI ≥40. Although this definition remedies some limitations of using weight alone, it does not account for body fat distribution, an independent predictor of health risk.6 Weight loss is often indicative of fat loss in younger populations, but weight loss in elderly individuals may be caused by the loss of fat mass, the loss of lean body mass, or both. In the case of From the aDivision of Cardiology, Duke University Medical Center, Durham, NC, and the bSt Lukes/Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, and cMt Sinai Hospital, New York, NY. Reprint requests: Sunil V. Rao, MD, Division of Cardiology, Duke University Medical Center, Box 31101, Durham, NC 27710. E-mail: [email protected] Am Heart J 2001;142:1102-7. Copyright © 2001 by Mosby, Inc. 0002-8703/2001/$35.00 + 0 4/1/119419 doi:10.1067/mhj.2001.119419
Multivariate relative risk of death from cardiovascular disease, cancer, and all other causes among men and women who had never smoked and who had no history of disease at enrollment, according to BMI. (Adapted with permission from Calle EE, Thun MJ, Petrelli JM, et al. Body-mass index and mortality in a prospective cohort of US adults. N Engl J Med 1999;341: 1097-110.)
elderly persons, assessing fat distribution by use of the waist-to-hip circumference ratio may be a better measure of obesity. Whatever the measurement used, however, the available evidence suggests that individuals
American Heart Journal Volume 142, Number 6
who are overweight or obese have an increased risk for cardiovascular morbidity and mortality.
Obesity and related conditions Any discussion of the impact of obesity on cardiovascular disease also requires a discussion of obesityrelated conditions such as diabetes mellitus and hypertension. Until recently the importance of obesity alone in predicting adverse cardiovascular outcomes has been a subject of debate because obesity influences the development of other established cardiovascular risk factors. Overweight, obesity, and abdominal distribution of fat are associated with type 2 diabetes mellitus, hypertension, and dyslipidemia. Additionally, newer putative risk factors for cardiovascular disease, such as levels of C-reactive protein (CRP) and lipoprotein(a) (Lp[a]), have also been shown to be elevated in obese individuals.
Glucose intolerance Several longitudinal population studies have demonstrated the association that exists between obesity and glucose intolerance.7,8 Data from NHANES III shows that 67% of individuals with type 2 diabetes mellitus have a BMI that meets the criteria for overweight and nearly half these persons have a BMI that meets the definition of obese.6 In the Iowa Women’s Health Study, women in the highest quintile of BMI and waist-to-hip ratio had a relative risk of 29 for development of diabetes mellitus over the 12-year follow-up period.7 Although the exact molecular mechanism by which obesity contributes to glucose intolerance remains elusive, it is likely that glucose intolerance results from a combination of genetic and molecular mechanisms in which the adipocyte is an active participant.9
Hypertension That a relationship exists between a person’s weight and blood pressure has been known for decades. A number of epidemiologic studies have established overweight and obesity as risk factors for hypertension.7,10,11 The precise mechanism by which increased weight contributes to higher blood pressure is not known, but evidence exists that the mechanism may be related to overactivity of the sympathoadrenal system.12 In animals, food intake produces the release of sympathetic hormones and insulin; insulin, in turn, further stimulates sympathetic outflow.13 Sympathetic activation and obesity both contribute to insulin resistance; as circulating insulin levels rise, a cycle of sympathetic overactivity and hyperinsulinemia develops that results in hypertension.14 Recently, the theory that hypertension contributes to obesity has been proposed.12
Rao et al 1103
According to this theory, the sympathetic overactivity seen in hypertension may lead to down-regulation of βreceptors, which influence the expenditure of calories. As these receptors are down-regulated, the hypertensive individual is less able to expend calories, which thereby results in weight gain.
Metabolic syndrome The strongest evidence for the association between obesity and dyslipidemia derives from the observation that obesity, dyslipidemia, glucose intolerance, and hypertension tend to cluster in certain individuals. In what has been termed the “metabolic syndrome” or “syndrome X,” the development of these powerful risk factors for CHD likely share a common pathophysiologic process. The hyperinsulinemia that results from obesity leads to increased production of very-low-density lipoprotein with subsequent hypertriglyceridemia and increased concentrations of intermediate and lowdensity lipoproteins (LDL).15 These LDL particles tend to be smaller, denser, and more atherogenic than other lipoproteins.16 Furthermore, there appears to be an inverse relationship between obesity and the serum concentration of high-density lipoprotein.17
Lipoprotein(a) Evidence has emerged that, in addition to being associated with abnormalities in the traditional lipid profile, obesity may be associated with elevated levels of Lp(a). Lp(a) resembles LDL but has the apoprotein B-100 attached to one end. It is structurally similar to plasminogen and may have some prothrombotic activity. Although far from conclusive, some studies have established a link between Lp(a) and CHD.18 The association between obesity and elevated levels of Lp(a) is suggested by a few small studies.19 The mechanism for the correlation between adiposity and Lp(a) has not been elucidated, but it has been observed that weight loss may result in reduced Lp(a) levels.20
C-reactive protein Another putative risk factor for cardiovascular disease in an individual is found in the level of CRP. The role of inflammation in atherogenesis is supported by population studies that demonstrate the association of CRP with coronary events.21,22 In NHANES III, obese individuals and individuals with high waist-tohip ratios had significantly higher levels of CRP; this relationship persisted after restricting the analysis to healthy, young, nonsmoking obese persons.23 Although high CRP levels are associated with features of the insulin resistance syndrome, most of this association is accounted for by an elevated BMI,24 thus
1104 Rao et al
suggesting that a state of low-grade inflammation may exist in overweight individuals. How the interaction between BMI and CRP contributes to cardiovascular disease remains unclear.
Evidence for obesity as an independent risk factor Despite the profound influence that obesity has on both traditional and newly discovered risk factors for CHD, many investigators and clinicians have viewed the impact of obesity on cardiovascular disease as being one that is indirect. Establishing the independence of obesity as a discrete risk factor for cardiovascular disease is difficult. Most studies have used mortality as an end point, but as Willett et al25 illustrate in a recent review on guidelines for healthy weight, this approach is rife with methodologic problems. These authors pinpoint 3 potential methodologic problems that can distort studies investigating the relationship between obesity and the risk for cardiovascular mortality. One such problem relates to what is called reverse causation, another relates to the issue of confounding variables, and a third problem arises from the process by which investigators make statistical adjustments for conditions related to obesity in the study population. Reverse causation has been cited as the reason for the U-shaped relationship between weight and the risk for mortality. Because patients tend to lose weight during chronic illnesses that are ultimately fatal, the appearance is created that persons with lower body weight have an increased mortality. Excluding patients from prospective studies who have lost significant weight in the recent past can often eliminate reverse causation. In addition, it can be helpful to adjust separately for weight loss and fat loss. For example, an analysis of 2 cohort studies found that, after adjustment for fat loss, weight loss was associated with an increased risk for mortality. Conversely, after adjustment for weight loss, fat loss was associated with a decreased risk for mortality.26 Like reverse causation, confounding variables may also lead investigators to draw false conclusions from study data. This is especially true when survival analyses do not adjust for smoking. As a group, smokers weigh less and have a higher mortality risk than do nonsmokers, which again produces the impression that persons with a lower weight have an increased mortality risk compared with persons with a higher weight. It is important to notice that when the Metropolitan Life Insurance Company conducted its studies to set standards for desirable weight in the US population, it did not include data about the smoking practices of their subjects.25 The third methodologic problem that can limit study conclusions involves the adjustments that investigators make for conditions related to obesity.
American Heart Journal December 2001
Willett et al25 point out that the practice of controlling for factors related to obesity serves to remove some of the adverse effects that result from the condition of overweight; it thereby produces the false impression that the effect of obesity on the risk for mortality is neutral. The danger in this premise is the implication that obesity without concomitant coronary risk factors is a benign condition. The available evidence indicates that this is not the case and that obesity itself independently increases a person’s risk for cardiovascular disease. One of the earliest epidemiologic studies to examine the influence of body weight on the development of cardiovascular disease was the Framingham Heart Study.27 This pioneering report was published soon after the Metropolitan Life Insurance Company had revised its standards for desirable weight. On the basis of survival data from its subscribers—data that suggested that a heavier weight was healthier than the weight that the company had previously prescribed— Metropolitan adjusted its table of desirable weights in an upward direction. For the Framingham trial, 5070 men and women with no cardiovascular disease at enrollment were followed up for 26 years; the objective was to investigate the development of cardiovascular disease in this population, defined as CHD, congestive heart failure, stroke, and claudication. It is interesting to note that the designers of the Framingham study used the Metropolitan Relative Weight (MRW), the percentage of desirable weight, to measure obesity in study subjects. By using MRW, the Framingham investigators found that, on average, the men and women in its study were 20% above their desirable weights. Women were heavier than men in the older age group. During the follow-up period, the majority of cardiovascular events that were observed were related to CHD (angina, unstable angina, myocardial infarction, and sudden death). The risk for cardiovascular disease increased with increasing MRW, and the most profound effect was seen in subjects younger than 50 years old. When the individual elements of the CHD end point were evaluated, a higher MRW was found to be related to an increased risk for development of each component. The risk for sudden death showed the steepest gradient. A higher risk for congestive heart failure and stroke, but not claudication, was also seen as MRW increased. The relationship between total cardiovascular disease and MRW persisted after adjustments for age, systolic blood pressure, serum cholesterol, cigarettes per day, glucose intolerance, and electrocardiographic left ventricular hypertrophy. The individual events of myocardial infarction, stroke, and cardiovascular death were associated with increasing MRW in the case of female subjects only, whereas MRW predicted sudden death in male subjects only. To further establish MRW as an
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independent risk factor, it was decided that the subset of patients completely free of cardiovascular risk factors at enrollment should be analyzed separately. Again, the risk for cardiovascular disease increased with increasing MRW. In addition, an increase in MRW after the age of 25 years independently predicted the risk for cardiovascular disease. Despite their detailed methods, the authors of the Framingham study were criticized for using multivariate regression to control for the adverse physiologic effects of obesity such as glucose intolerance, hypertension, and dyslipidemia. After this potential limitation in method was taken into account, the Nurses’ Health Study28 examined the relationship between obesity and mortality by using BMI as a measure of obesity, as shown in Figure 2. In this study a cohort of 115,195 women, all without cardiovascular disease at study inception, was followed up for 16 years. The primary end point in the study was all-cause mortality. Secondary end points were death from CHD, cardiovascular disease, and cancer. Weight was selfreported but was highly correlated with measured weight in a small sample of the study cohort. After adjustment for age, there was a J-shaped relationship seen between BMI and the risk for mortality. When the subset of women who had never smoked was analyzed separately, the increase in mortality risk at a low BMI disappeared. In a multivariate analysis a BMI >29 was associated with a relative risk of 2.1 for allcause mortality and 4.6 for death from CHD. Women who had never smoked and had a BMI of ≥32 were found to be at highest risk, with a relative risk of 5.8 for death from cardiovascular disease. Although the primary analysis did not control for hypertension, diabetes mellitus, or hypercholesterolemia, these risk factors were controlled for in a separate multivariate analysis where the relationship between BMI and mortality persisted. Consistent with the findings of the Framingham study, weight gain in adulthood was associated with increased mortality risk. The Nurses’ Health Study also measured the waist-to-hip ratio to determine whether fat distribution influenced outcome measures. Among women who had never smoked, this ratio was a strong predictor of death from CHD, with a higher ratio conferring a higher risk. The association between abdominal fat distribution and mortality effects has been addressed in several epidemiologic studies.7,29,30 As noted previously, the waist-to-hip ratio, like obesity, is associated with an increased risk for development of other traditional
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Figure 2
Relative risk of death from cardiovascular disease, cancer, and other causes, according to BMI among women who never smoked. Deaths from cardiovascular disease include those resulting from coronary heart disease, stroke, and other cardiovascular causes. (Adapted with permission from Manson JE, Willett WC, Stampfer MJ, et al. Body weight and mortality among women. N Engl J Med 1995;333:677-85.)
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cardiac risk factors such as glucose intolerance, hypertension, and dyslipidemia. Some observational studies have adjusted for these obesity-related conditions,7 others have not.29 In an adjusted analysis, an increased waist-to-hip ratio was associated with an increased risk for total mortality and mortality from CHD, thus indicating that, when this measure of adiposity proves to be in the high range, it also constitutes an independent risk factor for cardiovascular disease.
Summary Obesity is becoming increasingly prevalent in developed countries. Measures of obesity such as BMI and waist-to-hip ratio are associated with the development of risk factors for CHD. Observational studies have consistently shown that increasing BMI or android distribution of body fat is correlated with hypertension, glucose intolerance, and dyslipidemia. Moreover, newer cardiac risk factors such as Lp(a) and CRP are also present in higher concentrations in persons who are overweight or obese. Despite the commonly held belief that obesity without concomitant coronary risk factors is a benign condition, available evidence indicates that both a high BMI and a high waist-to-hip ratio are independent risk factors for CHD and mortality. The mechanisms by which increased adipose and android fat distribution lead to the development of coronary risk factors and increased risk for mortality is unclear. It is imperative that strategies be developed to identify, treat, and ultimately prevent obesity. In the coming years new management and therapeutic strategies for obesity will likely emerge. Both existing strategies and those that are developed in the future will need to be studied in randomized clinical trials so that their impact on morbidity and mortality outcomes in the setting of obesity can be rationally assessed.
References 1. Eckel RH. Obesity and heart disease: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1997;96:3248-50. 2. Eckel RH, Krauss RM. American Heart Association call to action: obesity as a major risk factor for coronary heart disease. Circulation 1998;97:2099-100. 3. Metropolitan Life Insurance Company. Metropolitan height and weight tables. Stat Bull Met Life Ins Co 1983;64:2-9. 4. World Health Organization. Obesity: preventing and managing the global epidemic. Report of a WHO consultation on obesity. Geneva, Switzerland, June 3-5, 1997. Geneva: WHO; 2000. WHO Technical Report Series No.: 894. 5. National Institutes of Health. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report. Obes Res 1998;6(Suppl):51-209S.
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6. National Task Force on Obesity. Overweight, obesity, and health risk. Arch Intern Med 2000;160:898-904. 7. Folsom AR, Kushi LH, Anderson KE, et al. Associations of general and abdominal obesity with multiple health outcomes in older women: the Iowa Women’s Health Study. Arch Intern Med 2000; 160:2117-28. 8. Ohlson LO, Larsson B, Svardsudd K, et al. The influence of body fat distribution on the incidence of diabetes mellitus: 13.5 years of follow-up of the participants in the study of men born in 1913. Diabetes 1985;34:1055-8. 9. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest 2000;106:473-81. 10. Kannel WB, Brand N, Skinner JJ, et al. The relation of adiposity to blood pressure and the development of hypertension. Ann Intern Med 1967;67:48-59. 11. Stamler R, Stamler J, Riedlinger WF, et al. Weight and blood pressure: findings in hypertension screening of 1 million Americans. JAMA 1978;240:1607-10. 12. Julius S, Valentini M, Palatini P. Overweight and hypertension: a 2way street? Hypertension 2000;35:807-13. 13. Young JB, Landsberg L. Stimulation of the sympathetic nervous system during sucrose feeding. Nature 1977;269:615-7. 14. Reaven G, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities: the role of insulin resistance and the sympathoadrenal system. N Engl J Med 1996;334:374-81. 15. DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173-94. 16. Smith SC Jr, Greenland P, Grundy SM. Prevention conference V, beyond secondary prevention: identifying the high-risk patient for primary prevention: executive summary. Proceedings of an American Heart Association conference; 1998 Oct 26-28; San Francisco Calif. Circulation 2000;101:111-6. 17. Wood PD, Stefanick ML, Williams PT, et al. The effects on plasma lipoproteins of a prudent weight-reducing diet, with or without exercise, in overweight men and women. N Engl J Med 1991;325: 461-6. 18. Stein JH, Rosenson RS. Lipoprotein Lp(a) excess and coronary heart disease. Arch Intern Med 1997;157:1170-6. 19. Wassef N, Sidhom G, Zakareya E, et al. Lipoprotein(a) in android obesity and NIDDM. Diabetes Care 1997;20:1693-6. 20. Zamboni M, Facchinetti R, Armellini F, et al. Effects of visceral fat and weight loss on lipoprotein(a) concentration in subjects with obesity. Obesity Res 1997;5:332-7. 21. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:115-26. 22. Danesh J, Collins R, Appleby P, et al. Association of fibrinogen, Creactive protein, albumin, or leukocyte count with coronary heart disease. JAMA 1998;279:1477-82. 23. Visser M, Bouter LM, McQuillan GM, et al. Elevated C-reactive protein levels in overweight and obese adults. JAMA 1999;282:2131-5. 24. Hak AE, Stehouwer CD, Bots ML, et al. Associations of C-reactive protein with measures of obesity, insulin resistance, and subclinical atherosclerosis in healthy, middle-aged women. Arterioscler Thromb Vasc Biol 1999;19:1986-91. 25. Willett W, Dietz WH, Colditz GA. Primary care: guidelines for healthy weight. N Engl J Med 1999;341:427-34. 26. Allison DB, Zannolli R, Faith MS, et al. Weight loss increases and fat loss decreases all-cause mortality rate: results from two independent cohort studies. Int J Obes Relat Metab Disord 1999;23:603-11.
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27. Hubert HB, Feinleib M, McNamara PM, et al. Obesity as independent risk factor for cardiovascular disease: a 26-year follow-up of the participants in the Framingham Heart Study. Circulation 1983; 67:968-77. 28. Manson JE, Willett WC, Stampfer MJ, et al. Body weight and mortality among women. N Engl J Med 1995;333:677-85. 29. Rimm EB, Stampfer MJ, Giovannucci E, et al. Body size and fat
distribution as predictors of coronary heart disease among middle-aged and older US men. Am J Epidemiol 1995;141:111727. 30. Larsson B, Svardssudd K, Welin L, et al. Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: a 13 year follow-up of participants in the population study of men born in 1913. BMJ Clin Res Ed 1984;288:1401-4.
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