Obesity and CV Disease 1.PPT
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  • Of all the major CV risk factors, obesity is probably the most neglected and most frustrating to treat. Yet it carries with it a significant health burden not only in terms of morbidity but also mortality.
  • In the next several minutes my task is to describe the alarming prevalence of obesity, try to explaain the pathophysiology linking obesity and cv disease and its impact on the mortality and morbidity and lasty, I will attempt to show the relationships bet obesity, insulin resistance, type 2 DM and metabolic syndrome.
  • Although the association of obesity and cardiovascular disease has been known for a long time, the medical community has not taken this condition serously until the last few years when the NHANES survey showed a tremendous increase in the prevalence of obesity and concomitantly an explosion in the incidence of Type 2 DM. The WHO and NHLBI of the NIH have classified obesity as an epidemic (which means… More than 60% of Americans are overweight with more than 25% cosidered as obese. Furthermore, the trend is towards a continuing fattening pof America. And from a global perspective the prevalence of obesity is also alarming.
  • This shows the prevalence rate of obesity. In 1991 only a handful of states have obesity rate > 15% but by 1998, the reverse is true and there are only a few states with obesity < 15%. Again depicting the enormitym of the problem.
  • When analyzing a problem or an opportunity, it is important to understand the trend. We have never had an epidemic like this that we have been able to track so thoroughly and see. Using 1985 as our benchmark, let’s watch America become obese before our eyes.
  • In 1991, four states had obesity prevalence rates of 15–19 percent and no states had rates at or above 20 percent.
  • By 1994, every state in the USA had at least 10% or more of the population was obese
  • 1997. The first instance of over 20% of population was obese
  • 2001. The first instance of over 25%
  • We have never had an epidemic like this that we have been able to track so thoroughly and see. In 2004 7 states had obesity prevalence rates of 15–19 percent 33 states had rates of 20–24 percent; and 9 states had rates more than 25 percent.
  • The problem however is not unique to America and in fact as I mentioned the trend is globally with obesity rates projected to double in 30 years.
  • . . . and Now By the year 2000, Colorado was the only state in the nation that had not reached the highest category ( > 15%) of obesity incidence. The trend toward rampant obesity in the past decade implies that factors in society are contributing to weight gain by creating an imbalance in energy intake vs energy expenditure. Such factors are not believed to be associated with a diminished individual motivation to maintain weight nor to genetic or biologic changes within a population. Following the survey, the Centers for Disease Control and Prevention emphasized the urgency of heightening the awareness of healthcare professionals to become actively involved in managing the obesity epidemic. Additionally, public health professionals, legislators, communities, and employers must assist in this endeavor. 1 1. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP. The continuing epidemics of obesity and diabetes in the United States. JAMA. 2001;286:1195-1200.
  • There are variuos ways of assessing obesity and this include:
  • How do we assess obesity? There are very accurate but impractical ways of assessing obesity as the hydrodensitometry or dual energy x-ray absorptiometry. In clinical practice however, body fat is estimated by body mass index (BMI) calc. By multiplying weight in lbs. by 703 divided by height in inches squared. Although this is not perfect as it cannopt distinguish fat from muscle mass, it correlates significantly with body fat, morbidity and mortality.
  • Weight levels have been classified by the WHO and NHLBI based on the BMI’s.
  • Now, why be concerned with obesity? Well firsat of all obesity and lack of exercise are among the classic risk factors of CAD. Together with DM, cig smoking, hbp, hyperlipidimia.
  • The next few slides will describe studies that show the consistent relationships between obesity and CV, risk factors and mortality and morbidity. First, a 10 year follow up for both men and women aged 40 – 65. At a BMI > 26 the risk of DM is 8 times higher, the risk of CHD is 2x higher whereas that of HBP and cholelitiasis is 2-3 times higher.
  • This next slide shows the mortality curves in both men and women with a linear correlation with the BMI’s.
  • Another slide in women 30-55 years of age showing the the relatioship between BMI and CVD. Notice that at a BMI of 25-28 which is only overweigh and not even obese the the combines rates of non fatal MI and fatal CHD is twice that of non-overweight patients and about 4x as muchc in the obese group.
  • Just a few words about obesity. There are basically two varieties, gynecoid or female pattern obesity in the lower body and arms and male pattern or android obesity. They have dramatically different effects on the metabolic syndrome and the predisposition to it.
  • And this is just a CT scan through a normal person with mostly organs and – organs with a little bit of scattered omental fat and Type 2 diabetes. You can see that their waist size might not be much different here, but in this person there’s a lot – sort of packed – the abdomen is packed with fat.
  • Apples vs Pears The reasons for differences in body fat distribution are not absolutely clear. Men are more apt to develop visceral or upper-body obesity —the classic “apple” shape—while women tend to have lower-body obesity or the “pear” shape. Thus, in the pathogenesis of visceral obesity, androgens appear to be a factor. Interestingly, women with polycystic ovarian syndrome have hyperandrogenemia and develop the characteristic visceral obesity. 1 Body fat distribution also may be influenced by corticosteroids and growth hormones, which promote the uptake of fatty acids into adipose tissue located in the upper body. 1 Fat storage abnormalities have been noted to occur in conjunction with visceral obesity. Fat that is concentrated in the abdomen is not held as tightly as it is in other areas of the body; consequently, abdominal adipose tissue appears to release excess fatty acids into the circulation. The resultant overload of fat that accumulates in tissues is theorized to lead to insulin resistance. Conversely, in Cushing disease or other forms of hyper-corticoidism, the level of insulin resistance exceeds the degree of obesity; however, excess adiposity, when it does occur, still gravitates to the abdomen. 2 Whether one chooses to believe that insulin resistance precedes upper body fat or vice versa, the fact is that obesity plays an integral part of insulin resistance —and p ersons with low body fat rarely display insulin resistance. 1 1. Grundy SM. Metabolic complications of obesity. Endocrine. 2000;13:155-165. 2. The University of Texas Southwestern Medical Center at Dallas Center For Human Nutrition.Metabolic Syndrome. Available at: http://swnt240.swmed.edu/humannutrition/Features/metabolicsyndrome.htm.
  • 
  • And this is a particularly metabolically adverse type of fat. And this just shows amount of visceral adipose tissue here. The CT scan’s showing a lot of visceral adipose. And here is a lean individual and you can see that this is glucose disposal, so worsening insulin resistance or improving glucose disposal has lower amounts of fat and there’s a fairly good correlation.
  • Certainly we have seen the number of individuals that are presenting and meet the definition of metabolic syndrome as rising and then as background then, the prevalence of diabetes really exploding worldwide across all the different continents. When we look at this, we’ve seen a steady rise since 1995 to the year 2000 and projected if things do not change by 2025, there’s literally going to be an explosion of diabetes and the consequent, morbidity and morality that follows from this.
  • This insulin resistance syndrome, also referred to as the metabolic syndrome or perhaps more appropriately the dysmetabolic syndrome, has been receiving increasing attention, especially in terms of its cardiovascular risk.
  • Reaven and Olefsky, early investigators on the insulin resistance syndrome, have defined the syndrome as a clinical syndrome in which the physiologic response in inadequate for the amount of insulin secreted, regardless of the nature of the defect.
  • rtunately, that is not the end of the insulin resistance story. T2DM is only the tip of the iceberg. Insulin resistance is also the basic underlying defect in a syndrome of multiple metabolic dysfunction leading to atherosclerosis. This is the dysmetabolic syndrome
  • The insulin resistance syndrome is reflected by both clinical and biochemical abnormalities, although diagnosis is usually made by clinical assessments. Clinical manifestations generally include the presence of central obesity, glucose intolerance, atherosclerosis, hypertension, and/or other syndromes such as polycystic ovarian syndrome among women.
  • These concepts have been integrated into the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) guidelines. The following criteria were set forth:
  • Now, we've already heard of the five markers for metabolic syndrome. And the National Health and Nutrition Education Study recently looked at these factors, and decided that 24 percent of people in this country are insulin resistant, but 44 percent of those over the age of sixty. And the criteria are clearly very simple: An increased waist circumference; over forty inches in a man and thirty-five in a woman. An increase in triglycerides. HDL below forty in a man; fifty in a woman. Elevated blood pressure. And elevated fasting glucose.
  • The prevalence of the metabolic syndrome, as defined by the ATPIII guidelines, is high in US adults. Almost half of adults 60 years and older have evidence of the metabolic syndrome.
  • As a result of this, we have the syndrome, which not only causes diabetes; it causes obviously hypertension the classic pictures the low HDL high triglycerides. And of importance is, even though the LDL is modestly elevated or even high normal, we know there are an increased number of LDL particles. And these particles are small, dense, and extremely atherogenic. Therefore, what we should see, when we lower insulin resistance, is an increase in the size of these particles, no decrease in the numbers, and an increase in LDL, and an increase in total cholesterol. The insulin resistance syndrome has been shown to be an independent risk factor for cardiac events, independent of hypertension and hyperlipidemia. And that's because the insulin resistance syndrome is associated with endothelial dysfunction. When you have insulin resistance, you produce superoxide, you quench nitric oxide, leading to vasoconstriction, clotting, and laying down of atheroma. Perhaps one of the most ignored aspects of the metabolic syndrome, and the diabetic patient in general, is that the metabolic syndrome is associated with left ventricular hypertrophy, which may partially explain the high incidence of congestive heart failure we see in the diabetic patient. And then an elevated PI-1 is another feature of the syndrome. And this is not just important in the vascular space, with the high PI-1 opposing the action of TPA, there is slowing of the breakdown of clot, but it's also very important in the vessel wall. Because if PI-1 is elevated in the vessel wall, there is a decreased formation of plasmin. And that plasmin is necessary to remove the collagen tissue from the atheromatous plaque, so that smooth muscle cells can move in and stabilize the plaque. So a high PI-1 in the vessel wall, is as very common in the diabetic patient, is associated with an increase in plaque rupture and cardiac events. And we now know that the elevated C-reactive protein is part of the insulin resistance syndrome. And we will talk about that, as well.
  • Metabolic Syndrome and Obesity: Twin Epidemics As the population in the United States grows older, high percentages of both men and women are affected by metabolic syndrome and obesity. The incidence of metabolic syndrome initially peaks in the age bracket of 60-69 years. For obesity, the peak occurrence is 50 to 59 years of age. In an overwhelming majority of patients with metabolic syndrome, the root cause of the problem is improper nutrition and inadequate physical activity. These causes also are major factors in obesity. Given the prevalence of metabolic syndrome, the importance of managing the obesity epidemic and raising the level of physical activity in the United States must be instilled. 1 1. Ford ES, Giles WH, Dieta WH. Prevalence of the metabolic syndrome among US adults. Findings From the Third National Health and Nutrition Examination Survey. JAMA. 2002;287:356-359. [[References to be included in lecture notes]]
  • This was a recently study published and it’s widely quoted, in JAMA just this year, 22% of Americans over age 20 have the metabolic syndrome. If you look at people over age 60, you know, it’s upwards of 50%. And this was actually a study that ended in the early nineties, so that if you look today, it’s probably higher than that. And I think actually, the average American,
  • So is it a big deal to have the metabolic syndrome? Well, in fact, it is from a cardiovascular standpoint. This was a study published just last year in Diabetes Care looking at a large population with – without the metabolic syndrome or with the metabolic syndrome. And this was the incidence of cardiovascular mortality over a four- or five-year period of time and you can see that it was substantially higher, six-fold higher in the people that had the metabolic syndrome. Well LDL, for instance, is a great target for treatment – and I’m all for using statins. You know, I mean we use a ton of statins, but it’s not a very good marker for predicting who’s going to have heart attacks and strokes and cardiac deaths. In fact, a better marker is the metabolic syndrome.
  • Certainly, Steve Hafner played a major role in identifying the risks that the diabetic face that it’s equivalent to those with known coronary heart disease. From the EAST/WEST study we see those individuals, nondiabetics with prior MI, the diabetics with no prior MI having a very similar risk and this has held up to other studies. So this certainly, once a patient goes onto full-blown diabetes, very high risk and we should be aggressively targeting these patients. But in also in recognizing patients with metabolic syndromes are at high risk, we need an equally aggressive pharmacologic and nonpharmacologic approach to these individuals.
  • The thing about the metabolic syndrome too is that this – I tell my patients, this is a great opportunity to take control of your life, to seize control of your destiny. We can prevent – I mean studies show, one study after another, that you can prevent Type 2 diabetes in the majority of people, randomized, double-blind studies, where you can prevent and it’s not only preventing Type 2 diabetes, but you prevent cardiovascular events. So management of the metabolic syndrome is really one of the key issues in general medicine today from my standpoint.
  • There are, of course, groups who say that this may be too high; that, in fact, you should take a fasting glucose of 100 or even 90 as a risk factor. But there are other features that should suggest that someone has the metabolic syndrome. For example, polycystic ovary disease. That affects eight percent of women. And the pathophysiology is that, with high insulin levels, you directly and indirectly stimulate the production of androgen from the ovary. You also decrease the sex hormone binding globulin production from the liver. This results in a higher free testosterone, which peripherally leads to acne, unwanted hair growth, etcetera. And the ovary suppresses ovulation, so that there is menstrual disturbance and infertility. But the key fact is that, after the menopause, these women have a 7.4-fold a 740 percent increase in myocardial infarction, because they are insulin resistant. An elevated uric acid we know is a risk factor for cardiac events, and is part of the metabolic syndrome. We believe this is because high insulin levels suppress the excretion of uric acid by the kidney. I've already mentioned albuminuria. We now know that fatty liver disease, or non-alcoholic steatosis, and the more serious form (N.A.S.H) non-alcoholic steatohepatitis, are both associated with the insulin resistance syndrome. I believe that we can add that to the list. And then, of course, the acanthosis nigracans, the ring-around-the-collar, the dark, velvety rash present in fourteen percent of African-Americans and Latinos, in grade eight, and not very much present in people of European origin though we do see it is a giveaway for the metabolic syndrome.
  • So there is reduced sodium excretion. And, of course, insulin is a salt-water-retaining hormone. So insulin's effect in the distal tubule will also lead to reduce sodium excretion. We know that high insulin levels stimulate the sympathetic nervous system. They also will increase the sodium and calcium content of the vascular smooth muscle cells; increase in the tone. In these cells, there is also peripheration of vascular smooth muscle cell. And it now appears that high insulin levels up-regulate the AT-1 receptor.
  • What causes the metabolic syndrome and the insulin resistance syndrome? Most people, if you ask, would simply say obesity. But there are many, many obese people out there who are not insulin resistant, and there are many thin people who are, in fact, insulin resistant. For example, we see many people with diabetes, from the Indian subcontinent, who have BMIs of nineteen or twenty, but who are clearly insulin resistant, because, in fact, the key is they have excess peritoneal fat. This peritoneal fat is extremely metabolically active, produced out of the cytokines, which ends up in a low-grade inflammatory response, which is the insulin resistance syndrome. Many of these cytokines, particularly TNF-alpha, cause a production from the peritoneal out of the sides of free fatty acids. With the elevation of free fatty acid, there is vast utilization of glucose by the muscle, and hyperinsulinemia ensues.

Transcript

  • 1. Obesity and Cardiovascular Disease Dionisio B. Yorro, Jr., M.D., FACC 16 th USTMAAA Convention Caesar’s Palace, LV, NV May 22-26, 2008
  • 2. Learning Objectives
    • Describe the epidemiology of obesity in the US and the increasing prevalence in the world.
    • Explain the relationships between obesity, insulin resistance, metabolic syndrome, cardiovascular disease, and other co-morbid conditions.
    • Emphasize the impact of obesity on mortality and morbidity.
    • Touch on the approach in the management of obesity.
  • 3. Epidemiology of Obesity
    • The WHO and NHLBI have classified obesity as an epidemic.
    • In 2002, about 64% of Americans are overweight, while 32% are obese.
    • 16% or 9 million kids are overweight.
    • There is a continuing trend towards an ever-fatter America.
    • By 2009, almost 70% of the population will be overweight or obese
    • Obesity is responsible for more than 300,000 deaths a year
    • From a global perspective, the increase in the prevalence of obesity is also alarming.
  • 4. Prevalence of Obesity Among US Adults From Years 1991, 1993, 1995, and 1998 (Reprinted with permission from Mokdad AH, et al. JAMA . 1999) < 10% 10% to 15% > 15% 1991 1993 1995 1998
  • 5. Obesity Trends Among U.S. Adults 1985 No Data <10% 10%–14%
  • 6. Obesity Trends Among U.S. Adults 1986 No Data <10% 10%–14%
  • 7. Obesity Trends Among U.S. Adults 1987 No Data <10% 10%-14%
  • 8. Obesity Trends Among U.S. Adults 1988 No Data <10% 10%–14%
  • 9. Obesity Trends Among U.S. Adults 1990 No Data <10% 10%–14%
  • 10. Obesity Trends Among U.S. Adults 1991 No Data <10% 10%–14% 15%–19%
  • 11. Obesity Trends Among U.S. Adults 1992 No Data <10% 10%–14% 15%–19%
  • 12. Obesity Trends Among U.S. Adults 1993 No Data <10% 10%–14% 15%–19%
  • 13. Obesity Trends Among U.S. Adults 1994 No Data <10% 10%–14% 15%–19%
  • 14. Obesity Trends Among U.S. Adults 1995 No Data <10% 10%–14% 15%–19%
  • 15. Obesity Trends Among U.S. Adults 1996 No Data <10% 10%–14% 15%–19%
  • 16. Obesity Trends Among U.S. Adults 1997 No Data <10% 10%–14% 15%–19% ≥20
  • 17. Obesity Trends Among U.S. Adults 1998 No Data <10% 10%–14% 15%–19% ≥20
  • 18. Obesity Trends Among U.S. Adults 1999 No Data <10% 10%–14% 15%–19% ≥20
  • 19. Obesity Trends Among U.S. Adults 2000 No Data <10% 10%–14% 15%–19% ≥20
  • 20. Obesity Trends Among U.S. Adults 2001 No Data <10% 10%–14% 15%–19% 20%–24% ≥25%
  • 21. (*BMI 30, or ~ 30 lbs overweight for 5’4” person) No Data <10% 10%–14% 15%–19% 20%–24% ≥25% Obesity Trends Among U.S. Adults 2002
  • 22. Obesity Trends Among U.S. Adults 2003 No Data <10% 10%–14% 15%–19% 20%–24% ≥25%
  • 23. Obesity Trends Among U.S. Adults 2004 No Data <10% 10%–14% 15%–19% 20%–24% ≥25%
  • 24. Obesity Rates Are Projected to Double Over the Next 30 Years (Sichieri R, et al. Am J Public Health . 1994) (Bennett SA, Magnus P. Med J Aust . 1994) (Prentice AM, Jebb SA. BMJ . 1995) (Mokdad AH, et al. JAMA . 1999) (Flegal KM, et al. Int J Obes Relat Metab Disord . 1998) ( NIH. Obes Res . 1998) 50 40 30 20 10 0 1960 1970 1980 1990 2000 2010 2020 2030 US England Australia Brazil Year BMI  30 (%)
  • 25. OBESITY, why?
  • 26. Bagel 140 calories 3-inch diameter Calorie Difference: 210 calories 350 calories 6-inch diameter 20 Years Ago Today
  • 27. Calorie Difference: 257 calories 590 calories Cheeseburger 20 Years Ago Today 333 calories
  • 28. Calorie Difference: 525 calories 1,025 calories 2 cups of pasta with sauce and 3 large meatballs 20 Years Ago Today 500 calories 1 cup spaghetti with sauce and 3 small meatballs Spaghetti and Meatballs
  • 29. 610 Calories 6.9 ounces Calorie Difference: 400 Calories French Fries 20 Years Ago Today 210 Calories 2.4 ounces
  • 30. Calorie Difference: 165 Calories 250 Calories 20 ounces 85 Calories 6.5 ounces Soda 20 Years Ago Today
  • 31. Calorie Difference: 500 calories 820 calories 320 calories Turkey Sandwich 20 Years Ago Today
  • 32. Coffee 20 Years Ago Coffee (with whole milk and sugar) Today Mocha Coffee (with steamed whole milk and mocha syrup) 45 calories 8 ounces 350 calories 16 ounces Calorie Difference: 305 calories
  • 33. Pepperoni Pizza 20 Years Ago Today 500 calories 850 calories Calorie Difference: 350 calories
  • 34. Chicken Caesar Salad 20 Years Ago Today 390 calories 1 ½ cups 790 calories 3 ½ cups Calorie Difference: 400 calories
  • 35. Causes of Overweight & Obesity
    • Science shows that genetics does play a role in obesity
      • However in most cases, both genes and behavior are necessary for a person to be overweight
    • Body weight is the result of a combination of influences:
      • genetic, metabolic, behavioral, environmental, cultural, and socioeconomic influences
    • Therefore behavioral and environmental factors provide the greatest “opportunity” for action and intervention
  • 36. Obesity Statistics: Prevalence in 2000 < 10% (1) > 15% (49) BMI > 30 kg/m 2 , or ~ 30 lb overweight for 5’4” person. Adapted from: Mokdad AH, et al. JAMA. 2001;286:1195-1200. Centers for Disease Control and Prevention. US Obesity Trends in Adults.
  • 37. Assessing Obesity
    • Measurement of body fat by:
      • hydrodensitometry
      • x-ray absorptiometry
      • bioelectrical impedance analysis (BIA)
      • skinfold thickness measurement
  • 38. Assessing Obesity
    • Waist circumference at level of iliac crest
      • Above 40 inches for men and 35 inches for women are indicative of health risk.
    • Waist-to-hip ratio: Circumference of the waist at the level of L3 divided by the circumference of the hip at the largest area of the gluteal region. (Helps to identify central or android obesity.)
      • For men waist-to-hip ratio > 1
      • For women waist-to-hip ratio > 0.85
  • 39. Assessing Obesity: BMI
    • Body mass index (BMI)
      • calculated as weight in kilos divided by height in meters squared.
      • evaluates weight relative to height
      • replaced % ideal body weight as the primary criterion for assessing obesity
      • correlates significantly with body fat, morbidity, and mortality
      • used most by researchers and health organizations in measuring and defining overweight and obesity.
    (Willett WC, et al. N Engl J Med . 1999) (NIH. Obes Res . 1998)
  • 40. Weight Classification by BMI Underweight < 18.5 Underweight Normal 18.5 – 24.9 Normal range Overweight 25.0 – 29.9 Preobese Obesity class 1 30.0 – 34.9 Obese class 1 Obesity class 2 35.0 – 39.9 Obese class 2 Obesity class 3 ≥ 40.0 Obese class 3 NHLBI = National Heart, Lung, and Blood Institute; WHO = World Health Organization. NHLBI Terminology BMI, kg/m 2 , Range WHO Classification (Reprinted with permission from Must A, et al. JAMA . 1999) (NIH. Obes Res . 1998) (World Health Organization. Obesity: preventing and managing the global epidemic. Report of a WHO Consultation presented at: the World Health Organization; June 3-5, 1997; Geneva, Switzerland. Publication WHO/NUT/NCD/98.1)
  • 41. Classic Risk Factors in CAD Diabetes Nicotine Obesity and lack of exercise Dyslipidemia Hypertension (JNC VI. Arch Intern Med . 1997) CAD
  • 42. Obesity and Overweight Increase the Risk of:
    • Hypertension
    • Stroke
    • Diabetes mellitus, Type 2
    • Metabolic syndrome
    • CV mortality
    • Cancer – endometrium, breast, prostate, and colon.
    • Gallbladder disease
    • Osteoarthritis
    • Respiratory diseases and sleep-apnea
  • 43. Relationship Between BMI and the Relative Risk of Comorbid Conditions  21 22 23 24 25 26 27 28 29 30 7 6 4 3 2 1 0 5 Type 2 diabetes Hypertension Cholelithiasis CHD Relative Risk BMI (Reprinted with permission from Willett WC, et al. N Engl J Med . 1999. Copyright © 1999 Massachusetts Medical Society. All rights reserved)
  • 44. Obesity and Mortality Risk, 1989 Men Women Digestive Disease Pulmonary Disease Cardiovascular Disease Gallbladder Disease Diabetes Mellitus Moderate Risk Very Low Risk Low Risk Moderate Risk High Risk Very High Risk 2.5 2.0 1.5 1.0 0 20 25 30 35 40 BMI (kg/m 2 ) (Reprinted with permission from Gray DS. Med Clin North Am . 1989) Mortality Ratio
  • 45. Obesity and Cardiovascular Disease 0 1 2 3 4 Relative Risk Relative Risk of Nonfatal MI and Fatal CHD (Combined) Based on BMI (Women) < 21 21 – 22.9 23 – 24.9 25 – 28.9  29 BMI (kg/m 2 ) MI = myocardial infarction. (Adapted with permission from Willett WC, et al. JAMA . 1995)
  • 46. How does obesity cause cardiovascular disease?
  • 47. Patterns of Body Fat Distribution Intrabdominal or Visceral type (android or “ apple shaped”) Lower body or external type (gynoid or “ pear shaped”)
  • 48. Visceral Fat Distribution Normal vs Obesity Normal Visceral obesity Courtesy of Wilfred Y. Fujimoto, MD.
  • 49. All Fat Cells Are Not Created Equal
    • Large Insulin-Resistant Adipocytes
    • Adrenergic Receptors 
    • Insulin-Mediated Antilypolysis
    • Catecholamine-Mediated Lipolysis 
    • Small Insulin-Sensitive Adipocytes
    • Adrenergic Receptors 
    Fatty Acids 
  • 50. BODY FAT DISTRBUTION
    • Men are apt to develop visceral type obesity while women develop the peripheral type
    • Androgens appear to influence this distribution
    • PCO with androgenemia predisposes to visceral type adiposity
    • Corticosteroids and growth hormone also tend to develop visceral obesity
  • 51. How does obesity cause cardiovascular disease?
  • 52.
    • Cytokines:
      • TNF-alpha
      • Interleukin 6
    • ‘ Adipokines:’
      • Resistin
      • Adiponectin
    • Pro-thrombotic mediators:
      • PAI-1
    Adipose Tissue
  • 53. Relationship Between Visceral Adipose Tissue and Insulin Action Banerji M et al. Am J Physiol 1997;273(2 pt 1):E425–E432. 18 16 14 12 10 8 6 4 2 0 1000 2000 3000 4000 5000 Visceral adipose tissue volume per unit surface area (mL/m 2 ) Glucose disposal (mg/kg LBM/min) Women Men
  • 54. Obesity and Insulin Resistance Hyperinsulinemia + Hyperglycemia Activation of the sympathetic nervous system Increase of arterial tone Na+ reabsorption Hypertension Overstimulation of pancreatic  -cell function Reduction of insulin secretion Type 2 Diabetes
  • 55. Worldwide Diabetes Prevalence Africa Americas Eastern Mediterranean Europe Southeast Asia 1995 2000 2025 (projected) 80 0 10 20 30 40 50 Estimated Prevalence (millions) 60 70 Western Pacific World Health Organization; 2001.
  • 56. What is the Metabolic Syndrome? Syndrome X Dysmetabolic Syndrome Insulin Resistance Syndrome
  • 57. The Metabolic Syndrome The Insulin Resistance Syndrome The Dysmetabolic Syndrome
  • 58. The Insulin Resistance Syndrome A syndrome in which the physiologic response is inadequate for the amount of insulin secreted Reaven, Olefsky
  • 59. The Metabolic Syndrome Associated With Insulin Resistance Insulin Resistance Hypertension Type 2 Diabetes Disordered Fibrinolysis Complex Dyslipidemia  TG, sdLDL,  HDL Endothelial Dysfunction Systemic Inflammation Athero - sclerosis Visceral Obesity Adapted from ADA. Diabetes Care. 1998;21:310-314. Pradhan et al. JAMA. 2001;286:327-334.
  • 60. Central obesity Glucose intolerance Atherosclerosis Hypertension Polycystic ovary syndrome Clinical Manifestations Lipid: Carbohydrate: Biochemical Abnormalities Fibrinolysis: Insulin resistance Hyperinsulinemia High TG Low HDL-C Small, dense LDL Increased PAI-1 The Insulin Resistance Syndrome
  • 61. Risk Factor Defining Level Abdominal obesity Waist Circumference Men >102 cm (>40 in) Women >88cm (>35 in) Triglycerides  150 mg/dL HDL-C Men <40 mg/dL Women <50 mg/dL Blood Pressure  130/  85 mmHg Fasting Glucose  110 mg/dL NCEP ATPIII. JAMA 2001;285:2486-2497 Risk Factors of the Metabolic Syndrome: ATPIII Definitions Metabolic syndrome: 3 or more
  • 62. Metabolic Syndrome NCEP ATP III Criteria NCEP ATP III. JAMA. 2001;285:2486–2497.
    • Risk Factor Defining Level
    • Abdominal Obesity (waist circumference)
      • Men >40 inches
      • Women >35 inches
    • Triglycerides > 150 mg/dL
    • HDL Cholesterol
      • Men <40 mg/dL
      • Women <50 mg/dL
    • Blood Pressure > 130/ > 85 mm Hg
    • Fasting Glucose > 110 mg/dL
     3 of the following
  • 63. Prevalence of the Metabolic Syndrome Among US Adults Prevalence (%) 0 5 10 15 20 25 30 35 40 45 20-29 30-39 40-49 50-59 60-69 >70 Men Women Age (years) Ford E et al. JAMA . 2002; 287: 356
  • 64. Insulin Resistance and Heart Disease
    • Diabetes
    • Hypertension
    • Low HDL
    • High triglycerides
    • Increased number of small, dense LDL particles
    • Endothelial dysfunction
    • LVH (left ventricular hypertrophy)
    • Increased PAI-1
    • Increased C-reactive protein
  • 65. Twin Epidemics: Parallels in Prevalence ~61% of US Adults Are Overweight or Obese 1 1. Available at: http://www.cdc.gov/nchs/products/pubs/pubd/hestats/obese/obse99.htm 2. Available at: http://www.cdc.gov/nchs/about/major/nhanes/overweight.pdf 3. Ford ES, et al. JAMA. 2002;287:356-359. 0 10 20 30 40 50 60 70 80 20-29 30-39 40-49 50-59 60-69 ≥ 70 Age, yr Prevalence, % Women Men Women Men Overweight/Obesity 2 Metabolic Syndrome 3
  • 66. Prevalence of the Metabolic Syndrome by ATP III Criteria — NHANES III Population Overall 22% for age 20 and older Age (yr) Prevalence (%) Adapted from: Ford ES et al. JAMA. 2002;287:356–359.
  • 67. Cardiovascular Mortality Associated With Metabolic Syndrome (MS) Diabetes Care 2001;24:683 p < 0.001
  • 68. Incidence of CHD Events in Patients With and Without Diabetes Incidence During Follow-up (%) (n=69) Nondiabetics with no prior MI Nondiabetics with prior MI Diabetics with no prior MI Diabetics with with prior MI 18.8 Haffner SM et al. N Engl J Med. 1998;339:229–234. (n=1304) (n=169) (n=890) 3.0 0.5 7.8 3.2 3.5 45.0 20.2 Events per 100 person-yr: P <.001* P <0.001 † * Non diabetics with vs without prior MI. † Diabetics with vs without prior MI.
  • 69. Goals for Managing the Metabolic Syndrome
    • An opportunity to prevent predictable complications:
        • Type 2 diabetes
        • Cardiovascular events
  • 70. Management of Metabolic Syndrome
    • While we are aware of the magnitude of this problem, we are still trying to figure out how to best manage this.
    • Weight loss, proper diet and exercise are the obvious recommendations.
    • There are a lot of questions that are unanswered. Is drug therapy helpful? Insulin sensitizers? Statins?
  • 71. Diseases Associated With Insulin Resistance
    • PCO
    • Elevated uric acid
    • Albuminuria
    • Nonalcoholic hepatic steatosis and NASH
    • Acanthosis nigricans
    • Metabolic syndrome
  • 72. Obesity Hypertension ?
  • 73. HYPERTENSION & OBESITY Epidemiological studies have shown a correlation between body weight and blood pressure — 70% of hypertension in men and 60% in women are associated with excess adiposity (Sharma AM, et al. J Hyptertens . 2001)
  • 74. Increased Prevalence of Hypertension* as a Correlate of BMI *Defined as mean SBP ≥ 140 mmHg or DBP ≥ 90 mmHg, or currently taking antihypertensive medication. BMI < 25 kg/m 2 BMI 25 – 26 kg/m 2 BMI 27 – 29 kg/m 2 BMI  30 kg/m 2 18.2 22.5 25.2 38.4 16.5 21.9 24 32.2 0 10 20 30 40 Men Women Hypertension (%) BMI Levels (NIH. Obes Res . 1998)
  • 75. Obesity and Hypertension Insulin Resistance + Hyperinsulinemia Activation of the sympathetic nervous system  Vasoconstriction  Cardiac output  Na+ reabsorption Blood Pressure (Landsberg L. J Hypertens. 2001)
  • 76. Mechanisms by Which Obesity May Cause Hypertension and Renal Injury by Activation of the Renin-Angiotensin System and Sympathetic Nervous System, Metabolic Abnormalities and Compression of the Kidney Obesity Renal medullary compression  Renin-angiotensin system activity  Sympathetic nervous system activity  Tubular NaCI reabsorption Renal vasodilation Volume expansion Lipids Glucose intolerance Glomerular hypertension Arterial hypertension Glomerulosclerosis  Glucose + (Engeli S, et al. Hypertension . 2000)
  • 77. Mechanism of Hypertension Associated With Insulin Resistance
    • Reduced sodium excretion
    • Stimulation of SNS
    • Increased Na and Ca content of VSMCs enhancing tone
    • Proliferation of VSMCs
    • Upregulation of AT1 receptor
  • 78. Obesity and Cardiovascular Risk Eccentric Hypertrophy Sodium Retention Volume Expansion Heart Rate  Endothelial Dysfunction Diabetes Mellitus Dyslipidemia Hypertension Cardiac Output  Visceral Obesity Atherosclerosis Arterial Resistance  Concentric Hypertrophy Congestive Heart Failure (CHF), Coronary Artery Disease (CAD), Sudden Death (Adapted with permission from Zhang R, Reisin E. Am J Hypertens . 2000)
  • 79. Issues in Choice of Antihypertensive Therapy for the Obese Hypertensive
    • Reduction in pre- and afterload
    • No neuroendocrine activation
    • Favorable metabolic effects
    • No weight gain
    • Reduction in renal hyperfiltration and microalbuminuria
    • 24-hour efficacy
    • Good tolerability
    • Reduction in mortality
    (Sharma AM, et al. J Hyptertens . 2001)
  • 80. Considerations in Selecting Pharmacological Agents For Treating Obesity-related Hypertension Agent Potential Benefits Potential Drawbacks Diuretics (low dose)  intravascular volume and cardiac output May antagonize enhanced SNS activity of obesity-related hypertension Potential for  in peripheral resistance and intravascular volume No excess risk of diabetes Verapamil  heart rate  peripheral resistance No excess risk of diabetes No dyslipidemic effects Regression of LVH Effects similar to those of ACEIs Possible improvement in insulin sensitivity Improvement in metabolic profile  SNS activity  SNS and RAS activity Possible dose-related worsening of insulin resistance and dyslipidemia  risk of both weight gain and diabetes Possible interference with carbohydrate and lipid metabolism Neuroendocrine activation None None Excess risk of cardiovascular events, particularly CHF? Possible impairment of glucose tolerance, weight gain Beta blockers CCBs ACEIs ARBs Alpha blockers Centrally-acting agents (Reprinted with permission from Sharma AM, et al. J Hypertens . 2001)
  • 81. Pharmacologic Treatment of Obesity Hypertension
    • ACEI/ARB ++++
    • Low-dose diuretic +++
    • CCB ++
    • Beta blocker +
    Treatment threshold: 135/85 mmHg!
  • 82. Potential Benefits From ACE Inhibition
    • Inhibition of the formation of angiotensin II by ACE
    • Enhancement of the effects of prostaglandin and nitric oxide
    • Inhibition of sympathetic activation
    • Afterload reduction
    • Regression of ventricular and vascular smooth muscle hypertrophy
    • Ventricular remodeling
    • Improvement of endothelial function
    • Reduction of proteinuria
    (Bakris GL, et al. Kidney Int . 1998) (Brown NJ, et al. Thromb Haemost . 1997) (Dzau VJ. Eur Heart J . 1998) (Emeis JJ, Tranquille N. Agents Actions . 1992) (Feener EP, et al. J Clin Invest . 1995) (Greenwald L, Becker RC. Am Heart J. 1994) (The Heart Outcomes Prevention Evaluation Study Investigators. New Engl J Med . 2000) (Kober L, et al. N Engl J Med . 1995) (Ridker PM, et al. Circulation . 1993)
  • 83. Obesity Assessment: Risk Factors Existing Disease Conditions* Other Obesity- associated Diseases Cardiovascular Risk Factors † Other Risk Factors Established CHD Other atherosclerotic diseases Type 2 diabetes Sleep apnea OB/GYN abnormalities Osteoarthritis Gallstones/ gall bladder disease Stress incontinence Hypertension ( SBP ≥ 140 mmHg or DBP ≥ 90 mmHg, or currently taking antihypertensive medication ) LDL cholesterol ≥ 160 mg/dL HDL cholesterol < 35 mg/dL Impaired fasting glucose 110 – 125 mg/dL Family history of premature CHD ‡ Age (men ≥ 45 years; women ≥ 55 years or menopausal) Serum triglycerides > 200 mg/dL Physical inactivity *Patients with these conditions are at very high risk for disease complications and mortality. † Patients with three of these factors are at high absolute risk. ‡ Definite MI or sudden death at/before 55 years in father or other male first degree relative or at/before 65 years of age in mother or other first degree female relative. (NIH. Obes Res . 1998)
  • 84. Controlling Obesity Can Drastically Reduce Medical Costs
    • Total direct and indirect costs of obesity: United States, estimated to be at least $99.2 billion (1995)
      • direct costs: 5.7%, National Health Expenditure
      • costs due obesity-associated diseases (eg, CHD, diabetes, osteoarthritis)
    • 6% – 10% weight loss reduces treatment costs*
      • $123 for the insulin-treated diabetic patient
      • $61 for the hyperlipidemic patient
      • $43 for the sulfonylurea-treated diabetic patient
    (Wolf AM, Colditz GA. Obes Res . 1998) (Greenway FL, et al. Obes Res . 1999 )
      • *Reduction in costs/month/patient.
  • 85. Health Benefits of Modest Weight Loss*
    • Possible  risk of death
    •  CHD risk
      •  MI rate
      •  stroke rate
      • improves serum lipids
    • Improves prognosis in type 2 diabetic patients
      •  glucose, insulin
    • Can significantly reduce sleep apnea
    •  osteoarthritis symptoms
    • Reduces relapse rate of asthma
    (Camargo CA, et al. Arch Intern Med . 1999) (Goldstein DJ. Int J Obes . 1992) (Suratt PM, Findley LJ. N Engl J Med . 1999) (Gelber AC. Am J Med . 1999) *Modest weight loss = minimum of 5 lbs.
  • 86. Management of Obesity: Treatment Options Modality Recommendation Reduced-calorie diet Reduce energy intake by 500 to 1,000 kcal/day to achieve a weight loss of 1 to 2 lbs/week over a 6-month period Start with 30 to 45 minutes moderate activity 3 to 5 days/week, and work up to at least 30 minutes moderate-intensity physical activity on most or all days/week Use multiple behavioral strategies (eg, self-monitoring of eating habits and physical activity) Recommend appropriate pharmacotherapy* for patients with BMI  30 kg/m 2 , or with BMI  27 kg/m 2 with one or more comorbid conditions Consider for patients with class 3 obesity, or class 2 obesity with comorbid conditions, for whom other treatments have failed Increased activity Behavior modification Pharmacotherapy Surgery (NIH. Obes Res . 1998) *In combination with diet, increased activity, and behavior modification.
  • 87. Actions and Adverse Effects of Weight Loss Agents Drug Action Sibutramine Serotonin-releasing agent Major Adverse Effects Possible increase in heart rate and blood pressure Serotonin-releasing agent Inhibits pancreatic lipase, decreases fat absorption Orlistat Serotonin and norepinephrine reuptake inhibitor Valvular heart disease Valvular heart disease Soft stools and anal leakage Decrease in absorption of fat-soluble vitamins Dexfenfluramine Fenfluramine (Xenical ® (orlistat) Capsules. [product information]. Nutley, NJ: Roche Laboratories Inc.; September 1999) (Meridia ® (sibutramine hydrochloride monohydrate). [product information]. Mt. Olive, NJ: Knoll Pharmaceutical Company; November 1999) (NIH. Obes Res . 1998)
  • 88. AHA Call to Action Statement: Obesity
    • Support more research into weight regulation, the causes of obesity, and the outcomes of obesity treatment
    • Recognize that the causes of obesity are complex and that both genetics and behavior are part of the emerging picture
    In light of the emergent evidence about the increasing prevalence of obesity and its link to CHD, we urge healthcare providers, legislators, insurers, and the public to take action on the following points: (Eckel RH, Krauss RM, for the AHA Nutrition Committee. Circulation . 1998)
  • 89. AHA Call to Action Statement: Obesity
    • Nurture efforts that encourage individuals to take small steps toward increasing physical activity
    • Encourage state and local authorities to provide more opportunities for safe, community-based physical activity programs
    • Eliminate complacency by healthcare providers and individuals about obesity
    (cont’d) (Eckel RH, Krauss RM, for the AHA Nutrition Committee. Circulation . 1998)
  • 90. AHA Call to Action Statement: Obesity
    • Make the treatment of obesity a shared responsibility between healthcare provider and individual — emphasize the “whole” person
    • Emphasize the total dietary picture to individuals
    • Educate the public about the importance of preventing obesity
    • Develop effective educational programs aimed at preventing the development of obesity in childhood
    (cont’d) (Eckel RH, Krauss RM, for the AHA Nutrition Committee. Circulation . 1998)
  • 91. Key Factors for Development of Insulin Resistance
    • Excess peritoneal fat
    • Excess inflammatory adipocytokines produced by peritoneal adipocytes
    • Elevated FFA
    • Hyperinsulinemia
    Bell DSH.