1. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Abdominal Obesity, Intra-abdominal Adiposity and Related Cardiometabolic Risk: Part I Jean-Pierre Després, PhD, FAHA Director of Research, Cardiology Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec Scientific Director, International Chair on Cardiometabolic Risk Québec, Canada

2. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org <21.0  29.0 BMI (kg/m 2 ) <22.0  35.0 BMI (kg/m 2 ) <19.0  32.0 BMI (kg/m 2 ) Relative Risk of Mortality, Coronary Heart Disease (CHD), and Type 2 Diabetes According to Body Mass Index (BMI) Mortality Adapted from Manson JE et al. N Engl J Med 1995; 333: 677–85 | Willett WC et al. JAMA 1995; 273: 461–5 | Colditz GA et al. Ann Intern Med 1995; 122: 481-6 CHDDiabetes Relative risk of: 2.0 1.5 1.0 0.5 0.0 4.0 3.0 2.0 1.0 0.0 8.0 6.0 4.0 2.0 0.0

3. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Is waist circumference better than body mass index to predict cardiometabolic risk?

4. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Saving and Overconsuming Energy

5. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Obesity: Body Mass Index (BMI) BMI (kg/m 2 )Risk of Comorbidities Healthy weight18.5 – 24.9Normal Overweight25.0 – 29.9Increased Obese Class I30.0 – 34.9High Obese Class II35.0 – 39.9Very High Obese Class III> 40.0Extremely High BMI = Adapted from the World Health Organization. Obesity: Preventing and Managing the Global Epidemic. Geneva: WHO, 2000 Weight (kg) Height (m 2 )

6. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org CholesterolDiabetesSmoking The “Heavyweights” of Modifiable Cardiovascular Disease (CVD) Risk Factors Hypertension Global CVD Risk LDLHDL

7. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Obesity: An Ill-defined Modifiable Cardiovascular Disease (CVD) Risk Factor Obesity BMI Others ? CholesterolDiabetesSmoking Hypertension LDLHDL Global CVD Risk BMI: body mass index

8. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Android (Apple) vs. Gynoid (Pear) Obesity A Tribute to a Pioneer Jean Vague (1947) Adapted from Vague J. Presse Med 1947; 30: 339–40

9. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Obesity as a Risk Factor for Type 2 Diabetes: Importance of Abdominal Fat Accumulation Another Pioneer…the Late IIIIII I III 13.5-year incidence of type 2 diabetes (%) (Overweight) (Lean) Body mass index tertiles Waist-to-hip ratio tertiles Per Björntorp Adapted from Ohlson LO et al. Diabetes 1985; 34: 1055-8

10. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Risk of Myocardial Infarction Across Quintiles of BMI and WHR: INTERHEART 4.0 3.0 2.5 2.0 1.5 Odds ratio (95% CI) 1.25 1.0 0.9 0.8 <2020–2323.1–2525.1–2727.1–29>30 BMI (kg/m 2 ) Adapted from Yusuf S et al. Lancet 2005; 366: 1640-9 Copyright 2005, with permission from Elsevier BMI: body mass index WHR: waist-to-hip ratio 3.5

11. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Abdominal Obesity and Coronary Heart Disease in Women: The Nurses’ Health Study LowMiddleHigh High (81.8 - <139.7) Middle (73.7 - <81.8) Low (38.1 - <73.7) (25.2 - <48.8)(22.2 - <25.2)(12.2 - <22.2) Waist girth tertiles (cm) Incidence rate per 100,000 person-years Body mass index tertiles (kg/m 2 ) Adapted from Rexrode KM et al. JAMA 1998; 280: 1843-8 Follow-up of 8 years 140 120 100 80 60 40 20 0

12. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Is total adiposity (body mass index, body fat mass) or subcutaneous fat better than intra- abdominal (visceral) fat to predict cardiometabolic risk?

13. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Intra-abdominal (Visceral) Fat: The Dangerous Inner Fat Intra-abdominal adipose tissue Subcutaneous adipose tissue Front Adapted from Lemieux I et al. Ann Endocrinol 2001; 62: 255-61 Back

14. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Association Between Fat Mass and Intra-abdominal (Visceral) Adipose Tissue in Men and Premenopausal Women Adapted from Lemieux S et al. Am J Clin Nutr 1993; 58: 463-7 Intra-abdominal adipose tissue (cm 2 ) 0 10 20 30 40 50 60 70 Fat mass (kg) 300 250 200 150 100 50 0 Women: r=0.85 Men: r=0.69

15. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Intra-abdominal (Visceral) Fat Accumulation in Equally Overweight Men Fat mass: 19.8 kg Intra- abdominal fat : 155 cm 2 Fat mass: 19.8 kg Intra- abdominal fat : 96 cm 2 Adapted from Després JP et al. In: AF Roche, SB Heymsfield, TG Lohman (eds.), Human Body Composition, Human Kinetics,149-66,1996

16. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Individual Variation in Subcutaneous / Intra-abdominal (Visceral) Fat Accumulation in Obese Women Adapted from Després JP Nutrition 1993; 9: 452-9

17. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Intra-abdominal (Visceral) Fat Increases the Risk of Type 2 Diabetes in Premenopausal Women Time (min.) Glucose (mmol/l) 0 1,2 1 306090120150180 10.0 9.0 8.0 7.0 6.0 5.0 4.0 Nonobese controls (1) Obese low intra-abdominal fat (2) Obese high intra-abdominal fat 1000 800 600 400 200 0 Time (min.) 0306090120150180 Insulin (pmol/l) 1,2 1 1 1 1 1 1 1 From Després JP. In: H Rifkin, JA Colwell, SI Taylor (eds.), Diabetes 1991, Elsevier Science Publishers BV Amsterdam, The Netherlands, 95-9, 1991 Reproduced with permission 1,2: significantly different from the corresponding subgroups 1 1

18. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Intra-abdominal (Visceral) Fat Increases Cardiovascular Risk in Premenopausal Women HDL cholesterol (mmol/l) Triglycerides (mmol/l) 1,2 1 Adapted from Després JP et al. Arteriosclerosis 1990; 10: 497-511 1,2 Nonobese controls (1) Obese low intra-abdominal fat (2) Obese high intra-abdominal fat 1.5 1.4 1.3 1.2 1.1 1.0 0.9 0.8 3.0 2.5 2.0 1.5 1.0 0.5 0.0 1,2: significantly different from the corresponding subgroup

19. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Features of the Metabolic Syndrome Commonly Found Among Intra-abdominally (Viscerally) Obese Patients Hypertriglyceridemia Insulin resistance Low HDL cholesterol Hyperinsulinemia Elevated apolipoprotein B Glucose intolerance Small, dense LDL particles Impaired fibrinolysis Inflammatory profile Endothelial dysfunction Genetic susceptibility to hypertension, type 2 diabetes, and coronary heart disease ultimately affects the clinical features of the metabolic syndrome Adapted from Lemieux I and Després JP. In: PG Kopelman (ed.), Management of Obesity and Related Disorders, Martin Dunitz, 45-63, 2001

20. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org The Atherogenic Metabolic Triad of Intra-abdominal (Visceral) Obesity Hyperinsulinemia Small, dense LDL particles Elevated apo B concentrations Beyond LDL cholesterol, blood pressure, type 2 diabetes… The atherogenic metabolic triad

21. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Risk of Ischemic Heart Disease (IHD) According to the Cumulative Number of “Traditional” and “Nontraditional” Risk Factors: The Québec Cardiovascular Study Adapted from Lamarche B et al. JAMA 1998; 279: 1955-61 Odds ratio* Traditional risk factors: LDL cholesterol, triglycerides and HDL cholesterol Nontraditional risk factors: Insulin, apolipoprotein B and small, dense LDL particles * Odds ratios are adjusted for systolic blood pressure, family history of IHD, and medication use 25 20 15 10 5 0 0 1 2 3 1.0 1.8 4.7 2.8 9.1 (p=0.01) 4.4 (p=0.01) 20.8 (p<0.001)

22. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org The Prevalent Form of the Metabolic Syndrome as Defined by NCEP-ATP III and IDF Pro-inflammatory state Elevated blood pressure Insulin resistance Atherogenic dyslipidemia NCEP-ATP III: National Cholesterol Education Program – Adult Treatment Panel III IDF: International Diabetes Federation Abdominal obesity Pro-thrombotic state

23. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Intra-abdominal (Visceral) Adipose Tissue Area and Waist Girth According to C-Reactive Protein (CRP) Quintiles Intra-abdominal adipose tissue (cm 2 ) CRP quintiles (1)(2)(3)(4)(5) 1 1 1 1,3 Waist circumference (cm) CRP quintiles (1)(2)(3)(4)(5) 1 1 1,2 1,2,3 Adapted from Lemieux I et al. Arterioscler Thromb Vasc Biol 2001; 21: 961-7 Legend: 1,2,3:significantly different from the corresponding quintiles

24. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Inflammation and Cardiovascular Disease: Is Abdominal Obesity the Missing Link? TNF-  IL-6 Atherogenic, insulin resistant “dysmetabolic milieu”  CRP ? ?   Risk of acute coronary syndrome ? Adipose tissue Adapted from Després JP Int J Obes 2003; 27: S22-4 Reproduced with permission CRP: C-reactive protein IL-6:interleukin-6 TNF-  :tumor necrosis factor- 

25. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Potential Contribution of Ectopic Fat Deposition to the Cardiometabolic Risk Profile of Intra-abdominally Obese Patients Altered cardiometabolic risk profile  Systemic free fatty acids Coronary atherosclerosis unstable plaque  Intra-abdominal (visceral) adipose tissue  Lipoprotein lipase Insulin resistance  Hepatic lipase Lipid deposition Insulin-resistant subcutaneous adipose tissue ?  Portal free fatty acids  Insulin  Glucose  Triglycerides  Apolipoprotein B Adapted from Després JP. Ann Med 2006; 38: 52-63 Reproduced with permission  Plasminogen activator inhibitor-1  Interleukin-6  Tumor necrosis factor-   Adiponectin Skeletal muscle Liver

26. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Intra-abdominal (Visceral) Fat: The Dangerous Inner Fat Intra-abdominal adipose tissue Subcutaneous adipose tissue Front Adapted from Lemieux I et al. Ann Endocrinol 2001; 62: 255-61 Back

27. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Intra-abdominal (Visceral) Fat is an Independent Predictor of All-cause Mortality in Men Subject ASubject B Subject B is at a 2-fold higher risk for mortality Risk of death Intra-abdominal fat (kg) Intra-abdominal fat is shown in red Adapted from Kuk JL et al. Obesity 2006; 14: 336-41 00.51.01.5

28. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org Intra-abdominal (Visceral) Fat is an Independent Predictor of All-cause Mortality in Men * Odds ratios are expressed per standard deviation for each variable Adapted from Kuk JL et al. Obesity 2006; 14: 336-41 Odds ratios for mortality* MODEL 1 1.8 1.4 0.8 1.8 1.0 0.6 1.3 MODEL 2 Control for age + follow-up timeControl for age, follow-up time, abdominal subcutaneous fat, intra- abdominal fat, and liver fat Intra-abdominal fatWaist circumference 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Odds ratios for mortality* Subcutaneous fat CTL / CTS (index of liver fat)

29. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org The Prevalent Form of the Metabolic Syndrome as Defined by NCEP-ATP III and IDF Pro-inflammatory state Elevated blood pressure Insulin resistance Atherogenic dyslipidemia NCEP-ATP III: National Cholesterol Education Program – Adult Treatment Panel III IDF: International Diabetes Federation Abdominal obesity Pro-thrombotic state

30. Source: International Chair on Cardiometabolic Risk www.cardiometabolic-risk.org  www.cardiometabolic-risk.org