1. METABOLIC SYNDROME Lajos Szollár Professor of Pathophysiology Semmelweis University, Faculty of Medicine Institute of Pathophysiology 2007 METABOLIC SYNDROME Lajos Szollár Professor of Pathophysiology Semmelweis University, Faculty of Medicine Institute of Pathophysiology 2007

2. The Metabolic Syndrome and Associated CVD Risk Factors Insulin Resistance Atherosclerosis Endothelial Dysfunction Hypertension Abdominal obesity Hyperinsulinaemia Dyslipidaemia high TGs small dense LDL low HDL-C Diabetes Hypercoagulability Deedwania PC. Am J Med 1998;105(1A);1S-3S.

3. World Health Organization Clinical Criteria for Metabolic Syndrome  Insulin resistance (T2DM, IFG, IGT, clamp) + any two of the following  BP > 140/90 mmHg or anti-HTN medication  Plasma TG > 1.7 mmol/L  HDL-C < 0.9 mmol/L (M); < 1.0 mmol/L (F)  BMI > 30 kg/m 2 or W/H >0.9 (M) or > 0.85 (F)  Urinary albumin > 20 mg/min or Alb/Cr > 30 mg/g

4. NCEP ATP III: The Metabolic Syndrome <40 mg/dL (1.0 mmol/L) <50 mg/dL (1.3 mmol/L) Men Women >102 cm (>40 in) >88 cm (>35 in) Men Women  110 mg/dL (6.0 mmol/L) Fasting glucose  130/  85 mm Hg Blood pressure HDL-C  150 mg/dL (1.7 mmol/L) TG Abdominal obesity (Waist circumference) Defining Level Risk Factor Recommends a diagnosis when 3 of these risk factors are present NCEP, Adult Treatment Panel III, 2001. JAMA 2001:285;2486-2497.

5. Updated ATPIII Criteria for Diagnosis of Metabolic Syndrome Measure (any 3 of the following)Categorical cutpoints Elevated waist circumference≥102 cm men ≥88 cm women Elevated triglycerides≥150 mg/dL (1.7 mmol/L) or on Rx for elevated TG Reduced HDL-C<40 mg/dL (1.03 mmol/L) men <50 mg/dL (1.3mmol/L) women or on Rx for reduced HDL-C Elevated blood pressure≥130 mm Hg systolic or ≥85 mm Hg diastolic or on antihypertensive Rx with history of hypertension Elevated fasting glucose≥100 mg/dL or on Rx for elevated glucose Grundy et al. Diagnosis and management of the metabolic syndrome. An AHA/NHLBI Scientific Statement Circulation 2005 112:2735-2752

6. International Diabetes Federation definition of the metabolic syndrome Central obesity (defined as waist circumference > 94cm for Europid men; > 80cm for Europid women; ethnicity specific values for other groups) Plus any two of the following four factors: Raised triglyceride level: > 150 mg/dL (1.7 mmol/L), or specific treatment for this lipid abnormality Reduced HDL cholesterol : < 40 mg/dL (1.03 mmol/L) in males and < 50 mg/dL (1.29 mmol/L) in females, or specific treatment for this lipid abnormality Raised blood pressure: systolic BP > 130 or diastolic BP > 85 mm Hg, or treatment of previously diagnosed hypertension Raised fasting plasma glucose > 100 mg/dL (5.6 mmol/L or previously diagnosed type 2 diabetes (if above 5.6 mmol/L, OGTT strongly recommended but not necessary to define presence of the syndrome) International Diabetes Federation. Worldwide definition of the metabolic syndrome. Available at: http://www.idf.org/webdata/docs/IDF_Metasyndrome_definition.pdf.http://www.idf.org/webdata/docs/IDF_Metasyndrome_definition.pdf.

7. Definitions of the Metabolic Syndrome National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). Circulation. 2002;106:3143-3421. International Diabetes Federation. 2005. www.idf.orgwww.idf.org Grundy SM, et al. Circulation. 2005;112:2735-2752. * Based on a Chinese, Malay, and Asian-Indian population † Or on drug treatment Metabolic syndrome ICD-9-CM code: 277.7 Components NCEP ATP III ≥3 IDF WC + ≥2 AHA-NHLBI ≥3 WC, cm >102 (m) >88 (f) Europid ≥94 (m) ≥80 (f) S. Asian* ≥90 (m) ≥80 (f) Japanese ≥85 (m) ≥90 (f)>102 (m) >88 (f) ‡ TG, mg/dL  150  150 † HDL-C, mg/dL <40 (m) <50 (f)<40 (m) <50 (f) † BP, mm Hg  130/  85  130 OR  85 † FPG, mg/dL  110  100 † ‡ ≥90cm (m) ≥80cm (f) for Asian Americans

8. From Després JP Ann Med (2006) 38:52-63 From Després JP Ann Med (2006) 38:52-63 Metabolic syndrome : confusion between definition and screening tools CLINICAL TOOLS TO FIND PATIENTS WITH THE METABOLIC SYNDROME NCEP-ATPIII Waist girth HDL-cholesterol Triglycerides Blood pressure Glucose AACE Glucose BMI HDL-cholesterol Triglycerides Blood pressure Other features of insulin resistance EGIR Insulin Waist girth Glucose HDL-cholesterol Triglycerides Blood pressure IDF Waist girth HDL-cholesterol Triglycerides Blood pressure Glucose HyperTG waist Waist girth Triglycerides Others ? WHO Insulin Glucose WHR, BMI HDL-cholesterol Triglycerides Blood pressure Microalbuminuria B Proinflammatory profile Atherogenic dyslipidemia Prothrombotic profile Insulin resistance/ Glucose intolerance } may evolve to type 2 diabetes CONCEPTUAL DEFINITION OF THE MOST PREVALENT FORM OF THE METABOLIC SYNDROME: ABDOMINAL OBESITY A Raised blood pressure (in about 50% of patients)

9. RiskRatio San Antonio Heart Study Hunt KJ et al. Circ 2004; 110: 1251-1257 0 1.0 2.0 3.0 4.0 5.0 2.71 1.63 ATP III Metabolic Syndrome and CVD Mortality WHO ATP III MS (3+) Abdominal obesity  TG  HDL-C  BP  Glucose

10. MetS CVD T2DM 5x 2x 3x Relative Risk

11. Prevalence of MI or Stroke and Components of the Metabolic Syndrome Ninomiya et. al. NHANES III (Circulation, 2004;109:42-46.) Abdominal obesity High triglycerides Low HDL-C High blood pressure Insulin resistance Metabolic Syndrome Odds Ratio 1.0 (P <0.001) (P <0.0001) (P <0.005) (P <0.04) 2.03.04.0 MEN Women

12. MetS CVD T2DM Atherogenic dyslipidemia? Elevated BP? Impaired fasting glucose? Prothrombotic state? Proinflammatory state? Abdominal obesity Insulin resistance Proinflammatory state? What are the mechanisms of higher risk? Glycation? AGEs? Glucose toxicity? Others?

13. Kalff KG, et al. Aviat Space Environ Med. 1999 Dec;70(12):1223-1226. Hansen BC. Ann N Y Acad Sci. 1999 Nov 18;892:1-24. The Metabolic Syndrome   Approximately 20% to 30% of the middle-aged population in highly industrialized countries has the metabolic syndrome   By the year 2010, the number of people with the metabolic syndrome in the US could rise to between 50 and 75 million Prevalence

14. NHANES III: Age-Specific Prevalence of the Metabolic Syndrome (ATP III) Data are presented as percentage (SE). Age, y 50 45 40 35 30 25 20 15 10 5 0 Prevalence, % Men Women Ford ES, et al. JAMA. 2002;287:356-359. 20-29 30-39 40-4950-5960-69> 70

15. NHANES III: Age-Adjusted Prevalence of 3 Risk Factors for the Metabolic Syndrome* *Criteria based on ATP III; diabetics were included in diagnosis; overall unadjusted prevalence was 21.8%. Prevalence, % 24.8 16.4 28.3 22.8 25.7 35.6 0 5 10 15 20 25 30 35 40 White 25.7% difference African AmericanMexican American Men Women 56.7% difference Ford ES, et al. JAMA. 2002;287:356-359.

16. Epidemiology of the Metabolic Syndrome  23.7% Overall  47,000,000 US residents have the syndrome Ford et al: JAMA 2002:287

17. Association of Multiple Risk Factor Clustering with Coronary Artery Disease (CAD) Jpn Circ J 2001 0 10 20 30 40 01234 Number of Risk Factors M u l t i v a r i a t e - a d j u s t e d O d d s R a t i o f o r C A D 1.0 5.1 9.7 31.3 Metabolic Syndrome

18. Cardiovascular Disease Mortality Increased in the Metabolic Syndrome Lakka HM, et al. JAMA. 2002;288:2709-2716. 15 10 5 0 02468 12 Cardiovascular Disease Mortality RR (95% Cl), 3.55 (1.98-6.43) Metabolic Syndrome Yes No Cumulative Hazard, % Follow-up, y

19. Prevalence of CHD risk factors: an evolving landscape Smoking Hypercholesterolemia Hypertension Type 2 diabetes Abdominal obesity Metabolic syndrome 1950’ – 60’ 1990’ – 00’… Statins Statins HT medication HT medication Smoking cessation Smoking cessation Sedentariness Sedentariness  Energy density  Energy density of food of food

20. Metabolic Syndrome is an independent predictor of Coronary Heart Disease (CHD) WOSCOPS trial (n=6,447 males, aged 45-64) P<.0001 5 yr CHD rate Prevalence of METS: 23.8% *L’Italien et al: American College of Cardiology 2003

21. Risk of ischemic heart disease (IHD) according to the cumulative number of “traditional” and “non-traditional” risk factors The Québec Cardiovascular Study Traditional: LDL-cholesterol, triglycerides and HDL-cholesterol Non-traditional: Insulin, apolipoprotein B and small, dense LDL particles * Odds ratios are adjusted for systolic blood pressure, family history of IHD and medication use and medication use 1.0 1.8 4.7 2.8 9.1 (0.01) 4.4 (0.01) 20.8 (<0.001) Odds ratio* 0123 Traditional risk factors Non-traditional risk factors 15 10 5 0 20 25 30 From Lamarche B et al. JAMA (1998) 279:1955-1961

22. Insulin Resistance Dysregulation of Risk Factor Parameters Elevated Blood Pressure Atherogenic Dyslipidemia Elevated Glucose Pro- thrombotic State Pro- inflammatory State Obesity

23. Metabolic syndrome  Android obesity  Atherogenic dyslipidaemia  TG > 1,7; HDL-C 1,2 g/L  Hypertension  Inzulin resistance / Hyperinsulinaemia  (FG, IGT, „clamp”, inzulin level, HOMA  Pro-inflammatory state  ESR; WBC; hsCRP > 5 mg/L  Prothrombotic state  Lp(a) > 40 mg/dL; fibr.:3,85 g/L; PAI-1, tPa  Microalbuminuria  Microvascular angina

26. Sex-specified waist circumferences denoting risk of metabolic complications with obesity Bjorntop, Lancet 350:423, 1997

27. Central Obesity: The Metabolic Syndrome (CETP)  VLDL-apoB ­ Intra-abdominal fat ­ Insulin resistance ­ Free fatty acids  Hepatic Lipase  TG  Small, dense LDL  HDL/HDL 2 Brunzell 2001

28. Obesity and CHD: 26 -Year Incidence of CHD in Men Incidence/1,000 Adapted from Hubert HB et al. Circulation 1983;67:968-977. Metropolitan Relative Weight of 110 is a BMI of approximately 25. 177 255 350 333 366 440 0 100 200 300 400 500 600 <2525-<3030+ <50 years50+ years BMI Level F ramingham Heart Study

29. Intra-abdominal (visceral) fat The dangerous inner fat! Back Visceral AT Subcutaneous AT Front

30. Fat mass : 19.8 kg VAT : 155 cm 2 Fat mass : 19.8 kg VAT : 96 cm 2

31. Assessment of accumulation of abdominal fat by measurement of waist at mid-distance between bottom of rib cage and iliac crest. Amount of visceral adipose tissue that can be assessed by CT can be estimated by waist measurement Despres et al. BMJ 322:716,2001

32. High visceral fat increases cardiovascular risk From Pouliot MC et al. Diabetes (1992) 41:826-834 1 1 1 1 1 1,2 1 1 1 (mmol/l) 0.0 3.0 6.0 9.0 12.0 15.0 -300306090120150180 Time (min) 1,2 Time (min) 0 200 400 800 1000 1200 600 1,2 1 Area 1,2 Area -300306090120150180 (pmol/l) InsulinGlucose 1 significantly different from Nonobese 2 significantly different from Obese with low visceral AT levels Nonobese Obese low VAT Obese high VAT VAT: visceral adipose tissue

33. 300 250 200 150 100 50 0 r = 0.80 6080100120 Waist circumference (cm) Visceral AT (cm 2 Visceral AT (cm 2 ) Front Back Waist Hip Subcutaneous AT Visceral AT Relationship between waist circumference and visceral adipose tissue accumulation Waist girth (cm) Insulin (pmol/L) Waist girth (cm) Apo B (g/L)

34. Average apo B (A) and fasting insulin (B) levels among deciles of waist circumference. C LDL particle diameter among deciles of TG concentration. Dotted lines mean apo B, fasting inslin and LDL peak particle diameter of overall cohort. Lemieux et al. Ciculation 102:179,2000

35. Metabolic syndrome  Android obesity  Atherogenic dyslipidaemia  TG > 1,7; HDL-C 1,2 g/L  Hypertension  Inzulin resistance / Hyperinsulinaemia  (FG, IGT, „clamp”, inzulin level, HOMA  Pro-inflammatory state  ESR; WBC; hsCRP > 5 mg/L  Prothrombotic state  Lp(a) > 40 mg/dL; fibr.:3,85 g/L; PAI-1, tPa  Microalbuminuria  Microvascular angina

36. Events/ 1,000 in 8 yr Assmann G et al. Am J Cardiol. 1992;70:733-737. TG (mg/dL) 44 93 132 81 0 50 100 150 <200 (157/3,593) 200-399 (84/903) 400-799 (14/106)  800 (3/37) Hypertriglyceridemia—An Independent Risk Factor for CHD: PROCAM Study

37. Triglyceride and CHD Risk PROCAM Study Assmann G, Schulte H. Am J Cardiol 1992;70:733–737. 24 31 116 245 0 50 100 150 200 250  5.0 > 5.0 LDL-C/HDL-C ratio Incidence per 1,000 (in 6 years) TG < 200 mg/dL TG  200 mg/dL

38. Cardiovascular Disease and HDL-C Levels HDL Cholesterol, mg/dL Rate per 1000 Kannel WB. Am J Cardiol. 1983;52:9B-12B. 0 20 40 60 80 100 120 140 160 <3435-54>55<3435-54>55 Men Women

39. Metabolic abnormalities associated with abdominal obesity Insulin resistance Insulin resistance Dyslipidaemia Dyslipidaemia Mild hypertension Mild hypertension Inflammation Inflammation

40. Dyslipidemia associated with abdominal obesity Increased plasma triglyceride Increased plasma triglyceride Increased plasma apoB Increased plasma apoB LDL fraction characterized by and small, dense particles LDL fraction characterized by and small, dense particles Decreased HDL cholesterol Decreased HDL cholesterol HDL fraction characterized by and small, dense particles HDL fraction characterized by and small, dense particles

41. Atherogenic Apo B-containing LPs VLDL VLDL Remnants IDL LDL; Dense LDL Enhanced Arterial Cholesterol Deposition Attenuated Reverse Cholesterol Transport Accelerated Atherogenesis Anti-atherogenic HDL Atherogenic Dyslipidaemia Metabolic Syndrome Hypercholesterolaemia Type II Diabetes Mixed Hyperlipidaemia Hypertriglyceridaemia

42. Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk 1% decrease in LDL-C reduces CHD risk by 1% 1% increase in HDL-C reduces CHD risk by 1%

43. High visceral fat increases cardiovascular risk From Pouliot MC et al. Diabetes (1992) 41:826-834 310 248 186 124 62 0 60 45 30 (mg/dl) HDL-cholesterol (mg/dl) Triglycerides NonobeseNonobeseObeseObese Low VAT High VAT Low VAT High VAT VAT: visceral adipose tissue

44. Relationships between LDL particle size vs triglycerides, HDL cholesterol and cholesterol/HDL cholesterol ratio LDL particle size (Å) 235240245250255260265270 Triglycerides (mmol/l) 0 1.0 2.0 3.0 4.0 5.0 r=-0.52p<0.0001 235240245250255260265270235240245250255260265270 Chol/HDL chol 2.0 4.0 6.0 8.0 10.0 0 0.5 1.0 1.5 2.0 2.5 HDL cholesterol (mmol/l) r=0.44p<0.0001 r=-0.45p<0.0001 LDL particle size (Å) From Després JP Ann Med (2001) 33:534-541

45. The small dense LDL is a key component of the metabolic syndrome

46. ApoB, proportion of small LDL and the risk of IHD 3.9 (<0.001) 3.9 (<0.001) 5.9 (<0.001) 5.9 (<0.001) 1.0 2.0 (0.12) 2.0 (0.12) < 116 > 116 < 40% > 40% 1.0 2.0 3.0 4.0 5.0 6.0 ApoB (mg/dl) RR of IHD LDL < 255 A St-Pierre et al, Circulation 2001

47. Apo B, LDL Diameter and CHD Risk Quebec Cardiovascular Study 2.00 0 1 2 3 4 5 6 7 >25.64  25.64 <120 mg/dL  120 mg/dL LDL peak particle diameter (nm) Odds Ratio for CHD Apo B 6.20 Lamarche B, et al. Circulation. 1997;95:69-75. 1.00 Larger LDL Smaller LDL

48. Metabolic syndrome  Android obesity  Atherogenic dyslipidaemia  TG > 1,7; HDL-C 1,2 g/L  Hypertension  Inzulin resistance / Hyperinsulinaemia  (FG, IGT, „clamp”, inzulin level, HOMA  Pro-inflammatory state  ESR; WBC; hsCRP > 5 mg/L  Prothrombotic state  Lp(a) > 40 mg/dL; fibr.:3,85 g/L; PAI-1, tPa  Microalbuminuria  Microvascular angina

50. Metabolic syndrome  Android obesity  Atherogenic dyslipidaemia  TG > 1,7; HDL-C 1,2 g/L  Hypertension  Inzulin resistance / Hyperinsulinaemia  (FG, IGT, „clamp”, inzulin level, HOMA)  Pro-inflammatory state  ESR; WBC; hsCRP > 5 mg/L  Prothrombotic state  Lp(a) > 40 mg/dL; fibr.:3,85 g/L; PAI-1, tPa  Microalbuminuria  Microvascular angina

51. Central Obesity: The Metabolic Syndrome (CETP)  VLDL-apoB ­ Intra-abdominal fat ­ Insulin resistance ­ Free fatty acids  Hepatic Lipase  TG  Small, dense LDL  HDL/HDL 2 Brunzell 2001

52. Obesity Primary (Genetic) Insulin Resistance Elevated Blood Pressure Atherogenic Dyslipidemia Elevated Glucose Pro- thrombotic State Pro- inflammatory State Physical Inactivity WHO

53. Risk of Major CHD Event Associated with High Insulin Levels in Non-diabetic Men Q1 to Q5 = quintiles of area under the curve (AUC) insulin (Q1=lowest quintile; Q5=highest quintile). Years Proportion with a major CHD event 0 0 5 0.05 0.10 0.15 0.20 0.25 1.00 10152025 Log rank: Overall P =.001 Q5 vs Q1 P <.001 Q1 Q2 Q3 Q4 Q5 Pyörälä M et al. Circulation 1998;98:398–404.

54. Central Obesity: The Metabolic Syndrome (CETP)  VLDL-apoB ­ Intra-abdominal fat ­ Insulin resistance ­ Free fatty acids  Hepatic Lipase  TG  Small, dense LDL  HDL/HDL 2 Brunzell 2001

55. Ser/Thr phosphorylation of the IRS molecules induces insulin resistance Le Roith et al., Diabetes Care 24:588 (2001)

56. Mechanism of fatty acid-induced insulin resistance in skeletal muscle as proposed by Randle et al. Shulman, J Clin Invest 106:171, 2000

57. FFA FA VLDL DNL Adipose tissue Muscle Liver Intestine TG mobilization by tissue lipases TG, CE ApoB Cytosolic TG stores Oxidation Lipases LPL Mechanisms of VLDL-apoB overproduction in Insulin Resistance Hepatic Insulin Resistance Adeli K. et al. (2000) J. Biol. Chem. 275: 8416-8425. Adeli K. et al. (2002) J. Biol. Chem. 277:793-803.

59. Atherogenic Lipoprotein Phenotype Predisposing factors Atherogenic potential Central obesity Male sex Liver fat Insulin resistance Low adiponectin Diet VLDL Chylos Chylo remnants Small,dense LDL Oxidised LDL Small,dense HDL High hepatic lipase Thrombosis Macrophage cholesterol Inflammation Artery wall retention Reverse cholesterol transport Anti-inflammatory actions Dyslipidemia in Metabolic Syndrome

60. Insulin resistance related to dyslipidemia and cardiovascular disease Ginsberg, J Clin Invest 106:453, 2000

61. IRS and Stress

62. Fatty acid-level elevating psychosocial stressors: Type A personality, anxiety, depression, hostility, job demand, vital exhaustion, differences in income Hemingway et al.,BMJ 318:1460 (1999)

64. Hopelessness in a healthy population (Kuopio) Everson SA & al Psychosom Med 1996;58:113

65. Degree of depression and CHD mortality Lespérance F & al.Circulation 2002;105:1049 BDI=Beck Depression Inventory P=0.01 P<0.001

66. AdiposeTissue Liver Cytokines Unstable Plaques Plaques  CRP Proinflammatory State  Apo B  HDL Prothrombotic State Diabetes

67. The Metabolic Syndrome Dysregulation of adipocytokines Portal FFA↑ Adiponectin↓ Insulin resistance Lipoprotein synthesis ↑ PAI-1 ↑ Adiponectin↓ Hypertension Impaired glucose tolerance Hyperlipidemia ？ Environmental Factors Genetic Factors Atherosclerosis Visceral Fat Accumulation TNF-  ↑

68. Atherogenic dyslipidemia  Triglycerides  HDL-cholesterol  Cholesterol/HDL-cholesterol ratio «Normal» LDL-cholesterol but  apo B Small, dense LDL and HDL Postprandial hyperlipidemia Insulin resistance Hyperinsulinemia Hyperglycemia Type 2 diabetes Thrombotic state  PAI-1  Fibrinogen Inflammatory state  CRP  Cytokines  risk of acute coronary syndrome Metabolic risk factorsAbdominal obesity Inflammation Lipid core Thin fibrous cap CORONARY ATHEROSCLEROSIS UNSTABLE PLAQUE

69. The metabolic syndrome … close to a consensus Visceral obesity Insulin resistance  Insulin  TG  HDL  Adiponectin Small, dense LDL  CRP The core components Pathophysiology The common form of the metabolic syndrome: high-risk visceral obesity The common form of the metabolic syndrome: high-risk visceral obesity CVD Diabetes Hypertension The definition: The core screening tools + NCEP-ATP III AHA, ADA, EASD IDF Hypertriglyceridemic waist NCEP-ATP III AHA, ADA, EASD IDF Hypertriglyceridemic waist The clinical identification:

70. Visceral obesity Insulin resistance  Insulin METABOLIC SYNDROME Thrombosis Inflam- mation  ApoB Dense LDL  TG  HDL  Blood pressure GLOBAL CARDIOMETABOLIC RISK Smoking Dyslipidemic states not related to MS* Hypertension* Age Male sex Diabetes Cardiovascular disease Diabetes Impaired fasting glucose Global Cardiometabolic Risk: Total Long-Term and Short Term (10-yr) Risk for T2DM and CVD LDLHDL

71. Deteriorated Impaired Improved Lipid profile Insulin sensitivity Insulinemia Glycemia Susceptibility to thrombosis Inflammation markers Endothelial function CHD RiskLow High Diet Physical activity Pharmacotherapy Abdominally obese High waist Reduced obese Low waist ~10% Weight loss ~ 30 Visceral AT loss Visceral adipose tissue Visceral adipose tissue Subcutaneous AT Adapted from Després et al. BMJ (2001) 322:716-720