Yaakov Henkin MD Soroka Medical Center Beer Sheva, Israel

1. Clinical studies in dyslipidemia Implications for treatment In the elderly Yaakov Henkin MD Soroka Medical Center Beer Sheva, Israel

2. גבר בן 78 היפרטנסיבי, מאוזן היטב ללא מחלות קרדיווסוקולריות אינו מעשן, BMI 29 ק"ג/מ2 Fasting glucose 122 mg/dL TC 234 mg/dL LDLc 150 “ HDLc 38 “ Trig 230 “

3. Total cholesterol 110 mg/dL

5. Percentage of deaths from CV disease in the USAfrom 1900 to 1950 Death from CV (%) Modified from Braunwald E, NEJM, 1997;337:1360

6. Framingham Heart Study

7. 10-Year % Probability of Event זכר יתר ל"ד כולסטרול עישון סוכרת זכר יתר ל"ד 0 זכר זכר יתר ל"ד כולסטרול זכר יתר ל"ד כולסטרול עישון גורמי הסיכון לטרשת עורקים • עיקריים • גיל • עישון • סוכרת • יתר לחץ דם • LDL גבוה • HDLנמוך • גורמי עזר • זכר • עודף משקל • חוסר פעילות גופנית • סיפור משפחתי Kannel. Am J Hypertens. 2000;13:3S-10S.

8. LDL:HDL ratio

9. INTERHEART STUDY Design Large international case-control study Participants 12,461 cases; 14,637 controls; 52 countries Objective To determine association of first MI with known risk factors Follow-up 4 years, February 1999–March 2003

10. INTERHEART Study

11. INTERHEART: 9 Modifiable factors account for 90% of first-MI risk worldwide 100 90 80 60 PAR (%) 50 36 40 33 20 18 20 14 12 10 7 0 Hyper-tension Smoking Fruits/veg Exercise Alcohol Abdominal obesity Psycho-social Lipids All 9 risk factors Diabetes Lifestyle factors N = 15,152 patients and 14,820 controls in 52 countries PAR = population attributable risk, adjusted for all risk factors Yusuf S et al. Lancet. 2004;364:937-52.

12. Population-attributable risk of acute MI in the overall population 66%

14. Cholesterol

15. 1910 HUMAN ATHEROSCLEROTIC AORTIC PLAQUES ARE • CHOLESTEROL RICH Adolf Windaus 15

16. Anitckow 1913 CHOLESTEROL FEEDING TO RABBITS HYPERCHOLESTEROLEMIA AND AORTIC ATHEROSCLEROSIS LDL Nikolai Anichkov 16

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18. Markers of risk 18

19. Plasma Lipoproteins • Spherical particles • Non-polar core: • cholesterol ester • triglyceride • Polar outer coat: • unesterified chol • phospholipids • proteins (apo) 19

20. Lipoprotein classes chylomicron B48 VLDL B100 Trig rich B100 IDL B100 Chol rich A LDL intrinsic HDL 20

21. מסלולים מטבוליים HDL pathway chylo VLDL Extrinsic pathway Intrinsic pathway IDL LDL “good” “ugly” X liver “bad” 21

22. Classification of dyslipidemias Hypertriglyceridemia Type IV / V Mixed Dyslipidemia Type III Type IIb B100 IDL B100 Hypercholesterolemia Type IIa moderate severe /CM VLDL B100 LDL 22

23. LPL B100 IDL HTGL B100 Bile acids Intrinsic Pathway VLDL B100 liver acetylCoA HMGCoAReductase chol intrahepatic LDL 23

24. סינדרומים קלינים 24

25. Elevated VLDLtype IV dyslipidemia Primary (genetic) Familial Hypertriglyceridemia (FHTG) Familial Combined Hyperlipidemia (FCHL) Secondary (acquired) Obesity Diabetes mellitus Insulin resistance syndrome Chronic renal failure high carbohydrate diets Ethanol Drugs: estrogen, beta-blockers, retinoids 25

26. B100 Familial Hypertriglyceridemia • Autosomal dominant • elevated Tg levels only • increased CHD risk ?? • Family: TG In 50% of family members • Few, large sized VLDL particles • overproduction of triglyceride • normal apo B levels B100 LDL 26

27. Familial Combined Hyperlipidemia • Autosomal dominant • usually manifests in adulthood • elevated chol and/or Tg levels • overproduction of apo B • Family: TG or chol or both • In 50% of family members • Many, normal sized VLDL particles • elevated apo B levels • increased CHD risk VLDL B100 B100 B100 B100 B100 LDL 27

28. Prothrombotic state insulin CRP Glucose intolerance Tg  HDL HTN The Metabolic Syndrome Genetic predisposition CHD diabetes 28

29. IDL metabolism liver 30% E 70% HTGL chol trig Bile acids 29

30. B100 LDL Apo E4 genotype liver 50% E 4 50% 30

31. LDL Metabolism liver chol B100 LDL Bile acids 31

32. LDL metabolism within Hepatic Cells 32

33. X X X X X X Defective receptor activity Defective apo B100 Hyper LDLemiaמנגנונים liver B100 oxidation LDL Foam cell 33

34. LDL Modifications LDL Oxidation inadequate methods to measure tissue oxidation antioxidants ?? LDL size & density type A: large, buoyant type B: small, dense hyper TG, DM, Insulin resistance familial combined hyperlipidemia CHD patients Lp(a) atherogenic thrombogenic LDL -S=S- 34

35. HDL Metabolism 1Reverse cholesterol transport LCAT Apo A PL Apo A PL HDL 3 esterified cholesterol Unesterified cholesterol ABC A1 Nascent HDL liver ABC = ATP binding cassette LCAT = Lecithin:Cholesterol Acetyltransferase 35

36. HDL Metabolism 2 Unesterified cholesterol Nascent HDL HDL 3 liver HDL 2 36

37. HDL Metabolism 3 liver HDL 2 SR-B1 CETP CETP = Cholesterol Ester Transfer Protein SR-B1= Scavenger receptor B1 37

38. Antiatherosclerotic mechanisms of HDL Reverse Cholesterol Transport direct (SRAP) indirect (via LDL, VLDL) Prevents LDL Oxidation paraoxinase Prevents synthesis of prothrombotic prostaglandins Increases synthesis of antithrombotic prostaglandins prostacycline 38

39. Causes of low HDL-C Genetic Hypertriglyceridemia Obesity Diabetes mellitus Insulin resistance syndrome cigarette smoking Diet: high CHO, high PUFA Drugs Anabolic steroids (testosterone, progestins) beta adrenergic blockers 39

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41. Relationship between HDL and Triglyceride-rich lipoproteins Trig HDL 41

42. הנחיות קליניותמניעה ראשונית טיפול בגורמי הסיכון האחרים טיפול תזונתי חישוב ה- global risk 42

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44. הנחיות קליניותמניעה שניונית טיפול בגורמי הסיכון האחרים טיפול תזונתי דל שומן / דיאטה “ים-תיכונית” אומגה 3 : 1 גרם ליום פיטוסטרולים: 2 גרם ליום טיפול תרופתי תמיד:כאשרLDLc > 100 mg/dL 44

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46. In high-risk persons • recommended LDL-C goal is <100 mg/dL • when risk is very high • an LDL-C goal of <70 mg/dL is a therapeutic option • This therapeutic option extends also to patients at very high risk who have a baseline LDL-C <100 mg/dL 46

47. פרמקולוגיה 47

48. מיקום הפעולה של התרופות acetylCoA chol  ezetimibe VLDL fibrates niacin IDL  statins resins LDL 48

49. Statins Acetoacetyl CoA + Acetyl CoA 3-Hydroxy-3-methylgluteryl CoA (HMG CoA) HMGCoA Reductase Mevalonic acid Ubiquinones Cholesterol 49

50. Absorption & Metabolism • Should be given in evening/ night • most cholesterol synthesis in early morning • Well absorbed orally • Excretion mostly hepatic, renal 10-33% • ↓ Lescol, lipitor • Penetration of BBB • ↓ water soluble (pravastatin)