St Joseph University - Faculty of Medicine Beirut, Lebanon .

1. St Joseph University - Faculty of Medicine Beirut, Lebanon. Selim JAMBART, MD, MS, FACE.

3. Phenotype I IIa IIb III IV V Lipoprotein elevated Chylomicrons LDL LDL and VLDL IDL VLDL VLDL and chylomicrons Serum cholesterol Serum triglyceride Atherogenicity None seen +++ +++ +++ + + Prevalence Rare Common Common Intermediate Common Rare average to average average to average to LDL – low-density lipoprotein; IDL – intermediate-density lipoprotein; VLDL – very low-density lipoprotein. (High-density lipoprotein (HDL) cholesterol levels are not consideredin the Fredrickson classification.) Adapted from Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391 Classification of Dyslipidaemias:Fredrickson (WHO) Classification

4. Combined hyperlipidemia • Inherited as autosomal dominant trait • Unknown genetic cause • Xanthomas are not a feature • This phenotype overlaps with and may be the same as • that observed in familial hypertriglyceridemia, both of them being • expressed in affected members of the same family (Multiple type) • *No extra vascular depots

5. Low HDL-cholesterol The atherogenic triad Small, dense LDL particles Elevated TG rich particles

6. Low HDL-cholesterol Impaired LPL function Small, dense LDL particles Elevated TG rich particles

7. ABC1 N-HDL LDL APO A CELL SR-B1 LCAT HL APO B HDL 3 REMNANTS VLDL IDL LCAT LPL CETP HDL 2 a CE PL CHYLO PLTP

8. muscle LPL +

9. muscle CHYLO FFA LPL +

10. muscle CHYLO FFA LPL + FFA

11. muscle CHYLO FFA LPL + FFA TG VLDL

12. muscle CHYLO FFA LPL + FFA TG LDL Receptor IDL LDL VLDL

13. muscle CHYLO FFA HDL 3 LPL + FFA HDL 2 TG LDL Receptor IDL LDL VLDL

14. muscle CHYLO FFA HDL 3 LPL + An ideal world FFA HDL 2 TG LDL Receptor IDL LDL VLDL

15. muscle LPL -

16. muscle CHYLO FFA LPL -

17. muscle CHYLO FFA LPL - FFA

18. muscle CHYLO FFA LPL - FFA TG +

19. muscle CHYLO FFA LPL - FFA TG + HL Scavenger Receptor VLDL LDL LDL C-Rich TG-Rich Small dense CETP

20. muscle CHYLO FFA HDL 3 LPL - FFA HDL 2 TG + HL Scavenger Receptor VLDL LDL LDL C-Rich TG-Rich Small dense CETP

21. muscle CHYLO FFA HDL 3 LPL - 40% in Lebanon FFA HDL 2 TG + HL Scavenger Receptor VLDL LDL LDL C-Rich TG-Rich Small dense CETP

22. Lipid levels in combined hyperlipidemiaare rarely alarming • Cholesterol: 225 mg/dl • Triglycerides: 220 mg/dl • LDL cholesterol: 144 mg/dl • HDL cholesterol: 37 mg/dl

23. TG-rich lipoproteins Atherogenic Particles In people with the triade profile we should consider the quality of lipoproteins rather than the quantity of blood lipids CHYLO VLDL β VLDL IDL LDL Small, dense LDL Consider « Non HDL Cholesterol » (equivalent to LDL + 30 mg/dl)

24. Large LDL VESSEL LUMEN Small LDL Penetration Endothelial Cells ARTERIAL INTIMA Accelerated oxidation FOAM CELL LESION Macrophage uptake Atherogenicity of Small, Dense LDL High proteoglycan binding affinity Small LDL particles penetrate arterial intima more readily, are retained preferentially, and are more susceptible to oxidation, leading to enhanced macrophage uptake and foam cell formation.

25. “Normal” LDL-C in people with impaired LPL can be misleading...small, dense LDL-C particles present in people with impaired LPLare more atherogenic than normal LDL-C Normal LPL Impaired LPL LDL particles LDL particles Small, dense LDL-C with more Apo-B • Apo-B • LDL-C ‘Normal’ LDL-cholesterolhowever: ‘Normal’ LDL-cholesterol Number of LDL-C particles Concentration of Apo-B Higher Lower CHD risk M. Austin JAMA 1988; 269: 1916

26. Elevated Triglyceride Levels are a Risk Factor for CHD 0 0.56 (50) 1.12 (100) 1.68 (150) 2.24 (200) 2.80 (250) 3.36 (300) Data are from a multivariate analysis and adjusted for age and smoking. Stampfer MJ et al. JAMA 1996;276:882–888.

27. Low HDL is an independent risk factor CHD risk 25mg/dL 45 mg/dL 65 mg/dL HDL-C 85 mg/dL 100 mg/dL 160 mg/dL 220 mg/dL LDL-C

28. Combined Hyperlipidemia = Impaired LPL function=Increased atherogenicity

29. Hyper TG, Low HDL-C Small dense LDL

30. CORONARY HEART DISEASE Non alcoholic fatty liver Polycistic ovaries Visceral Obesity Elevated fibrinogen,tissue factor & PAI 1 Impaired glucosetolerance; type 2 DM Hyperuricemia High blood pressure Microalbuminuria Hyper TG, Low HDL-C Small dense LDL HYPERINSULINISM INSULIN RESISTANCE GENES ENVIRONMENT Syndrome X=Polymetabolic syndrome=Deadly quartet=Dyslipidemic hypertension

31. Liver fat Adiponectin Inflammation Prothrombotic state Insulin resistance Type 2 DM Abdominal obesity Hypertension Dyslipidemia The triad isthe lipid expressionof insulin resistanceand the subsequent metabolic syndromeand is characteristic of diabetic dyslipidemia CVD Genetics + lifestyle

32. muscle CHYLO FFA HDL 3 LPL - FFA HDL 2 TG + HL Scavenger Receptor VLDL LDL LDL C-Rich TG-Rich Small dense CETP

33. Clinical identification of the metabolic syndrome (ATP III) • THREE OF THE FOLLOWING • Waist circumference • Men > 102 cm • Women > 88 cm • 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

34. Clinical identification of the metabolic syndrome (IDF- April 2005) • VISCERAL OBESITY • Waist circumference • Men > 94 cm • Women > 80 cm • + • TWO OF THE FOLLOWING • Triglycerides = > 150 mg/dl • HDL-Cholesterol • Men < 40 mg/dl • Women < 50 mg/dl • Blood pressure = >130/ = >85 mm Hg • Fasting glucose = >100 mg/dl

35. Liver fat Adiponectin Inflammation Prothrombotic state Insulin resistance Type 2 DM Abdominal obesity Hypertension Dyslipidemia CVD Genetics + lifestyle

36. The inflammatory atherosclerotic process Inflamm markers, CRP PLAQUE RUPTURE Lumen of blood vessel monocyte sdLDL MMP-9 endothelium sdLDL Inflamm cytokines, IL-6, TNFa MCP-1 VCAM Complex (vulnerable) plaque fatty streak chemotaxis Artery wall f m - differentiation O2 ROS PAI-1 TF ox-LDL Smooth muscle cells foam cell

37. Atherothrombosis is characterized by a sudden atherosclerotic plaque disruption leading to platelet activation and thrombus formation. We live with atherosclerosis but we die from thrombosis

38. Combined Hyperlipidemia = Impaired LPL function=Increased atherogenicity=Increased risk for atherothrombosis

39. Selected Features of NCEP ATP III Focus on Multiple Risk Factors • Diabetes: CHD risk equivalent • Metabolic syndrome • Framingham projections of 10-year CHD risk Modification of Lipid and Lipoprotein Classification • Optimal LDL cholesterol <100 mg/dL: changed from 100 mg/dl • Categorical low HDL cholesterol <40 mg/dl: raised from <35 mg/dl • Lower triglyceride classification cut points: More attention to moderate elevations. <150 mg/dl in diabetes NCEP ATP III guidelines. JAMA. 2001;285:2486-2497.

40. 28 27 26 25 24 23 R= –0.88 LDL diameter (nm) 0 1 2 3 4 5 6 Plasma TG (mmol/l) LDL diameter vs plasma TG Scheffer et al. Clin Chem 1997;43:1904–12

41. Effect of lipid-modifying therapies on lipids Therapy Bile acid sequestrants Nicotinic acid Fibrates Probucol Statins* Ezetimibe TC Down 20% Down 25% Down 15% Down 25% Down 15–30% - LDL Down 15–30% Down 25% Down 5–15% Down 10–15% Down 24–50% Down 18% HDL Up 3–5% Up 15–30% Up 20% Down 20–30% Up 6–12% Up 1% TG Neutral or up Down 20–50% Down 20–50% Neutral Down 10-29% Down 8% Patient tolerability Poor Poor to reasonable Good Reasonable Good Good TC-total cholesterol, LDL-low density lipoprotein, HDL-high density lipoprotein, TG-triglyceride. *Daily dose of 40mg of each drug. This slide does not include rosuvastatin. Adapted from Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391, Knopp RH. N Engl J Med 1999;341:498–511, Ezetimibe Prescribing Information. ,

42. Combined hyperlipidemia:shouldstatins or fibratesbe the first line therapy ?

43. StatinsMolecular mechanisms of actionSREBP feedback control

44. Pleiotropic parietal vascular effects of statins

45. Risk Reduction in Major Coronary Events in Key Statin Studies room for improvement Active n = Placebo n = 4S 431 622 WOSCOPS 174 248 CARE 212 274 AFCAPS/TexCAPS 116 183 LIPID 557 715 Statins used in the trials described were: 4S=simvastatin; WOSCOPS, CARE, LIPID=pravastatin, AFCAPS/TexCAPS=lovastatin 4S Group. Lancet 1994;344:1383–1389. Shepherd J et al.N Engl J Med 1995;333:1301–1307. Sacks FM et al.N Engl J Med 1996;35:1001–1009. LIPID Study Group. N Engl J Med 1998;339:1349–1357. Downs JR et al.JAMA 1998;279(20):1615–1622.

46. Regulation of lipoprotein metabolism by PPARa Fibrates PPAR PPAR PPARa RXR RXR A-I PPRE PPRE LPL PPAR PPAR RXR RXR C-III A-II PPRE PPRE TG rich particles HDL particles • Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC, Circulation, 1998, 98, 2088-2093

47. PPARa activators lower small dense LDL PPARa activator VLDL rich in apo C-III VLDL poor in apo C-III Cholesteryl ester TG CETP Cholesteryl ester CETP LDL Large buoyant LDL TG Small dense LDL LDL receptor Macrophage

48. Cell recruitment and activation • MPC-1, CCR2, • VCAM-1, ICAM-1, chemokines • Cholesterol efflux • Foam cell formation • Inflammatory response • Vasoconstriction • Cell migration • ABCA1, SR-BI, CD36 SR-A • TNFa, Interleukins, CRP, COX-2, • VCAM-1, TF, Fibrinogen, sPLA2 • ET-1, MMPs, Ets-1, TXS Direct vascular effects of activated PPARa • Thrombosis • Plaque stability • MMP-9, TXS, PAF, TF Barbier O.et al. Arterioscler Thromb Vasc Biol. 2002;22:717-26.

49. Mechanism of action of niacin on lipoprotein metabolism Niacin Niacin HDL receptor  Adipose tissue FA mobilisation  FA synthesis/ esterification  HDL-catabolism receptor  TG synthesis  Large TG-rich VLDL1  Assembly of ApoB containing lipoproteins/ ApoB degradation  HDL ApoA-I uptake/removal  Apo A-I/reverse cholesterol transport  VLDL, LDL  Small dense LDL Adapted from Kamanna VS, Kashyap ML. Curr Atheroscler Rep 2000;2:36-46

50. Risk reduction with statins: ~ 30% 70%Residual risk HDL-C increase / additional risk reduction 100% Further risk reduction with fibrates or nicotinic acid Combination is key