Your Cholesterol Profile

1. Your Cholesterol Profile Gary E. Foresman, MD February, 2011

2. Cholesterol Metabolism • Cholesterol is an alicyclic compound with a structure: • Perhydrocyclopentanophenanthrene nucleus of 4 fused rings (5-cholesten-3B-01)

3. Cholesterol Metabolism • Low solubility in water: 0.2mg / 100ml at 250 C • Solubility in blood is due to lipoproteins (LDL, VLDL) • Total cholesterol • Free 30% • Cholesterol Esters 70% (FA is Saturated or Unsaturated) • Long chain FA attached by ester bond to OH group on C-3 on the A-ring (usually linoleic acid) enhances hydrophobiticity.

4. Cholesterol Metabolism • Structure: • Bile concentration = 390 mg %

5. Cholesterol Metabolism • Cholesterol Functions: • Plasma and intracellular membranes (Free Unesterified form) B. Myelinated structures of brain and CNS C. Inner Mitrochrondrial Membrane D. Bile Acids E. Steroid Hormones and Sex Hormones F. Ergosterol ----- UV Skin--> Vitamin D3 (cholecalciferol) • Synthesis is greatest in: – Liver – Intestine – Adrenal Cortex – Reproductive Tissues (Ovary, Testes)

8. HMG-CoA Reductase Enzyme • Also called mevalonate: NADP+ oxidoreductase (a resident glycoprotein). • Requires NADPH as reductant -2 moles (4 E-) • Hydrolysis of thioester bond of HMG-CoA • Generates a primary alcohol residue : mevalonate • Irreversible RX • Produces (R) – (+) mevalonate with 6 C atoms • Rate limiting step • Intrinsic membrane protein of the ER (Endoplasmic Reticulum) whose carboxyl terminus extends into the cytosol and carries the enzyme’s active site. N-terminus anchors it to ER. • Phosphorylation regulates activity by AMP activated protein kinase that diminishes its catalytic activity

9. HMG-CoA Reductase Enzyme • Increased intracellular cholesterol stimulates the phosphorylation of HMGCoA Reductase • Most regulated enzyme known in humans: • Concentrations of products of mevalonate pathway • Cholesterol • Farnesyl Pyrophosphate (FPP) • Prenylated proteins • 2-cis geranylgeranyl PP (GGPP)  Dolichols • All-trans geranylgeranyl (GGPP)  Ubiquinone • Heme • Selenoproteins

17. Advanced Testing for Cardiovascular Risk The New Gold Standard for Lipoprotein Analysis

18. Total Cholesterol =VLDL+ LDL + HDL Evolution of Lipoprotein Testing Friedewald Equation: VLDL =TG/5 Calculated LDL= TC – (HDL + TG/5) “The Lipid Panel” Direct LDL is Better Consensus Statement of the American Diabetes Assoc. & American College of Cardiology Apo B 100 (est. of non-HDL Particles) is Better Yet Lipoprotein Particles Predict Risk Better than Cholesterol Lipoprotein Particle Numbers by Subgroup is Best

19. Centrifuge Tube with Mixture of Serum, Gradient and Dye Separated Lipoproteins Density (g/ml) 1.000 VLDL 1.006 Intense Gravitational Force LDL 1.030 1.063 600,000 G’s HDL 1.100 Proteins 1.300 Separation by Density

22. 50% of at Risk Individuals are Not Identified 50% of Heart Attack Victims have Normal Cholesterol NCEP Identified a Number of New LipoproteinRisk Factors – To Help Assess Those at Risk NCEP Guidelines for Cardiovascular Disease NCEP - ATP III

23. NCEP New Lipoprotein Risk Factors RLP (Remnant Lipoprotein) - - One of the Most Atherogenic Lipoproteins - Skips Oxidation Step in Forming Plaque Small Dense LDL– - 3-fold Greater Risk of CVD than Buoyant LDL - Penetrates Arterial Endothelial Lining Easily - Less Recognized by LDL Receptors therefore Increases Lp(a) - • Small Particles that are Easily Oxidized • Competes with Plasminogen, Prevents Fibrinolysis HDL 2b & 3 – - HDL 3 Picks Up Excess Cholesterol and Becomes HDL 2b in Reverse Cholesterol Transport High in 20% of population High in 25% of population High in 20% of population Low in 20% of population

24. Lp(a) Competes with Plasminogen and Prevents Fibrinolysis Many of the over 40 genetic variations of Lp(a) mimic plasminogen Plasminogen Fibrinogen Lp(a) Plasmin Fibrin Fibrinolysis Blood Clot (MI, Stroke or DVT) Possible Antithrombotic Therapy Indicated

25. To Determine the NCEP New Risk FactorsLipoprotein Subgroup Information is Needed: Advanced Lipoprotein Testing What are Lipoproteins and their Subgroups? How do they Cause Cardiovascular Disease?

26. Apolipoprotein A-1 (HDL) or B-100 (LDL) Triglyceride Cholesterol Ester Unesterified Cholesterol Phospholipid Lipoprotein Particles

27. Size (nm) Density (g/ml) 25 50 19 22 1.004 1.013 1.044 1.023 Buoyant LDL DenseLDL RLP VLDL Mean Endothelial Pore Size TG-rich Lipoproteins Atherogenic Particles

29. CETP in Cholesterol Metabolism LPL HL IDL LDL 1-2 VLDL HL Apo B-100 LDL 3-4 TG’s CETP Liver Liver CE Apo A-1 HDL2b HDL Enters Cells & Arterial Intima HDL3 Reverse Cholesterol Transport LCAT LCAT NascentHDL Brewer HB et al. Am J Cardiol 2003;92:10K-16K.

36. INFLAMMATION RUPTURES PLAQUE RLP LDL FOAM CELLS BUILD PLAQUE DENSE LDL FOAM CELL MACROPHAGE CELL OXIDIZED LDL Atherosclerotic Plaque Formation HDL REMOVES EXCESS LIPIDS ARTERIAL LUMEN Lp(a) MONOCYTE CELL DAMAGED ENDOTHELIUM CELLS ARTERIAL INTIMA

37. Healthy Profile Atherogenic Profile Dense LDL Buoyant LDL High HDL 2b High RLP Low HDL 2b Low RLP LPP showing NCEP’s New Lipoprotein Risk Factors Atherogenic Profile

39. Treatment of Dyslipidemia

40. Treatment of Dyslipidemia

41. Treatment of Dyslipidemia

42. Treatment of Dyslipidemia

44. Treatment of Dyslipidemia

45. Treatment of Dyslipidemia

46. Treatment of Dyslipidemia

49. Treatment of Dyslipidemia

50. Treatment of Dyslipidemia