Your Cholesterol Profile. Gary E. Foresman, MD February, 2011
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1 Your Cholesterol Profile Gary E. Foresman, MD February, 2011
2 Cholesterol Metabolism 1. Cholesterol is an alicyclic compound with a structure: a. Perhydrocyclopentanophenanthrene nucleus of 4 fused rings (5-cholesten-3B-01)
3 Cholesterol Metabolism 2. Low solubility in water: 0.2mg / 100ml at 250 C 3. Solubility in blood is due to lipoproteins (LDL, VLDL) 4. Total cholesterol a. Free 30% b. 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 5. Structure: 6. Bile concentration = 390 mg %
5 Cholesterol Metabolism 7. Cholesterol Functions: A. 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) 8. Synthesis is greatest in: Liver Intestine Adrenal Cortex Reproductive Tissues (Ovary, Testes)
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8 HMG-CoA Reductase Enzyme 1. Also called mevalonate: NADP+ oxidoreductase (a resident glycoprotein). 2. Requires NADPH as reductant -2 moles (4 E-) 3. Hydrolysis of thioester bond of HMG-CoA 4. Generates a primary alcohol residue : mevalonate 5. Irreversible RX 6. Produces (R) (+) mevalonate with 6 C atoms 7. Rate limiting step 8. 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. 9. Phosphorylation regulates activity by AMP activated protein kinase that diminishes its catalytic activity
9 HMG-CoA Reductase Enzyme 10. Increased intracellular cholesterol stimulates the phosphorylation of HMGCoA Reductase 11. 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
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17 Advanced Testing for Cardiovascular Risk The New Gold Standard for Lipoprotein Analysis
18 Evolution of Lipoprotein Testing The Lipid Panel Total Cholesterol = VLDL + LDL + HDL Friedewald Equation: VLDL = TG/5 Calculated LDL = TC (HDL + TG/5) 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 Separation by Density Centrifuge Tube with Mixture of Serum, Gradient and Dye Density (g/ml) Separated Lipoproteins Intense Gravitational Force 600,000 G s VLDL LDL HDL Proteins
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22 NCEP Guidelines for Cardiovascular Disease NCEP - ATP III 50% of at Risk Individuals are Not Identified 50% of Heart Attack Victims have Normal Cholesterol NCEP Identified a Number of New Lipoprotein Risk Factors To Help Assess Those at Risk
23 NCEP New Lipoprotein Risk Factors RLP (Remnant Lipoprotein) - High in 20% of population - One of the Most Atherogenic Lipoproteins - Skips Oxidation Step in Forming Plaque Small Dense LDL High in 25% of population - 3-fold Greater Risk of CVD than Buoyant LDL - Penetrates Arterial Endothelial Lining Easily - Less Recognized by LDL Receptors therefore Increases Lp(a) - High in 20% of population - Small Particles that are Easily Oxidized - Competes with Plasminogen, Prevents Fibrinolysis HDL 2b & 3 Low in 20% of population - HDL 3 Picks Up Excess Cholesterol and Becomes HDL 2b in Reverse Cholesterol Transport
24 Lp(a) Competes with Plasminogen and Prevents Fibrinolysis Many of the over 40 genetic variations of Lp(a) mimic plasminogen Fibrinogen Lp(a) Plasminogen Fibrin Plasmin Blood Clot (MI, Stroke or DVT) Fibrinolysis Possible Antithrombotic Therapy Indicated
25 Advanced Lipoprotein Testing To Determine the NCEP New Risk Factors Lipoprotein Subgroup Information is Needed: What are Lipoproteins and their Subgroups? How do they Cause Cardiovascular Disease?
26 Lipoprotein Particles Apolipoprotein A-1 (HDL) or B-100 (LDL) Cholesterol Ester Triglyceride Unesterified Cholesterol Phospholipid
27 Atherogenic Particles Size (nm) Density (g/ml) VLDL RLP Buoyant LDL Dense LDL TG-rich Lipoproteins Mean Endothelial Pore Size
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29 CETP in Cholesterol Metabolism Apo B-100 VLDL IDL HL LDL 1-2 HL LDL 3-4 Liver TG s CETP CE Liver Apo A-1 HDL2b Reverse Cholesterol Transport LCAT HDL3 LCAT HDL Enters Cells & Arterial Intima Nascent HDL Brewer HB et al. Am J Cardiol 2003;92:10K-16K.
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36 Atherosclerotic Plaque Formation INFLAMMATION RUPTURES PLAQUE ARTERIAL LUMEN HDL REMOVES EXCESS LIPIDS RLP FOAM CELLS BUILD PLAQUE LDL Lp(a) MONOCYTE CELL FOAM CELL DENSE LDL OXIDIZED LDL ARTERIAL INTIMA MACROPHAGE CELL
37 LPP showing NCEP s New Lipoprotein Risk Factors Healthy Profile Atherogenic Profile Buoyant LDL High HDL 2b Low RLP Atherogenic Profile High RLP Dense LDL Low HDL 2b
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39 Treatment of Dyslipidemia
40 Treatment of Dyslipidemia
41 Treatment of Dyslipidemia
42 Treatment of Dyslipidemia
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44 Treatment of Dyslipidemia
45 Treatment of Dyslipidemia
46 Treatment of Dyslipidemia
47 Date March of 2010 Aug. of 2010 Nov. of 2010 Feb. of 2011 Total Cholesterol Triglycerides HDL LDL LDL/HDL Trig/HDL *Add Lipitor 20mg and 3g/day Arctic Pure EPA/DHA *Patient switches to Kirkland Fish Oils
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49 Treatment of Dyslipidemia
50 Treatment of Dyslipidemia
51 Treatment of Dyslipidemia
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53 Treatment of Dyslipidemia
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55 Treatment of Dyslipidemia
56 Treatment of Dyslipidemia
57 Lipoprotein Particle Numbers Therapeutic Guidelines Lipoprotein Therapeutic Statins Niacin Fibrates Estrogens Resins Absorption Omega-3 s Alcohol Life Style Inhibitors EPA & DHA (moderate) Changes (diet & exercise) VLDL (Triglycerides) X X RLP (IDL) X X ** LDL I & II - buoyant ** LDL III - dense ** LDL IV or Lp(a) HDL 2b - buoyant HDL 2a & 3 Therapeutic Beneficial Little or No Effect X Negative Result *These guidelines provide some of the treatment options available to modify lipoprotein particle numbers determined by the LPP TM test. **Spectracell Laboratories observed response to treatment. The National Cholesterol Education Program (NCEP) guidelines provide dosage information on the treatment options.
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