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Jorge Mera, MD Presbyterian Hospital of Dallas October 11, 2005

This article discusses the relationship between abnormal concentrations of high-density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD), including the role of HDL-C as a risk factor, atherogenesis, HDL metabolism, causes of abnormal HDL-C levels, treatment options, mechanisms of used agents, novel targets for treatment, and treatment with available tools.

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Jorge Mera, MD Presbyterian Hospital of Dallas October 11, 2005

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  1. Interpretation and Management of Abnormal Concentrations of High Density Lipoprotein-Cholesterol (HDL-C) Jorge Mera, MD Presbyterian Hospital of Dallas October 11, 2005

  2. Interpretation and Management of Abnormal Concentrations of HDL-C • HDL-C as a risk factor for CHD • Atherogenesis • HDL Metabolism • Causes of abnormal HDL-C levels • Treatment • Mechanisms of used agents • Novel targets for treatment • Treatment with available tools

  3. Modifiable Dyslipidemia Raised LDL-C Raised TGs Low HDL-C Smoking Hypertension Diabetes mellitus Obesity Dietary factors Thrombogenic factors Sedentary lifestyle Risk Factors for CHD • Nonmodifiable • Age • Sex • Family history of premature CHD Wood DJ et al. Atherosclerosis. 1998;140:199-270.

  4. Dyslipidemia: Definition • Elevation above the 90th percentile of the general population of • Total cholesterol • LDL-cholesterol • Triglicyride • Apo-B • Lp(a) • Concentrations below the the 10th Percentile of the general population of • HDL –cholesterol • Apo A-1 • The above mentioned disorders can be Primary or Secondary to some underlying disease

  5. What is the Relation Between HDL-C and Coronary Heart Disease (CHD) • Primary reductions in HDL-C are common in patients with premature CHD • Low HDL levels are more common in patients with a first myocardial infarction (MI) than in age matched controls without CHD (19% vs 4 %)1 • In the Beza fibrate Infarction Prevention Study 52 % of patients with CHD and with normal LDL-C cholesterol had low HDL-C (below 35mg/dL) Genest,JJ et al, J Am Coll Cariol 1992;19:792

  6. What is the Relation Between HDL-C and Coronary Heart Disease (CHD) • The Incidence of CHD events in a normal population appears to be inversely related to the serum HDL-C concentration • Data from the Framingham Heart Study showed that the risk for MI increases by 25 % for every 5 mg/dL decrement in serum HDL-C below median values for men and women • HDL-C Levels are also predictive of Coronary events in patient with known CHD, specially in the subgroup with LDL-C < 125mg dL. (LIPID and CARE trials) • Concentrations of HDL-C > 75 mg/dL are associated with longevity and relative freedom from CHD

  7. Framingham Heart Study: Risk of CAD in Men Aged 50–70 by LDL-C and HDL-C Levels Castelli W. Can J Cardiol. 1988;4(suppl A):5A-10A.

  8. CHD Risk According to HDL-C Levels: Framingham Study 4.0 4.0 3.0 CHD Risk Ratio 2.0 2.0 1.0 1.0 0 65 25 45 HDL-C (mg/dL) Kannel WB. Am J Cardiol. 1983;52:9B–12B.

  9. Major Risk Factors (Excluding LDL-C) That Modify LDL-C Goals • Cigarette smoking • Hypertension (BP 140/90 mmHg or on antihypertensive medication) • Low HDL-C (<40 mg/dL)* • Family history of premature CHD • CHD in male first degree relative <55 years • CHD in female first degree relative <65 years • Age (men 45 years; women 55 years) *HDL-C 60 mg/dL counts as a “negative” risk factor; its presence removes 1 risk factor from the total count. HDL-C, high-density lipoprotein cholesterol.

  10. HDL AS CAD RISK FACTOR NCEP ATP III recognizes that any serum HDL level < 40 mg/dL constitutes an independent risk factor for CAD, and therapeutic effort should be made to raise HDL above this threshold. CAD, coronary artery disease.

  11. Framingham CHD Risk Assessment inMen Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA.SBP, systolic blood pressure. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

  12. Framingham CHD Risk Assessment inWomen Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

  13. Oxidized Low-Density Lipoprotein:A Potent Atherogen Bloodstream Endothelium * * * * * * O2- Oxidized LDL LDL Scavenger Receptor Lipoxygenase Macrophage Smooth Muscle Cells LDL, low-density lipoprotein. Courtesy of P Libby.

  14. Evolution of Atherosclerotic Plaque Libby P. The vascular biology of atherosclerosis. In: Braunwald E et al. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, PA: Elsevier; 2001:995-1009.

  15. Endothelial Cell Adhesion Molecules Vascular Lumen Bound Monocyte Circulating Monocyte Transmigration Endothelium ICAM – 1 VCAM – 1 ICAM – 1 VCAM – 1 MCP-1 Gradient Subendothelial Space Sphingomyelin Increase ICAM-1/VCAM-1 + TNF - a Sphingomyelinase Activate NF-kB Ceramide HDL3 inhibits Sphingosine 1-P Sphingosine Sphingosine Kinase HDL, high-density lipoprotein; MCP, monocyte chemotactic protein; VCAM, vascular adhesion molecule. Xia P et al. Biol Chem. 1999;274:33143-33147.

  16. Metabolism of ApoA-Containing Lipoproteins B B C-III C-II B HL HL LPL B LPL LDL 2 B C-II LDL 1 LPL C-III LDL 3 E E IDL VLDL C-II LDL 4 B B B Chol Chol Chol E CETP Chol VLDL B B CETP Oxidation LDL 5 TG Liver LDLr CD36 TG SR-BI SR-A Macrophage Cholesterol A-I A-I A-I Pool A-I LCAT LCAT A-I ABCA1 Chol A-II Nascent HDL Degradation HDL 3 HDL 2 Arterial Wall Adapted from B Brewer.

  17. Non-HDL-C B C-III C-II B HL HL LPL B LPL B C-II LDL 1 LPL C-III LDL 3 E E IDL VLDL C-II LDL 4 B B B Chol Chol Chol E CETP Chol VLDL B B CETP Oxidation LDL 5 TG Liver LDLr CD36 TG SR-BI SR-A Macrophage Cholesterol A-I A-I A-I Pool A-I LCAT LCAT A-I ABCA1 Chol A-II Nascent HDL Degradation HDL 3 HDL 2 Arterial Wall Adapted from B Brewer.

  18. Reverse Cholesterol Transport Tóth PP. Am J Cardiol. 2005. In press.

  19. Structure of HDL Particle A-I A-I CE TG A-II A-I, A-II, apolipoprotein A-I, A-II; CE, cholesteryl ester; TG, triglycerides.

  20. Production of HDL-C by Liver and Intestine Liver Intestine A-I A-I A-II HDL HDL

  21. HDL Metabolism and Reverse Cholesterol Transport Bile A-I A-I FC CE CE LCAT FC FC CE ABC1 Nascent HDL SR-BI Macrophage Mature HDL Liver ABC1, ATP-binding cassette protein 1; FC, free cholesterol; LCAT, lecithin-cholesterol acyltransferase; SR-BI, scavenger receptor class BI.

  22. Role of CETP in HDL Metabolism Bile Macrophage Mature HDL Nascent HDL A-I A-I FC CE CE LCAT FC FC CE ABC1 SR-BI SRA CETP Liver LDLR Oxidation CE B VLDL/LDL CETP, cholesteryl ester transfer protein; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; VLDL, very-low-density lipoprotein.

  23. Role of HL and LPL in HDL Metabolism Endothelium B C-II TG LPL B CM/VLDL A-I Phospholipids and apolipoproteins CMR/IDL PL CE TG A-I HDL2 HL PL CE Kidney HDL3 CM, chylomicron; CMR, chylomicron remnant; HDL, high-density lipoprotein; HL, hepatic lipase; IDL, intermediate-density lipoprotein; LPL, lipoprotein lipase; PL, phospholipase.

  24. HDL-C: Anti-Atherogenic Properties • HDL is Anti-Atherogenic by two main mechanisms • Reverse Cholesterol transport • Transporting Cholesterol from peripheral tissues (macrophages) back to the liver • Transferring cholesterol to VLDL, IDL or LDL via the Cholesterol Esther Transport Protein (CETP) • That cholesterol ideally will go back to the liver

  25. Primary (Genetic) Causes of Low HDL-C • ApoA-I • Complete ApoA-I deficiency • ApoA-I mutations (eg, ApoA-IMilano) • LCAT • Complete LCAT deficiency • Partial LCAT deficiency (fish eye disease) • ABC1 • Tangier disease • Homozygous • Heterozygous • Familial hypoalphalipoproteinemia (some families) • Unknown genetic etiology • Familial hypoalphalipoproteinemia (most families) • Familial combined hyperlipidemia with low HDL-C • Metabolic syndrome

  26. HDL Metabolism in LCAT Deficiency A-I Nascent HDL A-I CE LCAT FC FC ABC1 Macrophage Rapid catabolism

  27. HDL Metabolism in Tangier Disease Nascent HDL A-I A-I CE LCAT FC FC ABC1 Macrophage Rapid catabolism

  28. Tangiers Disease • Orange Tonsils • Hepatomegaly • Neuropathy • Low or absent HDL-C

  29. Familial Hypoalphalipoproteinemia • Dominant disorder; due to mutations in one allele of ABC1 gene in some families and of unknown genetic etiology in other families • Moderate reduction in HDL-C and ApoA-I • Increased risk of premature atherosclerotic vascular disease

  30. Secondary Causes of Low HDL-C • Smoking • Obesity (visceral fat) • Very-low-fat diet • Hypertriglyceridemia • Drugs • Beta blockers • Androgenic steroids • Androgenic progestins

  31. Primary (Genetic) Causes of High HDL-C • CETP • CETP deficiency • HL • HL deficiency • Unknown genetic etiology • Familial hyperalphalipoproteinemia

  32. CETP Deficiency • Autosomal co-dominant; due to mutations in both alleles of CETP gene • Markedly elevated levels of HDL-C and ApoA-I • Delayed catabolism of HDL CE and ApoA-I • HDL particles enlarged and enriched in CE • Evidence of protection against atherosclerosis is controversial

  33. HDL Metabolism in CETP Deficiency HDL Delayed catabolism A-I A-I LCAT CE FC FC CE ABC1 Nascent HDL Macrophage CETP B VLDL/LDL

  34. Familial Hyperalphalipoproteinemia • Autosomal dominant; molecular etiology unknown • Modest to marked elevations in HDL-C and ApoA-I • Selective increased synthesis of ApoA-I in some families • Associated with longevity and protection against atherosclerotic vascular disease in epidemiologic studies

  35. Secondary Causes of Increased HDL-C • Extensive regular aerobic exercise • Very-high-fat diet • Regular substantial alcohol intake • Estrogen replacement therapy • Drugs • Phenytoin

  36. Genes Involved in HDL MetabolismPotential Targets for Novel Therapies for Atherosclerosis • HDL-associated apolipoproteins — ApoA-I — ApoE HDL-modifying plasma enzymes and transfer proteins — LCAT — LPL — CETP — HL — Endothelial lipase • Cellular and cell-surface proteins that influence HDL metabolism — ABC1 — SR-BI

  37. TREATMENT OPTIONS

  38. Drug Effects on HDL:Niacin B C-II TG NIACIN LPL CM/VLDL Intestine B LDLR CMR/IDL NIACIN A-I A-I * CE LCAT FC FC CE ABC1 Liver Nascent HDL HL Macrophage Mature HDL *Inhibits uptake of ApoA-I but not CE. . Arterioscler Thromb Vasc Biol. 1999;19:1051–1059

  39. Side Effects of RR Niacin • Flushing, itching • Hepatitis • Glucose intolerance • Gout • Peptic ulcer activation RR, rapid-release.

  40. Tricks for Using Niacin • Use only the bedtime dose • Give all doses with food • Start low and increase slowly • Use only the sustained release • Give with ASA • Do not exceed 2 g QD of sustained-released Niacin • It is 2 times more effective than regular niacin BUT 10 times more hepatotoxic ASA, acetylsalicylic acid.

  41. + + CE FC Macrophage Drug Effects on HDL:Fibrates B FIBRATES C-II TG LPL CM/VLDL B Intestine LDLR CMR/IDL A-I FIBRATES A-I LCAT FC CE ABC1 Liver Nascent HDL HL Mature HDL Fenofibrate Clofibrate, Gemfibrozil

  42. + + CE FC Macrophage Drug Effects on HDL: Statins B C-II TG LPL CM/VLDL B Intestine LDLR STATINS CMR/IDL A-I A-I STATINS LCAT FC CE ABC1 Liver Nascent HDL ? HL Mature HDL STATINS

  43. They Cure Almost Every Lipid Problem That Ails You •  LDL-C •  TG •  HDL-C •  LDL particle size •  hs-CRP hs-CRP, high-sensitivity C-reactive protein; TG, triglycerides.

  44. Novel HDL Raising Therapies • ABCAI activators • PPAR-alpha agonists • Apo AI gene therapy • CETP inhibitors • Apo AI mimetics

  45. Peroxisome Proliferator Activated Receptors (PPAR) • PPAR agonists elicit their action by combining with an retinoid receptor (RXR) to form what are called response elements. These response elements regulate gene expression that are involved in lipid metabolism. Alpha agonists increase lipid metabolism to burn fat for energy. Gamma agonists effect not only glucose homeostasis, but also lipid metabolism in which fat is redistributed into subcutaneous fat cells. • PPAR: Fenofibric acid

  46. Peroxisome Proliferator Activated Receptors PPARg RXR PPARa RXR RXR, retinoid X receptor; TZDs, thiazolidinediones.

  47. Effects of PPAR-α Agonism • PPARa activation regulates expression of the five key genes involved in HDL metabolism. This results in: • increased levels of apo A-I and A-II; • increased LPL activity; • increased reverse cholesterol transport via • Increased expression of (i) the ABCA-1 receptor (cholesterol efflux via CERP) and • The Cla-1/SR-BI receptor (HDL capture and catabolism

  48. CETP: A Potential Therapeutic Target for thePrevention of Cardiovascular Disease Role of CETP in Lipoprotein Metabolism

  49. CETP • Lowers HDL-C • Increases LDL-C • Small dense LDL Pharmacologic inhibition of CETP increases HDL-C and lowers LDL-C

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