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1031 talk2

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1031 talk2

  1. 1. Anatomy of the Atherosclerotic PlaqueAnatomy of the Atherosclerotic Plaque Lumen Lipid Core Fibrous cap Shoulder Intima Media Elastic laminæ Internal External
  2. 2. Thrombosis of a DisruptedThrombosis of a Disrupted Atheroma, the Cause of Most AcuteAtheroma, the Cause of Most Acute Coronary Syndromes, Results from:Coronary Syndromes, Results from:  Weakening ofWeakening of the fibrous capthe fibrous cap  Thrombogenicity of the lipid core Illustration courtesy of Michael J. Davies, M.D.
  3. 3. Matrix Metabolism and Integrity ofMatrix Metabolism and Integrity of the Plaque’s Fibrous Capthe Plaque’s Fibrous Cap Libby P. Circulation 1995;91:2844-2850. + + + + + + – Synthesis Breakdown Lipid core IL-1 TNF-α MCP-1 M-CSF Fibrous capIFN-IFN-γγ CD-40L Collagen-degradingCollagen-degrading ProteinasesProteinases Tissue FactorTissue Factor ProcoagulantProcoagulant
  4. 4. Plaque Rupture with ThrombosisPlaque Rupture with Thrombosis Thrombus Fibrous cap 1 mm Lipid core Illustration courtesy of Frederick J. Schoen, M.D., Ph.D.
  5. 5. Potential Time Course of Statin EffectsPotential Time Course of Statin Effects * Time course established DaysDays YearsYears LDL-CLDL-C lowered*lowered* InflammationInflammation reducedreduced VulnerableVulnerable plaquesplaques stabilizedstabilized EndothelialEndothelial functionfunction restoredrestored IschemicIschemic episodesepisodes reducedreduced CardiacCardiac eventsevents reduced*reduced*
  6. 6. HDL Metabolism andHDL Metabolism and Reverse Cholesterol TransportReverse Cholesterol Transport A-I Liver CE CE CE FCFC LCAT FC Bile SR-BI A-I ABC1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I; CE = cholesteryl ester; FC = free cholesterol; LCAT = lecithin:cholesterol acyltransferase; SR-BI = scavenger receptor class BI ABC1 Macrophage Mature HDL Nascent HDL
  7. 7. Role of CETP in HDL MetabolismRole of CETP in HDL Metabolism A-I Liver CE CE FCFC LCAT FC Bile SR-BI A-I ABC1 Macrophage CE B CETP = cholesteryl ester transfer protein LDL = low-density lipoprotein LDLR = low-density lipoprotein receptor VLDL = very-low-density lipoprotein LDLR VLDL/LDL CETP Mature HDL Nascent HDL CE SRA Oxidation
  8. 8. CETP DeficiencyCETP 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 cholesteryl ester and apoA- I • HDL particles enlarged and enriched in cholesteryl ester • No evidence of protection against atherosclerosis; possible increased risk of premature atherosclerotic vascular disease
  9. 9. SummarySummary • HDL metabolism is complex • HDL-C and apoA-I levels are determined by both production and catabolic rates • Rates of reverse cholesterol transport cannot be determined solely by steady-state levels of HDL-C and apoA-I • Effect of genetic defects or of interventions that alter HDL metabolism on atherosclerosis depends on specific metabolic effects on HDL • Genes and proteins involved in HDL metabolism are potential targets for development of novel therapeutic strategies for atherosclerosis
  10. 10. • Increase apo A-I production • Promote reverse cholesterol transport • Delay catabolism of HDL HDL as a Therapeutic Target:HDL as a Therapeutic Target: Potential StrategiesPotential Strategies
  11. 11. A-I HDL and Reverse CholesterolHDL and Reverse Cholesterol TransportTransport LiverLiver CECECE FC LCATLCATFCFC BileBile SR-BISR-BI ABCA1ABCA1 MacrophageMacrophage MatureMature HDLHDL NascentNascent HDLHDL A-IA-I FC CECE FC
  12. 12. • Antioxidant effects • Inhibition of adhesion molecule expression • Inhibition of platelet activation • Prostacyclin stabilization • Promotion of NO production Mechanisms Other Than ReverseMechanisms Other Than Reverse Cholesterol Transport by Which HDLCholesterol Transport by Which HDL May be AntiatherogenicMay be Antiatherogenic
  13. 13. ApoA-I MutationsApoA-I Mutations • Modest to marked reduction in HDL-C and apoA-I • Rapid catabolism of apoA-I • Systemic amyloidosis • Premature atherosclerotic disease (rare)
  14. 14. • Small molecule upregulation of apo A-I gene transcription • Intravenous infusion of recombinant protein (wild-type apo A-I, apo A-IMilano) • Administration of peptides based on apo A-I sequence • Somatic gene transfer of apo A-I DNA (liver, intestine, muscle, hematopoetic cells) Approaches to Increasing Apo A-IApproaches to Increasing Apo A-I ProductionProduction
  15. 15. CETP DeficiencyCETP 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 cholesteryl ester and apoA- I • HDL particles enlarged and enriched in cholesteryl ester • No evidence of protection against atherosclerosis; possible increased risk of premature atherosclerotic vascular disease
  16. 16. Genes Involved in HDL MetabolismGenes Involved in HDL Metabolism Potential Targets for Development ofPotential Targets for Development of Novel Therapies for AtherosclerosisNovel Therapies for Atherosclerosis • HDL-associated apolipoproteins — ApoA-I — ApoE — ApoA-IV • HDL-modifying plasma enzymes and transfer proteins — LCAT — Lipoprotein lipase — CETP — Hepatic lipase — PLTP — Endothelial lipase • Cellular and cell-surface proteins that influence HDL metabolism — ABC1 — SR-BI
  17. 17. Gene Transfer of ApoA-I to LiverGene Transfer of ApoA-I to Liver Induces Regression of AtherosclerosisInduces Regression of Atherosclerosis in LDLRin LDLR–/––/– MiceMice 0 1 2 3 4 5 Baseline Adnull Aorticlesion(%) AdhapoA-I * * P ≤ 0.05 Tangirala R et al. Circulation 1999;100:1816–1822
  18. 18. Overexpression of LCAT PreventsOverexpression of LCAT Prevents Development of Atherosclerosis inDevelopment of Atherosclerosis in Transgenic RabbitsTransgenic Rabbits * P < 0.003 LCAT = lecithin-cholesterol acyltransferase; Tg = transgenic Hoeg JM et al. Proc Natl Acad Sci U S A. 1996;93:11448–11453 Copyright ©1996 National Academy of Sciences, USA. 0 10 20 30 40 50 Control LCAT Tg Atherosclerotic surfacearea(%) *
  19. 19. Inflammation and AtherosclerosisInflammation and Atherosclerosis  Inflammation may determine plaque stability - Unstable plaques have increased leukocytic infiltrates - T cells, macrophages predominate rupture sites - Cytokines and metalloproteinases influence both stability and degradation of the fibrous cap  Lipid lowering may reduce plaque inflammation - Decreased macrophage number - Decreased expression of collagenolytic enzymes (MMP-1) - Increased interstitial collagen - Decreased expression of E-selectin - Reduced calcium depositionLibby P. Circulation 1995;91:2844-2850. Ross R. N Engl J Med 1999;340:115-126.
  20. 20. • Reduced initiation and progression of atherosclerosis in transgenic mice and rabbits • Regression of pre-existing atherosclerosis in animals Increased Apo A-I Production isIncreased Apo A-I Production is Antiatherogenic in AnimalsAntiatherogenic in Animals
  21. 21. Lipid LevelsLipid Levels as the Targetas the Target AtherosclerosisAtherosclerosis as the Targetas the Target Treatment ApproachTreatment Approach  Measure and treat levels  Only patients with levels above normal benefit  Start on low dose and titrate  Goal is “normal” levels  Benefit same regardless of Rx  Based on epidemiologic and observational data  Find patients with disease or at risk  All patients benefit, regardless of lipid levels  Start on clinical trial– proven doses  Goal is getting on and staying on Rx  Statins have independent benefits  Based on randomized clinical trial evidence
  22. 22. Role of Lipoproteins inRole of Lipoproteins in InflammationInflammation
  23. 23. Atherosclerosis is an InflammatoryAtherosclerosis is an Inflammatory DiseaseDisease Ross R. N Engl J Med 1999;340:115-126. EndotheliumEndothelium Vessel LumenVessel Lumen IntimaIntimaFoam CellFoam Cell MonocyteMonocyte CytokinesCytokines Growth FactorsGrowth Factors MetalloproteinasesMetalloproteinases Cell ProliferationCell Proliferation Matrix DegradationMatrix Degradation MacrophageMacrophage
  24. 24. Lipoprotein Classes and InflammationLipoprotein Classes and Inflammation Doi H et al. Circulation 2000;102:670-676; Colome C et al. Atherosclerosis 2000; 149:295-302; Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994. HDLHDLLDLLDLChylomicrons,Chylomicrons, VLDL, andVLDL, and their catabolictheir catabolic remnantsremnants > 30 nm> 30 nm 20–22 nm20–22 nm Potentially proinflammatoryPotentially proinflammatory 9–15 nm9–15 nm Potentially anti-Potentially anti- inflammatoryinflammatory
  25. 25. Structure of LDLStructure of LDL Murphy HC et al. Biochemistry 2000;39:9763-970. Hydrophobic CoreHydrophobic Core of Triglyceride andof Triglyceride and Cholesteryl EstersCholesteryl Esters apoBapoB Surface MonolayerSurface Monolayer of Phospholipidsof Phospholipids and Freeand Free CholesterolCholesterol
  26. 26. Role of LDL in InflammationRole of LDL in Inflammation Steinberg D et al. N Engl J Med 1989;320:915-924. EndotheliumEndothelium Vessel LumenVessel Lumen LDLLDL LDL Readily Enter the Artery Wall Where They May be ModifiedLDL Readily Enter the Artery Wall Where They May be Modified LDLLDL IntimaIntima Modified LDLModified LDL Modified LDL are ProinflammatoryModified LDL are Proinflammatory Hydrolysis of PhosphatidylcholineHydrolysis of Phosphatidylcholine to Lysophosphatidylcholineto Lysophosphatidylcholine Other Chemical ModificationsOther Chemical Modifications Oxidation of LipidsOxidation of Lipids and ApoBand ApoB AggregationAggregation
  27. 27. LDLLDL LDLLDL Modified LDL Stimulate Expression ofModified LDL Stimulate Expression of MCP-1 in Endothelial CellsMCP-1 in Endothelial Cells Navab M et al. J Clin Invest 1991;88:2039-2046. EndotheliumEndothelium Vessel LumenVessel Lumen IntimaIntima MonocyteMonocyte Modified LDLModified LDL MCP-1MCP-1
  28. 28. LDLLDL LDLLDL Differentiation of Monocytes intoDifferentiation of Monocytes into MacrophagesMacrophages Steinberg D et al. N Engl J Med 1989;320:915-924. EndotheliumEndothelium Vessel LumenVessel Lumen IntimaIntima MonocyteMonocyte Modified LDLModified LDL Modified LDL PromoteModified LDL Promote Differentiation ofDifferentiation of Monocytes intoMonocytes into MacrophagesMacrophages MCP-1MCP-1 MacrophageMacrophage
  29. 29. LDLLDL LDLLDL Modified LDL Induces Macrophages to ReleaseModified LDL Induces Macrophages to Release Cytokines That Stimulate Adhesion MoleculeCytokines That Stimulate Adhesion Molecule Expression in Endothelial CellsExpression in Endothelial Cells Nathan CF. J Clin Invest 1987;79:319-326. EndotheliumEndothelium Vessel LumenVessel LumenMonocyteMonocyte Modified LDLModified LDL MacrophageMacrophage MCP-1MCP-1 AdhesionAdhesion MoleculesMolecules CytokinesCytokines IntimaIntima
  30. 30. LDLLDL LDLLDL EndotheliumEndothelium Vessel LumenVessel LumenMonocyteMonocyte MacrophageMacrophage MCP-1MCP-1 AdhesionAdhesion MoleculesMolecules Steinberg D et al. N Engl J Med 1989;320:915-924. Macrophages Express ReceptorsMacrophages Express Receptors That Take up Modified LDLThat Take up Modified LDL Foam CellFoam Cell Modified LDLModified LDL Taken up byTaken up by MacrophageMacrophage IntimaIntima
  31. 31. LDLLDL LDLLDL EndotheliumEndothelium Vessel LumenVessel LumenMonocyteMonocyte MacrophageMacrophage AdhesionAdhesion MoleculesMolecules Macrophages and Foam CellsMacrophages and Foam Cells Express Growth Factors andExpress Growth Factors and ProteinasesProteinases Foam CellFoam Cell IntimaIntima ModifiedModified LDLLDLCytokinesCytokines Cell ProliferationCell Proliferation Matrix DegradationMatrix Degradation Growth FactorsGrowth Factors MetalloproteinasesMetalloproteinases Ross R. N Engl J Med 1999;340:115-126. MCP-1MCP-1
  32. 32. EndotheliumEndothelium Vessel LumenVessel LumenMonocyteMonocyte MacrophageMacrophage MCP-1MCP-1AdhesionAdhesion MoleculesMolecules The Remnants of VLDL and ChylomicronsThe Remnants of VLDL and Chylomicrons are Also Proinflammatoryare Also Proinflammatory Foam CellFoam Cell IntimaIntimaModifiedModified RemnantsRemnantsCytokinesCytokines Cell ProliferationCell Proliferation Matrix DegradationMatrix Degradation Doi H et al. Circulation 2000;102:670-676. Growth FactorsGrowth Factors MetalloproteinasesMetalloproteinases Remnant LipoproteinsRemnant Lipoproteins RemnantsRemnants
  33. 33. Structure of HDL ParticleStructure of HDL Particle A-I A-I A-II A-I, A-II = apolipoprotein A-I, A-II; CE = cholesteryl ester; TG = triglycerides CE TG
  34. 34. Structure of HDLStructure of HDL Rye KA et al. Atherosclerosis 1999;145:227-238. Hydrophobic CoreHydrophobic Core of Triglyceride andof Triglyceride and Cholesteryl EstersCholesteryl Esters apoA-IIapoA-II Surface MonolayerSurface Monolayer of Phospholipidsof Phospholipids and Freeand Free CholesterolCholesterolapoA-IapoA-I
  35. 35. LDLLDL LDLLDL Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80. EndotheliumEndothelium Vessel LumenVessel LumenMonocyteMonocyte Modified LDLModified LDL MacrophageMacrophage MCP-1MCP-1 AdhesionAdhesion MoleculesMolecules CytokinesCytokines HDL Prevent Formation of Foam CellsHDL Prevent Formation of Foam Cells IntimaIntimaHDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux FoamFoam CellCell
  36. 36. LDLLDL LDLLDL Mackness MI et al. Biochem J 1993;294:829-834. EndotheliumEndothelium Vessel LumenVessel LumenMonocyteMonocyte Modified LDLModified LDL MacrophageMacrophage MCP-1MCP-1 AdhesionAdhesion MoleculesMolecules CytokinesCytokines HDL Inhibit the Oxidative Modification of LDLHDL Inhibit the Oxidative Modification of LDL FoamFoam CellCell HDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux IntimaIntima HDL InhibitHDL Inhibit OxidationOxidation of LDLof LDL
  37. 37. Inhibition of LDL Oxidation byInhibition of LDL Oxidation by HDL:HDL: Role of ParaoxonaseRole of Paraoxonase • Paraoxonase is transported in plasma as a component of HDL • Paraoxonase is known to inhibit the oxidative modification of LDL • Thus, the presence of paraoxonase in HDL may account for a proportion of the antioxidant properties of these lipoproteins Mackness MI et al. FEBS Lett 1991;286:152-154.
  38. 38. Role of HDL Apolipoproteins inRole of HDL Apolipoproteins in Removing Oxidized Lipids fromRemoving Oxidized Lipids from LDLLDL • CETP transfers oxidized lipids from LDL to HDL • The oxidized lipids in HDL are reduced by HDL apolipoproteins • The liver takes up reduced lipids from HDL more rapidly than from LDL Christison JK et al. J Lipid Res 1995;36:2017-2026; Gardner B et al. J Biol Chem 1998;273:6088-6095.
  39. 39. LDLLDL LDLLDL Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994. EndotheliumEndothelium Vessel LumenVessel Lumen MonocyteMonocyte Modified LDLModified LDL MacrophageMacrophage MCP-1MCP-1 AdhesionAdhesion MoleculesMolecules CytokinesCytokines Inhibition of Adhesion MoleculesInhibition of Adhesion Molecules IntimaIntima HDL InhibitHDL Inhibit OxidationOxidation of LDLof LDL HDL Inhibit Adhesion Molecule ExpressionHDL Inhibit Adhesion Molecule Expression FoamFoam CellCell HDL Promote Cholesterol EffluxHDL Promote Cholesterol Efflux
  40. 40. EndotheliumEndothelium Vessel LumenVessel Lumen MCP-1MCP-1 E-SelectinE-Selectin Charo IF. Curr Opin Lipidol 1992;3:335-343. Recruitment of Blood Monocytes byRecruitment of Blood Monocytes by Endothelial Cell Adhesion MoleculesEndothelial Cell Adhesion Molecules IntimaIntima VCAM-1VCAM-1 ICAM-1ICAM-1 StickingSticking MonocyteMonocyte RollingRolling TransmigrationTransmigration
  41. 41. HDL Inhibit Endothelial CellHDL Inhibit Endothelial Cell Sphingosine KinaseSphingosine Kinase Xia P et al. J Biol Chem 1999;274:33143-33147. SphingomyelinSphingomyelin CeramideCeramide SphingosineSphingosine Sph-1-PSph-1-P HDLHDL NF-NF-KKBB Adhesion ProteinAdhesion Protein SynthesisSynthesis SM-aseSM-ase Sph KinaseSph Kinase ++ TNFTNFαα XX
  42. 42. Heterogeneity of HDLHeterogeneity of HDL Rye KA et al. Atherosclerosis 1999;145:227-238. Apolipoprotein CompositionApolipoprotein Composition A-I HDLA-I HDL A-I/A-II HDLA-I/A-II HDL A-II HDLA-II HDL Particle ShapeParticle Shape DiscoidalDiscoidal SphericalSpherical Lipid CompositionLipid Composition TG, CE, and PLTG, CE, and PL Particle SizeParticle Size HDLHDL2b2b HDLHDL2a2a HDLHDL3a3a HDLHDL3b3b HDLHDL3c3c
  43. 43. Inhibition of Endothelial CellInhibition of Endothelial Cell VCAM-1 Expression by HDL:VCAM-1 Expression by HDL: Effect of HDL CompositionEffect of HDL Composition • Inhibition unaffected by replacing apoA-I with apoA-II • Inhibition unaffected by replacing apoA-I with SAA • Inhibition unaffected by varying the cholesteryl ester or triglyceride content of HDL • Inhibition ISIS affected by varying HDL phospholipids Baker PW et al. J Lipid Res 1999;40:345-353.
  44. 44. Additional Anti-inflammatoryAdditional Anti-inflammatory Properties of HDLProperties of HDL • HDL bind and neutralize proinflammatory lipopolysaccharides • The acute phase reactant SAA binds to plasma HDL, which possibly neutralizes the effects of SAA Baumberger C et al. Pathobiology 1991;59:378-383; Benditt EP et al. Proc Natl Acad Sci U S A 1977;74:4025-4028.
  45. 45. Animal StudiesAnimal Studies • Increasing the concentration of LDL or remnant particles in animal models results in expression of endothelial cell adhesion molecules at the sites where atherosclerotic lesions develop • Infusion or overexpression of apoA-I in animal models reduces oxidation of LDL and reduces endothelial cell adhesion molecule expression Sakai A et al. Arterioscler Thromb Vasc Biol 1997;17:310-316; Dimayuga P et al. Biochem Biophys Res Commun 1999;264:465-468; Cockerill GW et al. Circulation 2001;103:108- 112; Theilmeier G et al. FASEB J 2000;14:2032-2039.
  46. 46. Studies in HumansStudies in Humans • Treatments that reduce the level of LDL reduce the plasma levels of C-reactive protein and soluble adhesion molecules BUT • These effects may represent pleiotropic effects of lipid-modifying agents and be unrelated to the changes in lipoprotein levels Ridker PM et al.Ridker PM et al. CirculationCirculation 1998;98:839-844; Hackman A et al.1998;98:839-844; Hackman A et al. CirculationCirculation 1996;93:1334-1338.1996;93:1334-1338.
  47. 47. SummarySummary • The evidence that atherosclerosis is an inflammatory disorder is overwhelming • LDL are subject to proinflammatory modifications that may account for their atherogenicity • HDL have anti-inflammatory properties that may contribute to their ability to protect against atherosclerosis
  48. 48. ConclusionsConclusions • Strategies that reduce proinflammatory modifications to LDL may reduce atherosclerosis • Strategies that increase the anti-inflammatory properties of HDL may also reduce atherosclerosis • More research is needed to determine whether pharmacological increases in HDL are anti- inflammatory and reduce atherosclerosis
  49. 49. HDL as a Therapeutic TargetHDL as a Therapeutic Target
  50. 50. Is HDL-C Simply a Marker ofIs HDL-C Simply a Marker of Increased Cardiovascular Risk?Increased Cardiovascular Risk? • Smoke • Are sedentary • Are obese • Are insulin resistant or diabetic • Have hypertriglyceridemia • Have chronic inflammatory disorders Low HDL-C levels are commonly found in patients who:
  51. 51. Production of Apo A-I by Liver andProduction of Apo A-I by Liver and IntestineIntestine A-IA-I A-IIA-II LiverLiver IntestineIntestine HDLHDL A-IA-I HDLHDL
  52. 52. • Reduced initiation and progression of atherosclerosis in transgenic mice and rabbits • Regression of pre-existing atherosclerosis in animals Increased Apo A-I Production isIncreased Apo A-I Production is Antiatherogenic in AnimalsAntiatherogenic in Animals
  53. 53. • Increase apo A-I production • Promote reverse cholesterol transport • Delay catabolism of HDL HDL Metabolism as a TherapeuticHDL Metabolism as a Therapeutic Target: Potential StrategiesTarget: Potential Strategies
  54. 54. • Small molecule upregulation of apo A-I gene transcription • Intravenous infusion of recombinant protein (wild-type apo A-I, apo A-IMilano) • Administration of peptides based on apo A-I sequence • Somatic gene transfer of apo A-I DNA (liver, intestine, muscle, hematopoetic cells) Approaches to Increasing Apo A-IApproaches to Increasing Apo A-I ProductionProduction
  55. 55. • Increase apo A-I production • Promote reverse cholesterol transport • Delay catabolism of HDL HDL as a Therapeutic Target:HDL as a Therapeutic Target: Potential StrategiesPotential Strategies
  56. 56. A-I HDL and Reverse CholesterolHDL and Reverse Cholesterol TransportTransport LiverLiver CECECE FC LCATLCATFCFC BileBile SR-BISR-BI ABCA1ABCA1 MacrophageMacrophage MatureMature HDLHDL NascentNascent HDLHDL A-IA-I FC CECE FC
  57. 57. Regulation of Cholesterol Efflux inRegulation of Cholesterol Efflux in the Macrophagethe Macrophage FC FC oxysterols LXR/RXRLXR/RXR ABCA1 PPARsPPARs A-I
  58. 58. Pharmacologic Manipulation ofPharmacologic Manipulation of Cholesterol EffluxCholesterol Efflux LXR/RXR PPARsPPARs Fibrates, TZDs, new agentsFibrates, TZDs, new agents New agents A-I FC ABCA1
  59. 59. • Increase apo A-I production • Promote reverse cholesterol transport • Delay catabolism of HDL HDL as a Therapeutic Target:HDL as a Therapeutic Target: Potential StrategiesPotential Strategies
  60. 60. • Antioxidant effects • Inhibition of adhesion molecule expression • Inhibition of platelet activation • Prostacyclin stabilization • Promotion of NO production Mechanisms Other Than ReverseMechanisms Other Than Reverse Cholesterol Transport by Which HDLCholesterol Transport by Which HDL May be AntiatherogenicMay be Antiatherogenic
  61. 61. LiverLiver CECECE FCFCFC LCATLCATFCFC BileBile SR-BISR-BI A-I ABCA1ABCA1 MacrophageMacrophage A-IA-I TGTG CECE HDL Metabolism: IntravascularHDL Metabolism: Intravascular Remodeling of HDLRemodeling of HDL KidneyKidney PLPL FCFC PLPL
  62. 62. LiverLiver HLHL A-IA-I TGTG CECE HDL Metabolism: Role of HepaticHDL Metabolism: Role of Hepatic LipaseLipase KidneyKidney PLPL HDLHDL22 A-IA-I CECE PLPL HDLHDL33
  63. 63. LiverLiver CECECE FCFCFC LCATLCATFCFC BileBile SR-BISR-BI A-I ABCA1ABCA1 MacrophageMacrophage A-IA-I FC CECE HDL Metabolism: Role of CETPHDL Metabolism: Role of CETP FCFC KidneyKidney LDLRLDLR CE TG CETPCETP BB VLDL/LDLVLDL/LDL
  64. 64. HDL Metabolism in CETP DeficiencyHDL Metabolism in CETP Deficiency CE FCFCFC LCATLCAT A-I ABCA1ABCA1 MacrophageMacrophage A-IA-I CECE FCFC CE TG CETPCETP BB VLDL/LDLVLDL/LDL DelayedDelayed catabolismcatabolism X
  65. 65. 0 5 10 15 20 25 30 35 Okamoto H et al. Nature 2000;406:203-207. Inhibition of CETP by JTT-705 inInhibition of CETP by JTT-705 in Cholesterol-Fed Rabbits SignificantlyCholesterol-Fed Rabbits Significantly Reduced Aortic AtherosclerosisReduced Aortic Atherosclerosis %AorticLes Control SimvastatinJTT-705
  66. 66. HDL Metabolism: Influence of CETPHDL Metabolism: Influence of CETP InhibitionInhibition LiverLiver CECECE FCFCFC LCATLCATFCFC BileBile SR-BISR-BI A-I ABCA1ABCA1 MacrophageMacrophage A-IA-I FC CECE FCFC LDLRLDLR CE TG CETPCETP BB VLDL/LDLVLDL/LDL X
  67. 67. • Weight reduction and increased physical activity • LDL-C is primary target of therapy • Non-HDL-C is secondary target of therapy (if triglycerides ≥200 mg/dL) • Consider nicotinic acid or fibrates Management of Low HDL-CManagement of Low HDL-C Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
  68. 68. • Therapeutic lifestyle changes – Smoking cessation – Regular aerobic exercise – Weight loss – Alcohol use? Management of Low HDL-CManagement of Low HDL-C
  69. 69. • Therapeutic lifestyle changes • Pharmacologic therapy – Statins Management of Low HDL-CManagement of Low HDL-C
  70. 70. • Therapeutic lifestyle changes • Pharmacologic therapy – Statins – Fibrates Management of Low HDL-CManagement of Low HDL-C
  71. 71. • Therapeutic lifestyle changes • Pharmacologic therapy – Statins – Fibrates – Niacin Management of Low HDL-CManagement of Low HDL-C
  72. 72. • Lifestyle changes and secondary causes • Pharmacologic therapy – If LDL-C elevated: statin – If TG elevated: fibrate – If isolated low HDL-C: niacin • Combination therapy Management of Low HDL-CManagement of Low HDL-C
  73. 73. • LDL-C remains the primary target of lipid-altering therapies • HDL-C is an important CHD risk factor • Even small increases in HDL-C may confer substantial benefit • Intervention to raise HDL-C levels should be considered in high-risk patients SummarySummary
  74. 74. • 48-year-old man with metabolic syndrome and CHD • After therapeutic lifestyle changes and a starting dose of statin: Cholesterol 179 mg/dL Triglycerides 252 mg/dL LDL-C 97 mg/dL HDL-C 32 mg/dL Glucose 104 mg/dL Approach to the Patient with LowApproach to the Patient with Low HDL-CHDL-C
  75. 75. Drugs Main effects Sites of action abciximab anticoagulant stops platelet activation platelets amiloride (combination with frusemide is frumil) potassium sparing diuretic kidney (distal tubules) amiodarone class III anti-arrhythmic myocardium aspirin anticoagulant stops platelet activation platelets atropine (sometimes used to stop vagus bradycardia) parasympatholytic, increases heart rate pacemaker cells (sino-atrial node) captopril reduces arterial blood pressure relaxes vascular smooth muscle clopidogrel anticoagulant stops platelet activation platelets digitalis and ouabain increase cardiac contractility, delay AV node triggering all tissues, but the Na/Ca exchanger is mainly in heart dipyridamole (often used for X-ray imaging) coronary vasodilation coronary vasculature furosemide (= frusemide) diuretic kidney (loop of Henle) isoprenaline (and other adrenaline analogues) increase cardiac contractility many tissues losartan reduces arterial blood pressure relaxes vascular smooth muscle lovastatin reduces blood cholesterol levels liver morphine pain relief (mainly) brain nitroglycerine (and many other organic nitrates) reduce cardiac work load relaxes vascular smooth muscle propranolol reduces cardiac contractility, class II anti-arrhythmic many tissues quinidine, novocaine and other local anaesthetics class I anti-arrhythmics myocardium spironolactone (usually added to other diuretics) reduces diuretic potassium losses kidney (distal tubules) urokinase (streptokinase is cheaper but antigenic) dissolves blood clots (fibrinolytic) blood clots verapamil, nifedipine and other dihydropyridines reduce cardiac work load, class IV anti-arrhythmic myocardium; relax vascular smooth muscle warfarin anticoagulant vit. K antagonist liver Check list of common cardiac drugs
  76. 76. Plaque with multiple breaks in the cap and both an intraplaque and an intraluminal mural component of thrombosis
  77. 77. An episode of plaque disruption in which the torn cap projects into the lumen of the artery and thrombus is contained within the plaque core
  78. 78. Diagrammatic representation of stages of development of thrombosis after disruption
  79. 79. Schematic Time Course of HumanSchematic Time Course of Human AtherogenesisAtherogenesis Transition from chronic to acute atheromaTransition from chronic to acute atheroma Ischemic HeartIschemic Heart DiseaseDisease CerebrovascularCerebrovascular DiseaseDisease Peripheral VascularPeripheral Vascular DiseaseDisease
  80. 80. NormalNormal FattyFatty StreakStreak FibrousFibrous PlaquePlaque OcclusiveOcclusive AtheroscleroticAtherosclerotic PlaquePlaque PlaquePlaque Rupture/Rupture/ Fissure &Fissure & ThrombosisThrombosis MIMI StrokeStroke Critical LegCritical Leg IschemiaIschemia Clinically SilentClinically Silent CoronaryCoronary DeathDeath Increasing AgeIncreasing Age Effort AnginaEffort Angina ClaudicationClaudication UnstableUnstable AnginaAngina Atherosclerosis: A ProgressiveAtherosclerosis: A Progressive ProcessProcess Courtesy of P Ganz.
  81. 81. Libby P. Lancet. 1996;348:S4-S7. Media – T lymphocyte – Macrophage foam cell (tissue factor+ ) – “Activated” intimal SMC (HLA-DR+ ) – Normal medial SMC Fibrous cap Intima Lipid core Lumen The Anatomy of AtheroscleroticThe Anatomy of Atherosclerotic PlaquePlaque
  82. 82. Nissen et al. In: Topol. Interventional Cardiology Update. 14;1995. Angiographically InapparentAngiographically Inapparent AtheromaAtheroma
  83. 83. The Matrix Skeleton of UnstableThe Matrix Skeleton of Unstable Coronary Artery PlaqueCoronary Artery Plaque Davies MJ. Circulation. 1996;94:2013-2020. Fissures in the fibrous cap
  84. 84. Libby P. Circulation. 1995;91:2844-2850. Characteristics of Plaques Prone toCharacteristics of Plaques Prone to RuptureRupture – T lymphocyte – Macrophage foam cell (tissue factor+ ) – “Activated” intimal SMC (HLA-DR+ ) – Normal medial SMC “Stable” plaque “Vulnerable” plaque Lumen area of detail Media Fibrous cap Lumen Lipid core Lipid core
  85. 85. Libby P. Circulation. 1995;91:2844-2850. Proposed Mechanisms of EventProposed Mechanisms of Event Reduction by Lipid-Lowering TherapyReduction by Lipid-Lowering Therapy • Improved endothelium-dependent vasodilation • Stabilization of atherosclerotic lesions – especially nonobstructive, vulnerable plaques • Reduction in inflammatory stimuli – lipoproteins and modified lipoproteins • Prevention, slowed progression, or regression of atherosclerotic lesions
  86. 86. Atheroma are not merely filled withAtheroma are not merely filled with lipid, but contain cells whose functionslipid, but contain cells whose functions critically influence atherogenesis:critically influence atherogenesis: Intrinsic Vascular Wall Cells:  Endothelium  Smooth Muscle Cells Inflammatory Cells:  Macrophages  T Lymphocytes  Mast Cells
  87. 87. Cell Types in the Human AtheromaCell Types in the Human Atheroma Monocyte/Monocyte/ MacrophageMacrophage T-lymphocytesT-lymphocytesTunica Media Intima Smooth muscle cells EndotheliumEndothelium
  88. 88. NoNo symptomssymptoms ++ SymptomsSymptoms Schematic Time Course of HumanSchematic Time Course of Human AtherogenesisAtherogenesis Time (y)Time (y) SymptomsSymptoms Lesion initiationLesion initiation Ischemic HeartIschemic Heart DiseaseDisease CerebrovascularCerebrovascular DiseaseDisease Peripheral VascularPeripheral Vascular DiseaseDisease
  89. 89. Macrophage Functions inMacrophage Functions in AtherogenesisAtherogenesis AttachmentAttachment
  90. 90. Leukocyte–Endothelial AdhesionLeukocyte–Endothelial Adhesion MoleculesMoleculesMonoMono TT BB PMNPMN
  91. 91. Vascular Cell Adhesion Molecule 1Vascular Cell Adhesion Molecule 1 (VCAM-1)(VCAM-1)  Binds monocytes and lymphocytes - Cells found in atheroma  Expressed by endothelium over nascent fatty streaks  Expressed by microvessels of the mature atheroma
  92. 92. An atherogenic diet rapidly inducesAn atherogenic diet rapidly induces VCAM-1, a cytokine-regulatableVCAM-1, a cytokine-regulatable mononuclear leukocyte adhesionmononuclear leukocyte adhesion molecule, in rabbit aorticmolecule, in rabbit aortic endotheliumendothelium Li H et al. Arterioscler Thromb 1993;13:197-204.
  93. 93. VCAM-1 Expression in Rabbit AortaVCAM-1 Expression in Rabbit Aorta Li H et al. Arterioscler Thromb 1993;13:197-204. 3 weeks on atherogenic diet
  94. 94. PenetrationPenetration Macrophage Functions inMacrophage Functions in AtherogenesisAtherogenesis
  95. 95. Monocyte Chemoattractant Protein 1Monocyte Chemoattractant Protein 1 (MCP-1)(MCP-1)  A potent mononuclear cell chemoattractant  Produced by endothelial and smooth muscle cells  Localizes in human and experimental atheroma
  96. 96. Absence of monocyteAbsence of monocyte chemoattractant protein-1 reduceschemoattractant protein-1 reduces atherosclerosis in low-densityatherosclerosis in low-density lipoprotein receptor–deficient micelipoprotein receptor–deficient mice Gu L et al. Mol Cell 1998;2:275-281.
  97. 97. Reduced Lipid Deposition in MCP-1–Reduced Lipid Deposition in MCP-1– Deficient Atherosclerotic MiceDeficient Atherosclerotic Mice Gu L et al. Mol Cell 1998;2:275-281. LDL-R –/–LDL-R –/– MCP-1 +/+MCP-1 +/+ LDL-R –/–LDL-R –/– MCP-1 –/–MCP-1 –/–
  98. 98. Gu L et al. Mol Cell 1998;2:275-281. Reduced Lipid Deposition in MCP-1–Reduced Lipid Deposition in MCP-1– Deficient Atherosclerotic MiceDeficient Atherosclerotic Mice 0 5 10 15 20 25 30 OilRedStaining %AorticSurfaceStained Time on Diet: 12 – 14 weeks +/+ -/- ** * +/+ -/- 20 – 25 weeks *P = 0.001 compared to +/+ **p = 0.005 compared to +/+
  99. 99. Macrophage Functions inMacrophage Functions in AtherogenesisAtherogenesis Division
  100. 100. Molecular Mediators of AtherogenesisMolecular Mediators of Atherogenesis M-CSFMCP-1 VCAM-1
  101. 101. Matrix Metabolism and Integrity ofMatrix Metabolism and Integrity of the Plaque’s Fibrous Capthe Plaque’s Fibrous Cap Libby P. Circulation 1995;91:2844-2850. + + + + + + – Synthesis Breakdown Lipid core IL-1 TNF-α MCP-1 M-CSF Fibrous capIFN-IFN-γγ CD-40L Collagen-degradingCollagen-degrading ProteinasesProteinases Tissue FactorTissue Factor ProcoagulantProcoagulant
  102. 102. Increased Expression of InterstitialIncreased Expression of Interstitial Collagenase (CL) by Smooth MuscleCollagenase (CL) by Smooth Muscle Cells (SMC) and Macrophages (MCells (SMC) and Macrophages (Mφφ) in) in Human AtheromaHuman Atheroma Galis ZS et al. J Clin Invest 1994;94:2493-2503.

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