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Important or Imposter? HDL - Cholesterol. The wider roles of HDL.

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Presentation on theme: "Important or Imposter? HDL - Cholesterol. The wider roles of HDL."— Presentation transcript:

1 Important or Imposter? HDL - Cholesterol

2 The wider roles of HDL

3 HDL and Reverse Cholesterol Transport PhospholipidGlycosphingolipidCholesterol Lipid Raft Normal Cell Membrane Membrane rafts are small (10–200 nm), heterogeneous cholesterol & sphingolipid-enriched domains. ABCA1 Lipid-poor apoAI Nascent, discoidal HDL Diffusion SR-B1 CE LCAT Mature, spherical HDL ABCG1 Diffusion SR-B1

4 Pharmacologic Inhibition of CETP: A Novel HDL-raising Strategy A-I Liver CE FC LCAT FC Bile SR-BI A-I ABCA1 Macrophage CE FC Feces

5 Pharmacologic Inhibition of CETP: A Novel HDL-raising Strategy A-I Liver CE FC LCAT FC Bile SR-BI A-I ABCA1 Macrophage CE B LDLR VLDL/LDL CETP CE TG FC Feces

6 A-I CE FC LCAT Bile SR-BI A-I ABCA1 Macrophage Feces FC BA Liver receptor X (LXR) Promotes Reverse Cholesterol Transport: ABCG1 FC LXR LXR LXR ABCA1 LXR LXR

7 HDL Clinical Conditions CONDITIONHDL levelCVD risk Apo A1 deficiencyabsentsevere Tangiers disease (ABC A1 defect) very low? increased LCAT deficiency (& fish eye disease) very low? uncertain Apo A1 Milano (dimer formation) very low? reduced SRB1 deficiency (female infertility) very high? unaltered CETP deficiencyvery high? reduced

8 Beyond HDL-C: Laboratory assessment of reverse cholesterol efflux (by plasma)

9 HDL Therapy DRUG(S)Mechanism and HDL effectCVD effect Ezetimibe, fish oilNil relevant?Neutralmild benefit BAS resinsFXRMild increasemild benefit StatinsHMGCoARI Mod. increasemajor benefit FibratesPPAR alpha Mod. increasebenefit in MS NiacinReduced catabolism Increase?benefit CETP InhibitorsCETPIHuge increaseuncertain Novel (eg antiPCSK9)PCSK9Mild increaseuncertain

10 HDL Evidence: Epidemiology and trials STUDY or TRIALHDL observationCVD effect Observational (eg Framingham)inverse relationprotective Angiographic (Niacin, eg CLASS)large increaseregression (CETP, eg ILLUSTRATE)large increaseneutral RCT (Niacin, eg AIM-HIGH)large increaseflawed neutral (Fibrate, eg VA-HIT)small increase protective (Fibrate in MS, eg FIELD)small increaseprotective (Torcetrapib, eg ILLUMINATE)very large increasedetrimental (Dalcetrapib, eg DALOUTCOMES)large increaseneutral

11 Antioxidative Activity Antithrombotic Activity Potential Antiatherogenic Actions of HDL Anti-infectious Activity Endothelial Repair Chapman MJ, et al. Curr Med Res Opin. 2004;20: Assmann G, et al. Annu Rev Med. 2003;53: Antiapoptotic Activity Reverse Cholesterol Transport Cellular Cholesterol Efflux Anti-inflammatory Activity Vasodilatory Activity HDL Apo A-I Apo A-II

12 HDL composition is complex: Protein and phospholipid components

13 Could HDL become “dysfunctional”?

14

15

16 CHD RISK LDL- cholesterol (mg/dL) * Men aged HDL-C (mg/dL) Plasma HDL Predicts Events in Population Studies

17 Structure of HDL Surface monolayer of phospholipids and free cholesterol Hydrophobic core of triglyceride and cholesteryl esters apoA-I apoA-II Note: LFA1 denotes Lipid Free Apo Lipoprotein A1 r HDL denotes Reconstituted HDL

18

19 Non-occlusive Silastic Peri-arterial Carotid Collar in Male NZ White Rabbits Carotid artery Collar

20 Treated Artery Post Two Infusions of LFA1 B A C CD 18

21 Apo A1 Milano Infusions Lead to Significant Regression of Coronary Atherosclerosis (IVUS Study). Nissen, S. E. et al. JAMA 2003;290:

22 Cases

23 Mr A.M. Mr A.M. Is a 34 year old man of aboriginal descent who lives in rural NSW. His BP is 135 / 85. He was started on Rosuvastatin 20 mg because he has a very strong family history of premature cardiovascular disease (father, paternal aunt, 2 maternal uncles and older brother suffered onset of cardiovascular disease before age 45). Waistline is prominent and measures 98cms, but he is thin elsewhere. He had recurrent otitis media as a child and his dentition is poor. Follow-up lipids include TC=4.1, TG=2.9, HDL=0.5, LDL=2.3

24 Questions about Mr A.M. Is Mr A.M. eligible for Rosuvastatin according to Pharmaceutical Benefits Schedule Guidelines?Yes / No Mr A.M’s very low HDL-C is mainly due to A) Racial factors B) Intercurrent infectionC) Central Obesity / Lifestyle D) Mendelian genetic factorsE) Lack of exercise Which other racial groups have been documented to have relatively low HDL levels (2 correct). A) KiwisB) IndiansC) Finns D) Turkish E) Sub-Saharan Africans In rural NSW, the most feasible treatment to improve this man’s HDL-C is A) Fish oilB) An exercise programmeC) Niacin D) FibrateE) Antibiotic

25 Mr A.M’s very low HDL-C is mainly due to A) Racial factors B) Intercurrent infectionC) Central Obesity / Lifestyle D) Mendelian genetic factors E) Lack of exercise Is he eligible for Rosuvastatin according to Pharmaceutical Benefits Schedule Guidelines?Yes / No In rural NSW, the most feasible treatment to improve this man’s HDL-C is A) Fish oilB) An exercise programmeC) Niacin D) FibrateE) Antibiotic Mr A.M. is a 34 year old man of aboriginal descent who lives in rural NSW. His BP is 135/85. He was started on Rosuvastatin 20 mg because he has a very strong family history of premature cardiovascular disease (father, paternal aunt, 2 maternal uncles and older brother suffered onset of cardiovascular disease before age 45). Waistline is prominent and measures 98cms, but he is thin elsewhere. He had recurrent otitis media as a child and his dentition is poor. Follow-up lipids include TC=4.1, TG=2.9, HDL=0.5, LDL=2.3

26 Is Mr A.M. eligible for Rosuvastatin according to Pharmaceutical Benefits Schedule Guidelines? Yes / No

27 Is Mr A.M. eligible for Rosuvastatin according to Pharmaceutical Benefits Schedule Guidelines? Was “yes”, now “no” Family history of symptomatic CHD:before age 60 years in one or more first- degree relatives before age 50 years in one or more second-degree relatives ≤ 18 years at treatment initiation LDL-C > 4 mmol/L > 18 years at treatment initiation LDL-C > 5 mmol/Lortotal-C > 6.5 mmol/L ortotal-C > 5.5 mmol/L and HDL-C < 1 mmol/L

28 Close the Gap scheme In Nov 2008 COAG agreed to $1.6 billion for CTG Benefit: Lower or nil payment for PBS medicines Eligible: Aboriginal/ Torres Strait Islander of any age who present with chronic disease or at risk of chronic disease AND would have significant setback from disease if they did not have Rx or unlikely to comply with out such assistance Register: at GP in the Indigenous Health Incentive under PIP or Indigenous Health services. Prescriber: Any in a practice participating in IHI under PIP or any in HIS or any specialist in any location if the patient is registered and the patient has been referred a doctor in IHI program. Script: CTG For more information

29 Mr A.M’s very low HDL-C is mainly due to A) Racial factors B) Intercurrent infection C) Central Obesity / Lifestyle D) Mendelian genetic factors E) Lack of exercise

30 Mr A.M’s very low HDL-C is mainly due to.. Reasons for a preference for “A”, “B” or “C”

31 Which other racial groups have been documented to have relatively low HDL levels ? A) Kiwis B) Indians C) Finns D) Turkish E) Sub-Saharan Africans

32 Which other racial groups have been documented to have relatively low HDL levels “B” supported by INTERHEART, but difficult to compare, eg “D”. Acta Cardiol.Acta Cardiol Oct;62: Do Turkish adults really have lower serum levels of high-density lipoprotein cholesterol? Duran SDuran S, Memisogullari R, Coskun A, Yavuz O, Yuksel H.Memisogullari RCoskun AYavuz OYuksel H CONCLUSIONS: Our finding that the HDL-C level in this population was higher than the previously reported levels in Turkey indicates that HDL-C levels may not be as low as previously thought. We believe that lower HDL-C levels that were previously reported might be due to the difference between techniques of analysis, nutritional status, and percent of subjects who were fasting in the day of analysis or improper subject inclusion which did not reflect the Turkish population causing selection bias.

33 In rural NSW, the most feasible treatment to improve this man’s HDL-C is... A) Fish oil B) An exercise programme C) Niacin D) Fibrate E) Antibiotic

34 In rural NSW, the most feasible treatment to improve this man’s HDL-C is... The case for “D”Acyl-CoASynthase Acetyl CoA FFA apo A-I apo A-II ABCA1 apo C-III Apo A-V TG LiverCirculation … by controlling the expressio n of PPAR  target genes Results LPL Decreased small and dense LDL Particles LDL Increased VLDL Clearance Decreased VLDL Production VLDL Increased HDL Production HDL ABCG1 Decreased TG levels

35 More questions about Mr A.M. Mr A.M. has mild albuminuria. Would you add an antihypertensive, and if so, which of the following:A) NilB) Diuretic C) CCBD) ACEI E) Moxonidine His lipids remain unaltered but his eGFR declines slightly to 55mls / min. Would you addA) Fenofibrate 48mg B) Fenofibrate 145 mg, but cease if creatinine increased by 25 umol/l C) Fenofibrate 145mg, but continue if creatinine increased by < 25umol/l) D) Fenofibrate 145 mg no matter what E) More rosuvastatin CVD risk can’t be calculated because low HDL makes TC:HDL too high for risk calculators. To further assess risk in this rural setting, would you A) Test ABI and hs-CRP locally B) Refer for regional exercise stress test C) Refer to a more distant regional centre for imaging (IMT) D) Refer to capital city for CT angio or coronary calcium score E) Not perform any of these investigations

36 Mr A.M. has mild albuminuria. Would you add an antihypertensive, and if so, which of the following: A) Nil B) Diuretic C) CCB D) ACEI E) Moxonidine

37 Mr A.M. has mild albuminuria. Would you add an antihypertensive, and if so, which of the following: The case for “D” ease

38 Mr A.M’s lipids remain unaltered but his eGFR declines slightly to 55mls / min. Would you add A) Fenofibrate 48mg B) Fenofibrate 145 mg, but cease if creatinine increased by 25 umol/l C) Fenofibrate 145mg, but continue if creatinine increased by < 25umol/l) D) Fenofibrate 145 mg no matter what E) More rosuvastatin

39 Mr A.M’s lipids remain unaltered but his eGFR declines slightly to 55mls / min. Would you add... The case for “C”

40 CVD risk can’t be calculated because low HDL makes TC:HDL too high for risk calculators. To further assess risk in this rural setting, would you... A) Test ABI and hs-CRP locally B) Refer for regional exercise stress test C) Refer to a more distant regional centre for imaging (IMT) D) Refer to capital city for CT angio or coronary calcium score E) Not perform any of these investigations

41 CVD risk can’t be calculated because low HDL makes TC:HDL too high for risk calculators. To further assess risk in this rural setting, would you... A survey of opinions

42 Mr S.K. This 37 year old man of Greek descent had routine tests in his 20’s that revealed a very low HDL-C (<0.2 mmol/l). He is a smoker who drinks 20 gms alcohol per week. He trains regularly as a body-builder. A cardiologist was sufficiently concerned to arrange angiography at age 33, which was normal. On examination there are no relevant physical findings and lipids are TC=2.2, TG=2.2, HDL-C =0.08, LDL-C=1.0mmol/l.

43 Questions concerning Mr S.K. Is his lipid disorder.....Primary / Secondary Are there any simple tests that would provide a diagnosis? Yes/No Which drugs can DRASTICALLY reduce HDL-C? (More than 1 possible)A) DiureticsB) DanazolC) Beta blockers C) ProbocolE) Highly Active Antiretrovirals Your treatment would includeA) Quit smoking advice onlyB) NiacinC) StatinD) FibrateE) More alcohol

44 Is his lipid disorder.....Primary / Secondary Are there any simple tests that would provide a diagnosis? Yes/No Which drugs can DRASTICALLY reduce HDL-C? (More than 1 possible)A) DiureticsB) DanazoleC) Beta blockers C) Anabolic steroidsE) Highly Active Antiretrovirals Your treatment would includeA) Quit smoking advice only B) NiacinC) StatinD) FibrateE) More alcohol This 37 year old man of Greek descent had routine tests in his 20’s that revealed a very low HDL-C (<0.2 mmol/l). He is a smoker who drinks 20 gms alcohol per week. He trains regularly as a body-builder. A cardiologist was sufficiently concerned to arrange angiography at age 33, which was normal. On examination there are no relevant physical findings and lipids are TC=2.2, TG=2.2, HDL-C =0.08, LDL- C=1.0mmol/l.

45 Is Mr S.K’s his lipid disorder..... Primary Secondary

46 Is Mr S.K’s his lipid disorder..... The case for “primary” Apo A1 deficiencyabsent Tangiers disease (ABC A1 defect) very low LCAT deficiency (& fish eye disease) very low Apo A1 Milano (dimer formation) very low HDL Most secondary causes> 0.4 mmol/l

47 Are there any simple tests that would provide a diagnosis? Yes No

48 Are there any simple tests that would provide a diagnosis? The case for “no” Apo A1 deficiencyabsentWestern or IEF if sufficient Tangiers disease (ABC A1 defect) very lowMacrophge CE efflux LCAT deficiency (& fish eye disease) very lowPlasma activity if sufficient Apo A1 Milano (dimer formation) very lowIEF (Iso-electric focussing) Alternative proteomic and genetic techniques, but highly specialised

49 Which drugs can DRASTICALLY reduce HDL-C? (More than 1 possible) A) Diuretics B) Danazol C) Beta blockers D) Probocol E) Highly Active Antiretrovirals

50 Which drugs can DRASTICALLY reduce HDL-C? (More than 1 possible The case for “B” and D” J Allergy Clin Immunol.J Allergy Clin Immunol : Adverse effects of danazol prophylaxis on the lipid profiles of patients with hereditary angioedema. Széplaki GSzéplaki G, Varga L, Valentin S, Kleiber M, Karádi I, Romics L, Füst G, Farkas H.Varga LValentin SKleiber MKarádi IRomics LFüst GFarkas H Probucol, a powerful antioxidant, is a CETP and SR-B1inducer that dramatically reduces HDL-C (by 20-30%). Dayspring T et al

51 Your treatment for Mr S.K. would include.. A) Quit smoking advice only B) Niacin C) Statin D) Fibrate E) More alcohol

52 Your treatment for Mr S.K. would include.. All feasible, but “B” the most effective and “E” inappropriate? Hepatocyte Inhibits hepatic lipase activity which reduces lipolysis of large HDL No effect on increasing Apo A1 synthesis A-I CE HDL 2 apoA-I HDL 3 Nascent HDL

53 More questions concerning Mr S.K. Mr S.T’s plasma Testosterone was normal. Does this surprise you? Yes / No Mr S.T. Has managed to stop smoking. An exercise stress test was normal 2 years previously. On this review, the cardiologist repeated the CT coronary angiogram, which now shows a 25% RCA lesion composed of soft plaque. LDL-C remains 1.0 mmol/l Would you commence statin therapy?Yes / No Would you add any other agent? A) NiacinB) Fibrate C) Nothing elseD) Aspirin E) Seek Trial access to a CETP Inhibitor

54 Varnava AM et al. Circulation 2002;105: Glagov Phenomenon

55 14% 18% 68% Percent >70%50-70%<50% Lesion Severity Severity of Coronary Plaques before MI Ambrose et al. J Am Coll Cardiol 1988;12:56-62 Little et al. Circulation 1988;78: Nobuyoshi et al. J Am Coll Cardiol 1991;18: Giroud et al. Am J Cardiol 1992;62: Plaque severity and events

56 ECs SMCsMonocytesCAMs Matrix Foamcells Cytokines GrowthFactors T-lymphocytes ActivatedMacrophages TissueFactorClottingMMPsMatrixDegradation Normal Adhesion InfiltrationRupture Atherosclerosis is a chronic inflammatory disorder

57 Mr S.T’s plasma Testosterone was normal. Does this surprise you? Yes No

58 Mr S.T’s plasma Testosterone was normal. Does this surprise you? The case for “no”

59 Mr S.T. has managed to stop smoking. An exercise stress test was normal 2 years previously. On this review, the cardiologist repeated the CT coronary angiogram, which now shows a 25% RCA lesion composed of soft plaque. LDL-C remains 1.0 mmol/l Would you commence statin therapy? Yes No

60 Mr S.T. has managed to stop smoking. An exercise stress test was normal 2 years previously. On this review, the cardiologist repeated the CT coronary angiogram, which now shows a 25% RCA lesion composed of soft plaque. LDL-C remains 1.0 mmol/l Would you commence statin therapy? The case for “yes”

61 HDL remains unchanged. Would you add any other agent? A) Niacin B) Fibrate C) Nothing else D) Aspirin E) Seek Trial access to a CETP Inhibitor

62 HDL remains unchanged. Would you add any other agent? Each could be argued for and against


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