¿Sirve para algo elevar el HDL?

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Bloque: NUEVAS ESTRATEGIAS EN EL TRATAMIENTO DE LA CARDIOPATÍA ISQUÉMICA CRÓNICA.
Ponente: Dr. José ramón gonzález juanatey
Curso Medicina Cardiovascular que tuvo lugar el 8 y 9 octubre de 2012 en Barcelona
Enlace: www.riesgocardiovascular.com

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¿Sirve para algo elevar el HDL?

  1. 1. J.R.G. JUANATEYC.H.U.Santiago
  2. 2. ¿Sirve para algo elevar el HDL? 1 José R. González Juanatey Área Cardiovascular. Hospital Clínico Universitario de Santiago de Compostela J.R.G. JUANATEYC.H.U.Santiago
  3. 3. HDL y Enfermedad CV HDL y “Riesgo Residual” HDL y Riesgo CV. Los mecanismos HDL y Riesgo CV. Las implicaciones terapéuticas ¿Qué pasa con los fármacos y el HDL? J.R.G. JUANATEYC.H.U.Santiago
  4. 4. Framingham Study 3,0 2,0 Risk of CHD after FUTURE ? 4 Years* 1,0 25 45 65 HDL-C 0,0 85 (mg/dL) 100 160 220 LDL-C (mg/dL) *Risk of coronary heart disease (CHD) over 4 years of follow-up for men ages 50 to 70 Castelli WP. Can J Cardiol. 1988;4(Suppl A):5A–10A J.R.G. JUANATEYC.H.U.Santiago
  5. 5. LDLC Levels in 136,905 Patients Hospitalized With CAD: 2000- 2006 LDLC (mg/dL) < 130 130-160 > 160Sachdeva et al, Am Heart J 2009;157:111-7.e2.
  6. 6. HDL: as a main determinant of ACS Biochemical determinants of ACS vs non-ischemic chest pain ACS Non- ischemic chest pain J.R.G. JUANATEY Cordero A, et al. Rev Esp Cardiol; 2012; 65: 319-325C.H.U.Santiago
  7. 7. CV Risk beyond LDL LDL treatment reduces CV Risk Overall RR Risk factors Age Gender CV disease HT treat DM Etc.. Chol T TG LDL Diabetes HDL Physical inact TG Diet Obesity HT HDL Tobacco Residual Risk J.R.G. JUANATEYC.H.U.Santiago
  8. 8. CV Risk beyond LDL Etc.. TG Diabetes Physical inact Diet Obesity HT HDL Tobacco Residual Risk J.R.G. JUANATEYC.H.U.Santiago
  9. 9. CV Risk beyond LDL Etc.. TG Diabetes Physical inact Diet Obesity HT HDL Tobacco Residual Risk J.R.G. JUANATEYC.H.U.Santiago
  10. 10. Dislipidemias y riesgo global Tablas SCORE con inclusión del c-HDL No fumadora Fumadora No fumador Fumador Edad Edad J.R.G. JUANATEYC.H.U.Santiago
  11. 11. Dyslipidemia International Study Spain Patients treated with statins in Spain n: 3.617 (68,8% GP; 31,2% Inter Med, Cardiology, Endocrinology) 90% 85% 83% 80% 70% 70% 65% 66% 61% 60% 56% 51% 50% 42% 36% 36% 38% 40% 31% 30% 26% 24% 20% 14% 10% 0% ECV DM SCORE ≥ 5% Alto RCV CT > OT c-LDL > OT c-HDL < OT TG > OT González-Juanatey J.R, Millán J, Alegría E, Guijarro C, Lozano J.V y Vitale G. Prevalencia y características de la dislipemia en pacientes en J.R.G. JUANATEY prevención primaria y secundaria tratados con estatinas en España. Estudio DYSIS-España. Rev Esp Cardiol 2011; 64(4):286-294C.H.U.Santiago
  12. 12. Mecanismos protectores de las HDL HDL Vasodilatación Antitrombótica Antinflamatoria Antioxidante Transporte centrípeto del colesterol Protección frente a J.R.G. JUANATEY la aterosclerosisC.H.U.Santiago
  13. 13. Endothelial-Vasoprotective Effects of High-Density Lipoprotein Are Impaired in Patients With Type 2 Diabetes Mellitus but Are Improved After Extended-Release Niacin Therapy (A), Effect of HDL (50 µ/mL, 60 minutes, 37°C) (A), Endothelium-dependent relaxations of aortic from healthy subjects (n=10) and diabetic rings of wild-type mice in response to increasing patients (n=33) on endothelial cell NO production concentrations of HDL isolated from healthy as determined by ESR spectroscopy analysis subjects (n=5) or diabetic patients (n=5) are shown (A) P < 0.0001 P < 0.0001 (B) Endothelial NO Production HDL from Endothelium-dependent Diabetic (% of buffer- treated cells) Patients (%; aortic rings) Relaxation P = 0.007 HDL from Healthy Subjects PBS HDL HDL Healthy Diabetics HDL (µg/ml) Sorrentino SA et al. Circulation. 2010;121:110-122 J.R.G. JUANATEYC.H.U.Santiago
  14. 14. HDL y Aterosclerosis Transporte reverso de colesterol J.R.G. JUANATEYC.H.U.Santiago NEJM 2004;350:1491-94
  15. 15. Clinical Significance of High Density Lipoprotein Cholesterol in Patients with Low Low-Density Lipoprotein Cholesterol Miocardial injury or IHD hospitalization 25 p 0.04 cHDL categorias 4188 sujetos con 0.007 cHDL continuo tratamiento y cLDL 20 <60 mg/dl, seguidos All cause 1 año Event rate (%) 15 mortality 10 Unadjusted Rates of 5 the Combined Primary End Point 0 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 (n 1,082) Q2 (n 1,123) Q3 (n 939) Q4 (n 1,044) Media 28 mg/dl Media 36 mg/dl Media 43 mg/dl Media 63 mg/dl J.R.G. JUANATEYC.H.U.Santiago DeGoma EM et al JACC 2008;51:49-55
  16. 16. Conversion of Anti-Inflammatory and Pro-Inflammatory HDL Myeloperoxidase HDL=high-density lipoprotein Nitrotyrosine Chlortyrosine  Apo A1  Paraoxonase, other factors Apo A1  Pro-inflammatory factors, other factors Anti-inflammatory Pro-inflammatory Reprinted from Ansell BJ, et al. J Am Coll Cardiol. 2005; J.R.G. JUANATEY 46:1792–1798, with permission from Elsevier Limited.C.H.U.Santiago
  17. 17. HDL y Enfermedad CV HDL y “Riesgo Residual” HDL y Riesgo CV. Los mecanismos HDL y Riesgo CV. Las implicaciones terapéuticas ¿Qué pasa con los fármacos y el HDL? J.R.G. JUANATEYC.H.U.Santiago
  18. 18. J.R.G. JUANATEYC.H.U.Santiago
  19. 19. HDL: proposed anti-atherogenic effects 1. HDL-mediated promotion of RCT (reverse cholesterol transport) VLDL/ CE LDL CETP TG A-I ABCG1 FC A-I LDL-R PLTP CE FC CE Mature LCAT Nascent SR-BI? FC ABCA1 HDL HDL Bile SR-BI Macrophage Liver HDL 2. Direct HDL-mediated endothelial- protective effects Endothelial NO Endothelial Production Repair Anti-oxidant Anti-inflammatory Anti-thrombotic Effects Effects Effects J.R.G. JUANATEY Besler C et al. & Landmesser U. Curr Pharmacol Des 2010, Mar 3. (Epub ahead of print)C.H.U.Santiago
  20. 20. Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Atherosclerosis Efflux capacity NEJM 2011; 364: 127 J.R.G. JUANATEYC.H.U.Santiago
  21. 21. Modula;on  of   Monocyte/Macrophage   Phenotype   Immuno-­‐ Myelopoesis   modulatory   Regula;on   An;-­‐thrombo;c   HDL  /  Apo  A-­‐I   Preserva;on  of   Pro-­‐fibrinoly;c   pancrea;c  Beta-­‐ Pleiotropic   cells   Improved   Biological   endothelial  health   and  func;on   An;-­‐oxidant   An;-­‐inflammatory   S;mulate  cholesterol   efflux  and  reverse   J.R.G. JUANATEY cholesterol  transport  C.H.U.Santiago
  22. 22. HDL y Enfermedad CV HDL y “Riesgo Residual” HDL y Riesgo CV. Los mecanismos HDL y Riesgo CV. Las implicaciones terapéuticas ¿Qué pasa con los fármacos y el HDL? J.R.G. JUANATEYC.H.U.Santiago
  23. 23. LDL-cholesterol / HDL-cholesterol LDL-cholesterol / HDL-cholesterol and LDL-Cholesterol/HDL-Cholsterol and risk of coronary disease! coronary disease and risk risk of of coronary disease 1% decrease in LDL-C 1% increase reduces CHD risk in HDL-C by reduces CHD risk 1% by 2-3% Statin Statin! Therapeutic Therapeutic Therapy Opportunity ? Opportunity?! Therapy! J.R.G. JUANATEYC.H.U.Santiago
  24. 24. Pharmacotherapeu,c  Targe,ng  of  HDL   Recombinant  HDL   Apo  A-­‐I  mime,c   CETP  inhibi,on     (rAPO  A-­‐1  milano)   pep,des  (D4F,  others)   drugs,  vaccine   Plasma  derived  HDL   Niacin   Vascular  Protec,ve  Effects  of  HDL   and  its  Apolipoproteins:     LUV       (PL) An  idea  whose  ,me  for  tes,ng  is  here   Small  molecule   EL  inhibi,on     (APO  A-­‐1  inducer)   RXR,  PPAR  and   An,sense  oligo   LXR  Agonists   SR-­‐B1   Fibrates,  glitazones,   HDL-­‐related     upregula,on   glitazars   (Apo  A-­‐1)     Gene  therapy   HDL-­‐associated   an,oxidants   Delipida,on   J.R.G. JUANATEY Paraoxonase,  PAF-­‐ACH   Rimonabant  C.H.U.Santiago
  25. 25. Ejercicio y partículas LDL/HDL STRRIDE Efecto del nivel de ejercicio e intensidad sobre LDL - HDL J.R.G. JUANATEYC.H.U.Santiago STRRIDE: Studies of Targeted Risk Reduction Interventions through Defined Exercise Kraus WE et al. NEJM 2002;347:1483
  26. 26. Hipolipemiantes: efectos ↑HDL-c (%) Estatina s 35 Niacina +30 Cambio desde basal(%) +20 15 20 Fibratos 15 10 +10 ↓LDL-c (%) 5 ↓TG (%) 0 -10 5 5 7 20 -20 18 25 20 20 30 -30 -40 50 50 J.R.G. JUANATEY -50 55C.H.U.Santiago
  27. 27. Endothelial-Vasoprotective Effects of High-Density Lipoprotein Are Impaired in Patients With Type 2 Diabetes Mellitus but Are Improved After Extended- Release Niacin Therapy Effect of ER niacin therapy or placebo on endothelial-protective properties of HDL in diabetic patients (A) P = 0.008 (C) P = 0.04 Endothelial NO Production NADPH Oxidase Activity (pmol O2.- / 250,000 cells/ min]) (% of buffer-treated cells) HDL HDL HDL HDL HDL HDL HDL HDL Diabetics Diabetics Diabetics Diabetics Diabetics Diabetics Diabetics Diabetics Baseline 3 Months Baseline 3 Months Baseline 3 Months Baseline 3 Months Placebo ER-Niacin Placebo ER-Niacin J.R.G. JUANATEY Sorrentino SA et al. Circulation. 2010;121:110-122C.H.U.Santiago
  28. 28. Niacin therapy improves endothelial function in type-2 diabetics with low HDL P < 0.0001 15 Endothelium-dependent Vasodilation 10 FDD [%] 5 0 Diabetics Diabetics Diabetics Diabetics Baseline 3 Months Baseline 3 Months Placebo ER-Niacin J.R.G. Sorrentino SA et al. & Landmesser U. Circulation 2010; 121:110-22 JUANATEYC.H.U.Santiago
  29. 29. AIM-HIGH (NEJM 2011) J.R.G. JUANATEYC.H.U.Santiago
  30. 30. Study Design High Risk Patients (MI, Peripheral/Cerebrovascular Disease, or Diabetes + Vascular Disease) Unblinded Active Run-In ERN/LRPT 1g/20mg for 4 wks then ERN/LRPT 2g/40mg for 4 wks (On top of Simva 40mg +/- ezetimibe) ERN/LRPT 2g/40mg Simva 40 mg (On top of Simva 40mg (+/- ezetimibe) +/- ezetimibe) n= ~25,000 2,300 events 4 Year Median Follow-up Composite of non-fatal MI or coronary death; fatal or non- fatal stroke; or any revascularization procedure (including coronary or non-coronary angioplasty or grafting)
  31. 31.  HDL-c: Inhibición de CETP CETP Torcetrapid Dalcetrapid Anacetrapid Evacetrapid
  32. 32. CETP inhibitors in PublishedStudies
  33. 33. Dalcetrapib: CETP modulator vs CETP inhibitorsCETP Form triple No cholesterolinhibitors complexes torcetrapib transfer CETP inhibitors bind CETP and HDL together possible into a triple complex Fixed triple complex CETP becomes prevents any anacetrapib ‘saturated’ with triple cholesterol transfer complexes and so, cholesterol transfer activity is fully inhibitCETPmodulator Beneficial shape Allows transfer change between HDL’s Dalcetrapib binds in the dalcetrapid dalcetrapib tunnel of CETP inducing a CETP is still able to fixed conformational transfer cholesterol change between HDL sub- types CETP shape change prevents interaction with Produces Functional large diameter lipoproteins HDL such as LDL and VLDL
  34. 34. On Target Differentiation: HDL Composition 20000 0 20000 0 2.5 Control 5 Dalcetrapib 2.5 5 10 15000 15000 10 20 20 RFI RFI 10000 10000 Pre β HDL Pre β HDL 5000 5000 0 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 Fractions Fractions 20000 20000 0 Torcetrapib (CETPi) 0 2.5 Anacetrapib 2.5 5 15000 (CETPi) 5 10 15000 10 20 20 RFI RFI 10000 10000 5000 5000 0 0 1 3 5 7 9 11 13 15 17 19 21Fractions 29 31 33 35 37 39 41 43 45 47 23 25 27 1 3 5 7 9 11 13 15 17 19 21Fractions 29 31 33 35 37 39 41 43 45 47 23 25 27 1Dernicket al. Poster presented at 6th IAS-Sponsored Workshop on HDL. May 17-20, 2010; Whistler, BC, Canada; 2Barter et al. N Engl J Med. 2007;357:2109–2122.
  35. 35. Lipid Changes Following Treatment with CETP Inhibitors Dalcetrapib Torcetrapib Anacetrapib Evacetrapib HDL-C ApoA1 LDL-C Apo-B TG Total Cholesterol J.R.G. JUANATEYC.H.U.Santiago
  36. 36. ILLUSTRATE No effect of torcetrapib on atheroma volume assessed by IVUS Percent atheroma volume change Change in blood pressure 50 100 45 P=0.78Percent Atheroma 40 80 Atorvastatin only Patients (%) 35 Volume (%) Torcetrapib plus 30 60 atorvastatin 25 40 20 15 20 10 5 0 0 ≤-20 -15 -10 -5 0 5 10 15 20 25 Atorvastatin onlyAtorvastatin + Torcetrapib ≥26 Change in systolic blood (mmHg) (n=446) (n=464)•  No improvement in atheroma burden in the torcetrapib + atorvastatin group despite a 59% increase in HDL-C1•  A significant blood pressure increase was observed with torcetrapib + atorvastatin vs atorvastatin alone (P<0.001)1 1Nissen et al. N Engl J Med 2007;356:1304–1316; 2Barter et al. N Engl J Med. 2007;357:2109–2122. J.R.G. JUANATEYC.H.U.Santiago
  37. 37. Torcetrapib’s Failure Due to Off-Target Effects, Not CETP Inhibition J.R.G. JUANATEYC.H.U.Santiago
  38. 38. Dal-VESSEL: Change in Blood Pressure Dalcetrapibb 600 mg J.R.G. JUANATEYC.H.U.Santiago
  39. 39. DEFINE: Changes in Blood Pressure Over 18 Months Anacetrapib Anacetrapib J.R.G. JUANATEYC.H.U.Santiago
  40. 40. J.R.G. JUANATEYC.H.U.Santiago
  41. 41.  HDL-c: Inhibición de CETP J.R.G. JUANATEYC.H.U.Santiago
  42. 42. •  30,000 patients with occlusive arterial disease in North America, Europe and Asia •  Background LDL-lowering with atorvastatin •  Randomized to anacetrapib 100 mg vs. placebo •  Scheduled follow-up: 4 years •  Primary outcome: Coronary death, myocardial infarction or coronary revascularization www.revealtrial.org J.R.G. JUANATEYC.H.U.Santiago
  43. 43. HDL y Enfermedad CV HDL y “Riesgo Residual” HDL y Riesgo CV. Los mecanismos HDL y Riesgo CV. Las implicaciones terapéuticas ¿Qué pasa con los fármacos y el HDL? J.R.G. JUANATEYC.H.U.Santiago
  44. 44. LDL-cholesterol / HDL-cholesterol LDL-cholesterol / HDL-cholesterol and LDL-Cholesterol/HDL-Cholsterol and risk of coronary disease! coronary disease and risk risk of of coronary disease 1% decrease in LDL-C 1% increase reduces CHD risk in HDL-C by reduces CHD risk 1% by 2-3% Statin Statin! Therapeutic Therapeutic Therapy Opportunity ? Opportunity?! Therapy! J.R.G. JUANATEYC.H.U.Santiago
  45. 45. Effect of HDL on endothelial cell nitric oxide production ? HDL from Healthy subject HDL from Patient with CAD 30 minutes J.R.G. JUANATEYC.H.U.Santiago
  46. 46. Vascular effects of HDL in patients with coronary disease P < 0.05 25 P < 0.05 n.s. (changes vs. PBS-treated cells, in %) 20 Nitric oxide production 15 10 5 0 -5 -10 -15 HDL HDL HDL -20 Healthy Stable CAD ACS 100000 100000 100000 50000 50000 50000 Arbitrary Units Arbitrary Units 0 0 0 AU -50000 -50000 -50000 -100000 -100000 -100000 -150000 -150000 -150000 3450 3455 3460 3465 3470 3475 3480 3485 3450 3455 3460 3465 3470 3475 3480 3485 3450 3455 3460 3465 3470 3475 3480 3485 Magnetic field (G) Magnetic field (G) Magnetic field (G) (ESR spectroscopy measurement) J.R.G. JUANATEYC.H.U.Santiago Besler  et  al  2011   Besler C et al., In revision
  47. 47. Endothelial-Vasoprotective Effects of High-Density Lipoprotein Are Impaired in Patients With Type 2 Diabetes Mellitus but Are Improved After Extended-Release Niacin Therapy (A), Effect of HDL (50 µ/mL, 60 minutes, 37°C) (A), Endothelium-dependent relaxations of aortic from healthy subjects (n=10) and diabetic rings of wild-type mice in response to increasing patients (n=33) on endothelial cell NO production concentrations of HDL isolated from healthy as determined by ESR spectroscopy analysis subjects (n=5) or diabetic patients (n=5) are shown (A) P < 0.0001 P < 0.0001 (B) Endothelial NO Production HDL from Endothelium-dependent Diabetic (% of buffer- treated cells) Patients (%; aortic rings) Relaxation P = 0.007 HDL from Healthy Subjects PBS HDL HDL Healthy Diabetics HDL (µg/ml) Sorrentino SA et al. Circulation. 2010;121:110-122 J.R.G. JUANATEYC.H.U.Santiago
  48. 48. Conversion of Anti-Inflammatory and Pro-Inflammatory HDL “quality vs quantity” Myeloperoxidase HDL=high-density lipoprotein Nitrotyrosine Chlortyrosine  Apo A1  Paraoxonase, other factors Apo A1  Pro-inflammatory factors, other factors Anti-inflammatory Pro-inflammatory J.R.G. Ansell BJ, et al. J Am Coll Cardiol. 2005; 46:1792–1798. JUANATEYC.H.U.Santiago
  49. 49. HDL y Enfermedad CV HDL y “Riesgo Residual” HDL y Riesgo CV. Los mecanismos HDL y Riesgo CV. Las implicaciones terapéuticas ¿Qué pasa con los fármacos y el HDL? J.R.G. JUANATEYC.H.U.Santiago
  50. 50. Lipid Abnormalities - Predictors - LDL-C at goal + LDL-C at goal + LDL-C at goal + LDL-C at goal Low HDL-C + Low HDL-C High TG High TG OR (95%-CI) OR (95%-CI) OR (95%-CI) OR (95%-CI)Age ≥70 years 1.22 (1.14-1.30) n.s. 0.86 (0.79-0.93) 0.77 (0.69-0.87)Female Gender 0.77 (0.73-0.83) 0.55 (0.50-0.60) 0.80 (0.74-0.87) 0.70 (0.62-0.79)Family Hx of premature CHD 0.92 (0.86-0.98) 1.09 (1.00-1.19) n.s. n.s.Current smoker 0.86 (0.79-0.94) 1.15 (1.03-1.28) n.s. 1.32 (1.15-1.51)Sedentary lifestyle 0.86 (0.81-0.91) n.s. n.s. n.s.Alcohol > 2 units/week 0.83 (0.78-0.88) 0.62 (0.57-0.68) n.s. 0.73 (0.65-0.82)BMI ≥30 kg/m² (obesity) 1.26 (1.18-1.34) 1.40 (1.27-1.53) 1.44 (1.32-1.57) 1.47 (1.31-1.66)Waist circumference n.s. 1.42 (1.28-1.56) 1.36 (1.24-1.49) 1.59 (1.40-1.82)Hypertension 1.25 (1.16-1.34) 1.28 (1.16-1.42) 1.32 (1.20-1.46) 1.37 (1.19-1.57)Diabetes mellitus 1.53 (1.43-1.63) 1.76 (1.62-1.91) 1.67 (1.54-1.80) 1.98 (1.77-2.20) 1.60 1.59 1.27 1.54Ischemic heart disease (1.50-1.71) (1.46-1.72) (1.17-1.38) (1.38-1.72)Cerebrovascular disease 1.18 (1.06-1.31) n.s. n.s. n.s.Heart failure 0.78 (0.70-0.87) n.s. n.s. n.s.Peripheral artery disease 0.85 (0.77-0.95) n.s. n.s. n.s.BP ≥140/90 mmHG 0.65 (0.61-0.70) 0.81 (0.74-0.88) 0.89 (0.82-0.96) 0.88 (0.79-0.98)20-40 vs 10 mg Simva equ. 1.75 (1.59-1.92) 1.71 (1.46-1.99) 1.73 (1.50-2.00) 1.77 (1.43-2.19)≥ 80 vs 10 mg Simva equ. 2.67 (2.36-3.02) 2.85 (2.39-3.39) 2.29 (1.93-2.71) 2.69 (2.12-3.41)Ezetimibe 1.21 (1.09-1.34) 1.13 (1.00-1.28) 1.26 (1.12-1.42) n.s.Specialist (Card/Endo/Dia/Int) 1.19 (1.12-1.27) 1.19 (1.09-1.29) n.s. n.s.
  51. 51. Dyslipidemia International Study - Lipid Parameters - All High risk Diabetes CVD ESC-score patient <5% (n=21,264) (n=17,036) (n=4,486) (n=10,108) (n=4,228)TC not at goal [%]* 52.8 50.5 49.6 45.2 62.2LDL-c not at goal [%]† 48.0 46.2 44.2 41.4 55.2LDL-c at goal (%) 52.0 53.8 55.8 58.6 44.8Low HDL-c(<40 men/45 women) [%]‡ 26.5 28.4 29.9 30.9 18.7Elevated TG(>150 mg/dL) [%]§ 37.8 38.7 43.0 37.9 34.1Defined as CVD and diabetes mellitus and/or ESC Score ≥5%; *Total cholesterol ≥190 mg/dL in patients with ESC-Score <5%, andtotal cholesterol ≥175 mg/dL in patients with ESC-Score ≥5%, diabetes and/or CVD; †LDL-cholesterol ≥115 mg/dL in patients withESC-Score <5%, and LDL-cholesterol ≥100 mg/dL in patients with ESC-Score ≥5%, diabetes and/or CVD, data on 21,550 patientswere available; † Data on 20,385 patients were available, ‡Data on 20,388 patients were available, §Data on 20,489 patients wereavailable
  52. 52. HDL: as a main determinant of ACS Biochemical determinants of ACS vs non-ischemic chest pain Variables OR IC 95% p Female 0,36 0,23 - 0,57 <0,01 Atrial fibrillation 0,27 0,14 - 0,52 <0,01 Age 1,05 1,03 - 1,06 <0,01 Active smoking 1,73 1,00 - 2,99 0,05 Diabetes 1,75 1,10 - 2,80 0,02 Glucose >100 mg/dl 1,89 1,22 - 2,94 <0,01 HDL < 40 mg/dl 2,99 1,95 - 4,59 <0,01 Cordero A, et al. Rev Esp Cardiol; 2012; 65: 319-325 J.R.G. JUANATEYC.H.U.Santiago
  53. 53. HDL: as a main determinant of ACS Biochemical determinants of ACS vs non-ischemic chest pain ACS Non- ischemic chest pain J.R.G. JUANATEY Cordero A, et al. Rev Esp Cardiol; 2012; 65: 319-325C.H.U.Santiago
  54. 54. Residual Risk in ACS “Residual Risk” in ACS. Role of HDL HDL and CV Risk. The mechanisms HDL and CV Risk. The therapeutic implications The Future J.R.G. JUANATEYC.H.U.Santiago
  55. 55. HDL: principal determinante del SCA Determinantes bioquímicos de SCA vs. DT no isquémico J.R.G. Cordero A, et al. Rev Esp Cardiol; 2012; 65: 319-325 JUANATEYC.H.U.Santiago
  56. 56. HDL promotes endothelial repair 1.  HDL  s;mulates  endothelial  cell  prolifera;on  in  culture   (physiologic  levels  of  LDL  are  toxic)  Tauber  1980,  1981   2.HDL  s;mulates  endothelial  cell  migra;on  independent   of  prolifera;on;  effects  addi;ve  to  bFGF  and  mediated   by  different  signaling  pathways  Murugesan  1994,  Shaul   1997   3.HDL  s;mulates  endothelial  cell  progenitor  cells  (EPC)   Seetharam  2006,  Sumi  2007   4.Intramiocardial  injec;on  of  EPC  improves  refractory   angina  Losordo  2011   J.R.G. JUANATEYC.H.U.Santiago
  57. 57. The HDL-C paradox Low  HDL-­‐C  without  increased  atherosclerosis  risk   Apo  A-­‐I  milano  carriers   SRB-­‐1  overexpressing  mice   High  HDL-­‐C  without  reduced  atherosclerosis  risk   Human  subjects  with  high  HDL-­‐C  and  CAD/AMI   Carriers  of  certain  CETP  muta,ons   SRB-­‐1  gene  dele,on  in  animals   LCAT  overexpression   Torcetrapib  in  humans   Niacin  ?   Does  the  HDL  func,onality  ma_er:  Quan,ty  vs  Quality?   J.R.G. JUANATEYC.H.U.Santiago
  58. 58. HDL Becomes Pro-inflammatory During Acute Phase Response Van Lenten et al JCI 1995 Normal  HDL   Acute  Phase  HDL   Apo  A-­‐I   Acute  illness   PON   SAA   Inhibits  ox-­‐LDL  induced  subendothelial   Promotes  ox-­‐LDL  induced   monocyte  recruitment  in-­‐vivo                                             subendothelial  monocyte  recruitment    (an,-­‐inflammatory)   in-­‐vivo                                              (Pro-­‐inflammatory)   A  high  propor,on  of  CAD  pa,ents  have  dysfunc,onal  HDL   J.R.G. JUANATEYC.H.U.Santiago Circula,on  2003  
  59. 59. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with CAD Besler C al JCI 2011 HDL  of  CAD  pa,ents  and  ACS  pa,ents  lacks   endothelial  repair  and  an,-­‐inflammatory  ac,vity   HDL  of  CAD  ac,vated  endothelial  lec,n-­‐like  oxidized  LDL  receptor  (LOX  1),   triggering  endotehlial  PKCBII  ac,va,on,  whicvh  in  turn  inhibited  eNOS-­‐ac,va,ng   pathways  and  eNOS-­‐dependent  NO  produc,on     Reduced  HDL-­‐associated  paraoxonase  1  (PON  1)  ac,vity  as  one  molecular   mechanism  leading  to  the  genera,on  of  HDL  with  endothelial  PKCBII-­‐ac,va,ng   proper,es,  at  least  in  part  due  to  increased  forma,on  of  malondialdehyde  in  HDL   J.R.G. JUANATEYC.H.U.Santiago
  60. 60. HDL dysfunction – the true dysfunction – ? HDL therapeutic target The true therapeutic target? • Anti-atherogenic functions of HDL ? • “HDL  dysfunction“  in  cardiovascular   disease • Impact of HDL-targeted therapies on HDL dysfunction J.R.G. JUANATEYC.H.U.Santiago
  61. 61. Changes of HDL proteome in coronary disease Apolipoprotein C-III OS=Homo sapiens GN=APOC3 Alpha-2-macroglobulin OS=Homo sapiens… Serum amyloid A-4 protein OS=Homo sapiens GN=SAA4 Apolipoprotein L1 OS=Homo sapiens… Reduced in Serum albumin OS=Homo sapiens GN=ALB Apolipoprotein A-IV OS=Homo sapiens GN=APOA4 Increased in Antithrombin-III OS=Homo sapiens… ACS patients ACS patients Vesicular integral-membrane protein VIP36 OS=Homo sapiens… Inter-alpha-trypsin inhibitor heavy chain H4 OS=Homo… Apolipoprotein(a) OS=Homo sapiens GN=LPA Hemoglobin subunit alpha OS=Homo sapiens… GTP-binding protein SAR1a OS=Homo sapiens GN=SAR1A DPI of Desmoplakin OS=Homo sapiens GN=DSP Alpha-2-antiplasmin OS=Homo sapiens GN=SERPINF2 Anthrax toxin receptor 2 OS=Homo sapiens GN=ANTXR2 Apolipoprotein A-II OS=Homo sapiens… Complement component 4B (Childo blood group) OS=Homo… Haptoglobin-related protein OS=Homo sapiens GN=HPR Cathelicidin antimicrobial peptide OS=Homo… Protein AMBP OS=Homo sapiens GN=AMBP HLA class I histocompatibility antigen, A-24 alpha chain … Apolipoprotein D OS=Homo sapiens GN=APOD Complement C3 OS=Homo sapiens GN=C3 Complement component C9 OS=Homo sapiens GN=C9 Prenylcysteine oxidase 1 OS=Homo sapiens… Apolipoprotein B-100 OS=Homo sapiens GN=APOB Anthrax toxin receptor 1 OS=Homo sapiens GN=ANTXR1 Serum paraoxonase/lactonase 3 OS=Homo… Beta-2-glycoprotein 1 OS=Homo sapiens GN=APOH Serum paraoxonase/arylesterase 1 OS=Homo… Apolipoprotein C-IV OS=Homo sapiens GN=APOC4 Cholesteryl ester transfer protein OS=Homo sapiens GN=CETP Angiotensinogen OS=Homo sapiens GN=AGT Alpha-1-antichymotrypsin OS=Homo sapiens GN=SERPINA3 Alpha-1-acid glycoprotein 2 OS=Homo sapiens GN=ORM2 Apolipoprotein F (APOF), mRNA OS=Homo… Alpha-2-HS-glycoprotein OS=Homo sapiens GN=AHSG Long palate, lung and nasal epithelium carcinoma-associated… Integrin alpha-2 OS=Homo sapiens GN=ITGA2 Vitronectin OS=Homo sapiens GN=VTN Adipocyte plasma membrane-associated protein OS=Homo… IGK@ protein OS=Homo sapiens GN=IGK@ Haptoglobin OS=Homo sapiens GN=HP Beta-1A of Integrin beta-1 OS=Homo sapiens… C4b-binding protein alpha chain OS=Homo sapiens GN=C4BPA Serum amyloid A protein OS=Homo sapiens GN=SAA1 Sonic hedgehog protein OS=Homo sapiens… Platelet-activating factor acetylhydrolase OS=Homo sapiens… Lipopolysaccharide-binding protein OS=Homo sapiens GN=LBP Aminopeptidase N OS=Homo sapiens… Serotransferrin OS=Homo sapiens GN=TF Heparin cofactor 2 OS=Homo sapiens GN=SERPIND1 Endosialin OS=Homo sapiens GN=CD248 Apolipoprotein A-V OS=Homo sapiens GN=APOA5 Pulmonary surfactant-associated protein B OS=Homo sapiens… Phosphatidylinositol-glycan-specific… 0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 0 0,1 0,2 0,3 0,4 0,5 0,6 J.R.G. Riwnato M, Besler C et al. (submitted) JUANATEYC.H.U.Santiago
  62. 62. HDL characterisation: Functionally relevant changes Mechanisms of altered function of HDL ? “Lipidomics“ “Proteomics” HDL- cargo R.Laaksonen/ Functional A.von Eckardstein genomis Analysis of changes in Analysis of changes in HDL-associated HDL-associated lipids proteins J.R.G. JUANATEYC.H.U.Santiago
  63. 63. Atherosclerosis development results from dysbalance of increased foam cell formation and impaired HDL-dependent cholesterol efflux from lipid-laden macrophages J.R.G. JUANATEY Heinecke J, New Engl J Med 2011C.H.U.Santiago
  64. 64. Cholesterol efflux capacity of ApoB- depleted serum and coronary disease Khera AV et al.; N Engl J Med. 2011; 364(2):127-35 J.R.G. JUANATEYC.H.U.Santiago
  65. 65. Vascular effects of HDL in coronary disease -Study setup Patients with acute coronary syndrome (n=25) Patients with stable coronary disease (n=25) Healthy control subjects (n=25) Isolation of HDL2/3 (by sequential ultracentrifugation) Endothelial Function Vascular effects Anti-thrombotic (Endothelial cell NO effects production and vasoreactivity) ESR spectroscopy Tissue factor Organ chamber Arterial thrombosis Anti-oxidant Anti-inflammatory effects effects Effects on Re- (Endothelial cell (Endothelial cell Endothelialization superoxide production) inflammatory activation) ESR spectroscopy Monocyte adhesion Carotid artery injury J.R.G. JUANATEYC.H.U.Santiago VCAM-1 expression model in nude mice
  66. 66. Effect of HDL on endothelial cell nitric oxide production ? HDL from Healthy subject HDL from Patient with CAD 30 minutes J.R.G. JUANATEYC.H.U.Santiago
  67. 67. Vascular effects of HDL in patients with coronary disease P < 0.05 25 P < 0.05 n.s. (changes vs. PBS-treated cells, in %) 20 Nitric oxide production 15 10 5 0 -5 -10 -15 HDL HDL HDL -20 Healthy Stable CAD ACS 100000 100000 100000 50000 50000 50000 Arbitrary Units Arbitrary Units 0 0 0 AU -50000 -50000 -50000 -100000 -100000 -100000 -150000 -150000 -150000 3450 3455 3460 3465 3470 3475 3480 3485 3450 3455 3460 3465 3470 3475 3480 3485 3450 3455 3460 3465 3470 3475 3480 3485 Magnetic field (G) Magnetic field (G) Magnetic field (G) (ESR spectroscopy measurement) J.R.G. JUANATEYC.H.U.Santiago Besler  et  al  2011   Besler C et al., In revision
  68. 68. Effects of HDL on vascular inflammation: monocyte adhesion on TNFα-stimulated endothelial cells 35 n.s. Number of GCSF-labeled monocytes P < 0.05 P < 0.05 P < 0.05 30 per high power field 25 20 15 10 5 0 TNFα + TNFα + TNFα + Baseline TNFα Healthy Stable CAD ACS HDL HDL HDL J.R.G. JUANATEYC.H.U.Santiago Besler  eC al  2011   revision Besler t   et al., In
  69. 69. Endothelial binding of HDL in patients with coronary disease P<0.01 125I-HDL P<0.01 120 100 [in % HDL Healthy] Specific binding of 80 60 40 20 0 HDL HDL HDL Healthy sCAD ACS J.R.G. JUANATEYC.H.U.Santiago Besler  Ct  al  2011   revision Besler e et al., In
  70. 70. Leducq Transatlantic Network: HDL dysfunction in the pathophysiology in cardiovascular disease and as a novel treatment target Stanley Hazen Alan Tall Cleveland Clinic Columbia Univ., New York Jan A. Kuivenhoven Molecular mechanisms Molecular mechanisms of Amsterdam Univ. of HDL dysfunction vascular effects of HDL Effects of HDL-genes on HDL functions John Deanfield Alan Fogelman UCL,London Bart Staels UCLA Clinical implications of Lille, InsermNovel approaches to stimulate HDL dysfunction Novel molecular targets stimu- HDL functions lating HDL functions Ulf Landmesser Zurich Univ. Altered endothelial effects of HDL in cardiovascular disease Thomas Lüscher Zurich Univ. Vascular effects of HDL and its alterations J.R.G. JUANATEY Network Project Managment: Michaela KeelC.H.U.Santiago
  71. 71. Residual Risk in ACS “Residual Risk” in ACS. Role of HDL HDL and CV Risk. The mechanisms HDL and CV Risk. The therapeutic implications The Future J.R.G. JUANATEYC.H.U.Santiago
  72. 72. Intense statin therapy improves outcome –but  still  a  substantial  “residual”  risk Treating to New Targets N = 10,001 0.15 Moderate Statin Therapie (n = 4995) 22% Risk reduction HR = 0.78 (0.69–0.89) 0.10 P < 0.001 Major CV events (%) 0.05 Atorvastatin 80 mg (n = 4995) The forgotten majority 0.00 0 1 2 3 4 5 6 Follow-up (years) CHD death, MI, resuscitation after cardiac arrest, fatal/nonfatal stroke LaRosa JC et al. N Engl J Med. 2005;352:1425-35 J.R.G. JUANATEYC.H.U.Santiago
  73. 73. Pharmacotherapeu,c  Targe,ng  of  HDL   Recombinant  HDL   Apo  A-­‐I  mime,c   CETP  inhibi,on     (rAPO  A-­‐1  milano)   pep,des  (D4F,  others)   drugs,  vaccine   Plasma  derived  HDL   Niacin   Vascular  Protec,ve  Effects  of  HDL   and  its  Apolipoproteins:     LUV       (PL) An  idea  whose  ,me  for  tes,ng  is  here   Small  molecule   EL  inhibi,on     (APO  A-­‐1  inducer)   RXR,  PPAR  and   An,sense  oligo   LXR  Agonists   SR-­‐B1   Fibrates,  glitazones,   HDL-­‐related     upregula,on   glitazars   (Apo  A-­‐1)     Gene  therapy   HDL-­‐associated   an,oxidants   Delipida,on   J.R.G. JUANATEY Paraoxonase,  PAF-­‐ACH   Rimonabant  C.H.U.Santiago
  74. 74. Seven  Weekly  Reinfusions  of  ex-­‐vivo  Delipidated   HDL  in  ACS  Pa,ents   Normalize  average   %  Change  in  Atheroma   Preβ-­‐HDL   Volume  (IVUS)   3  +  21   12  +  37   Undelipidated   Delipidated   Control   Ac,ve  Rx   Plasma   Plasma   (n=12)   (n=14)   J.R.G. JUANATEY Waksman  R  et  al  JACC  2010  C.H.U.Santiago
  75. 75. Effects of HDL from healthy subjects and type-2 diabetics with metabolic syndrome (low HDL) on endothelial NO-Production P < 0.0001 P < 0.0001 Endothelial NO Production 200 [% of buffer- treated cells] 150 100 50 0 PBS HDL HDL Healthy Diabetics J.R.G. Sorrentino SA et al. & Landmesser U. Circulation 2010; 121:110-22 JUANATEYC.H.U.Santiago
  76. 76. CETP Inhibition and Lipoprotein Metabolism J.R.G. JUANATEY Adapted  from  Brewer  22004 Adopted from Brewer 004  C.H.U.Santiago
  77. 77. Residual Risk in ACS “Residual Risk” in ACS. Role of HDL HDL and CV Risk. The mechanisms HDL and CV Risk. The therapeutic implications The Future J.R.G. JUANATEYC.H.U.Santiago
  78. 78. A  Poten,al  New  Therapeu,c  Paradigm  for  Atherosclerosis   Acute/Subacute  Therapy   Rapid  Plaque  Remodeling   Regression  Stabiliza,on   Rou,ne  Rx   Lipid  deple,on   Reduced  Plaque   Inflamma,on   IV  HDL/Apo  A-­‐I   mime,c  pep,des   Oral  HDL  based  Rx   Long  term  Therapy   ¿  HDL  gene  therapy?   Sustained  plaque  remodeling   regresion  stabiliza,on   J.R.G. JUANATEYC.H.U.Santiago
  79. 79. Residual Risk in ACS “Residual Risk” in ACS. Role of HDL HDL and CV Risk. The mechanisms HDL and CV Risk. The therapeutic implications The Future J.R.G. JUANATEYC.H.U.Santiago
  80. 80. J.R.G. JUANATEYC.H.U.Santiago
  81. 81. Hipolipemiantes: efectos ↑HDL-c (%) Estatinas 35 Niacina +30 Cambio desde basal(%) +20 15 20 Fibratos 15 10 +10 ↓LDL-c (%) 5 ↓TG (%) 0 -10 5 5 7 20 -20 18 25 20 20 30 -30 -40 50 50 J.R.G. JUANATEY -50 55C.H.U.Santiago
  82. 82. J.R.G. JUANATEYC.H.U.Santiago
  83. 83. J.R.G. JUANATEYC.H.U.Santiago
  84. 84. J.R.G. JUANATEYC.H.U.Santiago
  85. 85. Riesgo residual lipídico en ICP-Bypass 16,2% Solo 25%   LDL>100 mg/dl Buen   control   5,7% 15,8% 7,2% Solo 7,11% 14,0% Solo 8,8% TG>150 mg/dl HDL<40 mg/dl Riesgo  residual:  29,9%     J.R.G. JUANATEYC.H.U.Santiago G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
  86. 86. Actual contribution of each risk factor in improving the UKPDS CHD risk score for Steno-2 intensive treatment arm HbA1c 13% Total cholesterol 48% Lipids 73% SBP 11% HDL cholesterol 25% Smoking 3% J.R.G. JUANATEYC.H.U.Santiago
  87. 87. Riesgo residual lipídico en diabéticos Pacientes no diabéticos Pacientes no diabéticos J.R.G. JUANATEYC.H.U.Santiago
  88. 88. Riesgo residual lipídico en diabéticos J.R.G. JUANATEYC.H.U.Santiago
  89. 89. Riesgo residual lipídico en diabéticos 47,0 (17,5) mg/dl 43,9 (14,8) mg/dl p<0,01 J.R.G. JUANATEYC.H.U.Santiago
  90. 90. HDL  Biology:  What  is  New   Lipid  Transport   Individuals  with  similar  HDL-­‐ C  levels  but  higher  total   macrophage  efflux  capacity   had  significantly  higher   ABCA1-­‐mediated  efflux   Higher  ABCA1-­‐mediated   efflux  was  directly   correlated  with  the  level  of   pre-­‐b-­‐1  HDL  in  serum   J.R.G. JUANATEYC.H.U.Santiago
  91. 91. HDL: proposed anti-atherogenic effects 1. HDL-mediated promotion of RCT (reverse cholesterol transport) VLDL/ CE LDL CETP TG A-I ABCG1 FC A-I LDL-R PLTP CE FC CE Mature LCAT Nascent SR-BI ? FC ABCA1 HDL HDL Bile SR-BI Macrophage HDL J.R.G. JUANATEYC.H.U.Santiago Besler C et al. & Landmesser U. Curr Pharmacol Des 2010, 16: 1480-93
  92. 92. Increased atherosclerosis in ABCA-1 /ABCG1 bone-marrow-deficient mice No significant differences in HDL plasma levels J.R.G. JUANATEYC.H.U.Santiago Yvan-Charvet L et al.; J Clin Invest. 2007;117(12):3900-8
  93. 93. Endothelial NO production – Anti-atherogenic effects Monocyt Platelets Inhibition of Leukocyte Inhibition of Thrombocyte adhesion und -infiltration adhesion and -aggregation Endothel NO Inhibition of VSMC proliferation Vascular smooth muscle cell Landmesser et al.; Circulation 2004 J.R.G. JUANATEYC.H.U.Santiago Landmesser et al., Curr Opinion Cardiol 2005; 20:547-51

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