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¿Sirve para algo elevar el HDL?

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Bloque: NUEVAS ESTRATEGIAS EN EL TRATAMIENTO DE LA CARDIOPATÍA ISQUÉMICA CRÓNICA. ...

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? ¿Sirve para algo elevar el HDL? Presentation Transcript

    • J.R.G. JUANATEYC.H.U.Santiago
    • ¿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
    • 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
    • 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
    • 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.
    • 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
    • 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
    • CV Risk beyond LDL Etc.. TG Diabetes Physical inact Diet Obesity HT HDL Tobacco Residual Risk J.R.G. JUANATEYC.H.U.Santiago
    • CV Risk beyond LDL Etc.. TG Diabetes Physical inact Diet Obesity HT HDL Tobacco Residual Risk J.R.G. JUANATEYC.H.U.Santiago
    • 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
    • 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
    • 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
    • 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
    • HDL y Aterosclerosis Transporte reverso de colesterol J.R.G. JUANATEYC.H.U.Santiago NEJM 2004;350:1491-94
    • 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
    • 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
    • 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
    • J.R.G. JUANATEYC.H.U.Santiago
    • 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
    • Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Atherosclerosis Efflux capacity NEJM 2011; 364: 127 J.R.G. JUANATEYC.H.U.Santiago
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • AIM-HIGH (NEJM 2011) J.R.G. JUANATEYC.H.U.Santiago
    • 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)
    •  HDL-c: Inhibición de CETP CETP Torcetrapid Dalcetrapid Anacetrapid Evacetrapid
    • CETP inhibitors in PublishedStudies
    • 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
    • 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.
    • 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
    • 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
    • Torcetrapib’s Failure Due to Off-Target Effects, Not CETP Inhibition J.R.G. JUANATEYC.H.U.Santiago
    • Dal-VESSEL: Change in Blood Pressure Dalcetrapibb 600 mg J.R.G. JUANATEYC.H.U.Santiago
    • DEFINE: Changes in Blood Pressure Over 18 Months Anacetrapib Anacetrapib J.R.G. JUANATEYC.H.U.Santiago
    • J.R.G. JUANATEYC.H.U.Santiago
    •  HDL-c: Inhibición de CETP J.R.G. JUANATEYC.H.U.Santiago
    • •  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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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.
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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  
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • CETP Inhibition and Lipoprotein Metabolism J.R.G. JUANATEY Adapted  from  Brewer  22004 Adopted from Brewer 004  C.H.U.Santiago
    • 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
    • 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
    • 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
    • J.R.G. JUANATEYC.H.U.Santiago
    • 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
    • J.R.G. JUANATEYC.H.U.Santiago
    • J.R.G. JUANATEYC.H.U.Santiago
    • J.R.G. JUANATEYC.H.U.Santiago
    • 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
    • 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
    • Riesgo residual lipídico en diabéticos Pacientes no diabéticos Pacientes no diabéticos J.R.G. JUANATEYC.H.U.Santiago
    • Riesgo residual lipídico en diabéticos J.R.G. JUANATEYC.H.U.Santiago
    • 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
    • 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
    • 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
    • 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
    • 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
    • HDL –effects on endothelial cell nitric oxide production in patients with CAD Healthy P<0.025 sCAD 30 ACS  Endothelial nitric oxide [in % of buffer-treated cells] 20 production 10 0 -10 -20 25  g/ml 50  g/ml 100  g/ml HDL HDL HDL J.R.G. JUANATEYC.H.U.Santiago Besler C et al. J Clin Invest (accept minor)
    • Effects of HDL on endothelial repair after arterial injury P < 0.05 P < 0.0001 Re-endothelialized area [in %] 30 25 20 15 10 5 0 PBS HDL HDL HDL Healthy Stable CADACS Quantification of re-endothelialized area 3 days after induction of carotid injury by Evan`s blue staining J.R.G. JUANATEYC.H.U.Santiago Besler C et al. J Clin Invest (accept minor)
    • HDL function (vascular effects) Which changes of HDL are mediating differences  in  HDL‘s   vascular effects ? J.R.G. JUANATEYC.H.U.Santiago
    • Correlation between apoB-deficient serum cholesterol efflux and HDL cholesterol Khera AV et al.; N Engl J Med. 2011; 364(2):127-35 J.R.G. JUANATEYC.H.U.Santiago
    • Summary 1. HDL from healthy subjects exerts several important anti-atherogenic effects beyond „reverse  cholesterol  transport“,  i.e.  stimulation   of endothelial NO production, anti- inflammatory and anti-thrombotic effects. 2. In patients with coronary disease or diabetes with  low  HDL,  HDL  becomes  „dysfunctional“,  i.e.   loses anti-atherogenic properties. 3. HDL-targeted treatment strategies should therefore be examined for their effect on vasoproetctive properties of HDL. ER-niacin therapy improves endothelial- protective effects of HDL in patients with diabetes and low HDL. J.R.G. JUANATEYC.H.U.Santiago
    • HDL function HDL function (vascular effects) (vascular effects) - The true therapeutic target ? J.R.G. JUANATEYC.H.U.Santiago
    • 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
    • Riesgo residual lipídico en pacientes con antecedentes de revascularización coronaria: Estudio ICP-Bypass Alberto  Cordero   Servicio  de  Cardiología   Hospital  Universitario  San  Juan   J.R.G. JUANATEYC.H.U.Santiago
    • Departamento de Cardiología Clínica Universitaria de Navarra J.R.G. JUANATEYC.H.U.Santiago
    • LDL-c y cardiopatía isquémica 30 Rx - Tratamiento con estatinas PRA - Pravastatina 4S - Placebo ATV - Atorvastatina Prevención secundaria 25 4S - Rx Tasa de episodios (%) 20 LIPID - Placebo 15 LIPID - Rx CARE - Placebo CARE - Rx CORONA - Placebo CORONA - Rx HPS - Rx HPS - Placebo 10 TNT – ATV10 WOSCOPS – Placebo TNT – ATV80 PROVE-IT - PRA Prevención primaria PROVE- AFCAPS - Placebo AFCAPS - Rx 6 WOSCOPS - Rx 5 IT – ATV ASCOT - Placebo ASCOT - Rx 0 40 60 80 100 120 140 160 180 200 Colesterol LDL alcanzado, (1,0) (1,6) (2,1) (2,6) (3,1) (3,6) (4,1) (4,7) (5,2) en mg/dl (mmol/l) J.R.G. Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-79 JUANATEYC.H.U.Santiago LaRosa JC, et al. N Engl J Med 2005;352:1425-35
    • LDL-c, HDL-c y cardiopatía isquémica 3.0 Riesgo relativo para IAM 2,9 2.5 2.0 1,9 1,2 1.5 1,5 0,6 0,9 1.0 0.5 0,4 0,7 23 mg/dl 0,3 46 mg/dl 0,1 0,2 0,3 66 mg/dl 0 c-HDL 100 mg/dl 160 mg/dl 220 mg/dl 85 mg/dl c-LDL J.R.G. JUANATEYC.H.U.Santiago Kannel W, et al. Am J Cardiol 1987;59:80
    • LDL-c, HDL-c y cardiopatía isquémica 21% pacientes presentan progresión de placas a pesar de LDL-c <70 mg/dl J.R.G. JUANATEYC.H.U.Santiago Bayturan O, et al. JACC 2010;55:2736-42
    • LDL-c, HDL-c y cardiopatía isquémica J.R.G. JUANATEYC.H.U.Santiago Barter P, et al. NEJM 2007;357:1301-10
    • Guías de dislipemia ESC 2011 J.R.G. JUANATEYC.H.U.Santiago Reiner, et al. E Heart J 2011;32:1769-1818
    • LDL-c, HDL-c y cardiopatía isquémica J.R.G. JUANATEYC.H.U.Santiago Hsia J, et al. J Am Coll Cardiol 2011;57:1666-75
    • LDL-c, HDL-c y cardiopatía isquémica Evolución en el perfil clínico de los pacientes con SCA J.R.G. JUANATEYC.H.U.Santiago Arós F, et al. Rev Esp Cardiol 2011;64:972-80
    • LDL-c, HDL-c y cardiopatía isquémica J.R.G. JUANATEYC.H.U.Santiago Stone G, et al. NEJM 2011;364:226-35
    • Riesgo residual 22% Reducción relativa de riesgo RIESGO RESIDUAL J.R.G. JUANATEYC.H.U.Santiago Fruchart JC, et al. Am J Cardiol 2008;102:1K-34K
    • Introducción J.R.G. JUANATEYC.H.U.Santiago González-Juanatey J.R, et al. Rev Esp Cardiol 2011; 2011;64:286-294
    • Dislipemia de la resistencia insulínica Lipolisis Dieta Obesidad de TG Genética AGLibres ADIPOCITOS VLDL Quilomicrones Insulina Glucosa Neoglucogénesis LPL + ↑TG CETP + ↓HDL Músculo liso VLDL LDL fenotipo B J.R.G. JUANATEYC.H.U.Santiago Cordero A, et al. Med Clin 2006;127:705-08
    • Dislipemia de la resistencia insulínica Tamaño de las partículas LDL colesterol Frecuencia (%) Frecuencia (%) Fenotipo B Fenotipo B Fenotipo A Fenotipo A Varones TG/HDL Mujeres TG/HDL J.R.G. JUANATEYC.H.U.Santiago Hanak V, et al. Am J Cardiol 2004;94:219-22
    • Dislipemia de la resistencia insulínica Partículas LDL pequeñas y densas = permeables y aterogénicas J.R.G. JUANATEYC.H.U.Santiago Libby P, Nature 2002;420:868-874
    • Dislipemia de la resistencia insulínica Distribución del TG/HDL y presencia de Sd. Metabólico J.R.G. JUANATEYC.H.U.Santiago Cordero A, et al. Am J Cardiol 2008;102:424-28
    • Dislipemia de la resistencia insulínica Distribución del TG/HDL en la población J.R.G. JUANATEYC.H.U.Santiago Cordero A, et al. Am J Cardiol 2008;102:424-28
    • Dislipemia de la resistencia insulínica Valor predictivo de IAM de TG/HDL ESC YIA 2009 J.R.G. JUANATEY Cordero A, et al. J Am Cardiol 2009; 104:1393-1397C.H.U.Santiago
    • Aterosclerosis: desequilibrio LDL y HDL J.R.G. JUANATEYC.H.U.Santiago Badimon JJ, et al Rev Esp Cardiol 2010;63:323-33
    • Riesgo residual lipídico (RRL) definido como: LDL <100 mg/dl • y HDL <40 mg/dl • y/o TG >150 mg/dl J.R.G. JUANATEYC.H.U.Santiago G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
    • 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
    • Riesgo residual lipídico en ICP-Bypass   Total   No RRL   RRL   p   N (%)   2292   1.606 (70,1%)   686 (29,9%)     Edad   65,5 ±12,4   66,1 ±12,2   64,1 ±12,7   <0,01   Varones (%)   78,2%   76,5%   82,0%   <0,01   Años evolución   3,3 ±4,2   3,4 ±4,3   3,0 ±3,9   0,03   ICP (%)   76,6%   74,6%   81,2%   <0,01   PA sistólica   132,3 ±18,6   133,1 ±18,5   130,3 ±18,6   0,01   PA diastólica   75,9 ±10,9   76,2 (10,9   75,1 ±10,9   0,02   IMC (kg/m2)   28,5 ±4,1   28,4 ±4,1   28,5 ±4,0   0,54   J.R.G. JUANATEYC.H.U.Santiago G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
    • Riesgo residual lipídico en ICP-Bypass   Total   No RRL   RRL   p   Sobrepeso (%)   49,3%   50,4%   46,8%   0,12   Obesidad (%)   29,1%   28,3%   30,9%   0,21   Obesidad abdominal   44,3%   43,9%   45,0%   0,66   Dislipemia (%)   71,7%   72,7%   69,3%   0,16   Diabetes (%)   33,2%   31,6%   37,0%   0,01   Hipertensión (%)   60,8%   61,1%   60,1%   0,65   Fumadores (%)   48,8%   47,5%   51,8%   0,06   Sedentarismo   42,4%   43,0%   41,1%   0,41   Consumo alcohol   28,6%   29,1%   27,4%   0,42   FG <60   22,8%   22,8%   22,6%   0,41   Otra ECV (%)   6,2%   5,7%   7,5%   0,12   J.R.G. JUANATEYC.H.U.Santiago G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
    • Riesgo residual lipídico en ICP-Bypass   Total   No RRL   RRL   p   Colesterol total (mg/dl)   169,4 ±40,2 181,2 ±39,6 144,3 ±27,9 <0,01 LDL (mg/dl)   95,6 ±33,5 106,7 ±34,2 73,8 ±17,5 <0,01 HDL (mg/dl)   46,0 ±16,7 49,5 ±15,0 39,0 ±17,9 0,14 122,0 112,0 151,0 Triglicéridos (mg/dl)   <0,01 (93,0-167,0) (88,0-149,8) (106,2-188,8) J.R.G. JUANATEYC.H.U.Santiago G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
    • Riesgo residual lipídico en ICP-Bypass   Total   No RRL   RRL   p   Glucemia (mg/dl)   123,8 ±3,9 122,5 ±44,2 126,5 ±43,2 0,12 HbA1c (%) en diabéticos   7,5 ±6,2 7,6 ±7,0 7,4 ±4,5 0,73 Creatinina (mg/dl)   1,1 ±0,5 1,0 ±0,4 1,2 ±0,7 0,04 F. glomerular (ml/min/1,72 m2)   76,9 ±27,4 77,0 ±28,7 76,7 ±24,4 0,80 ALT (UI/L)   31,0 ±22,1 30,6 ±19,1 31,7 ±27,7 0,33 AST (UI/L)   29,4 ±20,3 30,0 ±22,0 28,1 ±15,8 0,07 GGT (UI/L)   48,7 ±54,8 49,1 ±53,4 47,8 ±57,9 0,66 CK (mg(dl)   103,7 ±76,3 103,7 ±69,7 103,8 ±89,1 0,97 J.R.G. JUANATEYC.H.U.Santiago G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
    • Resultados: Control de FR p<0,01 p<0,01 p=0,07 p<0,01 en diabéticos p=0,68 J.R.G. JUANATEYC.H.U.Santiago G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
    • Resultados: hipolipemiantes   Total   No RRL   RRL   p   Atorvastatina   57,8%   56,1%   61,7%   0,01   dosis (mg/dl)   40,0 ±21,8   39,5 ±22,0   41,2 ±21,4   0,18   Sinvastatina   22,7%   23,0%   22,0%   0,61   dosis (mg/dl)   27,4 ±11,9   27,4 ±12,3   27,3 ±11,1   0,88   Pravastatina   6,2%   6,4%   6,0%   0,73   dosis (mg/dl)   28,9 ±10,7   28,7 ±10,6   29,5 ±11,2   0,70   Lovastatina   0,4%   0,4%   0,6%   0,49   dosis (mg/dl)   30,0 ±19,4   33,3 ±24,2   25,0 ±10,0   0,54   Fluvastatina   6,4%   6,9%   5,1%   0,10   dosis (mg/dl)   75,5 ±14,5   74,9 ±15,7   77,7 ±9,6   0,33   Ezetimibe   18,3%   19,7%   15,0%   <0,01   Fibratos   3,7%   3,2%   4,8%   0,06   J.R.G. JUANATEYC.H.U.Santiago G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
    • Factores asociados a la presencia de RRL Variables   HDL <40 mg/dl   TG>150 mg/dl   RRL   0,98 (0,98-0,99); p<0,01   0,98 (0,98-,99); p<0,01   0,99 (0,98-0,99); p=0,02   Edad   1,81 (1,39-2,34); p<0,01   1,14 (0,89-1,46); p=0,30   1,52(1,16-1,98); p<0,01   Sexo masculino   1,57 (1,14-2,15); p<0,01   1,39 (1,01-1,92); p=0,04   1,18 (0,85-1,63); p=0,33   Tabaquismo   1,32 (1,07-1,63); p<0,01   1,46 (1,19-1,80); p<0,01   1,35 (1,09-1,68); p<0,01   Diabetes   1,11 (0,87-1,41); p=0,40   1,22 (0,96-1,54); p=0,10   1,09 (0,85-1,40); p=0,48   IMC > 30kg/m2   1,07 (0,85-1,34); p=0,59   1,33 (1,06-1,68); p=0,01   1,07 (0,84-1,36); p=0,61   Obesidad abdominal   1,14 (0,93-1,40); p=0,22   1,06 (0,87-1,31); p=0,55   0,91 (0,73-1,13); p=0,38   Sedentarismo   1,18 (0,93-1,49); p=0,18   1,26 (1,00-1,60); p=0,05   1,40 (1,09-1,80); p<0,01   ICP   0,99 (0,97-1,02); p=0,44   1,02 (0,99-1,04); p=0,19   0,97 (0,94-0,99); p<0,01   Ezetimibe   1,25 (1,13-1,38); p<0,01   1,39 (1,24-1,57); p<0,01   1,04 (0,94-1,15); p=0,43   Fibratos   J.R.G. JUANATEYC.H.U.Santiago G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
    • Control de LDL-c y disfunción renal 4D=Die Deutsche Diabetes Dialyse Studie 40 Estudio AURORA Incidencia acumulada 60 35 Placebo Placebo Incidencia acumulada de end- 30 50 25 points primarios (%) 40 20 Atorvastatina Rosuvastatina 10 mgs 30 15 10 20 5 HR=0.96 (95% CI 0.84–1.11) 10 p=0.59 0 0 0 1 2 3 4 5 6 0 1 2 3 4 5 Años desde randomización Años desde randomización 25   SHARP trial Porcentaje  de  eventos  (%)     Ra;o  de  riesgo  0.83  (0.74  –  0.94)   20   Logrank  2P=0.0022   Placebo   15   Eze/simv   10   5   0   0   1   2   3   4   5   J.R.G. Años  de  seguimiento   JUANATEYC.H.U.Santiago
    • Control de LDL-c y disfunción renal   Total   GFR >60   GFR <60   p   N (%)   2,037   1573 (77.2%)   464 (22.8%)     Age   66.0 (11.0)   63.9 (10.8)   73.1 (8.3)   <0.01   Males   77.8%   83.3%   59.2%   <0.01   Systolic BP (mmHg)   132.4 (18.3)   131.9 (18.0)   134.1 (19.1)   0.03   Diastolic BP (mmHg)   75.8 (10.8)   75.9 (10.5)   75.6 (11.7)   0.55   Diabetes   33.9%   30.2%   46.6%   <0.01   Hypertension   33.9%   30.2%   46.6%   <0.01   Dyslipidemia   72.5%   71.5%   76.4%   0.08   Current smokers   10.5%   11.8%   5.8%   <0.01   Obesity   30.2%   29.7%   31.9%   0.36   Abdominal obesity   44.4%   42.0%   53.0%   <0.01   Sedentary lifestyle   42.4%   37.5%   59.1%   <0.01   Alcohol consumption   29.2%   32.0%   19.8%   <0.01   J.R.G. JUANATEYC.H.U.Santiago Cordero A, et al. submitted
    • Control de LDL-c y disfunción renal   Total   GFR >60   GFR <60   p   Creatinine (mg/dl)   1.08 (0.52)   0.94 (0.17)   1.57 (0.88)   <0.01   GFR (ml/min/1.71m2)   76.9 (27.4)   85.9 (24.2)   46.4 (10.8)   <0.01   Total cholesterol (mg/dl)   169.2 (40.3)   169.5 (40.3)   168.2 (40.6)   0.53   LDL (mg/dl)   95.4 (33.6)   96.1 (33.8)   93.2 (32.7)   0.13   HDL (mg/dl)   46.0 (16.9)   45.9 (16.7)   46.4 (17.6)   0.64   121.0   120.0   124.0   0.19   Triglycerides (mg/dl)   (93.0-167.0)   (93.0-165.0)   (94.0-174.0)   Glycemia (mg/dl)   123.2 (43.3)   121.2 (42.7)   129.0 (44.4)   <0.01   HbA1c (%)*   7.1 (1.3)   7.1 (1.3)   7.1 (1.4)   0.98   GGT (IU/L)   49.0 (55.4)   48.2 (55.5)   51.9 (55.1)   0.29   ALT (IU/L)   31.0 (22.3)   31.4 (23.4)   29.5 (178.0)   0.15   AST (IU/L)   29.3 (20.5)   29.6 (21.6)   28.6 (16.2)   0.41   J.R.G. JUANATEYC.H.U.Santiago Cordero A, et al. submitted
    • Control de LDL-c y disfunción renal   Total   GFR >60   GFR <60   p   Any statin   94.2%   94.9%   91.8%   0.01   Atorvastatin   58.8%   59.8%   55.2%   0.07   Simvastatin   21.7%   21.2%   23.3%   0.35   Pravastatin   6.0%   6.0%   6.0%   0.99   Lovastatin   0.4%   0.3%   0.5%   0.83   Fluvastatin   6.7%   6.8%   6.3%   0.67   Fibrates   3.9%   3.4%   5.8%   0.02   Ezetimibe   18.9%   19.4%   17.2%   0.30   Statins+ezetimibe   17.5%   18.1%   15.3%   0.16   J.R.G. JUANATEYC.H.U.Santiago Cordero A, et al. submitted
    • Control de LDL-c y disfunción renal LDL <100 mg/dl LDL <70 mg/dl p=0.20 p=0.99 p=0.19 p=0.02 p=0.25 p=0.52 p=0.37 p=0.05 J.R.G. JUANATEYC.H.U.Santiago Cordero A, et al. submitted
    • Control de LDL-c y disfunción renal Interacción de FG <60 ml/min/1,72m2 y Tto estatina+ezetimiba para la presencia de LDL-c <100 mg/dl p=0.02 J.R.G. JUANATEYC.H.U.Santiago Cordero A, et al. submitted
    • Control de LDL-c y disfunción renal Factores asociados independientemente a LDL-c <100 mg/dl   Total   GFR>60 ml/min/1.72m2   GFR<60 ml/min/1.72m2   1.26 (0.97-1.63); Diabetes   1.27 (0.95-1.71); p=0.11   1.19 (0.69-2.04); p=0.53   p=0.08   0.58 (0.44-0.78); Dislipemia   0.61 (0.44-0.84); p<0.01   0.46 (0.24-0.88); p=0.02   p<0.01   0.93 (0.69-1.26); Estatina+Ezetimibe   0.75 (0.54-1.06); p=0.10   2.44 (1.18-5.10); p=0.02   p=0.66   0.80 (0.62-1.02); Sedentarismo   0.76 (0.55-0.99); p=0.04   1.01 (0.58-1.77); p=0.97   p=0.07   J.R.G. JUANATEYC.H.U.Santiago Cordero A, et al. submitted
    • Control de LDL-c e inercia terapéutica J.R.G. JUANATEYC.H.U.Santiago Lazaro A, et al. Rev Esp Cardiol 2010;63:1428-37
    • Control de LDL-c e inercia terapéutica J.R.G. JUANATEYC.H.U.Santiago Lazaro A, et al. Rev Esp Cardiol 2010;63:1428-37
    • Dislipemia en la disfunción renal J.R.G. JUANATEYC.H.U.Santiago Ghandehari H, et al. Am Heart J 2008;156:112-9
    • Disfunción renal y Enf. cardiovascular EDAD FACTORES RIESGO CARDIOPATÍA DISFUNCIÓN ISQUEMICA RENAL Hipertrofia VI Homocisteína Proteína-C Anemia Microalbuminuria reactiva J.R.G. JUANATEYC.H.U.Santiago Martín A Cordero A, et al. Med Clin 2007;128:705-10
    • Dislipemia en la disfunción renal J.R.G. JUANATEYC.H.U.Santiago Keane WF, et al. Contrib Nephrol. 2011;171:135-42
    • Dislipemia en la disfunción renal Receptor periférico Receptor hepático J.R.G. JUANATEYC.H.U.Santiago Keane WF, et al. Contrib Nephrol. 2011;171:135-42
    • Dislipemia en la disfunción renal DISFUNCIÓN RENAL •   captación hepática de quilomicrones •   actividad LPL hepática •   actividad LPL tisular •   actividad LPL hepática •   expresión del receptor hepático de LDL •   absorción intestinal de colesterol J.R.G. JUANATEYC.H.U.Santiago Keane WF, et al. Contrib Nephrol. 2011;171:135-42
    • Dislipemia en la disfunción renal Filtrado Glomerular LDL-c Diálisis HDL-c Triglicéridos LDL pequeñas y densas J.R.G. JUANATEYC.H.U.Santiago Keane WF, et al. Contrib Nephrol. 2011;171:135-42
    • Conclusiones 1. El 30% de los pacientes con C. Isquémica tienen un Riesgo Residual lipídico y son, fundamentalmente varones con diabetes. 2. Además, el 25 % de los pacientes con C. Isquémica tienen disfunción renal, especialmente los enfermos con más factores de riesgo y enf. Cardiovascular. 3. Existe una interacción entre la disfunción renal y la asociación del tratamiento de estatina+ezetimibe y la presencia de LDL-c <100 mg/dl. J.R.G. JUANATEYC.H.U.Santiago
    • Riesgo residual lipídico en pacientes con antecedentes de revascularización coronaria: Estudio ICP-Bypass Alberto  Cordero   Servicio  de  Cardiología   Hospital  Universitario  San  Juan   J.R.G. JUANATEYC.H.U.Santiago