Lipid managment HDL-Cholesterol an enigma?

Transcription

1 Lipid managment HDL-Cholesterol an enigma? Ulf Landmesser, MD Chairman, Department of Cardiology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin

2 HDL and coronary disease an enigma? Statin therapy HDL?

3 HDL-cholesterol and coronary disease an enigma? 1. HDL-cholesterol the hypothesis 2. HDL-cholesterol in cardiovascular disease - Clinical trials - HDL function - HDL-C and genetic studies 3. Implications for therapeutic strategies

4 HDL-cholesterol and risk of coronary disease PROCAM Study: HDL-C is An Independent Predictor of CHD Risk Emerging Risk Factors Collaborations: Incidence of CHD Assmann G, Schulte H. Lipid Metabolism Disorders and Coronary Heart Disease. 2nd ed. Munich: Medizin, 1993 Di Angelantonio E et al.; JAMA 2009

5 HDL: proposed anti-atherogenic effects Bile VLDL/ LDL LDL-R FC 1. HDL-mediated promotion of macrophage cholesterol efflux CE TG CE SR-BI PLTP CETP A-I FC CE Mature HDL LCAT HDL A-I FC Nascent HDL ABCG1 ABCA1 SR-BI? Macrophage Besler C, Lüscher T, Landmesser U. EMBO Mol Medicine 2012; 4:

6 HDL: proposed anti-atherogenic effects Bile VLDL/ LDL LDL-R FC CE TG CE SR-BI Endothelial antiapoptotic effects Endothelial NO production 1. HDL-mediated promotion of macrophage cholesterol efflux PLTP CETP A-I FC CE Mature HDL LCAT HDL A-I FC Nascent HDL 2. HDL-mediated endothelial athero-protective effects Anti-inflammatory effects ABCG1 ABCA1 SR-BI? Macrophage Promotion of endothelial repair Anti-thrombotic effects Besler C, Lüscher T, Landmesser U. EMBO Mol Medicine 2012; 4:

7 Mechanisms of effects of HDL on endothelial cell nitric oxide (NO) production ABCG1 S1P3 AMPK Oxysterols Cave olin Yuhanna IS et al.; Nat Med 2001 Mineo e al.; J Biol Chem Nofer et al.; J. Clin. Invest Terasaka N et al.; J. Clin. Invest Terasaka N et al.; Arterioscler Thromb Vasc Biol Li D et al. Arterioscler Thromb Vasc Biol. 2010

8 HDL-cholesterol and coronary disease an enigma? 1. HDL-cholesterol the hypothesis 2. HDL-cholesterol in cardiovascular disease - Clinical trials - HDL function - HDL-C and genetic studies 3. Implications for therapeutic strategies

9 CETP-Inhibition with Torcetrapib: marked lipid changes Barter et al., N Engl J Med 2007; 357:

10 CETP-Inhibition with Torcetrapib: increase of major cardiovascular events in patients at high risk of coronary events Barter et al., N Engl J Med 2007; 357:

11 Proportional reduction in event rate (SE) LDL-C reduction and cardiovascular events 50% 40% 30% 20% 10% 0% 0,5 IMPROVE-IT % Reduction in LDL cholesterol (mmol/l) -20% ILLUMINATE 10

12 Incidence of the Primary Efficacy End Point. N Engl J Med 2012

13

14 HDL-cholesterol and coronary disease an enigma? 1. HDL-cholesterol the hypothesis 2. HDL-cholesterol in cardiovascular disease - Clinical trials - HDL function and - HDL-C and genetic studies 3. Implications for therapeutic strategies

15 Vascular effects of HDL in patients with coronary disease as compared to healthy subjects?

16 Endothelial effects of HDL - endothelial bioassays Patients with acute coronary syndrome (n=25) Patients with stable coronary disease (n=25) Healthy control subjects (n=25) Endothelial cell NO production Isolation of HDL 2/3 (by sequential ultracentrifugation) Vascular effects Antithrombotic effects Anti-oxidant effects (Endothelial cell superoxide production) Anti-inflammatory effects (Endothelial cell inflammatory activation) Effects on Endothelial Repair

17 Number of GCSF-labeled monocytes per high power field Role of HDL function versus HDL cholesterol levels? Different effects of HDL from patients with CAD P < 0.05 P < Baseline TNFα TNFα + Healthy HDL Effect of HDL on monocyte adhesion to TNFα-stimulated endothelial cells Besler C et al. & Landmesser U. J Clin Invest 2011;121:

18 Number of GCSF-labeled monocytes per high power field Role of HDL function versus HDL cholesterol levels? Different effects of HDL from patients with CAD P < 0.05 P < 0.05 n.s Baseline TNFα TNFα + Healthy HDL TNFα + Stable CAD HDL TNFα + ACS HDL Effect of HDL on monocyte adhesion to TNFα-stimulated endothelial cells Besler C et al. & Landmesser U. J Clin Invest 2011;121:

19 HDL function (vascular effects) Which changes of HDL are mediating differences in HDL s vascular effects?

20 Mechanisms leading to altered effects of HDL on endothelial nitric oxide availability in CAD Mineo C & Shaul PW. J Clin Invest 2011

21 Myeloperoxidase leads to oxidative inactivation of paraoxonase-1 (PON-1) analysis in coronary disease: A functional ternary complex of MPO-PON-1-HDL PON-1 partially inhibits MPO activity MPO inactivates PON-1 - oxidizes PON-1 on Tyrosin-71 Huang Y, et al. & Landmesser U, Hazen S. J Clin Invest 2013

22 HDL from patients with chronic kidney disease (CKD) promotes endothelial inflammatory activation: Speer T,* Rohrer L* et al. Immunity 2013; 38(4): Shroff R et al.; J Am Soc Nephrol Nov;25(11):

23

24 The complexity of the HDL-lipoprotein Triglycerids Esterified cholesterol Phospholipids Free cholesterol Cholesterol Ester Apo A1 PON-1 HDL-bound small molecules > 1000 different lipids (Phospholipid species, Cholesterol Ester, Trigylcerides, ) 70 different proteins (ApoA1, PON-1, ApoA2, ApoCIII, ApoE, ApoH,.) Changes in composition and modification of both, lipids and proteins of HDL in cardiovascular disease results in altered HDL function

25 HDL proteome alterations in patients with coronary disease Alpha-2-macroglobulin OS=Homo sapiens Apolipoprotein L1 OS=Homo sapiens Antithrombin-III OS=Homo sapiens Hemoglobin subunit alpha OS=Homo DPI of Desmoplakin OS=Homo sapiens Reduced in CAD patients Serum amyloid A-4 protein OS=Homo sapiens GN=SAA4 Apolipoprotein A-IV OS=Homo sapiens GN=APOA4 Inter-alpha-trypsin inhibitor heavy chain H4 OS=Homo GTP-binding protein SAR1a OS=Homo sapiens GN=SAR1A Increased in CAD patients Apolipoprotein A-II OS=Homo sapiens Anthrax toxin receptor 2 OS=Homo sapiens GN=ANTXR2 Cathelicidin antimicrobial peptide Haptoglobin-related protein OS=Homo sapiens GN=HPR Apolipoprotein D OS=Homo sapiens HLA class I histocompatibility antigen, A-24 alpha chain Prenylcysteine oxidase 1 OS=Homo Complement component C9 OS=Homo sapiens GN=C9 Serum paraoxonase/lactonase 3 OS=Homo Serum paraoxonase/arylesterase 1 Angiotensinogen OS=Homo sapiens GN=AGT Apolipoprotein F (APOF), mrna OS=Homo Integrin alpha-2 OS=Homo sapiens Clusterin IGK@ protein OS=Homo sapiens GN=IGK@ Beta-1A of Integrin beta-1 OS=Homo Sonic hedgehog protein OS=Homo sapiens Aminopeptidase N OS=Homo sapiens Endosialin OS=Homo sapiens GN=CD248 Phosphatidylinositol-glycan-specific 0 0,1 0,2 0,3 0,4 0,5 0,6 Anthrax toxin receptor 1 OS=Homo sapiens GN=ANTXR1 Apolipoprotein C-IV OS=Homo sapiens GN=APOC4 Alpha-1-antichymotrypsin OS=Homo sapiens ApoCIII Alpha-2-HS-glycoprotein OS=Homo sapiens GN=AHSG Vitronectin OS=Homo sapiens GN=VTN Haptoglobin OS=Homo sapiens GN=HP Serum amyloid A protein OS=Homo sapiens GN=SAA1 Lipopolysaccharide-binding protein OS=Homo sapiens Heparin cofactor 2 OS=Homo sapiens GN=SERPIND1 Pulmonary surfactant-associated protein B OS=Homo 0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 Riwanto M et al. & Circulation 2013; 127(8):

26 Potential mechanisms leading to altered effects of HDL on endothelial apoptosis in CAD Riwanto M et al. & Circulation 2013; 127(8):

27 Exome sequencing in 3734 persons: identification of several rare coding-sequence variants of APOC3. Carriers of an APOC3 mutation had Triglyceride levels that were 39% lower HDL cholesterol levels that were 22% higher LDL cholesterol levels that were 16% lower Circulating APOC3 levels that were 46% lower Risk of coronary heart disease reduced by 40% N Engl J Med Jul 3;371(1):22-31.

28 Role of APOC3 in lipid metanbolism Gaudet D et al. N Engl J Med 2014;371:

29 Association of baseline HDL cholesterol levels and risk of cardiovascular events in patients with a recent acute coronary syndrome on statin therapy? There was no significant association in either group between the baseline HDL cholesterol level (i.e., the level measured at randomization) and the risk of the primary end point N Engl J Med 2012, 367(22):

30 N Engl J Med Dec 18;371(25):

31 Lancet Aug 11; 380(9841): Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study

32 HDL-C association with myocardial infarction in genetic studies? Voight BF et al Lancet 2012; 380:

33 HDL-cholesterol and coronary disease: 1. HDL-cholesterol the hypothesis 2. HDL-cholesterol in cardiovascular disease - Clinical trials - HDL function - HDL-C and genetic studies 3. Implications for therapeutic strategies

34 Lipid-targeted Therapies What should be added to statins in patients with high vascular risk? Further LDL-C PCSK9 inhibition (Monoclonal Ab*) ApoB-100 Antisense oligonucleotides Statin therapy Combined LDL-C HDL-C CETP inhibition (Evacetrapib*, Anacetrapib*) TGRL HDL ApoCIII ApoA5 LPL *Clinical outcome trials ongoing MODIFIED FROM Landmesser U. Eur Heart J 2013

35 Exome Sequencing Project coordinated by the National Heart, Blood and Lung Institute At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III. Nature Feb 5;518(7537):102-6.

36 Lipid-targeted Therapies genetic association with CAD and clinical outcome studies Statins Liver Mevalonate HMG-CoA reductase HMG-CoA Ezetemibe NPC1L1 Cholesterol Cholesterol degradation PCSK9 CM ApoA5 ApoC3 LDLR Evolocumab Alirocumab Bococizumab CETP TG ISIS-ApoC3 RX ApoA5 ApoC3 VLDL HDL CE TGRL remnant removal ID L Dalcetrapib Torcetrapib Anacetrapib Evacetrapib Genetic association with CAD Reduction of CV events No reduction of CV events Therapy and/or effect on CV events evaluated LDL ApoC3 Intestine Atherosclerotic plaque Hewing, Landmesser U. In press

37 Summary and conclusion 1.The HDL-cholesterol hypothesis was derived largely from epidemiological studies in primary prevention and experimental studies testing vascular effects of HDL from healthy subjects. 2.The relation between HDL-C and cardiovascular events is at least attenuated in CAD. Vascular effects of HDL are heterogenous and are altered in patients with coronary disease and diabetes (i.e. HDL dysfunction). 3.HDL cholesterol is therefore not a reliable surrogate marker for therapeutic interventions. Genetic studies suggest that TRLs are on the causal pathway of CAD (LPL, ApoC3, ApoA5)

38 Thank you U N I V E R S I T Ä T S M E D I Z I N B E R L I N

39