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HDL-C concentration versus HDL particle function: What exactly does HDL functionality mean?

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HDL-C concentration versus HDL particle function: What exactly does HDL functionality mean?

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  1. HDL-C concentration versus HDL particle function: What exactly does HDL functionality mean? Prof. Ulf Landmesser University Hospital Zürich Zürich, Switzerland

  2. 2 Month later Occluded RCA Acute coronary syndromes result most frequently from coronary plaques without significant stenosis Plaque in mid RCA

  3. Intensive vs. moderate statin therapy and coronary disease 5 trials (intense vs. moderate statin) 39 612 individuals; median follow-up 5·1 years 21 trials (statin versus control) 129 526 individuals; median follow-up 4·8 years Risk reduction up to 40-50 % possible Lancet 2010 Nov 13;376(9753):1670-81.

  4. Low HDL remains a predictor of cardio-vascular risk in statin-treated patients Barter P et al., N Engl J Med 2007; 357: 1301-10

  5. HDL – a novel target in coronary disease ? HDL The “good“ cholesterol ?

  6. Atherosclerosis development:Dysbalance between increased foam cell formation and impaired HDL-dependent cholesterol efflux from lipid-laden macrophages Heinecke J, New Engl J Med 2011

  7. HDL-C concentration versus HDL particle function: What exactly does HDL functionality mean? • Anti-atherogenic effects of HDL ? • “HDL function“ in coronary disease ? • HDL-targeted therapy ?

  8. HDL: proposed anti-atherogenic effects SR-BI ? ABCG1 SR-BI LDL-R 1. HDL-mediated promotion of RCT (reverse cholesterol transport) VLDL/ LDL CE CETP TG A-I A-I FC PLTP CE FC LCAT Nascent HDL Mature HDL CE ABCA1 FC Bile HDL Macrophage Besler C et al. & Lüscher T, Landmesser U. Curr Pharmacol Des 2010, 16: 1480-93

  9. HDL-mediated regression of atherosclerosis in cholesterol-fed rabbits 90 days + HDL 90 days 60 days Badimon JJ et al.; J Clin Invest. 1990 Apr;85(4):1234-41

  10. Increased atherosclerosis in ABCA-1 /ABCG1 bone-marrow-deficient mice No significant differences in HDL plasma levels Yvan-Charvet L et al.;J Clin Invest. 2007;117(12):3900-8

  11. HDL: proposed anti-atherogenic effects SR-BI? ABCG1 SR-BI LDL-R 1. HDL-mediated promotion of RCT (reverse cholesterol transport) VLDL/ LDL CE CETP TG A-I A-I FC PLTP CE FC LCAT Nascent HDL Mature HDL CE ABCA1 FC Bile HDL Macrophage Liver 2. Direct HDL-mediated endothelial-protective potential anti-atherogenic effects Anti-apoptotic Effects Endothelial Repair Endothelial NO Production Anti-inflammatory Effects Anti-thrombotic Effects Besler C et al. & Lüscher T, Landmesser U. Curr Pharmacol Des 2010, 16: 1480-93

  12. Vasculoprotective effect of HDL: role of nitric oxide (NO) S1P3 ABCG1 AMPK Caveolin Oxy-sterols Yuhanna IS et al.; Nat Med 2001 Mineo e al.; J Biol Chem. 2003 Nofer et al.; J. Clin. Invest. 2004 Terasaka N et al.; J. Clin. Invest. 2008 Terasaka N et al.;Arterioscler Thromb Vasc Biol. 2010 Li D et al. Arterioscler Thromb Vasc Biol. 2010

  13. Endothelial NO production – Anti-atherogenic effects Monocyt Platelets Inhibition of Leukocyte adhesion und -infiltration Inhibition of Thrombocyte adhesion and -aggregation Endothel NO Inhibition of VSMC proliferation Vascular smooth muscle cell Landmesser et al.; Circulation 2004

  14. Endothelial dysfunction, nitric oxide, and coronary atherosclerosis Development of atherosclerosis Clinical events Summarized in: Landmesser et al. Circulation 2004; 109(21 Suppl 1):II27-33

  15. HDL-C concentration versus HDL particle function: What exactly does HDL functionality mean? • Anti-atherogenic effects of HDL ? • “HDL function“ in coronary disease ? • HDL-targeted therapy ?

  16. Effect of HDL on endothelial cell nitric oxide production in CAD ? HDL from Healthy subject HDL from CAD patient 30 minutes

  17. Endothelial effects of HDL in patients with stable coronary disease or acute coronary syndrome as compared to healthy subjects ?

  18. Study design: Endothelial effects of HDL - endothelial bioassays Endothelial Function (Endothelial cell NO production and vasoreactivity) Anti-thrombotic effects Anti-oxidant effects (Endothelial cell superoxide production) Anti-inflammatory effects (Endothelial cell inflammatory activation) Effects on Re-Endothelialization 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) Vascular effects ESR spectroscopy Organ chamber Tissue factor Arterial thrombosis Carotid artery injury model in nude mice Monocyte adhesion VCAM-1 expression ESR spectroscopy

  19. Characteristics of the study population Besler C et al. & von Eckardstein, Lüscher T, Landmesser U. J Clin Invest2011;121(7):2693-708

  20. HDL -endothelial effects in patients with coronary disease P < 0.05 P < 0.05 n.s. 25 20 15 10 5 Nitric oxide production (changes vs. PBS-treated cells, in %) 0 -5 -10 -15 Healthy HDL ACS HDL Stable CAD HDL -20 (ESR spectroscopy measurement) Besler C et al. & von Eckardstein, Lüscher T, Landmesser U. J Clin Invest2011;121(7):2693-708

  21. Healthy P<0.025 sCAD 30 ACS 20 10 production Endothelial nitric oxide [in % of buffer-treated cells] 0 -10 -20 D g/ml 25 m 50 m g/ml 100 m g/ml HDL HDL HDL HDL –effects on endothelial cell nitric oxide production in patients with CAD Besler C et al. & von Eckardstein, Lüscher T, Landmesser U. J Clin Invest2011;121(7):2693-708

  22. P < 0.05 n.s. P < 0.05 P < 0.05 Effects of HDL on vascular inflammation:monocyte adhesion on TNFα-stimulated endothelial cells 35 30 25 20 Number of GCSF-labeled monocytes per high power field 15 10 5 0 TNFα + TNFα + TNFα + TNFα Baseline Healthy Stable CAD ACS HDL HDL HDL Besler C et al. & von Eckardstein, Lüscher T, Landmesser U. J Clin Invest2011;121(7):2693-708

  23. 4 mm Evans blue staining Carotid injury model to examine in vivo endothelial repair capacity of HDL 4 mm Sorrentino SA et al.; Circulation 2007; 116(2):163-73 Sorrentino SA et al.; Circulation 2010; 121(1):110-22 Giannotti G et al.; Hypertension 2010; 55:1389-97

  24. Effects of HDL on endothelial repair after arterial injury P < 0.05 P < 0.0001 30 25 Re-endothelialized area [in %] 20 15 10 5 0 4 mm HDL HDL HDL PBS Healthy Stable CAD ACS Quantification of re-endothelialized area 3 days after induction of carotid injury by Evan`s blue staining Besler C et al. & von Eckardstein, Lüscher T, Landmesser U. J Clin Invest2011;121(7):2693-708

  25. HDL function(vascular effects)Which changes of HDL are mediatingdifferences in HDL‘s vascular effects ?

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

  27. P < 0.05 n.s. P < 0.05 n.s. HDL-associated paraoxonase activity and content Paraoxonase activity Paraoxonase-1 content 0.6 800 0.5 700 Paraoxonase-1 activity (Units/50μg HDL) 600 0.4 Paraoxonase-1 content of isolated HDL (in %) 500 0.3 400 300 0.2 200 0.1 100 0 0 Healthy ACS Stable CAD Healthy stable CAD ACS HDL HDL HDL HDL HDL HDL Besler C et al. & von Eckardstein, Lüscher T, Landmesser U. J Clin Invest2011;121(7):2693-708

  28. P<0.01 50 25 Endothelial nitric oxide production [in % of buffer-treated cells] 0 -25 HDL HDL D -/- Wild type PON1 HDL from paraoxonase-deficient micefails to stimulate endothelial NO production Besler C et al. & von Eckardstein, Lüscher T, Landmesser U. J Clin Invest2011;121(7):2693-708

  29. Mechanisms leading to HDL dysfunction with respect to effects on endothelial nitric oxide Mineo C & Shaul PW. J Clin Invest 2011

  30. Effects of HDL on endothelial apoptosis are eNOS-independent Riwanto M, Besler C et al. (submitted)

  31. Changes of HDL proteome in coronary disease Reduced in ACS patients Increased in ACS patients ApoCIII Clusterin Riwanto M, Besler C et al. (submitted)

  32. Effects of HDL from type-2 diabetics on endothelial NO-Production is impaired P < 0.0001 P < 0.0001 200 150 Endothelial NO Production [% of buffer- treated cells] 100 50 0 PBS HDL Healthy HDL Diabetics Sorrentino SA et al. Circulation 2010; 121:110-22

  33. P < 0.001 25 20 Impaired endothelial effects of HDL in patients with antiphospholipid syndrome 15 10 5 Endothelial NO production (changes vs. PBS-treated cells, in %) 0 -5 -10 -15 HDL Matched Control -20 HDL-APS Charakida M, Besler C et al. JAMA 2009; 302(11):1210-7

  34. Cholesterol efflux capacity of ApoB-depleted serum and coronary disease Khera AV et al.; N Engl J Med. 2011; 364(2):127-35

  35. Leducq Transatlantic Network: HDL dysfunction in the pathophysiology in cardiovascular disease and as a novel treatment target Stanley Hazen Cleveland Clinic Molecular mechanisms of HDL dysfunction Alan Tall Columbia Univ., New York Molecular mechanisms of vascular effects of HDL Jan A. Kuivenhoven John Kastelein Amsterdam Univ. Effects of HDL-genes on HDL functions John Deanfield UCL,London Clinical implications of HDL dysfunction Bart Staels Lille, Inserm Novel molecular targets stimu- lating HDL functions Alan Fogelman UCLA Novel approaches to stimulate HDL functions Thomas Lüscher Zurich Univ. Vascular effects of HDL and its alterations Ulf Landmesser Zurich Univ. Altered endothelial effects of HDL in cardiovascular disease Network Project Managment: Michaela Keel

  36. HDL-C concentration versus HDL particle function: What exactly does HDL functionality mean? • Anti-atherogenic effects of HDL ? • “HDL function“ in coronary disease ? • HDL-targeted therapy ?

  37. HDL metabolism – potential targets ? PL FC PL FC TG TG (1) apoA-I (lipid-free) (1) apoA-I (lipid-free) BA (2)ABCA1 ABCA1 FC CE Bile (5) SR-BI Nascent HDL LDLR TG-rich lipoproteins (e.g. VLDL) (2) ABCA1 PLTP ABCG1 VLDL/LDL apoB Peripheral tissues (including lipid-laden macrophages) (3) LCAT CE apoB CE (4) CETP Mature HDL Besler C, Lüscher T, Landmesser U. EMBO Mol Med 2011 (in press)

  38. HDL in genome-wide association studies LDL-Cholesterol associated SNPs and CAD HDL-Cholesterol associated SNPs and CAD Willer C et al; Nature Genetics, 2008; 40,161-169

  39. HDL metabolism – potential targets ? PL FC PL FC TG TG (1) apoA-I (lipid-free) (1) apoA-I (lipid-free) BA (2)ABCA1 ABCA1 FC CE Bile (5) SR-BI Nascent HDL LDLR TG-rich lipoproteins (e.g. VLDL) (2) ABCA1 PLTP ABCG1 VLDL/LDL apoB Peripheral tissues (including lipid-laden macrophages) (3) LCAT CE apoB CE (4) CETP Mature HDL Besler C, Lüscher T, Landmesser U. EMBO Mol Med 2011 (invited review)

  40. Summary • Intense statin-therapy can reduce cardiovascular events up to 40-50 %. • Low HDL-C levels are associated with an increased cardiovascular risk in patients with coronary disease and low LDL levels. Several potentially anti-atherogenic properties of HDL are impaired in patients with coronary disease or diabetes. 3. HDL-targeted therapy should therefore likely not only increase HDL-C levels, but also stimulate anti-atherogenic properties of HDL.