HDL: Improving endothelial function

Transcription

1 HDL: Improving endothelial function Thomas Münzel, Mainz 2. Medical Clinic Dome Mainz at night Fotos: Peter Pulkowski

2 HDL and Endothelial Function: Endothelial function Measurement Pathophysiology of endothelial dysfunction Endothelial function and prognosis HDL Stimulatory effects on NO production Antioxidant properties Influence on endothelial function Consequences of raising HDL on endothelial function Niacin CETP Inhibition, Torcetrapib, Dalcetrapib

3 Regulation of vascular tone via the endothelium

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5 Cardiovascular Risk factors and endothelial function: Circulation Apr 1;93(7):

6 The antioxidant Vitamin C Improves Endothelial Dysfunction

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9 Endothelial function, oxidative stress and prognosis!!

10 Maximal Forearm Blood Flow Endothelial function 15 5 Events No events + Vitamin C + Vitamin C Circulation 2001

11 Summary I: Endothelial function: Assessment technically easy Pathophysiology: Oxidative stress plays a crucial role Has prognostic meaning High oxidative stress in vascular tissue leads to more cardiovascular events

12 Therapy should be able to reduce superoxide and to stimulate NO production NO + O 2.- -> ONOO - HDL?

13 Reduced HDL Levels Increase Cardiovascular Risk Post Hoc Analysis of the Treating to New Targets (TNT) Study Relationship exists also in patients with statin therapy and an LDL<70 mg/dl Barter P et al., N Engl J Med 2007; 357:

14 HDL Restores Endothelial Dysfunction in Hypercholesterolemics 80 mg/kg iv over 4 h HDL-Cholesterol 1.2±01 mmol/l 2.1±01 mmol/l Spieker et al. Circulation 2002

15 (Circulation. 2003;107: )

16 Antiatherosclerotic effects of HDL

17 How does HDL stimulate NO production?

18 NATURE MEDICINE VOLUME 7 NUMBER 7 JULY 2001

19 HDL-treatment COS-M6 cells HDL causes enos-p at 1179

20 Mouse Aorta Endothelial Cells Deficient mice Mouse Aorta

21 HDL stimulates The efflux of 7-oxysterols -More NO -Less enos uncoupling From Besler et al EMBO Journal 2011

22 Endothelial NO Production [pmol NO / 500,000 cells/ h] Stiftung Effect of HDL from patients on endothelial NO production P < 0.01 P < PBS HDL Healthy HDL Diabetics Sorrentino SA*, Besler C* et al. & Landmesser U; Circulation 2010; 121(1):110-22

23 Antioxidant effects?

24 NADPH Oxidase - Kindling Radical for enos uncoupling

25 Healthy HDL inhibits NAD(P)H oxidase EPR spectra No stimulatory effects on NAD(P)H oxidase activity

26 Role of PON-1 for the effects of HDL on endothelial NO production D Endothelial NO production [in % of buffer-treated cells] [in % of buffer-treated cells] P<0.025 P<0.025 PBS HQ EDTA D Endothelial NO production HDL Wild type P<0.01 HDL PON-1 -/- + HDL Healthy Besler et al. J. clin. Invest. 2011, 121,

27 HDL-associated paraoxonase (PON)-1 activity and content Paraoxonase Paraoxonase activity [in % of Healthy HDL] Paraoxonase-1 activity Paraoxonase-1 content P<0.05 P< HDL Healthy P<0.05 HDL CAD HDL ACS Paraoxonase-1 content [in % of Healthy HDL] HDL Healthy P<0.05 HDL CAD HDL ACS Besler et al. J. clin. Invest. 2011, 121,

28 Oxidation of HDL and LDL by myeloperoxidase (MPO)- generated oxidants Paraoxonase- 1 (PON-1)

29 Alterations of the atheroprotective effects of HDL in patients with CAD

30 Effects of rhdl on endothelial function in patients with ACS

31 Changes in Lipidparameters

32 Fluss (Infusions-/Kontrollarm) Stiftung Effect of rhdl on Endothelial Function in Patients with Acute Coronary Syndrome N=10 N=19 Acetylcholin (µg/100ml VAV/Min) Na-Nitroprussid (µg/100ml VAV/Min) Chenévard et al. 2010

33 Implications of raising HDL

34 Drugs and HDL Statins: % Fibrates: % Nicotinic acid: % Bile acid sequests.: % PPAR % CB1-Antagonists: % CETP inhibitors: % Antiepileptics: + 140%

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36 Paraoxonase-1 activity [U/mg protein] Stiftung Effect of extended-release niacin therapy on HDL-associated PON-1 activity 100 n.s. P< HDL HDL HDL HDL Diabetes Diabetes Diabetes Diabetes Baseline 3 Months Baseline 3 Months Placebo ER-Nacin Sorrentino SA*, Besler C* et al. & Landmesser U; Circulation 2010; 121(1):110-22

37 107 patients with CAD Treated with Niacin ER for 12 weeks with 1000 mg/d Or Placebo

38 Changes in Lipidparameters

39 No effects on endothelial function

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41 Production, maturation and metabolism of HDL HDL interconversion & lipolysis of TGRL liver ABCA1 apoa-i LDL-R Selective uptake preb- HDL ABCA1 peripheral cells + LCAT HDL 3 ABCG1 (V)LDL CETP HDL 2 + LCAT SR-BI

42 Torcetrapib in high risk Patients - ILLUMINATE Patients without event(%) Patients at high cardiovascular risk; torcetrapib 60 mg Change in % Change in Lipid Levels * Total Cholesterol HDL * * LDL Major Cardiovascular Events (Death from ischemic heart disease Stroke, non-fatal MI, hospitalization from Unstable angina) 0 Atorvastatin n=7534 Atorvastatin + Torcetrapib n=7533 Rel. Risk +25%, p= Days Barter PJ: NEJM 2008

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44 Torcetrapib stimulates ROS production in vascular tissue ROS production Endothelial Dysfunction Enhanced Constriction Increased Endothelin-1 Levels

45 Reduced enos expression and NO production

46 Mechanisms of Endothelial Dysfunction and Hypertension with Torcetrapib Adrenal Gland Aldosterone NO ET-1 Kidney Relaxation Vasoconstriction

47 Patients with target low-density lipoprotein cholesterol (LDL-C) levels received dalcetrapib 600 mg/day or placebo for 36 weeks on top of standard therapy (including statins). 506 Patients were randomized

48 No improvement in FMD

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50 Must mean not the end of CETP inhibition

51 Summary II:?