Statins and endothelium function

Transcription

1 Statins and endothelium function Matthias Endres Berlin, Germany Klinik und Poliklinik für Neurologie Conflict of interest: research grant from AstraZeneca

2 from prevention to acute therapy... Pleiotropic (rapid) effects Risk reduction vs. outcome Discontinuation of statins Acute treatment Vascular repair and angiogenesis

3 Pleiotropic Effects Endres M JCBFM 2005 Platelet function Coagulation (PAI-1) Inflammation (hs-crp) Viscosity Endothelial function Collagen Macrophages MMPs Free Radicals LDL-C HDL-C TG

4 Inhibition of endothelial HMG-CoA reductase upregulates endothelial NO synthase expression enos kd Sim (µm) L-Mev Lov (µm) Ulrich Laufs Circulation, 1998

5 Acetyl-CoA Statins HMG-CoA Mevalonate Isopentenyl-PP Farnesyl-PP CHOLESTEROL Squalene Geranylgeranyl-PP Rho Rac enos NAD(P)H-ox Stroke

6 N Engl J Med 2008;359:

7 JUPITER Why Consider Statins for Low LDL, high hscrp Patients? AFCAPS/TexCAPS Low LDL Subgroups Low Low LDL, LDL, Low Low hscrp hscrp Low Low LDL, LDL, High High hscrp hscrp [A] [B] Statin Statin Effective Effective RR Statin Statin Not Not Effective Effective Ridker et al, New Engl J Med 2001;344:

8 JUPITER Primary Objectives Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin rosuvastatin 20 mg compared to placebo rate of first major cardiovascular events apparently healthy men and women with LDL < 130 mg/dl and hscrp > 2 mg/l N=17,802; n=89,890 screened N Engl J Med 2008;359:

9 JUPITER Effects of rosuvastatin 20 mg on LDL, HDL, TG, and hscrp hscrp (mg/l) LDL (mg/dl) LDL decrease 50 percent at 12 months hscrp decrease 37 percent at 12 months Months TG (mg/dl) HDL (mg/dl) HDL increase 4 percent at 12 months TG decrease 17 percent at 12 months Months N Engl J Med 2008;359:

10 JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Cumulative Incidence HR 0.56, 95% CI P < Placebo 251 / 8901 RRR: - 44 % ARR: % Rosuvastatin 142 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,631 8,412 6,540 3,893 1,958 1, ,901 8,621 8,353 6,508 3,872 1,963 1,

11 JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Cumulative Incidence HR 0.56, 95% CI P < NNT 5 : Placebo 251 / 8901 RRR: - 44 % ARR: % Rosuvastatin 142 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,631 8,412 6,540 3,893 1,958 1, ,901 8,621 8,353 6,508 3,872 1,963 1,

12 JUPITER Secondary Endpoint All Cause Mortality Ridker et al NEJM 2008 Cumulative Incidence HR 0.80, 95%CI P= Placebo 247 / % Rosuvastatin 198 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,847 8,787 6,999 4,312 2,268 1,602 1, ,901 8,852 8,775 6,987 4,319 2,295 1,614 1,

13 JUPITER Predicted Benefit Based on LDL Reduction vs Observed Benefit Ridker et al NEJM Proportional reduction in vascular event rate (95% CI) A-to-Z TNT IDEAL CTT PROVE-IT JUPITER PREDICTED ,5 1 Mean LDL cholesterol difference between treatment groups (mmol/l)

14 JUPITER Predicted Benefit Based on LDL Reduction vs Observed Benefit Ridker et al NEJM JUPITER OBSERVED Proportional reduction in vascular event rate (95% CI) A-to-Z TNT IDEAL CTT PROVE-IT JUPITER PREDICTED ,5 1 Mean LDL cholesterol difference between treatment groups (mmol/l)

15 JUPITER Implications for daily routine? Effective LDL-lowering by statin treatment decreases vascular events and mortality aggressive LDL-lowering is safe (also in primary prevention) low LDL (40 60 mg/dl) is well tolerated unclear: role of hscrp as risk marker in clinical practice

16 from prevention to acute therapy... Pleiotropic (rapid) effects Risk reduction vs. outcome Discontinuation of statins Acute treatment Vascular repair and angiogenesis

17 Preservation of rcbf during MCAo Control Statin J Clin Invest

18 Statin treatment decreases infarct size following MCA occlusion/reperfusion PNAS 1998 Stroke 2000 JCI 2000 Brain Res 2002 Stroke 2003 Vehicle Statin

19 Statin pre-treatment protects neurons from excitotoxic cell death J Neurochem 2005

20 Goldstein et al. Stroke 40;3526ff November 2009

21 Stroke Recurrence 35% Mortality 57% Milionis et al. Neurology 72;1816ff May 2009

22 from prevention to acute therapy... Pleiotropic (rapid) effects Risk reduction vs. outcome Discontinuation of statins Acute treatment Vascular repair and angiogenesis

23 Endothelial NO Production after Statin Withdrawal enos Activity [ 3 H] arginine-citrulline conversion 200 ** 150 * * * * 0 C Hours After Statin Treatment Circulation

24 Rho NO NO NO enos NO NO NO NO NO NO enos GGPP- GGPP-Rho GGPP-Rho GGPP- Rho enos GGPP GGPP GGPP GGPP GGPP Rho Rho Rho Rho Rho Statin Rho Rho Rho Rho Baseline Statin Treatment Statin Rebound Stroke

25 Effects of statin withdrawal on enos expression Aortic enos mrna (% ratio enos/enos mutant) 300 * * 0 C statin statin + 2 d statin + 4 d Circulation

26 Effects of statin withdrawal on stroke volume Lesion volume [mm 3 ] ** * Atorva [mg/kg] Treatment 14 d 14 d 14 d plus 2 14 d plus 4 Stroke

27 Early withdrawal of statin therapy in patients with Non-ST-segment elevation myocardial infarction In hospital death [%] # NRMI-4 matched population 5 ** Statins (before/after) No/No Yes/Yes Yes/No Patients (n) Spencer, Arch Intern Med

28 Influence of statin withdrawal on acute ischemic stroke outcome: a randomized controlled study Early neurological deterioration Bad Outcome deterioration [% of pts] mrs <2 [% of pts] Statins No/No Yes/Yes Yes/No No/No Yes/Yes Yes/No # of pts Blanco, Neurology, 2007

29 Stroke October 2006

30 Iv vs ip -Lower dose (2 log!) -Longer window (3hrs) Stroke 2008

31 (1) Immediate administration in patients with acute vascular syndromes including ischemic stroke, acute coronary syndrome, ST segment and non-st segment myocardial infarction; (2) Critically ill patients pretreated with statins whenever enteral administration is not possible (including via nasogastric tube); these could be patients with vascular disease, those undergoing major surgery, or trauma patients; (3) Pretreatment of patients undergoing surgery with a high vascular risk; (4) Perioperative treatment of patients with a high risk of atrial fibrillation. Cerebrovasc. Dis 2008

32 Vascular remodelling b Vehicle Statin Arterioscler Thromb Vasc Biol

33 Reendothelialization after Vascular Injury potential role of endothelial progenitor cells endothelial progenitor cells endothelial cells endothelial cell repair? neovascularization

34 A GFP Carotid artery lesion model B vwf * * Bone-marrow chimera Arterioscler Thromb Vasc Biol

35 Carotid artery lesion model GFP vwf A B Bone-marrow chimera After statin treatment Arterioscler Thromb Vasc Biol

36 from prevention to acute therapy... Pleiotropic (rapid) effects Risk reduction vs. outcome Discontinuation of statins Acute treatment Vascular repair and angiogenesis

37 299 Ischaemic stroke enos upregulation enos activation - statins - physical activity - nutrients - etc. - corticosteroids - oestrogen - statins - L-arginine days/weeks min/hours outcome preventive/prophylactic acute treatment Trends Neurosci

38 Thank you Karen Gertz Vincent Prinz Josef Priller Ulrich Laufs Michael A. Moskowitz Neurology Charité Psychiatry Charité Saarland University Homburg MGH, Charlestown VolkswagenFoundation, DFG, BMBF