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The inflammatory process and cardiovascular events : What are the targets for interventon ?

The inflammatory process and cardiovascular events : What are the targets for interventon ?. Prof. Ulf Landmesser University Hospital Zurich Zurich, Switzerland. The Inflammatory process and cardiovascular events: What are the targets for intervention ?.

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The inflammatory process and cardiovascular events : What are the targets for interventon ?

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  1. The inflammatoryprocess and cardiovascularevents: What are the targets forinterventon? Prof. Ulf Landmesser UniversityHospital Zurich Zurich, Switzerland

  2. The Inflammatory process and cardiovascular events: What are the targets for intervention ? • Inflammation in atherosclerosis – causal role ? • Targeting inflammation in atherosclerosis • A IL-1-beta; IL-6-receptor • (CANTOS trial: Canakinumab Anti-inflammatory Thrombosis Outcomes Study) • B Anti-inflammatory agents • (CIRT trial: Cardiovascular Inflammation Reduction Trial) • 3. Alteration of potential endogenous anti-inflammatory mechanisms in patients with coronary disease ?

  3. Role of inflammation in atherosclerosis ? - A fierce debate started in the 19th century - Both observed cellular inflammatory changes in the atherosclerotic vessel walls Rudolf Virchow Carl von Rokitansky „Inflammation accompanies atherosclerosis“ „Inflammation initiates atherosclerosis“ Rolitansky; A manual of pathologic anatomy. 1852 Virchow R. Der ateromatöse Prozess der Arterien. Wien Med Wschr 1856

  4. Atherosclerosis development: endothelial inflammatory activation - electron microscopy studies Subendothelial LDL particles Transmigration ofmonocytes Aldis JL, Nature. 2000 Feb 21;451(7181):904-13

  5. Early Atherosclerotic Lesions - endothelial inflammatory activation “Fatty streak” Macrophage staiing Atherosclerotic lesions begin as fatty streaks underlying the endothelium of large arteries Glass et al. Cell 2001; 104,503–516

  6. Immune components of the atherosclerotic plaque: Innate and adaptive immune response Hansson GK & Hermansson A. Nature Immunology 2011;12(3):204-212

  7. Cross talk between inflammatory cells and intrinsic vascular wall cells mediated by cytokines T Lymphocyte IL-2 Foreign class II HLA on the surface of vascular cells IL-2-R Antigen receptor IFN-γ LT TNF IL-1 IL-6 IL-1 IL-6 MPO Macrophage/Monocyte IL-1 TNF PDGFc TGF-α IL-1 PDGFc Endothelial Cell Smooth Muscle Cell Libby P. Arterioscler Thromb Vasc Biol. 2012;32:2045-2051

  8. Relative risk of future myocardial infarction is increased according to baseline IL-6 concentration Baseline IL-6 levels according to number of traditional risk factors Ridker P et al. Circulation 2000;101:1767-1772

  9. Receptor composition for Interleukin-6 signaling via the β-receptor subunit gp130 Jones S et al. J Clin Invest 2011;121(9):3375-3383

  10. IL6R genotype and risk of coronary heart disease IL6R SNP (rs7529229) Large-scale human genetic data are consistent with a causal association between IL6R-related pathways and coronary heart disease.

  11. Highlights - Hepatic IL-6 signaling improves local and systemic insulin action - Hepatocyte IL-6 signaling limits inflammatory cytokine expression in liver Given these complex effects of IL-6 signaling on hepatic metabolism and the initiation of a systemic inflammatory response upon inhibition of IL-6 signaling, caution should be warranted to potential diabetogenic side effects of newly evolv- ing therapies aiming to interfere with IL-6 signaling. Cell Metab. 2010 Sep 8;12(3):237-49.

  12. IL6R genotype and risk of coronary heart disease Association of IL6R rs7529229 with secondary and safety endpoints

  13. N Engl J Med. 2012 Dec 20;367(25):2385-95. Conclusions: Tocilizumab was efficacious in severe, persistent systemic JIA. Adverse events were common and included infection, neutropenia, and increased aminotransferase levels.

  14. Janus kinase (JAK)-inhibition as an anti-inflammatory treatment O'Shea JJ et al. N Engl J Med 2013;368:161-170.

  15. Conclusions In patientswithactive rheumatoid arthritis, tofacitinibmonotherapy was associat- edwithreductions in signsandsymptomsof rheumatoid arthritisandimprove- ment in physicalfunction

  16. Cross talk between inflammatory cells and intrinsic vascular wall cells mediated by cytokines T Lymphocyte IL-2 Foreign class II HLA on the surface of vascular cells IL-2-R Antigen receptor IFN-γ LT TNF IL-1 IL-6 IL-1 IL-6 Macrophage/Monocyte IL-1 TNF PDGFc TGF-α IL-1 PDGFc Endothelial Cell Smooth Muscle Cell Libby P. Arterioscler Thromb Vasc Biol. 2012;32:2045-2051

  17. Lipid mediators, inflammation and atherogenesis: Role of the NLRP3 inflammasom Weber C & Noels H. Nature Medicine 2011;17(11):1410-1422

  18. Balancing the IL-1β system in cardiovascular disease ? Ridker PM et al. American Heart Journal 2011;162(4):597-605

  19. Mechanisms of Canakinumab – an IL-1b targeted therapy Hoffmann HM. J Allergy Clin Immunol 2009; 124(6):1129-1138

  20. Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) – study design • → 1:1:1:1.5 allocation ratio betw • canakinumab 50 mg quartl. • canakinumab 150 mg quartl. • Canakinumab 300 mg quartl. • Placebo 17,200 randomized participants Ridker PM et al. American Heart Journal 2011;162(4):597-605

  21. Canakinumab: Dose-response effects of at 4 months for C-reactive protein (CRP), interleukin-6 (IL-6), and fibrinogen in placebo-subtracted analyses. Ridker P et al. Circulation 2012;126:2739-2748

  22. N Engl J Med. 2012 Dec 20;367(25):2396-406. Conclusions: These twophase 3 studiesshowtheefficacyofcanakinumab in systemic JIA withactivesystemicfeatures.

  23. The Inflammatory process and cardiovascular events: What are the targets for intervention ? • Inflammation in atherosclerosis – causal role ? • Targeting inflammation in atherosclerosis • A IL-1-beta; IL-6-receptor • (CANTOS trial: Canakinumab Anti-inflammatory Thrombosis Outcomes Study) • B Anti-inflammatory agents • (CIRT trial: Cardiovascular Inflammation Reduction Trial) • 3. Alteration of potential endogenous anti-inflammatory mechanisms in patients with coronary disease ?

  24. Reduced Risk for CVD associated with methotrexate use Micha R et al. Am J Cardiol 2011;108(9):1362-1370

  25. Mechanisms of anti-inflammatory effects exerted by low dose methotrexate Cutolo M et al. Ann Rheum Dis 2001;60:729–735

  26. The cardiovascular inflammation reduction trial (CIRT) – Study design - CIRT will enroll 7,000 patients across the United States and Canada over the next 2.5 years and will follow them for two to four years (average 2.5 years). Site selection will begin in November 2012, and patient recruitment will start in March 2013. Open labelactiverun-in low-dose methotrexate (5-15 mg wk-1) Randomized low-dose methotrexate15-20 mg wk-1 + folate Supported by the National Institutes of Health Ridker PM. J Throm Haemost 2009; 7 (Suppl. 1): 332–9

  27. The Inflammatory process and cardiovascular events: What are the targets for intervention ? • Inflammation in atherosclerosis – causal role ? • Targeting inflammation in atherosclerosis • A IL-1-beta; IL-6-receptor • (CANTOS trial: Canakinumab Anti-inflammatory Thrombosis Outcomes Study) • B Anti-inflammatory agents • (CIRT trial: Cardiovascular Inflammation Reduction Trial) • 3. Alteration of potential endogenous anti-inflammatory mechanisms in patients with coronary disease ?

  28. SR-BI ? SR-BI LDL-R ABCG1 HDL: proposed anti-atherogenic effects 1. HDL-mediatedpromotionof RCT (reversecholesteroltransport) VLDL/ LDL CE CETP A-I TG A-I FC PLTP CE FC LCAT Nascent HDL Mature HDL CE ABCA1 FC Bile HDL Macrophage 2. Direct HDL-mediated endothelial-protective potential anti-atherogeniceffects Anti-apoptotic Effects Endothelial Repair Anti-thrombotic Effects Endothelial NO Production Anti-inflammatory Effects Besler C et al. & Landmesser U. EMBO Mol Medicine 2012

  29. Role of HDL function versus HDL cholesterol levels ? Different effects of HDL from patients with CAD on inflammatory activation 35 P < 0.05 P < 0.05 30 25 20 per high power field Number of GCSF-labeled monocytes 15 10 5 0 TNFα + TNFα Baseline Healthy HDL Effect of HDL on monocyte adhesion to TNFα-stimulated endothelial cells Besler C et al. & Landmesser U. J ClinInvest2011;121: 2693-708

  30. Role of HDL function versus HDL cholesterol levels ? Different effects of HDL from patients with CAD on inflammatory activation n.s. 35 P < 0.05 P < 0.05 30 25 20 per high power field Number of GCSF-labeled monocytes 15 10 5 0 TNFα + TNFα + TNFα + TNFα Baseline Healthy Stable CAD ACS HDL HDL HDL Effect of HDL on monocyte adhesion to TNFα-stimulated endothelial cells Besler C et al. & Landmesser U. J ClinInvest2011;121: 2693-708

  31. Mechanismen pro-inflammatorischer vaskulärer Effekte des HDL bei Patienten mit koronarer Herzerkrankung Mineo C & Shaul PW. J ClinInvest2011 - Editorial zu: Besler C et al. & Landmesser U. J ClinInvest2011;121(7):2693-708

  32. Myeloperoxidase leads to oxidative inactivation of paraoxonase-1 (PON-1) in coronary disease Huang Y , Riwanto et al. & Landmesser U*, Hazen S*. J ClinInvest2013 (in press)

  33. Summary and conclusion • 1. Experimental and large-scalegeneticdatasuggest a causalroleofinflammation in atherosclerosis. • 2. Clinical studiesevaluatingwhetherclinicaloutcome in patientswithcoronarydiseasecanbeimprovedby anti-inflammatorystrategiesareunderway. • 3. An importantquestion will bewhetherefficacyisenoughtocounterbalance potential sideeffects, such asincreasedriskofinfection.

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