Inflammation in atherosclerosis – causal role ?

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 ?
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 ?

Role of inflammation in atherosclerosis
Role of inflammation in atherosclerosis ? - A fierce debate started in the 19th century - Both observed cellular inflammatory changes in the atherosclerotic vessel walls Mitte des 19. Jahrhunderts wurden zwei Hypothesen für die Entstehung der Atherosklerose postuliert. Von Rokitansky erklärte in seiner Inkrustations-hypothese, 1852 erstmals publiziert, die Intimaverdickungen, welche bereits makroskopisch sichtbar sind und ein Hauptcharakteristikum der Atherosklerose darstellen, durch Fibrinablagerungen, die im weiteren Verlauf von Fibroblasten organisiert werden und durch sekundäre Lipidakkumulation expandieren ( ). Einer der größten Kritiker dieser Theorie war Rudolf Virchow, der seine Auffassung von der Atherosklerose als eine Entzündung der Arterien 1856 erstmals veröffentlichte. Seine Hypothese von der arteriellen Verletzung schließt die konsequente Anwendung des von ihm weiterentwickelten Entzündungsbegriffes auf das Entstehen der atherosklerotischen Läsionen ein. ”Späterhin habe ich meine Auffassung der Entzündung weiter entwickelt und gefunden, dass man jeden activen, pathologischen Ernährungsvorgang, der aus Reizung hervorgeht, jede irritative Ernährungsstörung .... als entzündlich bezeichnen müsse. Nach dieser Auffassung gehört ein Theil der sogenannten Entzündungssymptome, nämlich Röthe (Wallung oder Stase), Schmerz und dem grösseren Anteile nach auch die Hitze der Reizung an ..., den wirklichen Mittelpunkt der Entzündung dagegen bildet die Ernährungsstörung. Insofern diese letztere activ und nicht etwa bloss durch den Entzündungsreiz passiv zu Stande kommt, so ist jedesmal ein progressiver Gang zu constatiren ....Untersuchen wir nun, ob an den Gefässen ein solcher activer pathologischer Ernährungsvorgang stattfinden könne, so müssen wir entschieden mit ja antworten.“ ( ) Virchow sah die Lipidablagerungen in der arteriellen Wand als von den Blutlipiden herrührende Veränderungen, welche nach seiner Auffassung durch Transduktion der Lipide und Komplexbildung mit sauren Mukopolysacchariden entstehen. Durch eine solche ”Verletzung“ der Arterien erklärte er die Akkumulation von Lipiden und die Entwicklung der atherosklerotischen Läsionen in der Intima und Media der Arterien ( ). Die von Ross 1973 entwickelte und 1986 bzw modifizierte und weiterentwickelte ”Response-to-injury“-Hypothese stellt nicht nur den heutigen Erkenntnisstand, sondern auch die Integration der Lipidhypothese Virchows mit der Inkrustationstheorie von Rokitanskys dar. Diese Frage war auch bereits Gegenstand heftiger Diskussionen zwischen den Vätern der modernen Pathologie Rudolf von Virchow und Karl von Rokitansky, wobei letzterer die entzündliche Komponente der Erkrankung für sekundär hielt und sich mit dieser Meinung durchsetzte. Aus heutiger Sicht könnte jedoch von Virchow recht behalten, der die Entzündung im Rahmen der Atherosklerose als das primäre Ereignis einschätzte. Demnach handelt es sich bei der Entstehung der Atherosklerose um einen komplexen Vorgang, der durch eine vielgestaltige Wechselwirkung zwischen Endothel, glatten Muskelzellen der Tunica media der Arterien, Blutplättchen, Monozyten bzw. Makrophagen, aktivierten T-Lymphozyten sowie Wachstums-faktoren und Zytokinen charakterisiert ist ( ). Der Prozeß beeinhaltet die Formation der atherosklerotischen Läsionen, beginnend mit dem Auftreten von isolierten Schaumzellen (Stadium #1 nach Stary), über deren Entwicklung zu den ”Fatty streaks“ (Stadium #2) und das Fortschreiten dieser Läsionen zu Präatheromen (Stadium #3) und Atheromen (Stadium #4) bis hin zu den Fibro-atheromen (Stadium #5) ( , ). Im Verlauf der Evolution und Progression der atherosklerotischen Läsionen kommt es zur Proliferation von glatten Muskelzellen, Makrophagen und Lymphozyten; zur Formation einer extrazellulären Matrix bestehend aus Kollagen, Proteoglykanen und elastischen Fasern sowie zur Akkumulation von Lipiden und freiem bzw. verestertem Cholesterin in den beteiligten Zellen und der umgebenden Matrix ( ). Das initiale Ereignis der Atherogenese besteht nach dem Paradigma der ”Response-to-injury“-Hypothese in einer ”Verletzung“ des Endothels durch verschiedene Risikofaktoren, welche zu einer endothelialen Dysfunktion führt, die eine Kette von zellulären Interaktionen triggert, welche in der Ausbildung der atherosklerotischen Läsionen kulminiert ( ). Eine Schlüsselkomponente dieser ”Verletzung“ ist mit großer Wahrscheinlichkeit oxidiertes LDL-Cholesterin ( ). Die endotheliale Dysfunktion manifestiert sich insbesondere an den Aufzweigungen des arteriellen Baumes und führt zum Erscheinen von spezifischen Adhäsionsmolekülen an der Oberfläche der Endothelzellen ( , , , ). Monozyten und T-Lymphozyten binden an diese Rezeptoren und wandern unter dem Einfluß von Zytokinen und Wachstumsfaktoren, die durch das alterierte Endothel freigesetzt werden, durch die endotheliale Barriere ( , , , ). Nachdem die Monozyten die Intima der Arterienwand erreicht haben, führt die Aufnahme von oxidiertem LDL-Cholesterin über den LDL- und den Scavenger-Rezeptor der Monozyten zur Formierung von isolierten Schaumzellen, dem Stadium #1 der atherosklerotischen Läsionen nach Stary, und später zur Bildung der ”Fatty streaks“ (Stadium #2), welche durch eine erhöhte Akkumulation von Makrophagen sowie dem Auftreten von Schichten von Schaumzellen und lipidbeladenen glatten Muskelzellen charakterisiert sind ( , , ). Die kontinuierliche Einwanderung von diesen Zellen und deren Proliferation unter dem Einfluß der sezernierten Zytokine und Wachstums-faktoren bewirkt die Progression zu der präatheromatösen Läsion (Stadium #3), in der sich zusätzlich zu den Komponenten der ”Fatty streaks“ multiple extrazelluläre Lipidablagerungen in muskuloelastischen Schichten finden. Das Atherom im engeren Sinne (Stadium #4) ist zudem noch durch Ausbildung eines Lipidkerns gekennzeichnet, welcher durch Vergrößerung und Konfluieren der Lipidansammlungen aus dem Stadium #3 entsteht. Die Entwicklung einer kollagenösen Deckplatte durch Veränderung der oberen Intima unterscheidet das Fibroatherom (Stadium #5) vom vorhergehenden Atherom ( ). (siehe ) Carl von Rokitansky Rudolf Virchow „Inflammation accompanies atherosclerosis“ „Inflammation initiates atherosclerosis“ Rolitansky; A manual of pathologic anatomy. 1852 Virchow R. Der ateromatöse Prozess der Arterien. Wien Med Wschr 1856

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

Early Atherosclerotic Lesions - endothelial inflammatory activation
“Fatty streak” Macrophage staiing (A) Cross section of a fatty streak lesion from the aorta of a cholesterol-fed rabbit immunostained for a macrophage-specific marker. (Micrograph courtesy of Wulf Palinski.) Rechts: LDL is subject to oxidative modifications in the subendothelial space, progressing from minimally modified LDL (mmLDL), to extensively oxidized LDL (oxLDL). Monocytes attach to endothelial cells that have been induced to express cell adhesion molecules by mmLDL and inflammatory cytokines. Adherent monocytes migrate into the subendothelial space and differentiate into macrophages. Uptake of oxLDL via scavenger receptors leads to foam cell formation. OxLDL cholesterol taken up by scavenger receptors is subject to esterification and storage in lipid droplets, is converted to more soluble forms, or is exported to extracellular HDL acceptors via cholesterol transporters, such as ABC-A1. Atherosclerotic lesions begin as fatty streaks underlying the endothelium of large arteries Glass et al. Cell 2001; 104,503–516

Immune components of the atherosclerotic plaque:
Innate and adaptive immune response Figure 1 Immune components of the atherosclerotic plaque. The atheroma has a core of lipids, including cholesterol crystals, living and apoptotic cells and a fibrous cap with smooth muscle cells and collagen. Plasma lipoproteins accumulate in the subendothelial region. Several types of cells of the immune response are present throughout the atheroma including macrophages, T cells, mast cells and DCs. The atheroma builds up in the intima, the innermost layer of the artery. Outside the intima, the media contains smooth muscle cells that regulate blood pressure and regional perfusion, and further abluminally, the adventitia continues into the surrounding connective tissue. Here, cells of the immune response accumulate outside advanced atheroma and may develop into tertiary lymphoid structures with germinal centers. APC, antigen-presenting cell. Hansson GK & Hermansson A. Nature Immunology 2011;12(3):

Cross talk between inflammatory cells and intrinsic vascular wall cells mediated by cytokines
T Lymphocyte Antigen receptor Foreign class II HLA on the surface of vascular cells Endothelial Cell Smooth Muscle Cell IL-1 TNF PDGFc TGF-α IL-2 IL-2-R IFN-γ LT Macrophage/Monocyte IL-1 IL-6 MPO IL-1 IL-6 Interleukin 6, an inflammatory cytokine produced mainly by T cells, macrophages, and adipocytes, promotes infl ammatory responses via the membrane-bound or circulating soluble interleukin-6 receptor (IL6R) on monocytes, hepatocytes, and endothelial cells2 Libby P. Arterioscler Thromb Vasc Biol. 2012;32:

Relative risk of future myocardial infarction is
increased according to baseline IL-6 concentration Median baseline IL-6 levels according to number of traditional risk factors present (hypertension, hyperlipidemia, smoking, diabetes, age >60 years, family history, and body mass index >27.3 kg/m2). Baseline IL-6 levels according to number of traditional risk factors Ridker P et al. Circulation 2000;101:

Receptor composition for Interleukin-6 signaling via the β-receptor subunit gp130
Figure 1 Receptor composition for cytokines signaling via the β-receptor subunit gp130. gp130-related cytokines (IL-6, IL-11, IL-27, CNTF, CLC, CT-1, LIF, OSM) bind membrane-bound receptor complexes, which all contain the receptor subunit gp130. These cytokines have diverse functions, not limited to but including the induction of acute phase response protein expression; lymphocyte activation; cytoprotective actions on cardiomyocytes, neuronal cells, and hepatocytes; bone metabolism; hematopoiesis; and liver development and regeneration. IL-6 trans-signaling through the IL-6/sIL-6R complex can fulfill functions of other gp130 cytokines, including blockade of embryonic stem cell differentiation. In addition, since gp130 is expressed in all cells of the body, the IL-6/sIL-6R complex can stimulate cells in additional tissues, which do not express IL-6R, LIF receptor (LIFR), OSMR, IL-11R, CNTF receptor (CNTFR), or the IL-27 receptor subunit WSX-1. Jones S et al. J Clin Invest 2011;121(9):

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

- Hepatic IL-6 signaling improves local and systemic insulin action
Highlights - Hepatic IL-6 signaling improves local and systemic insulin action - Hepatocyte IL-6 signaling limits inflammatory cytokine expression in liver We here propose that IL-6 may favor the recycling of cholesterol by human macrophages and thus contribute to the resolution of local inflammation by eliminating the proinflammatory material from the site of inflammation. Such a protective effect may be indeed beneficial in inflammatory atherosclerotic lesions in coronary artery disease patients. 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 Sep 8;12(3):

IL6R genotype and risk of coronary heart disease
Association of IL6R rs with secondary and safety endpoints

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

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

Conclusions In patients with active rheumatoid arthritis, tofacitinib monotherapy was associated with reductions in signs and symptoms of rheumatoid arthritis and improve- ment in physical function

Cross talk between inflammatory cells and intrinsic vascular wall cells mediated by cytokines
T Lymphocyte Antigen receptor Foreign class II HLA on the surface of vascular cells Endothelial Cell Smooth Muscle Cell IL-1 TNF PDGFc TGF-α IL-2 IL-2-R IFN-γ LT Macrophage/Monocyte IL-1 IL-6 IL-1 IL-6 Interleukin 6, an inflammatory cytokine produced mainly by T cells, macrophages, and adipocytes, promotes infl ammatory responses via the membrane-bound or circulating soluble interleukin-6 receptor (IL6R) on monocytes, hepatocytes, and endothelial cells2 Libby P. Arterioscler Thromb Vasc Biol. 2012;32:

Lipid mediators, inflammation and atherogenesis:
Role of the NLRP3 inflammasom Figure 4 Lipid mediators affect inflammation and atherogenesis through diverse signaling pathways. OxLDL binds CD36, inducing intracellular CD36-TLR4-TLR6 heterotrimerization, which activates NF-κB and chemokine expression by lesional macrophages. Atherogenic lipid mediators, such as oxLDL, oxidized phospholipids and lipoproteins and fatty acids, also trigger NADPH oxidase activation through a CD36-TLR2-TLR6 pathway, resulting in a sustained oxidative burst and apoptosis of ER-stressed cholesterol-overloaded foam cells. Furthermore, an intracellular excess of free cholesterol, for example due to defective cholesterol efflux by ABC transporters, can modify receptor presentation and signaling by increasing lipid raft formation, which in hematopoietic stem cells induces myeloproliferation due to enhanced IL-3 and GM-CSF-signaling. Also, intracellular cholesterol crystals can exert proatherogenic effects by stimulating IL-1β production by macrophages through NLRP3 inflammasome activation. Lipids can also affect endothelial cell functions—the phospholipase Lp-PLA2 hydrolyzes oxLDL-associated phospholipids into oxidized fatty acids and lysophosphatidylcholine (LPC), and the derivative lysophosphatidic acid (LPA) triggers endothelial cells to secrete and present CXCL1 for monocyte adhesio. Thus, oxLDL and associated lipids act on diverse cell types to instigate inflammation and proatherogenic processes. CASP1, caspase 1. Weber C & Noels H. Nature Medicine 2011;17(11):

Balancing the IL-1β system in cardiovascular disease ?
Balancing the IL-1β system and its contributions to human disease. MWS indicates Muckle-Wells syndrome; NOMID, neonatal-onset multisystem inflammatory disease. Ridker PM et al. American Heart Journal 2011;162(4):

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

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 The Canakinumab Anti-inflammatory Thrombosis Outcomes Study This study proposes to address directly whether, compared with placebo, IL-1β inhibition can reduce the rates of recurrent myocardial infarction, stroke and cardiovascular-associated death among stable patients with coronary artery disease on a background of standard-care therapy (P.M.R., T. Thuren, A. Zalewski and P.L., manuscript in preparation). Canakinumab, a human monoclonal antibody, neutralizes the pro-inflammatory cytokine IL-1β, which is implicated in atherothrombosis. Cholesterol crystals stimulate the NLRP3 inflammasome, which generates the active form of IL-1β (refs 95, 96) (Fig. 1c). Canakinumab significantly reduces levels of inflammatory biomarkers such as CRP, and is currently used to treat inherited IL-1β-driven inflammatory diseases such as Muckle–Wells syndrome. Because IL-1β may participate in autoimmune processes related to pancreatic dysfunction and insulin resistance, this study also has a secondary prespecified end point of new-onset diabetes. If successful, the trial would support the inflammatory hypothesis of atherothrombosis, and provide a new cytokine-based therapy for the secondary prevention of cardiovascular disease and new-onset diabetes. Ridker PM et al. American Heart Journal 2011;162(4):

Canakinumab: Dose-response effects of at 4 months for C-reactive protein (CRP), interleukin-6 (IL-6), and fibrinogen in placebo-subtracted analyses. Dose-response effects of canakinumab 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:

in systemic JIA with active systemic features.
N Engl J Med Dec 20;367(25): Conclusions: These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features.

Reduced Risk for CVD associated with methotrexate use
Figure 2. Risk for CVD associated with methotrexate use, including 8 prospective and 2 retrospective cohort studies, 66,334 participants, and 6,235 events. Random-effects meta-analysis was used to calculate the overall pooled RR, in the presence of statistical between-study heterogeneity (p 0.10). Solid diamonds and lines are study-specific RRs and 95% CIs, respectively; the size of each box is weighted by the inverse variance of each study. Dashed line and open diamond are pooled RR and 95% CI, respectively, combining each study-specific RR. *Assessed other RA medication compared to methotrexate as the reference group. The RR of methotrexate versus other RA medications was calculated by pooling the inverse RRs of all other RA medications, using fixed-effects meta-analysis. IHD ischemic heart disease. Micha R et al. Am J Cardiol 2011;108(9):

Mechanisms of anti-inflammatory effects
exerted by low dose methotrexate Figure 2 Anti-inflammatory effects exerted by low dose MTX at the level of the synovial tissue in RA. (A) MTX reduces monocytic cell growth and increases their apoptosis. (B) MTX decreases the IL1 and IL6 secretion and increases IL1ra production. At the same time,MTX increases IL4 and IL10 gene expression and decreases gene expression of proinflammatory Th1 cytokines (IL2 and IFNã). (C) MTX seems to exert indirect inhibition of COX-2 synthesis and neutrophil chemotaxis. (D) MTX exerts indirect inhibitory effects (through modulation of cytokines) on synovial metalloproteinase (MMP) production and stimulates their inhibitors (TIMP) (E).MTX = methotrexate; IL1ra = interleukin-1 receptor antagonist; IFNã = interferon ã;COX-2 = cyclo-oxygenase-2;MMP = metalloproteinase; TIMP = tissue inhibitor of metalloproteinase. Cutolo M et al. Ann Rheum Dis 2001;60:729–735

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 label active run-in low-dose methotrexate (5-15 mg wk-1) Randomized low-dose methotrexate mg wk-1 + folate Methotrexate is an inexpensive generic drug The cardiovascular inflammation reduction trial This trial proposes to randomly allocate stable patients with post-myocardial infarction, who are receiving a complete standard-care regimen (including high-dose statin therapy), to either low-dose methotrexate (10–15 mg per week) or placebo94. The treatment of rheumatoid arthritis routinely uses low-dose methotrexate, which has anti-inflammatory efficacy and an acceptable safety record among patients with similar age and co-morbidity status as individuals with stable coronary disease. Data from seven non-randomized observational cohorts of patients with rheumatoid arthritis or psoriatic arthritis demonstrate significant reductions in vascular event rates and cardiovascular death among individuals taking low-dose methotrexate rather than other disease-modifying agents. As low-dose methotrexate is a generic drug, a successful outcome for the trial would provide a simple, cost-effective method to address residual risk related to inflammation. Supported by the National Institutes of Health Ridker PM. J Throm Haemost 2009; 7 (Suppl. 1): 332–9

HDL: proposed anti-atherogenic effects
1. HDL-mediated promotion of RCT (reverse cholesterol transport) VLDL/ LDL CE CETP TG A-I ABCG1 A-I PLTP FC LDL-R CE FC CE Mature HDL LCAT Nascent HDL FC ABCA1 SR-BI ? Bile SR-BI HDL Macrophage 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. & Landmesser U. EMBO Mol Medicine 2012

Role of HDL function versus HDL cholesterol levels
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 TNFα + Baseline 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:

Role of HDL function versus HDL cholesterol levels
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 TNFα + TNFα + TNFα + Baseline TNFα 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 Clin Invest 2011;121:

Mechanismen pro-inflammatorischer vaskulärer Effekte des HDL bei Patienten mit koronarer Herzerkrankung Scavenger receptor Lox-1 Mineo C & Shaul PW. J Clin Invest Editorial zu: Besler C et al. & Landmesser U. J Clin Invest 2011;121(7):

Myeloperoxidase leads to oxidative inactivation of paraoxonase-1 (PON-1) in coronary disease
under inflammatory conditions, MPO-mediated oxidative inactivation contributes to modulation of PON1 in vivo. Huang Y , Riwanto et al. & Landmesser U*, Hazen S*. J Clin Invest (in press)

Summary and conclusion
1. Experimental and large-scale genetic data suggest a causal role of inflammation in atherosclerosis. 2. Clinical studies evaluating whether clinical outcome in patients with coronary disease can be improved by anti-inflammatory strategies are under way. 3. An important question will be whether efficacy is enough to counterbalance potential side effects, such as increased risk of infection.

Inflammation in atherosclerosis – causal role ?

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