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The inflammatory process and
cardiovascular events: What are
the targets for interventon?
Prof. Ulf Landmesser
University Hospital Zurich
Zurich, Switzerland
Seite 1
The Inflammatory process and
cardiovascular events:
What are the targets for intervention ?
1.
Inflammation in atherosclerosis – causal role ?
2. 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 ?
Seite 2
Role of inflammation in atherosclerosis ?
- A fierce debate started in the 19th century Both observed cellular inflammatory changes in the atherosclerotic vessel walls
Carl von Rokitansky
„Inflammation accompanies
atherosclerosis“
Rolitansky;
A manual of pathologic anatomy. 1852
Rudolf Virchow
„Inflammation initiates
atherosclerosis“
Virchow R. Der ateromatöse Prozess
der Arterien. Wien Med Wschr 1856
Seite 3
Atherosclerosis development: endothelial inflammatory
activation - electron microscopy studies
Subendothelial LDL particles
Transmigration
of monocytes
Aldis JL, Nature. 2000 Feb 21;451(7181):904-13
Seite 4
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
Seite 5
Seite 6
Immune components of the atherosclerotic plaque:
Innate and adaptive immune response
Hansson GK & Hermansson A. Nature Immunology 2011;12(3):204-212
Seite 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
MPO
IL-1
IL-6
Macrophage/Monocyte
IL-1
Endothelial Cell
TNF
PDGFc
TGF-α
IL-1
PDGFc
Smooth Muscle Cell
Libby P. Arterioscler Thromb Vasc Biol. 2012;32:2045-2051
Seite 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
Seite 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
Seite 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.
Seite 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.
Seite 12
IL6R genotype and risk of coronary heart disease
Association of IL6R rs7529229 with secondary and safety endpoints
Seite 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.
Seite 14
Janus kinase (JAK)-inhibition as an
anti-inflammatory treatment
O'Shea JJ et al. N Engl J Med 2013;368:161-170.
Seite 15
Conclusions
In patients with active rheumatoid arthritis, tofacitinib monotherapy was associat- ed with reductions
in signs and symptoms of rheumatoid arthritis and improve- ment in physical function
Seite 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
Endothelial Cell
TNF
PDGFc
TGF-α
IL-1
PDGFc
Smooth Muscle Cell
Libby P. Arterioscler Thromb Vasc Biol. 2012;32:2045-2051
Seite 17
Lipid mediators, inflammation and atherogenesis:
Role of the NLRP3 inflammasom
Weber C & Noels H. Nature Medicine 2011;17(11):1410-1422
Seite 18
Balancing the IL-1β system in
cardiovascular disease ?
Ridker PM et al. American Heart Journal 2011;162(4):597-605
Seite 19
Mechanisms of Canakinumab – an IL-1b targeted therapy
Hoffmann HM. J Allergy Clin Immunol 2009; 124(6):1129-1138
Seite 20
Canakinumab Anti-inflammatory Thrombosis
Outcomes Study (CANTOS) – study design
17,200
randomized
participants
→ 1:1:1:1.5 allocation ratio betw
•canakinumab 50 mg quartl.
•canakinumab 150 mg quartl.
•Canakinumab 300 mg quartl.
•Placebo
Ridker PM et al. American Heart Journal 2011;162(4):597-605
Seite 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
Seite 22
N Engl J Med. 2012 Dec 20;367(25):2396-406.
Conclusions: These two phase 3 studies show the efficacy of canakinumab
in systemic JIA with active systemic features.
Seite 23
The Inflammatory process and
cardiovascular events:
What are the targets for intervention ?
1.
Inflammation in atherosclerosis – causal role ?
2. 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 ?
Seite 24
Reduced Risk for CVD associated with methotrexate use
Micha R et al. Am J Cardiol 2011;108(9):1362-1370
Seite 25
Mechanisms of anti-inflammatory effects
exerted by low dose methotrexate
Cutolo M et al. Ann Rheum Dis 2001;60:729–735
Seite 26
The cardiovascular inflammation reduction trial (CIRT)
– Study design -
Open label active run-in
low-dose methotrexate (5-15 mg wk-1)
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.
Randomized
low-dose methotrexate
15-20 mg wk-1 + folate
Supported by the National Institutes of Health
Ridker PM. J Throm Haemost 2009; 7 (Suppl. 1): 332–9
Seite 27
Seite 28
The Inflammatory process and
cardiovascular events:
What are the targets for intervention ?
1.
Inflammation in atherosclerosis – causal role ?
2. 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 ?
Seite 29
HDL: proposed anti-atherogenic effects
1. HDL-mediated promotion of RCT
(reverse cholesterol transport)
VLDL/
LDL
CE
TG
PLTP
LDL-R
FC
Bile
CETP
CE
A-I
FC
A-I
CE
Mature
HDL
LCAT
FC
Nascent
HDL
SR-BI
HDL
ABCG1
ABCA1
SR-BI ?
Macrophage
2. Direct HDL-mediated endothelial-protective potential antiatherogenic effects
Anti-apoptotic
Effects
Endothelial NO
Production
Endothelial Repair
Anti-inflammatory
Effects
Anti-thrombotic
Effects
Besler C et al. & Landmesser U. EMBO Mol Medicine 2012
Seite 30
Role of HDL function versus HDL cholesterol levels ?
Number of GCSF-labeled monocytes
per high power field
Different effects of HDL from patients with CAD on inflammatory activation
35
P < 0.05
P < 0.05
30
25
20
15
10
5
0
Baseline
TNFα
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: 2693-708
Seite 31
Role of HDL function versus HDL cholesterol levels ?
Number of GCSF-labeled monocytes
per high power field
Different effects of HDL from patients with CAD on inflammatory activation
n.s.
35
P < 0.05
P < 0.05
30
25
20
15
10
5
0
Baseline
TNFα
TNFα +
Healthy
HDL
TNFα +
Stable CAD
HDL
TNFα +
ACS
HDL
Effect of HDL on monocyte adhesion to
TNFα-stimulated endothelial cells
Besler C et al. & Landmesser U. J Clin Invest 2011;121: 2693-708
Seite 32
Mechanismen pro-inflammatorischer vaskulärer Effekte
des HDL bei Patienten mit koronarer Herzerkrankung
Mineo C & Shaul PW. J Clin Invest 2011 - Editorial zu:
Besler C et al. & Landmesser U. J Clin Invest 2011;121(7):2693-708
Seite 33
Myeloperoxidase leads to oxidative inactivation of
paraoxonase-1 (PON-1) in coronary disease
Huang Y , Riwanto et al. & Landmesser U*, Hazen S*. J Clin Invest 2013 (in press)
Seite 34
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.