XVII. International Symposium on

Atherosclerosis (ISA)

Amsterdam, May 24-27, 2015

The pro-inflammatory state

as a risk factor for atherogenesis

Prof. Dr. Wolfgang Koenig, FESC, FAHA

Klinik für Herz- & Kreislauferkrankungen

Deutsches Herzzentrum München

Technische Universität München

Session: Inflammation, the Immune System & Atherosclerosis

Inflammation and Atherothrombosis

Peter Libby „A Fire Within“Scientific American; May 2002

Foam Cell

FattyStreak

IntermediateLesions

Atheroma FibrousPlaque

ComplicatedLesion/Rupture

Acute Phase Reactants

hsCRP, SAA, Fibrinogen, WBCC

Short-term vslong-term prediction

1° & Messenger Inflamm Chemokines

Cellular Adhesion Molecules

Plaque Destabilization +

Plaque Rupture

▪ IL-1▪ TNF-α

▪ IL-6▪ IL-18▪ MCP-1

▪ sICAM▪ sVCAM▪ sSelectins▪ ADMA

▪ IL-18▪ oxLDL▪ LpPLA2

▪ GPx-1

▪ MPO▪ MMPs▪ MCP-1▪ PlGF

▪ PAPP-A▪ sCD40L

▪ Neopterin

▪ sPLA2

+

Koe

nig

W &

Khu

seyi

nova

N A

TV

B 2

007;

27:1

5-26

Inflammation, Plaque Instability and Rupture:

From Foam Cell to Plaque Rupture

Labarrere & Zaloga. Am J Med 2004;117:499-507

Atherothrombosis:

a Systemic Low-Grade Inflammatory Disease

Chronic Inflammation

as a Risk Factor for Atherosclerosis

Clinical Evidence

If the „inflammation hypothesis“ is true,

chronic inflammatory diseases should be

associated with excess morbidity and

mortality from cardiovascular events.

Inflammation in Other Chronic,

Non-Infectious Diseases

Obesity Renal Insuffciency

Metabolic Syndrome Dementia

Type 2 Diabetes Depression

COPD Malignancies

Sleep Disorders RA, SLE, Psoriasis

Adiposetissue

TNF-α

IL-6

Resistin

Adiponectin

Leptin

mod. after Fasshauer et al. Dtsch Ärztebl

2004;101:3491-3495

Adipose tissue expresses variousproteins, so-called adipokines,

that are affecting energy metabolism and insulin sensitivity.

Adipokines: Obesity-Associated Hormones

CRP,

PAI-1

Kaplan-Meier Curves for CHD Events and Incident

T2DM stratified for CRP (</≥ 3 mg/L) and MetS

Sattar et al. Circulation 2003;108:414-419

% CHD Events14

12

10

8

6

4

2

0

8

6

4

2

0

% Incident Diabetes

0 1 2 3 4 5 6 0 1 2 3 4 5 6

Years Years

MS,

CRP≥3

MS,

CRP<3

no MS,CRP≥3

no MS,CRP<3

MS,

CRP≥3

MS,

CRP<3

no MS,CRP≥3

no MS,CRP<3

Inflammation in Type 2 Diabetes

IKKβ

NF-κB

Cytokines

•♦IL-6

•♦IL-1β

•♦TNF-α

•Resistin

♦IFN-γ

♦Lymphotoxins

IL-7, 8

IL-11, 12

IL-13, 15

IL-4

Chemokines

•♦MCP-1

♦MIP-1α, β

♦MIP-2

♦MIP-3α

Receptors

♦CD40

IL-6R, IL-1R

•TNFR p75

•TNFR p55

IFNα, β,γR

Surface Proteins

♦E-Selectin

♦P-Selectin

♦ICAM1

♦VCAM1

♦CD40 ligand

♦IgGs

Receptors

•IKKβ

•♦NF-κB RelA, p50

C-Jun, FosB, JunB

Others

•♦PAI1

•♦SAA

•♦CRP

♦Cox2

•♦iNOS

♦VEGF

♦A20

♦MMPs

Selected NF-κB responsive genes with potential roles in insulin resistance and T2D (•) or CHD (♦).

Herder et al. Clin Pharmacol & Therapeutics 2011;10.1038:1-15

Contribution of Novel Multiple Biomarkers to the

Prediction of Type 2 Diabetes

The Potential Role of Systemic Inflammation in

Chronic Obstructive Pulmonary Disease

High CRP is defined as >10 mg/L

Sin & Man. Circulation 2003;107:1514-1519

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

High Severe High CRPCRP Obstruction +Severe

Obstruction

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

High Moderate High CRPCRP Obstruction +Moderate

Obstruction

Car

diac

Infa

rctio

nIn

jury

Sco

re

P for trend=0.001 P for trend=0.001

Car

diac

Infa

rctio

nIn

jury

Sco

re

n=20

n=22

Elevated C-Reactive Protein in Patients

With Obstructive Sleep Apnoe (OSA)

Shamsuzzaman ASM et al. Circulation 2002;105:2462-2464

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

p<0.0003

Control subjects Patients with OSA

CR

P (

mg/

dL)

Renal Insufficiency (RI) and Inflammation: CHS

Shlipak et al. Circulation 2003;107:87-92

*Adjusted for age, race, sex, education, history of diabetes, history of hypertension, systolic and diastolic BP, LDL, HDL, triglycerides, smoking status, alcohol, physical activity in kilocalories, BMI, and cardiovascular disease status.

Data are presented as mean ± SEM. RI indicates renal insufficiency.

Biomarker * No RI RI P

CRP, mg/L 4.4 ± 0.2 (n=4936) 5.5 ± 0.3 (n=608) < 0.0001

Fibrinogen, mg/dL 331.7 ± 2.0 (n=4926) 331.7 ± 3.1 (n=607) < 0.0001

IL-6, pg/mL 2.7 ± 0.1 (n=2030) 3.1 ± 0.2 (n=245) 0.007

ICAM-1, ng/mL 329.9 ± 4.6 (n=1905) 339.0 ± 6.7 (n=252) 0.13

Factor VII, % 114.4 ± 0.8 (n=4896) 126.1 ± 21.2 (n=597) < 0.0001

Factor VIII, % 131.1 ± 1.5 (n=4352) 144.9 ± 2.0 (n=548) < 0.0001

PAP, nmol/L 6.4 ± 0.1 (n=2162) 7.7 ± 0.2 (n=274) < 0.0001

D-dimer, ng/mL 342.3 ± 32.2 (n=2143) 501.0 ± 47.2 (n=273) 0.0002

OR

(95

% C

I)

All Dementia Alzheimer‘s Disease

Association Between Midlife CRP Levels and Late-Life Dementia: Honolulu-Asia Aging Study (1,050)

0.00.51.01.52.02.53.03.54.04.55.05.56.0

Model 1 Model 2 Model 1 Model 2

Ref Ref Ref Ref

Quartile 1

Quartile 2

Quartile 3

Quartile 4

Model 1: Adjusted for level of education, midlife smoking status, midlife average cholesterol, midlife BP, age at examination 2, years of FU, any apo E ε4, and BMI at examination 2Model 2: model 1 and stroke, CHD, LVH, atrial fibrillation, DM, and ABI at the time of dementia assessment

Schmidt et al. Ann Neurol 2005;52:168-174

25 year FU

CRP, Depressed Mood and the Prediction of CHD

in Initially Healthy Men: MONICA/KORA 7.7 Yrs FU

Ladwig et al Eur Heart J 2005;26:2537-2542CPHR; CRP <1, 1-3 and > 3mg/L

Colorectal and Colon Cancer by Quartile of

Baseline C-Reactive Protein

0

1

2

3

4

5

6

7

8

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

All Participants p for Trend = 0.008Nonsmokers p for Trend = 0.004

Colorectal cancer Colon cancer

32/85 24/74 36/86 34/76 44/86 39/76 60/85 54/75 20/59 15/53 27/68 24/63 34/71 30/63 50/62 45/53

OR

(95

% C

I)

Q1 = <0.92mg/L Q2 = 0.92-1.93 mg/L Q3 = 1.94-3.69 Q4 = >3.69 mg/L

Erlinger et al. JAMA 2004;291:585-590

All Participants p for Trend = 0.002Nonsmokers p for Trend < 0.001

Pasceri & Yeh. et al. Circulation 100:2124-2126, 1999

Atherosclerosis and Rheumatoid Arthritis:

Do They Have Anything in Common?

Similarities Between Atherosclerosis and

Rheumatoid Arthritis

Macrophage activation: TNF-α ↑ ↑

Metalloproteinase expression ↑ ↑

Interleukin-6 ↑(UA) ↑

Mast-cell activation ↑ ↑

T-cell activation: Soluble IL-2 receptor ↑(UA) ↑

CD31DR ↑(UA) ↑

CD41CD282 ↑(UA) ↑

CD41IFNg ↑(UA) ↑

Th1/Th2 balance ↑ Th 1 ↑ Th 1

B-cell activation: Autoantibodies (oxLDL, HSP) 0 or ↑ 0 or ↑

Rheumatoid factor 0 ↑ ↑

C-reactive protein ↑ (UA) ↑

Adhesion molecules: VCAM-1,ICAM-1, E-, P-selectin ↑ ↑

Endothelin ↑ ↑

Neoangiogenesis ↑ ↑

Possible antigens HSP, Ox-LDL Infect. agents

Collagen II, Cartilage antigens, HSP, Infect. agents

Pasceri & Yeh. et al. Circulation 1999;100:2124-2126

Atherosclerosis Rheumatoid Arthritis

1.68 (1.34-2.11)†12.71,218nested case-

controlpopulation-

basedKremers

2.00 (1.23-3.29)If RA >10 yrs

3.10 (1.64-5.87)21114,342cohortNHSSolomon

1.61 (1.21-2.10)2.51,022cohortcommunity-based

Jarenros

RR (95% CI)FU (y) NDesignStudyAuthor

Chronic Rheumatoid Arthritis is Burdened

by an Excess Coronary Risk and Total Mortality†

Synergistic relationshipbetween RA and MI

(Kremers et al.)

No MI MI

Non RA 1.0 4.80 (3.54-6.50)RF-RA 1.38 (1.09-1.75) 4.27 (2.78-6.55)RF+RA 1.68 (1.34-2.11) 11.46 (7.85-16.72)

Anti-TNF-α treatment improves EC function in patients with RA

Methotrexat downregulates T-cell activation and reduces CV risk

Solomon et al. Circulation 2003;107:1303; Choi et al. Lancet 2002;359:1173;

Hürliman et al Circulaton 2003;106:2184; ACR 66th Annual Scientific Meeting; Oct 25-29, 2002

Is RA a Proatherogenic Disease?

Is Atherosclerosis an Extraarticular Feature of RA?

Of 21 observational studies, 17 show increased

standardized mortality compared to non-RA patients, of

which 35 to 50 percent of the excess being attributable

to CHD

Most studies suggest that this excess in the RA population is not accounted for by traditional CV risk factors

Van Doornum et al. Arthritis Rheum 2002;46:862-73

Del Rincoan et al. Arthritis Rheum 2001;44:2737-2745

Systemic Lupus Erythematosus (SLE)

and Cardiovascular Events

Women, aged 35-44 years with SLE had a relative risk for acute myocardila infarction of 52.4 (95% CI, 21.6-98.5) compared to women of similar age from the Framingham Offspring Study

Manzi et al. Am J Epidemiol 1997;145:408-415.

Risk of Myocardial Infarction

in Patients With Psoriasis

Gelfand et al. JAMA 2006;296:1735-1741.

Meta-analysis of the Influence of Diverse CID

Conditions on Multiple CV and T2DM Outcomes

Dregan et al. Circulation 2014;130:837-844CID = Chronic Inflammatory Disorder

Dose-Response Relationship Between Tertiles*

of Mean CRP Levels and Study Outcome

Dregan et al. Circulation 2014;130:837-844

Summary and Conclusion

Indeed, based on large and diverse prospective

observational studies, a pro-inflammatory state

is associated with an increased risk for clinical

manifestations of atherosclerosis

Yet the verdict is still out whether inflammation

is a causal factor in the complex pathophysiology

of atherosclerosis

Large randomized clinical trials are under way to

finally test this hypothesis