Inflammation and atherosclerosis - Semantic Scholar...CHS/RHPP (Tracy 1997) PHS (Ridker 1998) WHS...

Inflammation and atherosclerosis

Dr Khamis Al hashmi MD PhD.

Assistant professor

Department of Physiology and Clinical Physiology

COM&HS, SQU

IAS-OSLA Course “Lipid Metabolism and Cardiovascular Risk” Muscat, Oman, 8-10 February 2015

Outlines

• Process of Atherosclerosis

• Role of lipoproteins (LDL & VLDL) in inflammation

• Inflammatory marker as risk factors for CVD

• Inflammatory markers as target for therapy

Atherosclerosis

• Disease of cardiovascular system affecting vessel wall.

• It leads to the narrowing of arteries or complete blockage.

• Its main components are endothelial disfunction, lipid deposition, inflammatory reaction in the vascular wall.

• Remodeling of vessel wall.

Atherosclerosis

• Intense cross-talk between EC, VSMC, plasma-derived inflammatory cells, lymphocytes (involves array of chemokines, cytokines, growth factors).

• Attraction of cells to the sites of atherosclerotic lesion.

• Migration, proliferation, apoptosis, excess production of extracellular matrix.

Arterial wall: structure and function

The development of atherosclerosis

• The key event – damage to the endothelium caused by excess of lipoproteins, hypertension, diabetes, components of cigarette smoke.

• Endothelium becomes more permeable to lipoproteins. • Lipoproteins move below the endothelial layer (to intima). • Endothelium loses its cell-repelent quality. • Inflammatory cells move itno the vascular wall.

The development of atherosclerosis • Disfunctional endothelium express adhesion molecules –

selectins, mediated the „rolling“ interaction of cells. • The key molecule - vascular cell addhesion molecule-1

(VCAM-1) promotes monocytes adhesion (precursors of macrophages).

• Addhering cells are stimulated by monocyte chemoattractant protein-1 (MCP-1).

• Monocytes cross the endothelium, settle down in the intima.

Inflammation in atherosclerosis (mononuclear cells)

Fom the review article: Libby P.: Inflammation in atherosclerosis. Nature 420, 2002: 868-874

Endothelial cells undergo inflammatory activation, produce different leukocyte adhesion molecules (VCAM-1). Monocytes penetrate into tunica intima. Their receptor CCR2 interact with MCP-1

Inflammation in atherosclerosis (T-lymhocytes)


T-lymphocytes enter the intima facilitated by VCAM-1 and trio chemokines- IP-10 (inducible protein-1), Mig (monokine induced by interferon-g) and I-TAC (interferon-inducible T-cells a-chemoattractant). Trio chemokines bind to CXCR3 chemokine receptor expressed by T-cells in the atherogenic lesion.

Inflammation in atherosclerosis (mast cells)


Mast cells infiltrate to the intima. Chemoattractant eotaxin mediate migration of mast cells and interacts with the chemokine receptor CCR3. Resident mast cells in the intima degranulate, release TNF-a, heparin, and enzymes activating proMMPs.

The process of atherogenesis – an overview

The process of atherogenesis

• Lipid entry into the arterial wall is a key process in atherogenesis.

• Hypercholesterolemia – factor for VCAM-1 and MCP-1 induction.

• LDL and VLDL are most atherogenic, enter vascular wall more easily.

• LDL – in plasma are protected against oxidation by vit. E, ubiquinon, plasma antioxidants (b-carotene, vit. C).

• Out of plasma, LDL phospholipides and fatty acids oxidize.


• Activated macrophages produce enzymes – lipoxygenases, myeloperoxidase, NADPH oxidase ROS

• Oxidized LDL are cytotoxic to endothelial cells, mitogenic for macrophages.

• Oxidized LDL apolipoprotein apoB100 bind to the scavenger receptor.

• Scavenger receptors are not subjected to regulation by intracellular cholesterol level.

• Macrophages take up oxidized LDL, overload with lipids.


• Foam cells ruptured (apoptosis). • Lipid release to intima and their acumulation

becomes centre of atherosclerotic plaques.


• Plaque growth – periodically accelerated by a cycle of plaque rupture and thrombosis.

• This happens: – Active macrophages and T lymphocytes preferentially

reside at the edge of the plaque. – Macrophages secrete enzymes degrade extracellular

matrix of the cap (MMP – collagenases, gelatinases, and stromelysin)

– T-cells activated by macrophages secrete IFN-g and pro-inflammatory cytokines IL-1, IL-2, and TNF-a.


• IFN-g induces macrophage MMP expression. • IFN-g inhibits VSMC proliferation and collagen synthesis which

further weakening the cap. • VSMC undergo apoptosis. • After plaque rupture the area is exposed its interior to the

blood. • The interior of the plaque is highly thrombogenic – the small-

molecular-weight glycoprotein (tissue factor) initiates the extrinsic clotting cascade.

• Tissue factor complexes with factor VII/VIIa, factor IX and X are activated.

• Platelets are activated and thrombus forms quickly on the surface of a ruptured plaque.

• Thrombus completely occludes the arterial lumen. It cause tissue necrosis (myocardial infarction or brain stroke).

Role of lipoproteins in Inflammation

Lipoprotein Classes and Inflammation

Doi H, et al. Circulation. 2000;102:670-676; Colome C, et al. Atherosclerosis. 2000;49:295-302; Cockerill GW, et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994.

HDL LDL Chylomicrons, VLDL, and

their catabolic remnants

> 30 nm 20–22 nm

Potentially proinflammatory

9–15 nm Potentially anti-

inflammatory

Role of LDL in Inflammation

Steinberg D, et al. N Engl J Med. 1989;320:915-924.

Endothelium

Vessel Lumen

LDL

LDL Readily Enter the Artery Wall Where They May Be Modified

LDL

Intima

Modified LDL

Modified LDL Are Proinflammatory

Hydrolysis of Phosphatidylcholine to Lysophosphatidylcholine

Other Chemical Modifications

Oxidation of Lipids and Apo B

Aggregation

Slide source: www.lipidonline.org

LDL

LDL

Modified LDL Stimulate Expression of MCP-1 in Endothelial Cells

Navab M, et al. J Clin Invest. 1991;88:2039-2046.

Endothelium

Vessel Lumen

Intima

Monocyte

Modified LDL

MCP-1


LDL

LDL

Differentiation of Monocytes into Macrophages

Steinberg D, et al. N Engl J Med. 1989;320:915-924.

Endothelium

Vessel Lumen

Intima

Monocyte

Modified LDL

Modified LDL Promotes Differentiation of Monocytes into Macrophages

MCP-1

Macrophage


LDL

LDL

Modified LDL Induces Macrophages to Release Cytokines That Stimulate Adhesion Molecule Expression in Endothelial

Cells

Nathan CF. J Clin Invest. 1987;79:319-326.

Endothelium

Vessel Lumen Monocyte

Modified LDL

Macrophage

MCP-1

Adhesion Molecules

Cytokines

Intima


LDL

LDL Endothelium


Macrophage

MCP-1

Adhesion Molecules

Steinberg D et al. N Engl J Med 1989;320:915-924.

Macrophages Express Receptors That Take up Modified LDL

Foam Cell

Modified LDL Taken Up by Macrophage

Intima


LDL

LDL Endothelium


Macrophage

Adhesion Molecules

Macrophages and Foam Cells Express Growth Factors and Proteinases

Foam Cell

Intima Modified

LDL Cytokines

Cell Proliferation Matrix Degradation

Growth Factors Metalloproteinases

Ross R. N Engl J Med. 1999;340:115-126.

MCP-1


Endothelium


Macrophage

MCP-1 Adhesion Molecules

The Remnants of VLDL and Chylomicrons Are Also Proinflammatory

Foam Cell

Intima Modified Remnants Cytokines

Cell Proliferation Matrix Degradation

Doi H, et al. Circulation. 2000;102:670-676.

Growth Factors Metalloproteinases

Remnant Lipoproteins

Remnants


LDL

LDL

Miyazaki A, et al. Biochim Biophys Acta. 1992;1126:73-80.

Endothelium


Modified LDL

Macrophage


Cytokines

HDL Prevents Formation of Foam Cells

Intima HDL Promote Cholesterol Efflux

Foam Cell


LDL

LDL

Mackness MI, et al. Biochem J. 1993;294:829-834.

Endothelium


Modified LDL

Macrophage


Cytokines

HDL Inhibits the Oxidative Modification of LDL

Foam Cell

HDL Promotes Cholesterol Efflux Intima

HDL Inhibits

Oxidation of LDL


LDL

LDL

Cockerill GW, et al. Arterioscler Thromb Vasc Biol. 1995;15: 1987-1994.

Endothelium

Vessel Lumen

Monocyte

Modified LDL

Macrophage


Cytokines

Inhibition of Adhesion Molecules

Intima

HDL Inhibit Oxidation

of LDL

HDL Inhibits Adhesion Molecule Expression

Foam Cell

HDL Promotes Cholesterol Efflux


Inflammatory markers as risk for Cardiovascular diseases and target

for therapy

Risk Factors for Future Cardiovascular Events: WHS

Relative Risk of Future Cardiovascular Events

0

Ridker PM et al. N Engl J Med 2000;342:836-843.

Lipoprotein(a) Homocysteine IL-6 TC LDL-C sICAM-1 SAA Apo B TC:HDL-C hs-CRP hs-CRP + TC:HDL-C

1.0 2.0 4.0 6.0

hs-CRP as a Risk Factor for Future CVD

Relative Risk (upper vs lower quartile)

CHD Death

MI

Stroke

CHD

PVD

CVD

CHD

CHD

CHD

CHD

0

MRFIT (Kuller 1996)

PHS (Ridker 1997)

PHS (Ridker 1997)

CHS/RHPP (Tracy 1997)

PHS (Ridker 1998)

WHS (Ridker 1998, 2000)

MONICA (Koenig 1999)

Helsinki (Roivainen 2000)

Caerphilly(Mendall 2000)

Britain (Danesh 2000)

1.0 2.0 3.0 4.0 5.0 6.0

Relative Risks of Future MI among Apparently Healthy Middle-Aged Men: Physician’s Health Study

Relative Risk for Future MI

0 1.0 2.0 4.0 6.0

Lipoprotein(a)

Homocysteine

Fibrinogen

tPA Antigen

hs-CRP

hs-CRP + TC/HDL-C

Total Cholesterol

TC:HDL-C

Ridker PM. Ann Intern Med 1999;130:933-937. 1999 ACP-ASIM.

0.0

0.5

1.0

1.5

2.0

hs-CRP and Relative Risk of Recurrent Coronary Events: CARE

Ridker PM et al. Circulation 1998;98:839-844. 1998 Lippincott Williams & Wilkins.

1 0.66

P Trend = 0.044

0

1

2

3

Inflammation, Pravastatin, and Relative Risk of Recurrent Coronary Events: CARE

Ridker PM et al. Circulation 1998;98:839-844. 1998 Lippincott Williams & Wilkins.

Pravastatin

Rela

tive R

isk

Inflammation Absent

P Trend = 0.005

Placebo Pravastatin Placebo

Inflammation Present

Mean B

aseline (

mg/d

L)

Inflammation absent

Inflammation present

250

200

150

100

50

0 TC LDL-C HDL-C TG

Baseline Lipid Levels in Patients with and without Inflammation: CARE

Ridker PM et al. Circulation 1998;98:839-844.

Long-Term Effect of Pravastatin on hs-CRP: CARE Placebo and Pravastatin Groups

Adapted from Ridker PM et al. Circulation 1999;100:230-235. 1999 Lippincott Williams & Wilkins.

Pravastatin

Placebo

Media

n h

s-C

RP

Concentr

ation (

mg/d

L)

–21.6% (P=0.007)

0.25

0.24

0.23

0.22

0.21

0.20

0.19

0.18 Baseline 5 Years

CRP in Combination with LDL-C as a Method to Target Statin Therapy in Primary Prevention:

AFCAPS/TexCAPS


Study Group Lovastatin Placebo NNT

Low LDL-C/low CRP 0.025 0.022 _

Low LDL-C/high CRP 0.029 0.051 48

High LDL-C/low CRP 0.020 0.050 33

High LDL-C/high CRP 0.038 0.055 58

Median LDL-C = 149.1 mg/dL; Median CRP = 0.16 mg/dL

Event Rate

CRP in Combination with TC:HDL-C Ratio as a Method to Target Statin Therapy in Primary Prevention:

AFCAPS/TexCAPS


Study Group Lovastatin Placebo NNT

Low TC:HDL-C/low CRP 0.024 0.025 983

Low TC:HDL-C/high CRP 0.025 0.050 43

High TC:HDL-C/low CRP 0.021 0.050 35

High TC:HDL-C/high CRP 0.041 0.057 62

Median TC:HDL-C = 5.96; Median CRP = 0.16 mg/dL

Event Rate

0.0 0.5 1.0 1.5 2.0 2.5 0.0 0.5 1.0 1.5 2.0 2.5 0.0 0.5 1.0 1.5 2.0 2.5 0.0 0.5 1.0 1.5 2.0 2.5

0.0

0

0.0

2

0.0

4

0.0

6

0.0

8

0.1

0

0.0

2

0.0

4

0.0

6

0.0

8

0.1

0

Follow-Up (Years)

LDL > 1.8 mmol/L, CRP > 2 mg/L

LDL < 1.8mmo/L, CRP > 2 mg/L LDL > 1.8 mmol/L, CRP < 2 mg/L

LDL < 1.8mmol/L, CRP < 2 mg/L

Clinical Relevance of Achieved LDL and Achieved hsCRP

After Treatment with Statin Therapy PROVE IT–TIMI 22

Ridker et al NEJM 2005;352:20-28.

Rosuvastatin 20 mg (N=8901)

MI

Stroke

Unstable

Angina

CVD Death

CABG/PTCA

JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of

Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP

4-week

run-in

Ridker et al, Circulation 2003;108:2292-2297.

No Prior CVD or DM Men >50, Women >60

LDL 2 mg/L

JUPITER

Trial Design

Placebo (N=8901)

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,

Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,

Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,

United Kingdom, Uruguay, United States, Venezuela

JUPITER

Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Placebo 251 / 8901

Rosuvastatin 142 / 8901

HR 0.56, 95% CI 0.46-0.69

P < 0.00001

Number Needed to Treat (NNT5) = 25

- 44 %

0 1 2 3 4

0.0

0

0.0

2

0.0

4

0.0

6

0.0

8

Cu

mu

lati

ve I

nci

de

nce

Number at Risk Follow-up (years)

Rosuvastatin

Placebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157

8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

Summary • Several line of evidence indicate that

atherosclerosis is an inflammatory process

• Modified LDL is a key player in the trigger of inflammation and in progression of atherosclerosis

• Inflammatory markers such as hs-CRP are useful in cardiovascular risk stratification and found to be a useful target for therapeutic intervention.

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