Beruflich Dokumente
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review article
mechanisms of disease
Inflammation, Atherosclerosis,
and Coronary Artery Disease
Göran K. Hansson, M.D., Ph.D.
A C
Thrombus
Thrombus
Smooth-
* Endothelium muscle
cell
Ruptured
cap Lipid-rich core
Proteases,
prothrombotic
factors
T cell
Mast
cell
Macrophage
Microbes, autoantigens,
inflammatory molecules
than stenosis precipitates ischemia and infarction bosis: plaque rupture and endothelial erosion.
(Fig. 1). Coronary spasm may be involved to some Plaque rupture, which is detectable in 60 to 70 per-
extent, but most cases of infarction are due to the cent of cases,11 is dangerous because it exposes pro-
formation of an occluding thrombus on the sur- thrombotic material from the core of the plaque —
face of the plaque.10 phospholipids, tissue factor, and platelet-adhesive
There are two major causes of coronary throm- matrix molecules — to the blood (Fig. 1). Ruptures
from Th1 to Th2 may not necessarily lead to reduced Antiinflammatory Factors and Disease Activity
vascular disease. Powerful regulators built into the immune network
T-cell cytokines cause the production of large act as protective factors in atherosclerosis. They in-
amounts of molecules downstream in the cytokine clude two antiinflammatory cytokines, interleukin-
cascade (Fig. 5). As a result, elevated levels of inter- 10 and transforming growth factor b (TGF-b). Anti-
leukin-6 and C-reactive protein may be detected in body responses and metabolic factors can also
the peripheral circulation. In this way, the activation contribute to immune regulation. Gene targeting or
of a limited number of immune cells can initiate a pharmacologic inhibition of interleukin-10 aggra-
potent inflammatory cascade, both in the forming vates atherosclerosis in hypercholesterolemic mice
lesion and systemically. and exacerbates coronary thrombosis.48-50 Abroga-
tion of TGF-b signaling in T cells elicits a dramatic
phenotype, with rapid development of large, unsta-
Atherosclerotic ble atherosclerotic lesions.51 These effects indicate
plaque that T-cell–mediated immunity is under tonic inhibi-
Adipose tion by TGF-b and interleukin-10; removal of these
tissue
brakes on atherosclerosis accelerates the process.
Coronary Antibody-producing B cells, although not nu-
artery merous in lesions, contribute to antiatherosclerotic
activity, perhaps as a result of specific antibodies
against plaque antigens, binding of antibodies to
inhibitory Fc receptors, or cytokines produced by
B cells. Spleen B cells are particularly effective in-
Interferon-g, Interleukin-1 hibitors of atherosclerosis,52 possibly because
Interleukin-1, TNF
certain natural antibodies produced by some of
TNF
these cells recognize phosphorylcholine, a molecule
present in oxidized LDL, apoptotic cell membranes,
and the cell wall of Streptococcus pneumoniae.53 These
Interleukin-6
antibodies may contribute to the elimination of ox-
idized LDL and dead cells as well as to the defense
against pneumococcal infections. Interestingly, per-
sons who have undergone splenectomy have in-
creased susceptibility not only to pneumococcal in-
Liver
fections but also to CAD.54
infections and cad the plaque and may degrade its matrix. MMP activ-
Several studies have linked infections to atheroscle- ity is controlled at several levels: inflammatory cyto-
rosis and CAD. Elevated titers of antibodies against kines induce the expression of MMP genes, plasmin
chlamydia were found in patients with CAD,58 and activates proforms of these enzymes, and inhibitor
it was speculated that this microbe causes athero- proteins (tissue inhibitor of metalloproteinase) sup-
sclerosis. However, Chlamydia pneumoniae infection press their action. Similarly, cysteine proteases are
does not cause atherosclerosis in animals, although induced by certain cytokines and checked by inhib-
it may stimulate disease progression and plaque ac- itors termed “cystatins.”78 Several of these mole-
tivation.59,60 This could be due either to a direct ac- cules play decisive roles in the formation of aneu-
tion in plaques or to remote signaling by inflam- rysms, as shown by experiments in gene-targeted
matory mediators.61 Molecular mimicry between mice. However, mechanistic studies in models of
C. pneumoniae antigens and human molecules may atherosclerosis have yielded complex results, with
contribute to the activation of inflammation.62 certain MMPs reducing rather than increasing the
However, several recent secondary-prevention trials, size of the lesions. At the same time, these enzymes
including two reported in this issue of the Journal, clearly affect the composition of plaque. Therefore,
failed to prevent acute coronary syndromes by ad- they may represent future therapeutic targets. Study
ministering antibiotics targeting C. pneumoniae, sug- of plaque rupture in animal models should be help-
gesting that C. pneumoniae infection is not a predom- ful in determining the role of these proteases in the
inant cause of these syndromes.63-66 activation of plaque and myocardial infarction.
Herpes family viruses may also contribute to
CAD. Cytomegalovirus is found in lesions, can systemic indicators of inflammation
modulate immune-cell as well as vascular-cell activ- The inflammatory process in the atherosclerotic ar-
ity, and increases experimental atherosclerosis.67-69 tery may lead to increased blood levels of inflam-
Clinical data imply an important role for cytomeg- matory cytokines and other acute-phase reactants
alovirus in transplantation-related arteriosclerosis (Fig. 5). Levels of C-reactive protein and interleu-
causing graft rejection.70 More studies will be need- kin-6 are elevated in patients with unstable angina
ed to determine whether the virus is involved in and myocardial infarction, with high levels predict-
more common forms of CAD. Since several types ing worse prognosis.79-81 The levels of other inflam-
of pathogens may contribute to CAD, it is unlikely matory markers are also elevated in these patients,
that a single microbe causes atherosclerosis. In- including fibrinogen, interleukin-7, interleukin-8,
stead, the total burden of infection at various sites soluble CD40 ligand, and the C-reactive protein–
may affect the progression of atherosclerosis and related protein pentraxin 3.82-85 Levels of C-reactive
elicit clinical manifestations.71 protein are elevated in patients with unstable angina,
a condition that is probably dependent on coronary
acute coronary syndromes thrombosis of atherosclerotic plaques, but not in
those with variant angina caused by vasospasm.86
mechanisms of plaque rupture Therefore, elevated C-reactive protein levels in pa-
What causes a silent atherosclerotic lesion to rup- tients with acute coronary syndromes likely reflect
ture? Activated macrophages, T cells, and mast cells inflammation in the coronary artery rather than in
at sites of plaque rupture5,7,72 produce several types the ischemic myocardium.86 Activated T cells are
of molecules — inflammatory cytokines, proteases, also present and subgroups of inflammatory T cells
coagulation factors, radicals, and vasoactive mole- are increased in the blood of patients with acute
cules — that can destabilize lesions (Fig. 1). They coronary syndromes.87,88 Collectively, these find-
inhibit the formation of stable fibrous caps, attack ings suggest that inflammatory immune activation
collagen in the cap, and initiate thrombus forma- in coronary arteries initiates acute coronary syn-
tion.73-76 All these reactions can conceivably induce dromes, with circulating levels of inflammatory
the activation and rupture of plaque, thrombosis, markers reflecting the clinical course of the con-
and ischemia. dition.
Two types of proteases have been implicated as
key players in plaque activation: matrix metallopro- inflammatory markers and the risk of cad
teinases (MMPs) and cysteine proteases.77,78 Sev- Although the degree of active inflammation is in-
eral members of these families of enzymes occur in creased in activated plaques of patients with acute
mechanistic knowledge obtained before this ap- Supported by the Swedish Research Council and Heart–Lung
Foundation, the European Union, the National Institutes of Health,
proach can be tested in humans. and the Söderberg Foundation.
In conclusion, new knowledge about inflamma- I am indebted to Drs. Pål Aukrust, Petri Kovanen, Lars Rydén, and
tion in CAD has provided surprising insights into Lars Wallentin for their review of the manuscript and helpful sug-
gestions; to Dr. Erling Falk for kindly providing Figure 1A and 1B;
its pathogenesis, has offered new opportunities for and to all the colleagues, fellows, students, and assistants who have
diagnosis and prediction, and may lead to new treat- studied inflammatory mechanisms in atherosclerosis with me.
ments for this life-threatening disease.
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