From St George's Hospital Medical School, BHF Cardiovascular
Pathology Unit, Histopathology Department, London, UK.
Correspondence to Dr M.J. Davies, St George's Hospital Medical School, BHF Cardiovascular Pathology Unit, Histopathology Department, Cranmer Terrace, London SW17 ORE, UK.
The development of a
saccular (nondissecting) aortic aneurysm follows the
destruction of the connective tissue in the media, in particular the
elastic lamellae. The vessel wall is then unable to withstand the
expansile force of each systolic contraction. The current view
is that the great majority of aortic aneurysms, >90% of which
are below the renal arteries, are associated with
atherosclerosis.1 This view is
based on the fact that the lower abdominal aorta is the site at which
atherosclerosis first develops and confluent intimal
involvement becomes common by middle age. Resected abdominal aortic
aneurysms show advanced atherosclerosis with
mural thrombus in the wall. This view, however, is a paradox in that
atherosclerosis is an intimal disease, whereas in the
abdominal aorta, aneurysms are due to major medial damage.
There are also other reasons to believe that aortic aneurysms
have an additional component to their pathogenesis. Abdominal aortic
aneurysms are familial and under genetic influences unrelated
to lipid-related risk factors for atherosclerosis.
First-degree relatives of index cases with abdominal aortic
aneurysms have a significantly higher risk of developing a
similar lesion when compared with the general population. Prospective
family studies suggest a figure of 14.5% for offspring and 13% to
32% for siblings compared with the general population risk of 2% to
5%.2 3 4 Risk factors such as elevated plasma
cholesterol,
hypertriglyceridemia, hypertension, and
smoking are found in many subjects with abdominal aortic
aneurysms, yet 60% of cases have plasma
cholesterol levels of <240 mg/dL.1
Smoking is the single largest external contributor to the risk of
aortic aneurysm formation. These data suggest that there are
additional factors involved in aortic aneurysm
formation.5 Some of the factors are genetic. A
very small subgroup of saccular aneurysms are due to genes
controlling connective tissue structural proteins. The fibrillin gene
is largely responsible for dissection of the aorta, but occasional
families with saccular abdominal aneurysms are
known.6 Defects in the collagen III gene,
responsible for the Ehlers Danlos type IV syndrome, occasionally lead
to isolated aortic aneurysms, but a large genetic survey
suggested that <2% of human aortic abdominal aneurysms were
due to defects in type III collagen.7 A potential
locus for aortic saccular aneurysms has been identified on
chromosome 16 at or close to the haptoglobin gene, which might enhance
elastic degradation, but the exact mechanism is
unclear.8
The view has evolved that the medial destruction in aortic
aneurysms is due to an inflammatory response within the media
and adventitia.9 Medial and adventitial
infiltration by a mixture of chronic inflammatory cells including T and
B lymphocytes, mast cells, and macrophages is a very striking
feature of human atherosclerosis in the abdominal
aorta. These cells probably represent a response to oxidized
lipid leaching into the vessel wall from the intima. Antibodies to
oxidized LDL are produced locally within the adventitia.
The mode of action by which an inflammatory infiltrate destroys
connective tissue matrix is by proteolytic digestion. The best-studied
group of such enzymes involved are the metalloproteinases (MMPs). MMPs
are Zn2+- and
Ca2+-dependent enzymes, and at least 12 with
different molecular sizes have been sequenced.10
Each has different substrate preferences. Those with a particular
affinity for elastin are stromelysin 1 (MMP-3, 57 kD) and
metalloelastase (MMP-12, 57 kD). In the destruction of a connective
tissue matrix under pathologic conditions, however, a mixture of MMPs
are probably needed to break down additional components of the
connective tissue matrix, including collagen types I and III
(interstitial collagenase MMP-1, 55 kD),
collagen type IV (gelatinase B, MMP-9, 92 kD), laminin, proteoglycans
and fibronectin (stromelysins 1 to 3,
MMP-3).10 11 A constant feature of the MMPs is
that they are released from the inflammatory cells into the tissues as
an inactive zymogen, which is then converted into an active form. The
major activator of MMPs in tissues is plasmin generated by
the action of plasminogen activating factor on
plasminogen. Inhibitors of the proteins exist
and include
A wide range of cell types produce MMPs. One form (gelatinase A, MMP-9)
is produced by smooth muscle cells and is concerned with both cell
migration and proliferation after vascular injury. The main cell
capable of producing a wide range of MMPs in the aorta is the
macrophage. A range of inflammatory cytokines including
tissue necrosis factor-
The current hypothesis for aortic aneurysms is that the
inflammatory response in the vessel wall produces an overwhelming
degree of enzymatic degradation of the connective tissue matrix. Human
studies can only provide observational data to support this view. A
wide range of MMPs have been shown to be present in human aortic
aneurysm walls.6 11 12 13 Observational
studies on human aortic aneurysm do suggest acceleration of
connective tissue breakdown. Increased elastinolytic activity and
collagenolytic activity have been shown by functional assays in aortic
aneurysm walls.14 15 Gelatinase A (MMP-2)
and gelatinase B (MMP-9) were both studied in a comparison of samples
taken from small compared with large human aortic aneurysms. In
the larger expanding aneurysms, gelatinase B was increased and
associated with large numbers of
macrophages.16 Reduced amounts of TIMPs
have been shown within human aneurysm
walls.17 However, it is impossible to
differentiate between primary reduced amounts of inhibitor
and a secondary reduction caused by binding with increased MMP
production. Inhibition of proteolytic enzymes by
Experimental models would be a very desirable means of testing the
mechanisms involved in aneurysm formation. Some models have
been developed. Hyperlipidemia in rabbits will produce
extensive aortic atherosclerosis but does not produce
aortic aneurysms. The application of irritants such as
CaCl2 or agents such as thioglycollate, which
activate macrophages, to the adventitia will, however,
enhance aortic wall inflammation, after which aneurysms do
develop.19 In another
model20 a segment of guinea pig aorta had the
cells removed by treatment with 0.1% SDS, and the resulting tube of
extracellular connective tissue matrix was used as a xenograft into a
rat. The xenograft became an aneurysm as the result of a
progressive loss of elastin over the subsequent few weeks. Rat-to-rat
isografts prepared in an identical way do not become
aneurysmal. When the arterial xenograft was seeded
with synogenic rat smooth muscle cells that overproduce TIMPs-1,
aneurysm formation was inhibited. TIMPs-1 will inhibit MMPs 1,
9, 3, and 12 and thus will suppress proteolytic digestion of a wide
range of the components of the connective tissue matrix.
Further use of this model is reported in this issue of
Circulation by Allaire and
colleagues.21 The question being asked is whether
more upstream inhibition of MMPs would be effective in preventing
aneurysms. In the model, the graft was seeded with syngenic rat
smooth muscle cells overproducing PAI-1. In this way local plasmin
production would be inhibited, and if this is the main
activator of the MMPs, inhibition of aneurysm
formation would occur. In the study, unseeded grafts became
aneurysmal by 4 weeks. Within this time frame, inflammatory
cells infiltrate the media and elastic lamella destruction begins. The
zymograms of tissue extracts suggested the presence of MMPs 2, 3, and
9. In contrast, in seeded grafts the elastic pattern seen on histology
was preserved and aneurysm formation did not occur. The results
are entirely consistent with the view that prevention of
activation of MMPs is equally efficient in preventive terms compared
with inhibiting the active enzyme itself. Quantitative zymography
showed that tissue plasminogen activator and
the levels of activated MMPS were decreased in the seeded
grafts.
One problem with MMPs causing pathologic destruction within human
tissues is whether one type is dominant or whether concordant action
between several members of the group is needed. The experimental model
described highlights that stromelysin-1 (MMP-3), which has an initial
molecular weight of 57 kD, is present in large amounts and is
activated into lower-molecular-weight fragments (45, 28, and 24
kD) with activity against proteoglycans, type IV collagen fibronectin,
laminin, and elastin. Other studies on the disruption of human
atherosclerotic plaques within the intima have also found stromelysin
present in large amounts. The other MMP found in the model was
gelatinase B (MMP-9), which also has elastinolytic properties. This MMP
is also known to be associated with plaque
disruption.22 Therefore, the perception that
human aortic aneurysms are due to the overactivity of MMPs in
the vessel wall appears to be soundly based.
How does this view fit with the known genetic component of aortic
aneurysms? One explanation is that polymorphisms exist in
the tissue plasminogen activator/PAI-1 system,
allowing the local generation of plasmin to be enhanced. Although in
theory active generation of plasmin may remove fibrin rapidly from
plaques, reducing smooth muscle proliferation, it might also potentiate
activation of MMPs. Polymorphisms in the MMP genes themselves may
lead to forms less readily inhibited by TIMPs and therefore more
active. Any gene that led to nonfunctional TIMPs would equally
potentiate aneurysm formation. Single gene defects in the MMPs
or TIMPs are not yet identified as factors in causing aneurysm
formation, and polygenic influence seems more
likely.6 The role of smoking, which remains the
single largest external risk factor for abdominal aortic
aneurysms, remains to be elucidated. Good experimental models
at a molecular level will provide ways in which such factors can be
unraveled and drugs that inhibit MMP activity tested.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
© 1998 American Heart Association, Inc.
Editorials
Aortic Aneurysm Formation
Lessons From Human Studies and Experimental Models
Key Words: Editorials • aneurysm • aorta
2-macroglobulins,
1-antitrypsin, and specific
inhibitors known as TIMPs (tissue inhibitors of
metalloproteinases), which carefully regulate connective tissue
turnover in physiologic states. Plasminogen activating
inhibitors (PAI-1) also occur in tissues. Pathologic
destruction of the media would imply a considerable excess of active
MMPs over their specific inhibitors. Alternative pathways
of MMP activation include a membrane-bound, 66-kD MMP probably
concerned in very local dissolution of connective tissue matrix in
smooth muscle migration. Mast cells will also activate MMP
zymogen. (TNF-) and interleukin-6 upregulate MMP
production by macrophages. Such inflammatory foci also
contain high levels of plasminogen activating factor.
Neutrophils also secrete MMP-8, which has a powerful collagenolytic
function and is important in pulmonary emphysema. However,
neutrophils are relatively sparse in the vessel wall when compared with
the numbers of macrophages. 1-antitrypsin has been suggested to be
abnormal in patients with aortic aneurysms, giving an
interesting analogy with elastolytic activity in smoking and
emphysema.18 An analysis of the subtypes
of 1-antitrypsin in subjects with abdominal
aortic aneurysms did not, however, yield conclusive results,
but there was a small excess of patients with aneurysms who had
the MZ phenotype for 1-antitrypsin in
which enzyme levels are reduced. The figures were 3% to 4% frequency
in the general population against 11% in the 47 patients with aortic
aneurysms.
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