Aneurysm Papers of the Month - July 1995

Wow..  AAA research has finally matured to the point that the
papers of month are from the JCI x 2 and the Annals of Internal
Medicine.   

1. Evans JM, O'Fallon M, Hunder GG.  Increased incidence of aortic
aneurysms and dissection in giant cell (temporal) arteritis: A
population based study.  Ann Intern Med 1995; 122: 502-7.  

Abstract (condensed from authors): 

     Background:  The purpose was to determine the frequency of
aneurysmal diseases of the aorta in patients with temporal
arteritis in a population based cohort study of 96 residents of
Olmsted County, Minnesota.

     Results: Eleven of the 96 patients were found to have thoracic
AA's (TAA's), and five additional patients who did not have TAA's
developed AAA's.  The incidence of TAA was 999/100,000 person
years; and the incidence of AA was 555/100,000 person years. 
Compared with a cohort of persons of the same age and sex living in
Olmsted County, patients with temporal arteritis were 17x more
likely to develop TAA and 2.4x  more likely to develop AAA.

Comment by mdt:  The results are all the more remarkable because
the data were interpreted so conservatively.  Two of the 11
patients with TAA were not included in the analysis because they
were diagnosed at autopsy.  Another 11 patients with "dilated"
thoracic aortas were not included because the chest X-rays were not
available for review.  

     The authors frame their findings in the context of the
increased risk ratio for Ca lung in smokers (about 10x).  With the
most conservative interpretation of their data, the odds of TAA in
patients with temporal arteritis is increased 17x.  If the excluded
patients (death or unretrievable X-rays) were included, the
risk/odds ratio would be astonishing.

     There are *many* possible speculations based on these
findings.  I will limit discussion on my part to the two simplest
interpretations, keeping in mind that this is just scratching the
surface.  Suppose there is an aortic matrix protein, more abundant
in the thoracic aorta than in the abdominal aorta, that is also a
constituent of the temporal artery.  The most elementary scenario
is that in the course of development of a TAA, an epitope of this
protein is exposed and elicits an immune response.  IgG's,
macrophages, T-cells, et al home to other arterial sites that share
the epitope.  This migration sets off symptoms of temporal
arteritis before the TAA is even discovered, because the patients 
were not screened for TAA or AAA.  

     Another scenario (akin to some thinking about rheumatoid
arthritis over the last twenty years) is that the major
histocompatibility locus has regions in the class II, that share
susceptibility epitopes.  The shared epitope enables antigen-
presenting cells to hand off an aortic wall antigen to the T-cell
receptors, and the consequent immune response targets not only the
aorta but other arteries that have a closely related antigen that
can direct a homing response.

     We've got a lot to learn about all of this before the fat lady
sings.


2. Thompson RW, Holmes DR, Mertens RA, et al.  Production and
localization of 92-kDa gelatinase in abdominal aortic aneurysms: An
elastolytic metalloproteinase expressed by aneurysm-infiltrating
macrophages.  J Clin Invest 1995; 96: 318-26.  

Abstract (condensed from authors): 

     The production of MMP-2 and MMP-9 by organ cultures of normal,
atherooclusive (AOD), and aneurysmal (AAA) aortic specimens was
examined by substrate gel enzymography of the conditioned media. 
All tissues produced MMP-2.  AOD and AAA specimens secreted MMP-9,
but significantly more enzyme was released from AAA tissues.  ELISA
confirmed that AAA tissues released ~2x more MMP-9 than AOD tissues
and ~10x more than normal aorta.  By immunohistochemistry, MMP-9
was not detected in normal aorta and only occasionally in
neointimal lesions of AOD.  In all AAA specimens MMP-9 was readily
localized to macrophages at the medial-adventitial junction. 
Expression of MMP-9 mRNA in aneurysm-infiltrating macrophages was
confirmed by in situ hybridization.

Comment by mdt:  The authors confirm that MMP-9 is produced in AAA
by macrophages as previously reported by Newman et al (JVS 1994;
20: 814-20).  Incidentally, the term aneurysm-infiltrating
macrophages (or "AIM" cell) was coined by mdt in 1994: (Proteolytic
mechanisms in the pathogenesis of aortic aneurysms, in ANEURYSMS:
NEW FINDINGS AND TREATMENTS, eds. JST Yao & WH Pearce; Appleton &
Lange, Norwalk, 1994).  

3.  Schneiderman J, Bordin GM, Engelberg I, et al.  Expression of
fibrinolytic genes in atherosclerotic abdominal aortic aneurysm
wall: A possible mechanism for aneurysm expansion.  J Clin Invest;
1995; 96: 639-45.

Abstract (condensed from authors): 

     In situ hybridization was used to analyze the expression of
fibrinolytic genes in tissue from 8 AAA patients.  All specimens
exhibited specific areas of inflammatory infiltrates with
macrophage-like cells expressing u-PA and t-PA mRNA.  PAI-1 mRNA
was expressed at the base of necrotic atheroma and within some
inflammatory infiltrates where it frequently colocalized in regions
containing u-PA and t-PA mRNA expressing cells.  In these areas,
the distribution of transcripts for the PA's extended far beyond
the areas of PAI expression.  An abundance of capillaries was also
obvious in these inflammatory infiltrates.

Comment by mdt.  Reilly and others have previously reported the
expression of plasminogen activators in AAA disease (JVS 19: 865,
1994), and Jean-Claude and others have suggested a key role for
plasmin in the pathogenesis of AAA (Surgery 116:472, 1994). 
Abundant neo-vasa vasorum in AAA adventitia was previously noted by
Brophy et al (Ann Vasc Surg 1991; 5: 229-33); and Herron was the
first to postulate a significant pathophysiological role for the
endothelial cells in AAA disease (based on his finding that they
appeared to be the source of gelatinase-B)(Arteriosclerosis &
Thromb 1991; 11: 1667).  Subsequently, Newman et al described the
endothelial cell of the neovasa as a source of AAA collagenase (JVS
1994; 20: 814-20).  The present paper is certainly sound, but the
authors neglected to acknowledge important contributions of others in
this field, particularly Herron.