Acute Aortic Disease.. - Index of

Natural History of Thoracic Aortic Aneurysms 179
and high intraluminal pressure. Elastin degradation of the aortic wall manifests
first in the intima and media (medial degenerative disease), causing deterioration
of these layers (23). Disruption of the medial architecture does not directly result
in the loss of biomechanical function of the aortic wall or in clinically detectable
aortic dilation.
Elastin disruption and depletion is complete at the stage of relatively
small aneurysms, implying that loss or reorganization of the additional structural
components is important (24). Ultimately, the forces that lead to medial elastin
degradation also cause degradation of the elastic lamellae within the inner third of
the adventitia. This allows for damage to the collagen within the adventitial layer,
resulting in aneurysm formation. Since the strength of collagen is significantly
greater than elastin, degeneration, synthesis, and redeposition of poorly organized
collagen may account for the maintenance of collagen content in aneurysms
despite the significant elastin degradation.
Recent investigations at our own and other institutions have shed light on
certain additional cellular mechanisms that underlie aneurysm formation and
expansion. It has become clear in both the abdomen and the thorax that MMPs
participate in the destruction of the structural components of the aortic wall. These
proteolytic enzymes were discovered in tadpole tails, where they play a role in the
regenerative capacity of that organism.
MMPs initiate tissue remodeling by degradation of existing extra-cellular
macromolecules such as collagens and proteoglycans. Over 20 different MMPs
have been identified, with additional identifications occurring with regularity.
There is considerable consistency between species in the importance of these
enzymes. The MMPs are held in check in a homeostatic balance by the tissue
inhibitors of MMPs, or TIMPs.
Our group has demonstrated that in both aortic aneurysm and dissection
patients, the levels of certain key MMPs, including MMP-1 (collagenase) and
MMP-9 (gelatinase B), are elevated in the aortic wall, compared to control aortas
(25). In addition, the ratio of MMPs to TIMPs, a measure of the proteolytic state,
is also elevated. Those patients who had an aortic dissection had even higher levels
of MMPs than the aneurysm patients. In patients with bi-leaflet aortic valves, these
levels are also elevated compared to tri-leaflet aortic valves—perhaps explaining
the close relationship between bi-leaflet aortic valve and aortic dissection (26).
In our laboratories, we have also been analyzing the molecular biologic
events occurring during aneurysm formation and expansion (27–29). Specimens
of aortic aneurysms from various thoracic locations were harvested. These investigations
have shown that: (i) Although the aortic media becomes thinner, the total
amount of aortic medial tissue increases, due to the much larger diameter that the
aorta attains. (ii) An intense inflammatory process is involved in aneurysm
formation. There is prominent infiltration by interferon-γ-producing T-cells. (iii)
Programmed cell death, with apoptosis of vascular smooth muscle cells is not
seen, in contradistinction to findings in abdominal aortic aneurysms. This fundamental
difference in the biological response in thoracic compared to abdominal