Thoracic aortic aneurysm: reading the enemy's playbook

Abstract

Background: At the Yale University Center for Thoracic Aortic Disease, we have been using our clinical experience and laboratory investigations to shed light on the pathophysiology of thoracic aortic aneurysm (TAA), the clinical behavior of thoracic aortic aneurysm, and the optimal clinical management.

Materials and methods: The Yale database contains information on 3,000 patients with thoracic aortic aneurysm, with 9,000 patient-years of follow-up and 9,000 imaging studies. Advanced statistical techniques were applied to this information.

Results: Analysis yielded the following Yale-generated observations: (1) TAA is a genetic disease with a predominantly autosomal dominant mode of inheritance; (2) matrix metalloproteinase (MMP) enzymes are activated in the pathogenesis of TAA; (3) wall tension in TAA approaches the tensile limits of aortic tissue at a diameter of 6 cm; (4) by the time a TAA reaches a clinical diameter of 6 cm, 34 percent of affected patients have suffered dissection or rupture; (5) extreme physical exertion or severe emotion often precipitate acute dissection; and (6) single nucleotide polymorphisms (SNPs) and RNA expression profile changes are being identified that predispose a patient to TAA and can serve as biomarkers for screening for this virulent disease.

Conclusions: The "playbook" of TAA is gradually being read, with the help of scientific investigations, positioning practitioners to combat this lethal disease more effectively than ever before.

Figure 1

Growth rate of the aneurysmal thoracic aorta. This is a virulent, but indolent common process.

Figure 2

Measurement error from measuring across an oblique portion of the aorta: spurious-dotted lines; true solid lines.

Figure 3

Depiction of “hinge points” for lifetime natural history complications at various sizes of the aorta. The y-axis lists the probability of complication; complication refers to rupture or dissection. The x-axis shows aneurysm size. A. The ascending aorta. B. The descending aorta. Reproduced from Coady MA, Rizzo JA, Hammond GL, et al. What is the appropriate size criterion for resection of thoracic aortic aneurysm? J Thorac Cardiovasc Surg. 1997;113:476–91.

Figure 4

Yearly rates of rupture, dissection, or death related to aortic size. Reproduced from Elefteriades JA. Beating a sudden killer. Sci Am. 2005.

Figure 5

Guidelines for surgical intervention.

Figure 6

“Aortic size index” nomogram. Reproduced from Davies RR, Gallo A, Coady MA, et al. Novel measurement of relative aortic size predicts rupture of thoracic aortic aneurysms. Ann Thorac Surg. 2006;81:169-177.

Figure 7

Classic cystic medial necrosis. Note the dropout of medial cell bodies and the cystic spaces within the media.

Figure 8

Among the first 100 family pedigrees that we constructed, these 21 showed a family pattern for thoracic aortic aneurysm. Autosomal dominant inheritance predominates, but other patterns are discernable as well.

Figure 9

Note how the location of the proband aneurysms influences the location of aneurysms in the family members. Note that probands with ascending aneurysms have family members with ascending aneurysm, whereas probands with descending thoracic aneurysm are more likely to have family members with abdominal aortic aneurysm. See text. [6]

Figure 10

The RNA Signature test for thoracic aortic aneurysm. In the hierarchical cluster diagram on the left, each vertical line represents a patient (red are aneurysm patients, and blue are controls), and each horizontal line represents an RNA. In the grid, green indicates underexpression and red indicates overexpression. Note in the diagram on the left how the overexpression and underexpression cluster, depending on phenotype. In the figure on the right, note that if all the reds were together and all the blues were together, the test would have been 100 percent accurate. As it turns out, the overall accuracy was over 82 percent.

Figure 11

Note the elevation of MMP-1 and MMP-9 in the aneurysm patients. Note in the inset photograph how terribly thin this ascending aorta has become, permitting a ruler to be read right through the aortic wall. This is not a safe situation.

Figure 12

A. Distensibility values in normal aortas and aortic aneurysms of different diameters. Distensibility of ascending aortic aneurysms decreases rapidly as diameter increases, to very low values at dimensions greater than 6 cm. B. Exponential relationship between wall stress and aneurysm size in ascending aortic aneurysms. The dark columns represent a blood pressure of 100 mmHg, and the light columns represent a blood pressure of 200 mmHg. The lines at 800 kPa represents the maximum tensile strength of the human aorta.

Figure 13

Note the marked elevation in blood pressure for these three scientists as they lift various percentages of their body weight in the bench press. JAE represents the author.

Figure 14

Emotional or exertional events immediately preceding the onset of the pain of acute aortic dissection.

Figure 15

Overall schematic understanding of how aortic dissection picks a specific time to occur. See text.