Medline ® Abstracts for References 2-10

BACKGROUND: The emerging controversy concerning the causal role of atherosclerosis in the development of aortic aneurysms was examined using the accumulated clinical and autopsy data obtained during a 20-year follow-up of a cohort of more than 8,000 men of Japanese ancestry in Hawaii.

METHODS AND RESULTS: Analyses of 174 clinical incident events indicated that there were two types of aneurysmal disease, 151 aortic aneurysms and 23 aortic dissections. The baseline risk factors that predicted the clinical aortic aneurysms were the same factors that predicted aortic atherosclerosis in the same cohort, namely, high blood pressure, high serum cholesterol, and cigarette smoking. These same risk factors were also significantly associated with the occurrence of 27 aortic aneurysms among 293 autopsied men. The less common aortic dissections had an age-specific incidence pattern indicative of an innate susceptibility precipitated by an exposure to another factor. This pattern was consistent with the findings that the incidence of aortic dissections was predicted mainly by baseline high blood pressure.

CONCLUSIONS: From the perspective of prevention, it appears that the risk factors for aortic atherosclerosis and probably atherosclerosis itself are necessary elements in the causal pathway for the great majority of aortic aneurysms in this cohort.

The pathogenesis of abdominal aortic aneurysm involves many factors acting over time. However, destruction of elastin in the aortic wall is a key event that shifts the load produced by blood pressure on to collagen. This is exacerbated in the presence of hypertension. Smoking and age are further important factors, as is the site; elastic lamellae are relatively less common in the abdominal aorta. Once the shielding effect of elastin is lost, further dilatation and rupture of the aorta depend on the physical properties of the collagen present.

To examine the hypothesis that a tendency toward aneurysmal degeneration of the abdominal aorta may be inherited, we compared the family histories of 250 patients with abdominal aortic aneurysm (AAA) with those of 250 control subjects. Among the control subjects, six (2.4%) reported having a first-degree relative with an aneurysm, compared with 48 (19.2%) of the patients with AAA. After adjustment for age and sex, this corresponds to an estimated 11.6-fold increase in AAA risk among persons with an affected first-degree relative. This study suggests that the relatives of patients with AAA may themselves be at significantly increased risk for the development of aneurysmal degeneration. Because early diagnosis and elective management of AAA significantly prolong life, noninvasive screening to detect early AAA formation may be warranted in relatives of patients with AAA.

Fifty families were collected with clustering of abdominal aortic aneurysms in two or more first-order relatives. If only one gene is responsible for these patterns, it is likely to be autosomal. However, multigene mechanisms cannot be excluded.

The results of recent studies suggest that genetic factors may be important in the pathogenesis of abdominal aortic aneurysms. In the present report, the apparent mechanisms of inheritance in 16 families with a total of 41 affected individuals are summarized. The results suggest that there may be both X-linked and autosomal dominant forms of the disease, with the X-linked variant as the more common type. A multifactorial mechanism cannot be ruled out from the results of the present data.

To determine the clinical characteristics and factors influencing outcome in patients with atherosclerotic abdominal aortic aneurysms (AAA), 526 patients who underwent aneurysmal resection were retrospectively reviewed: Group I had clinical evidence of atherosclerotic occlusive disease; Group II had no evidence of atherosclerotic occlusive disease. The incidence of ruptured AAA, multiple aneurysms, and a family history of AAA was higher in Group II patients. We concluded that patients with AAA and without atherosclerotic occlusive disease in other areas represent a subgroup with peculiar clinical characteristics. In planning operative treatment and during the follow-up period, it should be kept in mind that Group II patients have a higher incidence of aneurysm rupture; the incidence of late pseudoaneurysm is higher; and there is a greater possibility of aneurysm in other arterial segments. It remains to be seen if the pathogenetic mechanism of AAA formation in Group II patients is different from that in Group I patients.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a relatively common disease, with 1% to 2% of the population harboring aneurysms. Genetic risk factors are likely to contribute to the development of AAAs, although no such risk factors have been identified.

METHODS AND RESULTS: We performed a whole-genome scan of AAA using affected-relative-pair (ARP) linkage analysis that includes covariates to allow for genetic heterogeneity. We found strong evidence of linkage (logarithm of odds [LOD]score=4.64) to a region near marker D19S433 at 51.88 centimorgans (cM) on chromosome 19 with 36 families (75 ARPs) when including sex and the number of affected first-degree relatives of the proband (N(aff)) as covariates. We then genotyped 83 additional families for the same markers and typed additional markers for all families and obtained a LOD score of 4.75 (P=0.00014) with sex, N(aff), and their interaction as covariates near marker D19S416 (58.69 cM). We also identified a region on chromosome 4 with a LOD score of 3.73 (P=0.0012) near marker D4S1644 using the same covariate model as for chromosome 19.

CONCLUSIONS: Our results provide evidence for genetic heterogeneity and the presence of susceptibility loci for AAA on chromosomes 19q13 and 4q31.