Ascending thoracic aneurysms are associated with decreased systemic atherosclerosis.

STUDY OBJECTIVES: We noted clinically that patients with aortic root aneurysms and dissections seemed to have little systemic atherosclerosis. It is our objective to determine whether there is a negative association between ascending thoracic aneurysms and systemic atherosclerosis. DESIGN: Atherosclerosis was quantified by evaluating non-contrast CT images of the chest and scoring the degree of calcifications as a marker for atherosclerosis in the coronary arteries and aorta. PATIENTS: The degree of calcification was compared in 64 patients with aortic root aneurysm (annuloaortic ectasia, 31 patients; type A dissection, 33 patients) vs 86 control subjects. Multivariable analysis was applied to test for an association between aortic root aneurysms and systemic calcification independent of risk factors for atherosclerosis. RESULTS: Multivariable analysis revealed that patients with ascending aortic aneurysms of the annuloaortic ectasia type and patients with type A dissections had significantly lower overall calcification scores in their arterial vessels compared to patients in the control group (p = 0.03 and p < 0.0001, respectively). These results were independent of all other risk factors for atherosclerosis. Smoking, dyslipidemia, diabetes, and age were all found to increase the degree of atherosclerosis (p < 0.01 to 0.05). CONCLUSIONS: Aortic root pathology (annuloaortic ectasia or type A dissection) is associated with decreased systemic atherosclerosis. It is possible that a mechanism exists whereby the same genetic mutations predisposing patients to ascending aortic aneurysms also exert a protective effect against systemic atherosclerosis.

Gene expression signature in peripheral blood detects thoracic aortic aneurysm.

BACKGROUND: Thoracic aortic aneurysm (TAA) is usually asymptomatic and associated with high mortality. Adverse clinical outcome of TAA is preventable by elective surgical repair; however, identifying at-risk individuals is difficult. We hypothesized that gene expression patterns in peripheral blood cells may correlate with TAA disease status. Our goal was to identify a distinct gene expression signature in peripheral blood that may identify individuals at risk for TAA. METHODS AND FINDINGS: Whole genome gene expression profiles from 94 peripheral blood samples (collected from 58 individuals with TAA and 36 controls) were analyzed. Significance Analysis of Microarray (SAM) identified potential signature genes characterizing TAA vs. normal, ascending vs. descending TAA, and sporadic vs. familial TAA. Using a training set containing 36 TAA patients and 25 controls, a 41-gene classification model was constructed for detecting TAA status and an overall accuracy of 78+/-6% was achieved. Testing this classifier on an independent validation set containing 22 TAA samples and 11 controls yielded an overall classification accuracy of 78%. These 41 classifier genes were further validated by TaqMan real-time PCR assays. Classification based on the TaqMan data replicated the microarray results and achieved 80% classification accuracy on the testing set. CONCLUSIONS: This study identified informative gene expression signatures in peripheral blood cells that can characterize TAA status and subtypes of TAA. Moreover, a 41-gene classifier based on expression signature can identify TAA patients with high accuracy. The transcriptional programs in peripheral blood leading to the identification of these markers also provide insights into the mechanism of development of aortic aneurysms and highlight potential targets for therapeutic intervention. The classifier genes identified in this study, and validated by TaqMan real-time PCR, define a set of promising potential diagnostic markers, setting the stage for a blood-based gene expression test to facilitate early detection of TAA.

Familial thoracic aortic aneurysms and dissections--incidence, modes of inheritance, and phenotypic patterns.

BACKGROUND: We examined the genetic nature and phenotypic features of thoracic aortic aneurysms (TAAs) and dissections in a large cohort of patients. METHODS: Interviews were conducted with 520 patients with TAAs and their pedigrees were compiled to identify family members with aneurysms. Study patients were divided into three groups: 101 non-Marfan patients, in 88 pedigrees, had a family pattern for TAA (familial group), 369 had no family pattern (sporadic group), and 50 had Marfan syndrome (MFS). We determined incidence of familial clustering, age at presentation, rate of aneurysm growth, incidence of hypertension, correlation of aneurysm sites among kindred, and pedigree inheritance patterns. RESULTS: An inherited pattern for TAA was present in 21.5% of non-MFS patients. The predominant inheritance pattern was autosomal dominant (76.9%), with varying degrees of penetrance and expressivity. The familial TAA group was significantly younger than the sporadic group (p < 0.0001), but not as young as the MFS group (p < 0.0001) (mean ages, 58.2 versus 65.7 versus 27.4 years). Among all 197 probands and kindred with aneurysm, 131 (66.5%) had TAA, 49 (24.9%) had abdominal aortic aneurysm (AAA), and 17 (8.6%) had cerebral or other aneurysms. Ascending aneurysm paired most commonly with ascending, and descending with abdominal. Abdominal aortic aneurysms (AAAs) and hypertension were more often associated with descending than with ascending TAAs (p < 0.001). Aortic growth rate was highest for the familial group (0.21 cm/y), intermediate for the sporadic group (0.16 cm/y), and lowest for the Marfan group (0.1 cm/y; p < 0.01). CONCLUSIONS: TAAs are frequently familial diseases. The predominant mode of inheritance is autosomal dominant. Familial TAAs have a relatively early age of onset. Aneurysms in relatives may be seen in the thoracic aorta, the abdominal aorta, or the cerebral circulation. Screening of first-order relatives of probands with TAA is essential. Familial TAAs tend to grow at a higher rate, exemplifying a more aggressive clinical entity.