Abstract. Although genetic variants are thought to contribute to the development of thoracic aortic aneurysm including dissection (TAA), it remains unclear whether gene polymorphisms are associated with the long-term outcome of TAA. The purpose of the present study was to identify genetic variants associated with the long-term outcome of medically treated patients with TAA. A total of 103 medically-treated patients with TAA (13 aneurysms and 90 dissections) were retrospectively studied for their outcomes (mean follow-up period, 24 months). The genotypes for 95 polymorphisms of 89 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Evaluation of genotype distributions by the Chi-square test and subsequent multivariable logistic regression analysis with adjustment for covariates revealed that the -340A→G polymorphism (rs514921) of the matrix metallopeptidase 1 gene (MMP1) was significantly (P=0.0288) associated with the outcome of TAA, with the minor G allele being related to a favorable outcome. The aneurysm diameter was significantly (P=0.0167) smaller in the combined group of the AG and GG genotypes for this polymorphism than in subjects with the AA genotype. Kaplan-Meier survival curves constructed according to MMP1 genotypes showed a more favorable outcome of TAA (log-rank P=0.0146) in subjects with the G allele of rs514921. Determination of genotype for this polymorphism may prove informative for assessment of the long-term outcome of TAA. IntroductionThoracic aortic aneurysm including dissection (TAA) is a serious condition that results from aortic atherosclerosis and is a leading cause of mortality (1). Recent studies on the genetic basis of familial TAA have focused on its relation to systemic connective tissue disorders such as the Marfan syndrome (2) and the Ehlers-Danlos syndrome (3). However, up to 19% of individuals with non-syndromic TAA referred for surgery have been found to have affected first-degree relatives (4). In addition to conventional risk factors for TAA including age, arteriosclerosis, hypertension, and inflammatory or autoimmune diseases, genetic epidemiological studies have suggested that genetic variants contribute to the initiation and progression of this condition (5,6). It has remained unclear, however, whether gene polymorphisms are associated with the long-term outcome of TAA.Although computed tomography (7) parameters are currently applied to prediction of the risk for TAA rupture, only the relative, not the individual, rupture risk can be determined (8). The identification of gene polymorphisms related to the long-term outcome of medically-treated TAA may therefore lead to a better understanding of the factors relevant to the progression and rupture of TAA, and consequently may better inform the selection of patients as candidates for surgical therapy because of a higher risk of rupture.We have now performed an association study for 95 polymorphisms of 89 candidat...

Abstract:Background: Increases in levels of matrix metalloproteinase (MMP) and tissue inhibitor of matrix metalloproteinase (TIMP) occur in acute aortic dissection (AAD); however, their association with prognosis in AAD remains largely unknown. We studied the use of MMP and TIMP in predicting long-term outcomes in medically controlled AAD patients.Methods: A total of 82 patients were enrolled (15 Stanford Type A and 67 type B, age 65.1±13.3). AAD was diagnosed by enhanced CT, with serial imaging studies during follow-up. Blood tests for MMP-2, MMP-9, TIMP-1, and TIMP-2 were performed within a week after symptom onset.Results: A poor outcome due to death or aortic surgical repair occurred in 17 patients, classified as an unfavorable group. The remaining 65 patients were classified into a favorable group. By multivariate analysis maximum dissection diameter (MDD), TIMP-1, and TIMP-2 were significantly associated with an unfavorable outcome (P < 0.001, P < 0.001, and P = 0.038, respectively). The ratio of TIMP-1 to TIMP-2 (cut-off value > 3.34) had significant predictive power (sensitivity 88.2%, specificity 80.0%). Patients with MDD 46.8 mm and a TIMP-1/TIMP-2 ratio 3.34 had a significantly poorer outcome (log rank P < 0.0001). Similarly, in Cox regression analysis AAD patients with MDD 46.8 mm and a TIMP-1/TIMP-2 ratio 3.34 had the highest risk for an unfavorable outcome (P < 0.001, hazard ratio 45.6, 95% confidence interval 5.96 to 348.42). Conclusion:In AAD a higher TIMP-1/TIMP-2 ratio was significantly associated with an increased risk of death or surgical repair.

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