木村 直行

OBJECTIVES: We aimed to determine whether non-A non-B aortic dissection (AD) differs in morphologic and haemodynamic properties from type B AD. METHODS: We simulated and compared haemodynamics of patients with acute type B or acute non-A non-B AD by means of computational fluid dynamics. Wall pressure and wall shear stress (WSS) in both the true lumen (TL) and false lumen (FL) at early, mid- and late systole were evaluated. Morphology, WSS and the FL/TL wall pressure ratio were compared between groups. RESULTS: Nineteen patients (type B, n = 7; non-A non-B, n = 12) were included. The median age (51 [46, 67] vs 53 [50, 63] years; P = 0.71) and a complicated course (14% vs 33%; P = 0.6) did not differ between the type B group and the non-A non-B group. However, the median entry tear width was increased in the non-A non-B group (9.7 [7.3, 12.7] vs 16.3 [11.9, 24.9] mm; P = 0.010). Streamlines showed, in patients with non-A non-B AD, blood from the TL flowed into the FL via the entry tear. Prevalence of a FL/TL wall pressure ratio >1.0 (type B versus non-A non-B) at early, mid- and late systole was 57% vs 83% (P = 0.31), 43% vs 83% (P = 0.13) and 57% vs 75% (P = 0.62), respectively. WSS did not differ between the groups. CONCLUSIONS: The increased FL/TL wall pressure ratio observed during systole in non-A non-B AD may beget a complicated presentation.

Rationale: Marfan syndrome (MFS) is a systemic connective tissue disorder notable for the development of aortic root aneurysms and the subsequent life-threatening complications of aortic dissection and rupture. Underlying fibrillin-1 gene mutations cause increased transforming growth factor-beta (TGF-beta) signaling. Although TGF-beta blockade prevents aneurysms in MFS mouse models, the mechanisms through which excessive TGF-beta causes aneurysms remain ill-defined. Objective: We investigated the role of microRNA-29b (miR-29b) in aneurysm formation in MFS. Methods and Results: Using quantitative polymerase chain reaction, we discovered that miR-29b, a microRNA regulating apoptosis and extracellular matrix synthesis/deposition genes, is increased in the ascending aorta of Marfan (Fbn1(C1039G/+)) mice. Increased apoptosis, assessed by increased cleaved caspase-3 and caspase-9, enhanced caspase-3 activity, and decreased levels of the antiapoptotic proteins, Mcl-1 and Bcl-2, were found in the Fbn1(C1039G/+) aorta. Histological evidence of decreased and fragmented elastin was observed exclusively in the Fbn1(C1039G/+) ascending aorta in association with repressed elastin mRNA and increased matrix metalloproteinase-2 expression and activity, both targets of miR-29b. Evidence of decreased activation of nuclear factor kappa B, a repressor of miR-29b, and a factor suppressed by TGF-beta, was also observed in Fbn1(C1039G/+) aorta. Furthermore, administration of a nuclear factor kappa B inhibitor increased miR-29b levels, whereas TGF-beta blockade or losartan effectively decreased miR-29b levels in Fbn1(C1039G/+) mice. Finally, miR-29b blockade by locked nucleic acid antisense oligonucleotides prevented early aneurysm development, aortic wall apoptosis, and extracellular matrix deficiencies. Conclusions: We identify increased miR-29b expression as key to the pathogenesis of early aneurysm development in MFS by regulating aortic wall apoptosis and extracellular matrix abnormalities. (Circ Res. 2012;110:312-324.)