Histopathology of aortic complications in bicuspid aortic valve versus Marfan syndrome: relevance for therapy?

Patients with bicuspid aortic valve (BAV) and patients with Marfan syndrome (MFS) are more prone to develop aortic dilation and dissection compared to persons with a tricuspid aortic valve (TAV). To elucidate potential common and distinct pathways of clinical relevance, we compared the histopathological substrates of aortopathy. Ascending aortic wall biopsies were divided in five groups: BAV (n = 36) and TAV (n = 23) without and with dilation and non-dilated MFS (n = 8). General histologic features, apoptosis, the expression of markers for vascular smooth muscle cell (VSMC) maturation, markers predictive for ascending aortic dilation in BAV, and expression of fibrillin-1 were investigated. Both MFS and BAV showed an altered distribution and decreased fibrillin-1 expression in the aorta and a significantly lower level of differentiated VSMC markers. Interestingly, markers predictive for aortic dilation in BAV were not expressed in the MFS aorta. The aorta in MFS was similar to the aorta in dilated TAV with regard to the presence of medial degeneration and apoptosis, while other markers for degeneration and aging like inflammation and progerin expression were low in MFS, comparable to BAV. Both MFS and BAV aortas have immature VSMCs, while MFS and TAV patients have a similar increased rate of medial degeneration. However, the mechanism leading to apoptosis is expected to be different, being fibrillin-1 mutation induced increased angiotensin-receptor-pathway signaling in MFS and cardiovascular aging and increased progerin in TAV. Our findings could explain why angiotensin inhibition is successful in MFS and less effective in TAV and BAV patients.

Ascending aorta dilation in association with bicuspid aortic valve: a maturation defect of the aortic wall.

OBJECTIVE: Patients with a bicuspid aortic valve have increased susceptibility to the development of ascending aortic dilation and dissection compared with persons with a tricuspid valve. To unravel a possible different mechanism underlying dilation in bicuspidy and tricuspidy, a comparison of the structure of the aortic wall was made. METHODS: Ascending aortic wall biopsies were divided into 4 groups: bicuspid (n=36) and tricuspid (n=23) without and with dilation. The expression of vascular smooth muscle cell maturation markers including lamin A/C, which plays a pivotal role in smooth muscle cell differentiation, and its splicing variant progerin indicative of aging, were studied immunohistochemically. Attention was also paid to the inflammatory status. RESULTS: There is a significant difference in the structure and maturation of the aortic wall in bicuspidy, persisting in the dilated aortic wall, presenting with a thinner intima, lower expression of α smooth muscle actin, smooth muscle 22α, calponin, and almost absent expression of smoothelin. We show for the first time significantly lowered lamin A/C expression in bicuspidy. Progerin was found to be significantly increased in the media of the dilated wall in tricuspidy, also showing increased periaortic inflammation. CONCLUSIONS: The structure of the nondilated and dilated aortic wall in bicuspidy and tricuspidy are intrinsically different, with the latter having more aspects of aging. In bicuspidy there is a defective smooth muscle cell differentiation possibly linked to lowered lamin A/C expression. Based on this vessel wall immaturity and increased susceptibility to dilation, different diagnostic and therapeutic approaches are warranted.

Bicuspid aortic valve: phosphorylation of c-Kit and downstream targets are prognostic for future aortopathy.

OBJECTIVES: The clinical course of many patients with a bicuspid aortic valve (BAV) is complicated by ascending aortic dilatation. Currently, the indication for aortic surgery is solely based on the aortic diameter and subsequently only a small proportion of BAV patients undergoing valve surgery require concomitant ascending aortic replacement based on these recommendations. Unfortunately, a substantial number of BAV patients still develop aortic dilatation in the future and would potentially benefit from a more aggressive approach towards ascending aortic replacement. We, therefore, designed this study to identify molecular biological markers in the aortic wall predictive of aortopathy in BAV. METHODS: Ascending aortic wall specimen of BAV (n = 36) and tricuspid aortic valve (TAV) (n = 23), both without and with (>44 mm) dilatation were investigated histologically and immunohistochemically for the expression of markers for vascular remodelling [transforming growth factor (TGF)-ß, phosphorylated Smad2, matrix metalloproteinase 9 (MMP9)], cellular differentiation [c-Kit, phosphorylated-c-Kit, hypoxia-inducable factor-1 alpha (HIF1α)] and haemodynamic influences on the aortic wall [endothelial nitric oxide (eNOS)]. RESULTS: All BAV patients showed significantly less inflammation (P < 0.001) and an altered intima/media ratio when compared with TAV patients. The expression of markers of a signalling pathway characteristic for cellular dedifferentiation, as exemplified by the marked expression of c-Kit, phosphorylated c-Kit and HIF1α; in the dilated BAV group was however completely comparable with only a subgroup of the non-dilated BAV (BAb), whereas the remainder of the non-dilated BAV group (BAa) was significantly distinct. This difference between the dilated BAV and BAa was further confirmed in the expression of TGF-ß, phosphorylated Smad2, MMP9 and eNOS. Besides the expression pattern, similarity in the dilated BAV and BAb was also noted clinically in the most common variant of commissure position and conjoined raphe of the BAV. Based on these observations, we consider the BAb group a likely candidate for future dilatation as opposed to the BAa group. CONCLUSIONS: Using a panel of molecular tissue markers, the non-dilated BAV patients can be divided into groups susceptible and non-susceptible to aortopathy.

Antimicrobial treatment to impair expansion of abdominal aortic aneurysm (AAA): a systematic review of the clinical evidence.

Antimicrobial treatment to attenuate expansion of abdominal aortic aneurysm has been suggested, especially with the focus on Chlamydophila. In this systematic literature review only four randomized trials were identified. In two small studies there is an indication of an effect of roxithromycin. In conclusion, however, more studies are needed, and they must be properly sized based on power calculations as well as antimicrobially relevant. Such trials are on the way both in Europe and the US, the results being awaited with interest.