Objective: The probability of aortic complications in patients with bicuspid aortic valve is higher in association with aortic regurgitation (AR) compared with aortic stenosis (AS) or normally functioning valves. The objective of this study was to determine whether this is related to the specific characteristics of aneurysmatic dilatation that includes AR or whether AR itself has a negative impact on the aortic wall, independent of aneurysmatic dilatation. Approach and Results: Nondilated aortic specimens were harvested intraoperatively from individuals with tricuspid aortic valves and either AS (n=10) or AR (n=16). For controls, nondilated aortas were harvested during autopsies from individuals with tricuspid aortic valves and no evidence of aortic valve disease (n=10). Histological and immunohistochemical analyses revealed that compared with control aortas, overall medial degeneration was more severe in AR-aortas ( P =0.005) but not AS-aortas ( P =0.23). This pathological remodeling included mucoid extracellular matrix accumulation ( P =0.005), elastin loss ( P =0.003), elastin fragmentation ( P =0.008), and decreased expression of fibrillin ( P =0.003) and collagen ( P =0.008). Furthermore, endothelial nitric oxide synthase expression was decreased in the intima ( P =0.0008) and in vasa vasorum ( P =0.004) of AR-aortas but not AS-aortas (all P >0.05). Likewise, subendothelial apoptosis was increased in AR-aortas ( P =0.03) but not AS-aortas ( P =0.50). Conclusions: AR has a negative effect on the nondilated ascending aortic wall. Accordingly, our results support the need for more detailed studies of the aortic wall in relation to aortic valve disease and may ultimately lead to more aggressive clinical monitoring and/or surgical criteria for patients with relevant AR.
We sought to determine whether there are differences in transforming growth factor-beta (TGFß) signaling in aneurysms associated with bicuspid (BAV) and unicuspid (UAV) aortic valves versus normal aortic valves. Ascending aortic aneurysms are frequently associated with BAV and UAV. The mechanisms are not yet clearly defined, but similarities to transforming growth factor-beta TGFß vasculopathies (i.e. Marfan, Loeys-Dietz syndromes) are reported. Non-dilated (ND) and aneurysmal (D) ascending aortic tissue was collected intra-operatively from individuals with a TAV (N = 10ND, 10D), BAV (N = 7ND, 8D) or UAV (N = 7ND, 8D). TGFß signaling and aortic remodeling were assessed through immuno-assays and histological analyses. TGFß1 was increased in BAV/UAV-ND aortas versus TAV (P = 0.02 and 0.04, respectively). Interestingly, TGFß1 increased with dilatation in TAV (P = 0.03) and decreased in BAV/UAV (P = 0.001). In TAV, SMAD2 and SMAD3 phosphorylation (pSMAD2, pSMAD3) increased with dilatation (all P = 0.04) and with TGFß1 concentration (P = 0.04 and 0.03). No relationship between TGFß1 and pSMAD2 or pSMAD3 was observed for BAV/UAV (all P > 0.05). pSMAD3 increased with dilatation in BAV/UAV aortas (P = 0.01), whereas no relationship with pSMAD2 was observed (P = 0.56). Elastin breaks increased with dilatation in all groups (all P < 0.05). In TAV, elastin degradation correlated with TGFß1, pSMAD2 and pSMAD3 (all P < 0.05), whereas in BAV and UAV aortas, elastin degradation correlated only with pSMAD3 (P = 0.0007). TGFß signaling through SMAD2/SMAD3 contributes to aortic remodeling in TAV, whereas TGFß-independent activation of SMAD3 may underlie aneurysm formation in BAV/UAV aortas. Therefore, SMAD3 should be further investigated as a therapeutic target against ascending aortic dilatation in general, and particularly in BAV/UAV patients.
ObjectivesAscending aortic aneurysms are associated with pre-existing conditions, including connective tissue disorders (i.e., Marfan syndrome) and bicuspid aortic valves. The underlying mechanisms remain uncertain. Even less is known regarding ascending aortic aneurysms in individuals with normal (i.e., tricuspid) aortic valves (TAV), and without known aneurysm-associated disorders. Regardless of etiology, the risk of aortic complications increases with biological age. Phenotypic modulation of smooth muscle cells (SMCs) is a feature of ascending aortic aneurysms, whereby contractile SMCs are replaced with synthetic SMCs that are capable of degrading the aortic wall. We asked whether age itself causes dysfunctional SMC phenotype modulation, independent of aortic dilatation or pre-existing aneurysm-associated diseases.MethodsNon-dilated ascending aortic samples were obtained intra-operatively from 40 patients undergoing aortic valve surgery (range: 20–82 years old, mean: 59.1 ± 15.2). Patients with known genetic diseases or aortic valve malformations were excluded. Tissue was divided, and a portion was formalin-fixed and immunolabeled for alpha-smooth muscle actin (ASMA), a contractile SMC protein, and markers of synthetic (vimentin) or senescent (p16/p21) SMCs. Another fragment was used for SMC isolation (n = 10). Cultured SMCs were fixed at cell passage 2 and stained for phenotype markers, or were cultured indefinitely to determine replicative capacity.ResultsIn whole tissue, ASMA decreased (R2 = 0.47, P < 0.0001), while vimentin increased (R2 = 0.33, P = 0.02) with age. In cultured SMCs, ASMA decreased (R2 = 0.35, P = 0.03) and vimentin increased (R2 = 0.25, P = 0.04) with age. p16 (R2 = 0.34, P = 0.02) and p21 (R2 = 0.29, P = 0.007) also increased with age in SMCs. Furthermore, the replicative capacity of SMCs from older patients was decreased compared to that of younger patients (P = 0.03).ConclusionBy investigating non-dilated aortic samples from individuals with normal TAVs, we found that age itself has a negative impact on SMCs in the ascending aortic wall, whereby SMCs switched from the contractile phenotype to maladaptive synthetic or senescent states with increased age. Therefore, based on our findings, modification of SMC phenotype should be studied as a therapeutic consideration against aneurysms in the future, regardless of etiology.
OBJECTIVES The unicuspid aortic valve (UAV) is a rare cardiac malformation and is associated with the formation of ascending aortic aneurysms. To characterize its associated aortic wall changes, normal and aneurysmatic ascending aortic wall specimens were analysed, focusing on the potential mechanisms of aneurysm formation. Patients with tricuspid aortic valve (TAV) served as controls. METHODS In a retrospective observational study, 74 specimens (dilated and non-dilated aortas; individuals with UAV and TAV) obtained intraoperatively were studied. Standard stains and immunohistochemical labelling of cleaved caspase-3, cluster of differentiation 31 and endothelial nitric oxide synthase (eNOS) were performed to assess the degree of apoptosis, distribution of eNOS within the aortic wall, smooth muscle cell (SMC) nuclei loss and mucoid extracellular matrix accumulation (MEMA). RESULTS Deeper ingrowth of vasa vasorum was found in dilated aortas. Interestingly, eNOS was expressed mostly in vasa vasorum. More apoptosis was seen in UAV aortas compared to TAV aortas (P < 0.001). Both UAV and TAV aortas were comparable regarding SMC nuclei loss (P = 0.419). In dilated compared to non-dilated aortas regardless valve morphology SMC nuclei loss was increased (P = 0.005) and more pronounced translamellar MEMA was present (P = 0.011). The highest grade of distribution (P = 0.043) and the highest severity (P = 0.005) regarding MEMA were seen in TAV dilated specimens compared to UAV dilated specimens. CONCLUSIONS Aneurysms with UAV show increased apoptosis, the role of which is unclear. Strikingly, more severe MEMA was found in TAV aneurysms compared to UAV aneurysms. Thus, UAV-associated aortic wall changes and resulting aneurysm may be less aggressive than aneurysms with TAV.
Background: Aortic complications are more likely to occur in patients with ascending aortic aneurysms and concomitant aortic regurgitation (AR). AR may have a negative impact on the aortic wall structure even in patients with tricuspid aortic valves and absence of aortic dilatation. It is unknown whether smooth muscle cell (SMC) changes are a feature of AR-associated aortic remodeling. Methods: Non-dilated aortic samples were harvested intra-operatively from individuals with normal aortic valves (n=10) or those with either predominant aortic stenosis (AS; n=20) or AR (n=35). Tissue from each patient was processed for immunohistochemistry or used for the extraction of medial SMCs. Tissue and cells were stained for markers of SMC contraction (alpha-smooth muscle actin; ASMA), synthesis (vimentin) and senescence (p16/p21). Replicative capacity was analyzed in cultured SMCs from AS- and AR-associated aortas. A sub-analysis compared SMCs from individuals with either TAVs or BAVs to rule out the effect of aortic valve morphology. Results: In aortic tissue samples, AR was associated with decreased ASMA and increased vimentin, p16 and p21 compared to normal aortic valves and AS. In cell culture, SMCs from AR-aortas had decreased ASMA and increased vimentin compared to SMCs from AS-aortas. AR-associated SMCs had increased p16 and p21 expression, and they reached senescence earlier than SMCs from AS-aortas. In AR, SMC changes were more pronounced with the presence of a BAV. Conclusions: AR itself negatively impacts SMC phenotype in the ascending aortic wall, which is independent of aortic diameter and aortic valve morphology. These findings provide insight into the mechanisms of AR-related aortic remodeling, and they provide a model for studying SMC-specific therapies in culture.
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