Focus on the unique mechanisms involved in thoracic aorticaneurysm formation in bicuspid aortic valve vs tricuspid aortic valvepatients: clinical implications of a pilot study

OBJECTIVES: The involvement of different factors in the onset of thoracic aortic aneurysm (TAA) in patients with a bicuspid aortic valve(BAV) vs those with a tricuspid aortic valve (TAV) is well recognized. However, the molecular, genetic and cellular mechanisms drivingTAA remain unclear. The aim of this study was to identify the different mechanisms involved in TAA development in patients with BAVvs TAV.METHODS: Aorta specimens and DNA samples were collected from 24 BAV (18 men and 6 women; mean age: 54.2 ± 14.39 years) and110 TAV (79 men and 31 women, mean age: 66 ± 9.8 years) patients. A control group of 128 subjects (61 men and 67 woman, meanage: 61.1 ± 5.8 years) was also enrolled. Histopathological and immunoistochemical analyses were performed, as well as genotyping of10 polymorphisms.RESULTS: In BAV-associated ascending aortas, significant severe plurifocal apoptosis of smooth muscle cells and matrix metalloproteinase-9 (MMP-9) amounts were detected. In contrast, TAV-associated ascending aortas were characterized by a significant severity ofelastic fragmentation, cystic medial necrosis, medial fibrosis and inflammation. In addition, in BAV cases, the −1562TMMP-9 and−735TMMP-2 alleles represent independent risk factors for TAA. The effects of these genotypes combined with hypertension andsmoking in BAV cases result in an increase in both the apoptosis (P = 0.0001) and levels of MMP-9 (P = 0.001). In TAV cases, the Dangiotensin-converting enzyme and +896A Toll-like receptor-4 alleles seem to be the predictive factors for TAA risk. They, combinedwith hypertension and age, significantly increase both the microscopic lesions and inflammation.CONCLUSIONS: Our data seem to suggest that TAA in BAV and TAV patients arises from different molecular, cellular and geneticmechanisms. They might help to identify the potential molecular and genetic biomarkers that are useful to detect BAV subjects at highTAA risk, to monitor and treat them differently from those with TAV, with approaches such as the complete removal of the ascendingaorta, including the aortic root with or without dilatation.