title: Focus on the unique mechanisms involved in thoracic aortic aneurysm formation in bicuspid aortic valve versus tricuspid aortic valve patients: clinical implications of a pilot study.
abstract: OBJECTIVE
  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 driving TAA remain unclear. The aim of this study was to identify the different mechanisms involved in TAA development in patients with BAV vs TAV.
  
  
  METHODS
  Aorta specimens and DNA samples were collected from 24 BAV (18 men and 6 women; mean age: 54.2 ± 14.39 years) and 110 TAV (79 men and 31 women, mean age: 66 ± 9.8 years) patients. A control group of 128 subjects (61 men and 67 woman, mean age: 61.1 ± 5.8 years) was also enrolled. Histopathological and immunohistochemical analyses were performed, as well as genotyping of 10 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 of elastic 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 and smoking 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 D angiotensin-converting enzyme and +896A Toll-like receptor-4 alleles seem to be the predictive factors for TAA risk. They, combined with 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 genetic mechanisms. They might help to identify the potential molecular and genetic biomarkers that are useful to detect BAV subjects at high TAA risk, to monitor and treat them differently from those with TAV, with approaches such as the complete removal of the ascending aorta, including the aortic root with or without dilatation.
authors.affiliation: Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, Italy. carmelarita.balistreri@unipa.it
authors.forename: Carmela Rita
authors.initials: CR
authors.lastname: Balistreri
authors.forename: Calogera
authors.initials: C
authors.lastname: Pisano
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Candore
authors.forename: Emiliano
authors.initials: E
authors.lastname: Maresi
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Codispoti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ruvolo
mesh_terms: D000328:Adult; D000368:Aged; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000473:pathology*; D001021:Aortic Valve / Q000002:abnormalities* / Q000473:pathology; D017209:Apoptosis / Q000502:physiology; D000082882:Bicuspid Aortic Valve Disease; D015897:Comorbidity; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006349:Heart Valve Diseases / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D006651:Histocytochemistry; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008875:Middle Aged; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014261:Tricuspid Valve / Q000002:abnormalities*
chemical_list: D020780:Matrix Metalloproteinase 9