Bicuspid aortopathy occurs in approximately 50% of patients with bicuspid aortic valve (BAV), the most prevalent congenital cardiac malformation. Although different molecular players and etiological factors (genetic and hemodynamic) have been suggested to be involved in aortopathy predisposition and progression, clear etiophysiopathological mechanisms of disease are still missing. The isogenic (genetically uniform) hamster (T) strain shows 40% incidence of BAV, but aortic dilatations have not been detected in this model. We have performed comparative anatomical, histological and molecular analyses of the ascending aorta of animals with tricuspid aortic valve (TAV) and BAV from the T strain (TTAV and TBAV, respectively) and with TAV from a control strain (HTAV). Aortic diameter, smooth muscle apoptosis, elastic waviness, and Tgf-β and Fbn-2 expression were significantly increased in T strain animals, regardless of the valve morphology. Strain and aortic valve morphology did not affect Mmp-9 expression, whereas Mmp-2 transcripts were reduced in BAV animals. eNOS protein amount decreased in both TBAV and TTAV compared to HTAV animals. Thus, histomorphological and molecular alterations of the ascending aorta appear in a genetically uniform spontaneous hamster model irrespective of the aortic valve morphology. This is a direct experimental evidence supporting the genetic association between BAV and aortic dilatation. This model may represent a population of patients with predisposition to BAV aortopathy, in which increased expression of Tgf-β and Fbn-2 alters elastic lamellae structure and induces cell apoptosis mediated by eNOS. Patients either with TAV or BAV with the same genetic defect may show the same risk to develop bicuspid aortopathy.

Bicuspid aortic valve (BAV) is the most prevalent human congenital cardiac malformation, predisposing to clinically relevant valvulopathies and aorthopathies. BAV aortopathy consists in aortic dilatation caused by medial cystic necrosis, characterized by elastic lamina (EL) disruption and smooth muscle cell (SMC) apoptosis. Although the pathogenetic mechanisms remain unknown for most patients, abnormal expression of several proteins such as TGFb, fibrillin, eNOS, and metalloproteases (MMP) have been assessed in affected patients. The so called genetic and hemodynamic hypotheses have been advanced to explain the etiology of BAV aortopathy. The former proposes that genetic defects cause abnormal formation of aortic valve primordia leading to BAV, together with structural alterations of the ascending aorta predisposing to aortopathy. The latter points to hemodynamic alterations produced by the abnormal valve morphology as the leading cause of aortic wall degeneration. Currently, no direct experimental evidence supports the genetic hypotheses for BAV aortopathy etiology. The only spontaneous model of BAV disease is an inbred strain of Syrian hamsters (T strain) with low penetrant (40%) BAV, in which conspicuous dilatations of the ascending aorta have not been detected. To identify possible alterations of the ascending aorta in this model, we have performed anatomical (diameter), histomorphological (elastic fiber waviness and apoptosis), and molecular (RT‐qPCR and protein expression and activity) quantitative analyses of the aorta of animals with normal and bicuspid valves belonging to both affected (T) and control strains. The diameter of the aorta was significantly higher in animals of the T strain, regardless of the aortic valve morphology. Medial EL fragmentation was not found in any specimen, but EL waviness was significantly increased in the convexity of the aorta of normal and BAV animals of the T strain. SMC apoptosis was also detected in the convex aortic region of the T strain, independently of the aortic valve morphology. eNOS protein expression and activity were significantly increased in the aorta of control animals. RT‐qPCR revealed increased expression of Tgf‐β and Fibrillin‐2 in the aorta of animals of the T strain, while Fibrillin‐1 expression did not change, resulting in a reduction in the Fibrillin‐1/Fibrillin‐2 expression ratio. Strain and aortic valve morphology did not affect Mmp‐9 expression, whereas Mmp‐2 transcripts were elevated only in animals with BAV. This animal model of BAV exhibits histomorphological and molecular alterations of the ascending aorta, which appear in isogenic animals irrespective of the aortic valve phenotype. Thus, this is a direct experimental evidence supporting the genetic association between BAV and predisposition to aortic dilatation. We hypothesize that T strain constitutes a model for a population of patients with predisposition to BAV aortopathy, in which defective expression of Tgf‐β and Fibrillin‐2 may alter the structure of the EL and cause an increase in cell...

The anatomical elements that in humans prevent blood backflow from the aorta and pulmonary artery to the left and right ventriclesare the aortic and pulmonary valves, respectively. Each valve regularly consists of three leaflets (cusps), each supported by its valvular sinus. From the medical viewpoint, each set of three leaflets and sinuses is regarded as a morpho-functional unit. This notion also applies to birds and non-human mammals. However, the structures that prevent the return of blood to the heart in other vertebrates are notably different. This has led to discrepancies between physicians and zoologists in defining what a cardiac outflow tract valve is. The aim here is to compare the gross anatomy of the outflow tract valvular system among several groups of vertebrates in order to understand the conceptual and nomenclature controversies in the field.

Bicuspid aortic valve (BAV) is the most prevalent human congenital cardiac malformation, which predisposes to ascending aortic dilatation (AD). Disease predisposition probably results from a congenital defect leading to anomalies in both, the morphology of the valve and the histology of the ascending aorta. Altered hemodynamics caused by the abnormal valve morphology would accelerate aortic media degeneration. AD in BAV patients results from medial smooth muscle cell (SMC) apoptosis probably caused by defective cell‐matrix adhesion. Alterations of the TGFβ pathway seem to be central in disease initiation and progression, affecting extracellular matrix homeostasis. However, currently there are neither clear pathophysiological mechanisms nor effective biomarkers of disease predisposition or progression.The only spontaneous animal model of BAV disease consists of an inbred (T) strain of Syrian hamsters with a high (40%) incidence of BAV. Although AD has never been described in this model, animals of the T strain show significant SMC apoptosis and altered elastic lamina in the aortic media, irrespective of aortic valve morphology. We reasoned that analysing differentially expressed proteins in the aortic wall of animals with normal aortic valve (TAV) of the T strain compared to a control strain would inform about 1) the validity of the T strain as a model for BAV aortopathy predisposition; 2) the congenital origin of AD associated to BAV; 3) the proteins involved in AD etiology, independent of the effect of hemodynamics.To this aim, we compared the proteome of the ascending aorta of animals with TAV of the T strain (n=6) and a control outbred strain (n=6) by three independent experiments of quantitative proteomics (ESI‐Quadrupole‐Orbitrap LFQ). The analysis yielded expression data for over 1,954 proteins. Of these, 57 proteins (2.9%) showed concordant expression in at least two of the three experiments and were deregulated over 2.6‐fold.Fourteen of these 57 proteins (24.6%) were previously proposed as AD biomarkers in patients. After database search, the 57 selected proteins were found to significantly interact (p<0.05 following FDR adjustment) within 16 molecular pathways and 27 biological processes on the STRING website. Most of these pathways and processes were relevant to AD pathophysiology, of note are the TGFβ non‐canonical pathways (10/57; 17.5%; p=0.043), programmed cell death (14/57; 24.6%; p=3.5e‐4), cell adhesion (15/57; 26.3%; p=2.4e‐4), supramolecular fiber organization (9/57; 15.8%; p=3.8e‐4) and stress fiber assembly (2/57; 3.5%; p=0.037).These results were obtained comparing the proteomes of aortas of individuals with TAV from an affected and a control strain. Thus, genetic rather than hemodynamic factors explain the structural abnormalities of the ascending aorta in this model. We propose that the T strain is an appropriate model for AD predisposition, as it replicates the ethiophysiological processes observed in patients. Deep study of our ascending aorta proteome analysis may uncover new molecular ...