Genetic basis, pathogenesis and histopathology of aortopathy in Bicuspid aortic valve and marfan syndrome

Aortic aneurysms are characterized by weakened aortic walls and are relatively common causes of death because of arterial dissection or rupture. The most common causes of thoracic aortic aneurysm are congenital genetic defects in the aortic wall. These can occur in association with pathological conditions such as Marfan syndrome (MFS) and bicuspid aortic valve (BAV). Many studies have observed similarities between the histology of the aneurysmal tissue of the aorta in MFS and BAV. In MFS, mutations in the gene encoding for the extracellular matrix protein fibrillin-1 have been detected; this mutation leads to dysregulation of transforming growth factor-beta (TGF-b) signaling. In contrast, the genetics underlying BAV are largely unknown. The current grading of aortic abnormalities during histopathological evaluation of BAV is based on conflicting reports. Thus, whether mechanisms related to the existing aneurysmal histological alterations in BAV are due to genetic etiology and/or wall stress induced by flow turbulence requires further investigation. The heritability of BAV is high, estimated at 0.75- 0.89. Family-based genome-wide analyses revealed a linkage between BAV and chromosomal regions 5q, 13q, and 18q in autosomal dominant inheritance with reduced penetrance and a non-Mendelian pattern. A male predominance of more than 3:1 has been reported for BAV, and this anomaly is very frequent in X0 Turner's syndrome (incidence rate: 22-34%), suggesting an X-linked contribution. In one family with Anderson syndrome four family members were described with BAV. In Anderson syndrome, a mutation in the potassium inwardly-rectifying channel, subfamily J, member 2 is observed. Mutations were detected in the transmembrane receptor NOTCH1. Moreover, mutations in the vascular smooth muscle cell alpha actin gene (ACTA2) have also been identified in patients with BAV and aortic aneurysms. Furthermore, BAV can manifest as part of defects in the left ventricular outflow tract spectrum including aortic coarctation, arch hypoplasia, and supravalvular and mitral valve stenosis. The UFD1L gene, which is highly expressed in the outflow tract during embryogenesis, is down-regulated in the cusps of patients with BAV compared with those of control patients. Heterozygous loss of Nkx2-5, Fgf8, and GATA5 in mice predisposes for the development of BAV. Tissue-specific deletion of the gene encoding activin receptor type 1 (Alk2/Acvr1) in the cushion mesenchyme is observed to result in formation of aortic valve defects including BAV. Endothelial nitric oxide synthase (eNOS) is also associated with the development of BAV in mice. A high incidence of aortic aneurysms was detected in eNOS/apolipoprotein E double-knockout mice. Recent studies also reported a significant decrease in the amount of the eNOS protein present in aneurysmal BAV aortic tissue compared with tricuspid aortic valve (TAV) tissue. Local differences in eNOS protein expression were observed in BAV compared with TAV aortic aneurysms, probably due to variations in aortic wall shear stresses. Dysregulated TGF-b activity, dysregulation of miRNAs, and loss of aortic medial elastic fibers are observed in ascending aortic aneurysms and acute aortic dissection (AAD). Patients with BAV are at an increased risk of developing AAD (5 to 9 times more than normal; 12.5 to 20.5 times more than patients with MFS). In this chapter, we review our present understanding of ascending thoracic aortic aneurysm pathogenesis. We discuss the genetic basis and basic pathology underlying BAV and ascending thoracic aortic aneurysms, and compare these to known mechanisms underlying other aortopathologies. Histopathological findings in dilated aortic walls of BAV were compared with dilated TAV and MFS.