Familial thoracic aortic dilation and bicommissural aortic valve: A prospective analysis of natural history and inheritance

Abstract

The autosomal dominant inheritance of bicommissural aortic valve (BAV) (Online Mendelian Inheritance in Man #109730) in some families is well-documented; however, the inheritance of BAV with thoracic aortic aneurysm (TAA) is less clear. Whether the aneurysm is secondary to hemodynamic perturbation related to the valve abnormality or a primary manifestation of the disorder remains controversial. Guidelines are needed regarding the follow-up and treatment of these patients and their families. Thirteen families with at least one individual with TAA and BAV (BAV/TAA) were evaluated prospectively by standard echocardiographic methods or clinical history. Affected status was determined by the presence of BAV or TAA or a history of dissection, rupture, or surgical repair. Six of 13 families had at least two family members with both BAV and TAA, often in successive generations. Informatively, all 13 families had at least one family member with TAA in the absence of BAV. Thirty-five percent (39/110) of family members had BAV/TAA or TAA, and the majority of families (11/13) had maximal dilatation above the sinotubular junction (STJ). Vascular dissection or rupture occurred in seven of 13 families and in individuals with structurally normal aortic valves. Two families had non-manifesting, obligate carriers. Three families have members with other left heart outflow tract anomalies. This study confirms autosomal dominant inheritance with incomplete penetrance for BAV/TAA in these families. Furthermore, our data suggest that the component features, BAV and TAA, are independent manifestations of a single gene defect. To avoid the risk of early death, it is essential that all first-degree relatives receive echocardiographic follow-up at regular intervals regardless of the presence or absence of a BAV. This assessment must include imaging of the aortic region above the STJ.

Systematic Review of Studies That Have Evaluated Screening Tests in Relatives of Patients Affected by Nonsyndromic Thoracic Aortic Disease

“…Our results also suggest that genetic testing and cardiac imaging with at least TTE should be offered to all FDRs and SDRs of patients with suspected NS‐TADs. Mutation carriers should undergo further imaging (MRI or CT scan), focusing on thoracic aorta and/or other arterial trees based on the causative gene mutation 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74. For example, ACTA2‐mutation carriers should be monitored for coronary artery disease and occlusive cerebrovascular disease, in addition to the currently recommended routine imaging tests 32.…”

Clinical and Genetic Aspects of Bicuspid Aortic Valve: A Proposed Model for Family Screening Based on a Review of Literature

“…Twenty four of the relatives (22%) were diagnosed with TAA in the presence of a normal tricuspid aortic valve. 32 In addition, Keane et al reported that aortic size in BAV patients was larger than in control patients. They observed comparable degrees of aortic regurgitation, stenosis or mixed lesions, and concluded that intrinsic pathology appears to be responsible for aortic enlargement.…”

“…This root phenotype has been proposed to be the form of bicuspid aortopathy most likely to be associated with a genetic cause. 3,13,20,24,[31][32][33] Although rare, the most feared complication in BAV patients is thoracic aortic dissection, which has been reported at young age. 34 Whereas the lifetime risk of aortic dissection in BAV patients was initially reported around 5%, recent studies show a lifetime risk of aortic dissection of less than 1% in BAV patients and a normal life expectancy.…”

“…21,32,59,60 Martin et al performed bivariate genetic analyses between aortic dimensions and BAV. Their results did not support a shared underlying genetic basis for BAV and aortic measures.…”

Altered aortic shape in bicuspid aortic valve relatives influences blood flow patterns

“…15 -19 While the familial association of BAV with aortopathy has been well described, few studies have addressed aortopathy in BAV relatives with normal, trileaflet aortic valves. 8,10,20,21 Biner et al demonstrated that the aortic root is functionally abnormal and dilated in up to 32% of FDRs. 21 However, other studies found a lower prevalence of aortic dilatation among BAV relatives.…”