Elevated expressions of osteopontin and tenascin C in ascending aortic aneurysms are associated with trileaflet aortic valves as compared with bicuspid aortic valves

Background: Bicuspid aortic valves predispose to ascending aortic aneurysms, but the mechanisms underlying this aortopathy remain incompletely characterized. We sought to identify epigenetic pathways predisposing to aneurysm formation in bicuspid patients.Methods: Ascending aortic aneurysm tissue samples were collected at the time of aortic replacement in subjects with bicuspid and trileaflet aortic valves. Genome-wide DNA methylation status was determined on DNA from tissue using the Illumina 450K methylation chip, and gene expression was profiled on the same samples using Illumina Whole-Genome DASL arrays. Gene methylation and expression were compared between bicuspid and trileaflet individuals using an unadjusted Wilcoxon rank sum test. Results: Twenty-seven probes in 9 genes showed significant differential methylation and expression (P<5.5x10-4). The top gene was protein tyrosine phosphatase, non-receptor type 22 (PTPN22), which was hypermethylated (delta beta range: +15.4 to +16.0%) and underexpressed (log 2 gene expression intensity: bicuspid 5.1 vs. trileaflet 7.9, P=2x10-5) in bicuspid patients, as compared to tricuspid patients. Numerous genes involved in cardiovascular development were also differentially methylated, but not differentially expressed, including ACTA2 (4 probes, delta beta range: -10.0 to -22.9%), which when mutated causes the syndrome of familial thoracic aortic aneurysms and dissectionsConclusions: Using an integrated, unbiased genomic approach, we have identified novel genes associated with ascending aortic aneurysms in patients with bicuspid aortic valves, modulated through epigenetic mechanisms. The top gene was PTPN22, which is involved in T-cell receptor signaling and associated with various immune disorders. These differences highlight novel potential mechanisms of aneurysm development in the bicuspid population.

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Abstract TP86: Prevalence of Bicuspid Aortic Valves and Thoracic Ascending Aortic Aneurysms in Patients Treated for Intracranial Aneurysms

Stroke ◽

10.1161/str.44.suppl_1.atp86 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Manu S Goyal ◽

Ravi Gottumukkala ◽

Sanjeev Bhalla ◽

Andrew M Kates ◽

Gregory J Zipfel ◽

...

Keyword(s):

Intracranial Aneurysms ◽

Aortic Aneurysms ◽

Chest Imaging ◽

Aortic Valves ◽

Cross Sectional ◽

Population Prevalence ◽

Prevalence Estimates ◽

Bicuspid Aortic Valves ◽

And Gender ◽

Clinical Records

INTRODUCTION: Prior studies have suggested an increased prevalence of intracranial aneurysms (ICA) in patients with bicuspid aortic valves (BAV) and thoracic ascending aortic aneurysms (TAA). We tested the hypothesis that if true, conversely, the prevalence of BAV and TAA should be increased in patients with ICA. METHODS: We identified and reviewed the clinical records of patients treated for an ICA at our institution between 2002 and 2011. Only those with an echocardiogram report in their clinical record were included for further analysis. The prevalence of BAV and TAA in this cohort was determined based on the echocardiogram reports, medical records, and, when available, cross-sectional chest imaging. Proportion confidence intervals were calculated and compared to population prevalence estimates. RESULTS: Of 1051 patients with ICA, 321 had available echocardiogram reports that included assessment of the aortic valve. Of these, 85 also had cross-sectional chest imaging. Of the 321 patients, 2 were reported to have a BAV (0.6%, 95% CI 0 - 2.5%), similar to population prevalence estimates for this condition. In this same cohort, there were 15 (4.7%, 95% CI 2.7 - 7.8%) patients with a TAA. Among the 85 patients with cross-sectional chest imaging, the prevalence of TAA exceeded that expected for a community age- and gender-matched population (see Figure, gray lines represent upper and lower limits of normal). CONCLUSIONS: This retrospective analysis suggests an increased prevalence of TAA, but not BAV, in patients with ICA.

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Natural History of Ascending Aortic Aneurysms (40-50 mm): Impact of Bicuspid Aortic Valves

10.22541/au.160507447.74467039/v1 ◽

2020 ◽

Author(s):

Tarek Malas ◽

Eric Dumont ◽

Siamak Mohammadi ◽

Pierre Voisine ◽

François Dagenais

Keyword(s):

Natural History ◽

Aortic Aneurysms ◽

Aortic Valves ◽

Bicuspid Aortic Valves ◽

History Of

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Bicuspid aortic valves and thoracic aortic aneurysms in patients with intracranial aneurysms

Neurology ◽

10.1212/wnl.0000000000001104 ◽

2014 ◽

Vol 84 (1) ◽

pp. 46-49 ◽

Cited By ~ 10

Author(s):

M. S. Goyal ◽

R. Gottumukkala ◽

S. Bhalla ◽

A. Kates ◽

G. J. Zipfel ◽

...

Keyword(s):

Intracranial Aneurysms ◽

Aortic Aneurysms ◽

Aortic Valves ◽

Thoracic Aortic Aneurysms ◽

Bicuspid Aortic Valves

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Bicuspid Aortic Valves Are Associated With Aortic Dilatation Out of Proportion to Coexistent Valvular Lesions

Circulation ◽

10.1161/circ.102.suppl_3.iii-35 ◽

2000 ◽

Vol 102 (suppl_3) ◽

Author(s):

Martin G. Keane ◽

Susan E. Wiegers ◽

Ted Plappert ◽

Alberto Pochettino ◽

Joseph E. Bavaria ◽

...

Keyword(s):

Aortic Stenosis ◽

Aortic Regurgitation ◽

Ventricular Outflow Tract ◽

Left Ventricular ◽

Aortic Aneurysms ◽

Aortic Dilatation ◽

Aortic Valves ◽

Bicuspid Aortic Valves ◽

Valvular Lesions ◽

Aortic Size

Background —Bicuspid aortic valves (BAVs) are associated with premature valve stenosis, regurgitation, and ascending aortic aneurysms. We compared aortic size in BAV patients with aortic size in control patients with matched valvular lesions (aortic regurgitation, aortic stenosis, or mixed lesions) to determine whether intrinsic aortic abnormalities in BAVs account for aortic dilatation beyond that caused by valvular hemodynamic derangement alone. Methods and Results —Diameters of the left ventricular outflow tract, sinus of Valsalva, sinotubular junction, and proximal aorta were measured from transthoracic echocardiograms in 118 consecutive BAV patients. Annular area was measured by planimetry, and BAV eccentricity was expressed as the ratio of the right leaflet area to the total annular area. Seventy-seven control patients with tricuspid aortic valves were matched for sex and for combined severity of regurgitation and stenosis. BAV patients (79 men and 39 women, aged 44.1±15.5 years) had varying degrees of regurgitation (84 patients [71%]) and stenosis (48 patients [41%]). Within the bicuspid group, multivariate analysis demonstrated that aortic diameters increased with worsening aortic regurgitation ( P <0.001) and advancing age ( P <0.05) but not with the severity of aortic stenosis. BAV patients had larger aortic diameters than did control patients at all ascending aortic levels measured ( P <0.01), despite advanced age in the control patients. Conclusions —Aortic dimensions are larger in BAV patients than in control patients with comparable degrees of tricuspid aortic valve disease. Although more severe degrees of aortic regurgitation are associated with aortic dilatation in BAV patients, intrinsic pathology appears to be responsible for aortic enlargement beyond that predicted by hemodynamic factors.

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