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Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve disease.

ABSTRACT: BACKGROUND:Ascending aortic aneurysms constitute an important hazard for individuals with a bicuspid aortic valve (BAV). However, the processes that degrade the aortic wall in BAV disease remain poorly understood. METHODS:We undertook in situ analysis of ascending aortas from 68 patients, seeking potentially damaging cellular senescence cascades. Aortas were assessed for senescence-associated-ß-galactosidase activity, p16Ink4a and p21 expression, and double-strand DNA breaks. The senescence-associated secretory phenotype (SASP) of cultured-aged BAV aortic smooth muscle cells (SMCs) was evaluated by transcript profiling and consequences probed by combined immunofluorescence and circular polarization microscopy. The contribution of p38 MAPK signaling was assessed by immunostaining and blocking strategies. FINDINGS:We uncovered SMCs at varying depths of cellular senescence within BAV- and tricuspid aortic valve (TAV)-associated aortic aneurysms. Senescent SMCs were also abundant in non-aneurysmal BAV aortas but not in non-aneurysmal TAV aortas. Multivariable analysis revealed that BAV disease independently associated with SMC senescence. Furthermore, SMC senescence was heightened at the convexity of aortas associated with right-left coronary cusp fusion. Aged BAV SMCs had a pronounced collagenolytic SASP. Moreover, senescent SMCs in the aortic wall were enriched with surface-localized MMP1 and surrounded by weakly birefringent collagen fibrils. The senescent-collagenolytic SMC phenotype depended on p38 MAPK signaling, which was chronically activated in BAV aortas. INTERPRETATION:We have identified a cellular senescence-collagen destruction axis in at-risk ascending aortas. This novel "seno-destructive" SMC phenotype could open new opportunities for managing BAV aortopathy. FUND: Canadian Institutes of Health Research, Lawson Health Research Institute, Heart and Stroke Foundation of Ontario/Barnett-Ivey Chair.

SUBMITTER: Balint B

PROVIDER: S-EPMC6562112 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve disease.

Balint Brittany B Yin Hao H Nong Zengxuan Z Arpino John-Michael JM O'Neil Caroline C Rogers Stephanie R SR Randhawa Varinder K VK Fox Stephanie A SA Chevalier Jacqueline J Lee Jason J JJ Chu Michael W A MWA Pickering J Geoffrey JG

EBioMedicine 20190509

<h4>Background</h4>Ascending aortic aneurysms constitute an important hazard for individuals with a bicuspid aortic valve (BAV). However, the processes that degrade the aortic wall in BAV disease remain poorly understood.<h4>Methods</h4>We undertook in situ analysis of ascending aortas from 68 patients, seeking potentially damaging cellular senescence cascades. Aortas were assessed for senescence-associated-ß-galactosidase activity, p16<sup>Ink4a</sup> and p21 expression, and double-strand DNA b ...[more]

PMID: 31078518

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Project description:BackgroundAlthough a bicuspid aortic valve (BAV) is known to be associated with progressive ascending aortic dilatation, the fate of the residual aorta after aortic valve and ascending aorta surgery is unknown. We reviewed surgical outcomes and explored serial changes in the size of the sinus of Valsalva (SOV) and distal ascending aorta (DAAo) in 89 patients with a BAV undergoing aortic valve replacement (AVR) and graft replacement (GR) of the ascending aorta.MethodsWe retrospectively examined patients who underwent AVR and GR of the ascending aorta for BAV-and related disease and thoracic aortic dilatation at our institution between January 2009 and December 2018. Patients who underwent AVR alone or required intervention for the aortic root and aortic arch and patients with connective tissue diseases were excluded. Aortic diameters were examined using computed tomography (CT). Late CT more than 1 year after surgery was performed in 69 patients (78%) with a mean follow-up of 4.9±2.8 years.ResultsThe surgical indication for aortic valve etiology was stenosis in 61 patients (69%), regurgitation in 10 (11%), and mixed in 18 (20%). Preoperative maximum short diameters of the ascending aorta, SOV, and DAAo were 47.3±4.7, 36.0±5.2, and 37.2±3.6 mm, respectively. The diameter of the SOV increased non-significantly by 0.08±0.45 mm per year [95% confidence interval (CI): -0.12 to 0.11, P=0.150], while that of the DAAo increased significantly by 0.11±0.40 mm per year (95% CI: 0.02-0.21, P=0.005). One patient required reoperation 6 years postoperatively due to a pseudo-aneurysm at the proximal anastomotic site. No patient required reoperation due to progressive dilatation of the residual aorta. According to the Kaplan-Meier analysis, the long-term survival rates were 98.9%, 98.9%, and 92.7% at 1, 5, and 10 years postoperatively, respectively.ConclusionsRapid dilatation of the residual aorta rarely occurred in patients with a BAV who underwent AVR and GR of the ascending aorta in the mid-term follow-up. For selected patients with a surgical indication for ascending aortic dilatation, simple AVR and GR of the ascending aorta may be sufficient surgical options.

Project description:BACKGROUND:Bicuspid aortic valve (BAV) disease is the most common congenital cardiac abnormality affecting 1-2% of the population and is associated with a significantly increased risk of ascending aortic aneurysm. However, predicting which patients will develop aneurysms remains a challenge. This pilot study aimed to identify candidate plasma biomarkers for monitoring ascending aortic diameter and predicting risk of future aneurysm in BAV patients. METHODS:Plasma samples were collected pre-operatively from BAV patients undergoing aortic valve surgery. Maximum ascending aortic diameter was measured on pre-operative transoesophageal echocardiography. Maximum diameter???45 mm was classified as aneurysmal. Sequential Window Acquisition of all THeoretical Mass Spectra (SWATH-MS), an advanced mass spectrometry technique, was used to identify and quantify all proteins within the samples. Protein abundance and aortic diameter were correlated using logistic regression. Levene's test was used to identify proteins demonstrating low abundance variability in the aneurysmal patients (consistent expression in disease), and high variability in the non-aneurysmal patients (differential expression between 'at risk' and not 'at risk' patients). RESULTS:Fifteen plasma samples were collected (seven non-aneurysmal and 8 aneurysmal BAV patients). The mean age of the patients was 55.5 years and the majority were female (10/15, 67%). Four proteins (haemoglobin subunits alpha, beta and delta and mannan-binding lectin serine protease) correlated significantly with maximal ascending aortic diameter (p?<?0.05, r?=?0.5-0.6). Five plasma proteins demonstrated significantly lower variability in the aneurysmal group and may indicate increased risk of aneurysm in non-aneurysmal patients (DNA-dependent protein kinase catalytic subunit, lumican, tetranectin, gelsolin and cartilage acidic protein 1). A further 7 proteins were identified only in the aneurysmal group (matrin-3, glucose-6-phosphate isomerase, coactosin-like protein, peptidyl-prolyl cis-trans isomerase A, golgin subfamily B member 1, myeloperoxidase and 2'-deoxynucleoside 5'-phosphate N-hydrolase 1). CONCLUSIONS:This study is the first to identify candidate plasma biomarkers for predicting aortic diameter and risk of future aneurysm in BAV patients. It provides valuable pilot data and proof of principle that could be used to design a large-scale prospective investigation. Ultimately, a more affordable 'off-the-shelf' follow-on blood assay could then be developed in place of SWATH-MS, for use in the healthcare setting.

Dataset Information

Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve disease.

Publications

Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve disease.

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