Harrison Oliver J, Cagampang Felino, Ohri Sunil K, Torrens Christopher, Salhiyyah Kareem, Modi Amit, Moorjani Narain, Whetton Anthony D, Townsend Paul A
Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
Department of Cardiac Surgery, University Hospital Southampton, Southampton General Hospital, Tremona Road, D-level, North Wing (MP 46), Southampton, UK.
J Cardiothorac Surg. 2018 Jun 22;13(1):76. doi: 10.1186/s13019-018-0762-1.
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.
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).
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).
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.
二叶式主动脉瓣（BAV）疾病是最常见的先天性心脏异常，影响1%-2%的人群，并且与升主动脉瘤风险显著增加相关。然而，预测哪些患者会发生动脉瘤仍然是一项挑战。这项前瞻性研究旨在识别用于监测BAV患者升主动脉直径和预测未来动脉瘤风险的候选血浆生物标志物。
在接受主动脉瓣手术的BAV患者术前采集血浆样本。在术前经食管超声心动图上测量升主动脉最大直径。最大直径≥45mm被归类为动脉瘤。使用先进的质谱技术——所有理论质谱的序列窗口采集（SWATH-MS）来识别和定量样本中的所有蛋白质。使用逻辑回归分析蛋白质丰度与主动脉直径的相关性。使用Levene检验来识别在动脉瘤患者中显示低丰度变异性（疾病中表达一致）以及在非动脉瘤患者中显示高变异性（“有风险”和“无风险”患者之间差异表达）的蛋白质。
共采集了15份血浆样本（7例非动脉瘤BAV患者和8例动脉瘤BAV患者）。患者的平均年龄为55.5岁，大多数为女性（10/15，67%）。四种蛋白质（血红蛋白α、β和δ亚基以及甘露聚糖结合凝集素丝氨酸蛋白酶）与升主动脉最大直径显著相关（p<0.05，r=0.5-0.6）。五种血浆蛋白在动脉瘤组中显示出显著更低的变异性，并且可能表明非动脉瘤患者发生动脉瘤的风险增加（DNA依赖性蛋白激酶催化亚基、核纤层蛋白、四连蛋白、凝溶胶蛋白和软骨酸性蛋白1）。另外7种蛋白质仅在动脉瘤组中被识别（Matrin-3、葡萄糖-6-磷酸异构酶、类肌动蛋白、肽基脯氨酰顺反异构酶A、高尔基体亚家族B成员1、髓过氧化物酶和2'-脱氧核苷5'-磷酸N-水解酶1）。
本研究首次识别出用于预测BAV患者主动脉直径和未来动脉瘤风险的候选血浆生物标志物。它提供了有价值的前瞻性数据和原理证明，可用于设计大规模前瞻性研究。最终，可以开发一种更经济实惠的“现成的”后续血液检测方法来替代SWATH-MS，用于医疗保健环境。
