Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6Z 2K5, Canada.
J Heart Lung Transplant. 2013 Jul;32(7):723-33. doi: 10.1016/j.healun.2013.04.011.
Coronary angiography remains the most widely used tool for routine screening and diagnosis of cardiac allograft vasculopathy (CAV), a major pathologic process that develops in 50% of cardiac transplant recipients beyond the first year after transplant. Given the invasiveness, expense, discomfort, and risk of complications associated with angiography, a minimally invasive alternative that is sensitive and specific would be highly desirable for monitoring CAV in patients.
Plasma proteomic analysis using isobaric tags for relative and absolute quantitation-matrix-assisted laser desorption ionization double time-of-flight mass spectrometry was carried out on samples from 40 cardiac transplant patients (10 CAV, 9 non-significant CAV, 21 possible CAV). Presence of CAV was defined as left anterior descending artery diameter stenosis ≥ 40% by digital angiography and quantitatively measured by blinded expert appraisal. Moderated t-test robust-linear models for microarray data were used to identify biomarkers that are significantly differentially expressed between patient samples with CAV and with non-significant CAV. A proteomic panel for diagnosis of CAV was generated using the Elastic Net classification method.
We identified an 18-plasma protein biomarker classifier panel that was able to classify and differentiate patients with angiographically significant CAV from those without significant CAV, with an 80% sensitivity and 89% specificity, while providing insight into the possible underlying immune and non-alloimmune contributory mechanisms of CAV.
Our results support of the potential utility of proteomic biomarker panels as a minimally invasive means to identify patients with significant, angiographically detectable coronary artery stenosis in the cardiac allograft, in the context of post-cardiac transplantation monitoring and screening for CAV. The potential biologic significance of the biomarkers identified may also help improve our understanding of CAV pathophysiology.
冠状动脉造影仍然是心脏移植后发生的主要病理过程——心脏移植后第一年超过 50%的心脏移植受者发生的心脏移植后冠状动脉疾病（CAV）的常规筛查和诊断的最广泛应用的工具。鉴于血管造影术具有侵袭性、费用高、不适和并发症风险，因此，对于监测心脏移植后患者的 CAV 而言，高度需要一种具有敏感性和特异性的微创替代方法。
对 40 名心脏移植患者（10 名 CAV、9 名非显著 CAV、21 名可能 CAV）的样本进行基于等重标记物相对和绝对定量-基质辅助激光解吸电离双飞行时间质谱的血浆蛋白质组分析。CAV 的存在通过数字血管造影术定义为左前降支直径狭窄≥40%，并通过盲法专家评估进行定量测量。使用稳健线性模型的微阵列数据中的适度 t 检验，以鉴定在有和无显著 CAV 的患者样本之间存在显著差异表达的生物标志物。使用弹性网络分类方法生成用于诊断 CAV 的蛋白质组面板。
我们鉴定了一个 18 种血浆蛋白生物标志物分类器面板，该面板能够对有和无显著 CAV 的患者进行分类和区分，其敏感性为 80%，特异性为 89%，同时深入了解了 CAV 的可能潜在的免疫和非同种免疫促发机制。
我们的结果支持蛋白质组生物标志物面板作为一种微创手段，在心脏移植后监测和筛查 CAV 的背景下，用于识别有明显、血管造影可检测的冠状动脉狭窄的心脏移植患者的潜在应用价值。鉴定出的生物标志物的潜在生物学意义也可能有助于提高我们对 CAV 病理生理学的理解。
