Analysis of Lumbar Spine Stenosis Speciments for Early Identification of TTR Cardiac Amyloidosis

项目摘要 腰椎管狭窄症（LSS）不成比例地影响老年人，是最常见的原因， 腰椎手术腰椎管狭窄症退变的生物学机制尚未完全阐明， 被充分阐明。新出现的数据表明，TTR淀粉样变性，其特征在于沉积的蛋白质， 错误折叠的蛋白质甲状腺素运载蛋白（TTR），是年龄依赖性的，未被识别，通常存在于 LSS中的手术标本（例如黄韧带）可能先于心脏病变的发生 几年的参与。然而，TTR淀粉样变性引起的LSS的比例并不理想 也不清楚在腰椎淀粉样蛋白沉积时是否存在心脏受累。 揭示腰椎管狭窄症和TTR淀粉样变性之间的联系可能提供一种可改变的 获得性退行性腰椎管狭窄症的生物学机制，并可能导致 新化合物的进一步临床试验防止淀粉样蛋白形成。此外，由于TTR淀粉样变性 导致心肌病，利用高度特异性的非侵入性成像测试（Tc-99焦磷酸 血管造影术或PYP），可以识别TTR心脏淀粉样变性，而不需要组织学;我们可能是 能够在出现明显心力衰竭之前识别出一组TTR心脏淀粉样蛋白患者。 在病程早期识别TTR心脏淀粉样变性是至关重要的， 治疗防止新的淀粉样蛋白沉积，但不能解决现有的淀粉样蛋白。因此，我们现在 建议在年龄>65岁的患者中进行前瞻性试点队列研究，这些患者接受LSS手术， 我们将使用病理学技术筛选甲状腺素运载蛋白淀粉样变性（ATTR）的手术标本 包括利用基于质谱的蛋白质组学分析进行组织分型。在病理学上 定义的ATTR疾病，我们将使用生物标志物，经胸， 超声心动图和焦磷酸锝心脏成像，并建立生化关联 疾病表型和TTR不稳定性之间的关系。这些研究的目的是：（1）证实以前的 据报道，在接受腰椎手术的老年患者中，TTR淀粉样蛋白沉积的患病率很高， 狭窄手术，以及（2）表征心脏表型并建立 病理学定义的TTR淀粉样变性患者的TTR稳定性。这项多学科研究可以 导致腰椎标本中TTR淀粉样蛋白的常规评价，ATTR心脏病患者 淀粉样蛋白在早期疾病状态下被诊断，老年人未来的疾病修饰干预措施 接受腰椎管狭窄症手术的成人患者。总的来说，这些研究将有助于精确地 改善老年LSS和TTR淀粉样心肌病患者预后的药物方法。

Project Summary Lumbar spinal stenosis (LSS) disproportionately affects older adults and is the most common reason for lumbar spine surgery. The biological mechanism underlying degeneration in lumbar spinal stenosis has not been fully elucidated. Emerging data suggest that TTR amyloidosis, characterized by deposition of the misfolded protein transthyretin (TTR), is age-dependent, unrecognized, and commonly present in the surgical specimens (e.g. ligamentum flavum) in LSS that may precede the development of cardiac involvement by several years. However, the proportion of LSS caused by TTR amyloidosis is not well defined nor it is clear if cardiac involvement is present at the time of amyloid deposits in the lumbar spine. Uncovering an association between lumbar spinal stenosis and TTR amyloidosis may provide a modifiable biological mechanism for acquired degenerative lumbar spinal stenosis and could lead the path toward further clinical trials of novel compounds prevent amyloid formation. Additionally, since TTR amyloidosis results in a cardiomyopathy, leveraging a highly specific non-invasive imaging test (Tc-99 pyrophosphate scintigraphy or PYP), that can identify TTR cardiac amyloidosis without the need for histology; we may be able to identify a group of patients with TTR cardiac amyloid before the development of overt heart failure. Identification of TTR cardiac amyloidosis early in their disease course is critical as multiple emerging therapies prevent new amyloid deposition but do not address existing amyloid. Accordingly, we now propose a prospective pilot cohort study in patients age >65 years old who are undergoing LSS surgery in which we will screen surgical specimens for transthyretin amyloidosis (ATTR) using pathologic techniques including tissue typing with mass spectrometry based proteomic analysis. In patients with pathologically defined ATTR disease, we will characterize their cardiac phenotype using biomarkers, transthoracic echocardiography and technetium pyrophosphate cardiac imaging and establish biochemical associations between disease phenotype and TTR instability. The aims of these studies are: (1) to confirm the previously reported high prevalence of TTR amyloid deposits among elderly patients undergoing lumbar spinal stenosis surgery, and (2) to characterize the cardiac phenotype and establish biochemical associations of TTR stability in patients with pathologically defined TTR amyloidosis. This multidisciplinary study could result in more routine evaluation for TTR amyloid in lumbar spine specimens, patients with ATTR cardiac amyloid being diagnosed at an earlier disease state and future disease-modifying interventions in older adult patients undergoing lumbar spinal stenosis surgery. Collectively, such studies will facilitate a precision medicine approach to improve outcomes in older adults with LSS and TTR amyloid cardiomyopathy.