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

项目摘要 腰椎管狭窄症(LSS)对老年人的影响不成比例，是 腰椎手术。腰椎管狭窄症退变的生物学机制尚未见报道 得到了充分的阐明。新出现的数据表明TTR淀粉样变性，其特征是沉积在 错误折叠蛋白转甲状腺素(TTR)，是一种年龄依赖性的，未被识别的，普遍存在于 手术标本(如黄韧带)可能是心脏发育的先兆 几年前就参与进来了。然而，由TTR淀粉样变性引起的LSS的比例并不好 目前也不清楚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淀粉样变性之间的关联可能提供一个可修改的 获得性退行性腰椎管狭窄的生物学机制 新化合物的进一步临床试验可以防止淀粉样蛋白的形成。此外，由于TTR型淀粉样变性 结果在心肌病中，利用高度特异的非侵入性成像测试(Tc-99焦磷酸 闪烁成像或PYP)，可以在不需要组织学的情况下识别TTR心脏淀粉样变性；我们可能 能够在一组TTR心脏淀粉样蛋白患者发展为显性心力衰竭之前进行识别。 TTR心脏淀粉样变性的早期诊断是至关重要的，因为它是多发性的 治疗方法可以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 建议对正在接受腰椎前路手术的65岁患者进行前瞻性先导队列研究 我们将使用病理学技术对手术标本进行转甲状腺蛋白淀粉样变性(Atr)的筛查。 包括基于质谱学的蛋白质组学分析的组织分型。在病理性的患者中 我们将使用生物标记物，经胸腔，确定他们的心脏表型 超声心动图和焦磷酸核素心脏成像及建立生化关联 疾病表型与TTR不稳定性之间的关系。这些研究的目的是：(1)确认以前的 据报道，在接受腰椎手术的老年患者中，TTR淀粉样沉积的患病率很高 狭窄手术，以及(2)表征心脏表型并建立生化关联。 病理明确的TTR淀粉样变性患者的TTR稳定性。这项多学科研究可能 结果在腰椎标本中对TTR淀粉样蛋白进行了更常规的评估，ATTR心脏病患者 老年人在早期疾病状态下被诊断为淀粉样蛋白和未来的疾病调整干预 接受腰椎管狭窄症手术的成年患者。总的来说，这样的研究将有助于准确地 改善老年LSS和TTR淀粉样心肌病患者预后的医学方法。

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.