Modulation of Cardiac Mechanics in AL Amyloidosis

描述（由申请人提供）：轻链淀粉样变性（AL）的轻链可变区基因使用决定了淀粉样蛋白沉积优先受影响的器官（器官向性）。具体来说，AL轻链的V λ II亚型与早期和主要的心脏受累以及较差的总生存率相关。器官趋向性可能导致临床表现和预后的个体间差异的机制尚不清楚。本资助申请的主要目的是确定特异性、克隆性轻链可变区基因是否影响心功能障碍的性质和程度，以及治疗后心功能的变化。为了与R21项目的既定目标保持一致，我们计划通过将新颖、灵敏、经过验证的成像技术与现有生物标本的分析相结合，从大量淀粉样蛋白临床（每年约120例AL患者）中具有良好特征的人类受试者组中产生有意义的新数据。这项建议是心脏影像学、基础和临床免疫学以及临床淀粉样变性研究人员之间新的协同合作的结果。具体目的：1)评价V lambda II亚型对AL患者收缩期和舒张期功能存在及严重程度的影响；2)评价V lambda II亚型是否影响高剂量化疗和外周血干细胞移植后收缩期和舒张期功能的改变。超声心动图和骨髓样本可在50例AL患者。R21机制将用于该群体骨髓样本的克隆轻链可变区基因分析。为了增加样本量，我们将通过前瞻性地再入组30例患者来补充现有数据库。我们将使用新颖的、敏感的成像技术（组织多普勒应变）来量化局部和全局心脏功能，以及高度敏感的生化技术（浊度法）来量化治疗前后克隆负担的变化。所有患者均有详细的血液学、肾功能和肝功能特征。这项探索性工作旨在利用独特的临床环境来生成试点数据，这些数据将用于为更大规模和更长期的临床试验设计基于假设的建议。本研究的长期目标是更好地了解影响AL心功能障碍发展的因素，以优化治疗策略以改善AL患者的临床结果。

DESCRIPTION (provided by applicant): Light chain variable region gene usage in light chain amyloidosis (AL) determines the organs preferentially affected by amyloid deposition (organ tropism). Specifically, the V lambda II subtype of AL light chains is associated with early and predominant cardiac involvement and poorer overall survival. The mechanism by which organ tropism may be responsible for the inter-individual variations in clinical presentation and prognosis remains unclear. The primary objective of this grant application is to determine whether specific, clonal light chain variable region genes influence the nature and extent of cardiac dysfunction, and the change in cardiac function in response to therapy. In keeping with stated objectives of the R21 program, we plan to generate meaningful new data from a well-characterized group of human subjects in a large volume Amyloid clinic (> 120 AL patients yearly), by combining novel, sensitive, well-validated imaging techniques with analysis of existing biological specimens. This proposal is the result of a new, synergistic collaboration between cardiac imaging, basic and clinical immunology, and clinical amyloidosis investigators. Specific Aims: 1) To evaluate the influence of the V lambda II subtype on the presence and severity of systolic and diastolic function in AL, 2) To evaluate whether the V lambda II subtype influences changes in systolic and diastolic function after high dose chemotherapy and peripheral blood stem cell transplant. Echocardiography and bone marrow samples are available in 50 AL patients. The R21 mechanism would be used to fund clonal light chain variable region gene analysis from bone marrow samples in this group. To increase sample size, we will supplement the existing database by prospectively enrolling an additional 30 patients. We will use novel, sensitive imaging (tissue Doppler strain) to quantify regional and global cardiac function, and highly sensitive biochemical techniques (nephelometry), to quantify changes in clonal burden, before and after therapy. All patients have detailed characterization of hematologic, renal and hepatic function. This exploratory effort seeks to exploit a unique clinical environment to generate pilot data that will be used to design hypothesis-based proposals for larger and longer-term clinical trials. The long-term goal of this research is to better understand the factors that influence the development of cardiac dysfunction in AL with the aim of optimizing treatment strategies to improve clinical outcomes in AL patients.