Modulation of Cardiac Mechanics in AL Amyloidosis

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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.