Amyloid light chain (AL) or primary amyloidosis is the most prevalent systemic amyloidosis worldwide. More than half of patients with AL amyloidosis present with cardiac involvement, resulting in the development of a rapidly progressive AL amyloid cardiomyopathy, with limited response to current therapies and median survival of 13 months. We have identified a potent cardiotoxic response in cardiomyocytes to human amyloidogenic light chain (AL-LC) isolated from patients with AL amyloid cardiomyopathy, as a critical component of the disease's pathogenesis. However, the mechanism underlying AL-LC induced cardiotoxicity have remained unclear. We have recently found that AL-LC cardiotoxicity culminates on the mitochondrial. Using comprehensive metabolomics approaches, we have found that AL-LC results in selective antagonism of mitochondrial ?-oxidation of long chain unsaturated fatty acids (LCUFA) with compensatory upregulation of an ER pathway of ?-oxidation, with marked increase in byproducts of ?-oxidation present in cellular models of AL-LC cardiotoxicity and patients with AL amyloid cardiomyopathy. In this proposal, we will leverage study of the largest amassed cohort of patients with AL amyloid cardiomyopathy, established cellular and animal models of AL-LC cardiotoxicity, and state of the art mass spectrometry based metabolomics to (1) define the in vivo metabolite signature of AL amyloid cardiomyopathy and to identify a first early diagnostic metabolite biomarker for this disease; (2) determine the functional significance of shifting lipid metabolism from mitochondrial ?-oxidation to ER ?-oxidation and the contribution of this process to the pathogenesis of AL-LC cardiotoxicity; and (3) to determine if bypassing or restoring mitochondrial ?-oxidation using approved agents may serve to protect against the development of AL amyloid cardiomyopathy. Our project is centered in line with the recent NIH's PA announcement (PA-13-286: Systemic Amyloidosis: Basic, Translational and Clinical Research [RO1]) and will provide unprecedented mechanistic, diagnostic and therapeutic insight into this disease process.

Public Health Relevance

Amyloid light chain (AL) or primary amyloidosis is the most common systemic amyloidosis and frequently results in the development of a progressive and fatal form of amyloid heart disease. Little is known about the mechanisms that cause this disease. This grant proposal aims to identify the mechanistic basis for amyloid heart disease and to develop biomarkers for diagnosis of amyloid heart disease and new approaches to treat this disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Wong, Renee P
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Brigham and Women's Hospital
United States
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