Novel Insights into the Pathogenesis of Light Chain Cardiac Amyloidosis

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DESCRIPTION (provided by applicant): Systemic amyloidosis is a rare disease that affects many organ systems, the most devastating and lethal of which is cardiac involvement. In response to statements from the U.S. House of Representatives Appropriations Committee on the need for additional research on amyloidosis, the Office of Rare Diseases (NIH) sponsored a workshop and the promotion of amyloidosis-related grants. Mechanisms of tissue damage caused by amyloid fibrils represents the most important and least understood aspect of amyloid pathophysiology. The current understanding of the mechanisms of cardiac dysfunction and myocardial damage in amyloidosis is limited and improved detection and treatment is needed. Cardiac amyloidosis is characterized by amyloid infiltration in the heart with disruption of the extracellular matrix. Systemic amyloidosis featuring cardiac involvement (AL-CMP) is due to immunoglobulin light chain protein deposition in the heart that manifests with congestive heart failure, arrhythmias and death within 6 months of diagnosis. While cardiac amyloidosis related to other non-light chain proteins i.e. amyloidosis associated with wild-type transthyretin (TTR): the senile systemic amyloidosis (SSA) or a mutant transthyretin (ATTR); the prognosis for patients with AL-CMP is inordinately worse. Our central hypothesis is that determinants of the proteolytic activity of the extracellular matrix, the matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) have distinct patterns and contribute to the pathogenesis of AL-CMP. In a cohort of patients that have been followed at the Amyloid Clinic at Boston Medical Center, we will determine the relationship between circulating MMP and TIMP levels and cardiac remodeling. In Aim 1, we will test the hypotheses that MMP and/or TIMP levels are altered in AL-CMP patients and are associated with more adverse structural remodeling. In Aim 2, we will test the hypotheses that change in MMP and TIMP levels (between baseline and post-therapy) are associated with clinical outcomes, disease progression (as determined by diastolic dysfunction on echocardiography) and BNP levels. We will measure cardiac specific MMP and TIMP levels at baseline, immediately post-therapy and 3, 6, and 12 months after discharge from the hospital and during periods of clinical decompensation that require hospitalization. These studies will provide new understanding into the pathophysiology of light chain deposition in systemic amyloidosis featuring cardiac involvement. Extracellular matrix proteolytic activation may play an important role in the functional and clinical manifestations of cardiac involvement and allow for future directed therapeutic interventions. PUBLIC HEALTH RELEVANCE: Systemic amyloidosis is a rare disease that affects many organ systems, the most devastating and lethal of which is cardiac involvement. Cardiac involvement and its resultant dysfunction is the least understood aspect of amyloid pathophysiology, therefore improved detection and treatment is needed. In response to statements from the U.S. House of Representatives Appropriations Committee on the need for additional research in amyloidosis, the Office of Rare Diseases (NIH) sponsored a workshop and is promoting amyloidosis-related grants and as a result amyloidosis is considered to be a high priority for research in the field.