Transthyretin (TTR)-associated amyloid cardiomyopathy (ATTR) is a disorder of protein folding related to aging and/or genetic mutation. Characterized by accumulation of insoluble amyloid fibrils in the heart, the principal clinical manifestations of ATTR cardiomyopathy are heart failure and death. ATTR is likely a more common disease of older Americans than is currently appreciated, as TTR amyloid aggregates can be found in up 25% of hearts over age 85 years. Further, specific mutations in the TTR gene are associated with ATTR cardiomyopathy, the most common being V122I, identified in 3-4% of African Americans. V122I ATTR carries significant morbidity and mortality, as reports suggest that elderly V122I carriers are at increased risk for heart failure and that median survival following diagnosis is 26 months. While a small retrospective report has suggested that 10% of African American heart failure patients over age 60 years may carry V122I, the proportion of elderly African American heart failure patients with ATTR remains undefined. Diagnosis of ATTR cardiomyopathy is challenging and requires a high degree of clinical suspicion with integration of cardiac imaging, genetic, and histologic test results. Conclusive identification of V122I ATTR requires pathologic diagnosis of amyloid tissue and confirmation of the TTR mutation - tests that are typically performed only in specialty referral centers. There is a critical but unmet clinical need to simplify the ATTR diagnostic algorithm. Cardiac specific biomarkers are useful for assessment of many forms of cardiomyopathy, but lack specificity for ATTR. Recently, retinol-binding protein 4 (RBP4) has been found to specifically bind and stabilize TTR, preventing misfolding and aggregation. While our preliminary data suggest that serum RBP4 levels may differentiate V122I ATTR from heart failure controls, RBP4 concentration as a screening test for ATTR has not been fully validated. An accurate diagnosis of V122I ATTR has implications for family members and alters clinical treatment, with new therapies available that can potentially halt disease progression. The central hypotheses of our application are that (1) the prevalence of ATTR cardiomyopathy among elderly African American heart failure patients approaches 10%, and (2) serum biomarker measurements can differentiate ATTR from other causes of cardiomyopathy.
In Aim 1, we will enroll 300 elderly African American patients with heart failure and determine TTR genotype and ATTR cardiomyopathy phenotype.
In Aim 2, we will measure RBP4 and TTR levels from patients recruited for Aim 1, as well as stored sera from known cases of V122I ATTR seen at the Boston University Amyloidosis Center, to test whether these biomarkers can differentiate V122I ATTR from other causes of heart failure. We anticipate that our findings will validate the hypothesis that ATTR represents a significant burden of disease in elderly African American heart failure patients and provide preliminary evidence that easily measureable serum biomarkers can screen for ATTR. These results may ultimately alter the standard of care for elderly African American patients with heart failure.
TTR cardiac amyloidosis (ATTR) is serious disease associated with aging and inherited genetic variation in the protein transthyretin (TTR) that causes heart failure and death. The most common TTR variation in the U.S., V122I, has been reproducibly observed in 3-4% of African Americans. From US Census data, > 130,000 African Americans over age 65 years carry the V122I variation and are at risk for ATTR. However, because ATTR is challenging to diagnose, we hypothesize that it is frequently un-recognized and thus the number of truly affected persons is unknown. We propose to conclusively define the prevalence V122I ATTR in elderly African Americans with heart failure and to explore whether a simple blood test can accurately differentiate V122I ATTR from other causes of heart failure. This work will provide important information about the burden of disease of V122I ATTR in the African American population.
