Heart failure with preserved ejection fraction (HFpEF) disproportionately afflicts older Black and Hispanic Americans. ATTR cardiac amyloidosis (ATTR CA) is caused by myocardial deposition of misfolded transthyretin protein (TTR or prealbumin) and is classified by the genetics of TTR into wild-type (ATTRwt) or mutant (ATTRm). ATTR CA, irrespective of genotype, is an age-dependent, often unrecognized, mechanism underlying HFpEF. While ATTRm CA results from point mutations that promote TTR misfolding and amyloid aggregation, factors that contribute to ATTRwt CA are not well defined. While previously thought to be untreatable, promising therapies in late-stage clinical trials will likely be most effective if administered early in disease course. Only a small proportion of individuals with wild-type TTR will develop ATTRwt CA, overwhelmingly reported in Caucasian males beyond age 60 years. However, as an autosomal protein, allele distribution is not sex specific. For ATTRm, a substitution of isoleucine for valine (V122I) is the most frequent TTR mutation in the US, observed exclusively in Black Americans with an allele frequency of 3.4%. But there are no data regarding the prevalence of ATTRwt CA in African Americans and no data for ATTR CA prevalence, irrespective of genotype, in the Hispanic population. One of the reasons for the knowledge deficit is the challenge of diagnosis. Endomyocardial biopsy, while nearly 100% sensitive and specific, is impractical as a screening test and genotyping alone of patients is insufficient to identify ATTR CA because wild-type patients develop disease. We have developed a highly accurate technique for ATTR CA identification using Tc99m-pyrophosphate (PYP) imaging that avoids the need for biopsy. Tc99m-PYP myocardial uptake can occur before echocardiographic or clinical changes, suggesting enhanced sensitivity. While studies using the technique have suggested that 10-15% of elderly hospitalized patients with HF may have ATTR CA, Tc99m- PYP has not been applied broadly in HF patients as a means to facilitate early diagnosis. In addition, we have also reported both a point-of-care diagnostic tool that utilizes a novel biomarker, retinol binding protein 4 (RBP4), and an assay to measure TTR stability. We hypothesize that a significant proportion of HF in elderly Blacks and Hispanics is caused ATTR CA. We propose to leverage our methodologies to establish the prevalence of ATTR CA and explore the relationship between RBP4 concentration and TTR stability in a prospective cohort study of elderly Black and Hispanic Americans with HF.
Aim 1 will determine the prevalence and clinical progression of ATTR CA relative to genotype, clarify sex distribution, and calibrate the aforementioned point-of-care diagnostic tool.
Aim 2 will explore the relationships between RBP4 concentration in serum and urine, TTR stability, and genotype in ATTR CA. Successful completion of these Aims will inform understanding of ATTR CA pathogenesis and may modify clinical practice, alter PYP indication labeling, and improve outcomes for older adult Black Americans and Hispanics with HF.
Heart failure with preserved ejection fraction (HFpEF) disproportionately afflicts older Black and Hispanic Americans for which there are no effective medical therapies. Cardiac amyloidosis is a cause of heart failure that we hypothesize is misdiagnosed in 10-15% of elderly patients, potentially comprising up to 500,000 people in the United States. In this application, we propose to recruit a cohort of elderly Black and Hispanic patients with heart failure to define the number of patients who have cardiac amyloidosis by utilizing highly sensitive heart imaging and blood tests that we have developed, and to explore differences in genetics and sex as they relate to heart failure disease progression in cardiac amyloidosis.
