PROJECT SUMMARY
Approximately 1.5 million of the 44 million Blacks in the United States are carriers of the valine-to-isoleucine
substitution at position 122 (V122I) in the transthyretin (TTR) protein. Virtually exclusive to Blacks, this is the
most common cause of hereditary cardiac amyloidosis (hATTR-CA) worldwide. hATTR-CA leads to worsening
heart failure (HF) and premature death. Fortunately, new therapies that stabilize TTR improve morbidity and
mortality in hATTR-CA, especially when prescribed early in the disease.(5) However, hATTR-CA is often
diagnosed at an advanced stage and conventional diagnostic tools lack diagnostic specificity to detect early
disease. Recent work from the author demonstrated that young V122I TTR carriers had indirect imaging and
biomarker evidence of cardiac amyloid infiltration. Thus, the overall objectives of this proposal are to determine
the presence of subclinical hATTR-CA and to identify biomarkers that indicate amyloid progression in V122I TTR
carriers. The central hypothesis of this proposal is that hATTR-CA has a long latency period that will be detected
through subclinical amyloidosis imaging and biomarker phenotyping. The central hypothesis will be tested by
pursuing 2 specific aims: Aim 1) determine the association of V122I TTR carrier status with CMRI evidence of
amyloid infiltration; Sub-aim 1) determine the association of V122I TTR carrier status with cardiac reserve; Aim
2) determine the association between amyloid-specific biomarkers and V122I TTR carrier status; and Sub-aim
2) determine the association of amyloid-specific biomarkers with imaging-based parameters and evaluate their
diagnostic utility for identifying subclinical hATTR-CA. In Aim 1, CMRI will be used to compare metrics associated
with cardiac amyloid infiltration between a cohort of V122I TTR carriers without HF formed by cascade genetic
testing and age-, sex-, and race-matched non-carrier controls. For Sub-Aim 1, a sub-sample of carriers and non-
carrier controls enrolled in Aim 1 will undergo novel exercise CMRI to measure and compare cardiac systolic
and diastolic reserve. Aim 2 involves measuring and comparing amyloid-specific biomarkers in V122I TTR
carriers without HF with samples matched non-carriers (both from Aim 1) and individuals with symptomatic V122I
hATTR-CA from our clinical sites. These biomarkers detect and quantify different processes of TTR
amyloidogenesis and include circulating TTR, retinol binding protein 4, TTR kinetic stability, and misfolded TTR
oligomers. Sub-aim 2 will establish the role of these biomarkers to detect imaging evidence of subclinical hATTR-
CA disease. The research proposed in this application is innovative, in the applicant's opinion, because it will
enroll a large population of V122I TTR carriers without HF through cascade genetic testing that will model clinical
care. Then, it will employ detailed, advanced imaging techniques with tissue characterization and novel
biomarkers that directly quantify processes of hATTR-CA disease progression to identify subclinical hATTR-CA.
Identifying evidence of cardiac amyloid progression prior to hATTR-CA disease onset will change how we think
about this disease and justify future research in screening and treatment strategies to prevent hATTR-CA.
