(P014) PLASMA PROTEOMIC PROFILING OF TRANSTHYRETIN AND LIGHT CHAIN AMYLOIDOSIS

Background: Transthyretin (TTR) amyloidosis, often referred to as ATTR amyloidosis, is a fatal and progressive multi-organ disease marked by the accumulation of misfolded TTR proteins that deposit as amyloid fibrils in multiple organs including the heart, nerves, gastrointestinal system, and musculoskeletal tissues. One of the most severe presentations is ATTR amyloid cardiomyopathy (ATTR-CM), a type of restrictive heart disease that is hard to diagnose because its symptoms mimic those of other heart conditions such as amyloid light chain (AL) amyloidosis. Given the current reliance on high-risk endomyocardial biopsies for diagnosis, developing a non-invasive blood test could accelerate early detection of the disease. Timely diagnosis is crucial, as patients at early stages show the greatest response to emerging treatments, including those focused on TTR production silencing, stabilization, and amyloid clearance from tissues.

METHODS AND RESULTS: A prospective cohort of eight ATTR-CM patients and eight amyloid light chain amyloidosis patients with cardiac involvement were recruited to participate using consecutive sampling. The circulating plasma proteome was subsequently analyzed using the SOMAScan aptamer-based proteomics assay, a technique utilizing modified single-stranded DNA-based aptamers, to measure protein levels of approximately 7,000 analytes simultaneously. Proteomic data were quantified in relative fluorescence units and log-transformed to address heteroscedasticity, with significant differences defined according to False Discovery Rate (FDR) adjusted p-values (p < 0.05) and fold-changes of (≥1.5). Over-representation analysis was conducted using ConsensusPathDB-human, incorporating multiple interaction networks and pathway databases. Significant enrichment sets (Q-value < 0.05) were identified, providing insights into the molecular interaction networks.

Proteomic analysis of plasma samples identified distinct profiles between ATTR-CM and AL amyloidosis, with 241 proteins exhibiting differential expression based on the aforenoted criteria. Notably, 159 proteins displayed increased counts in ATTR-CM plasma, including significant increases in T-complex protein 1 subunit epsilon, noelin-2, and plasma serine protease inhibitor, which showed the highest fold changes. Pathway analysis on differentially expressed proteins revealed significant alterations in pathways regulating metabolism (e.g., purine nucleotides, pyruvates, and glycolysis), actin/tubulin dynamics, and histidine degradation in those with ATTR-CM.

Conclusion: Our findings underscore the potential of using whole plasma proteomics for uncovering novel biomarkers in ATTR-CM and their potential to differentiate sub-types of amyloid cardiomyopathies. This approach could lead to the development of a non-invasive diagnostic test, crucial for early detection and management of the disease. Further research is needed to validate these biomarkers and explore their utility in clinical practice.