Characterization of the cardiac proteome of wild-type transthyretin amyloidosis cardiomyopathy

Abstract

IntroductionMyocardial accumulation of the protein transthyretin (TTR) can result in amyloid TTR cardiomyopathy (ATTR-CM), a form of restrictive heart disease with limited therapies and still generally poor clinical outcomes. The mechanisms by which TTR fibril accumulation elicits cardiac toxicity at the protein level remain largely unknown. Accordingly, we performed untargeted proteomics of ventricular myocardium from patients with ATTR-CM versus controls. MethodsMyocardial tissue from non-failing (NF) controls (n=7) and ATTR-CM (n=4) were assayed by mass spectrometry. HFrEF, HCM, and HFpEF proteomics were acquired from published databases. ResultsA total of 539/7093 (7.6% of total) proteins were found to be differentially expressed in ATTR-CM, 227/359 (42%) upregulated and 312/539 (58%) downregulated. Gene ontology pathway analysis found that downregulated proteins were enriched for oxidative phosphorylation and mitochondrial protein translation pathways, while upregulated proteins were enriched for enhanced endocytosis and intracellular vesicle mediated transport. The latter is not observed in other forms of heart failure. We further identify a profound downregulation of sarcomere protein content, which is also not seen in other cardiomyopathies. ConclusionThe ATTR-CM myocardial proteome identifies endocytosis and intracellular transport as uniquely upregulated processes, whereas sarcomere protein content is uniquely downregulated. Both maybe potential therapeutic targets.