Abstract Body: Introduction: Myocardial transthyretin (TTR) accumulation can cause amyloid TTR cardiomyopathy (ATTR-CM), a form of restrictive heart disease found in ~16% of patients diagnosed with heart failure with preserved ejection fraction (HFpEF). ATTR-CM can be classified as hereditary (mutation in TTR) or non-hereditary (wild-type TTR). The mechanisms underlying the pathogenesis of non-hereditary ATTR-CM (ATTRwt-CM) remain unknown. To address this knowledge gap, we performed an in-depth mass spectrometry (MS) proteomic study on myocardial tissue from ATTRwt-CM compared to non-failing (NF) donor control, heart failure with a reduced ejection fraction (HFrEF), and HFpEF.
Methods: Myocardial tissue lysates from NF controls (n=7) and ATTRwt-CM (n=4) were digested with trypsin and analyzed by label-free liquid chromatography-tandem mass spectrometry using an Evosep One LC coupled to an Orbitrap Astral MS. HFrEF and HFpEF proteome data were sourced from publicly available repositories.
Results: ATTRwt-CM patients and NF controls were age-matched (54.1 ± 11.5 vs 60.0 ± 17.9 years, p=0.41). A total of 539/7093 (7.6% of total) proteins were significantly altered (Q-value < 0.05), with upregulated expression occurring in 227 (42.1% of significant proteins; log₂-fold change: 1.10 ± 1.19) and downregulated expression in 312 (57.9% of significant proteins; log₂-fold change: -0.55 ± 0.27). Analysis of Gene Ontology Biological Processes (GO:BP) enriched pathways in downregulated proteins indicated reductions in oxidative phosphorylation, mitochondrial protein translation, and impaired transmembrane transport. Conversely, upregulated proteins correlated with enhanced endocytosis, intracellular vesicle mediated transport, and immune cell migration. Compared to other forms of heart failure, ATTRwt-CM exhibited distinct protein regulation but overlapping pathway impairment with reduced oxidative phosphorylation and a unique increase in endocytosis and inflammatory-response.
Conclusion: Myocardial tissue from patients with ATTRwt-CM shows signs of impaired oxidative phosphorylation, mitochondrial dysfunction, as well as augmented endocytosis, compared to NF controls, HFrEF, and HFpEF. Targeting these pathways could offer novel therapeutic strategies for addressing ATTRwt-CM.