1 Scopus citations

Abstract

Background: In vivo mechanisms of amyloid clearance and cardiac tissue damage in cardiac amyloidosis are not well understood. Objectives: We aimed to define and quantify the amyloid plaque proteome in cardiac transthyretin amyloidosis (ATTR) and light chain amyloidosis (AL) and identify associations with patient characteristics and outcomes. Methods: A proteomics approach was used to identify all proteins in cardiac amyloid plaques, and to compare both normal and diseased controls. All proteins identified within amyloid plaques were defined as the expanded proteome; only proteins that were enriched in comparison to normal and disease controls were defined as the amyloid-specific proteome. Results: Proteomic data from 292 patients with ATTR and 139 patients with AL cardiac amyloidosis were included; 160 and 161 unique proteins were identified in the expanded proteomes, respectively. In the amyloid-specific proteomes, we identified 28 proteins in ATTR, 19 in AL amyloidosis, with 13 proteins overlapping between ATTR and AL. ATTR was characterized by a higher abundance of complement and contractile proteins and AL by a higher abundance of keratins. We found that the proteome of kappa AL had higher levels of clusterin, a protective chaperone, and lower levels of light chains than lambda despite higher levels of circulating light chains. Hierarchical clustering identified a group of patients with worse survival in ATTR, characterized by high levels of PIK3C3, a protein with a central role in autophagy. Conclusions: Cardiac AL and ATTR have both common and distinct pathogenetic mechanisms of tissue damage. Our findings suggest that autophagy represents a pathway that may be impaired in ATTR and should be further studied.

Original languageEnglish (US)
Pages (from-to)632-643
Number of pages12
JournalJACC: CardioOncology
Volume2
Issue number4
DOIs
StatePublished - Nov 2020

Keywords

  • amyloidosis
  • cardiomyopathy
  • heart failure
  • proteomics

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Oncology

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