Association between proteomic biomarkers and myocardial fibrosis measured by MRI: the multi-ethnic study of atherosclerosis

Hooman Bakhshi, Sam A. Michelhaugh, Scott A. Bruce, Stephen L. Seliger, Xiaoxiao Qian, Bharath Ambale Venkatesh, Vinithra Varadarajan, Pramita Bagchi, Joao A.C. Lima, Christopher deFilippi

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Cardiac magnetic resonance imaging (CMR) determines the extent of interstitial fibrosis, measured by increased extracellular volume (ECV), and replacement fibrosis with late gadolinium myocardial enhancement (LGE). Despite advances in detection, the pathophysiology of subclinical myocardial fibrosis is incompletely understood. Targeted proteomic discovery technologies enable quantification of low abundance circulating proteins to elucidate cardiac fibrosis mechanisms. Methods: Using a cross-sectional design, we selected 92 LGE+ cases and 92 LGE− demographically matched controls from the Multi-Ethnic Study of Atherosclerosis. Similarly, we selected 156 cases from the highest ECV quartile and matched with 156 cases from the lowest quartile. The plasma serum proteome was analyzed using proximity extension assays to determine differential regulation of 92 proteins previously implicated with cardiovascular disease. Results were analyzed using volcano plots of statistical significance vs. magnitude of change and Bayesian additive regression tree (BART) models to determine importance. Findings: After adjusting for false discovery, higher ECV was significantly associated with 17 proteins. Using BART, Plasminogen activator inhibitor 1, Insulin-like growth factor-binding protein 1, and N-terminal pro-B-type natriuretic peptide were associated with higher ECV after accounting for other proteins and traditional cardiovascular risk factors. In contrast, no circulating proteins were associated with replacement fibrosis. Interpretations: Our results suggest unique circulating proteomic signatures associated with interstitial fibrosis emphasizing its systemic influences. With future validation, protein panels may identify patients who may develop interstitial fibrosis with progression to heart failure. Funding: This research was supported by contracts and grants from NHLBI, NCATS and the Inova Heart and Vascular Institute.

Original languageEnglish (US)
Article number104490
JournalEBioMedicine
Volume90
DOIs
StatePublished - Apr 2023

Keywords

  • Biomarkers
  • Cardiac MRI
  • Interstitial fibrosis
  • Myocardial fibrosis
  • Proteomic
  • Replacement fibrosis

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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