TY - JOUR
T1 - Association between proteomic biomarkers and myocardial fibrosis measured by MRI
T2 - the multi-ethnic study of atherosclerosis
AU - Bakhshi, Hooman
AU - Michelhaugh, Sam A.
AU - Bruce, Scott A.
AU - Seliger, Stephen L.
AU - Qian, Xiaoxiao
AU - Ambale Venkatesh, Bharath
AU - Varadarajan, Vinithra
AU - Bagchi, Pramita
AU - Lima, Joao A.C.
AU - deFilippi, Christopher
N1 - Funding Information:
This research was supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute , and by grants UL1-TR-000040 , UL1-TR-001079 , UL1-TR-001420 from the National Center for Advancing Translational Sciences ( NCATS ) and institutional grant provided by Inova Heart and Vascular institute. Dr. deFilippi received an internal seed grant award from the Inova Health System to fund the proteomic measurements used in this study.
Funding Information:
This research was supported by contracts and grants from NHLBI, NCATS and the Inova Heart and Vascular Institute.Dr. deFilippi receives funding from the National Center for Advancing Translational Science of the National Institutes of Health Award UL1TR003015, R01-HL154768-01 and R21 AG072095. Dr. deFilippi reports consulting fees from Abbott Diagnostics, FujiRebio, Ortho/Quidel Diagnostics, Roche Diagnostics and Siemens Healthineers, a travel grant from Olink and is on advisory boards for Abbott and Ortho/Quidel.Dr. Seliger has received funding from Roche Diagnostics.Drs. Seliger and deFilippi are co-owners on a patent awarded to the University of Maryland (US Patent Application Number: 15/309,754) entitled: “Methods for Assessing Differential Risk for Developing Heart Failure.”Dr.Bruce has received grant funding from Inova Heart and Vascular Institute which was awarded to Texas A&M University with him as the principal investigator.This research was supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040, UL1-TR-001079, UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS) and institutional grant provided by Inova Heart and Vascular institute. Dr. deFilippi received an internal seed grant award from the Inova Health System to fund the proteomic measurements used in this study. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.
Publisher Copyright:
© 2023 The Author(s)
PY - 2023/4
Y1 - 2023/4
N2 - 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.
AB - 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.
KW - Biomarkers
KW - Cardiac MRI
KW - Interstitial fibrosis
KW - Myocardial fibrosis
KW - Proteomic
KW - Replacement fibrosis
UR - http://www.scopus.com/inward/record.url?scp=85149225906&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85149225906&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2023.104490
DO - 10.1016/j.ebiom.2023.104490
M3 - Article
C2 - 36857966
AN - SCOPUS:85149225906
SN - 2352-3964
VL - 90
JO - EBioMedicine
JF - EBioMedicine
M1 - 104490
ER -