Proteomics of left ventricular structure in the Multi-Ethnic Study of Atherosclerosis

Tess E. Peterson; Joao A.C. Lima; Sanjiv J. Shah; David A. Bluemke; Alain G. Bertoni; Yongmei Liu; Debby Ngo; Vinithra Varadarajan; Josyf C. Mychaleckyj; Craig W. Johnson; Bruce M. Psaty; Clary B. Clish; Kent D. Taylor; Peter Durda; Russell P. Tracy; Robert E. Gerszten; Stephen S. Rich; Jerome I. Rotter; Wendy S. Post; James S. Pankow

doi:10.1002/ehf2.15073

Proteomics of left ventricular structure in the Multi-Ethnic Study of Atherosclerosis

Tess E. Peterson^*, Joao A.C. Lima, Sanjiv J. Shah, David A. Bluemke, Alain G. Bertoni, Yongmei Liu, Debby Ngo, Vinithra Varadarajan, Josyf C. Mychaleckyj, Craig W. Johnson, Bruce M. Psaty, Clary B. Clish, Kent D. Taylor, Peter Durda, Russell P. Tracy, Robert E. Gerszten, Stephen S. Rich, Jerome I. Rotter, Wendy S. Post, James S. Pankow^*

^*Corresponding author for this work

Medicine, Cardiology Division

Research output: Contribution to journal › Article › peer-review

Abstract

Aims: Proteomic profiling offers an expansive approach to biomarker discovery and mechanistic hypothesis generation for LV remodelling, a critical component of heart failure (HF). We sought to identify plasma proteins cross-sectionally associated with left ventricular (LV) size and geometry in a diverse population-based cohort without known cardiovascular disease (CVD). Methods and results: Among participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we quantified plasma abundances of 1305 proteins using an aptamer-based platform at exam 1 (2000–2002) and exam 5 (2010–2011) and assessed LV structure by cardiac magnetic resonance (CMR) at the same time points. We used multivariable linear regression with robust variance to assess cross-sectional associations between plasma protein abundances and LV structural characteristics at exam 1, reproduced findings in later-life at exam 5, and explored relationships of associated proteins using annotated enrichment analysis. We studied 763 participants (mean age 60 ± 10 years at exam 1; 53% female; 19% Black race; 31% Hispanic ethnicity). Following adjustment for renal function and traditional CVD risk factors, plasma levels of 3 proteins were associated with LV mass index at both time points with the same directionality (FDR < 0.05): leptin (LEP), renin (REN), and cathepsin-D (CTSD); 20 with LV end-diastolic volume index: LEP, NT-proBNP, histone-lysine N-methyltransferase (EHMT2), chordin-like protein 1 (CHRDL1), tumour necrosis factor-inducible gene 6 protein (TNFAIP6), NT-3 growth factor receptor (NTRK3), c5a anaphylatoxin (C5), neurogenic locus notch homologue protein 3 (NOTCH3), ephrin-B2 (EFNB2), osteomodulin (OMD), contactin-4 (CNTN4), gelsolin (GSN), stromal cell-derived factor 1 (CXCL12), calcineurin subunit B type 1 (PPP3R1), insulin-like growth factor 1 receptor (IGF1R), bone sialoprotein 2 (IBSP), interleukin-11 (IL-11), follistatin-related protein 1 (FSTL1), periostin (POSTN), and biglycan (BGN); and 4 with LV mass-to-volume ratio: RGM domain family member B (RGMB), transforming growth factor beta receptor type 3 (TGFBR3), ephrin-A2 (EFNA2), and cell adhesion molecule 3 (CADM3). Functional annotation implicated regulation of the PI3K-Akt pathway, bone morphogenic protein signalling, and cGMP-mediated signalling. Conclusions: We report proteomic profiling of LV size and geometry, which identified novel associations and reinforced previous findings on biomarker candidates for LV remodelling and HF. If validated, these proteins may help refine risk prediction and identify novel therapeutic targets for HF.

Original language	English (US)
Pages (from-to)	239-249
Number of pages	11
Journal	ESC Heart Failure
Volume	12
Issue number	1
DOIs	https://doi.org/10.1002/ehf2.15073
State	Published - Feb 2025

Funding

The MESA projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for the Multi-Ethnic Study of Atherosclerosis (MESA) projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided 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, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1TR001881, DK063491, and R01HL105756. 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 institutes can be found at http://www.mesa-nhlbi.org. Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1), and TOPMed MESA Multi-Omics (HHSN2682015000031/HSN26800004). Research reported in this publication was also supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Numbers T32 HL007779 and T32 HL007227. The MESA projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for the Multi\u2010Ethnic Study of Atherosclerosis (MESA) projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01\u2010HC\u201095159, 75N92020D00005, N01\u2010HC\u201095160, 75N92020D00002, N01\u2010HC\u201095161, 75N92020D00003, N01\u2010HC\u201095162, 75N92020D00006, N01\u2010HC\u201095163, 75N92020D00004, N01\u2010HC\u201095164, 75N92020D00007, N01\u2010HC\u201095165, N01\u2010HC\u201095166, N01\u2010HC\u201095167, N01\u2010HC\u201095168, N01\u2010HC\u201095169, UL1\u2010TR\u2010000040, UL1\u2010TR\u2010001079, UL1\u2010TR\u2010001420, UL1TR001881, DK063491, and R01HL105756. 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 institutes can be found at http://www.mesa\u2010nhlbi.org . Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL\u2010117626\u201002S1). Phenotype harmonization, data management, sample\u2010identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL\u2010120393\u201002S1), and TOPMed MESA Multi\u2010Omics (HHSN2682015000031/HSN26800004). Research reported in this publication was also supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Numbers T32 HL007779 and T32 HL007227.

Keywords

Biomarkers
Cardiovascular magnetic resonance imaging
Left ventricular remodelling
Proteomics

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/ehf2.15073

Cite this

Peterson, T. E., Lima, J. A. C., Shah, S. J., Bluemke, D. A., Bertoni, A. G., Liu, Y., Ngo, D., Varadarajan, V., Mychaleckyj, J. C., Johnson, C. W., Psaty, B. M., Clish, C. B., Taylor, K. D., Durda, P., Tracy, R. P., Gerszten, R. E., Rich, S. S., Rotter, J. I., Post, W. S., & Pankow, J. S. (2025). Proteomics of left ventricular structure in the Multi-Ethnic Study of Atherosclerosis. ESC Heart Failure, 12(1), 239-249. https://doi.org/10.1002/ehf2.15073

@article{8986e5b1bbf0456e916fb42a862b94b3,

title = "Proteomics of left ventricular structure in the Multi-Ethnic Study of Atherosclerosis",

abstract = "Aims: Proteomic profiling offers an expansive approach to biomarker discovery and mechanistic hypothesis generation for LV remodelling, a critical component of heart failure (HF). We sought to identify plasma proteins cross-sectionally associated with left ventricular (LV) size and geometry in a diverse population-based cohort without known cardiovascular disease (CVD). Methods and results: Among participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we quantified plasma abundances of 1305 proteins using an aptamer-based platform at exam 1 (2000–2002) and exam 5 (2010–2011) and assessed LV structure by cardiac magnetic resonance (CMR) at the same time points. We used multivariable linear regression with robust variance to assess cross-sectional associations between plasma protein abundances and LV structural characteristics at exam 1, reproduced findings in later-life at exam 5, and explored relationships of associated proteins using annotated enrichment analysis. We studied 763 participants (mean age 60 ± 10 years at exam 1; 53% female; 19% Black race; 31% Hispanic ethnicity). Following adjustment for renal function and traditional CVD risk factors, plasma levels of 3 proteins were associated with LV mass index at both time points with the same directionality (FDR < 0.05): leptin (LEP), renin (REN), and cathepsin-D (CTSD); 20 with LV end-diastolic volume index: LEP, NT-proBNP, histone-lysine N-methyltransferase (EHMT2), chordin-like protein 1 (CHRDL1), tumour necrosis factor-inducible gene 6 protein (TNFAIP6), NT-3 growth factor receptor (NTRK3), c5a anaphylatoxin (C5), neurogenic locus notch homologue protein 3 (NOTCH3), ephrin-B2 (EFNB2), osteomodulin (OMD), contactin-4 (CNTN4), gelsolin (GSN), stromal cell-derived factor 1 (CXCL12), calcineurin subunit B type 1 (PPP3R1), insulin-like growth factor 1 receptor (IGF1R), bone sialoprotein 2 (IBSP), interleukin-11 (IL-11), follistatin-related protein 1 (FSTL1), periostin (POSTN), and biglycan (BGN); and 4 with LV mass-to-volume ratio: RGM domain family member B (RGMB), transforming growth factor beta receptor type 3 (TGFBR3), ephrin-A2 (EFNA2), and cell adhesion molecule 3 (CADM3). Functional annotation implicated regulation of the PI3K-Akt pathway, bone morphogenic protein signalling, and cGMP-mediated signalling. Conclusions: We report proteomic profiling of LV size and geometry, which identified novel associations and reinforced previous findings on biomarker candidates for LV remodelling and HF. If validated, these proteins may help refine risk prediction and identify novel therapeutic targets for HF.",

keywords = "Biomarkers, Cardiovascular magnetic resonance imaging, Left ventricular remodelling, Proteomics",

author = "Peterson, {Tess E.} and Lima, {Joao A.C.} and Shah, {Sanjiv J.} and Bluemke, {David A.} and Bertoni, {Alain G.} and Yongmei Liu and Debby Ngo and Vinithra Varadarajan and Mychaleckyj, {Josyf C.} and Johnson, {Craig W.} and Psaty, {Bruce M.} and Clish, {Clary B.} and Taylor, {Kent D.} and Peter Durda and Tracy, {Russell P.} and Gerszten, {Robert E.} and Rich, {Stephen S.} and Rotter, {Jerome I.} and Post, {Wendy S.} and Pankow, {James S.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.",

year = "2025",

month = feb,

doi = "10.1002/ehf2.15073",

language = "English (US)",

volume = "12",

pages = "239--249",

journal = "ESC Heart Failure",

issn = "2055-5822",

publisher = "John Wiley and Sons Inc.",

number = "1",

}

Peterson, TE, Lima, JAC, Shah, SJ, Bluemke, DA, Bertoni, AG, Liu, Y, Ngo, D, Varadarajan, V, Mychaleckyj, JC, Johnson, CW, Psaty, BM, Clish, CB, Taylor, KD, Durda, P, Tracy, RP, Gerszten, RE, Rich, SS, Rotter, JI, Post, WS & Pankow, JS 2025, 'Proteomics of left ventricular structure in the Multi-Ethnic Study of Atherosclerosis', ESC Heart Failure, vol. 12, no. 1, pp. 239-249. https://doi.org/10.1002/ehf2.15073

TY - JOUR

T1 - Proteomics of left ventricular structure in the Multi-Ethnic Study of Atherosclerosis

AU - Peterson, Tess E.

AU - Lima, Joao A.C.

AU - Shah, Sanjiv J.

AU - Bluemke, David A.

AU - Bertoni, Alain G.

AU - Liu, Yongmei

AU - Ngo, Debby

AU - Varadarajan, Vinithra

AU - Mychaleckyj, Josyf C.

AU - Johnson, Craig W.

AU - Psaty, Bruce M.

AU - Clish, Clary B.

AU - Taylor, Kent D.

AU - Durda, Peter

AU - Tracy, Russell P.

AU - Gerszten, Robert E.

AU - Rich, Stephen S.

AU - Rotter, Jerome I.

AU - Post, Wendy S.

AU - Pankow, James S.

PY - 2025/2

Y1 - 2025/2

N2 - Aims: Proteomic profiling offers an expansive approach to biomarker discovery and mechanistic hypothesis generation for LV remodelling, a critical component of heart failure (HF). We sought to identify plasma proteins cross-sectionally associated with left ventricular (LV) size and geometry in a diverse population-based cohort without known cardiovascular disease (CVD). Methods and results: Among participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we quantified plasma abundances of 1305 proteins using an aptamer-based platform at exam 1 (2000–2002) and exam 5 (2010–2011) and assessed LV structure by cardiac magnetic resonance (CMR) at the same time points. We used multivariable linear regression with robust variance to assess cross-sectional associations between plasma protein abundances and LV structural characteristics at exam 1, reproduced findings in later-life at exam 5, and explored relationships of associated proteins using annotated enrichment analysis. We studied 763 participants (mean age 60 ± 10 years at exam 1; 53% female; 19% Black race; 31% Hispanic ethnicity). Following adjustment for renal function and traditional CVD risk factors, plasma levels of 3 proteins were associated with LV mass index at both time points with the same directionality (FDR < 0.05): leptin (LEP), renin (REN), and cathepsin-D (CTSD); 20 with LV end-diastolic volume index: LEP, NT-proBNP, histone-lysine N-methyltransferase (EHMT2), chordin-like protein 1 (CHRDL1), tumour necrosis factor-inducible gene 6 protein (TNFAIP6), NT-3 growth factor receptor (NTRK3), c5a anaphylatoxin (C5), neurogenic locus notch homologue protein 3 (NOTCH3), ephrin-B2 (EFNB2), osteomodulin (OMD), contactin-4 (CNTN4), gelsolin (GSN), stromal cell-derived factor 1 (CXCL12), calcineurin subunit B type 1 (PPP3R1), insulin-like growth factor 1 receptor (IGF1R), bone sialoprotein 2 (IBSP), interleukin-11 (IL-11), follistatin-related protein 1 (FSTL1), periostin (POSTN), and biglycan (BGN); and 4 with LV mass-to-volume ratio: RGM domain family member B (RGMB), transforming growth factor beta receptor type 3 (TGFBR3), ephrin-A2 (EFNA2), and cell adhesion molecule 3 (CADM3). Functional annotation implicated regulation of the PI3K-Akt pathway, bone morphogenic protein signalling, and cGMP-mediated signalling. Conclusions: We report proteomic profiling of LV size and geometry, which identified novel associations and reinforced previous findings on biomarker candidates for LV remodelling and HF. If validated, these proteins may help refine risk prediction and identify novel therapeutic targets for HF.

AB - Aims: Proteomic profiling offers an expansive approach to biomarker discovery and mechanistic hypothesis generation for LV remodelling, a critical component of heart failure (HF). We sought to identify plasma proteins cross-sectionally associated with left ventricular (LV) size and geometry in a diverse population-based cohort without known cardiovascular disease (CVD). Methods and results: Among participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we quantified plasma abundances of 1305 proteins using an aptamer-based platform at exam 1 (2000–2002) and exam 5 (2010–2011) and assessed LV structure by cardiac magnetic resonance (CMR) at the same time points. We used multivariable linear regression with robust variance to assess cross-sectional associations between plasma protein abundances and LV structural characteristics at exam 1, reproduced findings in later-life at exam 5, and explored relationships of associated proteins using annotated enrichment analysis. We studied 763 participants (mean age 60 ± 10 years at exam 1; 53% female; 19% Black race; 31% Hispanic ethnicity). Following adjustment for renal function and traditional CVD risk factors, plasma levels of 3 proteins were associated with LV mass index at both time points with the same directionality (FDR < 0.05): leptin (LEP), renin (REN), and cathepsin-D (CTSD); 20 with LV end-diastolic volume index: LEP, NT-proBNP, histone-lysine N-methyltransferase (EHMT2), chordin-like protein 1 (CHRDL1), tumour necrosis factor-inducible gene 6 protein (TNFAIP6), NT-3 growth factor receptor (NTRK3), c5a anaphylatoxin (C5), neurogenic locus notch homologue protein 3 (NOTCH3), ephrin-B2 (EFNB2), osteomodulin (OMD), contactin-4 (CNTN4), gelsolin (GSN), stromal cell-derived factor 1 (CXCL12), calcineurin subunit B type 1 (PPP3R1), insulin-like growth factor 1 receptor (IGF1R), bone sialoprotein 2 (IBSP), interleukin-11 (IL-11), follistatin-related protein 1 (FSTL1), periostin (POSTN), and biglycan (BGN); and 4 with LV mass-to-volume ratio: RGM domain family member B (RGMB), transforming growth factor beta receptor type 3 (TGFBR3), ephrin-A2 (EFNA2), and cell adhesion molecule 3 (CADM3). Functional annotation implicated regulation of the PI3K-Akt pathway, bone morphogenic protein signalling, and cGMP-mediated signalling. Conclusions: We report proteomic profiling of LV size and geometry, which identified novel associations and reinforced previous findings on biomarker candidates for LV remodelling and HF. If validated, these proteins may help refine risk prediction and identify novel therapeutic targets for HF.

KW - Biomarkers

KW - Cardiovascular magnetic resonance imaging

KW - Left ventricular remodelling

KW - Proteomics

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Proteomics of left ventricular structure in the Multi-Ethnic Study of Atherosclerosis

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