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. 2021 Feb 10;6(2):89-99.
doi: 10.1016/j.jacbts.2020.11.011. eCollection 2021 Feb.

Quantitative Proteomic Analysis of Diabetes Mellitus in Heart Failure With Preserved Ejection Fraction

Thomas C Hanff  1   2 , Jordana B Cohen  2   3 , Lei Zhao  4 , Ali Javaheri  5 , Payman Zamani  1 , Stuart B Prenner  1 , Ernst Rietzschel  6 , Yi Jia  7 , Alice Walsh  4 , Joseph Maranville  4 , Zhaoqing Wang  4 , Leonard Adam  4 , Francisco Ramirez-Valle  4 , Peter Schafer  4 , Dietmar Seiffert  4 , David A Gordon  4 , Mary E Cvijic  4 , Thomas P Cappola  1 , Julio A Chirinos  1
Affiliations

Quantitative Proteomic Analysis of Diabetes Mellitus in Heart Failure With Preserved Ejection Fraction

Thomas C Hanff et al. JACC Basic Transl Sci. .

Abstract

Diabetes mellitus (DM) is associated with a higher risk of heart failure hospitalization and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Using SomaScan assays and proteomics analysis of plasma from participants in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial and the Penn Heart Failure Study, this study identified 10 proteins with significantly different expression in patients with HFpEF and DM. Of these, apolipoprotein M was found to mediate 72% (95% CI: 36% to 100%; p < 0.001) of the association between DM and the risk of cardiovascular death, aborted cardiac arrest, and heart failure hospitalization.

Keywords: ApoM, apolipoprotein M; CI, confidence interval; CILP2, cartilage intermediate layer protein 2; DM, diabetes mellitus; HFpEF, heart failure with preserved ejection fraction; HR, hazard ratio; LASSO, least absolute shrinkage and selection operator; apolipoprotein M; diabetes; heart failure; mediation analysis; proteomics.

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Conflict of interest statement

Dr. Hanff is supported by the National Institutes of Health (grant HL-00789). Dr. Cohen is supported by K23-HL133843. Dr. Javaheri is supported by K08-HL138262. Dr. Zamani is supported by grant K23-HL-13055. Dr. Chirinos is supported by a research grant from Bristol-Myers Squibb and by grants R01-HL 121510- 01A1, R61-HL-146390, R01-AG058969, 1R01-HL104106, P01-HL094307, R03-HL146874-01, and R56-HL136730. Dr. Javaheri has been named co-inventor on the patent application for the use of fusion protein nanodiscs for the treatment of heart failure. Drs. Zhao, Walsh, Maranville, Wang, Adam, Ramirez-Valle, Schafer, Seiffert, Gordon, and Cvijic own stock in Bristol-Myers Squibb. Dr. Cappola has received research funding from Bristol-Myers Squibb. Dr. Zamani has consulted for Vyaire. Dr. Chirinos has been a consultant for Sanifit, Microsoft, Fukuda-Denshi, Bristol-Myers Squibb, OPKO Healthcare, Ironwood Pharmaceuticals, Pfizer, Akros Pharma, Merck, Bayer, JNJ, and Edwards Life Sciences; and received research grants from National Institutes of Health, American College of Radiology Network, Fukuda Denshi, Bristol-Myers Squibb, and Microsoft, and has been named as inventor in a University of Pennsylvania patent for the use of inorganic nitrates/nitrites for the treatment of heart failure and preserved ejection fraction. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Proteins Associated With Diabetes at Baseline in 2 Independent HFpEF Cohorts Volcano plots showing the strength (log2-fold change) and significance (-log10(P-value)) of univariate associations between proteins and diabetes. Shared proteins between the Penn Heart Failure Study (PHFS) and TOPCAT are labeled. HFpEF = heart failure with preserved ejection fraction; PHFS = Penn Heart Failure Study; TOPCAT=Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial.
Figure 2
Figure 2
Number of Overlapping Proteins in TOPCAT and the Penn Heart Failure Study PHFS = Penn Heart Failure Study; TOPCAT = Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial.
Figure 3
Figure 3
Mediation Pathway Diagram of Apolipoprotein M and Diabetes Mellitus in HFpEF Diabetes mellitus (DM) is associated with lower ApoM (0.59 SDs lower), whereas higher ApoM is protective against the composite outcome (hazard ratio [HR] 0.52 per SD). The indirect pathway through ApoM mediates 72% (95% CI: 36% to 100%) of the association between DM and the composite outcome. The total direct effect of DM on the outcome was insignificant after removing the effect of ApoM. Models are adjusted for sex, race/ethnicity, body mass index, smoking history, hyperlipidemia, statin use, and insulin use.
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