. 2023 Nov 20;14(1):7557.

doi: 10.1038/s41467-023-43363-3.

Eicosanoid and eicosanoid-related inflammatory mediators and exercise intolerance in heart failure with preserved ejection fraction

Emily S Lau^#^{1

2}, Athar Roshandelpoor^#³, Shahrooz Zarbafian^{1

4}, Dongyu Wang^{3

5}, James S Guseh^{1

2}, Norrina Allen⁶, Vinithra Varadarajan⁷, Matthew Nayor⁸, Ravi V Shah⁹, Joao A C Lima⁷, Sanjiv J Shah^{10

11}, Bing Yu¹², Mona Alotaibi¹³, Susan Cheng¹⁴, Mohit Jain¹⁵, Gregory D Lewis^{1

2}, Jennifer E Ho¹⁶

Affiliations

¹ Division of Cardiology, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts, 02114, USA.
² Cardiovascular Research Center, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA.
³ CardioVascular Institute, Division of Cardiology, Department of Medicine, 330 Brookline Avenue, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
⁴ Google LLC, 1600 Amphitheatre Parkway, Mountain View, CA, 94043, USA.
⁵ Department of Biostatistics, Boston University School of Public Health, 715 Albany Street, Boston, MA, 02118, USA.
⁶ Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 420 East Superior Street, Chicago, IL, 60611, USA.
⁷ Division of Cardiology, Department of Medicine Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD, 21205, USA.
⁸ Cardiology Division, Boston University School of Medicine, 715 Albany Street, Boston, MA, 02118, USA.
⁹ Vanderbilt Clinical and Translational Research Center (VTRACC), Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, 37232, USA.
¹⁰ Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, 420 East Superior Street, Chicago, IL, 60611, USA.
¹¹ Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 420 East Superior Street, Chicago, IL, 60611, USA.
¹² Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health School of Public Health, 1200 Pressler Street, Houston, TX, 77030, USA.
¹³ Division of Pulmonary and Critical Care and Sleep Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
¹⁴ Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, 127 South San Vincente Pavilion, Los Angeles, CA, 90048, USA.
¹⁵ Department of Medicine and Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
¹⁶ Cardiovascular Research Center, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. jho@bidmc.harvard.edu.

^# Contributed equally.

PMID: 37985769
PMCID: PMC10662264
DOI: 10.1038/s41467-023-43363-3

Eicosanoid and eicosanoid-related inflammatory mediators and exercise intolerance in heart failure with preserved ejection fraction

Emily S Lau et al. Nat Commun. 2023.

. 2023 Nov 20;14(1):7557.

doi: 10.1038/s41467-023-43363-3.

Authors

Affiliations

¹ Division of Cardiology, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts, 02114, USA.
² Cardiovascular Research Center, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA.
³ CardioVascular Institute, Division of Cardiology, Department of Medicine, 330 Brookline Avenue, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
⁴ Google LLC, 1600 Amphitheatre Parkway, Mountain View, CA, 94043, USA.
⁵ Department of Biostatistics, Boston University School of Public Health, 715 Albany Street, Boston, MA, 02118, USA.
⁶ Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 420 East Superior Street, Chicago, IL, 60611, USA.
⁷ Division of Cardiology, Department of Medicine Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD, 21205, USA.
⁸ Cardiology Division, Boston University School of Medicine, 715 Albany Street, Boston, MA, 02118, USA.
⁹ Vanderbilt Clinical and Translational Research Center (VTRACC), Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, 37232, USA.
¹⁰ Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, 420 East Superior Street, Chicago, IL, 60611, USA.
¹¹ Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 420 East Superior Street, Chicago, IL, 60611, USA.
¹² Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health School of Public Health, 1200 Pressler Street, Houston, TX, 77030, USA.
¹³ Division of Pulmonary and Critical Care and Sleep Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
¹⁴ Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, 127 South San Vincente Pavilion, Los Angeles, CA, 90048, USA.
¹⁵ Department of Medicine and Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
¹⁶ Cardiovascular Research Center, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. jho@bidmc.harvard.edu.

^# Contributed equally.

PMID: 37985769
PMCID: PMC10662264
DOI: 10.1038/s41467-023-43363-3

Abstract

Systemic inflammation has been implicated in the pathobiology of heart failure with preserved ejection fraction (HFpEF). Here, we examine the association of upstream mediators of inflammation as ascertained by fatty-acid derived eicosanoid and eicosanoid-related metabolites with HFpEF status and exercise manifestations of HFpEF. Among 510 participants with chronic dyspnea and preserved LVEF who underwent invasive cardiopulmonary exercise testing, we find that 70 of 890 eicosanoid and related metabolites are associated with HFpEF status, including 17 named and 53 putative eicosanoids (FDR q-value < 0.1). Prostaglandin (15R-PGF2α, 11ß-dhk-PGF2α) and linoleic acid derivatives (12,13 EpOME) are associated with greater odds of HFpEF, while epoxides (8(9)-EpETE), docosanoids (13,14-DiHDPA), and oxylipins (12-OPDA) are associated with lower odds of HFpEF. Among 70 metabolites, 18 are associated with future development of heart failure in the community. Pro- and anti-inflammatory eicosanoid and related metabolites may contribute to the pathogenesis of HFpEF and serve as potential targets for intervention.

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Conflict of interest statement

E.S.L. previously served on the advisory board for Astellas Pharma, unrelated to this work. S.Z.’s contributions to the manuscript reflect his work as a postdoctoral fellow at the Massachusetts General Hospital. The opinions and work presented do not represent Google LLC. R.V.S. is a co-inventor on a patent for ex-RNA signatures of cardiac remodeling with Cytokinetics, which is unrelated to this work. J.E.H. has received research funding from Bayer, AG unrelated to this work. M.J. currently holds equity and a leadership position at Sapient Bioanalytics, LLC, and is engaged in research related to the current study. The remaining authors declare no competing interests.

Figures

**Fig. 1. Volcano plot for associations of eicosanoid and eicosanoid-related metabolites with HFpEF status in the MGH CPET sample.**
A significant association was observed for 70 of 890 eicosanoids and eicosanoid-related metabolites in the primary model (adjusted for age, sex, and plate number, displayed in pink). Nonsignificant associations are denoted in gray (primary model). The dotted line denotes the level of significance (p-value < 0.008 equivalent to FDR q-value < 0.10 based on logistic regression model accounting for multiple hypothesis testing). HFpEF heart failure with preserved ejection fraction. Source data are provided as a Source Data file.

**Fig. 2. Heatmap for associations of the 70 HFpEF-related eicosanoid and eicosanoid-related metabolites with exercise traits in the MGH CPET sample.**
Color coding represents standardized ß-coefficient in primary model (X-SD change in exercise trait per 1-SD change in eicosanoid metabolite). Primary analyses are adjusted for age, sex, and plate number. Clustering is based on exercise traits (columns). Color scale indicates positive associations in red, and negative associations in blue. CO cardiac output, HR heart rate, PAP pulmonary artery pressure, PCWP pulmonary capillary wedge pressure, SBP systolic blood pressure. Source data are provided as a Source Data file.

**Fig. 3. Eicosanoid mediation model for the association of body mass index, diabetes, and hypertension with HFpEF.**
Mediation analyses identified 3 eicosanoid metabolites with known molecular identity, which were found to mediate >10% of the association of body mass index, diabetes, and hypertension with HFpEF, including 8(9)-EpETE and 12,13 diHOME. We display the eicosanoid mediation model for the most significant eicosanoid mediator of the association of body mass index, diabetes, and hypertension with HFpEF. In this figure, a represents the effect of the covariate on eicosanoid, b represents the effect of eicosanoid on HFpEF, c represents the total effect of the covariate on HFpEF, and c’ is the residual direct effect of the covariate on HFpEF (independent of mediated effects from eicosanoid). Red arrows represent direction of effect of association (e.g. BMI is positively associated with the eicosanoid mediator and with HFpEF. The eicosanoid mediators are negatively associated with HFpEF). Mediation effect considered significant if mediation effect p-value threshold < 0.05 by mediation analysis. Standardized beta-coefficients are shown. BMI body mass index, HFpEF heart failure with preserved ejection fraction.

**Fig. 4. Association of HFpEF-related eicosanoids and eicosanoid-related metabolites (from MGH CPET) with incident HF in MESA.**
Eicosanoids and eicosanoid-related metabolites chosen for analysis in MESA were significantly associated with HFpEF status in the MGH CPET cohort. Hazards ratios displayed represent hazards of developing HF per 1-SD increase in log-transformed eicosanoid and related metabolite in MESA. Data presented are HR (dots) with 95% confidence intervals (bars). Analyses are adjusted for age, sex, site, and plate number. p-value threshold < 0.05 considered significant based on Cox regression models. Eicosanoids and eicosanoid-related metabolites with directionally consistent associations in both the MGH CPET and MESA samples are denoted in red. Eicosanoids and eicosanoid-related metabolites with directionally discordant associations in the MGH CPET and MESA samples are denoted in gray. *denotes putative eicosanoid metabolite. **denotes putative eicosanoid-related metabolite. CI confidence interval, HF heart failure, ALA alpha-linoleic acid, LA linoleic acid. Source data are provided as a Source Data file.

**Fig. 5. Eicosanoid and eicosanoid-related inflammatory mediators are associated with HFpEF and related exercise traits.**
A directed nontargeted LC-MS lipidomics approach identified 70 distinct eicosanoid and eicosanoid-related metabolites that were associated with HFpEF status, of which 18 were also associated with the development of HF in the MESA community cohort. Further examination of the 70 HFpEF-related eicosanoid and related metabolites showed associations with distinct exercise traits characteristic of HFpEF and potential mediation of the association of cardiometabolic risk factors with HFpEF. Created with BioRender.com.

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References

1. Heidenreich PA, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ. Heart Fail. 2013;6:606–619. doi: 10.1161/HHF.0b013e318291329a. - DOI - PMC - PubMed
1. Ho JE, Redfield MM, Lewis GD, Paulus WJ, Lam CSP. Deliberating the diagnostic dilemma of heart failure with preserved ejection fraction. Circulation. 2020;142:1770–1780. doi: 10.1161/CIRCULATIONAHA.119.041818. - DOI - PMC - PubMed
1. Houstis NE, et al. Exercise intolerance in heart failure with preserved ejection fraction: diagnosing and ranking its causes using personalized O(2) pathway analysis. Circulation. 2018;137:148–161. doi: 10.1161/CIRCULATIONAHA.117.029058. - DOI - PMC - PubMed
1. Dhakal BP, et al. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction. Circ. Heart Fail. 2015;8:286–294. doi: 10.1161/CIRCHEARTFAILURE.114.001825. - DOI - PMC - PubMed
1. Nayor M, et al. Impaired exercise tolerance in heart failure with preserved ejection fraction. JACC: Heart Failure. 2020;8:605–617. - PMC - PubMed

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Eicosanoid and eicosanoid-related inflammatory mediators and exercise intolerance in heart failure with preserved ejection fraction

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Eicosanoid and eicosanoid-related inflammatory mediators and exercise intolerance in heart failure with preserved ejection fraction

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Abstract

Conflict of interest statement

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