Abstract
Epoxyeicosatrienoic acids (EETs) have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH). Heart failure with preserved ejection fraction (HFpEF) has shown an increased prevalence and worse prognosis over the decades. However, the role of sEH activity in HFpEF remains unclear. We enrolled 500 patients with HFpEF and 500 healthy controls between February 2010 and March 2016. Eight types of sEH-related eicosanoids were measured according to target metabolomics, and their correlation with clinical endpoints was also analyzed. The primary endpoint was cardiac mortality, and the secondary endpoint was a composite of cardiac events, including heart failure (HF) readmission, cardiogenic hospitalization, and all-cause mortality. Furthermore, the effect of sEH inhibitors on cardiac diastolic function in HFpEF was investigated in vivo and in vitro. Patients with HFpEF showed significantly enhanced EET degradation by the sEH enzyme compared with healthy controls. More importantly, sEH activity was positively correlated with cardiac mortality in patients with HFpEF, especially in older patients with arrhythmia. A consistent result was obtained in the multiple adjusted models. Decreased sEH activity by the sEH inhibitor showed a significant effective effect on the improvement of cardiac diastolic function by ameliorating lipid disorders in cardiomyocytes of HFpEF mouse model. This study demonstrated that increased sEH activity was associated with cardiac mortality in patients with HFpEF and suggested that sEH inhibition could be a promising therapeutic strategy to improve diastolic cardiac function. Clinical trial identifier: NCT03461107 (https://clinicaltrials.gov)
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Data Availability
The datasets generated during the current study are available from the corresponding author on reasonable request.
Change history
29 November 2022
A Correction to this paper has been published: https://doi.org/10.1007/s43657-022-00088-5
Abbreviations
- AA:
-
Arachidonic acid
- ALT:
-
Alanine aminotransferase
- AST:
-
Aspartate aminotransferase
- BHT:
-
Butylated hydroxytoluene
- CIs:
-
Confidence intervals
- CRP:
-
C-reactive protein
- CYP450:
-
Cytochrome P450
- DCM:
-
Dilated cardiomyopathy
- DHETs:
-
Dihydroxyeicosatrienoic acids
- EDTA:
-
Ethylenediaminetetraacetic acid
- EETs:
-
Epoxyeicosatrienoic acids
- FFAs:
-
Free fatty acids
- HCM:
-
Hypertrophic cardiomyopathy
- Hcy:
-
Homocysteine
- HDL:
-
High-density lipoprotein
- HF:
-
Heart failure
- HFpEF:
-
Heart failure with preserved ejection fraction
- HFrEF:
-
HF with reduced ejection fraction
- HR:
-
Hazard ratios
- LA:
-
Left atrial
- LC–MS/MS:
-
Liquid chromatography–tandem mass spectrometry
- LDL:
-
Low-density lipoprotein
- LV:
-
Left ventricular
- LVEF:
-
Ejection fraction of left ventricle
- NT-proBNP:
-
N-terminal B-type natriuretic peptide
- ORs:
-
Odds ratios
- PSM:
-
Propensity score matching
- SBP/DBP:
-
Systolic/diastolic blood pressure
- sEH:
-
Soluble epoxide hydrolase
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This work was supported by grants from the National Natural Science Foundation of China (81790624 [to D.W.W.], 81900342 [to L. P.] and 81790621 [to Y. Z.]).
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LP, CC, XZ, and DW designed the experiments and interpreted the results of the manuscript. ZS, CZ and ZW performed the animal experiments. LP, XZ, LN, and CL analyzed the data. LP, ZS, XZ, and DW prepared the figures and tables. LP, ZS, CZ, KA, YW, CC, YY, YZ, HJ, XJ, and JS revised the manuscript. All the authors approved the final article.
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Peng, L., Song, Z., Zhao, C. et al. Increased Soluble Epoxide Hydrolase Activity Positively Correlates with Mortality in Heart Failure Patients with Preserved Ejection Fraction: Evidence from Metabolomics. Phenomics 3, 34–49 (2023). https://doi.org/10.1007/s43657-022-00069-8
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DOI: https://doi.org/10.1007/s43657-022-00069-8