Increased Soluble Epoxide Hydrolase Activity Positively Correlates with Mortality in Heart Failure Patients with Preserved Ejection Fraction:Evidence from Metabolomics  

作　　者：Liyuan Peng Ziping Song Chengcheng Zhao Kudusi Abuduwufuer Yanwen Wang Zheng Wen Li Ni Chenze Li Ying Yu Yi Zhu Hualiang Jiang Jinshan Shen Xiangrui Jiang Chen Chen Xu Zhang Dao Wen Wang 

机构地区：[1]Division of Cardiology,Department of Internal Medicine,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China [2]Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders,Wuhan 430030,China [3]Department of Pharmacology,Tianjin Key Laboratory of Inflammation Biology,Key Laboratory of Immune Microenvironment and Disease(Ministry of Education),School of Basic Medical Sciences,Tianjin Medical University,Tianjin 300070,China [4]Tianjin Key Laboratory of Metabolic Diseases,Collaborative Innovation Center of Tianjin for Medical Epigenetics,Center for Cardiovascular Diseases,Department of Physiology and Pathophysiology,Research Center of Basic Medical Sciences,Tianjin Medical University,Tianjin 300070,China [5]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 200032,China [6]CAS Key Laboratory for Receptor Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 200032,China [7]Tianjin Key Laboratory of Metabolic Diseases,Key Laboratory of Immune Microenvironment and Disease-Ministry of Education,Department of Physiology and Pathophysiology,Collaborative Innovation Center of Tianjin for Medical Epigenetics,Tianjin Medical University,Tianjin 300070,China

出　　处：《Phenomics》2023年第1期34-49,共16页表型组学（英文）

基　　金：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.]).

摘　　要：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 activ-ity 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 mortal-ity.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://clini caltr ials.gov).

关 键 词：Soluble epoxide hydrolase Heart failure with preserved ejection fraction EICOSANOIDS Epoxyeicosatrienoic acids 

分 类 号：R541.6[医药卫生—心血管疾病]