title: ω3-Polyunsaturated fatty acids for heart failure: Effects of dose on efficacy and novel signaling through free fatty acid receptor 4.
abstract: Heart failure (HF) affects 5.7 million in the U.S., and despite well-established pharmacologic therapy, the 5-year mortality rate remains near 50%. Furthermore, the mortality rate for HF has not declined in years, highlighting the need for new therapeutic options. Omega-3 polyunsaturated fatty acids (ω3-PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are important regulators of cardiovascular health. However, questions of efficacy and mechanism of action have made the use of ω3-PUFAs in all cardiovascular disease (CVD) controversial. Here, we review recent studies in animal models of HF indicating that ω3-PUFAs, particularly EPA, are cardioprotective, with the results indicating a threshold for efficacy. We also examine clinical studies suggesting that ω3-PUFAs improve outcomes in patients with HF. Due to the relatively small number of clinical studies of ω3-PUFAs in HF, we discuss EPA concentration-dependency on outcomes in clinical trials of CVD to gain insight into the perceived questionable efficacy of ω3-PUFAs clinically, with the results again indicating a threshold for efficacy. Ultimately, we suggest that the main failing of ω3-PUFAs in clinical trials might be a failure to reach a therapeutically effective concentration. We also examine mechanistic studies suggesting that ω3-PUFAs signal through free fatty acid receptor 4 (Ffar4), a G-protein coupled receptor (GPR) for long-chain fatty acids (FA), thereby identifying an entirely novel mechanism of action for ω3-PUFA mediated cardioprotection. Finally, based on mechanistic animal studies suggesting that EPA prevents interstitial fibrosis and diastolic dysfunction, we speculate about a potential benefit for EPA-Ffar4 signaling in heart failure preserved with ejection fraction.
authors.affiliation: Department of Integrative Biology and Physiology, The University of Minnesota, United States. Electronic address: tdoconne@umn.edu.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: O'Connell
authors.affiliation: Department of Public Health Sciences and Cardiology Division, Department of Medicine, University of Rochester, United States.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Block
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, United States.
authors.forename: Shue P
authors.initials: SP
authors.lastname: Huang
authors.affiliation: Department of Nutritional Sciences, The Pennsylvania State University, United States. Electronic address: gcs13@psu.edu.
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Shearer
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D019587:Dietary Supplements; D004195:Disease Models, Animal; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage* / Q000378:metabolism*; D005355:Fibrosis; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D058990:Molecular Targeted Therapy; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; C519853:FFAR4 protein, human; D015525:Fatty Acids, Omega-3; D043562:Receptors, G-Protein-Coupled
keywords: Cardiac fibrosis; Eicosapentaenoic acid (EPA); Free-fatty acid receptor 4 (Ffar4); GPR120; Heart failure with preserved ejection fraction (HFpEF); Microvascular rarefaction