O'Connell Timothy D, Block Robert C, Huang Shue P, Shearer Gregory C
Department of Integrative Biology and Physiology, The University of Minnesota, United States.
Department of Public Health Sciences and Cardiology Division, Department of Medicine, University of Rochester, United States.
J Mol Cell Cardiol. 2017 Feb;103:74-92. doi: 10.1016/j.yjmcc.2016.12.003. Epub 2016 Dec 14.
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.
心力衰竭（HF）在美国影响着570万人，尽管药物治疗已很成熟，但5年死亡率仍接近50%。此外，HF的死亡率多年来并未下降，这凸显了对新治疗方案的需求。ω-3多不饱和脂肪酸（ω3-PUFAs）、二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）是心血管健康的重要调节因子。然而，关于其疗效和作用机制的问题使得ω3-PUFAs在所有心血管疾病（CVD）中的应用存在争议。在此，我们综述了近期在HF动物模型中的研究，这些研究表明ω3-PUFAs，尤其是EPA，具有心脏保护作用，结果显示存在疗效阈值。我们还研究了临床研究，这些研究表明ω3-PUFAs可改善HF患者的预后。由于关于ω3-PUFAs在HF中的临床研究相对较少，我们讨论了在CVD临床试验中EPA浓度对预后的依赖性，以深入了解临床上认为ω3-PUFAs疗效存疑的问题，结果再次表明存在疗效阈值。最终，我们认为ω3-PUFAs在临床试验中的主要失败可能是未能达到治疗有效浓度。我们还研究了机制研究，这些研究表明ω3-PUFAs通过游离脂肪酸受体4（Ffar4）发出信号，Ffar4是一种用于长链脂肪酸（FA）的G蛋白偶联受体（GPR），从而确定了ω3-PUFA介导心脏保护的全新作用机制。最后，基于机制性动物研究表明EPA可预防间质纤维化和舒张功能障碍，我们推测了EPA-Ffar4信号在射血分数保留的心力衰竭中的潜在益处。
