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 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 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 EPA prevents interstitial fibrosis and diastolic dysfunction, we speculate about a potential benefit for EPA-Ffar4 signaling in heart failure preserved with ejection fraction.

Effects of aspirin in combination with EPA and DHA on HDL-C cholesterol and ApoA1 exchange in individuals with type 2 diabetes mellitus

“…29 The causal mechanism(s) underlying the interaction between low-dose aspirin and these ω3 fatty acids is unknown but deserves future research given the importance of aspirin and seafood consumption in healthy cardiovascular regimens. 10,18 …”

“…Fish oil is also strongly regarded as having positive cardiovascular effects. 16–18 Among its beneficial effects are those that are anti-inflammatory and tissue-protective. 18 Our study aimed to examine the individual and combined effects of aspirin and fish oil ingestion on 2 cholesterol transport markers that predict cardiovascular disease events.…”

“…16–18 Among its beneficial effects are those that are anti-inflammatory and tissue-protective. 18 Our study aimed to examine the individual and combined effects of aspirin and fish oil ingestion on 2 cholesterol transport markers that predict cardiovascular disease events. They are high density lipoprotein (HDL-C) concentration 19 and HDL-apolipoprotein (apo)A-I exchange (HAE) 20 within adults with type 2 diabetes mellitus.…”

Free fatty acid receptor 4 is a nutrient sensor that resolves inflammation to maintain cardiac homeostasis

“…In one large clinical trial, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico-Heart Failure (GISSI-HF) (27), and several smaller trials, w3-PUFAs improved HF outcomes (28)(29)(30). In animal models, we have also demonstrated that EPA, in a concentrationdependent manner, prevents pathologic remodeling post-TAC (16,31,59). However, important questions remain regarding the mechanism underlying the benefit of w3-supplementation in HF.…”

Cardioprotective effects of omega‐3 fatty acids and ascorbic acid improve regenerative capacity of embryonic stem cell‐derived cardiac lineage cells

“…They have also been shown to induce transcriptional regulation of ARE‐dependent expression of several antioxidant enzymes, such as HO‐1 . Moreover, it has been suggested that cardioprotection also occurs through preventing collagen synthesis and cardiac fibrosis .…”