Open Access

ω‑3 fatty acids in atherosclerotic cardiovascular disease (Review)

  • Authors:
    • Xingxing Xie
    • Xue Liu
    • Rong Li
    • Ling Fan
    • Fujing Huang
  • View Affiliations

  • Published online on: April 19, 2024     https://doi.org/10.3892/br.2024.1782
  • Article Number: 94
  • Copyright: © Xie et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Atherosclerotic cardiovascular disease (ASCVD) is one of the most common chronic diseases in the world. Epidemiological evidence and clinical trials have shown that ω‑3 fatty acids have a variety of promoting effects in reducing the risk of ASCVD, but different conclusions of large randomized controlled trials make their clinical use in the prevention and treatment of ASCVD controversial. The present review focuses on the pharmacological mechanism, clinical trials and evidence value of clinical applications of ω‑3 fatty acids in order to provide theoretical and practical evidence for the clinical application strategy, and follow‑up research and development of ω‑3 fatty acids as anti‑ASCVD drugs.

1. Introduction

According to the World Health Organization, atherosclerotic cardiovascular (CV) disease (ASCVD) is one of the most common diseases in the world and also a notable cause of mortality, mostly occurring in low- and middle-income countries (1). Although statin therapy has been shown to reduce the risk of CV events by 25-45%, even when target low-density lipoprotein cholesterol (LDL-C) levels are met, a CV residual risk still exists (2). Genetic and epidemiological studies have shown that persistent CV residual risk may be associated with other forms of dyslipidemia, such as elevated levels of triglyceride (TG)-rich lipoproteins (TGRLs) (3,4). However, from a pharmacological aspect, the extent to which statins alone improve TG levels in patients with ASCVD is insufficient or even weak (5). At present, the therapeutic methods that may be used to reduce TG levels in the clinic mainly include niacin, fibrate and ω-3 fatty acid drugs (6). In recent years, ω-3 fatty acids have attracted increased attention in the prevention and treatment of ASCVD by lowering TG levels. In a large randomized CV outcome trial, the CV residual risk reduction effect of ω-3 fatty acids on patients with well-controlled LDL-C levels and elevated TG levels was studied, but the results did not show a consistent ASCVD risk reduction effect (7,8).

ω-3 polyunsaturated fatty acids (PUFAs) are part of the essential PUFAs of the body and have a number of effects apart from lowering TG levels. Among others, these fatty acids also have anti-inflammatory, anti-thrombotic, anti-oxidation and anti-arrhythmia effects, as well as being able to improve endothelial function and insulin resistance (9). ω-3 is the technical term used to describe the structure of a particular PUFA family, indicating the first double bond position of the fatty acid from the methyl end, between the third and fourth carbon (10). The main ω-3 fatty acids include α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The only way to obtain it is from dietary sources (11). The simplest ω-3 fatty acid is ALA, which exists in plants. After ingestion, the human body mainly metabolizes EPA in the liver and then further metabolizes DHA through various enzyme actions and β-oxidation (12). In the human body, the metabolism is affected by various factors, such as age, sex, hormonal changes and genetics, and the conversion rate of ALA to EPA and DHA is usually limited, resulting in certain health benefits of ALA (12). In healthy young men, only ~8% of ALA is converted to EPA and <4% is converted to DHA. In healthy women, the conversion rate of ALA is higher than that in adult men due to increased estrogen levels before menopause, and ~21% of ALA is converted to EPA and ~9% is converted to DHA (13,14). Both EPA and DHA may be beneficial for ASCVD treatment, but their mechanisms of action have not been fully elucidated. Existing studies have shown that DHA has a key role in the central nervous system and retina, and is also an essential fatty acid for fetal development (15). Unlike DHA, EPA is mainly concentrated in artery walls and atherosclerotic plaques, promoting the release of anti-inflammatory mediators (16). However, the benefits of a combination of EPA and DHA ω-3 fatty acids in the treatment of ASCVD are inconsistent with those of either EPA or DHA alone, possibly due to differences in the formulation, dosage or potential anti-regulatory effects of DHA. Therefore, in the present study, the application status of ω-3 fatty acid drugs was reviewed and the relevant knowledge of ω-3 fatty acid pharmacology, clinical trials and the main guidelines or consensus at home and in other countries for the treatment of ASCVD were summarized in order to provide references for the rational clinical application of ω-3 fatty acid drugs.

2. Clinical pharmacological effects of ω-3 fatty acids

Reducing TG levels

TGs are not directly involved in the process of atherosclerosis, but TGRLs, such as very LDL (VLDL), chylomicron and residual particles are causally related to the occurrence of ASCVD independently of LDL (17). TGRLs are aggregated by macrophages in the subendothelial layer and form foam cells, promoting the formation of fat streaks, which are early atherosclerotic plaque lesions. With the accumulation of plaque, when the plaque surface is eroded or ruptured, thrombosis is easily formed, and ASCVD and other CV events are triggered (18). EPA and DHA are potent fatty acid agonists of peroxisome proliferation-activated receptors (PPAR), which are part of the nuclear hormone receptor superfamily. Various genes involved in the regulation of lipid metabolism are formed by binding to PPAR reactivity regulatory elements to form active transcriptional complexes (19). PPAR-α, which is involved in fatty acid metabolism, is one of the isomers of PPAR. After activation, fatty acid β-oxidation in the liver increases, TG secretion decreases and lipase activity increases, accelerating VLDL clearance and increasing high-density lipoprotein cholesterol (HDL-C) (20). The synthesis pathways of various cholesterol and fatty acids, and the assembly of VLDL are regulated by sterol regulatory element binding protein-1 (SREBP-1) (21). In mouse models, ω-3 fatty acids reduce the expression of proteins involved in VLDL synthesis by activating PPAR-α and inhibiting SREBP-1, thereby reducing their release and lowering plasma TG levels (22). Therefore, ω-3 fatty acids reduce plasma TG levels by reducing VLDL production, increasing VLDL clearance, inhibiting lipogenesis, increasing β-oxidation and increasing lipase activity.

Anti-inflammatory

Atherosclerosis is essentially a chronic inflammatory disease, and reducing and eliminating inflammation is essential to restore homeostasis and combat chronic diseases (23). ω-3 fatty acids have a marked role in regulating lipid rafts and affecting cell membrane fluidity. They can integrate themselves into the phospholipid bilayer of the neutrophilic cell membrane and produce a series of hormone-like lipid mediators such as prostaglandins, which mainly exert anti-inflammatory effects on tissue injury and infection sites (24). ω-3 fatty acids can also regulate the production and secretion of cytokines and chemokines by changing gene regulation, weaken the M1 polarization of macrophages and promote M2 polarization, improve the function of macrophages and ultimately promote phagocytosis (24). ω-3 fatty acids promote the decomposition of lipids and reduction of inflammation by producing specialized lipid-promoting mediators, such as catabolism and protectors, and help restore homeostasis after tissue injury, thus reducing the formation of ASCVD (25). Resolvin E1 (RvE1) is a specialized pro-decomposition lipid mediator derived from EPA that has a key role in resolving inflammation and tissue homeostasis. T-helper type 17 (Th-17) cells have a tissue-destroying function in autoimmune and chronic inflammatory diseases by secreting interleukin (IL)-17. RvE1 has been shown to block T-cell activation, Th-17-cell stimulation and chemical attraction, thereby promoting the resolution of inflammation (26). Studies have found that if healthy participants receive >2 g ω-3 fatty acids per day, endotoxins stimulate monocytes, and tumour necrosis factor α, IL-1 and IL-6 are reduced, suggesting that ω-3 fatty acids may have an anti-inflammatory role by reducing the expression of pro-inflammatory cytokines and adhesion molecules at inflammatory sites (27). Other studies have reported anti-inflammatory mechanisms of ω-3 fatty acids, including the downregulation of nuclear factor κB (NF-κB) by ω-3 fatty acids after binding to g-protein-coupled receptor 120. NF-κB and activator protein 1 have an anti-inflammatory role (28-30). Through the polarization of CD4+T lymphocytes towards Th-2 cells, ω-3 fatty acids maintain a balance of Th-1 and -2 cells, promote the regression of inflammation and thus inhibit the development of atherosclerosis (31).

Improvement of endothelial function

Endothelial cell dysfunction has a causal relationship with atherosclerosis and is directly related to an increased risk of ASCVD (32); therefore, improving endothelial cell function is a new approach to enhance the benefits of ASCVD treatment. Vascular endothelial cells can synthesize and secrete vasodilator factors such as nitric oxide (NO) and vasodilator factors such as angiotensin II and endothelin-1. When the secretion of these two factors is unbalanced or the availability of NO is reduced, endothelial dysfunction is caused (33). NO is an important vascular endothelial protective factor, which can not only relax blood vessels and relieve vasospasm, but also protect vascular endothelium through anti-oxidation, anti-inflammatory and anti-platelet aggregation (34). As a signaling molecule, NO produces cyclic guanosine monophosphate by activating soluble guanosine cyclase, which activates downstream signaling molecules, causing vasodilation and reducing inflammation (35). ω-3 fatty acids have been shown to improve endothelial function through multiple mechanisms. On the one hand, ω-3 fatty acids can enhance vasodilation by increasing the activity of endothelial NO synthase. On the other hand, ω-3 fatty acids can reduce the vasoconstriction effect of endothelin-1 and reduce oxidative stress to improve endothelial function (25). In human endothelial cells, ω-3 fatty acids can inhibit the expression of pro-atherosclerotic and -inflammatory proteins induced by cytokines, thereby improving the vasomotor ability and arterial compliance of patients with ASCVD, and reducing the production of biomarkers of inflammation and oxidative stress (23).

3. ω-3 fatty acid clinical trials

For a long time, scientists have been committed to the study of the value of ω-3 fatty acids in the clinical prevention and treatment of ASCVD. As early as >30 years ago, Burr et al (36) found that deep-sea fatty fish or fish oil capsules were able to reduce the all-cause mortality of patients with myocardial infarction by ~29%. In the GISSI-P study conducted in Italy (37), 11,324 patients with myocardial infarction within 3 months were included and followed up for an average of 3.5 years. It was found that in the experimental group treated with 1.0 g/day ω-3 fatty acids (EPA/DHA, 1:2), the risk of primary endpoint events, death and CV-associated death was reduced by 15, 20 and 30%, respectively. In the JELIS study conducted in Japan (38), 18,645 patients aged 40-75 years with total cholesterol ≥6.5 mmol/l (251 mg/dl) were selected as study subjects and the experimental group was given 1.8 g/day EPA drug therapy, with an average follow-up of 4.6 years. The results showed that the EPA-treated group had a 19 and 28% lower risk of primary endpoint events and unstable angina, respectively, and no reduction in the risk of coronary artery death or myocardial infarction. Subsequently, between 2010 and 2013, several randomized controlled studies on ω-3 fatty acids published by Rauch et al (39), ORIGIN trial investigators et al (40) and the Risk and Prevention Study Collaborative Group et al (41) did not obtain the desired positive results. In a randomized, placebo-controlled trial conducted in 2018 in the UK (42), a total of 15,480 patients with diabetes aged ≥40 years and without ASCVD were included after being treated with 1.0 g/day ω-3 fatty acids (EPA+DHA) and followed for an average of 7.4 years. The results showed no marked reduction in the risk of serious vascular events. The following year, a randomized, placebo-controlled, 2x2 factorial design trial, VITALs, was conducted in the US, and a total of 25,871 patients aged ≥50 years without ASCVD and cancer were treated with 1.0 g/day ω-3 fatty acids (EPA+DHA) and followed up for an average of 5.3 years. The results showed that the risk of major adverse CV events was not markedly reduced (43). Inconsistent findings have led to controversy over the clinical value of ω-3 fatty acids in patients with ASCVD. More recently, with the publication of the important REDUCE-IT study (44), which showed improved CV benefits through the use of ω-3 fatty acids, the application of ω-3 fatty acids in ASCVD has once again attracted attention. REDUCE-IT was a multicenter randomized, double-blinded, placebo-controlled trial of 8,179 patients with CV disease or type 2 diabetes with CV risk factors. The fasting TG range after statin treatment was 1.5-5.6 mmol/l (135-500 mg/dl) and the LDL-C range was 1.1-2.6 mmol/l (41-100 mg/dl), treated with 4 g/d icosapent ethyl (IPE) or mineral oil, respectively, and the median follow-up was 4.9 years. The results showed that IPE markedly reduced the risk of primary endpoint events (such as CV death, non-fatal myocardial infarction, non-fatal stroke and coronary revascularization or unstable angina complex events) by 25% and also markedly reduced the risk of key secondary endpoint events, while no reduction in the risk of all-cause death was observed, and based on the REDUCE-IT study, IPE is the only ω-3 fatty acid approved by the Food and Drug Administration in the United States, Canada and the European Union for CV risk reduction indications in patients with CVD or diabetes with other ASCVD risk factors. The results of the STRENGTH (45) and OMEMI (46) studies published after the REDUCE-IT study did not achieve the expected significant effect in the CV effects of ω-3 fatty acids in patients with ASCVD. STRENGTH was a multicenter, double-blinded, placebo-controlled randomized clinical trial involving 13,078 at-risk patients with CV treated with statins with hypertriglyceridemia (HTG) and low HDL-C levels from 22 countries who were treated with 4 g/day ω-3 carboxylic acid or corn oil, respectively, with a median follow-up of 3.5 years. The results showed no benefit in the risk of major adverse CV events in the ω-3 carboxylic acid group. The OMEMI study was also a multicenter, randomized, double-blinded, placebo-controlled clinical trial involving 1,027 Norwegian patients aged 70-82 years with recent acute myocardial infarction who were treated with 1.8 g/day ω-3 fatty acids (EPA+DHA) and followed up for an average of 2 years. The results showed that ω-3 fatty acids did not reduce the risk of primary endpoint events.

4. Major national and international guidelines or consensus on the use of ω-3 fatty acids for the treatment of ASCVD

The ‘Guidelines for the Management of Dyslipidemia’ issued by the European Society of Cardiology and the European Atherosclerosis Society in 2019 proposed that patients with ASCVD and TG ranging from 1.5-5.6 mmol/l (135-500 mg/dl) after receiving statin therapy were at high or very high risk. The combination of ω-3 fatty acids (2 g IPE, twice daily) and statins should be considered for lipid-lowering therapy (47). The Guidelines for the Primary Prevention of CV Diseases in China released in 2020 suggest that individuals at high risk of ASCVD should be given a high dose of ω-3 fatty acids [IPE 2 g if the TG level is still >2.3 mmol/l (200 mg/dl) after receiving a moderate dose of statin therapy, 2 times daily] to further reduce the risk of ASCVD (48). The Chinese Expert Consensus on Secondary Prevention after Coronary Artery Bypass Transplantation published in 2020 proposed that for patients with ASCVD combined with HTG, supplementation with high-purity EPA ω-3 fatty acids may be considered for secondary prevention to further reduce CV events, while whether to supplement EPA+DHA mixed type was not mentioned (49). The Expert Consensus on the Comprehensive Management of Blood Pressure and Lipids in Chinese Hypertensive Patients released in 2021 pointed out that for patients with ASCVD, TG levels and the incidence of CV events may be reduced to a certain extent after treatment with a large dose of ω-3 fatty acids (IPE 2 g, twice a day) (50). The Expert Consensus on the Diagnosis and Treatment of Diabetes Combined with CV Diseases released in 2021 pointed out that patients with high or very high risk of CV disease, on the basis of receiving strict lifestyle intervention and statin therapy, if the TG level is still >2.3 mmol/l (200 mg/dl), the recommendation favors the use of high-dose ω-3 fatty acids (IPE 2 g, 2 times daily) to further reduce the risk of CV disease (51). According to the 2021 ‘Stroke Prevention Guidelines for Stroke and Transient Ischemic Attack Patients’ issued by the American Heart Association/American Stroke Association, for patients with ischemic stroke and transient ischemic attack, if the fasting TG range is 1.5-5.6 mmol/l (135-500 mg/dl) and the LDL-C range is 1.0-2.6 mmol/l (41-100 mg/dl), they had been using medium-high intensity statins and had glycosylated hemoglobin A1C levels of <10% without pancreatitis, atrial fibrillation and severe heart failure, a high dose of ω-3 fatty acid (IPE 2 g, twice daily) treatment was able to reduce the risk of stroke recurrence (52). The 2021 American College of Cardiology ‘Management Consensus on Reducing the Risk of ASCVD in Patients with persistent HTG’ points out that lifestyle interventions, TG lowering therapy with statins and prescription of pure fish oil preparations are needed to reduce the risk of ASCVD in patients with persistent HTG (53). The 2022 Diabetes Guidelines issued by the American Diabetes Association indicate that in patients with ASCVD or other CV risk factors who were treated with statins and had LDL-C under control but a TG range of 1.5-5.6 mmol/l (135-500 mg/dl), increased use of IPE may be considered to reduce CV risk (54). The Chinese expert consensus on the role of ω-3 fatty acids in the prevention and treatment of CV disease released in 2023 pointed out that patients with a high or very high risk of ASCVD, on the basis of strict lifestyle intervention and statin therapy, if the TG level is still >1.5 mmol/l (135 mg/dl), high doses of IPE (4 g/day) are recommended to further reduce CV risk (55). According to the Chinese Lipid Management Guidelines Issued by the Joint Expert Committee for the Revision of Chinese Lipid Management Guidelines in 2023, it is recommended to give a large dose of IPE (2 g, twice a day) to patients with ASCVD and high-risk groups if their TG level is still >2.3 mmol/l after receiving moderate-intensity statin therapy or high-purity ω-3 fatty acids, fibrates to further reduce the risk of ASCVD (56).

5. Summary and future perspectives

Although several large randomized controlled trials of ω-3 fatty acids for the prevention and treatment of ASCVD have reported mixed conclusions, in recent years, domestic and foreign expert consensus and guidelines still recommend the use of ω-3 fatty acids to prevent residual CV risk in patients with ASCVD who are unable to control high levels of TG after using statins and fibrates. The mechanism of action of ω-3 fatty acids is complex, and it is not yet clear which mechanism is responsible for reducing the risk of ASCVD. The effects of ω-3 fatty acids on lowering TG levels, their anti-inflammatory effects and ability to improve endothelial function may help explain their positive role in reducing the risk of ASCVD. With the continuous in-depth research on drug prevention and treatment of dyslipidemia and clinical management strategies, in addition to paying attention to the effect of conventional drug treatment, early risk warning and auxiliary management of ASCVD are also being carried out. Combined with current relevant research conclusions, ω-3 fatty acids show a high benefit-risk ratio in the prevention and treatment of ASCVD. It should be considered as an adjunct to lipid-lowering drug therapy such as statins. It is recommended that clinicians carefully consider this new treatment option, educate patients at risk of ASCVD regarding its important benefits and pay attention to the evaluation of patients with ASCVD in clinical care.

Acknowledgements

The authors are grateful for the strong support in literature retrieval, evaluation and language proofreading by Professor Zhigang Yu (Department of Pharmacy, Yaan People's Hospital, Yaan, China).

Funding

Funding: The present study was supported by the Science and Technology Plan Fund from the Yaan Science and Technology Bureau (grant no. 22KJJH0039) and the Beijing Medical Award Foundation ‘Rui Ying fifth phase’ scientific research project (grant no. YXJL-2023-0866-0316).

Availability of data and materials

Not applicable.

Authors' contributions

XX and XL performed the literature search and co-wrote the manuscript. RL, LF and FH performed the literature search and reviewed the literature and the manuscript. XX provided guidance for the study and revised the manuscript. All of the authors read and approved the final version of the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Li C, Liu X, Adhikari BK, Chen L, Liu W, Wang Y and Zhang H: The role of epicardial adipose tissue dysfunction in cardiovascular diseases: An overview of pathophysiology, evaluation, and management. Front Endocrinol (Lausanne). 14(1167952)2023.PubMed/NCBI View Article : Google Scholar

2 

Libby P: The changing landscape of atherosclerosis. Nature. 592:524–533. 2021.PubMed/NCBI View Article : Google Scholar

3 

Ganda OP, Bhatt DL, Mason RP, Miller M and Boden WE: Unmet need for adjunctive dyslipidemia therapy in hypertriglyceridemia management. J Am Coll Cardiol. 72:330–343. 2018.PubMed/NCBI View Article : Google Scholar

4 

Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration. Sarwar N, Sandhu MS, Ricketts SL, Butterworth AS, Di Angelantonio E, Boekholdt SM, Ouwehand W, Watkins H, Samani NJ, et al: Triglyceride-mediated pathways and coronary disease: Collaborative analysis of 101 studies. Lancet. 375:1634–1639. 2010.PubMed/NCBI View Article : Google Scholar

5 

Karlson BW, Palmer MK, Nicholls SJ, Lundman P and Barter PJ: A VOYAGER meta-analysis of the impact of statin therapy on low-density lipoprotein cholesterol and triglyceride levels in patients with hypertriglyceridemia. Am J Cardiol. 117:1444–1448. 2016.PubMed/NCBI View Article : Google Scholar

6 

Dong SJ, Bian JL, Chen HS and Zhang RS: A systematic review of omega-3 fatty acids combined with statins for treatment of dyslipidemia. J Clin Pharmacotherapy. 20:21–28. 2019.

7 

Mason RP, Sherratt SCR and Eckel RH: Rationale for different formulations of omega-3 fatty acids leading to differences in residual cardiovascular risk reduction. Metabolism. 130(155161)2022.PubMed/NCBI View Article : Google Scholar

8 

Mason RP and Eckel RH: Mechanistic insights from REDUCE-IT STRENGTHen the case against triglyceride lowering as a strategy for cardiovascular disease risk reduction. Am J Med. 134:1085–1090. 2021.PubMed/NCBI View Article : Google Scholar

9 

Tadic M, Sala C, Grassi G, Mancia G, Taddei S, Rottbauer W and Cuspidi C: Omega-3 fatty acids and coronary artery disease: More questions than answers. J Clin Med. 10(2495)2021.PubMed/NCBI View Article : Google Scholar

10 

Saini RK and Keum YS: Omega-3 and omega-6 polyunsaturated fatty acids: Dietary sources, metabolism, and significance-a review. Life Sci. 203:255–267. 2018.PubMed/NCBI View Article : Google Scholar

11 

Sheikh O, Vande Hei AG, Battisha A, Hammad T, Pham S and Chilton R: Cardiovascular, electrophysiologic, and hematologic effects of omega-3 fatty acids beyond reducing hypertriglyceridemia: As it pertains to the recently published REDUCE-IT trial. Cardiovasc Diabetol. 18(84)2019.PubMed/NCBI View Article : Google Scholar

12 

Baker EJ, Miles EA, Burdge GC, Yaqoob P and Calder PC: Metabolism and functional effects of plant-derived omega-3 fatty acids in humans. Prog Lipid Res. 64:30–56. 2016.PubMed/NCBI View Article : Google Scholar

13 

Innes JK and Calder PC: Marine omega-3 (N-3) fatty acids for cardiovascular health: An update for 2020. Int J Mol Sci. 21(1362)2020.PubMed/NCBI View Article : Google Scholar

14 

Calder PC: Very long-chain n-3 fatty acids and human health: Fact, fiction and the future. Proc Nutr Soc. 77:52–72. 2018.PubMed/NCBI View Article : Google Scholar

15 

Dyall SC: Long-chain omega-3 fatty acids and the brain: A review of the independent and shared effects of EPA, DPA and DHA. Front Aging Neurosci. 7(52)2015.PubMed/NCBI View Article : Google Scholar

16 

Mason RP, Sherratt SCR and Eckel RH: Omega-3-fatty acids: Do they prevent cardiovascular disease? Best Pract Res Clin Endocrinol Metab. 37(101681)2023.PubMed/NCBI View Article : Google Scholar

17 

Nordestgaard BG: Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: New insights from epidemiology, genetics, and biology. Circ Res. 118:547–563. 2016.PubMed/NCBI View Article : Google Scholar

18 

Ginsberg HN, Packard CJ, Chapman MJ, Borén J, Aguilar-Salinas CA, Averna M, Ference BA, Gaudet D, Hegele RA, Kersten S, et al: Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European atherosclerosis society. Eur Heart J. 42:4791–4806. 2021.PubMed/NCBI View Article : Google Scholar

19 

Dubois V, Eeckhoute J, Lefebvre P and Staels B: Distinct but complementary contributions of PPAR isotypes to energy homeostasis. J Clin Invest. 127:1202–1214. 2017.PubMed/NCBI View Article : Google Scholar

20 

Derosa G, Sahebkar A and Maffioli P: The role of various peroxisome proliferator-activated receptors and their ligands in clinical practice. J Cell Physiol. 233:153–161. 2018.PubMed/NCBI View Article : Google Scholar

21 

Jump DB: N-3 polyunsaturated fatty acid regulation of hepatic gene transcription. Curr Opin Lipidol. 19:242–247. 2008.PubMed/NCBI View Article : Google Scholar

22 

Mason RP, Jacob RF, Shrivastava S, Sherratt SCR and Chattopadhyay A: Eicosapentaenoic acid reduces membrane fluidity, inhibits cholesterol domain formation, and normalizes bilayer width in atherosclerotic-like model membranes. Biochim Biophys Acta. 1858:3131–3140. 2016.PubMed/NCBI View Article : Google Scholar

23 

Sherratt SCR, Libby P, Bhatt DL and Mason RP: A biological rationale for the disparate effects of omega-3 fatty acids on cardiovascular disease outcomes. Prostaglandins Leukot Essent Fatty Acids. 182(102450)2022.PubMed/NCBI View Article : Google Scholar

24 

Gutiérrez S, Svahn SL and Johansson ME: Effects of omega-3 fatty acids on immune cells. Int J Mol Sci. 20(5028)2019.PubMed/NCBI View Article : Google Scholar

25 

Lu LW, Quek SY, Lu SP and Chen JH: Potential benefits of omega-3 polyunsaturated fatty acids (N3PUFAs) on cardiovascular health associated with COVID-19: An update for 2023. Metabolites. 13(630)2023.PubMed/NCBI View Article : Google Scholar

26 

Oner F, Alvarez C, Yaghmoor W, Stephens D, Hasturk H, Firatli E and Kantarci A: Resolvin E1 regulates Th17 function and T cell activation. Front Immunol. 12(637983)2021.PubMed/NCBI View Article : Google Scholar

27 

Meydani SN, Endres S, Woods MM, Goldin BR, Soo C, Morrill-Labrode A, Dinarello CA and Gorbach SL: Oral (n-3) fatty acid supplementation suppresses cytokine production and lymphocyte proliferation: Comparison between young and older women. J Nutr. 121:547–555. 1991.PubMed/NCBI View Article : Google Scholar

28 

Williams-Bey Y, Boularan C, Vural A, Huang NN, Hwang IY, Shan-Shi C and Kehrl JH: Omega-3 free fatty acids suppress macrophage inflammasome activation by inhibiting NF-κB activation and enhancing autophagy. PLoS One. 9(e97957)2014.PubMed/NCBI View Article : Google Scholar

29 

Sung J, Jeon H, Kim IH, Jeong HS and Lee J: Anti-inflammatory effects of stearidonic acid mediated by suppression of NF-κB and MAP-kinase pathways in macrophages. Lipids. 52:781–787. 2017.PubMed/NCBI View Article : Google Scholar

30 

Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ, Watkins SM and Olefsky JM: GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 142:687–698. 2010.PubMed/NCBI View Article : Google Scholar

31 

Reilly NA, Lutgens E, Kuiper J, Heijmans BT and Jukema JW: Effects of fatty acids on T cell function: Role in atherosclerosis. Nat Rev Cardiol. 18:824–837. 2021.PubMed/NCBI View Article : Google Scholar

32 

Yubero-Serrano EM, Fernandez-Gandara C, Garcia-Rios A, Rangel-Zuñiga OA, Gutierrez-Mariscal FM, Torres-Peña JD, Marin C, Lopez-Moreno J, Castaño JP, Delgado-Lista J, et al: Mediterranean diet and endothelial function in patients with coronary heart disease: An analysis of the CORDIOPREV randomized controlled trial. PLoS Med. 17(e1003282)2020.PubMed/NCBI View Article : Google Scholar

33 

Vanhoutte PM, Shimokawa H, Feletou M and Tang EH: Endothelial dysfunction and vascular disease-a 30th anniversary update. Acta Physiol (Oxf). 219:22–96. 2017.PubMed/NCBI View Article : Google Scholar

34 

Mason RP, Dawoud H, Jacob RF, Sherratt SCR and Malinski T: Eicosapentaenoic acid improves endothelial function and nitric oxide bioavailability in a manner that is enhanced in combination with a statin. Biomed Pharmacother. 103:1231–1237. 2018.PubMed/NCBI View Article : Google Scholar

35 

Dang TA, Schunkert H and Kessler T: cGMP signaling in cardiovascular diseases: Linking genotype and phenotype. J Cardiovasc Pharmacol. 75:516–525. 2020.PubMed/NCBI View Article : Google Scholar

36 

Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, Elwood PC and Deadman NM: Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and reinfarction trial (DART). Lancet. 2:757–761. 1989.PubMed/NCBI View Article : Google Scholar

37 

No authors listed. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: Results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet. 354:447–455. 1999.PubMed/NCBI

38 

Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, et al: Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): A randomised open-label, blinded endpoint analysis. Lancet. 369:1090–1098. 2007.PubMed/NCBI View Article : Google Scholar

39 

Rauch B, Schiele R, Schneider S, Diller F, Victor N, Gohlke H, Gottwik M, Steinbeck G, Del Castillo U, Sack R, et al: OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation. 122:2152–2159. 2010.PubMed/NCBI View Article : Google Scholar

40 

ORIGIN Trial Investigators. Bosch J, Gerstein HC, Dagenais GR, Díaz R, Dyal L, Jung H, Maggiono AP, Probstfield J, Ramachandran A, et al: N-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 367:309–318. 2012.PubMed/NCBI View Article : Google Scholar

41 

Risk and Prevention Study Collaborative Group. Roncaglioni MC, Tombesi M, Avanzini F, Barlera S, Caimi V, Longoni P, Marzona I, Milani V, Silletta MG, et al: N-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 368:1800–1808. 2013.PubMed/NCBI View Article : Google Scholar

42 

ASCEND Study Collaborative Group. Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, Barton J, Murphy K, Aung T, Haynes R, et al: Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 379:1540–1550. 2018.PubMed/NCBI View Article : Google Scholar

43 

Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Albert CM, Gordon D, Copeland T, et al: Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 380:23–32. 2019.PubMed/NCBI View Article : Google Scholar

44 

Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, et al: Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 380:11–22. 2019.PubMed/NCBI View Article : Google Scholar

45 

Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ, Davidson MH, Kastelein JJP, Koenig W, McGuire DK, et al: Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: The STRENGTH randomized clinical trial. JAMA. 324:2268–2280. 2020.PubMed/NCBI View Article : Google Scholar

46 

Kalstad AA, Myhre PL, Laake K, Tveit SH, Schmidt EB, Smith P, Nilsen DWT, Tveit A, Fagerland MW, Solheim S, et al: Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: A randomized, controlled trial. Circulation. 143:528–539. 2021.PubMed/NCBI View Article : Google Scholar

47 

Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, et al: 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Eur Heart J. 41:111–188. 2020.PubMed/NCBI View Article : Google Scholar

48 

Chinese Society of Cardiology of Chinese Medical Association, Cardiovascular Disease Prevention and Rehabilitation Committee of Chinese Association of Rehabilitation Medicine, Cardiovascular Disease Committee of Chinese Association of Gerontology and Geriatrics, Thrombosis Prevention and Treatment Committee of Chinese Medical Doctor Association. Chinese Guideline on the primary prevention of cardiovascular diseases. Zhonghua Xin Xue Guan Bing Za Zhi. 48:1000–1038. 2020.PubMed/NCBI View Article : Google Scholar : (In Chinese).

49 

Working Group of the Chinese Expert Consensus on Secondary Prevention after Coronary Artery Bypass Surgery, The Task Force for Coronary Artery Disease of Chinese Association of Cardiovascular Surgeons and The Task Force for Coronary Artery Disease of Chinese Society of Thoracic and Cardiovascular Surgery. Chinese expert consensus on secondary prevention after coronary artery bypass surgery (2020). Chin J Thor Cardi Sur. 37:193–201. 2021.(In Chinese).

50 

Hypertension Group, Chinese Society of Cardiology, Editorial Board of Chinese Journal of Cardiology. Expert consensus on comprehensive management of blood pressure and lipids in Chinese patients with hypertension. Zhonghua Xin Xue Guan Bing Za Zhi. 49:554–563. 2021.PubMed/NCBI View Article : Google Scholar : (In Chinese).

51 

Centre for Capacity Building and Continuing Education, National Health Commission. Expert consensus on diagnosis and treatment of cardiovascular diseases in diabetic patients. Chin J Inter Med. 60:421–437. 2021.(In Chinese).

52 

Kleindorfer DO, Towfighi A, Chaturvedi S, Cockroft KM, Gutierrez J, Lombardi-Hill D, Kamel H, Kernan WN, Kittner SJ, Leira EC, et al: 2021 Guideline for the prevention of stroke in patients with stroke and transient ischemic attack: A guideline from the American heart association/American stroke association. Stroke. 52:e364–e467. 2021.PubMed/NCBI View Article : Google Scholar

53 

Virani SS, Morris PB, Agarwala A, Ballantyne CM, Birtcher KK, Kris-Etherton PM, Ladden-Stirling AB, Miller M, Orringer CE and Stone NJ: 2021 ACC expert consensus decision pathway on the management of ASCVD risk reduction in patients with persistent hypertriglyceridemia: A report of the American college of cardiology solution set oversight committee. J Am Coll Cardiol. 78:960–993. 2021.PubMed/NCBI View Article : Google Scholar

54 

American Diabetes Association Professional Practice Committee. 10. Cardiovascular disease and risk management: Standards of medical care in diabetes-2022. Diabetes Care. 45 (Suppl 1):S144–S174. 2022.PubMed/NCBI View Article : Google Scholar

55 

National Committee of Cardiometabolic Medicine Specialists Committee. The role of omega-3 fatty acids in the prevention and treatment of cardiovascular diseases. Chin J Cir. 38:116–130. 2019.(In Chinese).

56 

Li JJ, Zhao SP, Zhao D, Lu GP, Peng DQ, Liu J, Chen ZY, Guo YL, Wu NQ, Yan SK, et al: 2023 China Guidelines for Lipid Management. J Geriatr Cardiol. 20:621–663. 2023.PubMed/NCBI View Article : Google Scholar

Related Articles

Journal Cover

June-2024
Volume 20 Issue 6

Print ISSN: 2049-9434
Online ISSN:2049-9442

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Xie X, Liu X, Li R, Fan L and Huang F: &omega;‑3 fatty acids in atherosclerotic cardiovascular disease (Review). Biomed Rep 20: 94, 2024.
APA
Xie, X., Liu, X., Li, R., Fan, L., & Huang, F. (2024). &omega;‑3 fatty acids in atherosclerotic cardiovascular disease (Review). Biomedical Reports, 20, 94. https://doi.org/10.3892/br.2024.1782
MLA
Xie, X., Liu, X., Li, R., Fan, L., Huang, F."&omega;‑3 fatty acids in atherosclerotic cardiovascular disease (Review)". Biomedical Reports 20.6 (2024): 94.
Chicago
Xie, X., Liu, X., Li, R., Fan, L., Huang, F."&omega;‑3 fatty acids in atherosclerotic cardiovascular disease (Review)". Biomedical Reports 20, no. 6 (2024): 94. https://doi.org/10.3892/br.2024.1782