However, it has become increasingly clear that COVID-19 can also have significant effects on cardiovascular health. Individuals with pre-existing cardiovascular conditions are at higher risk of severe illness and death from COVID-19, and the virus can also cause new cardiovascular problems in otherwise healthy individuals.
In this context, there is a growing interest in the potential benefits of omega-3 fatty acids on cardiovascular health, including their role in reducing the risk of COVID-19-related complications.
Background
Cardiovascular disease is a major cause of morbidity and mortality worldwide. It is a complex condition that can have many underlying causes, including high blood pressure, high cholesterol levels, obesity, and diabetes. Omega-3 fatty acids have been shown to have several beneficial effects on cardiovascular health, including reducing blood pressure, triglycerides, and inflammation, as well as improving endothelial function and reducing the risk of arrhythmias.
Omega-3 and COVID-19
In addition to their established benefits on cardiovascular health, there is growing interest in the potential role of omega-3 fatty acids in reducing the risk of COVID-19-related complications. There are several reasons why omega-3 fatty acids may be beneficial in the context of COVID-19.
First, omega-3 fatty acids have anti-inflammatory properties, which may be particularly important in the context of COVID-19. The virus can cause an excessive inflammatory response, known as a cytokine storm, which can lead to severe lung damage and other complications. Omega-3 fatty acids have been shown to reduce inflammation in a variety of contexts, including in the lungs.
Third, omega-3 fatty acids have been shown to have immunomodulatory effects, which may be beneficial in the context of COVID-19. The virus can suppress the immune system, leading to an increased risk of secondary infections. Omega-3 fatty acids have been shown to modulate the immune response in a way that may be beneficial in preventing secondary infections.
Clinical Studies
A High N3PUFA Dose Can Be Essential in Protecting Cardiovascular Health from COVID-19
N3PUFA has conferred cardiovascular health by reducing inflammation, oxidative stress, improving arterial and endothelial functions, and reducing platelet aggregation [81]. Since our bodies cannot synthesize N3PUFAs, we highly rely on dietary intake to replenish them [85].
The epidemiological evidence has reported that intake of EPA and DHA from the diet is strongly associated with fatty fish consumption. In contrast, the intake of N3PUFA varies significantly among different populations and is generally lower than the recommended 0.2–0.5 g/day for general adults [92,93,94] (depending on the various authorities making the dietary recommendation guidelines) in most Western countries of which the main protein source is meat instead of fish [95,96]. The inclusion of supplements that contain EPA and DHA is essential if the daily recommendation cannot be met through food intake only.
However, controversies surrounding the clinical trials involving various N3PUFA daily doses emphasize the importance of high-dosage N3PUFAs in reducing CVD risks, including the combined stroke, MI, and death from CVD causes and major cardiovascular events. Therefore, to establish the dose that can demonstrate a clinically significant cardiovascular benefit, previous RCTs that studied the association between N3PUFA and CVD have been reviewed. Although there is a lack of consensus among scientists and clinicians, clear evidence from decades of studies is able to support recommendations.
Since the first landmark clinical trial that investigated the cardiovascular protective effect of N3PUFA in 1999, controversies have been reported. A GISSI-P study of an Italian population was the first study that demonstrated that 1 g of N3PUFA (a combination of EPA and DHA) supplementation per day significantly reduced the RR of death by 10% (95% CI: 1–18%) and severe cardiovascular events by 17% (95% CI: 3–29%), compared to the control group that consumed 300 mg/day of vitamin E [98].
A later GISSI-HF study again demonstrated a significant reduction in the hazard ratio (HR) of death and hospital admissions for cardiovascular reasons after subjects were on the same dose for 3.9 years [99]. The fundamental development of CVD treatment has been achieved, including aggressive therapy, since this GISSI-P study was published. Yokoyama et al. [99] also demonstrated in the 2007 JELIS study that the daily addition of 1.8 g EPA to standard statin medication per day significantly reduced the related risks of major coronary events in Japanese subjects who had equal to or higher than 6.5 mmol/L total cholesterol after a five-year follow-up. However, in the OMEGA study, where the majority of subjects received statin therapy at baseline, there was no significant improvement in sudden cardiac death, total mortality, or major adverse cerebrovascular and cardiovascular events (MACEs) [100]. There is a possibility that the pre-clinical trial optimal medical therapy could have contributed to this insignificant efficacy (Table 2).
Table 2. Characteristics of parallel-design RCTs of N3PUFA.
| Year | Trial | Population | No. of Subjects | Age (years) | Male (%) | Subject Characteristics | N3PUFA 1, Dose | Control | Study Period | Result |
|---|---|---|---|---|---|---|---|---|---|---|
| 1999 | GISSI-P [98] | Italian | 11,324 | 59 | 84.7 | Surviving recent (≤3 months) myocardial infarction | N3PUFA, 1 g/day | Vitamin E, 300 mg/day | 3.5 years | ↓ RR 2 of death = 10% (95% CI: 1–18%); ↓ RR of CVD = 17% (95% CI: 3–29%) |
| 2007 | JELIS [99] | Japanese | 18,645 | Average 61 | 31.4 | Total cholesterol ≥6.5 mmol/L | EPA 3, 1.8 g/day; statin | Statin only | 5 years | ↓ 19% RR in major cardiovascular events |
| 2008 | GISSI-HF [98,100] | Italian | 955 | ≥18 | 77.8 | With chronic heart failure of New York Heart Association classes II–IV, irrespective of cause, and left ventricular ejection fraction | N3PUFA, 1 g/day | Placebo | 3.9 years | ↓ HR 4 of death = 0.91 (95% CI: 0.833–0.998); ↓ HR of hospital admission for cardiovascular reasons = 0.92 (95% CI: 0.849–0.999) |
| 2010 | DOIT [101] | Norwegian | 563 | 64–76 | 100 | Without overt cardiovascular disease | N3PUFA, 2.4 g/day | Placebo (corn oil) | 3 years | ↓ HR of death = 0.57 (95% CI: 0.29–1.10); ↓ HR of cardiovascular events = 0.86 (95% CI: 0.57–1.38) |
| 2010 | SU.FOL.OM3 [102] | French | 2501 | 45–80 | 79.5 | With a history of myocardial infarction, unstable angina, or ischemic stroke | 5-methyltetrahydrofolate, 560 μg/day; vitamin B6, 3 mg/day; vitamin B12, 20 μg/day; N3PUFA, 0.6 g/day | Placebo | 4.7 years | No significant effect on major cardiovascular events |
| 2010 | Alpha-OMEGA [103] | Dutch | 4837 | 60–80 | 78.0 | Had a myocardial infarction, received state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy | N3PUFA, 0.376 g/day (EPA, 0.226 g/day; DHA 5, 0.150 g/day) | ALA, 1.9 g/day | NA | → HR of major cardiovascular events = 1.01 (95% CI: 0.87–1.17) |
| 2010 | OMEGA [104] | German | 3851 | 64 | 74.4 | 3 to 14 days after acute myocardial infarction | N3PUFA (EE form), 1 g/day | Placebo | 1 year | No significant difference in sudden cardiac death, total mortality, major adverse cerebrovascular and cardiovascular events |
| 2012 | ORIGIN [105] | Canadian | 12,536 | ≥50 | 40.0 | At high risk for cardiovascular events and had impaired fasting glucose, impaired glucose tolerance, or diabetes | N3PUFA (EE form), 0.9 g/day | Placebo | 6.2 years | → HR of time to death or admission to the hospital for cardiovascular causes, 0.97 (95% CI: 0.88–1.08) |
| 2013 | R and P [106] | Italian | 12,513 | ≥65 | 61.5 | with multiple cardiovascular risk factors or atherosclerotic vascular disease but not myocardial infarction | N3PUFA (EE form), 1 g/day | Placebo | 1 year | → HR of the rates of major cardiovascular events, 1.01 (95% CI: 0.93–1.10) |
| 2014 | AREDS-2 [107] | American | 4203 | 50–85 | 56.8 | With stable, existing CVD (>12 months since initial event) | N3PUFA, 1 g/day (EPA, 650 mg/day; DHA, 350 mg/day); lutein, 10 mg/day; zeaxanthin, 2 mg/day | Placebo | 4.8 years | → HR of risk of CVD or secondary CVD outcomes, 0.95; 95% CI, 0.78–1.17 |
| 2016 | OMEGA- REMODEL [108] | American | 358 | >21 | 65.0 | With an acute MI | N3PUFA, 4 g/day (EPA, 465mg/day; DHA, 375 mg/day) | Corn oil (linoleic acid, no N3PUFA, 600 mg/day) | 6 months | ↓ LVESVI 6 (–5.8%, p = 0.017); ↓ Non-infarct myocardial fibrosis (−5.6%, p = 0.026) |
| 2018 | ASCEND [109] | British | 15,480 | ≥40 | 62.6 | With diabetes but without evidence of atherosclerotic cardiovascular disease | N3PUFA, 1 g/day | Olive oil, 1 g/day | 7.4 years | No significant difference in serious vascular event or revascularization |
| 2019 | VITAL [110] | American | 25,871 | >50 (males) >55 (females) | 49.9 | Healthy | N3PUFA, 1 g/day; vitamin D3 2000 IU/day | Placebo | 5.3 years | No significant difference in serious vascular event; ↓ HR of MI = 0.71 (95% CI:0.59–0.9) |
| 2019 | REDUCE-IT [111] | 71% (US, Canada, Netherlands, Australia, New Zealand, and South Africa), 25.8% (Eastern European), 3.2% (Asia-Pacific) | 8179 | ≥45 (established CVD) ≥50 (established T2DM) | 71.2 | With established cardiovascular disease or with diabetes and other risk factors, receiving statin therapy, fasting triglyceride level of 135 to 499 mg per deciliter (1.52 to 5.63 mmol per liter), a low-density lipoprotein cholesterol level of 41 to 100 mg per deciliter (1.06 to 2.59 mmol per liter) | EPA (icosapent ethyl highly purified EPA formulation), 4 g/day | Placebo | 4.9 years | ↓ HR of major cardiovascular events = 0.75 (95% CI: 0.68–0.83) |
1 N3PUFA, n-3 polyunsaturated fatty acid; 2 RR, relative risk; 3 EPA, eicosapentaenoic acid; 4 HR, hazard ratio; 5 DHA, docosahexaenoic acid; 6 LVESVI, left ventricular systolic volume index. ↑ Statistically significant increase ↓ Statistically significant decrease → No statistically significant change
Notably, the study populations in large-scale studies that showed a significant reduction in CVD risk were from high seafood intake regions, such as the Italian populations in the GISSI-P and GISSI-HF studies and the Japanese population in the JELIS study, who potentially had higher baseline N3PUFA concentrations due to their high dietary supply (Table 1). Previous studies have raised the possibility that a threshold of endogenous levels may be required to show the statistical significance of N3PUFA on CVD risk. Populations with a higher baseline of N3PUFA reserves may need a lower dose of N3PUFAs to show statistically significant improvement in their cardiovascular health; on the contrary, Western populations with lower fatty fish consumption are likely to require a higher N3PUFA dose. A 2010 small RCT of elderly Norwegian males (n = 563) at high risk of developing CVD (72% without overt CVD), the DOIT study, reported a tendency towards reduction in all-cause mortality and cardiovascular events that reaching statistical significance after the subject was on a doubled dose (2.4 g/day) despite the smaller sample size [102]. The VITAL study [110] also showed that the subjects, who received the most cardiovascular benefit from a N3PUFA supplement, had the lowest baseline levels of N3PUFA concentration (Table 2).
The findings from later studies using low-dose N3PUFAs (0.376–1 g/day) failed to demonstrate its sufficiency for populations who had a lower average of fatty fish consumption to reach the same therapeutic benefit to lower cardiovascular risk [100,103,104,105,106,107,109,110] (Table 1), including the SU.FOL.OM3 study, Alpha-OMEGA study, OMEGA study, ORIGIN study, R and P study, AREDS-2 study, and ASCEND study. Although the VITAL study of the US cohort found that daily administration of 2000 IU/day of vitamin D3 and 1 g/day of N3PUFAs (a combination of EPA and DHA) did not significantly reduce the risk of CVD when compared to the placebo group after 5.3 years of intervention [110], a statistically significant decrease in the HR of MI was reported. It was not until the OMEGA-REMODEL study found that high-dose N3PUFAs (4 g/day of an EPA and DHA combination) appeared to be beneficial up to 6 months after acute MI, that a reduction in adverse left ventricular remodeling, non-infarct myocardial fibrosis, and serum biomarkers of systemic inflammation beyond the current guideline-based standard of care were demonstrated [108]. The most recently conducted multi-center REDUCE-IT study reported that a high N3PUFA dose of 4 g/day (icosapent ethyl, highly purified EPA) significantly reduced major cardiovascular events in a multi-population, particularly in US participants who had a low baseline N3PUFA level [111] (Table 2). The treatment cohort significantly reduced the primary endpoint (a composite of CVD death, non-fatal MI, non-fatal stroke, CV revascularization, or unstable angina) by 25% and the secondary endpoint MACE by 26% [111]. The sub-cohort of the US population experienced a reduced RR of all-cause mortality by 30% and absolute risk by 2.6% [111] (Table 2).
Recent meta-analyses have examined the potential sources of heterogeneity in the effects of N3PUFA on cardiovascular health. A 2019 meta-analysis by Hu and colleagues [112] conducted a meta-regression of 13 RCTs, excluding REDUCE-IT, and concluded that marine N3PUFA supplementation was negatively associated with the risk of MI (RR = 0.92, 95% CI: 0.86, 0.99; p = 0.020), CHD death (RR = 0.92, 95% CI: 0.86, 0.98; p = 0.014), total CHD (RR = 0.95, 95% CI: 0.91, 0.99; p = 0.008), CVD death (RR = 0.93, 95% CI: 0.88, 0.99; p = 0.013), and total CVD (RR = 0.97, 95% CI: 0.94, 0.99; p = 0.015). The negative association was further strengthened when the REDUCE-IT study was included [112]. Bernasconi and colleagues [113], in their updated 2020 meta-analysis, stated that N3PUFAs of an EPA and DHA combination statistically significantly reduced the risk of CVD and MI by 9% and 13%, respectively. Moreover, a dose-dependent association was reported between the reduction in MI risk (9% reduction) and an additional 1 g/day of N3PUFA [113], indicating that the higher dose provided significantly higher protection. One 2017 meta-analysis that reviewed the minimal dose required for a clinically meaningful change in triglyceride concentration suggested that the low dose of N3PUFA could explain the inconsistent results in previous RCTs (<1.5 g/day of an EPA and DHA combination) [114]. A recent update on the dose recommendation of N3PUFA reviewed the threshold of the baseline N3PUFA index (a calculated value to express the amount of systemic EPA and DHA in weight (%) present in the tissue cell membrane lipid fractions), and the suggested supplementation dose suggested of high-dose N3PUFAs (4 g/day) appeared to be more beneficial among people with low baseline N3PUFA (<8% N3PUFA index, a measurement of serum N3PUFA levels) [115]. In contrast, the low dose (1 g/day) only benefited people with a high baseline (≥8% N3PUFA index) [115]. Further work including clinical trials on high-dose concentrated ethyl ester (i.e., the EE form) N3PUFAs will be conducted and funded by Pharma New Zealand PNZ Limited (Hamilton, New Zealand).
Conclusions
COVID-19 can cause a hyperinflammatory response that leads to the formation of blood clots, which can affect blood vessels throughout the body, including those that supply the heart. There is growing evidence that COVID-19-related immunothrombosis can increase the risk of CVD. Patients with pre-existing CVD are at a higher risk of experiencing complications from COVID-19. It is vital for healthcare providers to monitor COVID-19 patients for signs of CVD and provide appropriate treatment to reduce the risk of complications.
At this time, there are no clear studies that demonstrate the positive effects of N3PUFA on COVID-19 patients. However, high dose concentrated N3PUFAs (4 g/day) have been shown to regulate and modulate certain negative immunological overreaction effects, limit coagulopathy, and influence cell signaling and gene expression. They are well known to have antithrombotic, anti-inflammatory, and pro-resolving properties, which can be advantageous for COVID-19 patients. The ingestion of N3PUFAs and/or their metabolites may prevent and manage cardiovascular and thrombotic issues in COVID-19 patients. It is, therefore, prudent to study the possible uses of fish oil/N3PUFA supplementation as an adjuvant to medication in COVID-19 patients at risk of vascular thrombotic events.
reference link :https://www.mdpi.com/2218-1989/13/5/630
