The beneficial effects of omega-3 polyunsaturated fatty acids on controlling blood pressure: An umbrella meta-analysis

Abstract

Several meta-analyses have revealed that n-3 PUFAs can lower blood pressure, but the findings are conflicting. In this regard, the present umbrella meta-analysis aimed was performed to clarify whether n-3 PUFAs have effects on blood pressure. PubMed, Scopus, Embase, Web of Science, and Google Scholar were used as international databases from inception to May 2022. To examine the effects of n-3 PUFA supplementation on blood pressure, a random-effects model was applied. The leave-one-out method was performed for the sensitivity analysis. The pooled estimate of 10 meta-analyses with 20 effect sizes revealed significant reductions in both systolic (ES = −1.19 mmHg; 95% CI: −1.76, −0.62, p < 0.001) and diastolic blood pressure (ES = −0.91 mmHg, 95% CI: −1.35, −0.47; p < 0.001) following n-3 PUFAs supplementation. In studies with a sample size of ≤ 400 participants and a mean age over 45, SBP and DBP were found to be substantially reduced. Overall, this umbrella meta-analysis indicates that n-3 PUFAs supplementation might play a role in improving DBP and SBP.

Introduction

Hypertension is among the most common health conditions worldwide affecting over 1 billion people and accounting for 9.4 million deaths annually (1). Elevated blood pressure is responsible for heart attacks, arrhythmias, stroke and premature death (2). Research shows that some recommendations such as healthy dietary habits, and smoking cessation can reduce blood pressure (BP), thereby decreasing hypertension and CVD risks (3).

Omega-3 polyunsaturated fatty acids (PUFAs) mainly consist of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and alpha-linolenic acid (ALA) (4). Diets deficient in n-3 PUFAs from seafood were classified as the sixth most significant dietary risk factor −1.5 million deaths and 33 million disability-adjusted life years worldwide were attributed to this (5). According to most national and international guidelines, adults should consume at least one serving of oily fish per week (≥ 250 mg/day of EPA and DHA) (6, 7). Despite this, an estimated 20% of the world’s population consumes less than 250 mg of EPA and DHA per day (8). Although the role of PUFAs in hypertension is still subject to an scientific debate, they have been shown to have multiple beneficial effects in cardiovascular disease (9). Additionally, they demonstrated that they had anti-inflammatory (10) and antithrombotic (11) properties, improved endothelial dysfunction (12) and positively affected resting heart rate (HR), HR variability (13, 14), heart rhythm (15), and cardiac remodeling (16). In terms of their antihypertensive properties, n-3 PUFAs were reported to modulate ion channels in blood vessels, thereby causing vasodilation (17). The red blood cell membrane omega-3 content of humans is associated with smaller brachial artery diameter (an independent predictor of cardiovascular events) and increased vasodilatory function (18). Omega-3 content in red blood cell membranes of humans is associated with smaller brachial arteries (an indicator of cardiovascular events) and increased vasodilation (18). Generally, n-3 PUFAs were shown to improve arterial compliance and reduce pulse wave velocity. Some benefits of omega-3-PUFAs may be mediated through downstream effects on BP (8, 19, 20). According to a report by Averna et al. (21) high-dose omega-3 fatty acids (Icosapent ethyl) may be considered a benefit to managing TG-rich lipoproteins. By TG-lowering, the risk of cardiovascular events decreases. In recent years, several systematic reviews and meta-analyses of randomized controlled trials have been performed investigating the effects of n-3 PUFAs supplementation on BP (22, 23), while In some studies, controversial results have been reported (24–26). Therefore, the present umbrella meta-analysis was performed to assess the explicit impact of n-3 PUFA supplementation on systolic BP (SBP) and diastolic BP (DBP) providing valid and authentic evidence.

Methods

The current umbrella of meta-analysis was performed based on the PRISMA. We registered our study protocol in PROSPERO (CRD42022311888).

Search strategy of literature

Searches were conducted in PubMed, Scopus, Embase, Web of Science, and Google Scholar databases to find relevant studies published inception to May 2022 The following search strategy using MeSH terms and keywords was applied; [“omega-3 fatty acid” (Mesh) OR “omega-3 fatty acid” (tiab) OR “fish oil” (tiab) OR “omega-3 polyunsaturated fatty acids” (tiab) OR “EPA” (Mesh) OR “DHA” (Mesh) OR “DHA” (tiab) OR “EPA” (tiab) AND “hypertension” (Mesh) OR “hypertension” (tiab) OR “HTN” (tiab) OR “blood pressure” (tiab) OR “BP” (tiab) OR “hypertens” (tiab) AND “systematic review” (Publication Type) OR “meta-analysis” (tiab)]. Additionally, we enhanced sensitivity of the search strategy by using the wildcard term “*”. To ensure no publications were missing, reference lists of relevant studies were manually screened. In this umbrella of meta-analysis, English-language articles were eligible.

Inclusion and exclusion criteria

A PICO analysis was conducted to summarize the results of the current umbrella meta-analysis. The PICO criteria were: population/patients (P: adults over 18 years’ old who received omega-3 PUFAs); intervention (I: omega-3 PUFAs therapy); comparison (C: control or placebo group); outcomes (O: BP including SBP and DBP). Our study included meta-analyses that assessed the effects of n-3 PUFA supplementation on BP (SBP and DBP) along with their effect sizes (ES) and corresponding confidence intervals (CI). In vivo, in vitro, and ex vivo studies, observational studies, quasi-experimental studies, case reports, and controlled clinical trials were excluded.

Evaluation of methodological quality

In terms of their methodology, two independent reviewers (VM and MV) performed AMSTAR2 (Assessing the Methodological Quality of Systematic Reviews) questionnaires to evaluate the quality of meta-analyses (27). The questionnaire consists of 16 questions that ask reviewers to answer “Yes” or “Partial Yes” or “No” or “No Meta-analysis.” Four categories were developed for the AMSTAR 2 checklist: “Critical low quality,” “low quality,” “moderate quality,” and “high quality.

Study selection and data extraction

Based on eligibility criteria, articles were screened by two independent reviewers (MV and VM). After reviewing based on their titles and abstracts, irrelevant studies were removed. Then, by evaluating the full text of the relevant articles, eligible studies for the umbrella of meta-analysis were identified. Finally, any disagreement was resolved by discussion and consulting with other researchers (PD). The first author’s name, the publication year, the sample size, the study location, supplementation dosages, and duration, as well as the ESs and CIs for SBP and DBP, are extracted from the selected meta-analyses.

Synthesis of data and statistical analysis

ESs and CIs were applied to estimate overall effect sizes. Cochran’s Q test and I² statistics were used to determine heterogeneity. When I²-value > 50% or the Q-test had p < 0.1, we considered between-study heterogeneity significant. The random-effects model was chosen when there was significant between-study heterogeneity. By performing subgroup analysis based on predefined variables including sample size, duration of intervention, health condition, the dose of supplementation, and mean age, potential sources of heterogeneity were detected. Sensitivity analysis was conducted to investigate the impact of one single study omission on the pooled effect size. Tests Egger’s and Begg’s were used to assessing a small-study effect. The publication bias was assessed by visual inspection of the funnel plots, and if any publication bias was detected, then a trim and fill test was carried out subsequently. In order to run the meta-analysis, we used STATA (version 16, Stata Corporation, College Station, TX, United States). In this study, p < 0.05 was considered statistically significant.

Results

Study selection and study characteristics

A total of 210 articles were found after searching the electronic databases. 173 articles were carefully screened with titles and abstracts, after removing 37 duplicate articles, of which 21 articles were selected for full-text evaluation. Finally, 10 meta-analyses were included in the current umbrella meta-analysis. Figure 1 illustrates the flow chart of PRISMA studies. The characteristics of the meta-analyses that were qualified are summarized in Table 1. All studies were carried out between 1989 and 2021, and the participants ranged in age from 34 to 55 years. There was an average amount of 2.2–6 g/day of administered n-3 PUFAs across studies. The duration of n-3 PUFA supplementation ranged from 4 to 29 weeks. The location of the studies performed were as follows: three in United States (25, 28, 29), two in China (24, 30), two in United Kingdom (22, 31), two in Canada (23, 26), and one in Australia (32). The quality of the randomized controlled trials (RCTs) included in the current study is presented in Table 1.

FIGURE 1

Methodological quality

Results of the quality assessment of the qualified studies using the AMSTAR2 questionnaire are presented in Table 2.

Impact of n-3 PUFAs on diastolic blood pressure

Overall, ten included meta-analyses with 20 effect sizes comprising a total of 6,334 subjects have examined the impact of n-3 PUFAs supplementation on DBP (Figure 2A). It was found that DBP was significantly reduced after n-3 PUFAs supplementation (ES = −0.91 mmHg, 95% CI: −1.35, −0.47; p < 0.001), with high heterogeneity between-studies (I² = 70.8%, p < 0.001). N-3 PUFA supplementation > 4,500 mg/day to hypertension subjects > 45 years of age and a sample size of ≤ 400 significantly reduced DBP (Table 3).

FIGURE 2

Impact of n-3 PUFAs on systolic blood pressure

The effect of n-3 PUFAs supplementation on SBP was investigated in ten meta-analyses with 20 effect sizes, including 6,734 subjects. The pooled estimate revealed that in subjects who consumed n-3 PUFAs supplements, SBP significantly was reduced (ES = −1.19 mmHg; 95% CI: −1.76, −0.62, p < 0.001) (Figure 2B). There was detected meaningful heterogeneity between the studies (I² = 71.2%, p < 0.001). Subgroup analysis showed that EPA supplementation (> 2,000 mg/day) in intervention duration of > 15-weeks, a mean age > 45 years, and a sample size of ≤ 400 participants contributes to a more pronounced influence in decreasing SBP (Table 3).

Sensitivity analysis and publication bias

Sensitivity analysis indicated that the effect of n-3 PUFAs supplementation on DBP and SBP levels was not significant (Supplementary File 1).

Egger’s test, unlike Begg’s, showed a significant small-study effect for DBP (p = < 0.001 and 0.626, respectively), and SBP (p = < 0.001 and 0.948, respectively). In addition, publication bias was detected through a visual assessment of the funnel plots (Figure 3). Trim and fill adjustment did not alter the overall effect size.

FIGURE 3

Discussion

The current umbrella meta-analysis of the n-3 PUFAs effect on BP indices summarized 10 meta-analyses including 131 trials. Although several studies have evaluated the effect of n-3 PUFAs on CVD risk factors, inconsistent findings have been achieved in terms of the effects of n-3 PUFAs on the BP because significant changes have not been observed consistently. Hence, we performed the present study to systematically assess the treatment effects of n-3 PUFAs on the BP in adults. Our results revealed that n-3 PUFAs supplementation can significantly decrease SBP, and DBP levels, with moderate confidence of evidence. Nevertheless, there was significant heterogeneity in the response which attributed to subject age, study population, study duration, sample size, and dosage of n-3 PUFAs. Moreover, we also perform subgroup analysis to gain further insight on the assessment of heterogeneity. Subgroup analysis revealed the effects of n-3 PUFAs were stronger in hypertensive patients, and among studies with a follow-up period of at least 10 weeks. Also, DBP and SBP were both reduced in studies lasting up to 10 weeks with daily dose of EPA > 2,000 mg/day. The quality of studies was assessed in all meta-analyses included in our study except for Morris et al. (28). Except three studies that used Jadad scale, other meta-analyses used Cochrane Collaboration’s tool to evaluate the different sources of bias in trials. Additionally, the majority of the included articles were of high risk of bias based on quality assessment.

High BP is a modifiable risk factor that can lead to cardiovascular disease (CVD), stroke, renal disease, and mortality (33, 34). In recent decades, several publications have showed that therapy with n-3 PUFAs positively effect on BP (22, 30, 35). Actually, several previous studies have reported that n-3 PUFAs may decrease CVDs risk factors by improving the inflammation (31), lipid, and glycemic profile (24, 36, 37), as well as decreasing BMI (38). In addition to above factors, the effects of n-3 PUFAs supplementation on apolipoproteins, particularly Apo-CIII has been found in recent meta-analysis (39). The findings of our study show that supplementation with n-3 PUFAs decreases DBP as well as SBP. While the magnitude of the detected effect seems small, it appears to be both clinically and statistically significant. According to previous meta-analysis, even a slight reduction in BP is helpful for CVD risk management and can efficiently decrease CVD events (40). A meta-analysis has reported that every 1 mmHg decrease in SBP leads to a nearly 2.5% sex- and age -specific reduction in vascular mortality (41). Consequently, n-3 PUFAs can be considered as an effective and without life-threatening side effects agent in control of BP.

Our results are consistent with three other meta-analyses (22, 30, 35). In the analysis of DBP, subgroup analyses indicated a stronger effect in patients with dyslipidemia, and hypertension, as well as in kidney transplant recipients. A BP lowering effect has been detected in both hypertensive and normotensive subjects, but the response appears more pronounced among hypertensive patients. Furthermore, supplementation of > 2,000 mg/d of EPA appears to be sufficient to reduce both DBP and SBP by 1.95 and 2.98 mmHg, respectively. Stratifying the meta-analysis based on the mean age of subjects revealed that n-3 PUFAs among participants with > 45 years had the most improving effect on SBP and DBP levels compared with younger participants. Long-term supplementation of n-3 PUFAs (10–15 week) led to a larger decrease in DBP levels than ≤ 10-week administration. However, given the findings of our subgroup analysis, it appears that short-term supplementation (≤ 10-week) with n-3 PUFAs, is more effective in decreasing SBP than long-term one. It should also be noted that most included meta-analysis in our review had participants with metabolic disorders, hypertension, and T2DM. Cornelissen and Fagard (42) have shown that hypertensive and normotensive participants may respond in different degrees to the same intervention. Hypertensive patients appear to be a better target population to study the hypotensive effect of n-3 PUFAs because they are more prone to changes in BP (43).

N-3 PUFAs may exert its hypotensive effects by several mechanisms. N-3 PUFAs may control the caveolae composition resulting in increased nitric oxide synthase (44). In particular, n-3 PUFAs stimulate expression and activity of endothelial nitric oxide synthase (45). The BP lowering effect of n-3 PUFAs might be ascribed to enhancements of endothelial and smooth muscle function together with lowered systemic vascular resistance (46). Also, n-3 PUFAs acts as a hypotensive agent through increasing synthesis of vasodilator mediators such as prostacyclin, and inhibiting vasoconstrictor mediators such as thromboxane which are associated with hypertension (47). Prostacyclin exerts its vasodilatory effects by activating prostacyclin receptors present on vascular smooth muscle cells and platelets, which therefore decreases peripheral vascular resistance and arterial stiffness (48). Furthermore, hypotensive property of n-3 PUFAs may be the result of its ability to significantly reduction of TC and LDL-C (31, 49). In a meta-analysis by Zhang et al. (24) significant reduction in serum TC level was observed following EPA supplementation 2 g/day. N-3 PUFAs supplementation possesses several antioxidant properties, combats intracellular reactive oxygen species, and can enhance other antioxidant defense, such as thioredoxin reductase 1, heme oxygenase-, and manganese superoxide dismutase, thus protecting endothelial cells from oxidative functional damages and regulating BP (50, 51). It has also been reported that n-3 PUFAs can counteract the release of pro-inflammatory cytokines in the myocardium and vascular endothelium, so restoring vascular reactivity and myocardial performance (50). Hence, the anti-inflammatory actions of n-3 PUFAs may be another putative way by which antihypertensive effects are exerted.

The main strength of this review was that this umbrella meta-analysis provided a comprehensive summary of the literature and its results and given the potential effect on the management and treatment of hypertension, this is a useful attempt. We revealed that there is sufficient evidence for n-3 PUFAs to elicit helpful effects on blood pressure. In the sensitivity analysis, no changes in the results were observed excluding each meta-analysis; this supports the robustness of our results. However, current study has several limitations. The analyses involved subjects with several health statuses such as T2DM, dyslipidemia, kidney transplant recipients, NAFLD, and metabolic syndrome. While this allowed more meta-analyses and subjects to be included for analysis, this could affect generalizability. However, we done random effects model in our analyses as well as explored for heterogeneity, the current findings are limited by possible residual confounding such as different background diets of participants. Finally, the proportion of n-6 PUFAs: n-3 PUFAs may play an important role in decreasing the risk factors of CVDs (52–54). However, we did not recognize any meta-analysis to involve the relationship between the ratio of n-3/n-6 PUFAs and BP.

Conclusion

In summary, this umbrella meta-analysis of 10 meta-analyses revealed that, compared with control, n-3 PUFAs intake was related to meaningfully greater degree of SBP, and DBP decrease, and this effect was more obvious in hypertensive subjects. Consequently, supplementation with n-3 PUFAs may be a useful adjuvant therapy in hypertensive patients.

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