According to the World Health Organization, cardiovascular disease (CVD) is the leading cause of death globally, taking the lives of nearly 18 million people each year. CVDs are a group of disorders that affect the heart and blood vessels, including coronary heart disease, stroke, atherosclerosis, high blood pressure, and other similar conditions. One of the most important behavioral risk factors and preventative strategies for CVD is diet. In fact, a large body of evidence has reported that nutrition might be the most preventative factor of CVD death and may even reverse heart disease after it has begun.
Various nutrients and bioactive compounds in food have been associated with beneficial effects on CVD outcomes. Among them, Omega-3 fatty acids and B vitamins have been recently investigated. While each may provide health benefits individually, new research is exploring their effects if combined.
The Impact of Omega-3s on CVD
Early epidemiological studies found that populations with significant dietary fish intake tend to have lower CVD incidence and mortality levels. A meta-analysis published in 2020 confirmed these outcomes, concluding that higher dietary intake of fish was negatively correlated with CVD incidence and mortality. Important bioactive compounds found in fish, such as the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been reported as potential agents in CVD risk reduction.
Furthermore, there is evidence from more recent human studies that demonstrate the positive effects of omega-3 intake on CVD risk factors. A meta-analysis of 38 randomized controlled trials reported reductions in serum triglycerides by 20-30% in healthy participants after consuming around 4g of EPA and DHA daily. Furthermore, several observational studies have found that serum DHA levels are a predictive marker of endothelial dysfunction, where low DHA levels are associated with greater dysfunction.
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Human studies have identified that persons with an Omega-3 Index of 6.5% are 90% less likely to have sudden cardiac death compared to persons with an Omega-3 Index of 3.3%. Similar results were seen in the Physician’s health study, where a 90% risk reduction for sudden cardiac death was seen in physicians with an Omega-3 Index of 6.87% compared to those that were 3.58% or lower. However, results are mixed, and not every study has concluded that omega-3s alone can contribute to CVD prevention.
The Impact of B Vitamins on CVD
Many B vitamins impact human health, but when it comes to CVD folate, B6 and B12 are the most reviewed. Several early observational studies have supported the role of B vitamins in reducing cardiovascular risk. The mechanism of action suggested is related to B vitamin’s role in lowering homocysteine concentrations. A meta-analysis of observational studies found that lowering plasma homocysteine levels by 25% may reduce the risk of coronary artery disease by 11% and stroke by 19%. Although B vitamin supplementation has been found to significantly lower homocysteine levels, their effect on cardiovascular outcomes has been mixed, except for stroke.
B12, for instance, has been tightly linked with ischemic stroke. Clinical data from a 2021 literature review strongly suggests that a deficiency in vitamin B12 is a risk factor for ischemic stroke and possible outcomes. While the exact mechanisms for this relationship have yet to be identified, the study’s authors suggest B12’s function in homocysteine homeostasis and myelination of neurons are likely to play a role.
Interestingly, a separate review published in 2020 found different results identifying B6 and folate as the key vitamins associated with a reduced risk of stroke. And this study’s inverse relationship between vitamins B6, folate, and stroke risk remained significant even after >10 years of follow-up.
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Studies Identify a Possible Compound Effect of Omega-3 and B Vitamins on Heart Health
Results from clinical trials have revealed a potential synergistic effect of B vitamins and omega-3s in relation to CVD. One study found that supplementation with B vitamins (B6 and folate) and fish oil for four weeks reduced the atherogenic index (the ratio of plasma triglycerides to HDL cholesterol – a strong marker in predicting CVD risk) by 24% compared to 12% from fish oil supplementation alone.
Similarly, another study found that supplementation with vitamin B12 and fish oil for eight weeks lowered plasma homocysteine more than individual supplementation with B12 or fish oil alone. But these are both risk factors. Does combining supplementation of B vitamins and omega-3s provide additional benefits in lowering risk for CVD? A new systematic review of clinical trials set out to find the answer.
NEW RESEARCH: Effects of combined supplementation with B vitamins and Omega-3s on CVD
The review included 15 studies that reported the effects of combined supplementation of B vitamins (vitamin B2, B6, folic acid, and B12) and omega-3 fatty acids in humans. The authors discussed two outcomes. First, they identified if combined supplementation affected CVD risk factors – indicators that have been found to influence risk for CVD, such as plasma homocysteine, circulating triglycerides, and C-reactive protein. Then they identified if combined supplementation influenced actual risk for CVD (incidence of CVD).
Several studies demonstrated that combined supplementation of B vitamins and omega-3s had diverse effects on CVD risk factors. The combination of supplements appears to have the most significant impact on homocysteine levels, with 13 (of 15) studies reporting homocysteine-lowering effects of combined supplementation.
Similarly, most studies examining the lowering effects of serum triglycerides and LDL cholesterol concentration found a positive impact on joint consumption of B vitamins and omega-3s. However, joint supplementation did not impact all risk factors. Insignificant changes were found in C-reactive protein and high-density lipoprotein cholesterol (HDL) levels with combination treatment.
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Although the review identified positive effects of combined supplementation on CVD risk factors, they concluded that there is insufficient data to determine whether combining B vitamins and omega-3s provide further benefits. The review revealed a lack of data related to this question. No studies were included that reported the effect of combined supplementation on the primary prevention of CVD (reducing disease incidence in healthy individuals). Moreover, only one study looked at the effect of combined supplementation on secondary prevention of CVD (reducing the impact of the disease or critical events in those who are already diagnosed). This trial included more than 2500 patients with a history of CVD and treated them with B vitamins and omega-3s for over four years. They reported that neither B vitamins nor omega-3s significantly decreased the risks of hard coronary events. The authors concluded that more research needs to be done to determine the true relationship between the combined effects of B vitamins and omega-3s on cardiovascular risk.
B vitamins & Omega-3s Are Metabolically Connected
Although the results of CVD risk were inconclusive, combined supplementation appears to support several risk factors. The review’s authors proposed that B vitamins and omega-3s might act synergistically in their roles in one-carbon metabolism, homocysteine homeostasis, and oxidative stress. B vitamins and DHA are essential in one-carbon metabolism, a series of interlinking metabolic pathways providing one-carbon units (methyl groups) for the synthesis of DNA, proteins, and other critical processes. There is considerable evidence from genetic and clinical studies pointing to the role of one-carbon metabolism in CVD development, particularly regarding blood pressure control.
Both B vitamins and omega-3s DHA and EPA are also associated with homocysteine homeostasis and inflammation. Homocysteine is a non-essential amino acid created during the synthesis of the amino acid methionine (which is essential). Homocysteine can accumulate in the blood if there are insufficient levels of vitamin cofactors (such as B vitamins) necessary for the metabolism of homocysteine to its end product. Elevated homocysteine is associated with the progression of several disease states, is an independent risk factor for CVD, and is linked to high blood pressure, increased oxidative stress, atherosclerosis, and endothelial dysfunction. B vitamins play an integral role in homocysteine metabolism, and supplementation with B vitamins has been found to lower plasma homocysteine levels.
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While the effects of omega-3 fatty acids alone on homocysteine levels appear to be null, the two are still connected. First, high levels of homocysteine have been found to increase the production of Reactive Oxygen Species (ROS) that damage polyunsaturated fatty acids (like omega-3s). But omega-3s can fight back.
It has been suggested that omega-3 fatty acids can modulate the expression of enzymes involved in homocysteine metabolism by regulating gene expression. Furthermore, Omega-3s can fight against ROS and further oxidative stress and inflammation by producing potent anti-inflammatory metabolites collectively named specialized pro-resolving mediators (SPMs). Therefore, combining B vitamins and omega-3s might reduce CVD risk via a cumulative reduction in proinflammatory cytokines, homocysteine levels, inflammation, and oxidative stress.
Understanding Study limitations
It’s important to understand some of the limitations in the research presented when considering the results of this review. The authors pointed out how the methods of nutrient supplementation differed among the studies. This review included supplementation in the form of capsules, enriched baked products, emulsified preparations, and enriched milk with different dosages, intervention duration, and combinations of the nutrients of concern. It can be hard to compare studies with different methods, amounts, treatment times, and nutrient delivery combinations.
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Next, there was a lack of randomized and placebo-controlled groups in some of the trials. Therefore, the “placebo effect” could not be ruled out, and an interaction effect could not be determined. Additionally, most of the participants with CVD in the studies also received up-to-date pharmacological treatments, which could mask the potential effects of nutrient supplementation on CVD outcomes. All that to say, the research should not stop here. It is difficult to draw definitive conclusions based on the current literature and the differences in methods and study design. More well-designed, high-quality trials are needed.
Conclusions
This review found that combined supplementation with B vitamins and omega-3s may be more effective at reducing plasma homocysteine, triglyceride, and LDL cholesterol levels than either supplement alone. However, there is no evidence at this time to conclude that joint supplementation can offer synergistic effects on preventing CVD and decreasing the relevant morbidity in susceptible populations. Finally, the authors suggest that focusing on healthy dietary patterns rather than individual nutrient supplementation will likely be more helpful in preventing or treating CVD in clinical practice. But the synergistic effects of omega-3s and B vitamins cannot be ruled out. Whether you are receiving your omega-3s and B vitamins from food or supplements, regular testing of your blood levels can help guide your intake to ensure you’re meeting your individual needs.
