January 2013

Omega-3s and cardiovascular disease: the heart of the matter

Are omega-3 polyunsaturated fatty acids derived from food sources other than fish as effective as the ones that are derived from fish? In a recent review in the Journal of Lipid Research, researchers from Oregon State University set out to assess the scientific data we have available to answer that question.

The review article by Donald B. Jump, Christopher M. Depner and Sasmita Tripathy was part of a thematic series geared toward identifying new lipid and lipoprotein targets for the treatment of cardiometabolic diseases.

Interest in the health benefits of omega-3 PUFA stemmed from epidemiological studies on Greenland Inuits in the 1970s that linked reduced rates of myocardial infarction (compared with rates among Western populations) to a high dietary intake of fish-derived omega-3 PUFA. Those studies have spurred hundreds of others attempting to unravel the effects of omega-3 PUFA on cardiovascular disease and its risk factors.

The omega-3 polyunsaturated fatty acid conversion pathway
The omega-3 polyunsaturated fatty acid (PUFA) conversion pathway.

Omega-3 in the diet
Fish-derived sources of omega-3 PUFA are eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid. These fatty acids can be found in nutritional supplements and foods such as salmon, anchovies and sardines.

Plant-derived sources of omega-3 PUFA are alpha-linolenic acid and stearidonic acid. Alpha-linolenic acid is an essential fatty acid. It cannot be synthesized in the body, so it is necessary to get it from dietary sources, such as flaxseed, walnuts, canola oil and chia seeds. The overall levels of fatty acids in the heart and blood are dependent on the metabolism of alpha-linolenic acid in addition to other dietary sources.

The heart of the matter
A study in 2007 established that dietary supplementation of alpha-linolenic acid had no effect on myocardial levels of eicosapentaenoic acid or docosahexaenoic acid, and it did not significantly increase their content in cardiac muscle (3). Furthermore, alpha-linolenic acid intake had no protective association with the incidence of coronary heart disease, heart failure, atrial fibrillation or sudden cardiac death (4, 5, 6). In general, it did not significantly affect the omega-3 index, an indicator of cardioprotection (3).

Why doesn’t supplementation of ALA affect the levels of fatty acids downstream in the biochemical pathway (see figure)? The data seem to point to the poor conversion of the precursor ALA to DHA, the end product of the omega-3 PUFA pathway.

DHA is assimilated into cellular membrane phospholipids and is also converted to bioactive fatty acids that affect several signaling mechanisms that control cardiac and vascular function. According to Jump, “One of the issues with ALA is that it doesn’t get processed very well to DHA.” This is a metabolic problem that involves the initial desaturation step in the pathway, which is catalyzed by the fatty acid desaturase FADS2.

Investigators have explored ways to overcome the metabolic bottleneck created by this rate-limiting step.

One approach involves increasing stearidonic acid in the diet, Jump says, because FADS2 converts ALA to SDA. While studies have shown that increasing SDA results in significantly higher levels of downstream EPA and DPA in blood phospholipids, blood levels of DHA were not increased (7).

FADS2 also is required for DHA synthesis at the other end of the pathway, where it helps produce a DHA precursor.

Consumption of EPA and DHA from fish-derived oil has been reported to increase atrial and ventricular EPA and DHA in membrane phospholipids (3), and heart disease patients who consumed EPA and DHA supplements had a reduction in coronary artery disease and sudden cardiac death (8).

“Based on the prospective cohort studies and the clinical studies,” Jump says, “ALA is not viewed as that cardioprotective.”

He continues, “It is generally viewed that EPA and DHA confer cardioprotection. Consumption of EPA and DHA are recommended for the prevention of cardiovascular diseases. The question then comes up from a metabolic perspective: Can these other sources of omega-3 PUFA, like ALA, be converted to DHA? Yes, they can, but they’re not as effective as taking an EPA- or DHA-containing supplement or eating fish containing EPA and DHA.” (Nonfish sources of EPA from yeast and DHA from algae are commercially available.)

It’s important to note that omega-3 PUFAs are involved in a variety of biological processes, including cognitive function, visual acuity and cancer prevention. The molecular and biochemical bases for their effects on those systems are complex and not well understood.

“These are very busy molecules; they do a lot,” Jump says. “They regulate many different pathways, and that is a problem in trying to sort out the diverse actions these fatty acids have on cells. Even the area of heart function is not fully resolved. While there is a reasonable understanding of the impact of these fatty acids on inflammation, how omega-3 fatty acids control cardiomyocyte contraction and energy metabolism is not well understood. As such, more research is needed.”

Elucidating the role of omega-3s in the heart: the next step
At the University of Maryland, Baltimore, a team led by William Stanley has made strides toward elucidating the role of PUFAs in heart failure.

Stanley’s research group focuses on the role of substrate metabolism and diet in the pathophysiology of heart failure and recently identified the mitochondrial permeability transition pore as a target for omega-3 PUFA regulation (9). The group is very interested in using omega-3 PUFAs to treat heart failure patients who typically have a high inflammatory state and mitochondrial dysfunction in the heart.

“It seems to be that DHA is really the one that is effective at generating resistance to stress-induced mitochondrial pore opening,” which is implicated in ischemic injury and heart failure (10), Stanley says. “It also seems to be that you’ve got to get the DHA in the membranes. You have to ingest it. That’s the bottom line.”

Stanley points out that ingesting DHA in a capsule form makes major diet changes unnecessary: “You can just take three or four capsules a day, and it can have major effects on the composition of cardiac membranes and may improve pump function and ultimately quality of life in these people. The idea would be that they would live longer or just live better.”

The impact and implications of omega-3 in the food industry
The big interest in DHA over the past 30 years has come from the field of pediatrics. Algae-derived DHA often is incorporated into baby formula for breastfeeding mothers who do not eat fish or for those that do not breastfeed at all. “In clinical studies, you see that the visual acuity and mental alertness of the babies are better when they’re fed DHA-enriched formula over the standard formula,” says Stanley.

Stanley continues: “The current evidence in terms of vegetable-derived omega-3s may be of particular value in developing countries where supplements for DHA (fish oil capsules) or access to high-quality fish may not be readily accessible.”

Food manufacturers in developing countries are beginning to shift to plant-derived omega-3 PUFAs, which are relatively cheap and widely available. Despite those moves, the effects may be limited by the inefficient biochemical processing of the fatty acid — an issue that researchers have yet to resolve.

  1.   1. Dyerberg, J. et al. Am. J. Clin. Nutr. 28, 958 – 966 (1975).
  2.   2. Dyerberg, J. et al. Lancet. 2, 117 – 119 (1978).
  3.   3. Metcalf, R. G. et al. Am. J. Clin. Nutr. 85, 1222 – 1228 (2007).
  4.   4. de Goede, J. et al. PLoS ONE. 6, e17967 (2011).
  5.   5. Zhao, G., et al. J. Nutr. 134, 2991 – 2997 (2004).
  6.   6. Dewell, A. et al. J. Nutr. 141, 2166 – 2171 (2011).
  7.   7. James, M. et al. J. Clin. Nutr. 77, 1140 – 1145 (2003).
  8.   8. Dewell, A. et al. J. Nutr. 141, 2166 – 2171 (2011).
  9.   9. GISSI-Prevenzione Investigators. Lancet. 354, 447 – 455 (1999).
  10. 10. Khairallah, R. J. et al. Biochim. Biophys. Acta. 1797, 1555 – 1562 (2010).
  11. 11. O’Shea, K. M. et al. J. Mol. Cell. Cardiol. 47, 819 – 827 (2010).

Shannadora HollisShannadora Hollis (sholl002@umaryland.edu) received her B.S. in chemical engineering from North Carolina State University and is a Ph.D. student in the molecular medicine program at the University of Maryland, Baltimore. Her research focuses on the molecular mechanisms that control salt balance and blood pressure in health and disease. She is a native of Washington, D.C., and in her spare time enjoys cooking, thrift-store shopping and painting.

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