Fish Oil and Heart Health

Lee Alcorn, Tammy Arellano Judy Chan, James Griffith, Lisa Marquand, and Long Tran
DFM 655
October 21, 2015
Complementary and Alternative Paper

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Contents
Fish Oil and Heart Health ............................................................................................................... 3
Historical Uses and Doses........................................................................................................... 3
Modern Uses and Doses.............................................................................................................. 4
Nutrition Facts............................................................................................................................. 5
Effectiveness and Efficacy .......................................................................................................... 5
Interactions and Side Effects....................................................................................................... 7
Discussion and Recommendations.............................................................................................. 8
References....................................................................................................................................... 9
Appendix....................................................................................................................................... 11

Fish Oil and Heart Health

Fish oil capsules have become a popular supplement over the last several decades,
recently achieving over one billion dollars in sales per year in the United States alone (Grey &
Bolland, 2014). Fish oil is touted to have positive effects on many health conditions, all with
varying degrees of scientific evidence; however, the most well-supported claims involve heart
and cardiovascular health (Natural Standard Research Collaboration, 2013). This is due to the
fact that oily fish (and fish oil derived from them) are high in certain types of omega-3 fatty acids
thought to aid against cardiovascular disease (United States Department of Agriculture and
United States Department of Health and Human Services, 2010). Currently, the efficacy of fish
oil supplementation on heart health is being called into question, especially by large metaanalytical studies (Rizos, Ntzani, Bika, Kostapanos, & Elisaf, 2012). Until more conclusive
research is conducted, it is important to review the history of fish oil use, further clarify its
effects on health and nutrition, and be aware of potential drug interactions or side effects.
Historical Uses and Doses
Fish oil has been used therapeutically as early as the mid-17th century for various
conditions. Rickets, described as early as 1650, was a medically-mysterious disease until the late
19th and early 20th centuries when the role of Vitamin D was discovered in bone health (Dunn,
1998). Animal experiments and folklore promoting the benefits of cod liver oil were important
elements in preventing rickets, as it was eventually discovered that the oil contained Vitamin D
(Rajakumar, 2003). Chronic rheumatism was first treated in England with cod liver oil by
physicians in 1789. Previous successful trials by Manchester Infirmary using cod liver oil led to
its popularity as the standard for treatment of chronic rheumatism (Guy, 1923).

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In 1923, Ruth A. Guy, M.D., advocated for dolphin liver oil against chronic eruptions of
the skin (skin rash). Many studies have found clinical imbalances of particular essential fatty
acids are related to dry, itchy, scaly skin, which can be an indication of deficiency of linoleic and
alpha-linolenic acid (Apostolos, 2009). Additionally, Fishermen in Scotland made butter from
the liver of codfish as a special delicacy, rather than for medicinal purposes (Guy, 1923). It
was not until the late 1970s when fish oil was thought to have a cardioprotective impact. The
Greenland-Inuit study (as reviewed by OKeefe & Harris, 2000) found lowered rates of
cardiovascular disease compared with Western trial subjects, inspiring further research into fish
oil. While it is difficult to find recorded doses for therapeutic use in historic data, some historical
research states whether fish oil was taken internally, externally, or both.
Modern Uses and Doses
Due to the increase in research into fish oil and cardiovascular disease, fish oil capsules
have become widely available. One of the most common uses of fish oil is decreasing high
triglycerides. Hypertriglyceridemia, the state of having a high triglyceride count in the blood, is
defined by having triglycerides greater than 500 mg/dL (Kris-Etherton et al. p.2753). Lovaza is
the prescription strength capsule most prescribed for patients with hypertriglyceridemia. A single
one gram capsule of Lovaza contains from 500 mg to 900 mg omega-3 fatty acids. The capsule
itself is not pure fish oil, but rather the derivatives of fish oil including a combination of ethyl
esters of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
The dietary guidelines for both fish and fish oil consumption with a focus on prevention
of cardiovascular disease vary by organization. The United States Food and Drug Administration
states that a cardioprotective dose would be 1 g/day of the combined EPA and DHA, which can
otherwise be obtained through diet alone, without supplementation (Kris-Etherton et al, p.2748).

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Nutrition Facts
For those taking fish oil, it is important to know the ingredients and sources of fish oil. It
is well known that whole fish is a good source of protein without any high saturated fat, and it
also contain good source of omega 3-fatty acids. Fish, like humans, do not produce omega-3s
themselves, but instead accumulate them from consuming marine microorganisms which contain
them, together with a high quantity of antioxidants such as iodide and selenium. Two major
omega-3 fatty acids found in fish are eicosapentaenoic acid (EPA) and docosahexaenoic acid
(DHA); both are polyunsaturated long-chain omega-3 fatty acids. Fatty fish or their fish oil
supplements are the best source to obtain EPA and DHA. Cold-water oily fish such as salmon,
herring, mackerel, anchovies, and sardines are the most widely available dietary source of EPA
and DHA. Oils from these fish have a profile of around seven times as much omega-3 oils as
omega-6 oils. Currently on the market, fish oil supplements generally contain 1,000 mg of fish
oil, but usually only 300 to 400 mg of DHA and EPA per serving. There are some supplements
available that contain up to 1,000 mg of EPA and DHA per capsule, but these are larger capsules
overall (1,200 - 1,300mg) (Roth & Harris, 2010).
Effectiveness and Efficacy
Much of the research on fish oil and cardiovascular health is focused on omega-3 fatty
acids, specifically EPA and DHA. These studies have shown that EPA and DHA can aid in the
maintenance of heart health with anti-inflammatory, anticoagulant, and antiarrhythmic
properties, as well as lowering triglycerides, improving endothelial function, and plaque
stabilization (Kromhout, Yasuda, Geleijnse, & Shimokawa, 2012).
Certain compounds made from omega-3s, such as prostaglandins, thromboxanes, and
leukotrienes (Medeiros & Wildman, 2012), produce an anti-inflammatory effect on the body -

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decreasing the risk of injury to blood vessels and plaque formation (Ellulu et al., 2015). If plaque
development has occurred, omega-3s can help stabilize the plaque, reducing the chances of it
rupturing and forming a clot. The stabilization is a result of lower macrophage infiltration of
plaque and a thicker fibrous cap covering the plaque which occurs with greater levels of EPA
and DHA in the tissues (Kromhout et al., 2012). The anti-coagulating properties of fish oil also
help to prevent the formation of blood clots. Research by Swann, Venton, and Le Breton showed
that omega-3s inhibited the synthesis of thromboxane a2 (TXA2) and had an antagonistic effect
on human platelet pro-aggregatory receptors (as cited in Kromhout et al., 2012). Thromboxanes,
TXA2 included, play a significant role in the aggregating function of platelets (Medeiros &
Wildman, 2012).
The potential antiarrhythmic effects of omega-3s may be due to effects on specific ion
channels of cardiac muscle cells (Kromhout et al., 2012). Billman, Kang, and Leaf found omega3s inhibit voltage-gated sodium channels, resulting in a longer refractory period and a greater
voltage for membrane depolarization (as cited in Kromhout et al., 2012). Omega-3s also affect
calcium channels in muscle cells causing a lowered amount of calcium in the cytosol, a key
component in the contraction of muscles, cardiac or skeletal (Kromhout et al., 2012).
In addition to the ethyl ester prescription variants already discussed, unaltered omega-3s
may also help lower high triglyceride levels, which have been linked to increased risk for heart
disease (Mayo Clinic, 2015). Omega-3s may decrease the assembly and secretion of very low
density lipoproteins and promote the breakdown of fat for energy, which leads to fewer fatty
acids available for triglyceride synthesis (Kromhout et al., 2012). Omega-3s may also improve
the function of the endothelium lining of blood vessels. EPA increases the production and release
of nitric oxide (NO) from endothelial cells, which acts to relax the endothelium, producing a

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smoother blood vessel for blood to flow (Kromhout et al., 2012). Li et al. found that DHA
altered the proteins synthesized within the cell, leading to an increase in endothelial NO
synthase, an enzyme that synthesizes NO in the human body (as cited in Kromhout et al., 2012).
NO relaxes the blood vessels and inhibits platelet aggregation and adhesion (Silverthorn, 2013).
Interactions and Side Effects
Possible major side effects of taking fish oil include increased risk of bleeding and altered
blood sugar levels (Mayo Clinic, 2013). Omega-3 fatty acids have been reported to reduce
thrombin generation when compared to a placebo control group (Gajos et al., 2011), which may
contribute to the increased risk for bleeding. Positive results of omega-3 on insulin sensitivity
have been reported in animals, but there is a lack of evidence of insulin sensitivity in humans
(Flachs, Rossmeisl, & Kopecky, 2014). Individuals taking anticoagulants, such as warfarin or
clopidogrel, or taking medications to help regulate blood glucose levels, or insulin, may be at
higher risk and should only take fish oil supplements under a physicians supervision until more
is known (Mayo Clinic, 2013). It has been suggested taking gingko biloba and fish oil
simultaneously may further increase risk of bleeding because of the potential blood-thinning
effects of each, but there is currently not much evidence to support this (Hurley, 2009). Other
side effects of fish oil include gas, bloating, belching, bad breath, diarrhea, heartburn, rash and
nosebleeds. These side effects do not typically pose serious health risks, but may cause
discomfort. While fish oil supplements are considered safe, the risk for major side effects
increases when taking high doses. Any individual considering taking fish oil supplements should
first consult their physician (Mayo Clinic, 2013).

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Discussion and Recommendations
While the hypothetical mechanisms behind the benefits of fish oil on cardiovascular health
appear sound, there is still much debate over whether they actually function as expected. The
center of the debate has been the size and potential biases present in certain famous fish oil
studies. A meta-analysis of fish oil research showing no beneficial effects was criticized for
excluding some of the largest studies supporting fish oil and only examining smaller studies
much shorter in duration (DiNicolantonio, OKeefe, & Lavie, 2012). The authors of the metaanalysis responded to this criticism by claiming that these studies, while very large, each had
poor research design - notably, the lack of placebo controls (Kwak & Myung, 2012).
Unfortunately, this line between smaller, well-controlled studies and larger, poorlycontrolled studies is where the evidence on fish oil supplementation currently balances. On the
other hand, the theories behind fish oil use tend to align with the current scientific understanding
of the cardiovascular system. Therefore, this paper generally recommends the use of fish oil
capsules when it comes to cardiovascular health, but only when suggested by a medical
professional. It is also recommended to research brands, ingredients, and dosages when
purchasing a fish oil supplement, especially as there may be a chance for drug interactions.
Finally, supplementing with fish oil capsules is likely unnecessary if already consuming fish
regularly in the diet (USDA and HHS, 2010; Visioli, Ris, Barassi, Marangoni, & Galli, 2003).

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Appendix