Heart disease continues to be the leading cause of death in the United States; responsible for 26% of all American deaths in 2006.1 Aspirin is a medication often taken by individuals wishing to reduce their risk for heart disease. Unfortunately, prolonged aspirin use has an increased risk for side effects. A safer substitute for aspirin may be supplementation with omega-3 fatty acids in the form of fish oil. Intake of omega-3 fatty acids are proven to reduce inflammatory markers, lower triglycerides, provide minimal reduction in systolic blood pressure along with increasing beneficial HDL cholesterol. As omega-3 fatty acids exert cardio-protective effects similar to aspirin while promoting additional cardiovascular benefits with minimal side effects, increasing omega-3 intake at an early age may decrease the long term risks associated with cardiovascular disease.
Aspirin was discovered in the mid 1800's but was not marketed and sold in tablet form until 1915. As the first pain medication widely distributed, its popularity paved the way for years of future research. Although aspirin was originally marketed for pain relief, it was found that aspirin had a wide range of effects on the human body. Today aspirin is used to relieve pain, lower fever, decrease inflammation and inactivate platelets resulting in reduced clotting. Multiple organizations ranging from the American Heart Association to the U.S. Preventative Services Task Force (USPSTF) recommend daily aspirin use by individuals deemed to be at high risk for heart disease.2,3 Numerous studies have shown that aspirin can decrease the chances of a cardiovascular event. Although daily aspirin use is deemed cardio-protective, the chances of side effects ranging from nausea and upset stomach to allergic reactions and gastrointestinal bleeding increase with each year of continuous use. The USPSTF recommends that daily aspirin should not be started until age 45 due to the increased risk of side effects.3 Unfortunately, cardiovascular disease begins in childhood as autopsy results have shown evidence of heart disease in individuals as young as 15 years old.4 Since heart disease begins at such an early age, the American Heart Association recommends assessing the cardiovascular risks for individuals starting at 20 years old, along with making recommendations relating to risk modification.
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Omega-3 Fatty Acids
A healthy diet plays an essential role in decreasing the chances of developing cardiovascular disease. An association with the consumption of seafood and a decreased risk of heart disease was suggested upon determining the composition of foods eaten by Eskimos in Greenland in the 1970's.5,6 Fatty fish contain eicosapentaenoic (EPA) and docosahexaenoic (DHA) omega-3 fatty acids which provide the cardiovascular protection. EPA and DHA fatty acids can be introduced into the body by eating fatty fish several times per week or with daily intake of a fish oil supplement with similar results.7 Flaxseed oil is high in α-linolenic acid (ALA), a precursor to omega-3 fatty acids. Supplementation with flaxseed oil can be used as a vegetable source for increasing levels of omega-3 fatty acids in the blood plasma.8,9 The effectiveness of this conversion depends on the availability of the of the enzyme δ-6-desaturase (Figure 1)10. As δ-6-desaturase has an affinity for linoleic acid (LA), diets high in saturated oils will reduce the likelihood that ALA will be converted into EPA and DHA.11 As EPA is a precursor to DHA, supplementation of EPA only will also result in increased plasma levels of DHA. Supplementation of DHA only will result in increased plasma levels of EPA, although the pathway for this conversion is not fully understood.11
Prevention of Heart Disease
High LDL cholesterol and triglyceride levels along with elevated blood pressure and increased levels of inflammatory markers are known to increase the risk of cardiovascular disease. Primary prevention refers to the actual prevention of a disease process while secondary prevention relates to the modification of risk factors to minimize the likelihood of disease. Primary prevention of cardiovascular disease would include healthy eating, exercise and avoidance of smoking. The addition of aspirin assists in primary cardiovascular prevention by decreasing the tendency of blood to clot through platelet inactivation and reduction of inflammation and the resultant vessel damage. Most heart disease is due to narrowing of the arteries through plaque deposition, and the addition of aspirin may reduce the amount of plaque. A study by Gurbel et al. found that the larger the daily dose of aspirin, the quicker the onset of protection.12 Unfortunately as many as 35% of the population may be aspirin resistant and are unable to benefit from aspirin's cardiovascular protection no matter the dose.12 A recent study conducted in Turkey found that aspirin resistance increased in people suffering from metabolic syndrome. The prevalence of aspirin resistance was 46.9 percent in the metabolic syndrome group and only 20 percent in the control group.13 It was also found that the strongest correlation to aspirin resistance was elevated fasting blood glucose.13 As fasting blood glucose increases, platelets activate due to tissue damage from elevated glucose.13 Although supplementation with fish oil has been deemed secondary prevention of heart disease, people that are unable to take aspirin due to young age, side effects, or aspirin resistance are the most likely to benefit from increased omega-3 intake.
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It was recently determined that omega-3 fatty exert antiplatelet effects similar to those of aspirin although the exact mechanisms have yet to be determined. While aspirin works by blocking the production of thromboxane A-2 through inhibition of cyclo-oxygenase-1, it is thought that Resolvin E1 (an EPA derived molecule) stops platelet aggregation through interaction with thromboxane receptors.14 By interacting directly with the thromboxane receptors rather than effecting cyclo-oxygenase-1, Resolvin E1 results in a similar antiplatelet effect to aspirin with a decreased risk of ulcer formation and gastrointestinal bleeding.14 Another study found that diets containing large amounts of DHA decreased the amount of factor VII available for initiation of the clotting cascade, further reducing the likelihood of clotting.15 It is interesting to note that omega-3 fatty acids provide an antiplatelet effect through two distinct mechanisms without significantly prolonging the bleeding time unlike aspirin.16 In fact, fish oil supplements tend to be well tolerated even at high doses with minimal side effects.
The ratio between omega-6 and omega-3 fatty acids consumed may play a role in the cardio-protective effects of fish oil. Common sources of omega-6 fatty acids include vegetable and seed oils along with chicken and eggs. A 3:1 ratio of omega-6 to omega-3 fatty acids provides the best protection against cardiovascular disease.15,17 It is estimated that the average American diet results in an intake closer to a 10:1 ratio of omega-6 to omega-3 fatty acids.18 As the ratio increases, inflammatory markers are released causing damage to cell walls and stimulate platelet coagulation.17 It was found that supplementation with less than 3 grams of fish oil a day could assist in bringing the omega-6 to omega-3 ratio back to the ideal 3:1 ratio.18 EPA delays the ability of neutrophils to migrate across epithelial tissue by altering the required prostaglandin signal thereby decreasing degranulation and the resultant inflammation.19 The neutrophils are not inactivated; rather a stronger inflammatory signal is required for neutrophil migration across the epithelial tissue to take place.19
Inflammation plays a crucial role in healing the body after injury. If the inflammation becomes chronic, inflammatory chemicals continue to be released which may increase the amount of plaque buildup in the vessels near the site of injury. Once the plaque has begun to develop, continued amounts of inflammation may lead to plaque rupture and clot formation. People with cardiovascular disease have an elevated C-reactive protein (CRP) level which a commonly measured inflammatory marker.17 It has been found that daily aspirin use can limit the amount of CRP circulating in the blood.19 Omega-3 fatty acids have not been shown to decrease CRP, although omega-3 fatty acids reduce inflammation through other mechanisms while providing plaque stabilization.20 It is suggested that fish oil supplementation may decrease inflammation by altering the way the immune cells respond to inflammation.21,22 A study by Massaro et al. determined that the presence of DHA decreased the enzymatic activity of COX 2 decreasing the amount of inflammation present.23
The ideal 3:1 ratio of omega-6 to omega-3 fatty acids assists in regulation of triglycerides.24 Triglycerides are one of the most common form of fat in the human body as they are found in the normal diet and can be synthesized from excess dietary calories. Once triglycerides are in the blood stream, they circulate until used for energy production or absorbed by adipose tissue for storage. Triglycerides are essential for normal cellular functioning but elevation above recommended levels increases the risk of developing heart disease. The American Heart Association recommends keeping triglyceride levels below 150 mg/dL in healthy individuals.25 Ingesting 1000 mg of DHA each day for six weeks can result in a 21 percent reduction in triglyceride levels.25 The effectiveness of supplementation with omega-3 fatty acids on triglyceride levels is dose-dependent, as increasing levels of omega-3 fatty acids are ingested, the lower the triglyceride levels will fall.24 Interestingly, individuals with the highest triglyceride levels had the greatest response to the fish oil.24 As omega-3 fatty acids provide such a profound triglyceride lowering effect, pharmaceutical companies have begun marketing prescription medications with omega-3 fatty acids as the active ingredient.
Altering Cholesterol Profile
Elevated cholesterol is considered a significant risk factor for cardiovascular disease. Low density lipoprotein (LDL) and high density lipoprotein (HDL) are the two forms of cholesterol commonly evaluated in the determination of risk for cardiovascular disease. It is generally accepted that low LDL and high HDL levels reduce the risk of cardiovascular disease. Omega-3 fatty acids are shown to raise the HDL cholesterol in individuals with low HDL levels by 7.1 percent.26 The effect on LDL cholesterol has been less pronounced with a few studies concluding that fish oil supplementation may actually raise LDL levels by as much as 10%.27 Direct measurement of blood LDL levels is difficult, therefore LDL levels are calculated using the Friedewald equation. The Friedewald equation is defined as:
LDL Cholesterol = Total Cholesterol - (HDL Cholesterol + 1/5 Triglycerides)
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The Friedewald formula provides an estimate of fasting LDL levels but becomes less accurate as measured triglyceride levels increase.28,29 As omega-3 fatty acids have the ability to dramatically lower triglyceride levels and slightly increase HDL levels, measured LDL levels may falsely appear to increase as the initial LDL levels may have been calculated inaccurately.26,27,28
Blood Pressure Effects
Hypertension or elevated blood pressure is a component of cardiovascular disease. It is estimated that more than 25% of the American population currently suffers from hypertension. The incidence increases as we age and a vast majority of the cases have no known cause. Hypertension is a significant risk factor for cardiovascular morbidity and mortality worldwide. Treatment options for hypertension include lifestyle modification and medication. While lifestyle modification usually is the initial approach to treatment, medications should not be withheld indefinitely. Blood pressure is recorded as the systolic/diastolic pressure. The systolic pressure is the maximal amount of pressure within the arteries when the heart is actively contracting, while the diastolic pressure is the pressure in the arteries when the heart is relaxed. The addition of omega-3 fatty acids has been shown to decrease diastolic blood pressure by two - five mmHg.30 It has been suggested that a small increase in blood pressure for about 30 minutes may occur following ingestion of aspirin when taken in the morning. One study actually found a 7 mmHg decrease in systolic pressure when the aspirin is taken at night.31 Although no clear evidence supports the use of aspirin for blood pressure control, it has been suggested that aspirin should not be used in patients whom hypertension is their only risk factor due to the increased possibility of bleeding.
Studies have suggested that omega-3 fatty acids have a direct effect on arrhythmias. Premature ventricular contractions (PVC) may be significantly decreased with the addition of fish oil supplementation by reducing the excitability of damaged tissue.32 Often tissue that is damaged due to a lack of blood flow changes its electrical properties resulting in multiple random electrical signals. It is these random electrical signals that are responsible for a large number of arrhythmias. Fish oil supplementation has been found to decrease the heart beat by more than 2 beats per minute and may assist in the reduction of arrhythmia through decreased oxygen consumption.30,32,33
Both aspirin and fish oil are effective at lowering the risks associated with cardiovascular disease. Both fish oil and aspirin work by different mechanisms for their effects. It is suggested that the risk of bleeding does not increase when both are taken together.15 Additional research should be conducted to determine proper dosing of aspirin and fish oil supplements for the greatest health benefits.
As there are multiple ways to incorporate omerga-3 fatty acids into one's diet, the decision over which method of supplementation may be difficult. While the American Heart Association recommends eating whole fish over fish oil supplements, numerous warnings have surfaced over mercury and other heavy metal contamination of fresh fish.25 Surprisingly, fish oil supplements have been found to be virtually free of heavy metals as the heavy metals have an affinity for proteins and the harvested oil is free of protein.7 As supplement manufacturers are not regulated by the FDA, it is always possible that contaminates could be introduced in the manufacturing process. As the supplement companies are responsible for properly labeling their product, it is possible that the listed ingredients may not be correct. Fish oil supplements should be made by a respected brand and the product should bear the USP seal or the GMP stamp. The USP seal and the GMP stamp signify that the fish oil supplement is labeled appropriately and of exceptional quality. These same standards are followed by pharmaceutical companies to ensure product safety and efficacy.
Commonly reported side effects from supplementation with fish oil include a fishy aftertaste, nausea, and diarrhea. Interestingly, anecdotal reports have stated that keeping the fish oil capsules in the freezer may reduce the likelihood of side effects. No studies to date have looked at whether freezing the fish oil alters the effectiveness of the EPA and DHA fatty acids. It is known that light and moisture can cause the oil to become rancid. As the oil becomes rancid, increased numbers of free radicals are developed which may degrade the EPA and DHA and make supplementation less effective.
As aspirin has been shown to provide cardio-protective effects, yet has a significant potential for side effects, emphasis should be placed on omega-3 fatty acid supplementation prior to age 45. By providing the ideal 3:1 ratio of omega-6 to omega-3 fatty acids at an early age allows for the potential of delaying aspirin treatment until later in life. As people continue to live longer, aspirin treatment should be used sparingly for those that will receive the greatest benefit while increased fish oil intake should be recommended prior to cardiovascular disease symptoms are present.