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. 2012 May-Jun;109(3):204–209.

Nutritional and Vitamin Supplements: Do They Prevent Coronary Artery Disease?

Craig William Raphael 1, Darcy Green Conaway 2,✉
PMCID: PMC6179702  PMID: 22860288

Abstract

This article will review background information and data supporting the use of fish oil, folic acid, coenzyme Q, and vitamins C, D, and E in the prevention and/or treatment of coronary artery disease.

Introduction

Numerous nutritional or vitamin supplements have been proposed as having beneficial effects on reducing coronary artery disease. This article will review background information and data supporting the use of fish oil, folic acid, coenzyme Q, and vitamins C, D, and E in the prevention and/or treatment of coronary artery disease (CAD).

Fish Oil

In 1969, it was observed that the Greenland Inuit and Okinawa Islanders had low risks of death from coronary artery disease (CAD) and it was postulated that their lowered risk was related to the abundant fish in their diet.1,2 This finding stimulated research into whether fish oils could be used to prevent CAD.

Fish oils are rich sources of long chain fatty acids called “essential” fatty acids that can only be obtained through diet or supplementation. Fish oils are interchangeably referred to as omega-3 fatty acids or n-3 polyunsaturated fatty acids (n-3 PUFAs). Three important n-3 PUFAs include eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha linoleic acid (ALA).3 EPA and DHA are synthesized by fresh water algae. Fish consume the algae, and man subsequently consumes fish as part of the food chain.3,4 ALA is not obtained from fish, but is found in flaxseed, walnuts, and other tree nuts.4 Humans convert ingested ALA to EPA and DHA, but the enzymatic pathways cannot produce enough EPA and DHA to sustain good health.2

When taken as supplements, EPA and DHA may reduce heart failure, whereas evidence regarding ALA is substantially weaker.4 It is proposed that low dose of n-3PUFAs (0.5–1g/day) decreases the incidence of sudden cardiac death.4 At higher doses (3–4g/day), n-3PUFAs can reduce triglyceride synthesis in the liver.3,4 Fish oils possess antiatherosclerotic, antiarrhythmic, and antithrombotic effects.1,4 The n-3 PUFAs incorporate within atherosclerotic plaques and stabilize plaque morphology, manifested histologically by reduced macrophages and foam cells. The n-3 PUFAs competitively inhibit arachidonic acid, decreasing synthesis of classical pro-inflammatory eicosanoids. They also suppress the pro-inflammatory cytokines IL-6, IL-1β, and TNFα.1,3,4,5 In addition, n-3 PUFAs stimulate synthesis of other eicosanoids called E-series and D-series resolvins that suppress pro-inflammatory effects of activated neutrophils, macrophages, dendritic cells and T cells.1,4,5 These anti-inflammatory effects may collectively suppress the development of CAD.

The sudden cardiac death that follows a myocardial infarction (MI) or heart surgery may involve generation of ventricular arrhythmias. The n-3 PUFAs exert several antiarrhythmic properties, including profound inhibition of sodium channels, and modulation of potassium channels, L-type calcium channels, sodium calcium exchanger proteins, and calcium handling proteins.1 The net effect is a shift in electrical potential across cell membranes, reducing the generation of action potentials.1 With acute injury, cardiomyocytes partially depolarize and lower this threshold for generating action potentials and arrhythmias. By producing a voltage dependent shift towards membrane hyperpolarization, fish oils inhibit the generation of arrhythmogenic action potentials.2 In a study of patients undergoing coronary artery surgery, post operative atrial fibrillation occurred in 33.3% of placebo-treated patients, but in only 15.2% of patients pre-treated with EPA and DHA.4 However, Kowey et al. treated 663 patients with paroxysmal atrial fibrillation or persistent atrial fibrillation with high dose (4g/day) EPA/DHA for six months and found no reduction in the subsequent development of symptomatic atrial fibrillation.6

In terms of anti-thrombotic effect, n-3 PUFAs reduce synthesis of thromboxane A2, decreasing the ability of platelets to aggregate and form blood clots.1 In addition, n-3 PUFAs produce a modest reduction in blood pressure through increased synthesis of the vasodilator nitric oxide.1 Several randomized clinical trials have demonstrated benefits of fish oil on CAD. The Diet and Reinfarction Trial (DART) in 1989 examined the cardiovascular (CV) benefit of supplementing the diet with fish twice a week in post-MI patients. Adding fish to the diet resulted in a 29% reduction in CV-related mortality.1,3,4 The GISSI-Prevenzione trial in 1999 monitored CV events (MI, unstable angina, sudden cardiac death, cardiac intervention, and/or stroke) in patients treated with 1 g/day of n-3PUFAs. After 3.5 years, there was a 45% reduction in sudden death and a 20% reduction in all-cause mortality.3 In another large study, the Japan EPA Lipid Intervention Study (JELIS), patients with hypercholesterolemia with or without pre-existing CAD decreased their risk of major CV events by 18% after taking 1.8 g of EPA daily.1,4 In contrast, Rauch et al. in 2010 treated 3551 post-MI patients with 1g/day of n-3 PUFAs plus state-of-the-art post-MI medical therapy for one year. Fish oil supplementation added no benefit regarding sudden cardiac death compared to standard post-MI treatment alone.7 In a similar trial of 4,837 post-MI patients treated with low dose fish oil for 40 months, Kromhout et al. found no benefit from adding fish oil to standard post-MI treatment.8

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Serum levels of homocysteine (Hcy) are controlled by folic acid (or Folate), a B vitamin that serves as a cofactor in the metabolism of Hcy to methionine.

Although results from clinical trials on fish oil supplementation have been controversial regarding prevention of CAD, the American Heart Association recommends consuming 1 serving of fatty fish or 1g of EPA/DHA-containing supplements twice a week for good cardiovascular health. For hypertriglyceridemia, 4g/day is currently recommended.3

Folic Acid

Dr. Kilmer McCully noted in 1969 that patients with the rare genetic disorder homocysteinuria had high levels of plasma homocysteine (Hcy) and a high incidence of MIs. 9,10 Others have noted that one-third of patients with atherosclerosis have elevated Hcy levels.11 When elevated 12% above normal, Hcy is associated with a three-fold increased risk of acute MIs. 11 In long term observational studies, high Hcy levels were found in patients with stroke, and low levels were associated with a reduced incidence of CAD and stroke. 9 In an ethnic population with a genetic defect that impairs Hcy metabolism, patients have very high levels of Hcy and increased risks of CAD.10 These observations led to the hypothesis that Hcy may be an independent risk factor for CAD and stroke, and may cause early manifestations of atherosclerosis. 11,12 At high levels, Hcy increases oxidative stress by increasing hydrogen peroxide production through increased oxidation of low-density lipoproteins (LDLs), thereby damaging endothelium and increasing the risk of thrombosis.9,12,13

Serum levels of Hcy are controlled by folic acid (or folate), a B vitamin cofactor for the metabolism of Hcy to methionine. Folate is obtained from consuming leafy green vegetables, fruits, legumes and ready to eat cereals. 14 Folate supplementation with 0.5–5mg/day has been shown to lower plasma Hcy by about 25%.12,13 The Nor wegian Vitamin Trial (NORVIT) in 2006 evaluated the efficacy of lowering Hcy levels with vitamin B supplements and monitored CV events in post MI patients.12 Patients received folate, vitamin B12, vitamin B6, or any combination of the three. Despite decreases in Hcy, treatment with these B vitamins during this 3.5 year trial failed to decrease the risk of CV events. In fact, there was a trend towards increasing CV events when patients took all three B vitamins together.12 The Heart Outcomes Prevention Evaluation (HOPE 2) study in 2006 looked at similar parameters, also failing to show CV improvement by lowering Hcy levels. 13

The two-year Vitamin Intervention in Stroke Prevention (VISP) study in 2004 examined whether folate, B6, and B12 would reduce the incidence of recurrent cerebral infarction in patients with CAD. Although treatment moderately reduced Hcy, high dose vitamin B therapy did not affect development of stroke, CAD, or death. The authors proposed that Hcy may be a marker for CV disease, without directly impacting the risk of CV disease.9 Mager et al. in 2009 also studied folate supplementation in patients with CAD and elevated Hcy levels. Unlike previous studies, folate reduced long term mortality from CAD. The authors proposed that this ten year trial allowed subtle improvements in CAD to become evident, changes not seen in shorter studies. In addition, patients with diseases associated with hyperhomocysteinemia (e.g. renal insufficiency, hypothyroidism) were excluded to avoid confounding the results. Finally, baseline Hcy levels in this study were 57% higher than those in the HOPE 2 study, and 47% higher than those in the NORVIT study, suggesting that patients in this trial had more significant CAD initially that could improve more dramatically after folate treatment. 10

Two important trials examined the effect of folate on peripheral vascular endothelial function in patients with CAD. Chambers et al. in 2000 measured brachial artery flow–mediated dilatation (FMD) in CAD patients before and eight weeks after daily treatment with folate and vitamin B12. These vitamins significantly increased brachial artery FMD. Furthermore, there was an inverse relationship between FMD and Hcy, suggesting that these vitamins may improve endothelial function by decreasing Hcy.11 In a similar study in 2002, Doshi et al. examined the effect of six weeks of high dose folate supplementation on brachial artery FMD.14 The treatment group’s FMD was decreased at baseline. After the initial folate dose, FMD increased markedly at two and four hours, with no additional improvement after six weeks of treatment. Similarly, plasma folate increased rapidly, stayed elevated for four hours, and remained at this level six weeks later. However, Hcy did not decrease during the first four hours, but decreased dramatically after six weeks of folate therapy. Thus, endothelial function, as measured by FMD, improved rapidly after folate treatment, before any reduction in Hcy occurred. No correlation was found between FMD improvement and Hcy reduction. These authors concluded that the majority of improvement in endothelial function may be a direct pharmacological action of folate rather than a reduction in Hcy. 14

Research studies suggesting folate supplementation to improve CAD have published conflicting results, and a proposed mechanism of action remains undefined. The American Heart Association has no specific recommendation about folate supplementation, but simply advises eating a healthy diet containing 400mcg of folate per day.

Coenzyme Q

Coenzyme Q (CoQ) is another dietary supplement sometimes used to treat patients with heart failure and heart attacks. CoQ is a fat soluble vitamin-like substance that is structurally similar to vitamins E and K. CoQ has a widespread presence throughout the body. CoQ serves as an essential cofactor in the production of ATP through oxidative phosphorylation of lipoproteins in mitochondria and cell membranes. The highest concentration of CoQ exists in the heart, liver, and kidney, organs that require high amounts of energy. 15

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CoenzymeQ (CoQ) is available from many manufacturers in supplement form.

The electron transport system produces reactive oxygen species through several pathways, and CoQ is an integral component of this process.16 Oxidative metabolism of LDLs is involved in the pathogenesis of atherosclerosis, and CoQ protects against atherogenesis by inhibiting excessive lipid peroxidation. 17 LDL is a complex containing large molecular weight proteins, lipids, and hydrophobic antioxidants such as CoQ and vitamin E. Lipid peroxidation of LDL begins at the luminal surface, then propagates down to the lipophilic core where CoQ exists, generating reactive molecules that damage the arterial wall. Uninhibited oxidative processes destabilize arterial plaques, possibly leading to an embolism or stroke. CoQ may decrease inflammation by inhibiting LDL oxidation at this core level, stabilizing the atheroma. The balance between pro-oxidant molecules and antioxidant defenses (CoQ and vitamin E) appears critical in determining the extent of arterial wall damage by this oxidative process.

Yalcin et al. in 2004 examined the plasma CoQ levels in patients with CAD and found significantly lower levels than in healthy controls.17 In another study, Kizhakekuttu et al. noted low levels of CoQ in older patients with CAD and hypertension (HTN).16 However, no causal relationship between CoQ and CAD was determined by these studies. 16,17 In addition, it has been shown that statin-type medications competitively inhibit biosynthesis of CoQ, thereby reducing CoQ levels and permitting increased oxidative damage within atherosclerotic plaques.15,18 Thus, for patients who take statin-type medications and have lipid abnormalities and atherosclerosis, it may be beneficial to take CoQ supplements to reduce their risk of oxidative damage within blood vessels. 15

The potential benefit of administering supplemental CoQ was studied by Singh et al. in 1998 and 2003 when they evaluated CV events occurring in patients after an acute MI.15 After one year, cardiac deaths, nonfatal MIs, and strokes were significantly lower in the CoQ treated group. The authors proposed that CoQ may reduce cardiac events by protecting the heart against thrombosis, improving endothelial function, and decreasing oxidative damage.15 Gundling in 1999 examined stable angina patients who performed exercise treadmill tests with and without CoQ treatment. Treatment with CoQ improved exercise time and prolonged the time it took to develop ST segment depression, suggesting that CoQ improved cardiac performance.19 Chello et al. (1994) pretreated patients undergoing bypass surgery and found that CoQ reduced the incidence of ventricular arrhythmias and decreased post-surgical cardiac enzymes, suggesting that CoQ partially protected the heart from damage following surgery. 20 Nevertheless, there is a paucity of data that convincingly demonstrates that CoQ directly impacts the risk of CAD, and therefore CoQ should not be considered a standard of care in treating patients with CAD.

Vitamin C

It is known that a diet enriched with vitamin C containing fruits and vegetables may lower the risk of CAD. Vitamin C and other antioxidants may reduce CAD by trapping free radicals and consequently preventing tissue damage within blood vessels. 21

Unfortunately, few clinical trials have examined vitamin C alone as a potential treatment for CAD. Prior to 2007, studies utilized vitamin cocktails containing vitamin C to treat the patients. These trials generally failed to find a CV benefit of these vitamin cocktails. 21 However, one large meta-analysis pooled data from nine trials and found that vitamin C supplementation at 700 mg/day was associated with a 25% reduction in CAD risk.21

The Physicians’ Health Study II in 2007 examined the effect of 14, 641 healthy physicians supplemented with 500 mg of vitamin C. Vitamin C had no effect on the development of MIs, CV mortality, or hemorrhagic stroke during this eight-year study. 21 Similar results were shown by Losonczy et al. in 1996, 22 and by the Women’s Antioxidant Cardiovascular study in 2007. 23 In 2002, Kurl et al. examined vitamin C levels and the development of stroke and hypertension in 2,419 healthy middle-age men. Low vitamin C levels were associated with an increased risk of stroke. In subjects with hypertension, low vitamin C further increased the risk of stroke. 24 In contrast, Kushi et al. (1996) examined 34,486 healthy post-menopausal women over seven years and found no association of vitamin C and CAD prevention.25

As with CoQ, the relationship between vitamin C and CAD is unclear and needs further investigation before recommendations can be made regarding taking vitamin C to prevent CAD.

Vitamin D

Vitamin D deficiency is present in 30–50% of the general population. Epidemiologic studies have suggested that poor vitamin D status is associated with poor CV outcomes in renal failure patients with CAD. In renal failure patients with CAD, severe vitamin D deficiencies led to a three to five fold increased risk of dying from sudden death or heart failure.26 In 2008, Pilz et al. also noted that low levels of vitamin D were associated with myocardial dysfunction, sudden cardiac death, and death due to heart failure.27 In 2010, Bair et al. reported that men and women with low vitamin D levels who took vitamin D supplements for one year had a reduced risk of developing CAD, heart failure, or death from heart disease. 28 In contrast, Bolland et al. in 2007 administered calcium plus vitamin D supplements to 36,282 women, irrespective of baseline vitamin D levels. After seven years, calcium supplementation with or without vitamin D supplementation was shown to increase the risk of MIs and stroke compared to subjects not taking calcium.29 Thus, calcium supplementation, but not vitamin D, was seen as a potential risk to the patients’ CV health.

The Institute of Medicine currently recommends a daily intake of 400–800 IU of vitamin D for adults for good health. In light of conflicting data, no guidelines have been made regarding vitamin D and the prevention of CAD.28

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Of the vitamin and dietary supplements discussed, none have undergone adequate clinical trials to unequivocally prove that they can reduce the risk of CAD. Thus, fish oil, folic acid, CoQ, and the vitamins C, D and E all still warrant further investigation before the American Heart Association can recommend them to prevent CAD.

Vitamin E

As with CoQ, vitamin E is of interest regarding CAD because it is also found in the LDL complex. In in vitro studies, vitamin E inhibits LDL oxidation. In patients with ischemic heart disease, vitamin E levels vary inversely with the degree of CAD.21

Vitamin E is a lipophilic molecule located deep within the LDL core.30 Evidence that vitamin E functions as an antioxidant has not been compelling. Vitamin E’s antioxidant effect has been demonstrated in animal models with mild atherosclerotic disease. In human studies, however, atherosclerotic heart disease is typically more advanced, limiting the potential benefit that vitamin E treatment might offer.30

In 1993, Stampfer et al. evaluated 85,000 women and monitored vitamin E intake and CV status. Over eight years, patients with the highest vitamin E plasma levels had a 43% lower risk of developing CAD compared to patients with normal levels. 30 Rim et al. in 1993 evaluated the risk of CAD in 39,910 men who took vitamin E supplements and found that taking at least 100 IU per day for two years reduced their risk of CAD. 30

The Alpha – Tocopherol, Beta Carotene Cancer Prevention Trial (ATBC) in 1994 studied 29,000 male smokers treated with low dose vitamin E (50 IU/day), 20 mg of beta carotene, the combination of the two, or placebo for up to eight years. Vitamin E treatment produced no effect on the risk of CAD, but increased the risk of death from hemorrhagic stroke, presumably by impairing platelet aggregation.31 In contrast, the Cambridge Heart Antioxidant Study (CHAOS 1996) examined higher dose vitamin E treatment (400 or 800 IU/day) in CAD patients and found that vitamin E reduced their risk of MI’s and CV events by 77% and 47% respectively. 31

Once again, randomized clinical trials have not provided clear and sufficient evidence to recommend the use of vitamin E as a preventive treatment for CAD.

Conclusion

Of the vitamin and dietary supplements discussed above, none have undergone adequate clinical trials to unequivocally prove that they can reduce the risk of CAD. Thus, fish oil, folic acid, CoQ, and the vitamins C, D, and E all still warrant further investigation before the American Heart Association can recommend them to prevent CAD.

Biography

Craig William Raphael is a fifth-year medical student at the University of Missouri Kansas City School of Medicine and Darcy Green Conaway, MD, MSMA member since 2011, is an Assistant Clinical Professor and Staff Cardiologist at the University of Missouri-Kansas City School of Medicine and at Truman Medical Center in Kansas City.

Contact: conawayd@umkc.edu

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Footnotes

Disclosure

None reported.

References

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