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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 Norwegian 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

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.

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

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.

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