Folic Acid Awareness: Heart Disease, Gene Mutations and Supplementation


Folic acid Awareness

National Folic Acid Awareness Week was observed from January 3rd – January 6th. I propose “folate” awareness and you’ll see why as you read on. Of the many micronutrients that we know about, folic acid is the only one that claims any space on the National Health Observances calendar. It’s with good reason we find folic acid on the calendar. Without adequate maternal consumption of folic acid, portions of the neural tube may fail to fuse during embryonic development. This can happen anywhere from the brain to the bottom of the spinal cord. You can think of the neural tube as the bony and soft tissue structures that surround and protect the delicate spinal cord. These neural tube defects (NTDs), with spina bifida being the most prevalent, are felt to be reduced by 50 percent with adequate folic acid intake.1 The US Public Health Service recommends that all women, capable of pregnancy take 400mcg of folic acid each day.1 The Institute of Medicine (IOM) Food and Nutrition Board’s recommended dietary allowance (RDA) for pregnant women is 600mcg.2 But the importance of proper folate status goes beyond preventing congenital anomalies such as NTDs. Folate is crucial for proper cell replication and division, prevention of a form of anemia called megaloblastic anemia, which is associated with oversized and fewer red blood cells, fatigue and shortness of breath if left untreated. My focus here is folate’s valuable role in cardiovascular health.

Cardiovascular Health and Folate

Low dietary folate intake is a known risk factor for vascular disease.3 Diets rich in folate have been linked to decreased rates of heart attacks, stroke and coronary artery disease.3 Further, a ten-year study following nearly 2,000 men found that those consuming the most dietary folate had a 55 percent reduced rate of heart attacks compared to those who consumed the least amount of folate.4 Folic acid research has shown it improves specific measurable end points. One being the thickness of the innermost lining of the vascular system. Ultrasound measurement of the carotid intima-media thickness (CIMT) is a predictor of early cardiovascular disease and cardiac events. The effect of folic acid was analyzed from ten randomized trials showing a reduction in CIMT.5 Another endpoint found improved with folic acid is endothelial function. The endothelium can be described as cells which line the vascular system. Under healthy conditions these cells are flexible enough to promote arterial dilation, proper immune regulation, and balance electrolytes within the vascular space. In the diseased state the endothelium becomes stiff and less able to dilate, is inflamed, and unable to properly control electrolytes. Not only is endothelial dysfunction characteristic of cardiovascular disease but, as so has contributed to some of the earliest changes that occur in cardiovascular disease. Folic acid in higher doses has been associated with improvements in endothelia functioning in individuals with and without cardiovascular disease.6

Forms of folate and Genetics

Folate is the umbrella term for a group of compounds having the properties of folic acid. Folic acid is the synthetic derivation used to fortify processed foods and in standard supplements. Other synthetic forms include folinic acid and levomefolic acid. The synthetic forms have no biological activity until they are converted into folates in the body. Folate is the active form that naturally occurs in foods. Folate’s synthetic counterpart is more absorbable than dietary folates but requires a two-step activation process in the body. Up to 32 percent of people in some populations have inherited a double mutation in the gene for the five, ten-methylenetetrahydrofolate reductase (MTHFR) enzyme. MTHFR is the enzyme that allows an important step in activation possible. This enzyme encourages the conversion of one biologically active form of folate to another. Both forms are critical but the second is associated with the cardiovascular benefits associated with folate. Individuals with double mutations in the MTHFR gene can have as much as a 65 percent reduction in functioning of the MTHFR enzyme. This common mutation is associated with reduced red blood cell folate levels. It is also associated with increased levels of homocysteine, the cardiovascular toxic metabolite of inappropriate metabolism of the amino acid methionine. Folate supplementation is known to reduce homocysteine in individuals with and without MTHFR mutations.8 Here is where you’ll find folate.

Getting Folate

Green leafy vegetables, salad greens, and spinach are excellent sources of folate. However, vegetables stored at room temperature lose much of their folate. Cooking them drastically lowers the amount of available folate also. Of all foods, chicken liver tops the list. Other dietary sources are brewer’s yeast, lentils, black-eyed peas, chickpeas, and citrus. Fortified grains and cereals contain variable amounts of synthetic folic acid.

Supplementing with Folate

The typical form of folate found in single nutrient and vitamin compounds is folic acid. Currently the adult RDA for folic acid is 200mcg a day. For pregnancy, or women capable of becoming pregnant, it’s 400mcg. There is concern that the RDA may not meet the daily folate requirements of individuals with MTHFR mutations. Fortunately, the active folate is increasingly found in supplement products and may serve to compensate individuals with the not-uncommon MTHFR mutation. Individuals with MTHFR mutations are ideal candidates for active folate supplementation but side effects such as anxiety, insomnia, and nausea may occur with improper dosing. Since most persons carrying the MTHFR mutation do so unwittingly, anyone who begins a folate regimen should dose low, go slow, and take it in combination with other B-vitamins to minimize side effects.

  • Pediatrics Folic Acid for the Prevention of Neural Tube Defects: August 1999, Volume 104 / issue 2
  • Institute of Medicine. Dietary reference intakes: folate, other B vitamins, and choline. In: Dietary Reference Intakes for Thiamin, Riboflavin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 1998:(8)32
  • McNeil CJ, Beattie JH, Gordon MJ, Pirie LP, Duthie SJ. Nutritional B vitamin deficiency disrupts lipid metabolism causing accumulation of proatherogenic lipoproteins in the aorta adventitia of ApoE null mice. Mol Nutr Food Res. 2012;56(7):1122-1130.  (PubMed)
  • Voutilainen S, Rissanen TH, Virtanen J, Lakka TA, Salonen JT. Low dietary folate intake is associated with an excess incidence of acute coronary events: The Kuopio Ischemic Heart Disease Risk Factor Study. Circulation. 2001;103(22):2674-2680.  (PubMed)
  • Qin X, Xu M, Zhang Y, et al. Effect of folic acid supplementation on the progression of carotid intima-media thickness: a meta-analysis of randomized controlled trials. Atherosclerosis. 2012;222(2):307-313.  (PubMed)
  • de Bree A, van Mierlo LA, Draijer R. Folic acid improves vascular reactivity in humans: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2007;86(3):610-617.  (PubMed)
  • Higdon, Jane et al. Linus Pauling Institute Micronutrient Information Center; Oregon State University, 2014 Dec. 23, 2016
  • Homocysteine Lowering Trialists’ Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr. 2005;82(4):806-812.  (PubMed)