By Kilmer McCully, M.D.
Because the B vitamins folic acid, pyridoxine ( vitamin B6 ) and cobalamin ( vitamin B12 ) are all involved in normal metabolism to prevent excessive production of homocysteine, the homocysteine theory of arteriosclerosis implicated deficiencies of these vitamins in human arteriosclerosis, heart attacks, strokes and amputations from vascular disease.
Because the sensitive vitamins folic acid and pyridoxine are destroyed by traditional methods of food processing, such as milling of grains, canning, extraction of sugars and oils from whole foods, and addition of chemical additives to bleach or preserve foods, this theory helped to explain the large increase in vascular disease in the early and mid 20th century.
Similarly, the decline in mortality from cardiovascular disease beginning in the 1950s can be attributed to the addition of the synthetic B vitamins to the food supply by fortification of processed foods. Important support for the homocysteine theory was provided by the Framingham Heart Study, which showed that deficiencies of these B vitamins are widespread in older participants, leading to elevation of homocysteine levels and increased risk of plaques.
Many hundreds of studies by investigators worldwide have now proven that elevated homocysteine levels increase the risk for heart disease, stroke, peripheral vascular disease, and reduce longevity in diverse populations. In 1998 the US Food and Drug Administration mandated the addition of folic acid to refined flour, rice and other grain foods, the first such action since niacin, thiamin, riboflavin and iron were mandated for addition to refined grain foods in 1941.
One of the rationales for adding folic acid is the demonstration that deficiency of dietary folic acid is implicated in susceptibility to birth defects of the neural tube type. An additional rationale, not officially cited by the FDA, was the hope that vascular disease incidence and complications might also be prevented in the US. Studies have indeed shown that birth defects have decreased about 19% in the US and up to 78% in Canada in Newfoundland since fortification by folic acid.
In a recent study by the Centers for Disease Control and Prevention in Atlanta, the declining incidence of mortality from stroke accelerated in 1998 in the US, but no change was found in the United Kingdom, where folic acid fortification is not mandated. In 2007 a meta-analysis, as reported in Lancet, concluded that trials yielding significant reduction in blood homocysteine levels from folic acid, pyridoxine, and cobalamin over a 3 to 5 year period produced significant reductions in mortality from stroke.
Trials with participants with a history of advanced vascular disease, heart attack and stroke, have been less successful. The Swiss Heart Study showed that restenosis following coronary angioplasty was benefited by B vitamins, but a later trial with stented patients showed no benefit.
In the 1970s, before my removal from Harvard medicine, and in the 1980s and 1990s my research groups at Massachusetts General Hospital and at the VA Medical Center in Providence made some additional discoveries in the homocysteine field. By using cultured cells from children with homocystinuria, we were able to demonstrate a new pathway for sulfur metabolism by showing that homocysteine thiolactone, the reactive anhydride of homocysteine, is a precursor of sulfate.
We discovered that this pathway is depressed in aging animals and completely blocked in cultured cancer cells. Using methods of organic synthesis, we developed and discovered new derivatives of homocysteine thiolactone, retinoic acid, and cobalamin named thioretinamide and thioretinaco. These compounds are effective in preventing arterial plaques in animals treated with homocysteine.
Theorizing that these compounds are deficient in cancer cells, we were able to decrease cancer formation from chemical carcinogens and to decrease growth of transplanted cancers in mice. These compounds have not as yet been tested in human trials.
Kilmer S. McCully, M.D.
Chief, Pathology and Laboratory Medicine Service
West Roxbury Veterans Affairs Medical Center