Folates and/or antioxidants and their role in protecting against cardiovascular iseases

Cardiovascular diseases (CVD) account for almost 35% of all deaths in France and nearly 50% in industrialized countries. Though CVD mortality has been decreasing over the past 50 years, the global burden of the CVD is still very high with an increase of the prevalence of atherosclerosis, a multifactorial, inflammatorydegenerative disease of arteries, characterized by the accumulation of lipids (cholesterol) and fibrous elements in the wall of large vessels. Atherosclerosis is the pathophysiological substrate of the majority of acute coronary syndromes and ischemic cerebral strokes.

Oxidative damage of the arterial wall by free radicals and the direct stimulation of endothelial cells by the acute-phase C-Reactive protein promote the expression of cellular adhesion molecules which facilitate the adhesion of monocytes and T cells to the arterial wall. Oxidative stress also appears responsible for the oxidation of LDL incorporated into the plaque. Possible causes of endothelial dysfunction also include high plasma homocysteinemia.

Reactive oxygen species (ROS) are thus thought to be implicated in the pathogenesis of atherosclerosis since they are capable of damaging biological macromolecules such as lipids (e.g. fatty acids in LDL particles). The organism maintains defence against ROS, including enzymes and low molecular-weight antioxidants. An important source of antioxidants is diet which contains numerous compounds exhibiting antioxidant activity. Natural antioxidants are a group of substances able to counteract the oxidative damage.

Many moieties seem to prevent or interrupt the peroxidative chain in the human body: tocopherol and its isomers, carotenoïds, ascorbic acid, glutathione and other sulphydryl-containing molecules, flavonoïds…

Consumption of fruit and vegetables, olive oil, cocoa, red wine, and tea is inversely correlated with heart disease rates. These foods are particularly rich in natural antioxidant nutrients, including ascorbate, the tocopherols, carotenoïds and flavonoïds, naturally occurring substances which provide texture, colour and taste to plant foods.

Folates (vitamin B9) are also involved in cardiovascular prevention, through its well-proven effect on plasma homocysteine concentration, since a high nutritional intake may decrease hyper homocysteinemia which favours endothelial dysfunction and thrombosis. Folates are mainly found in dark green vegetables, legumes, some fruit, and in some animal foods including certain fermented cheeses and liver.

Many data are currently available on the oxidation and inflammation hypothesis of atherosclerosis and on the role of diet. Numerous epidemiological, clinical and experimental studies confirm that oxidized lipids accumulate in atherosclerosis lesions at all stages and that dietary antioxidants may reduce atherosclerosis progression. Moreover, several studies have shown that subjects suffering from a symptomatic atherosclerosis or from coronary heart disease (CHD) had higher levels of oxidized substances or markers of oxidized LDL, and/or lower levels of antioxidants compared to healthy controls. Many epidemiological and clinical studies have shown that intake of antioxidant-rich foods, plant foods and particularly fruits and vegetables, are associated with lower occurrence of CVD. Similarly many studies have shown that high intake of folic acid may prevent strokes. But it is very difficult to separate the effect of one antioxidant from another and to attribute the observed benefit to a specific food since they are associated in those foods and in the global diet. Interventional randomized controlled trials have thus been conducted to prove the responsiveness of one or more antioxidants in reducing the progression of atherosclerosis or the occurrence of CHD. In many cases these studies have failed to demonstrate an effect. But the majority of these trials have used a high dose of one antioxidant, vitamin E or beta carotene. In some studies with tocopherol or high doses of beta carotene adverse effects or undesirable results occur, probably because a single high dose of one compound is not efficient and may sometimes exert a pro-oxidant effect. In other cases, it was proposed that the population had a too low cardiovascular risk; secondary prevention trials were performed but did not show an improvement in CVD.

This lack of clinical efficacy does not disprove the oxidative hypothesis. It is possible that investigated antioxidants are not the right ones, that their dosage, formulation and bioavailability are not appropriate; that patient selection was inadequate and treatment length insufficient to provide full beneficial effects. For example, neither synthetic beta carotene nor tocopherol is equivalent to the natural form. Moreover plant-foods antioxidants are quite numerous in vegetables and fruits, and interact between them with synergistic effects.

So the proper approach should be to test the benefit of high intakes of plant foods naturally rich in antioxidant and folates such as fruit and vegetables in randomized trials on subjects having low intakes of these foods, and to stratify the subjects according to their level of oxidative stress (because antioxidant should be useful when diet fails to meet the global antioxidant and folate requirements), then to identify these subgroups which were more likely to benefit from these kinds of foods, and finally to start at the earliest stage of the disease. The final public health objective should be to modify the global diet and lifestyle.