It is important to emphasize that it is not certain exactly where and how LDL cholesterol gets oxidized within the human body. More important, vitamin C is a water-soluble vitamin and is thus confined to the extracellular fluids but vitamin E gains entry into lipoproteins. It is known that large doses of beta-carotene do not prevent LDL oxidation. Thus, antioxidants have subtle and important differences that impact on their probable therapeutic benefits.
After the past few years of conflicting results, the critical question remains: Do antioxidants actually work? The role of antioxidants in protecting people against heart disease remains controversial. There appears to be little doubt, however, that antioxidants present in the Mediterranean diet possess cardioprotective effects; recent experimental work indicates that French red wines are cardioprotective beyond the effect on increasing HDL cholesterol. (See chapter entitled ‘‘Alcohol and the Heart.’’)

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• I. STATINS
  Statins are well-known, cholesterol-lowering agents. They are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is the key enzyme catabolizing the early rate-limiting step in the bio¬synthesis of cholesterol within the hepatocyte. They lower LDL cholesterol in blood and thus prevent heart attacks and death from myocardial infarction as well as strokes. More important, statins have been shown to prevent lipo-protein oxidation, and it is believed that some of their salutary effects may be related to this action. They appear to improve survival in patients with ischemic and non-ischemic heart failure. Nitric oxide synthesis is diminished in heart failure; statins enhance endothelial NO synthase (eNOS) activity and improve endothelial function (see the section Statins in the Dyslipidemia chapter).
• II. VITAMIN E
  Antioxidant nutrients, particularly vitamin E, are still widely used with the hope of preventing cancer, heart disease, and dementia. Although, clinical trials have not shown protection from cancer, the correct ‘‘protective’’ dose may not have been used in some trials. Also, the partially favorable effect of vitamin E on amyloid depo¬sition in the brain and its effect on dementia remains to be clarified.
• III. VITAMIN C
  Although vitamin C, ascorbic acid, is one of the most important antioxidants in extracellular fluids, it traps peroxyl radicals and inhibits lipid peroxidation. Several studies indicate that there is no apparent benefit in the prevention of cardiovascular disease with use of vitamin C.
• IV. BETA-CAROTENE
  Results of several clinical trials indicated that beta-carotene supplementation is not beneficial in the prevention of cardiovascular disease or its complications.
• V. MEDITERRANEAN DIET
  The Mediterranean diet contains a substantial amount of antioxidants and has been shown to be substantially cardioprotective. However, there are many other cardio-protective facets in this diet, including an abundance of beneficial alpha-linolenic acid (see the chapter Diets and Heart Disease).
• VI. DIETARY PLANT-DERIVED FLAVONOIDS
  These naturally derived products from several sources including red grape juice, red wine, soy products, and nuts (particularly almonds, walnuts, and hazel nuts), are receiving attention for their antioxidant and cardioprotec-tive properties.
• VII. FRENCH RED WINE
  French red wine appears to be more cardioprotective than wine from other countries. Although the data for differences in red and white wine remain controversial, and it appears that all alcoholic beverages carry some cardioprotective properties, it seems that French red wine possesses further cardioprotective properties.
• VIII. PROBUCOL
  Two small studies have demonstrated that probucol, a drug used in the 1970s for lowering serum cholesterol, which was abandoned because of adverse effects, has important additional antioxidant properties. Probucol significantly reduces restenosis when administered one month before and continued for six months after percutaneous trans-luminal coronary angioplasty (PTCA). The small group, 317 patients, used in these studies limits the conclusions regarding the benefits of this drug.
• BIBLIOGRAPHY
  Appeldoorn, C. C. M., Bonnefoy, A., Bianca, C. H. et al. Gallic acid antagonizes P-Selectin – mediated platelet – leukocyte interactions: Implications for the French paradox. Circulation, 111:106–112, 2005.