Oxidative Stress and the Role of Antioxidants in Cardiovascular Risk Reduction
Lori L. Schoonover, PharmD, BCPS, College of Pharmacy, Washington State University, Spokane, WA

Introduction: The contribution of oxygen free radicals to vascular damage is well described. The impact of dietary supplementation and treatment with antioxidants remains controversial. The vast amount of research being done in this field and the volume of information available to the lay public regarding antioxidant supplementation make it important to have a thorough understanding of the interactions between oxidative stress and antioxidants.

Oxidative Stress and Antioxidants: The condition of oxidative stress is an imbalance in the rate at which the intracellular content of reactive oxygen species (free radicals) increases relative to the capacity of the cell to eliminate free radicals. Antioxidant defenses to protect cells against the potential damage induced by oxygen free radicals can be categorised as either preventive antioxidants, which include the enzymes superoxide dismutase, catalase, and glutathione peroxidase, among others, or the chain-breaking antioxidants, such as vitamin E, ubiquinone, urate, and glutathione. The preventive antioxidants eliminate the species involved in the initiation of free radical chain reactions, whereas the chain-breaking antioxidants repair oxidising radicals directly.

The injury caused by oxidative stress can affect all organ systems. In cardiovascular diseases, the most well described and potentially far-reaching effects of oxidative stress are caused by the oxidation of low-density lipoproteins (LDL). The passage of LDL particles into the endothelial layer of blood vessels is well regulated. Once the cell has incorporated the appropriate amount of LDL particles, the receptors shut down. Cellular handling of oxidised LDL is different. Once LDL becomes oxidised it causes the release of chemotactic factors that attract monocytes. The monocytes cross into the endothelium and are differentiated into macrophages, which then convert into foam cells and become the basis for atherosclerotic plaque formation. The macrophages also induce the production of scavenger receptors that recognise oxidised LDL and incorporate it into the plaque. There is no known mechanism for the regulation of scavenger receptors, so oxidised LDL continues to be incorporated into the cell. Oxidised LDL causes the proliferation of smooth muscle cells and protein fibers that also contribute to development and progression of the atherosclerotic plaque. Oxidised LDL is thought to reduce nitric oxide production by the endothelium, which leads to vasoconstriction. Enhanced platelet aggregation is also induced by oxidised LDL.

Oxidation of LDL is a key factor in the development of atherosclerosis. Free radicals appear to be involved throughout the atherogenic process, beginning with endothelial dysfunction in an otherwise intact vessel and extending to rupture of a lipid-rich plaque, leading to myocardial infarction. Experimental and epidemiologic evidence supports the concept that antioxidants can attenuate the negative effects of oxidative stress. Reports of clinical studies of antioxidant supplementation have documented controversial and contradictory outcomes.

Antioxidant Vitamins : Vitamin E (a-tocopherol) is carried in LDL particles and is very effective in protecting LDL from oxidation. Additional benefits that vitamin E may provide are inhibition of smooth muscle cell proliferation and reduction of platelet adhesion. It has therefore been the antioxidant compound most intensively studied. Several clinical trials have been conducted to determine if vitamin E supplementation is effective in reducing cardiovascular events. The dosages, formulations, and lengths of treatment in different levels of disease severity have provided results that are inconsistent. Epidemiologic evidence is available to support the use of vitamin E for primary prevention. The results of prospective, randomised, controlled trials have been contradictory. Vitamin E at doses of 100-400 IU per day is generally considered safe. However, due to the lack of conclusive data in the setting of primary prevention of cardiovascular events, the American Heart Association recommends consumption of antioxidant-rich foods, as opposed to vitamin supplementation, in conjunction with other, more established interventions, such as low-dose aspirin, exercise, low-cholesterol diet, and smoking cessation.

Recently, the Heart Outcomes Prevention Trial (HOPE) results were published. [10] In this study, vitamin E was shown to be of no benefit in reducing cardiovascular events or mortality. It is important to recognise that this study enrolled patients with existing coronary heart disease (85% of patients) and those at highest risk for cardiovascular events (i.e., those with diabetes mellitus plus one other cardiovascular risk factor -- smoking, hypertension, elevated LDL cholesterol, or documented microalbuminuria). Due to the findings of this trial, it is becoming generally accepted that vitamin E has little, if any, role for secondary prevention.

Vitamin C likely has no effect in preventing coronary heart disease, according to epidemiologic and clinical intervention trials. Vitamin C, one of the primary water-soluble antioxidants, is potent and can provide electrons for the regeneration of vitamin E. This effect has led to the suggestion that vitamin E may prove more effective if clinical outcome data were assessed with the combination of vitamin E and vitamin C rather than with these vitamins individually.

Over 600 carotenoid compounds have been identified. [11] Carotenoids are fat-soluble plant pigments contained in many of the fruits and vegetables consumed in a normal diet. While there are many different carotenoid compounds, including lycopene, a-tocopherol, lutein, b-cryptoxanthin, and zeaxanthin, b-carotene is the most widely studied. b-carotene is the major vitamin A precursor and is carried in plasma and LDL particles. Carotenoids prevent lipid peroxidation by providing electrons to quench singlet oxygen.

The general conclusion from the clinical trials of b-carotene supplementation is that it does not lower the risk of coronary heart disease. In fact, in some trials b-carotene showed an increase in the risk of lung cancer in smokers and increased mortality associated with ischemic heart disease.

Lycopene, the substance that gives tomatoes their red color, appears to be a more potent antioxidant than b-carotene. Epidemiologic studies have correlated high tissue concentrations of lycopene with a lower risk of myocardial infarction. Prospective, controlled trials have not yet been completed with lycopene.

Coenzyme Q-10, also known as ubiquinone, is a fat-soluble antioxidant that is a free radical scavenger and can regenerate vitamin E. Coenzyme Q-10 has also been shown to inhibit platelet aggregation. The antioxidant actions of coenzyme Q-10 have been suggested to minimise the free radical damage induced by ischemia and reperfusion during angina and myocardial infarction. No large-scale, prospective trials have been reported on the ability of coenzyme Q-10 to affect the risk of cardiovascular events.

Synthetic Antioxidant Medications : Probucol has modest lipid-lowering properties. It was used for the treatment of hypercholesterolemia until more tolerable and effective cholesterol-lowering treatments, such as the HMG Co-A reductase inhibitors, or "statins," became available. Several studies have been conducted with probucol because it is a potent antioxidant. Probucol has been shown to prevent or reduce development or extension of atherosclerosis in animal models and in a few clinical trials. It is unlikely that this agent will be used clinically due to its adverse effect on high-density lipoproteins; however, these data support the concept that potent antioxidants may have direct effects on atherosclerosis.

Most of the other cholesterol-lowering therapies also demonstrated some antioxidant effects. The "statins" have been shown to increase the resistance of LDL to oxidation. An in vitro study of oxidation of LDL in diabetic patients showed that fenofibrate reduced oxidation of LDL, while pravastatin and simvastatin did not. It is suspected that the effects of "statins" on mortality reduction in cardiovascular disease or in patients at high risk for coronary disease is attributable at least in part to their antioxidant actions, though this remains to be proven.

The b-adrenegic blocking agents all have demonstrated in vitro antioxidant activity. The degree of antioxidant effect appears to be proportional to the lipophilicity of the compound. Carvedilol is one of the most lipophilic b blockers and exhibits the most marked effect on reducing LDL oxidation. Two of the carvedilol metabolites appear to have even more potent antioxidant properties than the parent compound. No clinical trials with carvedilol have been conducted to determine if these effects are beneficial for primary or secondary prevention of cardiovascular risks.

Angiotensin-converting enzyme (ACE) inhibitors have also been shown to produce antioxidant effects in vitro. Captopril was one of the first agents described to possess this action. This compound contains a sulphydryl group that may contribute to the antioxidant actions. However, other ACE inhibitors that do not contain a sulphydryl moiety, such as enalapril, have also demonstrated reduced LDL oxidation. The HOPE study that evaluated the use of vitamin E also included an arm in which patients were treated with the ACE inhibitor ramipril. The study was terminated early by the Data Safety and Monitoring Board because ramipril was shown to have an overwhelmingly positive impact on reducing the risk of cardiovascular events and mortality. The reduction of blood pressure in these patients accounted for only about 20% of the beneficial effect. It is not known what the other contributing factors of ACE inhibition were, but they may have involved the antioxidant properties of these drugs, though no clinical studies have been conducted.

Angiotensin II (AGII) is thought to increase LDL oxidation. The AGII receptor antagonists, such as losartan, may also possess antioxidant actions through inhibiting the binding of AGII to its receptor, though no clinical studies have been conducted.

Oxidative stress is one of the main culprits responsible for the development of coronary atherosclerosis. Conflicting data exist on the benefits of vitamin E for primary prevention of cardiovascular disease. More recent data have established that vitamin E probably has little benefit in secondary prevention. Other vitamin supplements, such as b-carotene and vitamin C, provide no protection against cardiovascular risk and are not indicated. Newer vitamin supplements and medicinal products are currently being evaluated. It is clear that oxidative stress is an important contributor to coronary heart disease. The challenge is to find potent, safe, and effective antioxidants that can be given to counteract the effects of the damaging oxygen free radicals.