Antioxidants and coronary artery disease: from pathophysiology to preventive therapy

Abstract

Oxidant stress in the cardiovascular system may occur when antioxidant capacity is insufficient to reduce reactive oxygen species and other free radicals. Oxidant stress has been linked to the pathogenesis of atherosclerosis and incident coronary artery disease. As a result of this connection, early observational studies focused on dietary antioxidants, such as β-carotene, α-tocopherol, and ascorbic acid, and demonstrated an inverse relationship between intake of these antioxidants and major adverse cardiovascular events. These findings supported a number of randomized trials on the use of selected antioxidants as primary or secondary prevention strategies to decrease cardiac risk; however, many of these studies reported disappointing results with little or no observed risk reduction in antioxidant-treated patients. Several plausible explanations for these findings have been suggested, including incorrect antioxidant choice or dose, synthetic versus dietary antioxidants as the intervention, and patient selection, all of which will be important to consider when designing future clinical trials. This review will focus on the contemporary evidence that is the basis for our current understanding of the role of antioxidants in cardiovascular disease prevention.

Figure 1. Antioxidant signaling and mechanisms of atherosclerosis

Cells generate a number of oxidizing species that can modify proteins, lipids, and DNA such as superoxide (•O₂^-) that is dismutated to hydrogen peroxide (H₂O₂), which is also an oxidant that is reduced to water by the glutathione peroxidases (GPx). This involves a series of coupled reactions that requires the small molecule antioxidant reduced glutathione (GSH) that is generated through the actions of glutathione reductase (GSSG Red) and glucose-6-phosphate dehydrogenase (G6PD). GSH is also required for the antioxidant actions of ascorbic acid and to regenerate α-tocopherol, which reduces oxidized lipids (LOO•) that are generated by hydroxyl radicals (•OH^-). These oxidized lipids are reduced (LOOH) through a series of reactions that involves the antioxidant β-carotene. When there is an increase in reactive oxygen species (ROS) generation and/or a decrease in antioxidant capacity, then oxidant stress occurs. This facilitates the development of atherosclerosis by causing oxidation of proteins, lipids, and DNA as well as promoting inflammation and vascular dysfunction (reviewed in [1]).

Figure 2. Outcomes from contemporary trials of antioxidants to prevent antioxidant disease

A comparison of relative risk for adverse cardiovascular events across a range of contemporary randomized clinical trials of antioxidants supplements to prevent cardiovascular disease. Adapted from [31-35, 37, 39, 41].

Figure 3. Mediterranean diet and cardiovascular outcomes

Individuals enrolled in the PREvención con DIetaMEDiterránea (PREDIMED) study were randomized to a Mediterranean diet supplemented with extra-virgin olive oil or nuts versus a low-fat diet and followed for a median of 4.8 years. The primary endpoint was a composite of myocardial infarction, stroke, or cardiovascular death. The primary endpoint was adjusted for sex, age, family history of premature coronary disease, tobacco use, body mass index, waist-to-height ratio, and the presence of hypertension, hyperlipidemia, and diabetes at baseline. Adapted from [51].