Oxidative Stress and Inflammation in Heart Disease: Do Antioxidants Have a Role in Treatment and/or Prevention?

Inflammation triggered by oxidative stress is the cause of much, perhaps even most, chronic human disease including human aging. The oxidative stress originates mainly in mitochondria from reactive oxygen and reactive nitrogen species (ROS/RNS) and can be identified in most of the key steps in the pathophysiology of atherosclerosis and the consequential clinical manifestations of cardiovascular disease. In addition to the formation of atherosclerosis, it involves lipid metabolism, plaque rupture, thrombosis, myocardial injury, apoptosis, fibrosis and failure. The recognition of the critical importance of oxidative stress has led to the enthusiastic use of antioxidants in the treatment and prevention of heart disease, but the results of prospective, randomized clinical trials have been overall disappointing. Can this contradiction be explained and what are its implications for the discovery/development of future antioxidant therapeutics?

Novel astaxanthin prodrug (CDX-085) attenuates thrombosis in a mouse model.

BACKGROUND: Cardiovascular disease remains the leading cause of morbidity and premature mortality in most industrialized countries as well as in developing nations. A pro-oxidative state appears to promote and/or exacerbate vascular disease complications. Furthermore, a state of low-grade chronic inflammation can promote increased oxidative stress and lead to endothelial cell and platelet dysfunction ultimately contributing to thrombogenesis. OBJECTIVES: In this study, the effect of a proprietary astaxanthin prodrug (CDX-085) on thrombus formation was investigated using a mouse model of arterial thrombosis. The influence of free astaxanthin, the active drug of CDX-085, on human endothelial cells and rat platelets was evaluated to investigate potential mechanisms of action. METHODS AND RESULTS: Oral administration of CDX-085 (0.4% in chow, approximately 500 mg/kg/day) to 6-8 week old C57BL/6 male mice for 14 days resulted in significant levels of free astaxanthin in the plasma, liver, heart and platelets. When compared to control mice, the CDX-085 fed group exhibited significant increases in basal arterial blood flow and significant delays in occlusive thrombus formation following the onset of vascular endothelial injury. Primary human umbilical vein endothelial cells (HUVECs) and platelets isolated from Wistar-Kyoto rats treated with free astaxanthin demonstrated significantly increased levels of released nitric oxide (NO) and significantly decreased peroxynitrite (ONOO-) levels. CONCLUSION: Observations of increased NO and decreased ONOO- levels in endothelial cells and platelets support a potential mechanism of action for astaxanthin (CDX-085 active drug). These studies support the potential of CDX-085 and its metabolite astaxanthin in the treatment or prevention of thrombotic cardiovascular complications.

Astaxanthin: a novel potential treatment for oxidative stress and inflammation in cardiovascular disease.

Oxidative stress and inflammation are implicated in several different manifestations of cardiovascular disease (CVD). They are generated, in part, from the overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that activate transcriptional messengers, such as nuclear factor-kappaB, tangibly contributing to endothelial dysfunction, the initiation and progression of atherosclerosis, irreversible damage after ischemic reperfusion, and even arrhythmia, such as atrial fibrillation. Despite this connection between oxidative stress and CVD, there are currently no recognized therapeutic interventions to address this important unmet need. Antioxidants that provide a broad, "upstream" approach via ROS/RNS quenching or free radical chain breaking seem an appropriate therapeutic option based on epidemiologic, dietary, and in vivo animal model data. However, human clinical trials with several different well-known agents, such as vitamin E and beta-carotene, have been disappointing. Does this mean antioxidants as a class are ineffective, or rather that the "right" compound(s) have yet to be found, their mechanisms of action understood, and their appropriate targeting and dosages determined? A large class of potent naturally-occurring antioxidants exploited by nature-the oxygenated carotenoids (xanthophylls)-have demonstrated utility in their natural form but have eluded development as successful targeted therapeutic agents up to the present time. This article characterizes the mechanism by which this novel group of antioxidants function and reviews their preclinical development. Results from multiple species support the antioxidant/anti-inflammatory properties of the prototype compound, astaxanthin, establishing it as an appropriate candidate for development as a therapeutic agent for cardiovascular oxidative stress and inflammation.

Predictors of women's exercise maintenance after cardiac rehabilitation.

PURPOSE: Less than 50% of persons who participate in cardiac rehabilitation (CR) programs maintain an exercise regimen for as long as 6 months after completion. This study was conducted to identify factors that predict women's exercise following completion of a CR program. METHODS: In this prospective, descriptive study, a convenience sample of 60 women were recruited at completion of a phase II CR program. Exercise was measured using a heart rate wristwatch monitor over 3 months. Predictor variables collected at the time of the subjects' enrollment were age, body mass index, cardiac functional status, comorbidity, muscle or joint pain, motivation, mood state, social support, self-efficacy, perceived benefits or barriers, and prior exercise. RESULTS: Of women, 25% did not exercise at all following completion of a CR program and only 48% of the subjects were exercising at 3 months. Different predictors were found of the various dimensions of exercise maintenance. Predictors of exercise frequency were comorbidity and instrumental social support. Instrumental social support was the only predictor of exercise persistence. Comorbidity was the only predictor of exercise intensity. The only predictor of the total amount of exercise was benefits or barriers. CONCLUSIONS: Interventions aimed at increasing women's exercise should focus on increasing their problem-solving abilities to reduce barriers to exercise and increase social support by family and friends. Because comorbidity was a significant predictor of exercise, women should be encouraged to use exercise techniques that reduce impact on muscles and joints (eg, swimming) or exercising for short periods several times a day.