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M Balasubramanyam

Antioxidants and Cardiovascular Disease Where Do We Stand?

Introduction

clinical trial outcomes.

Antioxidants have been widely promoted as a preventive therapy for a wide range of conditions, including cardiovascular disease. Unfortunately, while there is ample evidence from basic research and observational studies to support the role of antioxidants in preventing heart disease, the results from clinical trials on humans have been inconclusive and even discouraging. However, this does not mean that ‘oxidation hypothesis’ of atherosclerosis development and progression is wrong. This communication is an attempt to review some scientific evidence in this area with an emphasis on a consensus at the interface of basic science and

Oxidation and heart disease

Address for correspondence: Dr M Balasubramanyam, Senior Scientist, Madras Diabetes Research Foundation, Chennai - 600 086. E-mail: [email protected]

Oxidation is defined as removal of electrons from a molecule. Oxidation can instigate tissue damage by modifying a number of molecular species, such as lipids, proteins and nucleic acid, leading to several diseases including atherosclerosis 1. The majority of heart diseases arise from atherosclerosis, or the formation of plaque from fatty particles accumulated along the blood vessel wall. An acute heart attack occurs when this atherosclerotic plaque erodes and ruptures, leading to the build up of blood clots at the rupture site, a process called thrombosis. Numerous studies have suggested that oxidation of LDL cholesterol by free radicals plays a major role in the formation, progression and rupture of these plaques 2. Antioxidants, on the other hand,

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On the basis of the above considerations, there are evidence to indicate that enhanced oxidative stress is detectable in patients with risk factors for atherosclerosis and we need to monitor, measure and document both oxidative damage and antioxidant status through refined and validated biomarkers. have the ability to inhibit oxidant formation, interfere with oxidant activities once they were formed, and even repair oxidant-induced injury3. This is what prompted much of the research focus on the idea of consuming exogenous antioxidants such as vitamin E, vitamin A and vitamin C as a therapeutic option to counteract oxidative damage. Most of the current literature addresses the role of these three vitamins and beta carotene, and hence the term ‘antioxidants’ in

Review Article this article refers to this limited list of compounds.

Observational studies of antioxidants A large number of observational epidemiological studies have evaluated potential relationships between dietary intake antioxidants and cardiovascular events. These studies include: The Rotterdam study, The Iowa Women/s Health Study, Established Population for Epidemiologic Studies of the Elderly, Finnish study, Health Professional Follow-up Study, Nurses’ Health Study, The first National Health and Nutrition Examination Survey, Scottish Heart Health Study and The WHO/ Monica project. These studies revealed a lower risk of cardiovascular diseases with higher

intakes of antioxidant vitamins, especially vitamin E. However, observational studies are often inherently limited by a number of confounding variables: a) They tend to rely on subjective data such as patients’ 24-hour recall of dietary intake, b) study subjects’ healthier living habits, i.e., they exercise, limit their fat intake, and do not smoke and c) the compound nature of the diet, i.e., importance of other dietary factors. Nevertheless, some of the larger observational studies of antioxidants are worthy of recognition and qualify for extended randomized controlled trials.

Interventional studies Some of the larger randomized trials that addressed the use of antioxidants for disease prevention

are shown in Table 1. In these trials, surrogate endpoints, such as analysis of atherosclerosis progression, or hard endpoints, such as vascular death and myocardial infarction, have been examined in order to evaluate the clinical benefit of antioxidant vitamins. Since epidemiological studies documented that regular consumption of vitamin E reduced the risk of cardiovascular events4, majority of antioxidant trails have used vitamin E. However, interventional clinical trials that have explored the benefits of antioxidants, have provided conflicting results: a) Studies that showed neither harm nor benefit, b) studies that showed possible benefit and c) studies that showed possible deleterious effects (Table 1). Lack of beneficial effect of vitamin E and beta carotene on

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Table 1

Antioxidant Interventional Studies 1. Studies that showed neither harm nor benefit


Heart Protection Study (HPS)
Primary Prevention Project (PPP)
Heart Outcomes Prevention Evaluation (HOPE)
Gruppo Italiano per lo Studio della Sopravvivenza nell’

Infarto miocardico (GISSI)
Women’s Health Study
Physician’s Health Study

2. Studies that showed possible benefit


The Cambridge Heart Antioxidant Study (CHAOS)
Antioxidant Supplementation in Atherosclerosis

Prevention study (ASAP)
Chinese Nutrition Intervention Trials

Cardiovascular Disease in End-Stage Renal Disease (SPACE) 3. Studies that showed possible deleterious benefit


Beta Carotene And Retinal Efficacy Trial (CARET)
Alpha Tocopherol Beta Carotene Cancer Prevention

Study (ATBC)
HDL Atherosclerosis Treatment Study (HATS)

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Secondary Prevention with Antioxidants of

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cardiovascular mortality and morbidity in the long term was also revealed in a recent metaanalysis5. Of even greater concern is the news that antioxidants may not be as harmless as it was thought. Moreover, the HATS trial raised the intriguing possibility that the beneficial cardiovascular effect of simvastatin or niacin could be attenuated with the concurrent use of antioxidants6. Thus, although early observational studies showed a potential link between antioxidant consumption and decreased cardiovascular mortality, prospective randomized trials in humans have failed to show that giving antioxidants supplements confers any significant clinical benefit. However, the failure of vitamin E or beta carotene to reduce the incidence of cardiovascular endpoints does not necessarily mean that the ‘oxidation hypothesis’ (the concept that antioxidants can be used to prevent or heal oxidative damage) is wrong. What they really mean and the lesson from the clinical trials is this: ‘Antioxidant studies need a change of direction’. The following are some of the shortcomings of the past clinical studies and recommendations for future studies: Antioxidant clinical trials failed to monitor markers of oxidation: Clinical trials have attempted to measure the effectiveness of antioxidants in terms of clinical endpoints. In other words, none of the trials have attempted to monitor markers of oxidation. This is one of the flaws in the design of antioxidant studies

so far. It is analogous to testing a lipid-lowering drug without measuring lipid levels, or testing antihypertensive and antidiabetic drugs without measuring blood pressure and blood sugar levels, respectively. Trials performed on established disease: Most supplementation trials were done in people with symptoms, and it may be easier to prevent the onset of the disease than to reverse an established atherosclerotic lesion. There may be a flaw in the choice of antioxidants: There is considerable evidence that the so-called antioxidants such as vitamin E do not effectively block relevant intracellular oxidation pathways. It has also been demonstrated that vitamin E has little effect on oxidants derived from nitric oxide7,8 or on pathways catalyzed by myeloperoxidase9. Moreover, under circumstances the antioxidants such as vitamin E and vitamin C can actually promote rather than inhibit oxidation10,11. Antioxidants trials should monitor bioavailability: There is very little information on antioxidant bioavailability in vivo in humans, and this should be a major target for future research. Bioavailability is the sum of absorption from the gut, transport in the blood, cellular uptake and metabolism. These processes are ill-defined for many antioxidants. Specific measures of oxidative stress should be monitored: Future clinical trials that attempt to prove benefits of antioxidant therapy need to employ measurement of specific biomarkers or fingerprints

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of oxidative stress. This biomarker panel includes F2-isoprostanes, nitrotyrosine and myeloperoxidase to mention a few important ones. F2-isoprostane levels have been shown increased in people with coronary artery disease, as well as in those with cardiovascular disease risk factors 12. Nitrotyrosine, an inflammatory product generated by protein modification by oxidants derived from nitric oxide, is associated with coronary artery disease, and is modulated by statin therapy 8 . Enrichment of myeloperoxidase has been shown in human atheroma and in the circulation of people at risk for cardiovascular disease 13. Thus, there is a need for the refinement of methods (biomarkers) for measuring free-radical-mediated damage to nucleic acids, proteins and polyunsaturated fatty acids in humans in vivo suitable for use in clinical studies. We need targeted antioxidants: Conventional antioxidants only intercept reactive oxidants by scavenging them before they can damage targets in vivo. Instead, we need antioxidants that can interfere with the cellular sources of reactive oxygen species (ROS) or reactive nitrogen species (RNS). More importantly, we need intracellularly acting antioxidants, such as mitochondrially-targeted ones. Many strategies are being developed for the targeted delivery of antioxidants to mitochondria. In one study 14, mitochondrially targeted vitamin E (MitoVit E) has been shown 350-fold more potent than the water-soluble vitamin E analog trolox, indicating that

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mitochondrially targeted antioxidants may ultimately prove useful in the therapeutic options.

proven to be beneficial: Whole grains, fruits, vegetables and other dietary sources.

Conclusion

References

On the basis of the above considerations, there is evidence to indicate that enhanced oxidative stress is detectable in patients with risk factors for atherosclerosis and we need to monitor, measure and document both oxidative damage and antioxidant status through refined and validated biomarkers. These markers will certainly be useful in future studies to identify patients who might benefit from antioxidant therapy, as well as to serve as fingerprints to gauge the effectiveness of antioxidant interventions. Therefore, future clinical trials of antioxidants should not be discouraged but nurtured with proper design and specific measurements. There might be more scope in the future for the use of antioxidants in clinical medicine, once the developments in research areas such as clinical proteomics, nutrigenomics, pharmacogenomics and intracellular drug delivery systems reach a stage of translational applications. Until such definite scientific evidence is available for monitoring oxidative damage and prescribing antioxidants in heart disease, the most prudent recommendation for the general public is to get antioxidants from sources that have been clinically

1.

2.

3.

4.

5.

6.

7.

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Halliwell B and Gutteridge JM.Free Radicals in Biology Medicine 2nd Edition, Clarendon Press, Oxford 1989. Chisolm GM and Steinberg D. The oxidative modification hypothesis of atherogenesis: An overview.Free Radic. Biol. Med. 2000;28: 1815-1826. Halliwell B and Gutteridge JM. The definition and measurement of antioxidants in biological systems. Free Radic. Biol. Med. 1995; 18:125-126. Jha P, Flather M, Lonn E, Farkouh M and Yusuf S. The antioxidant vitamins and cardiovascular disease. A critical review of epidemiologic and clinical trial data. Ann. Intern. Med. 1995;123: 860-872. Vivekananthan DP, Penn MS, Sapp SK, Hsu A and Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: Meta-analysis of randomized trials. Lancet 2003; 361:2017-2023. Cheug MC, Zhao XQ, Chait A, Albers JJ and Brown BG. Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL. Atheroscler. Thromb. Vasc. Biol. 2001;21: 1320-1326. Leeuwenburgh C, Hardy MM, Hazen SL, Wagner P, Oh-ishi S, Steinbrecher UP and Heinecke JW. Reactive nitrogen intermediates promote low density lipoprotein oxidation in human atherosclerotic intima. J. Biol. Chem. 1997;272: 1433-1436.




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Shishehbor MH, Aviles RJ, Brennan ML Fu X, Goormastic M, Pearce GL, Gokce N, Keaney JF Jr, Penn MS, Sprecher DL, Vita JA and Hazen SL. Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy. JAMA 2003;289:1675-1680.

9.

Shishehbor MH, Brennan ML, Aviles RJ, Fu X, Penn MS, Sprecher DL and Hazen SL. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 2003;108: 426-431.

10. Thomas SR and Stocker R. Molecular action of vitamin E in lipoprotein oxidation: Implications for atherosclerosis. Free Radic. Biol. Med. 2000; 28:1795-1805. 11. Podmore ID, Griffiths HR, Herbert KE, Mistry N, Mistry P and Lunec J. Vitamin C exhibits pro-oxidant properties. Nature 1998;392 (6676):559. 12. Keaney JF Jr, Larson MG, Vasan RS, Wilson PW, Lipinska I, Corey D, Massaro JM, Sutherland P, Vita JA and Benjamin EJ; Framingham Study. Obesity and systemic oxidative stress: Clinical correlates of oxidative stress in the Framingham Study. Arterioscler. Thromb. Vasc. Biol. 2003;23(3): 434-439. 13. Brennan ML and Hazen SL. Emerging role of myeloperoxidase and oxidant stress markers in cardiovascular risk assessment. Curr. Opin. Lipidol. 2003;14: 353-359. 14. Jauslin ML, Meier T, Smith RA and Murphy MP. Mitochondriatargeted antioxidants protect Friedreich Ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants. FASEB J. 2003;17: 1972-1974.