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(Circulation. 2003;107:926.)
© 2003 American Heart Association, Inc.

Antioxidants and Atherosclerosis

Don’t Throw Out the Baby With the Bath Water

I. Jialal, MD, PhD; S. Devaraj, PhD

From the Laboratory for Atherosclerosis and Metabolic Research, UC Davis Medical Center, Sacramento, Calif.

Correspondence to Ishawarlal Jialal, MD, PhD, Laboratory for Atherosclerosis and Metabolic Research, UC Davis Medical Center, 4365 Second Ave, Research One Building, Room 3000, Sacramento, CA 95817. E-mail ishwarlal.jialal{at}ucdmc.ucdavis.edu

Key Words: Editorials • antioxidants • atherosclerosis

Several lines of evidence support a role for oxidative stress and inflammation in atherogenesis. Epidemiological studies suggest that low levels of antioxidants are associated with increased risk for cardiovascular disease (CVD), and that increased intakes appear to be protective. In supplementation studies in humans, alpha-tocopherol (AT), the major form of vitamin E, decreases lipid peroxidation (low-density lipoprotein [LDL] oxidation and F2-isoprostanes) and platelet aggregation and adhesion and is antiinflammatory.¹

See p 947

However, results of prospective antioxidant clinical trials have been disappointing. The Table summarizes the large prospective trials with antioxidants published to date, including the article by Salonen et al² that appears in this issue of Circulation.

View this table: [in this window] [in a new window]   Summary of Prospective Antioxidant Clinical Trials

Before this recent report of Salonen et al,² there have been 10 previous studies that used various combinations of antioxidants, including AT, ascorbic acid (AA), and beta-carotene (BC) on cardiovascular events (CVE). Of the 10 studies, 3 showed a benefit with regards to the primary endpoint (Table).

In the Cambridge Heart AntiOxidant Study (CHAOS), patients received placebo or natural AT (RRR-AT) at a dose of either 400 or 800 IU/d.³ AT supplementation resulted in a significant increase in plasma AT levels and a significant 47% reduction in the primary endpoint, defined as combined endpoint of cardiovascular death and non-fatal myocardial infarction. However, there was no significant effect on cardiovascular mortality. The Secondary Prevention with Antioxidants of Cardiovascular disease in End-stage renal disease (SPACE) study⁴ was a double-blind, placebo-controlled, randomized, secondary prevention trial in hemodialysis patients. The primary endpoint was a composite variable consisting of myocardial infarction (fatal and non-fatal), ischemic stroke, peripheral vascular disease, and unstable angina. In addition to a significant increase in AT levels, RRR-AT (800 IU/d) significantly decreased the primary endpoint by 54%. The third study that revealed a positive result with antioxidant supplementation was the Transplant Associated Arteriosclerosis Study,⁵ which tested the effect of combined supplementation with the RRR-AT (800 IU/d) and ascorbic acid (AA) (1 gram/d) on the progression of arteriosclerosis in cardiac transplant patients. Both AA and AT levels increased significantly in the supplemented group. During 1 year of treatment, the primary endpoint of coronary intimal index increased in the placebo group but did not change significantly in the treatment group.

However, despite the fact that the results these 3 studies were positive, the majority of studies have been negative with regard to the primary endpoint of CVE^6–12 (Table). With regard to other endpoints, in the Alpha-Tocopherol Beta-Carotene cancer prevention study (ATBC) in patients with previous CVD, there was a significant reduction in non-fatal myocardial infarction.¹³ In the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico (GISSI), there was a significant (20%) reduction in cardiovascular death.⁷ In the Primary Prevention Project (PPP), there was a significant (46%) reduction in peripheral arterial disease.⁹ Finally, in the HDL Atherosclerosis Treatment Study (HATS),¹¹ there was a significant reduction in mean change in minimal luminal diameter (P<0.05) (Table).

In this issue of Circulation is the most recent study, the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study,² which was a randomized trial of the effect of AT and AA on the 6-year progression of carotid atherosclerosis in 440 hypercholesterolemic patients (including smokers and postmenopausal women between the ages of 45 and 69 years). The combination of RRR-AT (272 IU/d) and AA (500 mg/d) resulted in a significant increase in plasma levels of AT and AA. Furthermore, the group that received the combined antioxidants had a significant decrease in the rate of progression of carotid intimal medial thickness (30% treatment effect) compared with placebo. However, this effect was confined to men. Interestingly, the effect was larger in subjects with either low baseline plasma AA levels or common carotid artery plaque. Although both antioxidant levels increased to a similar extent, isoprostane levels were decreased only in men. A clear explanation for this finding was not provided. Also, no deleterious effect on high-density lipoprotein cholesterol was observed with combined supplementation of RRR-AT and AA. Thus, this data replicates their 3-year findings, confirming that supplementation with both AT and slow-release AA decreases atherosclerosis progression in hypercholesterolemic subjects. The strengths of the 6-year ASAP study include a cohort of patients with increased oxidative stress due to hypercholesterolemia or smoking, excellent follow-up (>83% of patients completed the study), patients who were seen regularly throughout the 6-year study period, and antioxidants given with meals ensuring optimum absorption. There are certain weaknesses, however, even in this study that has incorporated measures of antioxidant levels, biomarkers of oxidative stress, and a population at high risk for oxidative stress. It would have been ideal if at the outset, both groups received either placebo or the combination of AA and AT, because only 34% of the patients in the AA+AT supplementation received both vitamins from the outset. Thus, the majority of patients received either AA or AT alone for the first 3 years of the study. Although during the first 3 years of the study, it seemed that these antioxidant levels resulted in a significant increase in plasma AA and AT levels and a decrease in various measures of oxidative stress, including LDL oxidation and F2-isoprostanes, it is unclear at 6 years what the benefit of the antioxidants was on measures of oxidative stress, as this is not reported. However, the benefits already seen in the first 3 years regarding a decrease in the measures of oxidative stress probably persist at 6 years. Although the doses of AT used in this study would not be anticipated to have antiinflammatory effects, it would be interesting if the investigators had reported on some valid measures of inflammation.

Many factors could account for the lack of benefit on the primary endpoint in most of the studies. For instance, in all studies where there was a benefit on the primary endpoint (Table), a significant increase in the respective plasma antioxidant levels was reported. However, in only 4 of the 7 negative studies were antioxidant levels reported (Table). In the Vitamin E Atherosclerosis Prevention Study (VEAPS), plasma levels of AT increased significantly in both the placebo group (33%) and the AT group, and thus it is hard to determine the effect of this on the primary endpoint.¹² Also, only 3 studies reported biomarkers of oxidative stress.

Studies included both males and females (Table), and because the rates of cardiovascular disease are lower in women than in men, this could have a bearing on the primary endpoint as seen in the ASAP study.² Furthermore, it would be most prudent to conduct studies with antioxidant supplementation in individuals with increased oxidative stress (diabetes, end-stage renal disease, coronary artery disease, etc). No measure of biomarkers of inflammation was reported in any of the studies, and it has recently been shown that AT is indeed antiinflammatory, reducing monocyte pro-inflammatory cytokines and high-sensitive C-reactive protein levels.¹⁴ Also, as AT is a fat-soluble vitamin, it should be ingested with meals, as reported in the ASAP study. As previously shown, with respect to AT supplementation and LDL oxidation, there are responders and non-responders, and this could explain the null results in certain studies.¹⁵

The form of AT might be crucial with regards to non-antioxidant effects. Although both RRR- and synthetic AT (all-rac-AT) have been shown by various groups to decrease LDL oxidation, with respect to cell signaling and inflammation (inhibition of protein kinase-C and decreasing the release of pro-inflammatory cytokines), it might be crucial for AT to transfer from the plasma membrane to the cytosol. The importance of intracellular transfer of AT by tocopherol-associated protein (TAPS) might be crucial in this regard.¹⁶ Thus, with regards to non-responders in these trials (cardiovascular endpoints or biomarkers), this might be due to mutations in TAPS and other relevant biomolecules that are important in orchestrating both the antioxidant and non-antioxidant effects of AT.

The doses of antioxidants used varied considerably, and this could have an impact on the results. It seems that there might be a threshold dose of AT that might be effective, ie, 800 IU/d. Also, the form of AT might be very important, especially for cell signaling, because most of the reported antiinflammatory effects of AT seem to be due to RRR-AT.¹⁷ In this regard, we have shown that 400 IU of all-rac-AT failed to have any significant antiinflammatory effects.¹⁸ Also, of the 7 studies with a negative result on the primary endpoint, 5 used all-rac-AT, which comprises 8 stereoisomers, whereas all 4 studies showing a positive effect used RRR-AT.

It is clear that the antioxidant cocktails have no benefit in the prevention of CVD.^6,10,11 Furthermore, the antioxidant BC has been shown to increase lung cancer and CVD mortality and, in the ATBC study, appeared to attenuate the benefit of AT.¹³

The finding of the ATBC study of a significant increase in hemorrhagic strokes in male smokers with all-rac-AT is sobering.¹⁹ In this regard, however, it should also be pointed out that in none of the other 10 studies, including the secondary prevention studies in which the patients were taking antiplatelet agents and much higher doses of AT, was an increase in hemorrhagic strokes evidenced. However, this unexpected finding will clearly be settled in ongoing clinical trials.

In conclusion, although much effort has been directed at proving the benefits of antioxidants, the findings to date are far from clear. However, it should be pointed out that there does not seem to be any major harm inflicted with AT and AA supplementation to date. Previous findings showing a potential interaction between statins and antioxidants have been put to rest by the large Heart Protection Study and the recent ASAP study, which showed no effect on high-density lipoprotein cholesterol. Future studies looking at antioxidants and CVE should use high dose of RRR-AT (800 IU/d) or the combination of RRR-AT (600 to 800 IU/d) plus AA (500 mg/d), because the latter would prevent any perceived pro-oxidant effect of AT. However, prescribing antioxidants such as AT and AA as an adjunctive therapy in primary prevention must await the results of ongoing clinical trials with these agents.

Acknowledgments

This work was supported by National Institutes of Health Grant NIHK24AT00596.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

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Related Article:

Six-Year Effect of Combined Vitamin C and E Supplementation on Atherosclerotic Progression: The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study

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Circulation 2003 107: 947-953. [Abstract] [Full Text]

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