Long-term vitamin E supplementation fails to reduce lipid peroxidation in people at cardiovascular risk: analysis of underlying factors

Background

The "oxidative hypothesis" of atherosclerosis proposes that oxidative modification of lipids in low-density lipoproteins (LDL) contributes to atherogenesis [1, 2]. Antioxidants that are effective against lipid peroxidation should therefore reduce atherosclerosis and hence afford protection from cardiovascular diseases (CVD)[1]. In contrast to a) epidemiological evidence that antioxidants taken with the diet or as supplements reduce cardiovascular (CV) risk [3], and b) experimental data supporting its anti-atherogenic properties [4], vitamin E failed to show any beneficial effect in recent large intervention studies [5]. In two large-scale trials, long-term supplementation with vitamin E (300–400 lU/day) failed to reduce cardiovascular events in post-myocardial infarction patients (GISSI-Prevenzione [6]) and in subjects at high CV risk (HOPE [7]). In the trial conducted by our group (Primary Prevention Project, PPP [8]), vitamin E (300 mg/day) taken over three years also showed no effect on the incidence of cardiovascular events in individuals with one or more major risk factors (see Methods). Therefore, the question whether vitamin E had an effective in vivo antioxidant action in the populations under study in these trials is under debate [9–12].

When these studies were designed, the antioxidant efficacy of vitamin E in humans had not been demonstrated in vivo because of the lack of reliable methods [13]. Measurement of urinary or circulating F2-isoprostanes (iPF₂ or F₂-isoP) is now accepted as a reliable tool for evaluating the rate of lipid peroxidation in vivo[9, 14–16]. Using urinary excretion of 8-epi-PGF_2α (also termed iPF_2α-III or 15-F_2t-isoP) as a biomarker, it has been shown that short-term administration of vitamin E (600 mg/day for 14 days) reduced in vivo lipid peroxidation in some clinical settings where oxidative stress is abnormally high, e.g., diabetes mellitus (-37%), hypercholesterolemia (-58%) and cystic fibrosis (-42%) [17–19]. In contrast, vitamin E had no antioxidant activity in conditions where lipid peroxidation was normal [20]. No data are available on the antioxidant effect of longer-term supplementation with vitamin E in subjects at moderate/high cardiovascular risk.

Using a highly selective and validated mass spectrometric assay for 8-epi-PGF_2α[21], we measured in vivo lipid peroxidation in PPP trial participants who had taken vitamin E daily for about three years vs those who did not take vitamin E.

Methods

PPP...