Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS)

Stephens, Nigel; Parsons, Ann; Brown, M. J.; Schofield, Peter M.; Kelly, Frank J.; Cheeseman, Kevin H.; Mitchinson, M. J.

doi:10.1016/s0140-6736(96)90866-1

Cited by 1,911 publications

(499 citation statements)

References 28 publications

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“…As such, antioxidant therapy has been successful for the above cardiometabolic disorders by clinical trials or basical science studies 51, 52, 53, 54, 55. Additonally, Keyamura et al.…”

Section: Discussionmentioning

confidence: 99%

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Hsu

Zhao²,

Lin

et al. 2016

JAHA

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BackgroundAsymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered a risk factor for the pathogenesis of cardiovascular diseases. Simvastatin, a lipid‐lowering drug with other pleiotropic effects, has been widely used for treatment of cardiovascular diseases. However, little is known about the effect and underlying molecular mechanisms of ADMA on the effectiveness of simvastatin in the vascular system.Methods and ResultsWe conducted a prospective cohort study to enroll 648 consecutive patients with coronary artery disease for a follow‐up period of 8 years. In patients with plasma ADMA level ≥0.49 μmol/L (a cut‐off value from receiver operating characteristic curve), statin treatment had no significant effect on cardiovascular events. We also conducted randomized, controlled studies using in vitro and in vivo models. In endothelial cells, treatment with ADMA (≥0.5 μmol/L) impaired simvastatin‐induced nitric oxide (NO) production, endothelial NO synthase (eNOS) phosphorylation, and angiogenesis. In parallel, ADMA markedly increased the activity of NADPH oxidase (NOX) and production of reactive oxygen species (ROS). The detrimental effects of ADMA on simvastatin‐induced NO production and angiogenesis were abolished by the antioxidant, N‐acetylcysteine, NOX inhibitor, or apocynin or overexpression of dimethylarginine dimethylaminohydrolase 2 (DDAH‐2). Moreover, in vivo, ADMA administration reduced Matrigel plug angiogenesis in wild‐type mice and decreased simvastatin‐induced eNOS phosphorylation in aortas of apolipoprotein E–deficient mice, but not endothelial DDAH‐2‐overexpressed aortas.ConclusionsWe conclude that ADMA may trigger NOX‐ROS signaling, which leads to restricting the simvastatin‐conferred protection of eNOS activation, NO production, and angiogenesis as well as the clinical outcome of cardiovascular events.

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“…As such, antioxidant therapy has been successful for the above cardiometabolic disorders by clinical trials or basical science studies 51, 52, 53, 54, 55. Additonally, Keyamura et al.…”

Section: Discussionmentioning

confidence: 99%

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Hsu

Zhao²,

Lin

et al. 2016

JAHA

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“…However, in the GISSI-Prevenzione trial [77], using higher doses of vitamin E (300 mg/d), the mortality group was similar to the placebo group. In contrast, the rate of nonfatal myocardial infarctions was significantly reduced in the CHAOS study using 400 and 800 IU of vitamin E per day [78]. Vitamin E is nontoxic [79] and in animal experiments has been shown to be neither mutagenic, teratogenic, nor carcinogenic.…”

Section: Vitamin Ementioning

confidence: 99%

Natural and synthetic substances related to human health (IUPAC Technical Report)

Topliss¹,

Am²,

Ernst³

et al. 2002

Pure and Applied Chemistry

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Republication or reproduction of this report or its storage and/or dissemination by electronic means isAbstract: There is a widespread belief on the part of the general public that natural substances are inherently superior to synthetic substances with regard to efficacy and safety in matters related to human health. This question is examined by reviewing the therapeutic use of drugs and herbal medicine preparations, the role of vitamins and nutrients, and the effects of toxic substances. A comparison of the characteristics of natural and synthetic substances within these categories shows a similar range of favorable and unfavorable effects. It is apparent that molecular structure and dose determine the effect of substances on human health, not whether they are of natural or synthetic origin. INTRODUCTION (J. G. Topliss)

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“…It is well established that subclinical heart disease is associated with abnormal acute-phase markers e.g. low albumin (Phillips et al 1989;Kuller et al 1991;Gillum & Makuc, 1992), elevated fibrinogen (Yarnell et al 1991) and leucocyte counts (Sipe, 1985), thus it is possible that subclinical disease may in some way reduce the available vitamin E. Furthermore, there is also some evidence which suggests that vitamin E supplementation was of benefit in preventing new attacks of IHD in a secondary prevention trial (Stephens et al 1996). Nevertheless, a study from my own laboratory, which examined blood from 200 randomly-selected subjects in Belfast and Toulouse, found absolutely no difference in either vitamin E or vitamin E : cholesterol between the the urban group were from Chiang Mai, the rural group from a district approximately 120…”

Section: Vitamin Ementioning

confidence: 99%

Impact of disease on markers of micronutrient status

Thurnham

1997

Proc. Nutr. Soc.

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Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS)

Cited by 1,911 publications

References 28 publications

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Natural and synthetic substances related to human health (IUPAC Technical Report)

Impact of disease on markers of micronutrient status

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