Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease

Title, Lawrence M.; Cummings, Peter M.; Giddens, Karen; Genest, Jacques; Nassar, B.A.

doi:10.1016/s0735-1097(00)00809-3

Cited by 197 publications

(117 citation statements)

References 57 publications

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“…While previous studies have suggested that the benefits of folic acid on FMD are partly dependent on its homocysteine-lowering effect, 7,8 our present study suggests the effects are independent of homocysteine-lowering, confirming the findings of the other recent diabetic studies. 25,26 It has been realized that the oxidative stress of diabetes may lead to oxidation of tetrahydrobiopterin, an essential co-factor of eNOS, resulting in the uncoupling of the eNOS enzyme and a loss of NO availability.…”

Section: Discussionsupporting

confidence: 92%

“…Our FMD results demonstrate considerable inter-patient variation of FMD with a wide range of values noted with folic acid and placebo, which is similar to that seen in other studies which have used similar methodology. 7,8,21,23,25,[28][29][30] Despite this variability, our study was sufficiently powered to demonstrate the absolute 2.6% increase in FMD with as few as 18 patients in this cross-over design. 31,32 On the other hand, as our study was only powered according to the effect on FMD, this small sample size may have been insufficient to demonstrate a significant secondary effect on the inflammatory markers.…”

Section: Discussionmentioning

confidence: 88%

“…[7][8][9][10] However, when we started our study, there was limited information in subjects with diabetes mellitus. Using forearm plethysmography, van Etten et al 17 demonstrated that subjects with type 2 diabetes have impaired endothelium-dependent, serotonin-induced vasodilation and mildly reduced endotheliumindependent vasodilation in response to sodium nitroprusside.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3]6 We and others have demonstrated that folic acid can significantly improve endothelium-dependent vasodilation in patients with coronary artery disease, [7][8][9][10] asymptomatic hyperhomocysteinemia, 11,12 and asymptomatic familial hypercholesterolemia. 13,14 While this benefit may in part be related to homocysteinelowering, 7,8 other studies suggest that the restoration of endothelial function by folates may be independent of its homocysteine-lowering effect. 10,14 In fact, 5-methyltetrahydrofolate, the active metabolite of folic acid, may have direct effects on uncoupled eNOS, which results in increased release of NO and decreased release of superoxide anion.…”

Section: Introductionmentioning

confidence: 99%

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Folic acid improves endothelial dysfunction in type 2 diabetes - an effect independent of homocysteine-lowering

Title

Giddens

et al. 2006

Vasc Med

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Diabetes is associated with endothelial dysfunction, which in part may be related to uncoupling of the endothelial nitric oxide (NO) synthase enzyme, thus reducing the availability of NO. As folates may potentially reverse the uncoupling of NO synthase, we wanted to determine whether folic acid supplementation could modulate endothelial function and markers of inflammation in patients with type 2 diabetes without vascular disease. Nineteen patients with type 2 diabetes were treated with folic acid (10 mg/day for 2 weeks) versus placebo in a randomized, placebo-controlled, cross-over study with an 8-week washout period between treatments. Fasting endothelium-dependent flow-mediated dilatation (FMD) of the brachial artery, endothelium-independent nitroglycerin-mediated dilatation (NMD), plasma homocysteine, serum lipids, folate, and inflammatory markers (high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, interleukin-18, tumor necrosis factor-alpha) were assessed after each 2-week treatment period. Folic acid supplementation significantly increased folate levels and lowered plasma homocysteine levels. Folic acid significantly improved FMD compared to placebo (5.8 Ϯ 4.8% vs 3.2 Ϯ 2.7%, p ϭ 0.02). There were no significant effects of folic acid supplementation on lipids, NMD, or the inflammatory markers. There was no relationship between the change in homocysteine and the improvement in FMD. Thus, 2 weeks of folic acid supplementation can improve endothelial dysfunction in type 2 diabetics independent of homocysteinelowering, but does not modulate markers of inflammation.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Folic acid improves endothelial dysfunction in type 2 diabetes - an effect independent of homocysteine-lowering

Title

Giddens

et al. 2006

Vasc Med

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“…The subject of pharmacological treatment of endothelial dysfunction has been reviewed by myself and others recently (52,94,95). Suffice it to say, interventions associated with favourable cardiovascular outcomes have been associated with attenuation of endothelial dysfunction for the most part (96)(97)(98)(99)(100)(101). The notable exception to this is hormone replacement therapy, which has been associated with improvement in endothelium-dependent vasomotion, but not cardiovascular outcome.…”

Section: Relationship Of Endothelial Function To Risk Factors and Thementioning

confidence: 99%

Arterial stiffness or endothelial dysfunction as a surrogate marker of vascular risk

Anderson

2006

Canadian Journal of Cardiology

154

113

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T he understanding of the pathophysiology of atherosclerosis and its vascular complications has increased dramatically over the past decade. Numerous measurable biomarkers play a role in the atherosclerosis process, and are associated with clinically important vascular events. Not only has their evaluation advanced our knowledge of the atherosclerotic process but it has also accelerated a search for new diagnostic tools to aid in risk stratification. Putative factors include soluble biomarkers and imaging assessments of vascular structure and function. The endothelium plays a key role in vascular homeostasis through the release of a variety of paracrine factors that interact with platelets, inflammatory cells and the vessel wall. The endothelium's central location allows it to sense and respond to a variety of perturbations. Endothelial dysfunction is an early marker of disease. Risk factors can also affect mechanical properties such as arterial stiffness, which is now recognized as a major contributor to systolic hypertension in elderly people. Methods of assessing endothelial function and arterial stiffness are available for clinical research and recent evidence suggests that these measures may provide important prognostic information. ATTRIBUTES OF A SURROGATE BIOMARKEREpidemiological studies, such as Framingham, have allowed longitudinal assessment of cardiovascular events and the development of simple scoring tables for risk calculation (1,2). These factors involved include blood pressure, lipid profile, smoking status and age. More recently, many factors thought to be associated with the atherosclerotic process have been studied. Some of these have been shown to correlate with clinical outcomes and have been deemed biomarkers (3,4). However, association does not necessarily imply causation and, due to a variety of limitations, most of these markers will not be useful for the clinical evaluation of risk or drug therapy (5). To become clinically important, a biomarker must fulfill the criteria for a surrogate marker. A surrogate substitutes for clinically important end points with respect to how an individual feels, functions or survives. Classic examples include blood pressure and low density lipoprotein cholesterol. These are targets of treatment. A surrogate should meet the following criteria:• Adds independent information above currently used criteria;• Is reliably and reproducibly measured;• Accounts for a significant proportion of disease risk;• Provides good predictive value;• Is reasonably associated with the underlying pathophysiology;• If it is to be used in risk prevention, is present before the clinical appearance of the outcome; and• Is available and practical for widespread application (5-8). ADVANCES IN VASCULAR BIOLOGY

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Natural Limits of Pregnancy Testing in Relation to the Expected Menstrual Period

Wilcox

Baird²,

Dunson³

et al. 2001

JAMA

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Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease

Abstract: Folic acid supplementation significantly improved endothelial dysfunction in patients with coronary atherosclerosis. Further clinical trials are required to determine whether folic acid supplementation may reduce cardiovascular events.

Cited by 197 publications

References 57 publications

Folic acid improves endothelial dysfunction in type 2 diabetes - an effect independent of homocysteine-lowering

Folic acid improves endothelial dysfunction in type 2 diabetes - an effect independent of homocysteine-lowering

Arterial stiffness or endothelial dysfunction as a surrogate marker of vascular risk

Natural Limits of Pregnancy Testing in Relation to the Expected Menstrual Period

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