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Effect of vitamin C on endothelial function in health and disease: A systematic review and meta-analysis of randomised controlled trials

  • Ammar W. Ashor
    Correspondence
    Corresponding author. Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle on Tyne NE4 5PL, UK. Tel.: +44 0191 248 1131.
    Affiliations
    Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle on Tyne NE4 5PL, UK

    College of Medicine, University of Al-Mustansiriyah, Baghdad, Iraq
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  • Jose Lara
    Affiliations
    Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle on Tyne NE4 5PL, UK
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  • John C. Mathers
    Affiliations
    Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle on Tyne NE4 5PL, UK
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  • Mario Siervo
    Affiliations
    Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle on Tyne NE4 5PL, UK
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      Highlights

      • Vitamin C supplementation improved endothelial function (EF).
      • The effect of vitamin C appeared to be dependent on health status.
      • Stronger effects in those with cardio-metabolic disorders.
      • No effect of vitamin C was observed in healthy volunteers.
      • Vitamin C dose greater than 500 mg/d was associated with beneficial effects on EF.

      Abstract

      Background

      Observational studies indicate that higher vitamin C intake is associated with reduced risk for cardiovascular diseases. However, randomised controlled trials (RCT) examining the effect of vitamin C on endothelial function (EF) have reported inconsistent results. The aims of this systematic review and meta-analysis were to determine the effect of vitamin C supplementation on EF and to investigate whether the effect was influenced by health status, study duration, dose and route of vitamin C administration.

      Methods

      We searched the Medline, Embase, Cochrane Library, and Scopus databases from inception to May 2013 for studies that met the following criteria: 1) RCT with adult participants, 2) vitamin C administered alone, 3) studies that quantified EF using commonly applied methods including ultrasound, plethysmography and pulse wave analysis.

      Results

      Pooling the data from 44 clinical trials showed a significant positive effect of vitamin C on EF (SMD: 0.50, 95% CI: 0.34, 0.66, P < 0.001). Stratification of the analysis by health outcome revealed improved EF in atherosclerotic (SMD: 0.84, 95% CI: 0.41, 1.26, P < 0.001), diabetic (SMD: 0.52, 95% CI: 0.21, 0.82, P < 0.001) and heart failure patients (SMD: 0.48, 95% CI: 0.08, 0.88, P < 0.02) after vitamin C supplementation. The effect size appeared to be unaffected by study design, duration, baseline plasma vitamin C concentration or route of administration of vitamin C. The meta-regression showed a significant positive association between vitamin C dose and improvement in EF (β: 0.00011, 95% CI: 0.00001, 0.00021, P = 0.03).

      Conclusions

      Vitamin C supplementation improved EF. The effect of vitamin C supplementation appeared to be dependent on health status, with stronger effects in those at higher cardiovascular disease risk.
      PROSPERO Database registration: CRD42013004567, http://www.crd.york.ac.uk/prospero/

      Keywords

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      References

        • Dahlof B.
        Cardiovascular disease risk factors: epidemiology and risk assessment.
        Am J Cardiol. 2010; 105: 3A-9A
        • Pober J.S.
        • Min W.
        • Bradley J.R.
        Mechanisms of endothelial dysfunction, injury, and death.
        Annu Rev Pathol. 2009; 4: 71-95
        • Cangemi R.
        • Angelico F.
        • Loffredo L.
        • Del Ben M.
        • Pignatelli P.
        • Martini A.
        • et al.
        Oxidative stress-mediated arterial dysfunction in patients with metabolic syndrome: effect of ascorbic acid.
        Free Radic Biol Med. 2007; 43: 853-859
        • Protogerou A.D.
        • Lekakis J.P.
        • Kontoyanni D.D.
        • Stamatelopoulos K.S.
        • Papaioannou T.G.
        • Tsotsoros N.D.
        • et al.
        Acute administration of vitamin C prolongs the duration of forearm reactive hyperemia in patients with hypercholesterolemia.
        Hellenic J Cardiol. 2002; 43: 108-115
        • Raitakari O.T.
        • Adams M.R.
        • McCredie R.J.
        • Griffiths K.A.
        • Stocker R.
        • Celermajer D.S.
        Oral vitamin C and endothelial function in smokers: short-term improvement, but no sustained beneficial effect.
        J Am Coll Cardiol. 2000; 35: 1616-1621
        • Silvestro A.
        • Scopacasa F.
        • Oliva G.
        • De Cristofaro T.
        • Iuliano L.
        • Brevetti G.
        Vitamin C prevents endothelial dysfunction induced by acute exercise in patients with intermittent claudication.
        Atherosclerosis. 2002; 165: 277-283
        • Versari D.
        • Daghini E.
        • Virdis A.
        • Ghiadoni L.
        • Taddei S.
        Endothelium-dependent contractions and endothelial dysfunction in human hypertension.
        Br J Pharmacol. 2009; 157: 527-536
        • Forstermann U.
        Nitric oxide and oxidative stress in vascular disease.
        Pflugers Arch. 2010; 459: 923-939
        • Siervo M.
        • Stephan B.C.
        • Feelisch M.
        • Bluck L.J.
        Measurement of in vivo nitric oxide synthesis in humans using stable isotopic methods: a systematic review.
        Free Radic Biol Med. 2011; 51: 795-804
        • May J.M.
        • Harrison F.E.
        Role of vitamin C in the function of the vascular endothelium.
        Antioxid Redox Signal. 2013; 19: 2068-2083
        • Salonen R.M.
        • Nyyssonen K.
        • Kaikkonen J.
        • Porkkala-Sarataho E.
        • Voutilainen S.
        • Rissanen T.H.
        • et al.
        Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study.
        Circulation. 2003; 107: 947-953
        • Wang Y.
        • Chun O.K.
        • Song W.O.
        Plasma and dietary antioxidant status as cardiovascular disease risk factors: a review of human studies.
        Nutrients. 2013; 5: 2969-3004
        • Watanabe H.
        • Kakihana M.
        • Ohtsuka S.
        • Sugishita Y.
        Randomized, double-blind, placebo-controlled study of the preventive effect of supplemental oral vitamin C on attenuation of development of nitrate tolerance.
        J Am Coll Cardiol. 1998; 31: 1323-1329
        • Darko D.
        • Dornhorst A.
        • Kelly F.J.
        • Ritter J.M.
        • Chowienczyk P.J.
        Lack of effect of oral vitamin C on blood pressure, oxidative stress and endothelial function in type II diabetes.
        Clin Sci. 2002; 103: 339-344
        • Magen E.
        • Viskoper R.
        • Mishal J.
        • Priluk R.
        • Berezovsky A.
        • Laszt A.
        • et al.
        Resistant arterial hypertension and hyperlipidemia: atorvastatin, not vitamin C, for blood pressure control.
        Isr Med Assoc J. 2004; 6: 742-746
        • Higgins J.P.T.
        • Green S.
        Guide to the contents of a cochrane protocol and review.
        Cochrane handbook for systematic reviews of interventions. John Wiley & Sons, Ltd, 2008: 51-79
        • Liberati A.
        • Altman D.G.
        • Tetzlaff J.
        • Mulrow C.
        • Gotzsche P.C.
        • Ioannidis J.P.
        • et al.
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
        BMJ. 2009; 339: b2700
        • Crowther M.
        • Lim W.
        • Crowther M.A.
        Systematic review and meta-analysis methodology.
        Blood. 2010; 116: 3140-3146
        • Cummings P.
        Arguments for and against standardized mean differences (effect sizes).
        Arch Pediatr Adolesc Med. 2011; 165: 592-596
        • Elbourne D.R.
        • Altman D.G.
        • Higgins J.P.
        • Curtin F.
        • Worthington H.V.
        • Vail A.
        Meta-analyses involving cross-over trials: methodological issues.
        Int J Epidemiol. 2002; 31: 140-149
        • Begg C.B.
        • Mazumdar M.
        Operating characteristics of a rank correlation test for publication bias.
        Biometrics. 1994; 50: 1088-1101
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • DuPont J.J.
        • Farquhar W.B.
        • Townsend R.R.
        • Edwards D.G.
        Ascorbic acid or L-arginine improves cutaneous microvascular function in chronic kidney disease.
        J Appl Physiol. 2011; 111: 1561-1567
        • Holowatz L.A.
        • Kenney W.L.
        Local ascorbate administration augments NO- and non-NO-dependent reflex cutaneous vasodilation in hypertensive humans.
        Am J Physiol Heart Circ Physiol. 2007; 293: H1090-H1096
        • Holowatz L.A.
        • Kenney W.L.
        Oral atorvastatin therapy increases nitric oxide-dependent cutaneous vasodilation in humans by decreasing ascorbate-sensitive oxidants.
        Am J Physiol Regul Integr Comp Physiol. 2011; 301: R763-R768
        • Holowatz L.A.
        • Thompson C.S.
        • Kenney W.L.
        Acute ascorbate supplementation alone or combined with arginase inhibition augments reflex cutaneous vasodilation in aged human skin.
        Am J Physiol Heart Circ Physiol. 2006; 291: H2965-H2970
        • Schindler T.H.
        • Nitzsche E.U.
        • Munzel T.
        • Olschewski M.
        • Brink I.
        • Jeserich M.
        • et al.
        Coronary vasoregulation in patients with various risk factors in response to cold pressor testing: contrasting myocardial blood flow responses to short- and long-term vitamin C administration.
        J Am Coll Cardiol. 2003; 42: 814-822
        • Basili S.
        • Tanzilli G.
        • Mangieri E.
        • Raparelli V.
        • Di Santo S.
        • Pignatelli P.
        • et al.
        Intravenous ascorbic acid infusion improves myocardial perfusion grade during elective percutaneous coronary intervention. Relationship with oxidative stress markers.
        JACC: Cardiovasc Interv. 2010; 3: 221-229
        • Ward N.C.
        • Hodgson J.M.
        • Croft K.D.
        • Burke V.
        • Beilin L.J.
        • Puddey I.B.
        The combination of vitamin C and grape-seed polyphenols increases blood pressure: a randomized, double-blind, placebo-controlled trial.
        J Hypertens. 2005; 23: 427-434
        • Gori T.
        • Stolfo G.
        • Sicuro S.
        • Dragoni S.
        • Lisi M.
        • Forconi S.
        • et al.
        Nitroglycerin protects the endothelium from ischaemia and reperfusion: human mechanistic insight.
        Br J Clin Pharmacol. 2007; : 145-150
        • Johnson B.D.
        • Mather K.J.
        • Newcomer S.C.
        • Mickleborough T.D.
        • Wallace J.P.
        Brachial artery flow-mediated dilation following exercise with augmented oscillatory and retrograde shear rate.
        Cardiovasc Ultrasound. 2012; 10
        • Kelly R.P.
        • Poo Yeo K.
        • Isaac H.B.
        • Lee C.-Y.J.
        • Huang S.H.
        • Teng L.
        • et al.
        Lack of effect of acute oral ingestion of vitamin C on oxidative stress, arterial stiffness or blood pressure in healthy subjects.
        Free Radic Res. 2008; 42: 514-522
        • Lisi M.
        • Dragoni S.
        • Leone M.C.
        • Munzel T.
        • Parker J.D.
        • Gori T.
        Acute (but not chronic) smoking paradoxically protects the endothelium from ischemia and reperfusion: insight into the “smoking paradox”.
        Clin Res Cardiol. 2013; 102: 387-389
        • Singh N.
        • Graves J.
        • Taylor P.D.
        • MacAllister R.J.
        • Singer D.R.J.
        Effects of a 'healthy' diet and of acute and long-term vitamin C on vascular function in healthy older subjects.
        Cardiovasc Res. 2002; 56: 118-125
        • Wilkinson I.B.
        • Megson I.L.
        • MacCallum H.
        • Sogo N.
        • Cockcroft J.R.
        • Webb D.J.
        Oral vitamin C reduces arterial stiffness and platelet aggregation in humans.
        J Cardiovasc Pharmacol. 1999; 34: 690-693
        • Antoniades C.
        • Tousoulis D.
        • Tountas C.
        • Tentolouris C.
        • Toutouza M.
        • Vasiliadou C.
        • et al.
        Vascular endothelium and inflammatory process, in patients with combined Type 2 diabetes mellitus and coronary atherosclerosis: the effects of vitamin C.
        Diabet Med. 2004; 21: 552-558
        • Schneider M.P.
        • Delles C.
        • Schmidt B.M.W.
        • Oehmer S.
        • Schwarz T.K.
        • Schmieder R.E.
        • et al.
        Superoxide scavenging effects of N-acetylcysteine and vitamin C in subjects with essential hypertension.
        Am J Hypertens. 2005; 18: 1111-1117
        • Ceriello A.
        • Esposito K.
        • Piconi L.
        • Ihnat M.
        • Thorpe J.
        • Testa R.
        • et al.
        Glucose “peak” and glucose “spike”: impact on endothelial function and oxidative stress.
        Diabetes Res Clin Pract. 2008; 82: 262-267
        • De Marchi S.
        • Prior M.
        • Rigoni A.
        • Zecchetto S.
        • Rulfo F.
        • Arosio E.
        Ascorbic acid prevents vascular dysfunction induced by oral glucose load in healthy subjects.
        Eur J Intern Med. 2012; 23: 54-57
        • Mullan B.A.
        • Ennis C.N.
        • Fee H.J.P.
        • Young I.S.
        • McCance D.R.
        Protective effects of ascorbic acid on arterial hemodynamics during acute hyperglycemia.
        Am J Physiol Heart Circ Physiol. 2004; 287: H1262-H1268
        • Mullan B.A.
        • Ennis C.N.
        • Fee H.J.P.
        • Young I.S.
        • McCance D.R.
        Pretreatment with intravenous ascorbic acid preserves endothelial function during acute hyperglycaemia (R1).
        Clin Exp Pharmacol Physiol. 2005; 32: 340-345
        • Bayerle-Eder M.
        • Pleiner J.
        • Mittermayer F.
        • Schaller G.
        • Roden M.
        • Waldhäusl W.
        • et al.
        Effect of systemic vitamin C on free fatty acid-induced lipid peroxidation.
        Diabetes Metab. 2004; 30: 433-439
        • Pleiner J.
        • Schaller G.
        • Mittermayer F.
        • Bayerle-Eder M.
        • Roden M.
        • Wolzt M.
        FFA-induced endothelial dysfunction can be corrected by vitamin C.
        J Clin Endocrinol Metab. 2002; 87: 2913-2917
        • Pleiner J.
        • Mittermayer F.
        • Schaller G.
        • MacAllister R.J.
        • Wolzt M.
        High doses of vitamin C reverse Escherichia coli endotoxin-induced hyporeactivity to acetylcholine in the human forearm.
        Circulation. 2002; 106: 1460-1464
        • Pleiner J.
        • Mittermayer F.
        • Schaller G.
        • Marsik C.
        • MacAllister R.J.
        • Wolzt M.
        Inflammation-induced vasoconstrictor hyporeactivity is caused by oxidative stress.
        J Am Coll Cardiol. 2003; 42: 1656-1662
        • Arcaro G.
        • Cretti A.
        • Balzano S.
        • Lechi A.
        • Muggeo M.
        • Bonora E.
        • et al.
        Insulin causes endothelial dysfunction in humans: sites and mechanisms.
        Circulation. 2002; 105: 576-582
        • Kanani P.M.
        • Sinkey C.A.
        • Browning R.L.
        • Allaman M.
        • Knapp H.R.
        • Haynes W.G.
        Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans.
        Circulation. 1999; 100: 1161-1168
        • Pleiner J.
        • Schaller G.
        • Mittermayer F.
        • Marsik C.
        • MacAllister R.J.
        • Kapiotis S.
        • et al.
        Intra-arterial vitamin C prevents endothelial dysfunction caused by ischemia-reperfusion.
        Atherosclerosis. 2008; 197: 383-391
        • Antoniades C.
        • Tousoulis D.
        • Tentolouris C.
        • Toutouza M.
        • Marinou K.
        • Goumas G.
        • et al.
        Effects of antioxidant vitamins C and E on endothelial function and thrombosis/fibrinolysis system in smokers.
        Thromb Haemost. 2003; 89: 990-995
        • Pellegrini M.P.
        • Newby D.E.
        • Johnston N.R.
        • Maxwell S.
        • Webb D.J.
        Vitamin C has no effect on endothelium-dependent vasomotion and acute endogenous fibrinolysis in healthy smokers.
        J Cardiovasc Pharmacol. 2004; 44: 117-124
        • Tousoulis D.
        • Antoniades C.
        • Tentolouris C.
        • Tsioufis C.
        • Toutouza M.
        • Toutouzas P.
        • et al.
        Effects of combined administration of vitamins C and E on reactive hyperemia and inflammatory process in chronic smokers.
        Atherosclerosis. 2003; 170: 261-267
        • Anderson R.A.
        • Evans L.M.
        • Ellis G.R.
        • Khan N.
        • Morris K.
        • Jackson S.K.
        • et al.
        Prolonged deterioration of endothelial dysfunction in response to postprandial lipaemia is attenuated by vitamin C in Type 2 diabetes.
        Diabet Med. 2006; 23: 258-264
        • Ceriello A.
        • Novials A.
        • Ortega E.
        • Canivell S.
        • Pujadas G.
        • La Sala L.
        • et al.
        Vitamin C further improves the protective effect of GLP-1 on the ischemia-reperfusion-like effect induced by hyperglycemia post-hypoglycemia in type 1 diabetes.
        Cardiovasc Diabetol. 2013; 12: 97
        • Chen H.
        • Karne R.J.
        • Hall G.
        • Campia U.
        • Panza J.A.
        • Cannon 3rd, R.O.
        • et al.
        High-dose oral vitamin C partially replenishes vitamin C levels in patients with Type 2 diabetes and low vitamin C levels but does not improve endothelial dysfunction or insulin resistance.
        Am J Physiol Heart Circ Physiol. 2006; 290: H137-H145
        • Guazzi M.
        • Berti M.
        • Belletti S.
        • Reina G.
        • Guazzi M.D.
        Exercise metaboreflex activation and endothelial function impairment in atrial fibrillation.
        Am J Physiol Heart Circ Physiol. 2006; 291: H2396-H2402
        • Lu Q.
        • Björkhem I.
        • Wretlind B.
        • Diczfalusy U.
        • Henriksson P.
        • Freyschuss A.
        Effect of ascorbic acid on microcirculation in patients with Type II diabetes: a randomized placebo-controlled cross-over study.
        Clin Sci. 2005; 108: 507-513
        • Mullan B.A.
        • Young I.S.
        • Fee H.
        • McCance D.R.
        Ascorbic acid reduces blood pressure and arterial stiffness in type 2 diabetes.
        Hypertension. 2002; 40: 804-809
        • Tousoulis D.
        • Antoniades C.
        • Tountas C.
        • Bosinakou E.
        • Kotsopoulou M.
        • Toutouzas P.
        • et al.
        Vitamin C affects thrombosis/fibrinolysis system and reactive hyperemia in patients with type 2 diabetes and coronary artery disease.
        Diabetes Care. 2003; 26: 2749-2753
        • Tousoulis D.
        • Antoniades C.
        • Vasiliadou C.
        • Kourtellaris P.
        • Koniari K.
        • Marinou K.
        • et al.
        Effects of atorvastatin and vitamin C on forearm hyperaemic blood flow, asymmentrical dimethylarginine levels and the inflammatory process in patients with type 2 diabetes mellitus.
        Heart. 2007; 93: 244-246
        • Duffy S.J.
        • Gokce N.
        • Holbrook M.
        • Hunter L.M.
        • Biegelsen E.S.
        • Huang A.
        • et al.
        Effect of ascorbic acid treatment on conduit vessel endothelial dysfunction in patients with hypertension.
        Am J Physiol Heart Circ Physiol. 2001; 280: H528-H534
        • Gokce N.
        • Keaney Jr., J.F.
        • Frei B.
        • Holbrook M.
        • Olesiak M.
        • Zachariah B.J.
        • et al.
        Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease.
        Circulation. 1999; 99: 3234-3240
        • Hamabe A.
        • Takase B.
        • Uehata A.
        • Kurita A.
        • Ohsuzu F.
        • Tamai S.
        Impaired endothelium-dependent vasodilation in the brachial artery in variant angina pectoris and the effect of intravenous administration of vitamin C.
        Am J Cardiol. 2001; 87: 1154-1159
        • Ellis G.R.
        • Anderson R.A.
        • Chirkov Y.Y.
        • Morris-Thurgood J.
        • Jackson S.K.
        • Lewis M.J.
        • et al.
        Acute effects of vitamin C on platelet responsiveness to nitric oxide donors and endothelial function in patients with chronic heart failure.
        J Cardiovasc Pharmacol. 2001; 37: 564-570
        • Hornig B.
        • Arakawa N.
        • Kohler C.
        • Drexler H.
        Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure.
        Circulation. 1998; : 363-368
        • Nightingale A.K.
        • Blackman D.J.
        • Field R.
        • Glover N.J.
        • Pegge N.
        • Mumford C.
        • et al.
        Role of nitric oxide and oxidative stress in baroreceptor dysfunction in patients with chronic heart failure.
        Clin Sci. 2003; 104: 529-535
        • Nightingale A.K.
        • Crilley J.G.
        • Pegge N.C.
        • Boehm E.A.
        • Mumford C.
        • Taylor D.J.
        • et al.
        Chronic oral ascorbic acid therapy worsens skeletal muscle metabolism in patients with chronic heart failure.
        Eur J Heart Fail. 2007; 9: 287-291
        • Williams M.J.A.
        • Sutherland W.H.F.
        • McCormick M.P.
        • De Jong S.A.
        • McDonald J.R.
        • Walker R.J.
        Vitamin C improves endothelial dysfunction in renal allograft recipients.
        Nephrol Dial Transplant. 2001; 16: 1251-1255
        • Fletcher A.E.
        • Breeze E.
        • Shetty P.S.
        Antioxidant vitamins and mortality in older persons: findings from the nutrition add-on study to the Medical Research Council Trial of Assessment and Management of Older People in the Community.
        Am J Clin Nutr. 2003; 78: 999-1010
        • Osganian S.K.
        • Stampfer M.J.
        • Rimm E.
        • Spiegelman D.
        • Hu F.B.
        • Manson J.E.
        • et al.
        Vitamin C and risk of coronary heart disease in women.
        J Am Coll Cardiol. 2003; 42: 246-252
        • Knekt P.
        • Ritz J.
        • Pereira M.A.
        • O'Reilly E.J.
        • Augustsson K.
        • Fraser G.E.
        • et al.
        Antioxidant vitamins and coronary heart disease risk: a pooled analysis of 9 cohorts.
        Am J Clin Nutr. 2004; 80: 1508-1520
        • Frei B.
        • Birlouez-Aragon I.
        • Lykkesfeldt J.
        Authors' perspective: what is the optimum intake of vitamin C in humans?.
        Crit Rev Food Sci Nutr. 2012; 52: 815-829
        • Cook N.R.
        • Albert C.M.
        • Gaziano J.M.
        • Zaharris E.
        • MacFadyen J.
        • Danielson E.
        • et al.
        A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study.
        Arch Intern Med. 2007; 167: 1610-1618
        • Sesso H.D.
        • Buring J.E.
        • Christen W.G.
        • Kurth T.
        • Belanger C.
        • MacFadyen J.
        • et al.
        Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial.
        JAMA. 2008; 300: 2123-2133
        • Michels A.J.
        • Frei B.
        Myths, artifacts, and fatal flaws: identifying limitations and opportunities in vitamin C research.
        Nutrients. 2013; 5: 5161-5192
        • Michels A.J.
        • Hagen T.M.
        • Frei B.
        Human genetic variation influences vitamin C homeostasis by altering vitamin C transport and antioxidant enzyme function.
        Annu Rev Nutr. 2013; 33: 45-70
        • May J.M.
        How does ascorbic acid prevent endothelial dysfunction?.
        Free Radic Biol Med. 2000; 28: 1421-1429
        • Padayatty S.J.
        • Katz A.
        • Wang Y.
        • Eck P.
        • Kwon O.
        • Lee J.H.
        • et al.
        Vitamin C as an antioxidant: evaluation of its role in disease prevention.
        J Am Coll Nutr. 2003; 22: 18-35
        • d'Uscio L.V.
        • Milstien S.
        • Richardson D.
        • Smith L.
        • Katusic Z.S.
        Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity.
        Circ Res. 2003; 92: 88-95
        • Muller-Delp J.M.
        Ascorbic acid and tetrahydrobiopterin: looking beyond nitric oxide bioavailability.
        Cardiovasc Res. 2009; 84: 178-179
        • Murphy M.E.
        Ascorbate and dehydroascorbate modulate nitric oxide-induced vasodilations of rat coronary arteries.
        J Cardiovasc Pharmacol. 1999; 34: 295-303
        • Halliwell B.
        Oxidative stress in cell culture: an under-appreciated problem?.
        FEBS Lett. 2003; 540: 3-6
        • Lindblad M.
        • Tveden-Nyborg P.
        • Lykkesfeldt J.
        Regulation of vitamin C homeostasis during deficiency.
        Nutrients. 2013; 5: 2860-2879
        • Frikke-Schmidt H.
        • Lykkesfeldt J.
        Role of marginal vitamin C deficiency in atherogenesis: in vivo models and clinical studies.
        Basic Clin Pharmacol Toxicol. 2009; 104: 419-433
        • Levine M.
        • Padayatty S.J.
        • Espey M.G.
        Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries.
        Adv Nutr. 2011; 2: 78-88
        • Monsen E.R.
        Dietary reference intakes for the antioxidant nutrients: vitamin C, vitamin E, selenium, and carotenoids.
        J Am Diet Assoc. 2000; 100: 637-640
        • Brubacher D.
        • Moser U.
        • Jordan P.
        Vitamin C concentrations in plasma as a function of intake: a meta-analysis.
        Int J Vitam Nutr Res. 2000; 70: 226-237
        • Davignon J.
        • Ganz P.
        Role of endothelial dysfunction in atherosclerosis.
        Circulation. 2004; 109: III27-32
        • Price K.D.
        • Price C.S.
        • Reynolds R.D.
        Hyperglycemia-induced latent scurvy and atherosclerosis: the scorbutic-metaplasia hypothesis.
        Med Hypotheses. 1996; 46: 119-129
        • Wilson J.X.
        Regulation of vitamin C transport.
        Annu Rev Nutr. 2005; 25: 105-125
        • Shantsila E.
        • Wrigley B.J.
        • Blann A.D.
        • Gill P.S.
        • Lip G.Y.
        A contemporary view on endothelial function in heart failure.
        Eur J Heart Fail. 2012; 14: 873-881
        • Fischer D.
        • Rossa S.
        • Landmesser U.
        • Spiekermann S.
        • Engberding N.
        • Hornig B.
        • et al.
        Endothelial dysfunction in patients with chronic heart failure is independently associated with increased incidence of hospitalization, cardiac transplantation, or death.
        Eur Heart J. 2005; 26: 65-69
        • Conney A.H.
        • Reidenberg M.M.
        Cigarette smoking, coffee drinking, and ingestion of charcoal-broiled beef as potential modifiers of drug therapy and confounders of clinical trials.
        J Pharmacol Exp Ther. 2012; 342: 9-14
        • Solzbach U.
        • Hornig B.
        • Jeserich M.
        • Just H.
        Vitamin C improves endothelial dysfunction of epicardial coronary arteries in hypertensive patients.
        Circulation. 1997; 96: 1513-1519
        • Taddei S.
        • Virdis A.
        • Ghiadoni L.
        • Magagna A.
        • Salvetti A.
        Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension.
        Circulation. 1998; 97: 2222-2229
        • Juraschek S.P.
        • Guallar E.
        • Appel L.J.
        • Miller 3rd, E.R.
        Effects of vitamin C supplementation on blood pressure: a meta-analysis of randomized controlled trials.
        Am J Clin Nutr. 2012; 95: 1079-1088
        • Houston M.C.
        The role of cellular micronutrient analysis, nutraceuticals, vitamins, antioxidants and minerals in the prevention and treatment of hypertension and cardiovascular disease.
        Ther Adv Cardiovasc Dis. 2010; 4: 165-183
        • Neunteufl T.
        • Heher S.
        • Katzenschlager R.
        • Wolfl G.
        • Kostner K.
        • Maurer G.
        • et al.
        Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain.
        Am J Cardiol. 2000; 86: 207-210
        • Modena M.G.
        • Bonetti L.
        • Coppi F.
        • Bursi F.
        • Rossi R.
        Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women.
        J Am Coll Cardiol. 2002; 40: 505-510
        • Inaba Y.
        • Chen J.A.
        • Bergmann S.R.
        Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis.
        Int J Cardiovasc Imaging. 2010; 26: 631-640
        • Nuesch E.
        • Trelle S.
        • Reichenbach S.
        • Rutjes A.W.
        • Tschannen B.
        • Altman D.G.
        • et al.
        Small study effects in meta-analyses of osteoarthritis trials: meta-epidemiological study.
        BMJ. 2010; 341: c3515
        • Lau J.
        • Ioannidis J.P.
        • Terrin N.
        • Schmid C.H.
        • Olkin I.
        The case of the misleading funnel plot.
        BMJ. 2006; 333: 597-600