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
- Cardiovascular disease risk factors: epidemiology and risk assessment.Am J Cardiol. 2010; 105: 3A-9A
- Mechanisms of endothelial dysfunction, injury, and death.Annu Rev Pathol. 2009; 4: 71-95
- Oxidative stress-mediated arterial dysfunction in patients with metabolic syndrome: effect of ascorbic acid.Free Radic Biol Med. 2007; 43: 853-859
- Acute administration of vitamin C prolongs the duration of forearm reactive hyperemia in patients with hypercholesterolemia.Hellenic J Cardiol. 2002; 43: 108-115
- Oral vitamin C and endothelial function in smokers: short-term improvement, but no sustained beneficial effect.J Am Coll Cardiol. 2000; 35: 1616-1621
- Vitamin C prevents endothelial dysfunction induced by acute exercise in patients with intermittent claudication.Atherosclerosis. 2002; 165: 277-283
- Endothelium-dependent contractions and endothelial dysfunction in human hypertension.Br J Pharmacol. 2009; 157: 527-536
- Nitric oxide and oxidative stress in vascular disease.Pflugers Arch. 2010; 459: 923-939
- Measurement of in vivo nitric oxide synthesis in humans using stable isotopic methods: a systematic review.Free Radic Biol Med. 2011; 51: 795-804
- Role of vitamin C in the function of the vascular endothelium.Antioxid Redox Signal. 2013; 19: 2068-2083
- 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
- Plasma and dietary antioxidant status as cardiovascular disease risk factors: a review of human studies.Nutrients. 2013; 5: 2969-3004
- 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
- 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
- Resistant arterial hypertension and hyperlipidemia: atorvastatin, not vitamin C, for blood pressure control.Isr Med Assoc J. 2004; 6: 742-746
- Guide to the contents of a cochrane protocol and review.Cochrane handbook for systematic reviews of interventions. John Wiley & Sons, Ltd, 2008: 51-79
- The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.BMJ. 2009; 339: b2700
- Systematic review and meta-analysis methodology.Blood. 2010; 116: 3140-3146
- Arguments for and against standardized mean differences (effect sizes).Arch Pediatr Adolesc Med. 2011; 165: 592-596
- Meta-analyses involving cross-over trials: methodological issues.Int J Epidemiol. 2002; 31: 140-149
- Operating characteristics of a rank correlation test for publication bias.Biometrics. 1994; 50: 1088-1101
- Measuring inconsistency in meta-analyses.BMJ. 2003; 327: 557-560
- Ascorbic acid or L-arginine improves cutaneous microvascular function in chronic kidney disease.J Appl Physiol. 2011; 111: 1561-1567
- 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
- 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
- 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
- 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
- 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
- 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
- Nitroglycerin protects the endothelium from ischaemia and reperfusion: human mechanistic insight.Br J Clin Pharmacol. 2007; : 145-150
- Brachial artery flow-mediated dilation following exercise with augmented oscillatory and retrograde shear rate.Cardiovasc Ultrasound. 2012; 10
- 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
- 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
- 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
- Oral vitamin C reduces arterial stiffness and platelet aggregation in humans.J Cardiovasc Pharmacol. 1999; 34: 690-693
- 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
- Superoxide scavenging effects of N-acetylcysteine and vitamin C in subjects with essential hypertension.Am J Hypertens. 2005; 18: 1111-1117
- Glucose “peak” and glucose “spike”: impact on endothelial function and oxidative stress.Diabetes Res Clin Pract. 2008; 82: 262-267
- Ascorbic acid prevents vascular dysfunction induced by oral glucose load in healthy subjects.Eur J Intern Med. 2012; 23: 54-57
- Protective effects of ascorbic acid on arterial hemodynamics during acute hyperglycemia.Am J Physiol Heart Circ Physiol. 2004; 287: H1262-H1268
- Pretreatment with intravenous ascorbic acid preserves endothelial function during acute hyperglycaemia (R1).Clin Exp Pharmacol Physiol. 2005; 32: 340-345
- Effect of systemic vitamin C on free fatty acid-induced lipid peroxidation.Diabetes Metab. 2004; 30: 433-439
- FFA-induced endothelial dysfunction can be corrected by vitamin C.J Clin Endocrinol Metab. 2002; 87: 2913-2917
- High doses of vitamin C reverse Escherichia coli endotoxin-induced hyporeactivity to acetylcholine in the human forearm.Circulation. 2002; 106: 1460-1464
- Inflammation-induced vasoconstrictor hyporeactivity is caused by oxidative stress.J Am Coll Cardiol. 2003; 42: 1656-1662
- Insulin causes endothelial dysfunction in humans: sites and mechanisms.Circulation. 2002; 105: 576-582
- Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans.Circulation. 1999; 100: 1161-1168
- Intra-arterial vitamin C prevents endothelial dysfunction caused by ischemia-reperfusion.Atherosclerosis. 2008; 197: 383-391
- Effects of antioxidant vitamins C and E on endothelial function and thrombosis/fibrinolysis system in smokers.Thromb Haemost. 2003; 89: 990-995
- Vitamin C has no effect on endothelium-dependent vasomotion and acute endogenous fibrinolysis in healthy smokers.J Cardiovasc Pharmacol. 2004; 44: 117-124
- Effects of combined administration of vitamins C and E on reactive hyperemia and inflammatory process in chronic smokers.Atherosclerosis. 2003; 170: 261-267
- 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
- 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
- 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
- Exercise metaboreflex activation and endothelial function impairment in atrial fibrillation.Am J Physiol Heart Circ Physiol. 2006; 291: H2396-H2402
- 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
- Ascorbic acid reduces blood pressure and arterial stiffness in type 2 diabetes.Hypertension. 2002; 40: 804-809
- 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
- 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
- Effect of ascorbic acid treatment on conduit vessel endothelial dysfunction in patients with hypertension.Am J Physiol Heart Circ Physiol. 2001; 280: H528-H534
- Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease.Circulation. 1999; 99: 3234-3240
- 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
- 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
- Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure.Circulation. 1998; : 363-368
- Role of nitric oxide and oxidative stress in baroreceptor dysfunction in patients with chronic heart failure.Clin Sci. 2003; 104: 529-535
- Chronic oral ascorbic acid therapy worsens skeletal muscle metabolism in patients with chronic heart failure.Eur J Heart Fail. 2007; 9: 287-291
- Vitamin C improves endothelial dysfunction in renal allograft recipients.Nephrol Dial Transplant. 2001; 16: 1251-1255
- 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
- Vitamin C and risk of coronary heart disease in women.J Am Coll Cardiol. 2003; 42: 246-252
- Antioxidant vitamins and coronary heart disease risk: a pooled analysis of 9 cohorts.Am J Clin Nutr. 2004; 80: 1508-1520
- Authors' perspective: what is the optimum intake of vitamin C in humans?.Crit Rev Food Sci Nutr. 2012; 52: 815-829
- 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
- 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
- Myths, artifacts, and fatal flaws: identifying limitations and opportunities in vitamin C research.Nutrients. 2013; 5: 5161-5192
- Human genetic variation influences vitamin C homeostasis by altering vitamin C transport and antioxidant enzyme function.Annu Rev Nutr. 2013; 33: 45-70
- How does ascorbic acid prevent endothelial dysfunction?.Free Radic Biol Med. 2000; 28: 1421-1429
- Vitamin C as an antioxidant: evaluation of its role in disease prevention.J Am Coll Nutr. 2003; 22: 18-35
- Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity.Circ Res. 2003; 92: 88-95
- Ascorbic acid and tetrahydrobiopterin: looking beyond nitric oxide bioavailability.Cardiovasc Res. 2009; 84: 178-179
- Ascorbate and dehydroascorbate modulate nitric oxide-induced vasodilations of rat coronary arteries.J Cardiovasc Pharmacol. 1999; 34: 295-303
- Oxidative stress in cell culture: an under-appreciated problem?.FEBS Lett. 2003; 540: 3-6
- Regulation of vitamin C homeostasis during deficiency.Nutrients. 2013; 5: 2860-2879
- Role of marginal vitamin C deficiency in atherogenesis: in vivo models and clinical studies.Basic Clin Pharmacol Toxicol. 2009; 104: 419-433
- Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries.Adv Nutr. 2011; 2: 78-88
- Dietary reference intakes for the antioxidant nutrients: vitamin C, vitamin E, selenium, and carotenoids.J Am Diet Assoc. 2000; 100: 637-640
- Vitamin C concentrations in plasma as a function of intake: a meta-analysis.Int J Vitam Nutr Res. 2000; 70: 226-237
- Role of endothelial dysfunction in atherosclerosis.Circulation. 2004; 109: III27-32
- Hyperglycemia-induced latent scurvy and atherosclerosis: the scorbutic-metaplasia hypothesis.Med Hypotheses. 1996; 46: 119-129
- Regulation of vitamin C transport.Annu Rev Nutr. 2005; 25: 105-125
- A contemporary view on endothelial function in heart failure.Eur J Heart Fail. 2012; 14: 873-881
- 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
- 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
- Vitamin C improves endothelial dysfunction of epicardial coronary arteries in hypertensive patients.Circulation. 1997; 96: 1513-1519
- Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension.Circulation. 1998; 97: 2222-2229
- Effects of vitamin C supplementation on blood pressure: a meta-analysis of randomized controlled trials.Am J Clin Nutr. 2012; 95: 1079-1088
- 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
- Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain.Am J Cardiol. 2000; 86: 207-210
- Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women.J Am Coll Cardiol. 2002; 40: 505-510
- Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis.Int J Cardiovasc Imaging. 2010; 26: 631-640
- Small study effects in meta-analyses of osteoarthritis trials: meta-epidemiological study.BMJ. 2010; 341: c3515
- The case of the misleading funnel plot.BMJ. 2006; 333: 597-600
Article info
Publication history
Published online: April 16, 2014
Accepted:
April 5,
2014
Received in revised form:
April 5,
2014
Received:
February 11,
2014
Footnotes
☆The material presented in this manuscript is original and it has not been submitted for publication elsewhere while under consideration by Atherosclerosis.
Identification
Copyright
© 2014 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
