(Circulation. 2001;103:e117.)
© 2001 American Heart Association, Inc.
Correspondence |
Vitamin C and Coronary Microcirculation
Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1372, MarkL@intra.niddk.nih.gov
To the Editor:
In their study on the short-term effects of vitamin C on coronary microcirculation, Kaufmann et al1 used adenosine to increase myocardial blood flow, which was assessed by positron emission tomography. When compared with controls, smokers showed an attenuated response that was corrected by 3 g of vitamin C given intravenously over 10 minutes. The authors conclude that cigarette smoke causes oxidant damage that is reversed by vitamin C.
Unfortunately, the study conditions are not
physiological, which is a consequence of the
sigmoidal vitamin C dose-concentration relationship. When vitamin C is
given orally, it is completely absorbed until the dose exceeds 200
mg.2 Consumption of 200 mg of
vitamin C daily, which occurs in a typical Mediterranean diet, results
in a plasma concentration of 
70 µmol/L. Many cells, such as
neutrophils, actively transport vitamin C and saturate before plasma.
Saturation of cells by 70 µmol/L corresponds to the maximal velocity
of the main tissue vitamin C transporter, sodium-dependent
vitamin C transporter
2.3 4 Higher
vitamin C doses do not increase long-term plasma vitamin C
concentrations because of decreased absorption and increased renal
excretion, which begin when plasma concentrations exceed 60 to 70
µmol/L. With an oral dose of 1.25 g, less than half the dose is
absorbed, and all that is absorbed is
excreted.2 In contrast, when
vitamin C is given intravenously, the limiting absorptive
mechanisms are bypassed, and much higher plasma concentrations are
achieved. Thus, when 1.25 g of vitamin C is given
intravenously over 5 minutes, a peak plasma concentration
of 700 µmol/L is attained, which falls to 200 µmol/L in 2
hours.2 Almost the entire
dose is excreted in the urine in 12 hours. We estimate that 3 g of
vitamin C given intravenously, as was done in Kaufmann et
al’s1 study, will result in
a plasma concentration of 1500 µmol/L, which will fall by perhaps
a few hundred micromoles per liter during the course of the
study.
These vitamin C concentrations, which are 10 to 20 times those that can be obtained by oral intake, are clearly unphysiological. The response of the tissues to such pharmacological concentrations5 may have little bearing on vitamin C actions at the more modest physiological concentrations. Although this study demonstrates the utility of using high-dose intravenous vitamin C to produce antioxidant effects in experimental situations, it does not show that vitamin C has such actions at physiological concentrations and, unfortunately, it cannot form the basis for using vitamin C in primary or secondary prevention of coronary heart disease. A healthy diet containing at least 5 servings of varied fruits and vegetables a day will supply all the vitamin C we need.
References
-
Kaufmann
PA, Gnecchi-Ruscone T, di Terlizzi M, et al. Coronary heart
disease in smokers: vitamin C restores coronary
microcirculatory function.
Circulation. 2000;102:1233–1238.
[Abstract/Free Full Text]
-
Levine M,
Conry-Cantilena C, Wang Y, et al. Vitamin C pharmacokinetics in healthy
volunteers: evidence for a recommended dietary allowance.
Proc Natl Acad Sci
USA. 1996;93:3704–3709.
[Abstract/Free Full Text]
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Tsukaguchi H,
Tokui T, Mackenzie B, et al. A family of mammalian Na+-dependent
L-ascorbic acid transporters.
Nature. 1999;399:70–75.[Medline]
[Order article via Infotrieve]
-
Daruwala R, Song
J, Koh WS, et al. Cloning and functional characterization of the human
sodium-dependent vitamin C transporters hSVCT1 and hSVCT2.
FEBS Lett. 1999;460:480–484.[Medline]
[Order article via Infotrieve]
-
Padayatty SJ,
Levine M. Reevaluation of ascorbate in cancer treatment: emerging
evidence, open minds and serendipity. J Am Coll Nutr. 2000;19:423–425.
[Abstract/Free Full Text]
Response
Hammersmith Hospital, Imperial College School of Medicine, London, UK
Department of Cardiology, University Hospital, Zurich, Switzerland
Klinik und Poliklinik fur Nuklearmedizin, Universitat Muenster, Muenster, Germany
We appreciate Drs Padayatty and Levine’s interest in our article.R1 We share their concerns about the direct extrapolation of our experimental data into daily clinical practice. In fact, in the discussion section of the article, we stated that "our study design does not allow us to comment on the long-term effects of vitamin C." However, the aim of our study was to prove the hypothesis that the noxious effects of cigarette smoke on the function of the coronary microcirculation are due, at least in part, to oxidative stress. Because smokers have reduced plasma and tissue levels of vitamin C, we thought to provide a supplement of this natural antioxidant at a dose that has previously been shown to improve endothelial dysfunction in smokers.R2 Although we agree that the plasma concentration of vitamin C achieved after such a high intravenous dose is not physiological, it had no appreciable effect in nonsmokers. Therefore, we believe that the effect of vitamin C on flow reserve in smokers was indeed due to its scavenging and antioxidant properties and that, at least in our study population, the impairment of the coronary microcirculation in smokers was still reversible, as proven by the normalization of flow reserve observed after the intravenous administration of vitamin C.
Although we agree that higher vitamin C doses do not increase long-term plasma vitamin C concentrations in healthy volunteers because of decreased absorption and increased renal excretion, this does not necessarily apply to smokers, who have reduced plasma and tissue levels of this vitamin. This depletion is thought to be due to increased consumption as the result of greater oxidative stress and to dietary differences.R3 This questions, in daily practice, the value of theoretically valid recommendations such as "a healthy diet containing at least 5 servings of varied fruits." Therefore, we believe that only a study testing the potential effect of long-term supplementation of vitamin C on coronary flow reserve in smokers could properly address the concerns of Drs Padayatty and Levine.
References
-
Kaufmann
PA, Gnecchi-Ruscone T, di Terlizzi M, et al. Coronary heart
disease in smokers: vitamin C restores coronary
microcirculatory function.
Circulation. 2000;102:1233–1238.
-
Solzbach U, Hornig
B, Jeserich M, et al. Vitamin C improves endothelial
dysfunction of epicardial coronary arteries in hypertensive
patients. Circulation. 1997;96:1513–1519.
[Abstract/Free Full Text]
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Kritchevsky SB,
Shimakawa T, Tell GS, et al. Dietary antioxidants and carotid artery
wall thickness: the ARIC study: atherosclerosis risk in
communities study. Circulation. 1995;92:2141–2150.
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