Published online before print January 19, 2004, doi: 10.1161/01.HYP.0000112025.25724.8a
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(Hypertension. 2004;43:e5.)
© 2004 American Heart Association, Inc.
Hypertension Electronic Pages |
Letter: Vitamin C in Heart Failure: Hype or Hope?
Wales Heart Research Institute,, University of Wales College of Medicine, Cardiff, UK
To the Editor:
Free radical-mediated oxidative processes are believed to play a key role in the pathogenesis of many cardiovascular disorders, including congestive heart failure.1 Consequently, a large number of mechanistic studies have investigated the potential benefits of antioxidant treatment. In NHANES 1, individuals reporting a high dietary intake of antioxidants (including vitamin C [VC]) had a significantly lower death rate from all causes, especially coronary heart disease.2 However, subsequent prospective, randomized clinical trials in high-risk populations failed to confer a benefit.3
In this light, we read with great interest the article by Piccirillo et al4 demonstrating that a short (presumably intravenous) infusion of 2.5 g VC (as corrected by the authors) improved baroreflex sensitivity (BRS) and vagal sinus modulation in patients with congestive heart failure. The former finding largely confirms our own recent work, showing that acute administration of 2 g VC (raising plasma levels from 60.2±30.1 to 786±415.3 µmol/L; P<0.001) improves BRS.5 As Piccirillo et al discuss, key issues are to "understand whether the beneficial effect persists during chronic oral administration and whether it helps to improve survival." So far as the former is concerned, we recently also demonstrated that long-term oral VC treatment (4 g/d, raising plasma ascorbic acid values from 42.7±13 to 127.3±59.5 µmol/L; P<0.001) failed to improve BRS.5 This failure in our view makes it the more important to understand the mechanism that underlies the improvement after short-term VC treatment. One obvious explanation might be the absence of free-radical scavenging at lower concentrations6; however, this becomes questionable, given that Piccirillo et al found an almost identical improvement, despite using a VC dose that was 2 orders of magnitude lower (did the authors measure the plasma VC levels achieved?).
The mechanisms by which VC improves a variety of established cardiovascular risk factors, such as increased arterial stiffness,7 and surrogate markers, such as those of oxidative stress,8 flow-mediated dilatation,9 or increased platelet aggregation,10 are frankly not entirely understood and might be due to the aforementioned antioxidative and free radical-scavenging effects8 or to increased nitric oxide bioavailability11 resulting from increased nitric oxide production via upregulation of endothelial nitric oxide synthase gene expression and/or increased tetrahydrobiopterin stabilization.12 Finally, the site of action of VC actually administered might be central rather than peripheral.13 However, the failure so far of long-term VC treatment regimens to translate into better outcomes in at risk-populations is both disappointing and puzzling. Do we have reason to believe that this would be any different in patients with congestive heart failure?
References
1. Keith M, Geranmayegan A, Sole MJ, Kurian R, Robinson A, Omran AS, Jeejeebhoy KN. Increased oxidative stress in patients with congestive heart failure. J Am Coll Cardiol. 1998; 31: 1352–1356.
1. Enstrom JE, Kanim LE, Klein MA. Vitamin C intake and mortality among a sample of the United States population. Epidemiology. 1992; 3: 194–202.[Medline] [Order article via Infotrieve]
1. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360: 23–33.[CrossRef][Medline] [Order article via Infotrieve]
1. Piccirillo G, Nocco M, Moise A, Lionetti M, Naso C, Di Carlo S, Marigliano V. Influence of vitamin C on baroreflex sensitivity in chronic heart failure. Hypertension. 2003; 41: 1240–1245.
1. Nightingale AK, Blackman DJ, Field R, Glover NJ, Pegge N, Mumford C, Schmitt M, Ellis GR, Morris-Thurgood JA, Frenneaux MP. Role of nitric oxide and oxidative stress in baroreceptor dysfunction in patients with chronic heart failure. Clin Sci (Lond). 2003; 104: 529–535.[Medline] [Order article via Infotrieve]
1. Sherman DL, Keaney JF, Biegelsen ES, Duffy SJ, Coffman JD, Vita JA. Pharmacological concentrations of ascorbic acid are required for the beneficial effect on endothelial vasomotor function in hypertension. Hypertension. 2000; 35: 936–941.
1. Wilkinson IB, Megson IL, MacCallum H, Sogo N, Cockcroft JR, Webb DJ. Oral vitamin C reduces arterial stiffness and platelet aggregation in humans. J Cardiovasc Pharmacol. 1999; 34: 690–693.[CrossRef][Medline] [Order article via Infotrieve]
1. Landmesser U, Merten R, Spiekermann S, Buttner K, Drexler H, Hornig B. Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation. 2002; 106: 3073–3078.
1. Hornig B, Arakawa N, Kohler C, Drexler H. Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure. Circulation. 1998; 97: 363–368.
1. Ellis GR, Anderson RA, Chirkov YY, Morris-Thurgood J, Jackson SK, Lewis MJ, Horowitz JD, Frenneaux MP. 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.[CrossRef][Medline] [Order article via Infotrieve]
1. MacKenzie A, Martin W. Loss of endothelium-derived nitric oxide in rabbit aorta by oxidant stress: restoration by superoxide dismutase mimetics. Br J Pharmacol. 1998; 124: 719–728.[CrossRef][Medline] [Order article via Infotrieve]
1. Heller R, Unbehaun A, Schellenberg B, Mayer B, Werner-Felmayer G, Werner ER. L-Ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem. 2001; 276: 40–47.
1. Boscan P, Allen AM, Paton JF. Baroreflex inhibition of cardiac sympathetic outflow is attenuated by angiotensin II in the nucleus of the solitary tract. Neuroscience. 2001; 103: 153–160.[CrossRef][Medline] [Order article via Infotrieve]
Response
Dipartimento di Scienze dell’Invecchiamento,, Policlinico Umberto I, Università La Sapienza, Rome, Italy
Letters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment.
Current knowledge provides no information on whether vitamin C at low plasma concentrations modulates central nervous system activity. Clearly, the chronic and massive sympathetic nervous system modulation, especially in New York Heart Association classes III and IV, makes it hard to believe (albeit possible) that the benefits induced by vitamin C in these subjects persist in time. Yet rather than being discouraged by the disappointing results from clinical trials,1 we should consider that orally administered vitamin C (250 mg/d) probably cannot establish the plasma ascorbic acid levels needed to alter endothelial function and thereby modulate autonomic cardiovascular control. Besides, we tested the neuroautonomic effects of vitamin C only at a high intravenous dose (2.5 g) in a single infusion2 and did not test lower doses or the plasma levels achieved. Our choice also receives support from the report of Nightingale et al3 that oral vitamin C given at 4 g/d failed to raise plasma concentrations sufficiently to benefit baroreflex sensitivity. Last, even if we were to find an oral dose or bioavailability able to induce a stable increase in plasma vitamin C concentrations, we consider it highly unlikely that the benefit could persist over time.
In identifying the mechanism underlying these neuroautonomic changes, we agree with Nightingale et al3 and report in a manuscript shortly due for publication4 that vitamin C probably alters autonomic nervous system function through its central or peripheral actions, or both, on nitric oxide. Like Nightingale et al,3 we found that vitamin C at a high intravenous dose (2.5 g) substantially improved baroreflex sensitivity (by 
23%).2 Previous evidence has shown that in subjects with a low ejection fraction (<35%), increasing baroreflex sensitivity by >3 ms/mm Hg lowers the risk of sudden cardiac death.5 These findings now warrant a controlled clinical trial to investigate whether vitamin C, given in short courses at high doses, alters the risk of sudden cardiac death in patients with acute coronary artery syndromes.
References
1. MRC/BRC Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002; 360: 23–33.[CrossRef][Medline] [Order article via Infotrieve]
1. Piccirillo G, Nocco M, Moisè A, Lionetti M, Naso C, Di Carlo S, Marigliano V. Influence of vitamin C on baroreflex sensitivity in chronic heart failure. Hypertension. 2003; 41: 1240–1245.
1. Nightingale AK, Blackman DJ, Field R, Glover NJ, Pegge N, Mumford C, Schmitt M, Ellis GR, Morris-Thurgood JA, Frenneaux MP. Role of nitric oxide and oxidative stress in baroreceptor dysfunction in patients with chronic heart failure. Clin Sci (Lond). 2003; 104: 529–535.[Medline] [Order article via Infotrieve]
1. Piccirillo G, Quaglione R, Fimognari F, Moisè A, Malavasi M, Lionetti M, Naso C, Di Carlo S, Nocco M, Magrì D. Influence ofL-arginine and vitamin C on the autonomic nervous system in chronic heart failure secondary to ischemic cardiomyopathy.Am J Cardiol. In press.
1. La Rovere MT, Pinna GD, Hohnloser SH, Marcus FI, Mortara A, Nohara R, Bigger T, Camm J, Schwartz PJ. Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias. Circulation. 2001; 103: 2072–2077.
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