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CLINICAL STUDY

Neutrophil superoxide anion–generating capacity, endothelial function and oxidative stress in chronic heart failure: effects of short- and long-term vitamin C therapy

Gethin R. Ellis, MRCP^a, Richard A. Anderson, MRCP^a, Derek Lang, PhD^a, Daniel J. Blackman, MRCP^a, R. H. Keith Morris, MSc, Jayne Morris-Thurgood, PhD^a, Ian F. W. McDowell, MD^a, Simon K. Jackson, PhD^a, Malcolm J. Lewis, MB, DSc^a and Michael P. Frenneaux, MD, FRCP, FACC^a

^a Cardiovascular Sciences Research Group, Wales Heart Research Institute, University of Wales College of Medicine, Cardiff, Wales, United Kingdom
School of Biomedical Sciences, University of Wales Institute of Cardiff, Cardiff, Wales, United Kingdom

Manuscript received October 28, 1999; revised manuscript received April 24, 2000, accepted June 9, 2000.

Reprint requests and correspondence: Prof. M.P. Frenneaux, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff, Wales, United Kingdom CF14 4XN
daviesja3{at}cf.ac.uk

OBJECTIVES

First, we sought to study the effects of short- and long-term vitamin C therapy on oxidative stress and endothelial dysfunction in chronic heart failure (CHF), and second, we sought to investigate the role of neutrophils as a cause of oxidative stress in CHF.

BACKGROUND

Oxidative stress may contribute to endothelial dysfunction in CHF. Vitamin C ameliorates endothelial dysfunction in CHF, presumably by reducing oxidative stress, but this is unproven.

METHODS

We studied 55 patients with CHF (ischemic and nonischemic etiologies) and 15 control subjects. Flow-mediated dilation (FMD) in the brachial artery was measured by ultrasound wall-tracking, neutrophil superoxide anion (O₂^–) generation by lucigenin-enhanced chemiluminescence and oxidative stress by measurement of free radicals (FRs) in venous blood using electron paramagnetic resonance (EPR) spectroscopy and plasma thiobarbituric acid reactive substances (TBARS). Measurements were performed at baseline in all subjects. The effects of short-term (intravenous) and long-term (oral) vitamin C therapy versus placebo were tested in patients with nonischemic CHF.

RESULTS

At baseline, FRs were higher in patients with CHF than in control subjects (p < 0.01), TBARS were greater (p < 0.005), neutrophil O₂^–-generating capacity was enhanced (p < 0.005) and FMD was lower (p < 0.0001). Compared with placebo, short-term vitamin C therapy reduced FR levels (p < 0.05), tended to reduce TBARS and increased FMD (p < 0.05), but did not affect neutrophil O₂^–-generating capacity. Long-term vitamin C therapy reduced FR levels (p < 0.05), reduced TBARS (p < 0.05) and improved FMD (p < 0.05), but also reduced neutrophil O₂^–-generating capacity (p < 0.05). Endothelial dysfunction was not related to oxidative stress, and improvements in FMD with vitamin C therapy did not relate to reductions in oxidative stress.

CONCLUSIONS

Oxidative stress is increased in ischemic and nonischemic CHF, and neutrophils may be an important cause. Vitamin C reduces oxidative stress, increases FMD and, when given long term, decreases neutrophil O₂^– generation, but the lack of a correlation between changes in endothelial function and oxidative stress with vitamin C implies possible additional non-antioxidant benefits of vitamin C.

Abbreviations and Acronyms   CHF = chronic heart failure   CAD = coronary artery disease   eNOS = endothelial nitric oxide synthase   EPR = electron paramagnetic resonance   FMD = flow-mediated dilation   FRs = free radicals   O2– = superoxide anion   NO = nitric oxide   NYHA = New York Heart Association   TBARS = thiobarbituric acid reactive substances

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