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CLINICAL RESEARCH: HEART FAILURE

Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase-Derived Superoxide and Vascular Endothelial Dysfunction in Human Heart Failure

Rafa Dworakowski, MD, PhD^_*, Simon Walker^_*, Aziz Momin, FRCS^_*, Jatin Desai, FRCS^_*, Ahmed El-Gamel, FRCS^_*, Olaf Wendler, MD, PhD^_*, Mark T. Kearney, MD, FRCP and Ajay M. Shah, MD, FMedSci^_*,_*

^_* Cardiovascular Division, King’s College London School of Medicine, London, United Kingdom
Leeds Institute for Genetics, Health and Therapeuticss, University of Leeds, Leeds, United Kingdom.

Manuscript received October 1, 2007; revised manuscript received December 12, 2007, accepted December 17, 2007.

^_* Reprint requests and correspondence: Prof. Ajay M. Shah, Cardiovascular Division, James Black Centre, King’s College London, 125 Coldharbour Lane, London SE5 9NU, U.K. (Email: ajay.shah{at}kcl.ac.uk).

Objectives: We investigated the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in endothelial dysfunction in human heart failure.

Background: Vascular endothelial dysfunction in human heart failure contributes to increased tone, exercise limitation, and dysregulation of venous capacitance and vascular volume. The NADPH oxidases (Nox) are an important source of oxidative stress, but their role in the endothelial dysfunction of human heart failure remains unknown.

Methods: Endothelium-dependent and -independent vasorelaxation were assessed in saphenous vein segments obtained from consecutive patients with heart failure (n = 19) or normal left ventricular function (control; n = 35) undergoing coronary artery bypass graft. Saphenous vein superoxide production was measured by lucigenin-enhanced chemiluminescence and messenger ribonucleic acid expression of relevant transcripts quantified by real-time polymerase chain reaction.

Results: Heart failure patients had significantly worse endothelial function than control subjects (15.2 ± 3% vs. 40.5 ± 8.4% relative relaxation; p < 0.05), elevated C-reactive protein (CRP) levels (8.6 ± 2.7 mg/l vs. 2.6 ± 0.4 mg/l; p < 0.05), over 2-fold higher NADPH-dependent superoxide generation (p < 0.05), and significantly higher expression of the Nox4 isoform and regulatory subunit p67phox. Superoxide levels were positively correlated with New York Heart Association functional class (r = 0.684; p < 0.05) and CRP (r = 0.501; p < 0.005; n = 32).

Conclusions: Venous endothelial dysfunction in human heart failure is associated with increased Nox-derived superoxide generation. Inflammatory mechanisms may be involved in the increased reactive oxygen species generation.

Abbreviations and Acronyms   CABG = coronary artery bypass graft   CHF = chronic heart failure   CRP = C-reactive protein   DPI = diphenyleneiodonium   EF = ejection fraction   IL = interleukin   LV = left ventricle/ventricular   NADPH = nicotinamide adenine dinucleotide phosphate   NO = nitric oxide   NOS = nitric oxide synthase   Nox = nicotinamide adenine dinucleotide phosphate oxidase(s)   ROS = reactive oxygen species   SNP = sodium nitroprusside   TNF = tumor necrosis factor

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J. Am. Coll. Cardiol. 2008 51: A33-A34. [Full Text] [PDF]