Iron chelation improves endothelial function in patients with coronary artery disease.
BACKGROUND
Some epidemiological studies have shown that increased iron stores are associated with increased cardiovascular events. Redox-active iron may contribute to lipid peroxidation, endothelial cell activation, and generation of reactive oxygen species (especially hydroxyl radical, via Fenton chemistry). Increased oxidative stress is associated with impaired action of endothelium-derived nitric oxide in patients with atherosclerosis.


RESULTS
To test the hypothesis that reducing vascular iron stores would reverse endothelial dysfunction, we examined the effects of the iron chelator deferoxamine (500 mg intra-arterially over 1 hour) on vasomotor function in forearm resistance vessels of patients with coronary artery disease by venous occlusion plethysmography. Patients with coronary artery disease had impaired endothelium-dependent vasodilation in response to methacholine compared with healthy control subjects (P<0.001). Deferoxamine infusion decreased serum iron levels (P<0.001). Deferoxamine improved the blood flow response to methacholine in patients with coronary artery disease (P<0.01 by 2-way repeated-measures ANOVA) but had no effect on the response to sodium nitroprusside. In normal volunteers, deferoxamine had no effect on the response to methacholine. The nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine abolished augmentation of the methacholine response associated with deferoxamine. The hydroxyl radical scavenger mannitol had no effect on the methacholine response.


CONCLUSIONS
Deferoxamine improved nitric oxide-mediated, endothelium-dependent vasodilation in patients with coronary artery disease. These results suggest that iron availability contributes to impaired nitric oxide action in atherosclerosis.
Duffy
S J
SJ
Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
Biegelsen
E S
ES
Holbrook
M
M
Russell
J D
JD
Gokce
N
N
Keaney
J F
JF
Vita
J A
JA
D000328:Adult; D001783:Blood Flow Velocity / Q000187:drug effects; D003327:Coronary Disease / Q000097:blood / Q000503:physiopathology*; D003676:Deferoxamine / Q000008:administration & dosage*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007261:Infusions, Intra-Arterial; D007501:Iron / Q000097:blood; D007502:Iron Chelating Agents / Q000008:administration & dosage*; D008297:Male; D016210:Methacholine Chloride; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D010991:Plethysmography; D014664:Vasodilation / Q000187:drug effects; D014666:Vasomotor System / Q000187:drug effects* / Q000503:physiopathology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D016210:Methacholine Chloride; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D007501:Iron; D019001:Nitric Oxide Synthase; D003676:Deferoxamine