Activation of inducible NOS in peripheral vessels and outcomes in heart failure patients.
BACKGROUND
Activation of inducible nitric oxide synthase (iNOS) has been reported in congestive heart failure (CHF) conditions. However, it is unknown whether activation of iNOS affects prognosis of CHF patients. We prospectively studied the influence of activation of iNOS in the forearm on the outcome of CHF patients.


RESULTS
Forearm blood flow (FBF) responses to 3 doses of acetylcholine (ACh) and nitroglycerin (NTG), and 4 doses of a selective iNOS inhibitor (aminoguanidine: Amn) and a nonselective NOS inhibitor (L-NMMA) were examined using plethysmography in 68 patients with CHF from idiopathic dilated cardiomyopathy. Plasma brain natriuretic peptide (BNP) and tumor necrosis factor-alpha (TNF-alpha) were also measured in all patients. During the mean follow-up period of 3.8 years, 25 patients were hospitalized for worsening heart failure and 9 of these patients died. Patients with adverse events had a diminished vasodilator response to ACh (P < .001) compared to patients without adverse events. Amn significantly decreased FBF (P < .001) in patients with adverse events, but not in patients without adverse events. FBF responses to NTG and L-NMMA were not significantly different between the 2 groups. When grouped by maximum FBF responses to each drug above and below the median value, multivariate Cox proportional hazards model analyses for cardiac event showed a significance in the FBF response to Amn (adjusted hazard ratio 5.89, P < .001). FBF responses to maximum dose of Amn significantly correlated with BNP and TNF-alpha levels (both P < .001).


CONCLUSIONS
CHF patients with vascular iNOS activation, as demonstrated by a greater vasoconstrictor response to Amn, had poor outcomes. Activation of iNOS in peripheral vessels, associated with proinflammatory cytokines in accordance to the severity of heart failure, is a marker for, or contributes to, adverse events in patients with CHF.
Ishibashi
Yutaka
Y
Divisions of Cardiovascular Medicine, Department of Internal Medicine, Shimane University Faculty of Medicine, Shimane, Japan. yuyu@med.shimane-u.ac.jp
Takahashi
Nobuyuki
N
Tokumaru
Atsushi
A
Karino
Kenji
K
Sugamori
Takashi
T
Sakane
Takeshi
T
Kodani
Nobuhiro
N
Kunizawa
Yoshitsugu
Y
Yoshitomi
Hiroyuki
H
Sato
Hidetoshi
H
Oyake
Nobuyuki
N
Murakami
Yo
Y
Shimada
Toshio
T
D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D002311:Cardiomyopathy, Dilated / Q000150:complications; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D005500:Follow-Up Studies; D005542:Forearm / Q000098:blood supply* / Q000502:physiology; D006146:Guanidines / Q000494:pharmacology; D006333:Heart Failure / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005996:Nitroglycerin / Q000494:pharmacology; D011446:Prospective Studies; D016896:Treatment Outcome; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D006146:Guanidines; D014662:Vasoconstrictor Agents; D019323:omega-N-Methylarginine; D052247:Nitric Oxide Synthase Type II; D005996:Nitroglycerin; D000109:Acetylcholine; C004479:pimagedine