Carvedilol decreases elevated oxidative stress in human failing myocardium.
BACKGROUND
Oxidative stress has been implicated in the pathogenesis of heart failure. However, direct evidence of oxidative stress generation in the human failing myocardium has not been obtained. Furthermore, the effect of carvedilol, a vasodilating beta-blocker with antioxidant activity, on oxidative stress in human failing hearts has not been assessed. This study was therefore designed to determine whether levels of lipid peroxides are elevated in myocardia of patients with dilated cardiomyopathy (DCM) and whether carvedilol reduces the lipid peroxidation level. Methods and Results- Endomyocardial biopsy samples obtained from 23 patients with DCM and 13 control subjects with normal cardiac function were studied immunohistochemically for the expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. Expression of HNE-modified protein was found in all myocardial biopsy samples from patients with DCM. Expression was distinct in the cytosol of cardiac myocytes. Myocardial HNE-modified protein levels in patients with DCM were significantly increased compared with the levels in control subjects (P<0.0001). Endomyocardial biopsy samples from 11 patients with DCM were examined before and after treatment (mean, 9+/-4 months) with carvedilol (5 to 30 mg/d; mean dosage, 22+/-8 mg/d). After treatment with carvedilol, myocardial HNE-modified protein levels decreased by 40% (P<0.005) along with amelioration of heart failure.


CONCLUSIONS
Oxidative stress is elevated in myocardia of patients with heart failure. Administration of carvedilol resulted in a decrease in the oxidative stress level together with amelioration of cardiac function.
Nakamura
Kazufumi
K
Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan. ichibun@cc.okayama-u.ac.jp
Kusano
Kengo
K
Nakamura
Yoichi
Y
Kakishita
Mikio
M
Ohta
Keiko
K
Nagase
Satoshi
S
Yamamoto
Mika
M
Miyaji
Katsumasa
K
Saito
Hironori
H
Morita
Hiroshi
H
Emori
Tetsuro
T
Matsubara
Hiromi
H
Toyokuni
Shinya
S
Ohe
Tohru
T
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000447:Aldehydes / Q000032:analysis / Q000276:immunology; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use*; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000077261:Carvedilol; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011412:Propanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D011506:Proteins / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
D000319:Adrenergic beta-Antagonists; D000447:Aldehydes; D000975:Antioxidants; D002227:Carbazoles; D011412:Propanolamines; D011506:Proteins; D014665:Vasodilator Agents; D000077261:Carvedilol; C027576:4-hydroxy-2-nonenal