Probucol attenuates left ventricular dysfunction and remodeling in tachycardia-induced heart failure: roles of oxidative stress and inflammation.
BACKGROUND
Oxidative stress and inflammation are potentially involved in the pathogenesis of heart failure (HF). We examined whether antioxidant and antiinflammatory treatment with probucol decreases myocardial oxidative stress and inflammation and attenuates the progression of left ventricular (LV) dysfunction and remodeling (dilatation) in tachycardia-induced HF.


RESULTS
We studied 3 groups of dogs: a sham-operated control group and 2 other groups that underwent ventricular pacing at 240 bpm with and without probucol treatment (100 mg/kg IP per week) for 4 weeks. Dogs that underwent ventricular pacing for 4 weeks developed signs of HF, such as a reduction in the LV ejection fraction and increases in the LV end-diastolic dimension and LV end-diastolic pressure. Myocardial oxidative stress, as measured by electron spin resonance spectroscopy with 4-hydroxy-2,2,6,6,-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO), was significantly increased. There was an increase in myocardial monocyte infiltration, monocyte chemoattractant protein-1 expression, and renin-angiotensin system and matrix metalloproteinase activity. Probucol treatment prevented increases in oxidative stress, inflammation, and matrix metalloproteinase activity and attenuated LV dysfunction and remodeling.


CONCLUSIONS
Probucol attenuated LV dysfunction and remodeling, possibly through its antioxidant and/or antiinflammatory effects in ventricular pacing-induced HF. These data suggest that inflammatory disorders, which cause an abnormal interaction between failing myocardium and activated monocytes, have an important role in the progression of HF.
Nakamura
Ryo
R
Department of Cardiovascular Medicine, School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Egashira
Kensuke
K
Machida
Youji
Y
Hayashidani
Shunji
S
Takeya
Motohiro
M
Utsumi
Hideo
H
Tsutsui
Hiroyuki
H
Takeshita
Akira
A
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D002304:Cardiac Pacing, Artificial; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000276:immunology* / Q000503:physiopathology; D018932:Chemokine CCL2 / Q000378:metabolism; D004285:Dogs; D004452:Echocardiography; D004578:Electron Spin Resonance Spectroscopy; D006439:Hemodynamics / Q000187:drug effects; D007249:Inflammation / Q000150:complications; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009000:Monocytes / Q000276:immunology; D018384:Oxidative Stress; D011341:Probucol / Q000494:pharmacology*; D012084:Renin-Angiotensin System; D013610:Tachycardia / Q000150:complications; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D020257:Ventricular Remodeling
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D018932:Chemokine CCL2; D020782:Matrix Metalloproteinases; D011341:Probucol