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TOXICOLOGICAL SCIENCES 85, 976–982 (2005) doi:10.1093/toxsci/kfi139 Advance Access publication March 2, 2005

CO Inhalation at Dose Corresponding to Tobacco Smoke Worsens Cardiac Remodeling after Experimental Myocardial Infarction in Rats
´ Alain Mirza,* Veronique Eder,*,† Gael Y Rochefort,*,† Jean-Marc Hyvelin,‡ Marie Christine Machet,* ¨ Laurent Fauchier,* and Pierre Bonnet*,†
´,*Laboratoire de Physiopathologie de la Paroi Arterielle (LABPART), Faculte de Medecine, 2 bis Boulevard Tonnelle 37032 Tours, Indre et Loire, France; †Institut Federatif de Recherche 135, Imagerie et Exploration Fonctionnelle; and ‡Department of Physiology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland Received December 7, 2004; accepted February 13,2005

We hypothesized that inhalation of carbon monoxide (CO) (500 ppm), similar to that in tobacco smoke, disturbs the cardiovascular adaptation after myocardial infarction by increasing remodeling. Four groups of rats were assessed. Two groups had myocardial infarction induced by the ligation of the left coronary artery: the first group was exposed to air (infarcted air group, n = 12), and thesecond was exposed to CO (infarcted CO group, n = 11). They were compared to two sham-operated groups, a control air group (n = 10), and a control CO group (n = 7) exposed (3 weeks) to CO. Aerobic endurance capacity was assessed in both the infarct CO and infarct air group (endurance capacity = 0.043 ± 0.006 m.minÿ1.gÿ1 vs. 0.042 ± 0.005 m.minÿ1.gÿ1, not significant). In the infarcted CO groupcompared to the infarcted air group, the dilatation of the left ventricle observed 3 weeks after infarction was increased, (left ventricular diastolic (LVD) diameter (D) = 9 ± 0.4 vs. 7 ± 0.4 mm, p < 0.05; left ventricular systolic (LVS) diameter (D) = 6 ± 0.6 vs. 4.1 ± 0.4, p < 0.05), and the diastolic posterior wall thickness was augmented (posterior wall diastolic thickness = 1.7 ± 0.1 vs. 1.3 ±0.1 mm, p < 0.05). Hemodynamic pressure measurements in both ventricles and pulmonary artery showed elevated diastolic pressure after CO exposure compared to air exposure (LVD pressure = 32 ± 1.6 vs. 19 ± 2.3 mm Hg, p < 0.05; right ventricular diastolic pressure = 16 ± 1.6 vs. 8.6 ± 1.6 mm Hg, p < 0.05; pulmonary arterial pressure in diastole (PAD) = 27 ± 1.6 vs. 20 ± 2.3 mm Hg, p < 0.05). In theinfarcted CO group, the infarct size increased. Echocardiography and histology showed hypertrophy of the contralateral wall similar to that observed in the noninfarcted control CO group. In conclusion, chronic CO inhalation worsens heart failure in rats with myocardial infarction by an increase in the infarct size and hypertrophy remodeling. Key Words: remodeling; heart failure; infarction.lated with an adverse outcome (Wellenius et al., 2004). The gas component of cigarette smoke contains 2 to 6% CO; smokers inhale concentrations as high as 400 ppm and have elevated carboxyhemoglobin levels (Coburn et al., 1965). CO is considered to be a toxic pollutant and poisons by binding the iron-containing heme group of hemoglobin and other enzymes (Ernst and Zibrak, 1998; Villamor et al.,2000), resulting in hypoxemia. Effect of tobacco smoke on myocardial infarct size increase has been well demonstrated in rats (Wellenius et al., 2004; Zhu et al., 1994). CO also induces cardiac hypertrophy, predominantly in the left ventricle by an unknown mechanism (Penney et al., 1984). Surprisingly, no previous study focused on the effects of CO on cardiac remodeling after myocardial infarction.Remodeling includes hypertrophy of the cardiomyocytes, growth of the capillary network, and an increase in interstitial collagen into the noninfarcted myocardium. These compensatory mechanisms may be beneficial early after infarction, but may have adverse effects when activated for a long time (Cleutjens et al., 1999). The impact of CO on post infarct remodeling might be an important issue for...
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