Study of atorvastatin effects on isoproterenol induced heart failure in rats

Abstract

Introduction Despite progresses in treatment and control of heart failure, morbidity and mortality from the disease is still high. Statins have been shown to reduce morbidity and mortality in cardiovascular diseases such as atherosclerosis and coronary artery events. Statins have many effects beyond lipid-lowering that make them of potential benefit in patients with heart failure. The effect of atorvastatin on cardiac remodeling, function, homodynamic parameters, lipid peroxidation and coenzyme Q10 content of myocardium in isoproterenol-induced heart failure was evaluated in the present study.Methods A subcutaneous injection of isoproterenol (5 mg/kg/day) for 10 days was used for the induction of heart failure. Rats were randomly assigned to control, treatment with atorvastatin (5, 10, 20 mg/kg/day) and treatment with atorvastatin plus coenzyme Q10 (10 mg/kg/day) and coenzyme Q10 (10 mg/kg/day). To evaluate the cardiac left ventricular function, a Mikro Tip catheter transducer (Millar Instruments, INC) was advanced to the lumen of the left ventricle. Coenzyme Q10 content of myocardium was measured by HPLC method with UV detector after hemodynamic parameters measurements. Malondialdehyde (MDA) content of myocardium was evaluated for determination of coenzyme Q10 antioxidative effect.Results Histopathological analysis showed a marked attenuation of myocyte necrosis and interstitial fibrosis in all atorvastatin and atorvastatin plus coenzyme Q10 treated groups (P<0.001). A low dose of atorvastatin (5 mg/kg/day) significantly improved the left ventricular systolic pressure, contractility and relaxation (P <0.01). On the contrary, a high dose of atorvastatin (20 mg/kg/day) worsened the isoproterenol-induced left ventricular dysfunction by a further reduction of LVdP/dtmax from+278094 to+1588248 (mm Hg/s; P<0.01) and LVdP/dtmin from 2007190 to 2939291 (mm Hg/s; P<0.05). Co-administration of coenzyme Q10 with atorvastatin reversed the hemodynamic depression and the left ventricular dysfunction to a high level (P<0.001). There was a lower level of LVEDPs in the atorvastatin + coenzyme Q10 treated groups (31 and 41.4 versus 83.5 and 143.6 mm Hg, respectively). A high dose of atorvastatin (20 mg/kg/day) significantly reduced the myocardium content of coenzyme Q10 as compared with isoproterenol treated group (p<0.001). Compared with atorvastatin alone-treated animals, co-administration of coenzyme Q10 with atorvastatin improved the level of coenzyme Q10 in the myocardium (p<0.05, p<0.001). Increasing the dose of atorvastatin also led to an increase in MDA content of myocardium (p<0.01). Serum lipid profile showed no changes in atorvastatin treated groups.Discussion The results of this study demonstrated thatatorvastatin therapy attenuated myocardial necrosis and fibrosis in isoproterenol-induced heart failure. However, a high dose of the drug considerably worsened the left ventricular dysfunction and hemodynamic depression, which was reversed by coenzyme Q10 co-administration. High doses of atorvastatin reduce coenzyme Q10 content of myocardium and increase lipid peroxidation in myocardium which is reversed by coenzyme Q10 co-administration.