Fluvastatin, a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, Attenuates Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction

Abstract

Background-Short-term administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, has been shown to attenuate ischemia-reperfusion injury. However, the effects of long-term administration of statins on left ventricular (LV) remodeling and failure after myocardial infarction remain unknown. Methods and Results-Mice were subjected to coronary artery ligation and were treated for 4 weeks with vehicle or fluvastatin (10 mg/kg per day PO). Fluvastatin increased survival (61% versus 86%; PϽ0.05) without affecting the infarct size (52Ϯ2% versus 49Ϯ3%; PϭNS). Fluvastatin not only attenuated LV dilatation but also decreased LV end-diastolic pressure and lung weight. Furthermore, it reduced cardiac myocyte hypertrophy and interstitial fibrosis of the noninfarcted LV and also improved LV ejection performance. LV matrix metalloproteinase (MMP)-2 and MMP-13 were increased in myocardial infarction, which was attenuated in fluvastatin-treated mice. Conclusions-Fluvastatin increased survival in a murine model of postinfarct heart failure, which was associated with the amelioration of LV structural remodeling and contractile failure. Moreover, these effects were associated with the attenuation of increased MMP activity. Thus, long-term treatment with fluvastatin might be beneficial also in patients with heart failure and might improve their long-term survival.

Long-Term Inhibition of Rho-Kinase Suppresses Left Ventricular Remodeling After Myocardial Infarction in Mice

“…First, despite the beneficial effect of fasudil on LV remodeling, overall prognosis was unchanged. Because LV end-diastolic pressure in the MI group was slightly but significantly lower in the present study compared with our previous studies, 18,19 the extent of heart failure may be less compared with that in those studies, and the development of heart failure may be slowly progressing. Thus, a longer period of observation would be needed to evaluate the prognostic effect of fasudil in the present model.…”

“…15 A 1.4F micromanometertipped catheter (Millar Instruments) was inserted into the right carotid artery and then advanced into the LV to measure LV pressures. 18,19 We did not measure brain natriuretic peptide levels in the present study.…”

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

“…Whereas the cardioprotective effects of statins, independent of their hypolipidaemic effects, have already been demonstrated in several normocholesterolaemic models [14,15,38], this is the first animal study demonstrating the pleiotropic effects of statins in a model characterised by increased LDL-cholesterol levels.…”

“…Many of these pleiotropic effects are mediated by antagonism of isoprenoid-mediated activation of small GTPbinding proteins, such as RHO family members, including ras-related C3 botulinum toxin substrate (RAC1) and ras homologue gene family, member A (RHOA) [11], activation of the latter being associated with decreased endothelial nitric oxide synthase (eNOS) expression and activity [12,13]. The cardioprotective effects of statins, independent of their hypolipidaemic effects, have already been demonstrated in normocholesterolaemic animal models of hypertrophy [14] and myocardial infarction [15]. However, their pleiotropic effects have not been investigated before in an animal model associated with increased LDL-cholesterol.…”

Statin-Induced Improvement of Endothelial Progenitor Cell Mobilization, Myocardial Neovascularization, Left Ventricular Function, and Survival After Experimental Myocardial Infarction Requires Endothelial Nitric Oxide Synthase

“…S tatin treatment has been suggested to exert beneficial effects on left ventricular (LV) function and remodeling after experimental myocardial infarction (MI), 1,2 raising the possibility that statins may aid in the prevention and treatment of heart failure. 3 In patients with heart failure, statin therapy is associated with improved LV function 4 and survival.…”