Endothelial dysfunction characterizes heart failure (HF). Simvastatin (Sim) increases endothelial nitric oxide (NO) independent of lipid-lowering. We evaluated the effect of Sim on cardiac function, apoptosis, and NO availability in HF. Five-month-old cardiomyopathic (CM) hamsters were divided into 2 groups: Sim (20 mg/kg, 6 weeks, n = 6) and Untreated (n = 6). Age-matched normal hamsters served as controls (n = 6). Serial echocardiograms were performed to measure LV function. Myocardial apoptosis, eNOS, and capillary density were measured at 6 weeks. Cardiomyopathic hamsters had lower LV shortening fraction (SF) compared with controls (17 ± 3% vs 59 ± 2%), higher LV end-diastolic volume (30 ± 3 vs 6 ± 2 mL/m2), and lower LV mass/volume ratio (0.5 ± 0.04 vs 0.72 ± 0.02 mg/ml, P < 0.001). During follow-up, SF decreased (9 ± 2%) and LV volume increased (38 ± 1 mL/m2) in untreated hamsters (P < 0.05 from baseline) but did not change significantly in the Sim group (P < 0.05 vs untreated). Myocardial caspase-3 activity was higher and apoptotic nuclear density was lower in Sim compared with untreated CM hamsters (0.072 ± 0.02% vs 0.107 ± 0.03%, P < 0.01). Myocardial capillary density was highest in the Sim group (P < 0.05). eNOS expression was not different between groups. Sim retards the progression of HF in CM hamsters. This may be related to an increase in coronary microvasculature, increase in NO availability, and decreased apoptosis.
Hydroxy-methyl-glutaryl Coenzyme A reductase inhibitors or statins are drugs designed to inhibit the rate-limiting enzyme of cholesterol synthesis in the liver, thereby decreasing the hepatic production of LDL and lowering the circulating levels of LDL. In normocholesterolemic animals, statin therapy has been shown to protect against stroke, 1 ischemia-reperfusion injury of the heart, 2 and vascular inflammatory responses 3,4 through mechanisms that may be mediated by an increase in endothelium-derived nitric oxide (NO) production. Heart failure is characterized by down-regulation of NO production and endothelial NO synthase (eNOS) gene expression. 5–8 The lack of NO contributes to myocardial apoptosis or programed cell death, a critical event in cardiac remodeling and progression of heart failure. 9 Our previous studies have shown that NO-mediated regulation of apoptotic enzyme activity is reduced in failing hearts. 10 Statins up-regulate endothelial NO production independent of their lipid-lowering action and recent experimental studies have demonstrated their angiogenic potential. 11–13 Although statins have been studied in heart failure following myocardial infarction, 14,15 their effect on cardiac function in a nonischemic, genetic model of heart failure has not been well studied.
The cardiomyopathic (CM) Syrian hamster (BIOTO2) is a widely studied model of heart failure. The disease in this strain of hamsters has phenotypic features of dilated CM in humans. The cardiac phenotype is characterized by early hypertrophy at 2 months of age that progresses to a dilated CM by 5 to 6 months with progression to end-stage heart failure by 9 months of age. The disease is caused by an inherited autosomal recessive mutation in the gene coding for delta-sarcoglycan, a component of the dystrophin complex. 16,17 These animals die prematurely from progressive myocardial necrosis and heart failure. A recent study reported early onset of vascular dysfunction that preceded the development of decompensated heart failure. 18
We have previously demonstrated that progression from compensated heart failure in 4-month-old hamsters to decompensated heart failure in 9-month-old hamsters using serial echocardiography is associated with increased caspase 3 activity, which is a common downstream effector enzyme of apoptosis. 10 For this study, we observed 6-month-old hamsters for the pathophysiologic events that contribute to the transition from compensated to decompensated heart failure and the ability of a statin drug to prevent this transition. Our study was designed to assess the effect of Sim on LV function and remodeling in CM hamster hearts, and the role of increased nitric oxide and reduced apoptosis in mediating these effects of Sim.
From the *Department of Pediatrics, †Medicine, and ‡Pathology, Columbia University, New York, New York; and §Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Received for publication July 7, 2003; accepted December 8, 2003.
This work was presented in part at the Annual Meeting of the American College of Cardiology, Chicago, March 2003.
Reprints: Seema Mital, MD, FACC, CHONY-2 North, 3959 Broadway New York, NY 10032 (e-mail: firstname.lastname@example.org).