Simvastatin preserves cardiac function in genetically determined cardiomyopathy.
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.
Abraham
Seena S
SS
Department of Pediatrics, Columbia University, New York, New York, USA.
Osorio
Juan C
JC
Homma
Shunichi
S
Wang
Jie
J
Thaker
Harshwardhan M
HM
Liao
James K
JK
Mital
Seema
S
D043925:Angiogenesis Inducing Agents; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D009202:Cardiomyopathies / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D006224:Cricetinae; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019821:Simvastatin / Q000627:therapeutic use*; D016277:Ventricular Function, Left / Q000187:drug effects*
D043925:Angiogenesis Inducing Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009569:Nitric Oxide; D019821:Simvastatin; D053148:Caspase 3; D020169:Caspases