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PRECLINICAL STUDIES

Chronic Monotherapy With Rosuvastatin Prevents Progressive Left Ventricular Dysfunction and Remodeling in Dogs With Heart Failure

Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Henry Ford Health System, Detroit, Michigan.

Manuscript received November 27, 2006; revised manuscript received April 9, 2007, accepted April 10, 2007.

^_* Reprint requests and correspondence: Dr. Hani N. Sabbah, Cardiovascular Research, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202. (Email: hsabbah1{at}hfhs.org).

Objectives: This study examined the effects of long-term monotherapy with rosuvastatin (RSV) on the progression of left ventricular (LV) dysfunction and remodeling in dogs with heart failure (HF).

Background: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or "statins" possess other noncholesterol-lowering properties that include inhibiting proinflammatory cytokines, attenuating LV hypertrophy, and stimulating the release of bone marrow-derived stem cells (BMSCs).

Methods: Twenty-one dogs with microembolization-induced HF were randomized to 3 months oral monotherapy with low-dose (LD) RSV (0.5 mg/kg once daily, n = 7), high-dose (HD) RSV (3.0 mg/kg once daily, n = 7), or to no therapy (control group, n = 7). The change () from pre- to post-therapy (treatment effect) in LV end-diastolic volume (EDV) and end-systolic volume (ESV) and ejection fraction (EF) was measured. Protein level of tumor necrosis factor (TNF)- in LV tissue and the number of circulating Sca-1–positive BMSCs was also determined. Blood and LV tissue from 6 normal dogs was obtained and used for comparison.

Results: There were no differences in EDV, ESV, and EF between control group and LD RSV. In contrast, EDV and ESV were significantly lower, and EF was significantly higher in HD RSV compared with control group. High-dose, but not LD, RSV also normalized protein levels of TNF- and was associated with a significant increase in the number of circulating BMSCs.

Conclusions: In dogs with HF, chronic therapy with HD RSV prevents progressive LV dysfunction and dilation. This benefit may be partly derived from normalization of TNF- expression and partly from increased mobilization of BMSCs.

Abbreviations and Acronyms   BMSC = bone marrow-derived stem cell   CVD = cardiovascular disease   ECM = extracellular matrix   EDV = end-diastolic volume   EF = ejection fraction   EPC = endothelial progenitor cell   ESV = end-systolic volume   HD = high-dose   HF = heart failure   HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A   LD = low-dose   LV = left ventricular/ventricle   MCSA = myocyte cross-sectional area   MI = myocardial infarction   MMP = matrix metalloproteinase   ODD = oxygen diffusion distance   RSV = rosuvastatin   TNF = tumor necrosis factor   VFIF = volume fraction of interstitial fibrosis   VFRF = volume fraction of replacement fibrosis

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