Chronic monotherapy with rosuvastatin prevents progressive left ventricular dysfunction and remodeling in dogs with heart failure.
OBJECTIVE
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 (Delta) 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)-alpha 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 DeltaEDV, DeltaESV, and DeltaEF between control group and LD RSV. In contrast, DeltaEDV and DeltaESV were significantly lower, and DeltaEF was significantly higher in HD RSV compared with control group. High-dose, but not LD, RSV also normalized protein levels of TNF-alpha 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-alpha expression and partly from increased mobilization of BMSCs.
Zacà
Valerio
V
Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Henry Ford Health System, Detroit, Michigan, USA.
Rastogi
Sharad
S
Imai
Makoto
M
Wang
Mengjun
M
Sharov
Victor G
VG
Jiang
Alice
A
Goldstein
Sidney
S
Sabbah
Hani N
HN
D000818:Animals; D017023:Coronary Angiography; D004285:Dogs; D005464:Fluorobenzenes / Q000008:administration & dosage*; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D020257:Ventricular Remodeling / Q000187:drug effects*
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D000068718:Rosuvastatin Calcium; D020778:Matrix Metalloproteinase 2