Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure
| Autor: | Victor G. Sharov, Sanjaya Khanal, Hideaki Morita, Sidney Goldstein, Makoto Imai, George Suzuki, Timothy P. O'Neill, Anastassia Todor, Sharad Rastogi, Hani N. Sabbah |
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| Rok vydání: | 2006 |
| Předmět: |
Coronary angiography
medicine.medical_specialty Physiology Matrix metalloproteinase inhibitor Embolism Hemodynamics Gene Expression Matrix metalloproteinase Matrix Metalloproteinase Inhibitors Coronary Angiography Electrocardiography Ventricular Dysfunction Left Dogs Physiology (medical) Internal medicine medicine Animals Protease Inhibitors RNA Messenger Heart Failure Ejection fraction medicine.diagnostic_test Dose-Response Relationship Drug Ventricular Remodeling Extramural business.industry medicine.disease Heart failure Chronic Disease Cardiology Disease Progression Cardiology and Cardiovascular Medicine business |
| Zdroj: | American journal of physiology. Heart and circulatory physiology. 290(6) |
| ISSN: | 0363-6135 |
| Popis: | Matrix metalloproteinases (MMPs) contribute to the progression of left ventricular (LV) dysfunction and remodeling associated with heart failure (HF). The present study examined the long-term effects of a selective MMP inhibitor PG-530742 (PG) on the progression of LV dysfunction and remodeling in dogs with HF. Chronic HF [LV ejection fraction (LVEF), ≤36%] was produced by multiple sequential intracoronary microembolizations in 24 dogs. Two weeks after the last embolization, dogs were randomized to 3 mo of therapy with either high-dose (HD) PG (3.5 mg/kg, n = 8), low-dose (LD) PG (0.2 mg/kg, n = 8), or to a matched placebo (PL, n = 8). PG has been shown to produce complete inhibition of MMP-2, -3, -9, and -13, while sparing MMPs-1 and -7. Hemodynamic and echocardiographic measurements were made before and 3 mo after initiating therapy. In PL and LD dogs, LVEF decreased significantly, and LV end-systolic volume (ESV) and LV end-diastolic volume (EDV) increased significantly during the 3-mo follow-up period. Whereas in HD dogs ejection fraction increased from 36 ± 1 to 40 ± 1% ( P = 0.003), EDV and ESV decreased (59 ± 4 vs. 57 ± 4 ml, P = 0.02; and 38 ± 2 vs. 34 ± 2 ml, P = 0.00001, respectively). When compared with controls, HD-treated dogs showed 30% reduction in replacement fibrosis, 29% reduction in interstitial fibrosis, and 28% reduction in myocyte cross-sectional area. mRNA expression of selective MMPs was also reduced in LV tissue in HD- but not LD-treated dogs. In conclusion, in dogs with moderate HF, long-term monotherapy with HD selective MMP inhibitor PG prevents LV remodeling and the progression of global LV dysfunction. |
| Databáze: | OpenAIRE |
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