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Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure.
. 2006 Jun; 290(6):H2522-7.

Abstract

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.

Authors+Show Affiliations

Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, MI 48202, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16428338

Citation

Morita, Hideaki, et al. "Selective Matrix Metalloproteinase Inhibition Attenuates Progression of Left Ventricular Dysfunction and Remodeling in Dogs With Chronic Heart Failure." American Journal of Physiology. Heart and Circulatory Physiology, vol. 290, no. 6, 2006, pp. H2522-7.
Morita H, Khanal S, Rastogi S, et al. Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure. Am J Physiol Heart Circ Physiol. 2006;290(6):H2522-7.
Morita, H., Khanal, S., Rastogi, S., Suzuki, G., Imai, M., Todor, A., Sharov, V. G., Goldstein, S., O'Neill, T. P., & Sabbah, H. N. (2006). Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure. American Journal of Physiology. Heart and Circulatory Physiology, 290(6), H2522-7.
Morita H, et al. Selective Matrix Metalloproteinase Inhibition Attenuates Progression of Left Ventricular Dysfunction and Remodeling in Dogs With Chronic Heart Failure. Am J Physiol Heart Circ Physiol. 2006;290(6):H2522-7. PubMed PMID: 16428338.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure. AU - Morita,Hideaki, AU - Khanal,Sanjaya, AU - Rastogi,Sharad, AU - Suzuki,George, AU - Imai,Makoto, AU - Todor,Anastassia, AU - Sharov,Victor G, AU - Goldstein,Sidney, AU - O'Neill,Timothy P, AU - Sabbah,Hani N, Y1 - 2006/01/20/ PY - 2006/1/24/pubmed PY - 2006/6/23/medline PY - 2006/1/24/entrez SP - H2522 EP - 7 JF - American journal of physiology. Heart and circulatory physiology JO - Am. J. Physiol. Heart Circ. Physiol. VL - 290 IS - 6 N2 - 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. SN - 0363-6135 UR - https://www.unboundmedicine.com/medline/citation/16428338/Selective_matrix_metalloproteinase_inhibition_attenuates_progression_of_left_ventricular_dysfunction_and_remodeling_in_dogs_with_chronic_heart_failure_ L2 - https://journals.physiology.org/doi/10.1152/ajpheart.00932.2005?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -