Published online before print December 19, 2002, doi: 10.1161/01.RES.0000052312.41419.55
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on May 13, 2002
Revised on December 4, 2002
Accepted on December 4, 2002
Selective Matrix Metalloproteinase Inhibition With Developing Heart Failure. Effects on Left Ventricular Function and Structure
Mary K. King ;
From the Division of Cardiothoracic Surgery (M.K.K., M.L.C., A.G., J.H.M., H.R.G., R.M., M.R.Z., F.G.S.), Medical University of South Carolina, Charleston, SC; and Pharmaceutical Research Division (T.P.O'.N.), Procter and Gamble, Mason, Ohio.
The matrix metalloproteinases (MMPs) are an endogenous family of proteolytic enzymes implicated to contribute to LV remodeling. However, broad-spectrum MMP inhibition (MMPi), particularly inhibition of interstitial collagenase (MMP-1), may not be clinically applicable. This study examined the effects of selective MMPi (sparing MMP-1) in a model of developing congestive heart failure. Pigs were randomly assigned to 3 groups: (1) rapid pacing for 3 weeks (240 bpm, n=10); (2) selective MMPi (20 mg/kg per day-PO;PGE7113313) and rapid pacing (n=12); and (3) controls (n=10). LV peak wall stress increased from controls with rapid pacing (140±6 versus 319±18 g/cm2; P<0.05) and was reduced with selective MMPi (208±9 g/cm2; P<0.05. Preload recruitable stroke work was reduced with rapid pacing (4.3±0.4 versus 1.2±0.2 dyne · cm/mm Hg; P<0.05) and was increased with selective MMPi (2.6±0.3 dyne · cm/mm Hg; P<0.05). Plasma norepinephrine increased by 6-fold in the rapid pacing group (P<0.05) and was reduced from untreated values with selective MMPi (P<0.05). At the myocardial level, myocyte cross-sectional area was increased with selective MMPi but fibrillar collagen volume fraction remained unchanged relative to control values. These results suggest that targeting a selective portfolio of myocardial MMP species for inhibition may provide a more rational therapeutic strategy in the setting of congestive heart failure.
Key words: left ventricular systolic function • diastolic function • myocardial stiffness • myocardial structure • matrix metalloproteinases • heart failure
This article has been cited by other articles:
 |
|
 |
|
  J. A. Zavadzkas, R. A. Plyler, S. Bouges, C. N. Koval, W. T. Rivers, C. U. Beck, E. I. Chang, R. E. Stroud, R. Mukherjee, and F. G. Spinale Cardiac-restricted overexpression of extracellular matrix metalloproteinase inducer causes myocardial remodeling and dysfunction in aging mice Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1394 - H1402. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Braunwald Biomarkers in Heart Failure N. Engl. J. Med., May 15, 2008; 358(20): 2148 - 2159. [Full Text] [PDF]
|
|
|
|
 |
|
 F. G. Spinale Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function Physiol Rev, October 1, 2007; 87(4): 1285 - 1342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. Spruill, A. S. Lowry, R. E. Stroud, C. E. Squires, I. M. Mains, E. C. Flack, C. Beck, J. S. Ikonomidis, A. J. Crumbley, P. J. McDermott, et al. Membrane-type-1 matrix metalloproteinase transcription and translation in myocardial fibroblasts from patients with normal left ventricular function and from patients with cardiomyopathy Am J Physiol Cell Physiol, October 1, 2007; 293(4): C1362 - C1373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. K. Graham and A. W. Trafford Spatial disruption and enhanced degradation of collagen with the transition from compensated ventricular hypertrophy to symptomatic congestive heart failure Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1364 - H1372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. W. Cheng, K. Obata, M. Kuzuya, H. Izawa, K. Nakamura, E. Asai, T. Nagasaka, M. Saka, T. Kimata, A. Noda, et al. Elastolytic Cathepsin Induction/Activation System Exists in Myocardium and Is Upregulated in Hypertensive Heart Failure Hypertension, November 1, 2006; 48(5): 979 - 987. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Roig Usefulness of neurohormonal markers in the diagnosis and prognosis of heart failure Eur. Heart J. Suppl., September 1, 2006; 8(suppl_E): E12 - E17. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Hudson, P. W. Armstrong, W. Ruzyllo, J. Brum, L. Cusmano, P. Krzeski, R. Lyon, M. Quinones, P. Theroux, D. Sydlowski, et al. Effects of Selective Matrix Metalloproteinase Inhibitor (PG-116800) to Prevent Ventricular Remodeling After Myocardial Infarction: Results of the PREMIER (Prevention of Myocardial Infarction Early Remodeling) Trial J. Am. Coll. Cardiol., July 4, 2006; 48(1): 15 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Morita, S. Khanal, S. Rastogi, G. Suzuki, M. Imai, A. Todor, V. G. Sharov, S. Goldstein, T. P. O'Neill, and H. N. Sabbah Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2522 - H2527. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Vanhoutte, M. Schellings, Y. Pinto, and S. Heymans Relevance of matrix metalloproteinases and their inhibitors after myocardial infarction: A temporal and spatial window Cardiovasc Res, February 15, 2006; 69(3): 604 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Hajjar and J. A. Leopold Xanthine Oxidase Inhibition and Heart Failure: Novel Therapeutic Strategy for Ventricular Dysfunction? Circ. Res., February 3, 2006; 98(2): 169 - 171. [Full Text] [PDF]
|
|
|
|
 |
|
 L. Gullestad, T. Ueland, J. G. Fjeld, E. Holt, T. Gundersen, K. Breivik, M. Folling, A. Hodt, R. Skardal, J. Kjekshus, et al. Effect of Thalidomide on Cardiac Remodeling in Chronic Heart Failure: Results of a Double-Blind, Placebo-Controlled Study Circulation, November 29, 2005; 112(22): 3408 - 3414. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. M. Schiotz Thorud, A. Stranda, J.-A. Birkeland, P. K. Lunde, I. Sjaastad, S. O. Kolset, O. M. Sejersted, and P. O. Iversen Enhanced matrix metalloproteinase activity in skeletal muscles of rats with congestive heart failure Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2005; 289(2): R389 - R394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Heymans, F. Lupu, S. Terclavers, B. Vanwetswinkel, J.-M. Herbert, A. Baker, D. Collen, P. Carmeliet, and L. Moons Loss or Inhibition of uPA or MMP-9 Attenuates LV Remodeling and Dysfunction after Acute Pressure Overload in Mice Am. J. Pathol., January 1, 2005; 166(1): 15 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Jayasankar, Y. J. Woo, L. T. Bish, T. J. Pirolli, M. F. Berry, J. Burdick, R. C. Bhalla, R. V. Sharma, T. J. Gardner, and H. L. Sweeney Inhibition of Matrix Metalloproteinase Activity by TIMP-1 Gene Transfer Effectively Treats Ischemic Cardiomyopathy Circulation, September 14, 2004; 110(11_suppl_1): II-180 - II-186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Nerheim, S. Birger-Botkin, L. Piracha, and B. Olshansky Heart Failure and Sudden Death in Patients With Tachycardia-Induced Cardiomyopathy and Recurrent Tachycardia Circulation, July 20, 2004; 110(3): 247 - 252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chandrashekhar, S. Sen, R. Anway, A. Shuros, and I. Anand Long-Term caspase inhibition ameliorates apoptosis, reduces myocardial troponin-I cleavage, protects left ventricular function, and attenuates remodeling in rats with myocardial infarction J. Am. Coll. Cardiol., January 21, 2004; 43(2): 295 - 301. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. M. Yarbrough, R. Mukherjee, G. P. Escobar, J. T. Mingoia, J. A. Sample, J. W. Hendrick, K. B. Dowdy, J. E. McLean, A. S. Lowry, T. P. O'Neill, et al. Selective Targeting and Timing of Matrix Metalloproteinase Inhibition in Post-Myocardial Infarction Remodeling Circulation, October 7, 2003; 108(14): 1753 - 1759. [Abstract] [Full Text] [PDF]
|
|