Angiotensin-Converting Enzyme and Matrix Metalloproteinase Inhibition with Developing Heart Failure: Comparative Effects on Left Ventricular Function and Geometry1

  1. James H. McElmurray III2,
  2. Rupak Mukherjee2,
  3. R. Brent New2,
  4. Angela C. Sampson2,
  5. Mary K. King2,
  6. Jennifer W. Hendrick2,
  7. Aron Goldberg2,
  8. Thomas J. Peterson4,
  9. Hussein Hallak4,
  10. Michael R. Zile3 and
  11. Francis G. Spinale2
  1. Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina

    Abstract

    The progression of congestive heart failure (CHF) is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) contribute to tissue remodeling and therefore MMP inhibition may serve as a useful therapeutic target in CHF. Angiotensin converting enzyme (ACE) inhibition favorably affects LV myocardial remodeling in CHF. This study examined the effects of specific MMP inhibition, ACE inhibition, and combined treatment on LV systolic and diastolic function in a model of CHF. Pigs were randomly assigned to five groups: 1) rapid atrial pacing (240 beats/min) for 3 weeks (n = 8); 2) ACE inhibition (fosinopril, 2.5 mg/kg b.i.d. orally) and rapid pacing (n = 8); 3) MMP inhibition (PD166793 2 mg/kg/day p.o.) and rapid pacing (n = 8); 4) combined ACE and MMP inhibition (2.5 mg/kg b.i.d. and 2 mg/kg/day, respectively) and rapid pacing (n = 8); and 5) controls (n = 9). LV peak wall stress increased by 2-fold with rapid pacing and was reduced in all treatment groups. LV fractional shortening fell by nearly 2-fold with rapid pacing and increased in all treatment groups. The circumferential fiber shortening-systolic stress relation was reduced with rapid pacing and increased in the ACE inhibition and combination groups. LV myocardial stiffness constant was unchanged in the rapid pacing group, increased nearly 2-fold in the MMP inhibition group, and was normalized in the ACE inhibition and combination treatment groups. Increased MMP activation contributes to the LV dilation and increased wall stress with pacing CHF and a contributory downstream mechanism of ACE inhibition is an effect on MMP activity.

    Footnotes

    • Send reprint requests to: Francis G. Spinale, M.D., Ph.D., Cardiothoracic Surgery and Physiology, Medical University of South Carolina, Strom Thurmond Research Building, 770 MUSC Complex, Suite 625, Charleston, SC 29425.

    • ↵1 Supported by National Institutes of Health Grant HL-59165, HL-57952 (F.G.S.), and PO1 HL48788 (M.R.Z.) and an unrestricted Basic Research Grant from Parke-Davis (F.G.S.).

    • ↵2 Present address: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC 29425. F.G.S. is an Established Investigator of the American Heart Association.

    • ↵3 Present address: Division of Cardiology, Medical University of South Carolina, Charleston, SC 29425.

    • ↵4 Present address: Pharmaceutical Research Division, Parke-Davis, Ann Arbor, MI 48105.

    • Abbreviations:
      CHF
      congestive heart failure
      LV
      left venticular
      ACE
      angiotensin-converting enzyme
      MMP
      matrix metalloproteinase
      Ang-I
      angiotensin I
      PRSWR
      preload recruitable stroke work relation
      Vcfc
      velocity of circumferential fiber shortening
      Kc
      chamber stiffness constant
      Km
      myocardial stiffness constant
      TIMP
      tissue inhibitor of matrix metalloproteinase
      AP-1
      activator protein 1
      • Received April 22, 1999.
      • Accepted July 13, 1999.
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    1. JPET November 1, 1999 vol. 291 no. 2 799-811
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