The impact of angiotensin-converting enzyme inhibitor therapy on the extracellular collagen matrix during left ventricular assist device support in patients with end-stage heart failure

J Am Coll Cardiol. 2007 Mar 20;49(11):1166-74. doi: 10.1016/j.jacc.2006.10.071. Epub 2007 Mar 7.

Abstract

Objectives: We hypothesized that angiotensin-converting enzyme inhibition (ACE-I) during left ventricular assist device (LVAD) support in patients with end-stage heart failure prevents potentially deleterious effects on the extracellular matrix.

Background: Left ventricular assist device-induced mechanical unloading increases myocardial collagen and stiffness and may contribute to the low rate of recovery.

Methods: Heart samples obtained before and after LVAD implantation were divided into groups depending on whether the patients received (n = 7) or did not receive (control; n = 15) ACE-I. At transplant, ex vivo pressure-volume relationships were measured and chamber and myocardial stiffness constants determined. Myocardial tissue content of angiotensin (Ang) I and II, matrix metalloproteinase (MMP)-1, tissue inhibitor of MMPs (TIMP)-1, and total and cross-linked collagen was measured.

Results: Duration of support was comparable between ACE-I and control subjects (96 +/- 65 days vs. 109 +/- 22 days). Pre-LVAD Ang I and II and total and cross-linked collagen were similar between groups. Post-LVAD, Ang II was reduced in the ACE-I group but increased in control subjects (181 +/- 7 fmol/g vs. 262 +/- 41 fmol/g; p < 0.05). Similarly, cross-linked collagen decreased during LVAD support in the ACE-I group. Left ventricular (LV) mass and myocardial stiffness were lower in the ACE-I group. ACE-I normalized the LV and right ventricular (RV) MMP-1/TIMP-1 ratio. Collagen content and characteristics of the RV were not affected by ACE-I.

Conclusions: ACE-I therapy was associated with decreased Ang II, myocardial collagen content, and myocardial stiffness during LVAD support. This is the first demonstration of a pharmacologic therapy that can impact myocardial properties during mechanical unloading, and it could foster new lines of investigation in strategies of enhancing myocardial recovery during LVAD support.

MeSH terms

  • Adult
  • Aged
  • Analysis of Variance
  • Angiotensin I / drug effects
  • Angiotensin I / metabolism
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Biomarkers / metabolism
  • Biopsy, Needle
  • Case-Control Studies
  • Collagen / drug effects
  • Collagen / metabolism
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism*
  • Female
  • Heart Failure / drug therapy*
  • Heart Failure / mortality
  • Heart Failure / pathology
  • Heart Failure / surgery
  • Heart-Assist Devices*
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Myocardial Contraction / drug effects
  • Postoperative Care
  • Preoperative Care
  • Probability
  • Prognosis
  • Reference Values
  • Retrospective Studies
  • Sensitivity and Specificity
  • Severity of Illness Index
  • Survival Rate
  • Tissue Inhibitor of Metalloproteinase-1 / drug effects
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism*
  • Treatment Outcome

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Biomarkers
  • Tissue Inhibitor of Metalloproteinase-1
  • Collagen
  • Angiotensin I