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CLINICAL RESEARCH: HEART FAILURE

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

Stefan Klotz, MD^_*, A.H. Jan Danser, PhD, Robert F. Foronjy, MD^_*, Mehmet C. Oz, MD, Jie Wang, MD, PhD^_*,, Donna Mancini, MD^_*, Jeanine D'Armiento, MD, PhD^_* and Daniel Burkhoff, MD, PhD^_*,,_*

^_* Department of Medicine
Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York
Department of Pharmacology, Erasmus Medical Center, Rotterdam, the Netherlands
The Jack H. Skirball Center for Cardiovascular Research, Cardiovascular Research Foundation, Orangeburg, New York

Manuscript received July 21, 2006; revised manuscript received October 4, 2006, accepted October 9, 2006.

^_* Reprint requests and correspondence: Dr. Daniel Burkhoff, Jack H. Skirball Center for Cardiovascular Research, Cardiovascular Research Foundation, 8 Corporate Drive, Orangeburg, New York 10962 (Email: db59{at}columbia.edu).

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.

Abbreviations and Acronyms   ACE-I = angiotensin-converting enzyme inhibition   Ang = angiotensin   CHF = chronic heart failure   ECM = extracellular matrix   EDPVR = passive end-diastolic pressure-volume relationship   LV = left ventricle/ventricular   LVAD = left ventricular assist device   MMP = matrix metalloproteinase   RV = right ventricle/ventricular   TIMP = tissue inhibitor of matrix metalloproteinases

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