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.
OBJECTIVE
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.
Klotz
Stefan
S
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Danser
A H Jan
AH
Foronjy
Robert F
RF
Oz
Mehmet C
MC
Wang
Jie
J
Mancini
Donna
D
D'Armiento
Jeanine
J
Burkhoff
Daniel
D
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000803:Angiotensin I / Q000187:drug effects / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D001707:Biopsy, Needle; D016022:Case-Control Studies; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D006353:Heart-Assist Devices; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D011182:Postoperative Care; D011300:Preoperative Care; D011336:Probability; D011379:Prognosis; D012016:Reference Values; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D015996:Survival Rate; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000187:drug effects / Q000378:metabolism*; D016896:Treatment Outcome
D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D019715:Tissue Inhibitor of Metalloproteinase-1; D003094:Collagen; D000803:Angiotensin I