Circulation. 2001;104:1147-1152
doi: 10.1161/hc3501.095215
doi: 10.1161/hc3501.095215
(Circulation. 2001;104:1147.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Downregulation of Matrix Metalloproteinases and Reduction in Collagen Damage in the Failing Human Heart After Support With Left Ventricular Assist Devices
From the Cardiovascular Institute (Y.Y.L., Y.F., C.F.M., P.W., W.R., R.L.K., A.M.F.) and Department of Neurology (W.P.), University of Pittsburgh School of Medicine, Pittsburgh, Pa, and the Center for Anesthesiology Research (C.S.M.), Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Arthur M. Feldman, MD, PhD, Division of Cardiology, University of Pittsburgh School of Medicine, 572 Scaife Hall, 200 Lothrop St, Pittsburgh, PA 15213. E-mail feldmanam{at}msx.upmc.edu
Background—— Left ventricular assist device (LVAD) support of the failing heart induces salutary changes in myocardial structure and function. Matrix metalloproteinases (MMPs) are increased in the failing heart and are induced by stretch in cardiac cells in vitro. We hypothesized that mechanical unloading may affect LV plasticity by regulating MMPs and their substrates.
Methods and Results—— LV samples were collected from patients with dilated cardiomyopathy (DCM, n=14) or ischemic cardiomyopathy (ICM, n=16) at the time of implantation of the LVAD and again during cardiac transplantation. MMP-1, -3, and -9 were measured by ELISA, MMP-2 and -9 gelatinolytic activity by gelatin zymography, and tissue inhibitors of metalloproteinases (TIMPs) by Western blot. Total soluble and insoluble collagens were separated by pepsin solubilization, and the contents were determined by quantification of hydroxyproline. The undenatured soluble collagen was measured by Sircol collagen assay. The results showed that MMP-1 and -9 were decreased, whereas TIMP-1 and -3 were increased, but there was no change in MMP-2 and -3 and TIMP-2 and -4 after LVAD support. The undenatured collagen was increased, with the ratio of undenatured to total soluble collagens increased in ICM and that of insoluble to total soluble collagens increased in DCM after LVAD support.
Conclusions—— The reduced MMPs and increased TIMPs and ratios of undenatured to total soluble collagens and insoluble to total soluble collagens after LVAD support suggest that reduced MMP activity diminished damage to the matrix. These changes may contribute to the functional recovery and LV plasticity after LVAD support.
Key Words: collagen • metalloproteinases • remodeling • heart-assist device • heart failure
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