Downregulation of matrix metalloproteinases and reduction in collagen damage in the failing human heart after support with left ventricular assist devices

Background-Left ventricular assist device (LVAD) support of the failing hea rt induces salutary changes in myocardial structure and function. Matrix me talloproteinases (MMPs) are increased in the failing heart and are induced by stretch in cardiac cells in vitro. We hypothesized that mechanical unloa ding may affect LV plasticity by regulating MMPs and their substrates. Methods and Results-LV samples were collected from patients with dilated ca rdiomyopathy (DCM, n = 14) or ischemic cardiomyopathy (ICM, n= 16) at the t ime of implantation of the LVAD and again during cardiac transplantation. M MP-1, -3, and -9 were measured by ELISA, MMP-2 and -9 gelatinolytic activit y 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 o f hydroxyproline. The undenatured soluble collagen was measured by Sircol c ollagen 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, w ith the ratio of undenatured to total soluble collagens increased in ICM an d 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 L VAD support suggest that reduced MMP activity diminished damage to the matr ix. These changes may contribute to the functional recovery and LV plastici ty after LVAD support.