Downregulation of Matrix Metalloproteinases and Reduction in Collagen Damage in the Failing Human Heart After Support With Left Ventricular Assist Devices

Abstract

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, nϭ14) or ischemic cardiomyopathy (ICM, nϭ16) 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 insolubleto 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 Ⅲ metalloproteinases Ⅲ remodeling Ⅲ heart-assist device Ⅲ heart failure L eft ventricular assist devices (LVADs) provide mechanical support for the failing heart and serve as a bridge to cardiac transplantation, with the potential to be a destiny therapy for heart failure. [1][2][3] Recent reports demonstrate that LVAD support may be associated with adaptive remodeling of the ventricular myocardium, including reduced LV mass, wall thickness, and myocyte diameter; changes in LV pressure-volume relationships; and reversal of LV chamber dilation and molecular remodeling of proteins involved in Ca 2ϩ cycling. [3][4][5][6][7][8][9][10] In addition, LVAD support has been associated with salutary changes in cardiomyocyte function. Indeed, a small subgroup of patients can be successfully weaned from LVAD after recovery of ventricular function. 6,[11][12][13][14] Although it has been suggested that these beneficial changes are attributed to chronic unloading of the ventricular myocardium, the molecular mechanisms that play a role in LVAD-induced myocardial plasticity and LV remodeling remain undefined. See p 1089We hypothesized that the myocardial remodeling that occurs with LVAD unloading might be attributable to alterations in the components of the extracellular matrix, and specifically in the activity of matrix metalloproteinases (MMPs) and the physical pr...

Type IV collagen degradation in the myocardial basement membrane after unloading of the failing heart by a left ventricular assist device

“…So, both WB and gel zymography showed an increase in active MMP. This change in active MMP is confirmed by others in heart failure 39,40 and during LVAD support 36 by gel zymography. WB and gel zymography differed in the detected amount of inactive MMP.…”

“…The differences in this association between the BM and collagen fibers may be due to alterations of the BM but may also be caused by the changes in the ECM. 15,36,37 With IHC, we showed a significant reduction of type IV collagen immunoreactivity in the BM after LVAD support. However, laminin was still present in the BM after unloading of the heart.…”

“…[35][36][37] In a previous study of our group, 15 we have shown that reverse remodeling of type I and III collagen in the ECM follows a biphasic pattern. Initially, an increase of type I and III collagen turnover takes place, which is paralleled by an increase of the ECM volume.…”

β-Adrenergic Activation Initiates Chamber Dilatation in Concentric Hypertrophy

“…15,25,[27][28][29] In the present study, chronic ISO administration resulted in marked increases in myocardial collagen concentrations and consequent increments in both soluble (noncrosslinked) and insoluble (crosslinked) myocardial collagen concentrations. This is in contrast to the myocardial collagen change noted in age-matched untreated SHR, in which although myocardial collagen concentrations were increased, the enhanced crosslinked properties of collagen (decreased solubility) resulted in increments in the crosslinked, but not in the noncrosslinked portion of myocardial collagen.…”

Improvement in collagen metabolism after 12 weeks’ cardiac resynchronization therapy in patients with ischaemic cardiomyopathy

“…4,6 Human and animal studies have suggested that regulating the composition of ECM can provide new insights into the prevention of cardiac remodelling in ischaemia. [14][15][16] Invasive myocardial biopsy has been the gold standard for evaluating myocardial fibrosis and tissue repair. However, noninvasive ways of assessing collagen metabolism (by measuring the biomarkers MMP and TIMP) have been developed and may replace myocardial biopsy.…”