Relationship Between Myocardial Redox State and Matrix Metalloproteinase Activity in Patients on Left Ventricular Assist Device Support

Abstract

Background: Redox aminothiols have been reported to modulate the activity of recombinant metalloproteinases (MMP). The aim of the present study was to investigate the effects of myocardial redox state on the activities of MMP-2 and -9 implicated in cardiac remodeling in end-stage heart failure patients supported by left ventricular assist device (LVAD). Methods and Results:During heart transplant (HT) surgery, myocardial specimens (MS) from right ventricular walls and LV walls were obtained from 7 LVAD recipients (LVAD group, MS n=35) and from 7 stable HT candidates on medical therapy (MT group, MS n=35). Myocardial MMP-2 and -9 activities and expression, tissue inhibitor of MMP (TIMP)-1 and -4, transforming growth factor (TGF)-β1 and aminothiol concentrations were measured. MMP-2 and -9 activities were evaluated also by incubating MS with different amounts of reduced and oxidized glutathione (GSH). MMP-2 and -9 activities and expression were lower in the LVAD group, whereas myocardial TIMP-1 and -4 concentrations were comparable to those of MT patients. Higher GSH and TGF-β1 concentrations were found in LVAD-recipients. Only GSH concentrations were inversely related to MMP-2 and -9 activities. In vitro, GSH had an inhibitory effect on MMP-2 and -9 activities.Conclusions: LVAD recipients show reduced myocardial MMP-2 and -9 activities and expression when compared to medically treated patients. Changes of myocardial redox state, predominantly GSH-dependent, appear to modulate MMP-2 and -9 activities by an inhibitory effect dependent on thiol content. These data support a role of GSH cycle in modulating the extracellular matrix in end-stage heart failure patients supported by LVAD. (Circ J 2011; 75: 2387 - 2396

Effects of Left Ventricular Assist Device (LVAD) Placement on Myocardial Oxidative Stress Markers

“…Even though signs of reverse remodelling are present in the contractile proteins, the LVAD does not appear to improve oxidative stress levels in the myocardium. This result is similar to that seen by Caruso et al [29], showing that LVAD recipients had increases in the myocardial redox state compared to heart failure patients without LVAD support.…”

Reduced Endoglin Activity Limits Cardiac Fibrosis and Improves Survival in Heart Failure

“…Previous studies have shown increased cardiac expression of profibrogenic genes including TGFβ1 in patients with end-stage heart failure referred for LVAD support 23, 24 . In both studies, higher levels of TGFβ1 were observed in subjects requiring LVAD support until cardiac transplantation, suggesting that TGFβ1 may limit myocardial recovery by promoting tissue fibrosis.…”

New methodologies to accurately assess circulating active transforming growth factor-β1 levels: implications for evaluating heart failure and the impact of left ventricular assist devices

“…Moreover, data demonstrating that myocardial TGF-β1 levels are elevated in LVAD patients suggest that the hemodynamic benefits of LVAD insertion may not reverse the increase in myocardial TGF-β1 associated with HF. 39…”