Ischaemia–reperfusion injury activates matrix metalloproteinases in the human heart

Abstract

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) regulate matrix remodelling in the heart and play a pivotal role in myocardial dysfunction immediately following ischaemia-reperfusion injury ex vivo in rats. We investigated the changes in MMPs and TIMPs in acute myocardial ischaemia-reperfusion injury in humans. Fifteen patients with stable angina undergoing coronary artery bypass graft surgery with cardiopulmonary bypass were enrolled. Left ventricular stroke work index was monitored prior to bypass and for 24 h following reperfusion. Left atrial biopsy samples were obtained at the start of bypass before cardioplegia and within 10 min after removal of the aortic cross-clamp. Plasma samples were collected from the radial artery and coronary sinus 1, 5, and 10 min following removal of the cross-clamp. In cardiac biopsies there was a marked increase in 72 kDa MMP-2 and 92 kDa MMP-9 activities, and a decrease in TIMP-1 upon reperfusion. Increased MMP activity correlated positively with cross-clamp duration and inversely with cardiac mechanical function 3 h following reperfusion. TIMP-1 correlated inversely with cross-clamp time and positively with cardiac mechanical function. Plasma samples revealed a significant increase in both 92 kDa MMP-9 and 64 kDa MMP-2 activities 1 min following removal of cross-clamp. Reperfusion following cardioplegia activates MMPs in the myocardium and plasma of patients undergoing coronary artery bypass grafting. This is the first correlation of MMP myocardial activity with cardiac function in humans. The early increase in MMP activity produces a proteolytic environment that may contribute to myocardial stunning injury in humans.