sPLA2 as a prognostic factor in myocardial infarction
09 / 2000 - 06 / 2005
During acute myocardial infarction (AMI), inflammatory mediators play a key role in the tissue response to cell damage in ischemia. However, this inflammatory response probably not only is restricted to irreversibly damaged cardiomyocytes. We hypothesize that also reversibly damaged cardiomyocytes in the borderzone of the infarction site undergo changes at the level of the plasma membrane that induce an inflammatory response. Via immunohistochemical studies of the heart of AMI patients that died subsequent to myocardial infarction, changes in cardiomyocytes were found (in ischemic area and in its borderzone) that enhance inflammation, namely 'flip-flop' of cell membranes (=exchange of phospholipids of inner and outer leaflet of the plasma membrane); binding of the acute phase protein C-reactive protein (CRP); complement activation; expression of ICAM-1 on cardiomyocytes and activation of neutrophils. In agreement herewith are our studies in serum in patients with AMI and in tissue homogenates of infarcted areas of the (human) heart. In both studies CRP-mediated complement activation was found. A crucial point in the above mentioned inflammatory response is the flip-flop of the membrane and subsequent binding of CRP (resulting in complement activation, which induces ICAM-1 upregulation and neutrophil activation). For this a role of secretory phospholipase A2 (sPLA2) is hypothesized, since this enzyme hydrolyzes phospholipids of flip-flopped membranes, thereby generating binding sites for CRP. We indeed recently have found sPLA2 depositions in the human ischemic heart (earlier and beyond the area of positivity of CRP). Furthermore an increase in sPLA2 in patients with AMI was found in serum. Therefore a clinical study is proposed to evaluate sPLA2 as an independent prognostic factor in patients with AMI. Next to this, in an in vitro study, the hypothesis of the mechanism of flip-flop of the membrane resulting in sPLA2 binding and activation will be studied at a cellular level.