Plasma matrix metalloproteinases as predictors of prognosis and left ventricular remodelling after acute myocardial infarction

Introduction: Matrix metalloproteinases (MMPs) are a family ofzinc dependant endopeptidases which selectively degrade components ofthe extracellular matrix. Degradation ofthis matrix is central to several aspects ofcardiovascular disease including adverse left ventricular remodelling, a process which is intimately linked to prognosis. The basis ofthis thesis was to investigate the role ofMMP's and their natural inhibitors tissue inhibitors ofmetalloproteinases (T!MP's) in the process of left ventricular remodelling, clinical heart failure and adverse prognosis post acute myocardial infarction (AMI). Methods: We recruited patients post AMI. Stage I aimed to examine the temporal profile of several MMP's and their relationship with markers ofLV function, volumes and remodelling in a limited population size (n=9I). Stage 2 investigated a more extensive population (n=404), concentrating on a limited number ofMMP's/TIMP's and included clinical follow up to identify subjects with adverse prognosis. All patients were recruited from the CCU units ofthe University Hospitals ofLeicester. All donated venous blood samples at 0-12hrs, 12-24hrs and at 24hr intervals post symptoms until discharge for measurement ofMMP/TIMP's and underwent echocardiographic studies during their index admission and at follow up. During stage 2 all subjects were additionally followed for the clinical endpoints ofdeath or heart failure. We also performed a retrospective analysis ofthe effects ofdiabetes and stress hyperglycaemia on metalloproteinase expression and LV dysfunction post MI. Results: We present convincing data to implicate the MMP system in both LV remodelling and adverse prognosis post AMI. Stage I demonstrates individual temporal profiles of MMP's and presents data on determinants ofMMP expression. We show an association between MMP-9 and LV dysfunction, volumes and remodelling post AMI. Stage 2 confirms both this data and observes similar results for TIMP-I. In addition we demonstrate the association between both MMP-9 and TIMP-I with adverse prognosis and compare with N terminal pro BNP as a prognostic marker. Our retrospective audit ofthe effects ofdiabetes and stress hyperglycaemia is a hypothesis generating chapter which presents association between post MI hyperglycaemia, elevated MMP's and adverse LV function. Summary: Altered MMP/TIMP expression occurs post AMI and is associated with LV dysfunction and remodelling, and with adverse prognosis. The MMP system may represent a potential therapeutic target post AMI.EThOS - Electronic Theses Online ServiceGBUnited Kingdo