Matrix metalloproteinase-2 (MMP2) and myocardial dysfunction associated with urgent cardiac surgery

Student thesis: Doctoral ThesisDoctor of Medicine

Abstract

Background: Current management of patients presenting with acute coronary syndrome (ACS) includes aggressive and expeditious revascularisation, including surgical revascularisation. However, early surgery following ACS is associated with high mortality, as subsequent global ischaemia induced during surgery is imposed on infarcted myocardium. Emerging evidence suggests that matrix metalloproteinases (MMPs), especially MMP2, may have an important role in the acute myocardial dysfunction seen after global ischaemia-reperfusion injury, by targeting intracellular functional and structural proteins.
Aims: To investigate whether MMP2 has a causative role in heart dysfunction when previously infarcted hearts were subjected to further global ischaemia-reperfusion, as occurs in cardiac surgery, with and without cardioplegic protection.
Methods and Results: MI was surgically induced in male Wistar rats, (250-350 g body weight) by in vivo ligation of the left anterior descending artery. The animals were recovered for 7 days prior to excision of hearts and isolated Langendorff perfusion, followed by induction of further global ischaemia and reperfusion. The recovery of mechanical function (left ventricular developed pressure: LVDP) of the heart was assessed during reperfusion. MMP2 activity was also measured during the early reperfusion phase in the heart tissues. Infarcted hearts had less capacity to recover function after an additional period of global ischaemia, which was associated with higher MMP2 activity in the infarcted hearts compared to normal hearts. Inhibition of MMP2 improved recovery of function. When an MMP inhibitor was used as an adjunct to St Thomas’ Hospital cardioplegia, there was a trend towards improved recovery if the inhibitor was present before, during and after ischaemia.
Conclusion: MMP2 has a role in causing cardiac dysfunction when infarcted hearts were subjected to further global ischaemia-reperfusion. Inhibition of MMP2 resulted in improved recovery of the function of the hearts during reperfusion. With cardioplegia, MMP2 inhibition before, during and after ischaemia was crucial to improve cardioprotection during early reperfusion.
Date of Award3 Jun 2013
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorJames Clark (Supervisor) & David Chambers (Supervisor)

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