UVM Theses and Dissertations
Format:
Print
Author:
French, Christopher J.
Dept./Program:
Cell and Molecular Biology Program
Year:
2011
Degree:
Ph. D.
Abstract:
Acute myocardial infarction (MI) is one of the leading causes of death worldwide. The advent ofthrombolytic therapy and more recently percutaneous coronary interventions (PCI) have dramatically improved outcomes after acute MI. However, the mortality rate still remains around 5-10% and late mortality associated with heart failure secondary to left ventricular negative remodeling may occur. Further reduction in the risk ofdeath and subsequent heart failure can be achieved by defining additional methods to salvage myocardium after acute myocardial infarction.
It has been proposed that in addition to necrotic cell death, cardiomyocytes undergo apoptotic cell death in response to ischemia. However, the magnitude of apoptosis and its impact on infarct size following myocardial infarction have not been well elucidated. In our studies we demonstrate that contrary to the conventional wisdom, apoptosis is not a major contributor to myocardial cell death early after persistent ischemia or ischemia followed by reperfusion. We show that necrosis is the main mechanism of cell death following MI, and that anti-apoptotic interventions are not likely to preserve substantial amounts of myocardium after MI.
Autophagy, a key process ofcell regulation, has been thought to be cardioprotective by removing damaged organelles following an insult. However, its extent after transient or persistent myocardial ischemia has not been well established. Our results demonstrate that autophagy is downregulated in the peri-infarct zone following persistent and transient ischemia and virtually absent in the center, of zones of infarction.
For the last 50 years limiting cardiomyocyte cell death has been the major focus oftherapeutic interventions following MI. Surprisingly, the death of the cardiac microvasculature has largely been ignored. We observed serendipitously that gross hemorrhage occurred in mice lacking plasminogen activator inhibitor type-I (PAl-1) around 48 hours after persistent ischemia. This led us to hypothesize that the defect in the fibrinolytic system of PAI-I mice was unmasking a loss of integrity of the cardiac microvasculature, a phenomenon that we have termed vascular rhexis. We demonstrate in this dissertation that vascular rhexis occurs in normal mice that are subjected to persistent ischemia or ischemia followed by reperfusion. The delayed death of the vasculature compared to the earliertime point of cardiomyocyte cell death is of significance because it unveils a new window of opportunity to protect the heart after MI. We postulate that attenuation of vascularrhexis is an attractive therapeutic target to limit the effects of the deleterious consequences of MI.
In summary, in this dissertation we delineate the mechanisms of cell death in the heart following myocardial infarction and their contribution to infarct size. In addition, we have identified a phenomenon we call vascular rhexis which we believe is a major contributor to cardiac dysfunction after MI and possibly amenable to attenuation.
It has been proposed that in addition to necrotic cell death, cardiomyocytes undergo apoptotic cell death in response to ischemia. However, the magnitude of apoptosis and its impact on infarct size following myocardial infarction have not been well elucidated. In our studies we demonstrate that contrary to the conventional wisdom, apoptosis is not a major contributor to myocardial cell death early after persistent ischemia or ischemia followed by reperfusion. We show that necrosis is the main mechanism of cell death following MI, and that anti-apoptotic interventions are not likely to preserve substantial amounts of myocardium after MI.
Autophagy, a key process ofcell regulation, has been thought to be cardioprotective by removing damaged organelles following an insult. However, its extent after transient or persistent myocardial ischemia has not been well established. Our results demonstrate that autophagy is downregulated in the peri-infarct zone following persistent and transient ischemia and virtually absent in the center, of zones of infarction.
For the last 50 years limiting cardiomyocyte cell death has been the major focus oftherapeutic interventions following MI. Surprisingly, the death of the cardiac microvasculature has largely been ignored. We observed serendipitously that gross hemorrhage occurred in mice lacking plasminogen activator inhibitor type-I (PAl-1) around 48 hours after persistent ischemia. This led us to hypothesize that the defect in the fibrinolytic system of PAI-I mice was unmasking a loss of integrity of the cardiac microvasculature, a phenomenon that we have termed vascular rhexis. We demonstrate in this dissertation that vascular rhexis occurs in normal mice that are subjected to persistent ischemia or ischemia followed by reperfusion. The delayed death of the vasculature compared to the earliertime point of cardiomyocyte cell death is of significance because it unveils a new window of opportunity to protect the heart after MI. We postulate that attenuation of vascularrhexis is an attractive therapeutic target to limit the effects of the deleterious consequences of MI.
In summary, in this dissertation we delineate the mechanisms of cell death in the heart following myocardial infarction and their contribution to infarct size. In addition, we have identified a phenomenon we call vascular rhexis which we believe is a major contributor to cardiac dysfunction after MI and possibly amenable to attenuation.