Myocardial ischemia-reperfusion injury: Development of a new mathematical model and application to investigations of arrhythmogenesis and therapeutic alternatives.

摘要

Myocardial ischemia-reperfusion (IR) injury represents a constellation of pathological changes that occur when previously ischemic myocardium experiences a restoration of perfusion. IR injury can manifest as a variety of cardiac arrhythmias, decreased force development, or increased necrosis. Research over the past few decades has identified many of the processes that occur during ischemia and reperfusion, and has led to numerous preclinical and clinical studies targeting many different aspects of proposed IR injury pathways. However, despite some preclinical successes in mitigating IR injury, no therapy has yet been successfully translated to the clinical setting.;In order to overcome some of the limitations inherent to traditional laboratory techniques in the study of IR injury, we have developed an improved mathematical model of the cardiomyocyte which simulates ischemia and reperfusion in a more realistic manner than was possible with existing models. We have also used this model to investigate inhibition of the sodium-proton exchanger (NHE), which has been proposed as a therapeutic option to mitigate IR injury. NHE inhibitors have had mixed results in preclinical experiments and have yet to be shown to be effective in the clinical setting. Our modeling suggests that NHE inhibition may be detrimental, or at best not significantly helpful, as inhibiting NHE during reperfusion also impairs intracellular pH recovery, which affects numerous cellular components. We have also used the model to investigate the relative importance of pH and phosphometabolite recovery during reperfusion on action potential morphology, intracellular sodium, and intracellular calcium concentration during reperfusion. Our simulations suggest that phosphometabolite recovery is much more beneficial than pH recovery in terms of restoring normal action potential morphology. Finally, we were able to suggest possible beneficial alternatives for the mitigation of sodium overload during reperfusion.;The model that we present here is one that should prove useful for others wishing to study myocardial ischemia and reperfusion, as it represents many different aspects of the pathophysiology and can be easily modified to simulate a wide variety of ischemia and reperfusion scenarios. The simulations presented here also highlight the promise of applying the tools of computational biology, as they afford more global views and insights that would be more difficult to glean using the traditional tools of experimental biology. The findings of these simulations can be used to inform future experiments.