Modelling myocardial ischaemia and reperfusion.

Substrate depletion and increased intracellular acidity are believed to underlie clinically important manifestations of myocardial ischaemia. Recent advances in measuring ion concentrations and metabolite changes have provided a wealth of detail on the processes involved. Coupled with the rapid increase in computing power, this has allowed the development of a mathematical model of cardiac metabolism in normal and ischaemic conditions. Pre-existing models of cardiac cells such as Oxsoft HEART contain highly developed dynamic descriptions of cardiac electrical activity. While biophysically detailed, these models do not yet incorporate biochemical changes. Modelling of bioenergetic changes was based and verified against whole heart NMR spectroscopy. In the model, ATP hydrolysis and generation are calculated simultaneously as a function of [Pi]i. Simulation of pH regulation was based on the pHi dependency of acid efflux, examined in time-course studies of pHi recovery (measured in myocytes with the fluorophore carboxy-SNARF-1) from imposed acid and alkali loads. The force-[Ca2+]i relationship of myofibrils was used as the basis of modelling H+ competition with Ca2+, and thus of pH effects on contraction. This complex description of biochemically important changes in myocardial ischaemia was integrated into the OXSOFT models. The model is sufficiently complete to simulate calcium-overload arrhythmias during ischaemia and reperfusion-induced arrhythmias. The timecourse of both metabolite and pH changes correlates well with clinical and experimental studies. The model possesses predictive power, as it aided the identification of electrophysiological effects of therapeutic interventions such as Na(+)-H+ block. It also suggests a strategy for the control of cardiac arrhythmias during calcium overload by regulating sodium-calcium exchange. In summary, we have developed a biochemically and biophysically detailed model that provides a novel approach to studying myocardial ischaemia and reperfusion.

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