Ch'en F F, Vaughan-Jones R D, Clarke K, Noble D
University Laboratory of Physiology, University of Oxford, UK.
Prog Biophys Mol Biol. 1998;69(2-3):515-38. doi: 10.1016/s0079-6107(98)00023-6.
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.
底物耗竭和细胞内酸度增加被认为是心肌缺血临床重要表现的基础。测量离子浓度和代谢物变化的最新进展为相关过程提供了丰富的细节。再加上计算能力的迅速提高，这使得能够建立正常和缺血条件下心脏代谢的数学模型。先前的心脏细胞模型，如Oxsoft HEART，包含了对心脏电活动的高度发达的动态描述。虽然这些模型在生物物理学上很详细，但尚未纳入生化变化。生物能量变化的建模是基于全心脏核磁共振波谱并经过验证的。在该模型中，ATP水解和生成作为[Pi]i的函数同时计算。pH调节的模拟基于酸流出对细胞内pH（pHi）的依赖性，这是在对施加酸和碱负荷后pHi恢复的时程研究中（用荧光团羧基-SNARF-1在心肌细胞中测量）进行研究的。肌原纤维的力-[Ca2+]i关系被用作模拟H+与Ca2+竞争的基础，从而也是pH对收缩影响的基础。对心肌缺血中具有生化重要性的变化的这种复杂描述被整合到OXSOFT模型中。该模型足够完整，能够模拟缺血期间的钙超载心律失常和再灌注诱导的心律失常。代谢物和pH变化的时间进程与临床和实验研究相关性良好。该模型具有预测能力，因为它有助于识别诸如Na(+)-H+阻断等治疗干预的电生理效应。它还提出了一种通过调节钠钙交换来控制钙超载期间心脏心律失常的策略。总之，我们已经开发了一个在生化和生物物理学上详细的模型，为研究心肌缺血和再灌注提供了一种新方法。
