Impairment of cellular metabolism in ischemic myocardium has a profound impact on cellular electrophysiology and contractility. Despite a wealth of available data, the multifactorial consequences of impaired metabolism are such that the sequence of events leading from coronary artery occlusion to life-threatening disturbances to the electrical rhythm and reduced pumping capacity remains poorly understood.
We are using integrative mathematical modelling to provide a framework within which to assess the quantitative contribution of different consequences of impaired metabolism to the overall deterioration of myocyte function during ischemia. This framework uses thermodynamically constrained models of energy consuming fluxes, including the Na-K pump (Prog Biophys Mol Biol 85 387 2004) and SERCA (Biophys J 96 2029 2009) and other metabolite-sensitive processes to couple cardiac cellular bioenergetics to electrophysiology and excitation-contraction coupling (Prog Biophys Mol Biol 97 348 2008; Tran et al. submitted).
We have applied this modelling framework to investigate the metabolic origins and functional consequences of several features of impaired myocyte physiology, including acidosis (Biophys J 90 3074 2006) and hyperkalemia (Am J Physiol 293 H3036 2007) arising over the first 15 minutes of zero flow ischemia, and subsequent calcium overload and calcium-dependent alternans (Terkildsen et al. in prep). These studies allow us to assess the quantitative contribution of changes to energy metabolism, pH regulation, ion homeostasis and electrophysiology to the development of ischemic heart disease.
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