Abstract
Heart disease remains the leading cause of death globally. Although reperfusion following myocardial ischemia can prevent death by restoring nutrient flow, ischemia/reperfusion injury can cause significant heart damage. The mechanisms that drive ischemia/reperfusion injury are not well understood; currently, few methods can predict the state of the cardiac muscle cell and its metabolic conditions during ischemia. Here, we explored the energetic sustainability of cardiomyocytes, using a model for cellular metabolism to predict the levels of ATP following hypoxia. We modeled glycolytic metabolism with a system of coupled ordinary differential equations describing the individual metabolic reactions within the cardiomyocyte over time. Reduced oxygen levels and ATP consumption rates were simulated to characterize metabolite responses to ischemia. By tracking biochemical species within the cell, our model enables prediction of the cell's condition up to the moment of reperfusion. The simulations revealed a distinct transition between energetically sustainable and unsustainable ATP concentrations for various energetic demands. Our model illustrates how even low oxygen concentrations allow the cell to perform essential functions. We found that the oxygen level required for a sustainable level of ATP increases roughly linearly with the ATP consumption rate. An extracellular O2 concentration of ∼0.007 mm could supply basic energy needs in non-beating cardiomyocytes, suggesting that increased collateral circulation may provide an important source of oxygen to sustain the cardiomyocyte during extended ischemia. Our model provides a time-dependent framework for studying various intervention strategies to change the outcome of reperfusion.
Highlights
Ischemic heart disease was the leading cause of death in 2012 and the most rapidly increasing cause of death during 2000 –2012 [1, 2]
We have developed a model of cardiomyocyte metabolism that accounts for cytoplasmic metabolism via glycolysis, mitochon
The concentration of ATP is maintained by a sequence of three energy buffers: we observe a drop in creatine phosphate, followed by the fall of glycogen, and a rise in AMP as ADP is sacrificed
Summary
Ischemic heart disease was the leading cause of death in 2012 and the most rapidly increasing cause of death during 2000 –2012 [1, 2]. As the heart is saved, reperfusion carries the risk of damaging additional heart tissue. Various proposals for novel reperfusion techniques have been advanced, but our understanding of ischemia/ reperfusion injury and our ability to mitigate its risk are significantly lacking (4 –9). It is imperative we identify the quantitative conditions that exist in the cardiomyocyte following a period of ischemia. An alternative approach is taken by Karlstadt et al [18] to construct an extensive model that identifies minimum substrate and oxygen requirements for normal function of the cardiomyocyte, but it does not address the changes that develop during hypoxia. Zhou et al [19] use their model to illustrate the transition from oxygenated conditions to partial deoxygenation
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