Integrative simulation analysis of myocardial ischaemia-reperfusion injury

Cardiac ischaemia, reduced coronary blood flow, causes significant damages to the heart, and paradoxically reperfusion, restored flow after ischaemia, often results in more severe injury. Although the mechanisms underlying cardiac ischaemia-reperfusion injury have been intensively investigated, effective therapeutic strategies applicable during reperfusion to mitigate this damage have not been established yet. To obtain more insights into the mechanisms underlying ischaemia-reperfusion injury, and to explore effective methods to relieve reperfusion injury, we developed a comprehensive mathematical model of ventricular myocyte, implementing excitation-contraction (E-C) coupling, cytosolic and mitochondrial pH regulation, pH dependence of major components of E-C coupling and cellular energy metabolism, including mitochondrial oxidative phosphorylation. The mathematical model successfully reproduced experimentally observed findings on cardiac ischaemia-reperfusion injury, such as intracellular and extracellular acidosis, cytosolic Na⁺ overload, cytosolic Ca²⁺ overload, mitochondrial dysfunction, action potential shortening and contraction failure. It was found that the reperfusion-induced exacerbation of Na⁺ _i, Ca²⁺ _i overloads was mainly caused by insufficient production of NADH, which is used in mitochondrial oxidative phosphorylation to synthesize ATP for Na⁺/K⁺ pump and sarcoplasmic/endoplasmic reticulum Ca²⁺ pump (SERCA) to expel accumulated cytosolic Na⁺ and Ca²⁺, respectively. It was suggested that the preservation of mitochondrial NADH production, attenuation of ATP consumption via SERCA or contraction for a short period or activation of the Na⁺/K⁺ pump during reperfusion mitigates reperfusion injury. KEY POINTS: Experimental data on cardiac ischaemia-reperfusion injury are available. No effective methods applicable during reperfusion were available for mitigating the injury. We developed a comprehensive cardiomyocyte model to simulate the injury. Na⁺ and Ca²⁺ overloads and contraction failure could be reproduced by the model. It was found that correcting ATP supply-consumption imbalance during reperfusion, that is, preservation of mitochondrial NADH production, attenuation of ATP consumption or activation of the Na⁺/K⁺ pump, was effective at mitigating the injury.