Mathematical Modeling of Ischemia-Reperfusion Injury and Postconditioning Therapy.

Reperfusion (restoration of blood flow) after a period of ischemia (interruption of blood flow) can paradoxically place tissues at risk of further injury: so-called ischemia-reperfusion injury or IR injury. Recent studies have shown that postconditioning (intermittent periods of further ischemia applied during reperfusion) can reduce IR injury. We develop a mathematical model to describe the reperfusion and postconditioning process following an ischemic insult, treating the blood vessel as a two-dimensional channel, lined with a monolayer of endothelial cells that interact (respiration and mechanotransduction) with the blood flow. We investigate how postconditioning affects the total cell density within the endothelial layer, by varying the frequency of the pulsatile flow and the oxygen concentration at the inflow boundary. We find that, in the scenarios we consider, the pulsatile flow should be of high frequency to minimize cellular damage, while oxygen concentration at the inflow boundary should be held constant, or subject to only low-frequency variations, to maximize cell proliferation.

Diabetic inhibition of preconditioning- and postconditioning-mediated myocardial protection against ischemia/reperfusion injury.

Ischemic preconditioning (IPC) or postconditioning (Ipost) is proved to efficiently prevent ischemia/reperfusion injuries. Mortality of diabetic patients with acute myocardial infarction was found to be 2-6 folds higher than that of non-diabetic patients with same myocardial infarction, which may be in part due to diabetic inhibition of IPC- and Ipost-mediated protective mechanisms. Both IPC- and Ipost-mediated myocardial protection is predominantly mediated by stimulating PI3K/Akt and associated GSK-3ß pathway while diabetes-mediated pathogenic effects are found to be mediated by inhibiting PI3K/Akt and associated GSK-3ß pathway. Therefore, this review briefly introduced the general features of IPC- and Ipost-mediated myocardial protection and the general pathogenic effects of diabetes on the myocardium. We have collected experimental evidence that indicates the diabetic inhibition of IPC- and Ipost-mediated myocardial protection. Increasing evidence implies that diabetic inhibition of IPC- and Ipost-mediated myocardial protection may be mediated by inhibiting PI3K/Akt and associated GSK-3ß pathway. Therefore any strategy to activate PI3K/Akt and associated GSK-3ß pathway to release the diabetic inhibition of both IPC and Ipost-mediated myocardial protection may provide the protective effect against ischemia/reperfusion injuries.

From Bench to Bedside: Seeing the Future of Ischaemic Post-Conditioning as a Novel Cardioprotective Therapy

In order to improve the survival of patients suffering from an acute myocardial infarction; it is crucial to limit the size of strategies have been developed; but very few of these have been successfully translated from bench to bedside. This review aims to evaluate the translation of a novel therapy; ischaemic post-conditioning that can reduce infarct size and salvage myocardial function after acute myocardial ischaemia; from bench to bedside. The phenomenon of postconditioning refers to staccato bouts of ischaemia at the onset of reperfusion. By elucidating the signalling mechanisms involved in the post-conditioning process; it has been possible to determine several pharmacological agents that deliver an equivalent level of protection. Following a large number of successful initial laboratory testis; small clinical the breakthroughs required for this effective laboratory phenomenon to translate into meaningful clinical therapies can only be achieved by careful application of data obtained in basic research and controlled trials