Ischaemic and hypoxic conditioning: potential for protection of vital organs

Abstract

New findings: What is the topic of this review? Remote ischaemic preconditioning (RIPC) and hypoxic preconditioning as novel therapeutic approaches for cardiac and neuroprotection. What advances does it highlight? There is improved understanding of mechanisms and signalling pathways associated with ischaemic and hypoxic preconditioning, and potential pitfalls with application of these therapies to clinical trials have been identified. Novel adaptations of preconditioning paradigms have also been developed, including intermittent hypoxia training, RIPC training and RIPC-exercise, extending their utility to chronic settings.

Abstract: Myocardial infarction and stroke remain leading causes of death worldwide, despite extensive resources directed towards developing effective treatments. In this Symposium Report we highlight the potential applications of intermittent ischaemic and hypoxic conditioning protocols to combat the deleterious consequences of heart and brain ischaemia. Insights into mechanisms underlying the protective effects of intermittent hypoxia training are discussed, including the activation of hypoxia-inducible factor-1 and Nrf2 transcription factors, synthesis of antioxidant and ATP-generating enzymes, and a shift in microglia from pro- to anti-inflammatory phenotypes. Although there is little argument regarding the efficacy of remote ischaemic preconditioning (RIPC) in pre-clinical models, this strategy has not consistently translated into the clinical arena. This lack of translation may be related to the patient populations targeted thus far, and the anaesthetic regimen used in two of the major RIPC clinical trials. Additionally, we do not fully understand the mechanism through which RIPC protects the vital organs, and co-morbidities (e.g. hypercholesterolemia, diabetes) may interfere with its efficacy. Finally, novel adaptations have been made to extend RIPC to more chronic settings. One adaptation is RIPC-exercise (RIPC-X), an innovative paradigm that applies cyclical RIPC to blood flow restriction exercise (BFRE). Recent findings suggest that this novel exercise modality attenuates the exaggerated haemodynamic responses that may limit the use of conventional BFRE in some clinical settings. Collectively, intermittent ischaemic and hypoxic conditioning paradigms remain an exciting frontier for the protection against ischaemic injuries.

Keywords: blood flow restriction exercise; cardioprotection; cerebroprotection; intermittent hypoxia; remote ischaemic preconditioning.

Figure 1.. Intermittent hypoxia-initiated cerebroprotection against cerebral ischemia-reperfusion injury cascade.

Red font: Cerebral artery occlusion interrupts supply of O₂ and metabolic substrates for ATP production. The resultant decrease in free energy (ΔG_ATP) disables astrocytic glutamate uptake and neuronal Ca²⁺ management. Reperfusion initiates ROS formation, exacerbating the Ca²⁺ mal-distribution and ATP depletion. Blue font: IH activates several mechanisms that suppress elements of the ischemia-reperfusion injury cascade. Bold blue font denotes factors directly activated by intermittent hypoxia. Blue arrows indicate induction of cerebroprotective mediators and effectors. Broken lines indicate suppression of brain injury by cerebroprotective effectors. Abbreviations are defined in the text.

Figure 2.. Sympathetic and arterial pressure response to remote ischemic preconditioning exercise.

Panel A: The increase in circulating norepinephrine (NE) observed with conventional aerobic treadmill exercise (CE) was attenuated with blood flow restriction exercise (BFRE) by the end of the exercise bout. Circulating [NE] did not change over the remote ischemic preconditioning (RIPC) protocol. * denotes P ≤ 0.03 for CE and BFRE vs. RIPC within time point; † denotes P = 0.06 for CE vs. BFRE within time point. Panel B: Mean arterial pressure (MAP) increased with both CE (closed circle) and BFRE (open circle), but was lower with BFRE compared to CE during multiple reperfusion periods. MAP slowly increased across the RIPC protocol (triangles). * denotes P ≤ 0.09 for CE and BFRE vs. RIPC; # denotes P ≤ 0.04 for CE vs. RIPC; † denotes P ≤ 0.08 for CE vs. BFRE. The occlusion periods are denoted by the vertical grey bars. Reproduced with permission from (Sprick & Rickards, 2017a).