The challenge of translating ischemic conditioning from animal models to humans: the role of comorbidities

Abstract

Following a period of ischemia (local restriction of blood supply to a tissue), the restoration of blood supply to the affected area causes significant tissue damage. This is known as ischemia-reperfusion injury (IRI) and is a central pathological mechanism contributing to many common disease states. The medical complications caused by IRI in individuals with cerebrovascular or heart disease are a leading cause of death in developed countries. IRI is also of crucial importance in fields as diverse as solid organ transplantation, acute kidney injury and following major surgery, where post-operative organ dysfunction is a major cause of morbidity and mortality. Given its clinical impact, novel interventions are urgently needed to minimize the effects of IRI, not least to save lives but also to reduce healthcare costs. In this Review, we examine the experimental technique of ischemic conditioning, which entails exposing organs or tissues to brief sub-lethal episodes of ischemia and reperfusion, before, during or after a lethal ischemic insult. This approach has been found to confer profound tissue protection against IRI. We discuss the translation of ischemic conditioning strategies from bench to bedside, and highlight where transition into human clinical studies has been less successful than in animal models, reviewing potential reasons for this. We explore the challenges that preclude more extensive clinical translation of these strategies and emphasize the role that underlying comorbidities have in altering the efficacy of these strategies in improving patient outcomes.

Keywords: Comorbidities; Ischemic postconditioning; Ischemic preconditioning; Remote ischemic preconditioning.

Fig. 1.

Schematic diagram of IPC, iPOST and RIPC protocols. Schematic representation of the differing protocols of ischemic conditioning: light blue represents pre-ischemia; black the ischemic insult; black lines represent the application of sub-lethal ischemia; dark blue the reperfusion phase. (a) Ischemia-reperfusion with no ischemic conditioning. (b) Ischemic preconditioning (IPC), with sub-lethal ischemia applied before the insult (black lines). (c) Ischemic post-conditioning (iPOST), with sub-lethal ischemia applied after the insult (black lines). (d) Remote ischemic preconditioning (RIPC), where the sub-lethal ischemia is applied distal to and prior to the area and time of ischemia. (e) Remote ischemic post-conditioning, where the sub-lethal ischemia is applied distal to and subsequent to the area and time of ischemia.

Box 2 Fig.

Source data derived from: Bromage et al., 2014; Giricz et al., 2014; Hausenloy, 2013; Lecour, 2009; Sluijter et al., 2014. Abbreviations: Akt, serine/threonine protein kinase, also known as protein kinase B (PKB); Bcl-2, B-cell lymphoma 2 gene; BAD, Bcl-2-associated death promoter; BAX, BCL2-associated X protein; eNOS, endothelial nitric oxide synthase; ERK 1/2, extracellular signal regulated kinases 1/2; G-PCR, G-protein coupled receptor; GSK3β, glycogen synthase kinase-3β; iNOS, inducible nitric oxide synthase; JAK, Janus kinase; K_ATP, mitochondrial potassium ATP channel; MEK1/2, mitogen-activated protein kinase kinase; MPTP, mitochondrial permeability transition pore; PI3K, phosphatidylinositol-(4,5)-bisphosphate 3-kinase; PKCε, protein kinase Cε; PKG, cGMP-dependent protein kinase; ROS, reactive oxygen species; SDF-1α; stromal-cell-derived factor 1α; STAT3, signal transducer and activator of transcription 3; SR, sarcoplasmic reticulum; TNFα, tumour necrosis factor α; TNF-R, TNF receptor.

Fig. 2.

Challenges and potential solutions to translating ischemic conditioning studies from ‘bench to bedside’. Flowchart summarizing the main challenges related to the testing of ischemic conditioning strategies in animal studies (preclinical stage) and to the translation of these approaches into clinical trials (early translation stage, Phase I/II trials). Possible solutions to optimize both the preclinical research stage and the planning of clinical trials are also shown. Should a particular strategy of ischemic conditioning successfully pass the Phase I/II clinical trial phases, future challenges to wider diffusion (late translation stage) include the need for guideline development and adoption of standardized protocols by national and international guideline bodies.