Remote Ischemic Conditioning and the Long Road to Clinical Translation

Garratt, Kirk N.; Whittaker, Peter; Przyklenk, Karin

doi:10.1161/circresaha.115.308102

Cited by 26 publications

(23 citation statements)

References 21 publications

(28 reference statements)

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“…Clinical trials investigating the efficacy of RIC in myocardial IRI have had mixed results, 11 , 14 which has been attributed to clinical variables, including propofol administration 36 . However, each of the factors described above may influence outcome through lack of generalizability or unconscious bias, 19 and therefore indirectly impact upon attempts to translate RIC to humans in clinical trials 16 …”

Section: Discussionmentioning

confidence: 99%

“…Although cardiac surgery may be an inappropriate setting for RIC, given the small peri-operative injury and lack of injurious warm ischaemia-reperfusion, 16 these findings have prompted an interrogation of the pre-clinical evidence base for RIC and a perceived lack of systematic pre-clinical characterization of the optimal RIC stimulus 16 . This is in contrast to direct ischaemic conditioning that, despite being limited by the necessity to intervene before the index ischaemia, has been thoroughly characterized 17 …”

Section: Introductionmentioning

confidence: 99%

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Remote ischaemic conditioning reduces infarct size in animalin vivomodels of ischaemia-reperfusion injury: a systematic review and meta-analysis

et al. 2016

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AimsThe potential of remote ischaemic conditioning (RIC) to ameliorate myocardial ischaemia-reperfusion injury (IRI) remains controversial. We aimed to analyse the pre-clinical evidence base to ascertain the overall effect and variability of RIC in animal in vivo models of myocardial IRI. Furthermore, we aimed to investigate the impact of different study protocols on the protective utility of RIC in animal models and identify gaps in our understanding of this promising therapeutic strategy.Methods and resultsOur primary outcome measure was the difference in mean infarct size between RIC and control groups in in vivo models of myocardial IRI. A systematic review returned 31 reports, from which we made 22 controlled comparisons of remote ischaemic preconditioning (RIPreC) and 21 of remote ischaemic perconditioning and postconditioning (RIPerC/RIPostC) in a pooled random-effects meta-analysis. In total, our analysis includes data from 280 control animals and 373 animals subject to RIC. Overall, RIPreC reduced infarct size as a percentage of area at risk by 22.8% (95% CI 18.8–26.9%), when compared with untreated controls (P < 0.001). Similarly, RIPerC/RIPostC reduced infarct size by 22.2% (95% CI 17.1–25.3%; P < 0.001). Interestingly, we observed significant heterogeneity in effect size (T2 = 92.9% and I2 = 99.4%; P < 0.001) that could not be explained by any of the experimental variables analysed by meta-regression. However, few reports have systematically characterized RIC protocols, and few of the included in vivo studies satisfactorily met study quality requirements, particularly with respect to blinding and randomization.ConclusionsRIC significantly reduces infarct size in in vivo models of myocardial IRI. Heterogeneity between studies could not be explained by the experimental variables tested, but studies are limited in number and lack consistency in quality and study design. There is therefore a clear need for more well-performed in vivo studies with particular emphasis on detailed characterization of RIC protocols and investigating the potential impact of gender. Finally, more studies investigating the potential benefit of RIC in larger species are required before translation to humans.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Remote ischaemic conditioning reduces infarct size in animalin vivomodels of ischaemia-reperfusion injury: a systematic review and meta-analysis

et al. 2016

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“…The potential reasons for this discrepancy have been discussed in detail. [245][246][247][248] Importantly, both ERICCA and RIPHeart not only failed to find benefit from remote ischemic conditioning on mortality, myocardial infarction, and stroke at hospital discharge 38 or after 12 months, 37 but they also failed to see an acute benefit in terms of a reduction of troponin release, such that from the lack of an acute protection, no better clinical outcome was to be expected. The most likely reason for the failure to see protection in terms of troponin release and clinical outcome is the use of propofol anesthesia in 90% of ERICCA patients and all patients per-protocol in RIPHeart.…”

Section: Current State Of Translation For Remote Ischemic Conditioningmentioning

confidence: 99%

Time to Give Up on Cardioprotection?

Heusch

Rassaf

2016

Circulation Research

170

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Abstract:The mortality from acute myocardial infarction (AMI) remains significant, and the prevalence of postmyocardial infarction heart failure is increasing. Therefore, cardioprotection beyond timely reperfusion is needed. Conditioning procedures are the most powerful cardioprotective interventions in animal experiments. However, ischemic preconditioning cannot be used to reduce infarct size in patients with AMI because its occurrence is not predictable; several studies in patients undergoing surgical coronary revascularization report reduced release of creatine kinase and troponin. Ischemic postconditioning reduces infarct size in most, but not all, studies in patients undergoing interventional reperfusion of AMI, but may require direct stenting and exclusion of patients with >6 hours of symptom onset to protect. Remote ischemic conditioning reduces infarct size in patients undergoing interventional reperfusion of AMI, elective percutaneous or surgical coronary revascularization, and other cardiovascular surgery in many, but not in all, studies. Adequate dose-finding phase II studies do not exist. There are only 2 phase III trials, both on remote ischemic conditioning in patients undergoing cardiovascular surgery, both with neutral results in terms of infarct size and clinical outcome, but also both with major problems in trial design. We discuss the difficulties in translation of cardioprotection from animal experiments and proof-ofconcept trials to clinical practice. Given that most studies on ischemic postconditioning and all studies on remote ischemic preconditioning in patients with AMI reported reduced infarct size, it would be premature to give up on cardioprotection. (Circ Res. 2016;119:676-695.

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“…Patient outcome after myocardial surgery was significantly improved when RIPC was applied before surgery [27]. However, recently conflicting results have been reported showing that RIPC does not always mediate protection [38,39,40,41]. Data from animal and human studies demonstrated the need for careful interpretation because of translational differences [38,39,40,41,42,43].…”

Section: Introductionmentioning

confidence: 99%

“…However, recently conflicting results have been reported showing that RIPC does not always mediate protection [38,39,40,41]. Data from animal and human studies demonstrated the need for careful interpretation because of translational differences [38,39,40,41,42,43]. RIPC improves microcirculation by an increase in tissue oxygenation and capillary blood flow in the skin [44] and skin flaps [45], and forms a novel target for skin flap transplantation [46] and the healing of diabetic foot ulcers [47,48].…”

Section: Introductionmentioning

confidence: 99%

Effects of Remote Ischemic Preconditioning on Heme Oxygenase-1 Expression and Cutaneous Wound Repair

Cremers

Wever

Wong

et al. 2017

IJMS

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Skin wounds may lead to scar formation and impaired functionality. Remote ischemic preconditioning (RIPC) can induce the anti-inflammatory enzyme heme oxygenase-1 (HO-1) and protect against tissue injury. We aim to improve cutaneous wound repair by RIPC treatment via induction of HO-1. RIPC was applied to HO-1-luc transgenic mice and HO-1 promoter activity and mRNA expression in skin and several other organs were determined in real-time. In parallel, RIPC was applied directly or 24h prior to excisional wounding in mice to investigate the early and late protective effects of RIPC on cutaneous wound repair, respectively. HO-1 promoter activity was significantly induced on the dorsal side and locally in the kidneys following RIPC treatment. Next, we investigated the origin of this RIPC-induced HO-1 promoter activity and demonstrated increased mRNA in the ligated muscle, heart and kidneys, but not in the skin. RIPC did not change HO-1 mRNA and protein levels in the wound 7 days after cutaneous injury. Both early and late RIPC did not accelerate wound closure nor affect collagen deposition. RIPC induces HO-1 expression in several organs, but not the skin, and did not improve excisional wound repair, suggesting that the skin is insensitive to RIPC-mediated protection.

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Remote Ischemic Conditioning and the Long Road to Clinical Translation

Cited by 26 publications

References 21 publications

Remote ischaemic conditioning reduces infarct size in animalin vivomodels of ischaemia-reperfusion injury: a systematic review and meta-analysis

Remote ischaemic conditioning reduces infarct size in animalin vivomodels of ischaemia-reperfusion injury: a systematic review and meta-analysis

Time to Give Up on Cardioprotection?

Effects of Remote Ischemic Preconditioning on Heme Oxygenase-1 Expression and Cutaneous Wound Repair

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