Across-Species Transfer of Protection by Remote Ischemic Preconditioning With Species-Specific Myocardial Signal Transduction by Reperfusion Injury Salvage Kinase and Survival Activating Factor Enhancement Pathways

Skyschally, Andreas; Gent, Sabine; Amanakis, Georgios; Schulte, Christiane; Kleinbongard, Petra; Heusch, Gerd

doi:10.1161/circresaha.117.306878

Cited by 143 publications

(157 citation statements)

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“…Even among mammalian hearts, those of rodents are further away from human hearts than those of larger mammals, not only in terms of heart rate and anatomy, but also in their cardioprotective signaling. 28,166 The pig heart closely resembles the human heart in heart rate, myocardial and coronary anatomy, 18 but-in contrast to the human heart-the coronary circulation constricts in response to acetylcholine 167 and does not constrict in response to α-adrenergic activation. 168 Dogs have an extensive innate collateral circulation, different from a healthy human heart but comparable to many human hearts with longstanding coronary atherosclerosis.…”

Section: Translation From Experimental Animal Data To the Diseased Pamentioning

confidence: 99%

“…169 Primate hearts have a surprising resistance to myocardial ischemia/reperfusion injury and develop much smaller infarcts after 90 minutes coronary occlusion than, for example, pigs. 170 Also with respect to cardioprotective signaling both the reperfusion injury salvage kinase pathway 171 and 28,166 but only the survivor activating factor enhancement pathway seems to be cardioprotective in pigs. 166,173,174 Whereas in the survivor activating factor enhancement pathway the signal transducer and activator of transcription 3 is a central element, it is signal transducer and activator of transcription 5 that is activated in the human heart by remote ischemic preconditioning.…”

Section: Translation From Experimental Animal Data To the Diseased Pamentioning

confidence: 99%

“…170 Also with respect to cardioprotective signaling both the reperfusion injury salvage kinase pathway 171 and 28,166 but only the survivor activating factor enhancement pathway seems to be cardioprotective in pigs. 166,173,174 Whereas in the survivor activating factor enhancement pathway the signal transducer and activator of transcription 3 is a central element, it is signal transducer and activator of transcription 5 that is activated in the human heart by remote ischemic preconditioning. 35 Thus, there is no single species that comes closest to the human heart in all important aspects related to myocardial ischemia/reperfusion.…”

Section: Translation From Experimental Animal Data To the Diseased Pamentioning

confidence: 99%

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Time to Give Up on Cardioprotection?

Heusch

Rassaf

2016

Circulation Research

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176

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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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Section: Translation From Experimental Animal Data To the Diseased Pamentioning

confidence: 99%

Section: Translation From Experimental Animal Data To the Diseased Pamentioning

confidence: 99%

Section: Translation From Experimental Animal Data To the Diseased Pamentioning

confidence: 99%

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Time to Give Up on Cardioprotection?

Heusch

Rassaf

2016

Circulation Research

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176

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“…However, the underlying signal transduction is species specific. Whereas in rodents the activation of the reperfusion injury salvage kinase and the survivor activating factor enhancement pathway was identified as causal for cardioprotection by remote ischemic conditioning, in pigs only the activation of the survivor activating factor enhancement pathway was causally involved, as reflected by the phosphorylation of signal transducer and activator of transcription (STAT)3 in left ventricular myocardial biopsies 18, 19, 20…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial and Contractile Function of Human Right Atrial Tissue in Response to Remote Ischemic Conditioning

Kleinbongard

Gedik

Kirca

et al. 2018

JAHA

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BackgroundRemote ischemic preconditioning (RIPC) by repeated brief cycles of limb ischemia/reperfusion attenuates myocardial ischemia/reperfusion injury. We aimed to identify a functional parameter reflecting the RIPC‐induced protection in human. Therefore, we measured mitochondrial function in right atrial tissue and contractile function of isolated right atrial trabeculae before and during hypoxia/reoxygenation from patients undergoing coronary artery bypass grafting with RIPC or placebo, respectively.Methods and ResultsOne hundred thirty‐seven patients under isoflurane anesthesia underwent RIPC (3×5 minutes blood pressure cuff inflation on the left upper arm/5 minutes deflation, n=67) or placebo (cuff uninflated, n=70), and right atrial appendages were harvested before ischemic cardioplegic arrest. Myocardial protection by RIPC was assessed from serum troponin I/T concentrations over 72 hours after surgery. Atrial tissue was obtained for isolation of mitochondria (RIPC/placebo: n=10/10). Trabeculae were dissected for contractile function measurements at baseline and after hypoxia/reoxygenation (60 min/30 min) and for western blot analysis after hypoxia/reoxygenation (RIPC/placebo, n=57/60). Associated with cardioprotection by RIPC (26% decrease in the area under the curve of troponin I/T), mitochondrial adenosine diphosphate–stimulated complex I respiration (+10%), adenosine triphosphate production (+46%), and calcium retention capacity (+37%) were greater, whereas reactive oxygen species production (−24%) was less with RIPC than placebo. Contractile function was improved by RIPC (baseline, +7%; reoxygenation, +24%). Expression and phosphorylation of proteins, which have previously been associated with cardioprotection, were not different between RIPC and placebo.ConclusionsCardioprotection by RIPC goes along with improved mitochondrial and contractile function of human right atrial tissue.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT01406678.

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“…These mechanisms include the release of a number of protective autocoids such as adenosine (19) and nitric oxide (20), the activation of the innate immune system (21), activation of the reperfusion injury salvage kinase pathway (22) and the inhibition of the mitochondrial permeability transition pore (23). Moreover, we have recently reported the renoprotective effect of remote perconditioning by modulation of inflammatory cytokines in the kidney (24) and attenuated oxidative damages in more distantly located organs, such as the liver (25).…”

Section: Discussionmentioning

confidence: 99%

Involvement of neuronal pathways in the protective effects of hindlimb perconditioning during renal ischemia

Sedaghat

Kadkhodaee

Seifi

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Remote ischemic perconditioning (RPEC) is a therapeutic intervention that has been demonstrated to reduce renal ischemia/reperfusion (I/R) injury. However, the underlying renal protective mechanism remains unclear. The present study hypothesized that RPEC may utilize neural pathways to transfer the protective signal from the perconditioned hindlimb to the kidney. Following a right nephrectomy, rats were randomly allocated into five groups (n=6). The sham group underwent the surgical protocol only. In all other groups, the left renal pedicle was clamped for 45 min and reperfused for 24 h. The I/R control group then underwent 45 min ischemia and 24 h reperfusion (I/R) with no more intervention but the I/R-NR control group underwent the ischemia and reperfusion followed by left femoral nerve (FN) and sciatic nerve (SN) resection. The RPEC group underwent ischemia and reperfusion followed by four cycles of 5 min occlusions of the left femoral artery and 5 min reperfusion. Finally, the RPEC-NR group underwent ischemia and reperfusion followed by left FN and SN resection. Following 24 h, renal functional indices, plasma blood urea nitrogen (BUN) and creatinine (Cr) levels, urinary N-acetyl-β-glucosaminidase (NAG) release and histopathological changes were assessed. Compared with the sham group, ischemia and reperfusion in the sham and I/R control groups resulted in renal dysfunction, indicated by significantly increased levels of BUN and Cr. This was accompanied by increased urinary NAG activity and morphological damage observed in control groups. In the RPEC group, renal histology and function were significantly improved compared with the control groups. However, FN and SN resection eliminated the protection of the kidney, which was induced by RPEC. In conclusion, remote hindlimb ischemic perconditioning reduced renal I/R injury in the rat kidney in a manner that potentially involves a neural pathway.

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Across-Species Transfer of Protection by Remote Ischemic Preconditioning With Species-Specific Myocardial Signal Transduction by Reperfusion Injury Salvage Kinase and Survival Activating Factor Enhancement Pathways

Abstract: Rationale: Reduction of myocardial infarct size by remote ischemic preconditioning (RIPC), that is, cycles of ischemia/reperfusion in an organ remote from the heart before sustained myocardial ischemia/reperfusion, was confirmed in all species so far, including humans. Objective:

Cited by 143 publications

References 47 publications

Time to Give Up on Cardioprotection?

Time to Give Up on Cardioprotection?

Mitochondrial and Contractile Function of Human Right Atrial Tissue in Response to Remote Ischemic Conditioning

Involvement of neuronal pathways in the protective effects of hindlimb perconditioning during renal ischemia

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