Remote ischemic preconditioning preserves mitochondrial function and activates pro-survival protein kinase Akt in the left ventricle during cardiac surgery: A randomized trial

Slagsvold, Katrine Hordnes; Moreira, José Bianco Nascimento; Rognmo, Øivind; Høydal, Morten A.; Bye, Anja; Wisløff, Ulrik; Wahba, Alexander

doi:10.1016/j.ijcard.2014.09.206

Cited by 40 publications

(42 citation statements)

References 41 publications

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“…In mitochondria taken from isolated perfused rat hearts after RIPC in vivo, there was a preserved mitochondrial respiration after ischemia/reperfusion 38. In mitochondria taken from atrial tissue of patients undergoing cardiac surgery with RIPC, there was also a preserved respiration when the atrial tissue was obtained after aortic cross‐clamping, but not when obtained before aortic cross‐clamping 39, 40. However, these studies have failed to confirm cardioprotection by RIPC and thus could not establish a relation between improved mitochondrial function and protection, as would be determined by triphenyl tetrazolium chloride staining in rats38 or biomarker (creatine kinase and its isoenzyme, MB, and troponin) release in patients 39, 40…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Discrete working definitions of AKI were reclassified as stage I, II, or III based on previous definitions described by the Acute Kidney Injury Advisory Group . Other end point definitions were those used in the individual trials and are summarized in Table …”

Section: Methodsmentioning

confidence: 99%

“…19 Other end point definitions were those used in the individual trials and are summarized in Table 1. [20][21][22][23][24][25][26][27][28][29][30][31][32][33]…”

Section: Study Selectionmentioning

confidence: 99%

Clinical Outcomes of Remote Ischemic Preconditioning Prior to Cardiac Surgery: A Meta‐Analysis of Randomized Controlled Trials

Pierce

Bole

Patel

et al. 2017

JAHA

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BackgroundMultiple randomized controlled trials of remote ischemic preconditioning (RIPC) prior to cardiac surgery have failed to demonstrate clinical benefit. The aim of this updated meta‐analysis was to evaluate the effect of RIPC on outcomes following cardiac surgery.Methods and ResultsSearches of PubMed, Cochrane, EMBASE, and Web of Science databases were performed for 1970 to December 13, 2015. Randomized controlled trials comparing RIPC with a sham procedure prior to cardiac surgery performed with cardiopulmonary bypass were assessed. All‐cause mortality, acute kidney injury (AKI), and myocardial infarction were the primary outcomes of interest. We identified 21 trials that randomized 5262 patients to RIPC or a sham procedure prior to undergoing cardiac surgery. The majority of patients were men (72.6%) and the mean or median age ranged from 42.3 to 76.3 years. Of the 9 trials that evaluated mortality, 188 deaths occurred out of a total of 4210 randomized patients, with 96 deaths occurring in 2098 patients (4.6%) randomized to RIPC and 92 deaths occurring in 2112 patients (4.4%) randomized to a sham control procedure, demonstrating no significant reduction in all‐cause mortality (risk ratio [RR], 0.987; 95% CI, 0.653–1.492, P=0.95). Twelve studies evaluated AKI in 4209 randomized patients. In these studies, AKI was observed in 516 of 2091 patients (24.7%) undergoing RIPC and in 577 of 2118 patients (27.2%) randomized to a sham procedure. RIPC did not result in a significant reduction in AKI (RR, 0.839; 95% CI, 0.703–1.001 [P=0.052]). In 6 studies consisting of 3799 randomized participants, myocardial infarction occurred in 237 of 1891 patients (12.5%) randomized to RIPC and in 282 of 1908 patients (14.8%) randomized to a sham procedure, resulting in no significant reduction in postoperative myocardial infarction (RR, 0.809; 95% CI, 0.615–1.064 [P=0.13]). A subgroup analysis was performed a priori based on previous studies suggesting that propofol may mitigate the protective benefits of RIPC. Three studies randomized patients undergoing cardiac surgery to RIPC or sham procedure in the absence of propofol anesthesia. Most of these patients were men (60.3%) and the mean or median age ranged from 57.0 to 70.6 years. In this propofol‐free subgroup of 434 randomized patients, 71 of 217 patients (32.7%) who underwent RIPC developed AKI compared with 103 of 217 patients (47.5%) treated with a sham procedure. In this cohort, RIPC resulted in a significant reduction in AKI (RR, 0.700; 95% CI, 0.527–0.930 [P=0.014]). In studies of patients who received propofol anesthesia, 445 of 1874 (23.7%) patients randomized to RIPC developed AKI compared with 474 of 1901 (24.9%) who underwent a sham procedure. The RR for AKI was 0.928 (95% CI, 0.781–1.102; P=0.39) for RIPC versus sham. There was no significant interaction between the two subgroups (P=0.098).ConclusionsRIPC does not reduce morbidity or mortality in patients undergoing cardiac surgery with cardiopulmonary bypass. In the subgroup of studies in which propofol was not...

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“…Although the intracardiac signal transduction of the conditioning phenomena seems largely similar, 28,30 the transfer factor(s) from the distant organ or tissue to the heart in remote ischemic conditioning is/are still enigmatic, but seem(s) to involve both neuronal and humoral signaling. There are obvious species differences in the signal transduction of the conditioning phenomena, and only little information is available on the signal transduction in the human heart: protein kinase C, 31,32 the reperfusion injury salvage kinase pathway, 33,34 the signal transducer and activator of transcription 5, 35 and the mitochondria 36 seem to be involved. The translation of cardioprotection by the conditioning phenomena and by drugs that recruit part of their signaling to the clinical arena has been difficult to date.…”

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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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Remote ischemic preconditioning preserves mitochondrial function and activates pro-survival protein kinase Akt in the left ventricle during cardiac surgery: A randomized trial

Cited by 40 publications

References 41 publications

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

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

Clinical Outcomes of Remote Ischemic Preconditioning Prior to Cardiac Surgery: A Meta‐Analysis of Randomized Controlled Trials

Time to Give Up on Cardioprotection?

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