Does Remote Ischaemic Preconditioning Protect Kidney and Cardiomyocytes After Coronary Revascularization? A Double Blind Controlled Clinical Trial

Kottenberg

Thielmann

et al. 2017

Sci Rep

Remote ischemic preconditioning (RIPC) by repeated brief cycles of limb ischemia/reperfusion may reduce myocardial ischemia/reperfusion injury and improve patients‘ prognosis after elective coronary artery bypass graft (CABG) surgery. The signal transducer and activator of transcription (STAT)5 activation in left ventricular myocardium is associated with RIPC´s cardioprotection. Cytokines and growth hormones typically activate STATs and could therefore act as humoral transfer factors of RIPC´s cardioprotection. We here determined arterial plasma concentrations of 25 different cytokines, growth hormones, and other factors which have previously been associated with cardioprotection, before (baseline)/after RIPC or placebo (n = 23/23), respectively, and before/after ischemic cardioplegic arrest in CABG patients. RIPC-induced protection was reflected by a 35% reduction of serum troponin I release. With the exception of interleukin-1α, none of the humoral factors changed in their concentrations after RIPC or placebo, respectively. Interleukin-1α, when normalized to baseline, increased after RIPC (280 ± 56%) but not with placebo (97 ± 15%). The interleukin-1α concentration remained increased until after ischemic cardioplegic arrest and was also higher than with placebo in absolute concentrations (25 ± 6 versus 16 ± 3 pg/mL). Only interleukin-1α possibly fulfills the criteria which would be expected from a substance to be released in response to RIPC and to protect the myocardium during ischemic cardioplegic arrest.

Section: Introductionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 81%

Potential humoral mediators of remote ischemic preconditioning in patients undergoing surgical coronary revascularization

Kottenberg

Thielmann

et al. 2017

Sci Rep

“…Remote ischemic conditioning by repetitive limb ischemia/reperfusion also reduces myocardial damage in patients undergoing elective interventional2 or surgical coronary revascularization3, 4, 5, 6 and in those with reperfused acute myocardial infarction 7, 8, 9, 10, 11, 12, 13. Cardioprotection was confirmed by reduced release of cardiac biomarkers2, 3, 4, 5, 6, 10 or by increased salvage in cardiac imaging7, 8, 9, 11 but also resulted in improved short‐5, 8 and more long‐term2, 4, 13, 14, 15 clinical outcome in retrospective analyses. Recently, the first prospective, randomized trial on patients with reperfused acute myocardial infarction confirmed improved clinical outcome as a primary end point of remote ischemic conditioning during follow‐up for 3.6 years 13.…”

Section: Introductionmentioning

confidence: 99%

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

Kleinbongard

Kirca

et al. 2018

JAHA

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.

“…The reduction of myocardial ischemia/reperfusion injury by remote ischemic conditioning has been demonstrated in patients undergoing elective interventional 5 or surgical coronary revascularization 6 – 9 , and in patients with acute myocardial infarction 10 – 15 . The protection was confirmed by a reduction in cardiac biomarker release 5 – 9 , 14 or by cardiac imaging 10 , 12 , 13 , 15 , and it was associated with improved short- 8 , 12 and long-term clinical outcome 5 , 7 , 11 . In contrast, two recent large-scaled randomized trials in patients undergoing cardiac surgery, ERICCA and RIPHeart, failed to confirm reduced biomarker release and improved clinical outcome with remote ischemic preconditioning (RIPC) 16 , 17 .…”

Section: Introductionmentioning

confidence: 99%

Proteomics/phosphoproteomics of left ventricular biopsies from patients with surgical coronary revascularization and pigs with coronary occlusion/reperfusion: remote ischemic preconditioning

Krüger

Thielmann

et al. 2017

Sci Rep

Remote ischemic preconditioning (RIPC) by repeated brief cycles of limb ischemia/reperfusion reduces myocardial ischemia/reperfusion injury. In left ventricular (LV) biopsies from patients undergoing coronary artery bypass grafting (CABG), only the activation of signal transducer and activator of transcription 5 was associated with RIPC’s cardioprotection. We have now used an unbiased, non-hypothesis-driven proteomics and phosphoproteomics approach to analyze LV biopsies from patients undergoing CABG and from pigs undergoing coronary occlusion/reperfusion without (sham) and with RIPC. False discovery rate-based statistics identified a higher prostaglandin reductase 2 expression at early reperfusion with RIPC than with sham in patients. In pigs, the phosphorylation of 116 proteins was different between baseline and early reperfusion with RIPC and/or with sham. The identified proteins were not identical for patients and pigs, but in-silico pathway analysis of proteins with ≥2-fold higher expression/phosphorylation at early reperfusion with RIPC in comparison to sham revealed a relation to mitochondria and cytoskeleton in both species. Apart from limitations of the proteomics analysis per se, the small cohorts, the sampling/sample processing and the number of uncharacterized/unverifiable porcine proteins may have contributed to this largely unsatisfactory result.