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

Abstract

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.

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

“…It uses human atrial trabeculae isolated from right atrial appendages harvested at the time of cardiac surgery [ 440 ]. The human atrial model has proved to be a unique translational tool, confirming in humans what has been shown in cell models and in vitro/in vivo animal studies [ 253 ].…”

Cardioprotective effect of succinate dehydrogenase inhibition in rat hearts and human myocardium with and without diabetes mellitus

“…Our data demonstrate that pre-ischemic administration of DiMAL, mimicking preconditioning, is cardioprotective both in rats and in human cardiac tissue with an efficacy comparable to IPC. Remote IPC, postconditioning, hypothermia and cyclosporine A can induce the same level of cardioprotection as DiMAL 33,34 . The additive effect of hypothermia and DiMAL on infarct size was protective by distinct mechanisms.…”

RIPC provides neuroprotection against ischemic stroke by suppressing apoptosis via the mitochondrial pathway

“…Recent studies have shown that plasma or plasma dialysate from pigs undergoing RIPC not only reduces infarct size and mitochondrial ROS production but also improves ADP-stimulated complex I respiration, ATP production and calcium retention capacity in isolated perfused rat hearts subjected to 30 min of global ischemia followed by 120 min of reperfusion; in addition, these studies have shown that the plasma dialysate increases the viability of mouse cardiomyocytes after hypoxia/reoxygenation 50,51 . A clinical study has demonstrated that RIPC also improves mitochondrial and contractile function in right atrial tissue in patients www.nature.com/scientificreports www.nature.com/scientificreports/ with double-or triple-vessel coronary artery disease 52 . Therefore, mitochondria are fundamental targets for cardioprotective strategies, and conservation of mitochondrial function is the focus of treatments to reduce IRI 53 .…”