Cardiac protective effects of remote ischaemic preconditioning in children undergoing tetralogy of fallot repair surgery: a randomized controlled trial

Wu, Qingping; Wang, Tingting; Chen, Shiqiang; Zhou, Quanjun; Li, Haobo; Hu, Na; Feng, Yuan; Dong, Nianguo; Yao, Shanglong; Xia, Zhengyuan

doi:10.1093/eurheartj/ehx030

Cited by 69 publications

(70 citation statements)

References 54 publications

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“…In our previous study in human left ventricular myocardium, we have demonstrated an association of increased STAT5 phosphorylation with cardioprotection by RIPC 21. This association of increased STAT5 phosphorylation with RIPC was recently confirmed in myocardial tissue from the right ventricular outflow tract of children undergoing cardiac surgery under cardiopulmonary bypass along with increased phosphorylation of AKT, eNOS, and STAT3 48. In the present study, however, we analyzed expression and phosphorylation of potential signaling proteins in human atrial trabeculae at only 1 time point (ie, after in vitro hypoxia/reoxygenation).…”

Section: Discussionsupporting

confidence: 57%

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: Discussionsupporting

confidence: 57%

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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“…Pepe and colleagues performed RIPC in children as young as 1 month (average 7 months age) undergoing tetralogy of Fallot repair, and found no differences in phosphorylated Akt or STAT3 between the control and RIPC groups [97]. Yet, Wu and colleagues demonstrated significant STAT3 activation in similar clinical settings but with older children (average 10-to 11-month-old children) [98]. Long-term regular RIPC was demonstrated to increase STAT3 in arterial samples discarded from patients undergoing CABG [99].…”

Section: Discussionmentioning

confidence: 99%

Remote Ischemic Preconditioning Induces Cardioprotective Autophagy and Signals through the IL-6-Dependent JAK-STAT Pathway

Billah

Ridiandries

Allahwala

et al. 2020

IJMS

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Autophagy is a cellular process by which mammalian cells degrade and assist in recycling damaged organelles and proteins. This study aimed to ascertain the role of autophagy in remote ischemic preconditioning (RIPC)-induced cardioprotection. Sprague Dawley rats were subjected to RIPC at the hindlimb followed by a 30-min transient blockade of the left coronary artery to simulate ischemia reperfusion (I/R) injury. Hindlimb muscle and the heart were excised 24 h post reperfusion. RIPC prior to I/R upregulated autophagy in the rat heart at 24 h post reperfusion. In vitro, autophagy inhibition or stimulation prior to RIPC, respectively, either ameliorated or stimulated the cardioprotective effect, measured as improved cell viability to mimic the preconditioning effect. Recombinant interleukin-6 (IL-6) treatment prior to I/R increased in vitro autophagy in a dose-dependent manner, activating the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway without affecting the other kinase pathways, such as p38 mitogen-activated protein kinases (MAPK), and glycogen synthase kinase 3 Beta (GSK-3β) pathways. Prior to I/R, in vitro inhibition of the JAK-STAT pathway reduced autophagy upregulation despite recombinant IL-6 pre-treatment. Autophagy is an essential component of RIPC-induced cardioprotection that may upregulate autophagy through an IL-6/JAK-STAT-dependent mechanism, thus identifying a potentially new therapeutic option for the treatment of ischemic heart disease.

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“…For example, in humans, RIPC has been shown to increase the phosphorylation of STAT5, and in rats and pigs, RIPC has been shown to increase the phosphorylation of STAT3 [14]. However, a recent study of ours in patients showed that RIPC, when applied about one hour before open heart surgery can significantly increase the cardiac phosphorylation/activation of both STAT3 and STAT5 and reduce the myocardial I/RI in children with tetralogy of Fallot [49]. It has also been shown that STAT3 played a central role in the development of postpartum cardiomyopathy [50].…”

Section: Discussionmentioning

confidence: 99%

Repeated Non-Invasive Limb Ischemic Preconditioning Confers Cardioprotection Through PKC-Ԑ/STAT3 Signaling in Diabetic Rats

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Protein kinase C(PKC)-ε activation is a mechanism of preconditioning cardioprotection but its role in repeated non-invasive limb ischemic preconditioning (rNLIP) mediated cardioprotection against myocardial ischemia/reperfusion (I/R) injury in diabetes is unknown. Methods: Eight-week streptozotocin-induced diabetic and non-diabetic Sprague-Dawley rats were subjected to I/R without or with rNLIP. In vitro, H9C2 cells were cultured with high glucose (HG) and subjected to hypoxia/re-oxygenation (H/R) without or with PKC-ε or STAT3 gene knock-down in the absence or presence of remote time hypoxia preconditioning (HPC). Results: Diabetic rats displayed larger post-ischemic myocardial infarct size and higher troponin-I release with concomitant cardiac PKC-ԑ overexpression and activation manifested as increased membrane translocation, while phosphorylated STAT3 (p-STAT3) and Akt (p-Akt) were lower compared to non-diabetic rats (all P<0.05). rNLIP reduced infarct size in both non-diabetic and diabetic rats. rNLIP reduced post-ischemic cardiac PKC-ԑ activation in diabetic while increased PKC-ԑ activation in non-diabetic rats, resulting in increased cardiac p-STAT3 and p-Akt. In H9C2 cells, HG increased PKC-ԑ expression and exacerbated post-H/R injury, accompanied with reduced p-STAT3 and p-Akt, which were all reverted by HPC. These HPC protective effects were abolished by either PKC-ԑ or STAT3 gene knock-down, except that PKC-ԑ gene knock-down reverted HG and H/R-induced reduction of p-STAT3. Conclusion: rNLIP attenuates diabetic heart I/R injury by mitigating HG-induced PKC-ԑ overexpression and, subsequently, activating STAT3.

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Cardiac protective effects of remote ischaemic preconditioning in children undergoing tetralogy of fallot repair surgery: a randomized controlled trial

Cited by 69 publications

References 54 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

Remote Ischemic Preconditioning Induces Cardioprotective Autophagy and Signals through the IL-6-Dependent JAK-STAT Pathway

Repeated Non-Invasive Limb Ischemic Preconditioning Confers Cardioprotection Through PKC-Ԑ/STAT3 Signaling in Diabetic Rats

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