Transient mitochondrial permeability transition pore opening after neonatal cardioplegic arrest

Leung, Chung Ho; Wang, Lixing; Fu, Yaqin Yana; Yuen, William; Caldarone, Christopher A.

doi:10.1016/j.jtcvs.2010.08.030

Cited by 8 publications

(4 citation statements)

References 31 publications

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“…The majority of experimental studies investigating the cardioprotective effects of CsA have focused on reducing myocardial infarct size using an animal model of IRI, which most closely recapitulates the acute IRI experienced by the STEMI patient undergoing PPCI. However, CsA has also been reported to protect the heart against acute IRI in other experimental settings such as neonatal cardioplegic arrest and reperfusion (Oka et al ., 2008; Leung et al ., 2011) and resuscitated cardiac arrest (Cour et al ., 2011). By measuring the mitochondrial entrapment of titriated glucose at reperfusion following cardioplegic arrest, Leung and co‐workers (Leung et al ., 2011) demonstrated that in a neonatal rabbit model of cardioplegic arrest and reperfusion, CsA‐sensitive mPTP opening occurs at the time of myocardial reperfusion, providing preliminary experimental evidence that treatment with CsA or another mPTP inhibitor may be beneficial in terms of reducing perioperative myocardial injury in neonates undergoing corrective cardiac surgery for congenital heart disease.…”

Section: Protecting the Heart In Other Settings Using Csamentioning

confidence: 99%

“…However, CsA has also been reported to protect the heart against acute IRI in other experimental settings such as neonatal cardioplegic arrest and reperfusion (Oka et al ., 2008; Leung et al ., 2011) and resuscitated cardiac arrest (Cour et al ., 2011). By measuring the mitochondrial entrapment of titriated glucose at reperfusion following cardioplegic arrest, Leung and co‐workers (Leung et al ., 2011) demonstrated that in a neonatal rabbit model of cardioplegic arrest and reperfusion, CsA‐sensitive mPTP opening occurs at the time of myocardial reperfusion, providing preliminary experimental evidence that treatment with CsA or another mPTP inhibitor may be beneficial in terms of reducing perioperative myocardial injury in neonates undergoing corrective cardiac surgery for congenital heart disease. In another study, Cour and colleagues (Cour et al ., 2011) found that administering either intravenous CsA (5 mg·kg −1 ) or N‐methyl‐4‐isoleucine cyclosporin (NIM811) (2.5 mg·kg −1 ) at the time of reperfusion following a 15 min period of primary asphyxial in situ cardiac arrest in rabbits improved survival, reduced myocardial necrosis and inhibited mPTP opening in isolated cardiac mitochondria.…”

Section: Protecting the Heart In Other Settings Using Csamentioning

confidence: 99%

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Cyclosporin A and cardioprotection: from investigative tool to therapeutic agent

Hausenloy

Boston-Griffiths

Yellon

2012

British J Pharmacology

118

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Ischaemic heart disease (IHD) is the leading cause of death and disability worldwide. The pathophysiological effects of IHD on the heart most often result from the detrimental effects of acute ischaemia-reperfusion injury (IRI) on the myocardium. Therefore, novel therapeutic targets for protecting the myocardium against acute IRI are required to reduce injury to the heart, preserve cardiac function and improve clinical outcomes in patients with IHD. In this regard, the mitochondrial permeability transition pore (mPTP) has emerged as a critical target for cardioprotection which is readily amenable to intervention at the time of myocardial reperfusion. The formation and opening of the mPTP at the onset of myocardial reperfusion is a major determinant of mitochondrial dysfunction and cardiomyocyte death in the setting of acute IRI. The seminal discovery in the late 1980s that mPTP opening could be pharmacologically inhibited by the immunosuppressive agent, cyclosporin A (CsA), has been fundamental in the elucidation of the critical role of the mPTP as a mediator of acute IRI and, therefore, a viable target for cardioprotection. Its initial role as an investigative tool was used to identify mitochondrial cyclophilin D to be a regulatory component of the mPTP. The mPTP as a viable target for cardioprotection has recently been translated into the clinical setting with CsA reducing myocardial infarct size in patients. In this article, we review the intriguing role of CsA as a tool for investigating the mPTP as a target for cardioprotection and its potential role as a therapeutic agent for patients with IHD.

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Section: Protecting the Heart In Other Settings Using Csamentioning

confidence: 99%

Section: Protecting the Heart In Other Settings Using Csamentioning

confidence: 99%

Cyclosporin A and cardioprotection: from investigative tool to therapeutic agent

Hausenloy

Boston-Griffiths

Yellon

2012

British J Pharmacology

118

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“…The PTP has long been a target for the protection of both myocytes and mitochondria during ischemia and reperfusion (27). Opening of the PTP results in mitochondrial calcium overload, release of reactive oxygen species, and apoptosis (28,29) in both adults and children. The use of pharmacology to prevent PTP opening has not significantly impacted clinical outcomes in adult cardiac ischemia (30).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial ATP Synthase Tetramer Disassembly following Blood-Based or del Nido Cardioplegia during Neonatal Cardiac Surgery

Simon¹,

Beutner²,

Swartz³

et al. 2022

J Extra Corpor Technol

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Conservation of mitochondrial adenosine triphosphate (ATP) synthase proteins during ischemia is critical to preserve ATP supply and ventricular function. Following myocardial ischemia in adults, higher order ATP synthase tetramer proteins disassemble into simpler monomer units, reducing the efficiency of ATP production. However, it is unknown if myocardial ischemia following the use of cardioplegia results in tetramer disassembly in neonates, and whether it can be mitigated by cardioplegia if it does occur. We investigated myocardial ATP synthase tetramer disassembly in both a neonatal lamb cardiac surgery model and in neonatal children requiring cardiac surgery for the repair of congenital heart disease. Neonatal lambs (Ovis aries) were placed on cardiopulmonary bypass (CPB) and underwent cardioplegic arrest using a single dose of 30 mL/kg antegrade blood-based potassium cardioplegia (n = 4) or a single dose of 30 mL/kg antegrade del Nido cardioplegia (n = 6). Right ventricular biopsies were taken at baseline on CPB (n = 10) and after approximately 60 minutes of cardioplegic arrest before the cross clamp was released (n = 10). Human right ventricular biopsies (n = 3) were taken following 40.0 ± 23.1 minutes of ischemia after a single dose of antegrade blood-based cardioplegia. Protein complexes were separated on clear native gels and the tetramer to monomer ratio quantified. From the neonatal lamb model regardless of the cardioplegia strategy, the tetramer:monomer ratio decreased significantly during ischemia from baseline measurements (.6 ± .2 vs. .5 ± .1; p = .03). The del Nido solution better preserved the tetramer:monomer ratio when compared to the blood-based cardioplegia (Blood .4 ± .1 vs. del Nido .5 ± .1; p = .05). The tetramer:monomer ratio following the use of blood-based cardioplegia in humans aligned with the lamb data (tetramer:monomer .5 ± .2). These initial results suggest that despite cardioprotection, ischemia during neonatal cardiac surgery results in tetramer disassembly which may be limited when using the del Nido solution.

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“…Unlike in post-cardiac arrest myocardial dysfunction, apoptosis in the context of mPTP opening is much more common in the neonatal myocardium after cardioplegic arrest [94]. Inhibition of mPTP opening in neonatal cardioplegic arrest in rabbits with cyclosporine A improves myocardial function and CI respiration and reduces ROS production [94,95]. In a direct comparison of neonatal (6–8 days) and young adult (6–8 weeks) lambs who underwent cardioplegic arrest for cardiopulmonary bypass, neonatal myocardium exhibited more evidence of mPTP opening, characterized by increased cytochrome c release, caspase activity, and apoptosis [96].…”

Section: Role Of the Mitochondrial Permeability Transition Porementioning

confidence: 99%

Age-Dependent Myocardial Dysfunction in Critically Ill Patients: Role of Mitochondrial Dysfunction

Lautz

Zingarelli

2019

IJMS

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Myocardial dysfunction is common in septic shock and post-cardiac arrest but manifests differently in pediatric and adult patients. By conventional echocardiographic parameters, biventricular systolic dysfunction is more prevalent in children with septic shock, though strain imaging reveals that myocardial injury may be more common in adults than previously thought. In contrast, diastolic dysfunction in general and post-arrest myocardial systolic dysfunction appear to be more widespread in the adult population. A growing body of evidence suggests that mitochondrial dysfunction mediates myocardial depression in critical illness; alterations in mitochondrial electron transport system function, bioenergetic production, oxidative and nitrosative stress, uncoupling, mitochondrial permeability transition, fusion, fission, biogenesis, and autophagy all may play key pathophysiologic roles. In this review we summarize the epidemiologic and clinical phenotypes of myocardial dysfunction in septic shock and post-cardiac arrest and the multifaceted manifestations of mitochondrial injury in these disease processes. Since neonatal and pediatric-specific data for mitochondrial dysfunction remain sparse, conclusive age-dependent differences are not clear; instead, we highlight what evidence exists and identify gaps in knowledge to guide future research. Finally, since focal ischemic injury (with or without reperfusion) leading to myocardial infarction is predominantly an atherosclerotic disease of the elderly, this review focuses specifically on septic shock and global ischemia-reperfusion injury occurring after resuscitation from cardiac arrest.

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Transient mitochondrial permeability transition pore opening after neonatal cardioplegic arrest

Cited by 8 publications

References 31 publications

Cyclosporin A and cardioprotection: from investigative tool to therapeutic agent

Cyclosporin A and cardioprotection: from investigative tool to therapeutic agent

Mitochondrial ATP Synthase Tetramer Disassembly following Blood-Based or del Nido Cardioplegia during Neonatal Cardiac Surgery

Age-Dependent Myocardial Dysfunction in Critically Ill Patients: Role of Mitochondrial Dysfunction

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