Ex Vivo Heart Preservation: Impact of an Acellular Hemoglobin-Based Oxygen Carrier on Myocardial Function and Energy Metabolism

2013 ◽  
Vol 32 (4) ◽  
pp. S95
Author(s):  
C.W. White ◽  
B. Xiang ◽  
P. Mundt ◽  
R.C. Arora ◽  
G. Tian ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Myocardial Function ◽  
Ex Vivo ◽  
Oxygen Carrier ◽  
Heart Preservation

scholarly journals Zebrafish as a New Tool in Heart Preservation Research

2021 ◽  
Vol 8 (4) ◽  
pp. 39
Author(s):  
Luciana Da Silveira Cavalcante ◽  
Shannon N. Tessier
Keyword(s):  
New Technologies ◽  
Ex Vivo ◽  
Machine Perfusion ◽  
Life Saving ◽  
First Choice ◽  
Heart Preservation ◽  
End Stage Heart Failure ◽  
Ischemia Tolerance ◽  
The 1960S ◽  
End Stage

Heart transplantation became a reality at the end of the 1960s as a life-saving option for patients with end-stage heart failure. Static cold storage (SCS) at 4–6 °C has remained the standard for heart preservation for decades. However, SCS only allows for short-term storage that precludes optimal matching programs, requires emergency surgeries, and results in the unnecessary discard of organs. Among the alternatives seeking to extend ex vivo lifespan and mitigate the shortage of organs are sub-zero or machine perfusion modalities. Sub-zero approaches aim to prolong cold ischemia tolerance by deepening metabolic stasis, while machine perfusion aims to support metabolism through the continuous delivery of oxygen and nutrients. Each of these approaches hold promise; however, complex barriers must be overcome before their potential can be fully realized. We suggest that one barrier facing all experimental efforts to extend ex vivo lifespan are limited research tools. Mammalian models are usually the first choice due to translational aspects, yet experimentation can be restricted by expertise, time, and resources. Instead, there are instances when smaller vertebrate models, like the zebrafish, could fill critical experimental gaps in the field. Taken together, this review provides a summary of the current gold standard for heart preservation as well as new technologies in ex vivo lifespan extension. Furthermore, we describe how existing tools in zebrafish research, including isolated organ, cell specific and functional assays, as well as molecular tools, could complement and elevate heart preservation research.

Abstract 403: Leveraging the Zebrafish to Overcome Barriers in Heart Transplantation

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Shannon N Tessier ◽  
Luciana Da Silveira Cavalcante ◽  
Casie A Pendexter ◽  
Stephanie E Cronin ◽  
Reinier J de Vries ◽  
...  
Keyword(s):  
Heart Transplantation ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Complex Structure ◽  
Scale Up ◽  
Adult Zebrafish ◽  
Zebrafish Larvae ◽  
Preservation Method ◽  
Heart Preservation

Cardiac transplantation is the only curative therapy for patients with end-stage heart disease; however, there is a severe shortage of viable donor organs. Heart transplantation faces many interwoven challenges, including both biological factors and research limitations. For example, ischemia-reperfusion injury plays a role in early graft dysfunction and is associated with rejection episodes in heart transplantation. Moreover, experimental transplantation relies heavily on animal studies that are laborious and expensive, prohibiting the discovery of novel, bold solutions. We propose that the zebrafish, Danio rerio , would be a valuable tool for the field since it’s amenable to high-throughput screens, captures the complex structure of organs, and offers a suite of tools to monitor the biology of cardiac injury. Here, we develop a new subzero heart preservation method by strategically leveraging animal models from zebrafish to mammalian hearts. Using zebrafish larvae, we screened for agents which preserve hearts at -10°C. As a result of these screens, we identified promising preservative cocktails which restored heartbeat in 82% of larvae immediately post-recovery. Next, we excised adult zebrafish hearts and developed methods to mimic the ex vivo handling practices of hearts destined for transplant using a heart-on-a-plate assay. Using this assay, we carried forward promising agents identified in our initial zebrafish larvae screen to isolated adult zebrafish hearts that were cooled to -10°C and held for up to 24 hours. After rewarming, heart rate was restored and metabolic rate of zebrafish hearts was like time-matched controls (0.213 ± 0.047 and 0.275 ± 0.060, respectively, p = 0.200). Finally, we report our preliminary scale-up efforts whereby rodent hearts are stored for up to 24 hours at -10°C and viability were assessed by the TUNEL assay. The data shows high viability of cardiomyocytes post-preservation, as compared to controls. In summary, we present data to illustrate our efforts in leveraging the zebrafish to aid new discoveries in subzero heart preservation. Similar efforts to model heart transplantation in zebrafish may provide a different vantage point and enable us to make advances faster.

scholarly journals Comparison of the Effects of Cyclosporin a on the Metabolism of Perfused Rat Brain Slices during Normoxia and Hypoxia

2002 ◽  
Vol 22 (3) ◽  
pp. 342-352 ◽  
Author(s):  
Natalie Serkova ◽  
Paul Donohoe ◽  
Sven Gottschalk ◽  
Carsten Hainz ◽  
Claus U. Niemann ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Cyclosporin A ◽  
Rat Brain ◽  
Ex Vivo ◽  
Brain Slices ◽  
High Energy ◽  
Metabolic Effects ◽  
Resonance Spectroscopy ◽  
Buffer Solution ◽  
Mitochondrial Energy Metabolism

The authors evaluated and compared the metabolic effects of cyclosporin A in the rat brain during normoxia and hypoxia/reperfusion. Ex vivo31P magnetic resonance spectroscopy experiments based on perfused rat brain slices showed that under normoxic conditions, 500 μg/L cyclosporin A significantly reduced mitochondrial energy metabolism (nucleotide triphosphate, 83 ± 9% of controls; phosphocreatine, 69 ± 9%) by inhibition of the Krebs cycle (glutamate, 77 ± 5%) and oxidative phosphorylation (NAD+, 65 ± 14%) associated with an increased generation of reactive oxygen species (285 ± 78% of control). However, the same cyclosporin A concentration (500 μg/L) was found to be the most efficient concentration to inhibit the hypoxia-induced mitochondrial release of Ca2+ in primary rat hippocampal cells with cytosolic Ca2+ concentrations not significantly different from normoxic controls. Addition of 500 μg/L cyclosporin A to the perfusion medium protected high-energy phosphate metabolism (nucleotide triphosphate, 11 ± 15% of control vs. 35 ± 9% with 500 μg/L cyclosporin A) and the intracellular pH (6.2 ± 0.1 control vs. 6.6 ± 0.1 with cyclosporin A) in rat brain slices during 30 minutes of hypoxia. Results indicate that cyclosporin A simultaneously decreases and protects cell glucose and energy metabolism. Whether the overall effect was a reduction or protection of cell energy metabolism depended on the concentrations of both oxygen and cyclosporin A in the buffer solution.

Opioid preconditioning: myocardial function and energy metabolism

2001 ◽  
Vol 72 (5) ◽  
pp. 1576-1582 ◽  
Author(s):  
Daniel C Sigg ◽  
James A Coles ◽  
William J Gallagher ◽  
Peter R Oeltgen ◽  
Paul A Iaizzo
Keyword(s):  
Energy Metabolism ◽  
Myocardial Function

Interferon-beta affects mitochondrial activity in CD4+lymphocytes: Implications for mechanism of action in multiple sclerosis

2014 ◽  
Vol 21 (10) ◽  
pp. 1262-1270 ◽  
Author(s):  
Aiden Haghikia ◽  
Simon Faissner ◽  
Derek Pappas ◽  
Bartosz Pula ◽  
Denis A Akkad ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Energy Metabolism ◽  
Mitochondrial Function ◽  
Interferon Beta ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Mitochondrial Activity ◽  
Mitochondrial Energy Metabolism ◽  
The Impact

Background:Whereas cellular immune function depends on energy supply and mitochondrial function, little is known on the impact of immunotherapies on cellular energy metabolism.Objective:The objective of this paper is to assess the effects of interferon-beta (IFN-β) on mitochondrial function of CD4+T cells.Methods:Intracellular adenosine triphosphate (iATP) in phytohemagglutinin (PHA)-stimulated CD4+cells of multiple sclerosis (MS) patients treated with IFN-β and controls were analyzed in a luciferase-based assay. Mitochondrial-transmembrane potential (ΔΨm) in IFN-β-treated peripheral blood mononuclear cells (PBMCs) was investigated by flow cytometry. Expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) in CD4+cells of IFN-β-treated individuals and correlations between genetic variants in the key metabolism regulator PGC-1α and IFN-β response in MS were analyzed.Results:IFN-β-treated MS patients exhibited a dose-dependent reduction of iATP levels in CD4+T cells compared to controls ( p < 0.001). Mitochondrial effects were reflected by depolarization of ΔΨm. Expression data revealed changes in the transcription of OXPHOS-genes. iATP levels in IFN-β-responders were reduced compared to non-responders ( p < 0.05), and the major T allele of the SNP rs7665116 of PGC-1α correlated with iATP-levels.Conclusion:Reduced iATP-synthesis ex vivo and differential expression of OXPHOS-genes in CD4+T cells point to unknown IFN-β effects on mitochondrial energy metabolism, adding to potential pleiotropic mechanisms of action.

Effects of indomethacin on energy metabolism in rat jejunal tissue in vivo

2002 ◽  
Vol 102 (5) ◽  
pp. 541-546 ◽  
Author(s):  
Molly JACOB ◽  
Ingvar BJARNASON ◽  
Robert J. SIMPSON
Keyword(s):  
Energy Metabolism ◽  
Oxygen Uptake ◽  
Mitochondrial Function ◽  
Clinical Medicine ◽  
Ex Vivo ◽  
Energy Charge ◽  
Early Event ◽  
Sprague Dawley ◽  
Lactate Levels

The non-steroidal anti-inflammatory drugs (NSAIDs) are a widely used group of drugs in clinical medicine. However, their propensity to cause gastrointestinal damage limits their clinical utility. The pathogenesis of this toxicity is not well established. It has been postulated that an early event in the development of damage is an effect of these drugs on mitochondrial function. The present paper sets out to evaluate the effects of indomethacin, a commonly used NSAID, on energy metabolism in vivo. Indomethacin was administered to male Sprague-Dawley rats, either intrajejunally or orally, and indices of mitochondrial function were determined. The parameters chosen for this purpose were oxygen uptake by, lactate levels in and the energy charge of jejunal tissue. Oxygen uptake by and energy charge in jejunal tissue were unaffected at 1 and 3h after dosing by gavage with indomethacin. The drug significantly affected the tissue lactate/pyruvate ratio at 3h (but not at 1h) after oral dosing. Effects of indomethacin on jejunum incubated ex vivo were found to be reversible. The data suggest that indomethacin affects mitochondrial function in vivo, but that compensatory changes in glycolytic rate maintain energy charge.

scholarly journals Mitochondrial permeability transition pores: The role in heart energy metabolism.

2020 ◽  
Author(s):  
Miroslav Ferko ◽  
Natália Andelová
Keyword(s):  
Energy Metabolism ◽  
Acute Phase ◽  
Myocardial Function ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Energy Metabolism ◽  
Mitochondrial Permeability ◽  
Pathological Conditions ◽  
Protective Processes ◽  
Permeability Transition Pores

Substantial evidence has revealed that mitochondrial permeability transition pores (mPTPs) are associated with signaling pathway of cardioprotective models and seem to be an end-effector of cardioprotection. Experimental streptozotocin-induced diabetes mellitus (D) was shown to provide sufficient protection to the myocardium via compensatory mechanisms enabling mitochondria to produce energy under pathological conditions during the acute phase. The hypothesized involvement of mPTPs in these processes prompted us to use liquid chromatography and mass spectrometry-based proteomic analysis to investigate the effects of the acute-phase D condition on the structural and regulatory components of this multienzyme complex and the changes caused by compensation events. We detected ADT1, ATP5H, ATPA, and ATPB as the most abundant mPTP proteins. The between-group differences in protein abundance of the mPTP complex as a whole were significantly upregulated in the D group when compared with the control (C) group (p = 0.0106), but fold changes in individual protein expression levels were not significantly altered except for ATP5H, ATP5J, and KCRS. However, none of them passed the criterion of a 1.5-fold change in differential expression for biologically meaningful change. Visualization of the (dis-)similarity between the C and D groups and pairwise correlations revealed different patterns of protein interactions under the C and D conditions which may be linked to endogenous protective processes, of which beneficial effects on myocardial function were previously confirmed. Our results point to the involvement of mPTP proteins in the endogenous protective processes leading to the preservation of myocardial function under pathological conditions. Proteomic studies with respect to the correlation of mPTP proteins were shown to be one of the most promising options for the advancement of mPTP regulation mechanisms. Subtle changes in mPTP protein expressions, as well as mutual relationships between proteins, may be sufficient to contribute to preserving mitochondrial energy metabolism under the increased energy load represented by experimental D.

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