Metabolic Considerations in Direct Procurement and Perfusion Protocols with DCD Heart Transplantation.

Heart transplantation with donation after circulatory death (DCD) provides excellent patient outcomes and increases donor heart availability. However, unlike conventional grafts obtained through donation after brain death, DCD cardiac grafts are not only exposed to warm, unprotected ischemia, but also to a potentially damaging pre-ischemic phase after withdrawal of life-sustaining therapy (WLST). In this review, we aim to bring together knowledge about changes in cardiac energy metabolism and its regulation that occur in DCD donors during WLST, circulatory arrest, and following the onset of warm ischemia.

A tomographic microscopy-compatible Langendorff system for the dynamic structural characterization of the cardiac cycle.

Introduction: Cardiac architecture has been extensively investigated using a broad spectrum of imaging techniques. Nevertheless, the heart is a dynamic system and the structural mechanisms governing the cardiac cycle can only be unveiled when investigating it as such.

Methods: This work presents the customization of an isolated, perfused heart system compatible with synchrotron-based X-ray phase contrast imaging (X-PCI).

Mitochondrial Damage-associated Molecular Patterns as Potential Biomarkers in DCD Heart Transplantation: Lessons From Myocardial Infarction and Cardiac Arrest.

Heart transplantation with donation after circulatory death (DCD) has become a real option to increase graft availability. However, given that DCD organs are exposed to the potentially damaging conditions of warm ischemia before procurement, new strategies for graft evaluation are of particular value for the safe expansion of DCD heart transplantation. Mitochondria-related parameters are very attractive as biomarkers because of their intimate association with cardiac ischemia-reperfusion injury.

Effects of graft preservation conditions on coronary endothelium and cardiac functional recovery in a rat model of donation after circulatory death.

Background: Use of cardiac grafts obtained with donation after circulatory death (DCD) could significantly improve donor heart availability. As DCD hearts undergo potentially deleterious warm ischemia and reperfusion, clinical protocols require optimization to ensure graft quality. Thus, we investigated effects of alternative preservation conditions on endothelial and/or vascular and contractile function in comparison with the current clinical standard.

The blood oxygen level dependent (BOLD) effect of in-vitro myoglobin and hemoglobin.

The presence of deoxygenated hemoglobin (Hb) results in a drop in T2 and T2* in magnetic resonance imaging (MRI), known as the blood oxygenation level-dependent (BOLD-)effect. The purpose of this study was to investigate if deoxygenated myoglobin (Mb) exerts a BOLD-like effect. Equine Met-Mb powder was dissolved and converted to oxygenated Mb.

Cardiac Graft Assessment in the Era of Machine Perfusion: Current and Future Biomarkers.

Heart transplantation remains the treatment of reference for patients experiencing end-stage heart failure; unfortunately, graft availability through conventional donation after brain death is insufficient to meet the demand. Use of extended-criteria donors or donation after circulatory death has emerged to increase organ availability; however, clinical protocols require optimization to limit or prevent damage in hearts possessing greater susceptibility to injury than conventional grafts. The emergence of cardiac ex situ machine perfusion not only facilitates the use of extended-criteria donor and donation after circulatory death hearts through the avoidance of potentially damaging ischemia during graft storage and transport, it also opens the door to multiple opportunities for more sensitive monitoring of graft quality.

Circulating extracellular vesicles as non-invasive biomarker of rejection in heart transplant.

Background: Circulating extracellular vesicles (EVs) are raising considerable interest as a non-invasive diagnostic tool, as they are easily detectable in biologic fluids and contain a specific set of nucleic acids, proteins, and lipids reflecting pathophysiologic conditions. We aimed to investigate differences in plasma-derived EV surface protein profiles as a biomarker to be used in combination with endomyocardial biopsies (EMBs) for the diagnosis of allograft rejection.

Methods: Plasma was collected from 90 patients (53 training cohort, 37 validation cohort) before EMB.

Heart Transplantation With Donation After Circulatory Death.

Heart transplantation remains the preferred option for improving quality of life and survival for patients suffering from end-stage heart failure. Unfortunately, insufficient supply of cardiac grafts has become an obstacle. Increasing organ availability with donation after circulatory death (DCD) may be a promising option to overcome the organ shortage.

Differential effects of ischemia/reperfusion on endothelial function and contractility in donation after circulatory death.

Background: Donation after circulatory death (DCD) could significantly improve cardiac graft availability. However, DCD hearts undergo potentially deleterious warm ischemia/reperfusion (I/R). As endothelial damage is a key factor in cardiac I/R injury, we aimed to investigate the tolerance of cardiac and endothelial function after various durations of warm ischemia to improve the timing and choice of cardioprotective therapies.

Cardioprotective reperfusion strategies differentially affect mitochondria: Studies in an isolated rat heart model of donation after circulatory death (DCD).

Donation after circulatory death (DCD) holds great promise for improving cardiac graft availability; however, concerns persist regarding injury following warm ischemia, after donor circulatory arrest, and subsequent reperfusion. Application of preischemic treatments is limited for ethical reasons; thus, cardioprotective strategies applied at graft procurement (reperfusion) are of particular importance in optimizing graft quality. Given the key role of mitochondria in cardiac ischemia-reperfusion injury, we hypothesize that 3 reperfusion strategies-mild hypothermia, mechanical postconditioning, and hypoxia, when briefly applied at reperfusion onset-provoke mitochondrial changes that may underlie their cardioprotective effects.

Development of a cardiac loading device to monitor cardiac function during ex vivo graft perfusion.

Background: Ex vivo heart perfusion systems, allowing continuous perfusion of the coronary vasculature, have recently been introduced to limit ischemic time of donor hearts prior to transplantation. Hearts are, however, perfused in an unloaded manner (via the aorta) and therefore, cardiac contractile function cannot be reliably evaluated.

Objectives: We aim to develop a ventricular loading device that enables monitoring of myocardial function in an ex vivo perfusion system.

Controlled Reperfusion Strategies Improve Cardiac Hemodynamic Recovery after Warm Global Ischemia in an Isolated, Working Rat Heart Model of Donation after Circulatory Death (DCD).

Donation after circulatory death (DCD) could improve cardiac graft availability, which is currently insufficient to meet transplant demand. However, DCD organs undergo an inevitable period of warm ischemia and most cardioprotective approaches can only be applied at reperfusion (procurement) for ethical reasons. We investigated whether modifying physical conditions at reperfusion, using four different strategies, effectively improves hemodynamic recovery after warm ischemia.

Oxygen-transfer performance of a newly designed, very low-volume membrane oxygenator.

Objectives: Oxygenation of blood and other physiological solutions are routinely required in fundamental research for both in vitro and in vivo experimentation. However, very few oxygenators with suitable priming volumes (<2-3 ml) are available for surgery in small animals. We have designed a new, miniaturized membrane oxygenator and investigated the oxygen-transfer performance using both buffer and blood perfusates.

Efficacy of mechanical postconditioning following warm, global ischaemia depends on circulating fatty acid levels in an isolated, working rat heart model†.

Objectives: The number of heart transplantations is limited by donor organ availability. Donation after circulatory determination of death (DCDD) could significantly improve graft availability; however, organs undergo warm ischaemia followed by reperfusion, leading to tissue damage. Laboratory studies suggest that mechanical postconditioning [(MPC); brief, intermittent periods of ischaemia at the onset of reperfusion] can limit reperfusion injury; however, clinical translation has been disappointing.

Heart transplantation with donation after circulatory determination of death.

The constant shortage of available organs is a major obstacle and limiting factor in heart transplantation; the discrepancy between the number of donors and potential recipients leads to waiting-list mortality of 10-12% per year in Europe and the USA. If adopted for heart transplantation, donation after circulatory determination of death (DCDD) would be expected to improve the availability of organs substantially for both adults and children. With DCDD, however, hearts to be transplanted undergo a period of warm ischaemia before procurement, which is of particular concern because tissue damage occurs rapidly and might be sufficient to preclude transplantation.

Cardiac transplantation with hearts from donors after circulatory declaration of death: haemodynamic and biochemical parameters at procurement predict recovery following cardioplegic storage in a rat model.

Objectives: Donation after circulatory declaration of death (DCDD) could significantly improve the number of cardiac grafts for transplantation. Graft evaluation is particularly important in the setting of DCDD given that conditions of cardio-circulatory arrest and warm ischaemia differ, leading to variable tissue injury. The aim of this study was to identify, at the time of heart procurement, means to predict contractile recovery following cardioplegic storage and reperfusion using an isolated rat heart model.

Early reperfusion hemodynamics predict recovery in rat hearts: a potential approach towards evaluating cardiac grafts from non-heart-beating donors.

Aims: Cardiac grafts from non-heartbeating donors (NHBDs) could significantly increase organ availability and reduce waiting-list mortality. Reluctance to exploit hearts from NHBDs arises from obligatory delays in procurement leading to periods of warm ischemia and possible subsequent contractile dysfunction. Means for early prediction of graft suitability prior to transplantation are thus required for development of heart transplantation programs with NHBDs.

Development of an ultra mini-oxygenator for use in low-volume, buffer-perfused preparations.

Introduction: Small animal models are widely used in basic research. However, experimental systems requiring extracorporeal circuits are frequently confronted with limitations related to equipment size. This is particularly true for oxygenators in systems with limited volumes.

5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside reduces glucose uptake via the inhibition of Na+/H+ exchanger 1 in isolated rat ventricular cardiomyocytes.

AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is activated by an increased AMP/ATP ratio. AMPK is now well recognized to induce glucose uptake in skeletal muscle and heart. 5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) is phosphorylated to form the AMP analog ZMP, which activates AMPK.

5-Aminoimidazole-4-carboxamide 1-beta -D-ribofuranoside (AICAR) stimulates myocardial glycogenolysis by allosteric mechanisms.

We tested the hypothesis that activation of AMP-activated protein kinase (AMPK) promotes myocardial glycogenolysis by decreasing glycogen synthase (GS) and/or increasing glycogen phosphorylase (GP) activities. Isolated working hearts from halothane-anesthetized male Sprague-Dawley rats perfused in the absence or presence of 0.8 or 1.