A clinically relevant sheep model of orthotopic heart transplantation 24 h after donor brainstem death

BACKGROUND: Heart transplantation (HTx) from brainstem dead (BSD) donors is the gold-standard therapy for severe/end-stage cardiac disease, but is limited by a global donor heart shortage. Consequently, innovative solutions to increase donor heart availability and utilisation are rapidly expanding. Clinically relevant preclinical models are essential for evaluating interventions for human translation, yet few exist that accurately mimic all key HTx components, incorporating injuries beginning in the donor, through to the recipient. To enable future assessment of novel perfusion technologies in our research program, we thus aimed to develop a clinically relevant sheep model of HTx following 24 h of donor BSD. METHODS: BSD donors (vs. sham neurological injury, 4/group) were hemodynamically supported and monitored for 24 h, followed by heart preservation with cold static storage. Bicaval orthotopic HTx was performed in matched recipients, who were weaned from cardiopulmonary bypass (CPB), and monitored for 6 h. Donor and recipient blood were assayed for inflammatory and cardiac injury markers, and cardiac function was assessed using echocardiography. Repeated measurements between the two different groups during the study observation period were assessed by mixed ANOVA for repeated measures. RESULTS: Brainstem death caused an immediate catecholaminergic hemodynamic response (mean arterial pressure, p = 0.09), systemic inflammation (IL-6 - p = 0.025, IL-8 - p = 0.002) and cardiac injury (cardiac troponin I, p = 0.048), requiring vasopressor support (vasopressor dependency index, VDI, p = 0.023), with normalisation of biomarkers and physiology over 24 h. All hearts were weaned from CPB and monitored for 6 h post-HTx, except one (sham) recipient that died 2 h post-HTx. Hemodynamic (VDI - p = 0.592, heart rate - p = 0.747) and metabolic (blood lactate, p = 0.546) parameters post-HTx were comparable between groups, despite the observed physiological perturbations that occurred during donor BSD. All p values denote interaction among groups and time in the ANOVA for repeated measures. CONCLUSIONS: We have successfully developed an ovine HTx model following 24 h of donor BSD. After 6 h of critical care management post-HTx, there were no differences between groups, despite evident hemodynamic perturbations, systemic inflammation, and cardiac injury observed during donor BSD. This preclinical model provides a platform for critical assessment of injury development pre- and post-HTx, and novel therapeutic evaluation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40635-021-00425-4

New Horizons in the Pathogenesis, Pathophysiology and Treatment of Familial Hypercholesterolaemia

Familial Hypercholesterolaemia (FH) is an autosomal-dominant genetic disease and represents the most common genetic disorder: heterozygous 1/250 births, homozygous 1/300, 000 births. FH is characterized by high to very high low-density lipoprotein cholesterol (LDL-C), which is the main cause of increased incidence of premature atherosclerotic Cardiovascular Disease (CVD) or aortic stenosis.The aim of the review was to investigate the pathogenesis and the pathophysiology of FH.The most common (60-80%) FH cause is mutations of the LDL Receptor (LDLR) protein (6 classes with a different number of receptors and functionality). Moreover, mutations in apolipoprotein B (APOB)

ECMO use in COVID-19: lessons from past respiratory virus outbreaks-a narrative review

The spread of coronavirus disease 2019 (COVID-19) continues to grow exponentially in most countries, posing an unprecedented burden on the healthcare sector and the world economy. Previous respiratory virus outbreaks, such as severe acute respiratory syndrome (SARS), pandemic H1N1 and Middle East respiratory syndrome (MERS), have provided significant insights into preparation and provision of intensive care support including extracorporeal membrane oxygenation (ECMO). Many patients have already been supported with ECMO during the current COVID-19 pandemic, and it is likely that many more may receive ECMO support, although, at this point, the role of ECMO in COVID-19-related cardiopulmonary failure is unclear. Here, we review the experience with the use of ECMO in the past respiratory virus outbreaks and discuss potential role for ECMO in COVID-19

Investigation of heparin-loaded poly(ethylene glycol)-based hydrogels as anti-thrombogenic surface coatings for extracorporeal membrane oxygenation

Extracorporeal membrane oxygenation (ECMO), a critical life-sustaining tool, faces significant challenges for the maintenance of normal haemostasis due to the large volume of circulating blood continuously in contact with artificial surfaces, hyperoxia and excessive shear stresses of the extracorporeal circuit. From a biomaterials perspective, it has been hypothesised that drug eluting coatings composed of haemocompatible hydrogels loaded with an anticoagulant drug could potentially enhance the haemocompatibility of the circuit. Poly(ethylene glycol) (PEG) has been well established as a biocompatible and anti-fouling material with wide biomedical application. Unfractionated heparin is the most commonly used anticoagulant for ECMO. In the present study, the feasibility of using heparin-loaded PEG-based hydrogels as anti-thrombogenic surface coatings for ECMO was investigated. The hydrogels were synthesised by photopolymerisation using poly(ethylene glycol) diacrylate (PEGDA) as the crosslinking monomer and poly(ethylene glycol) methacrylate (PEGMA) as the hydrophilic monomer, with heparin loaded into the pre-gel solution. Factors which could affect the release of heparin were investigated, including the ratio of PEGDA/PEGMA, water content, loading level of heparin and the flow of fluid past the hydrogel. Our results showed that increased crosslinker content and decreased water content led to slower heparin release. The hydrogels with water contents of 60 wt% and 70 wt% could achieve a sustained heparin release by adjusting the ratio of PEGDA/PEGMA. The anticoagulation efficacy of the released heparin was evaluated by measuring the activated clotting time of whole blood. The hydrogels with desirable heparin release profiles were prepared onto poly(4-methyl-1-pentene) (PMP) films with the same chemical composition as the PMP ECMO membranes. The coatings showed sustained heparin release with a cumulative release of 70-80% after 7 days. Haemocompatibility tests demonstrated that PEG hydrogel coatings significantly reduced platelet adhesion and prolonged plasma recalcification time. These results suggest that heparin-loaded PEG hydrogels are potential anti-thrombogenic coatings for ECMO.</p

Heart failure supported by veno-arterial extracorporeal membrane oxygenation (ECMO): a systematic review of pre-clinical models

Objectives Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly being used to treat patients with refractory severe heart failure. Large animal models are developed to help understand physiology and build translational research projects. In order to better understand those experimental models, we conducted a systematic literature review of animal models combining heart failure and VA-ECMO. Studies selection A systematic review was performed using Medline via PubMed, EMBASE, and Web of Science, from January 1996 to January 2019. Animal models combining experimental acute heart failure and ECMO were included. Clinical studies, abstracts, and studies not employing VA-ECMO were excluded. Data extraction Following variables were extracted, relating to four key features: (1) study design, (2) animals and their peri-experimental care, (3) heart failure models and characteristics, and (4) ECMO characteristics and management. Results Nineteen models of heart failure and VA-ECMO were included in this review. All were performed in large animals, the majority (n = 13) in pigs. Acute myocardial infarction (n = 11) with left anterior descending coronary ligation (n = 9) was the commonest mean of inducing heart failure. Most models employed peripheral VA-ECMO (n = 14) with limited reporting. Conclusion Among models that combined severe heart failure and VA-ECMO, there is a large heterogeneity in both design and reporting, as well as methods employed for heart failure. There is a need for standardization of reporting and minimum dataset to ensure translational research achieve high-quality standards

A comprehensive evaluation of hemodynamic energy production and circuit loss using four different ECMO arterial cannulae

Objective: Pulsatile-flow veno-arterial extracorporeal membrane oxygenation (V-A ECMO) has shown encouraging results for microcirculation resuscitation and left ventricle unloading in patients with refractory cardiogenic shock. We aimed to comprehensively assess different V-A ECMO parameters and their contribution to hemodynamic energy production and transfer through the device circuit. Methods: We used the i-cor® ECMO circuit, which composed of Deltastream DP3 diagonal pump and i-cor® console (Xenios AG), the Hilite 7000 membrane oxygenator (Xenios AG), venous and arterial tubing and a 1 L soft venous pseudo-patient reservoir. Four different arterial cannulae (Biomedicus 15 and 17 Fr, Maquet 15 and 17 Fr) were used. For each cannula, 192 different pulsatile modes were investigated by adjusting flow rate, systole/diastole ratio, pulsatile amplitudes and frequency, yielding 784 unique conditions. A dSpace data acquisition system was used to collect flow and pressure data. Results: Increasing flow rates and pulsatile amplitudes were associated with significantly higher hemodynamic energy production (both p < 0.001), while no significant associations were seen while adjusting systole-to-diastole ratio (p = 0.73) or pulsing frequency (p = 0.99). Arterial cannula represents the highest resistance to hemodynamic energy transfer with 32%–59% of total hemodynamic energy generated being lost within, depending on pulsatile flow settings used. Conclusions: Herein, we presented the first study to compare hemodynamic energy production with all pulsatile ECLS pump settings and their combinations and widely used yet previously unexamined four different arterial ECMO cannula. Only increased flow rate and amplitude increase hemodynamic energy production as single factors, whilst other factors are relevant when combined.</p