Publications by authors named "Darren H Freed"

106 Publications

Sternal Bone Marrow Harvesting and Culturing Techniques from Patients Undergoing Cardiac Surgery.

Micromachines (Basel) 2021 Jul 28;12(8). Epub 2021 Jul 28.

Division of Cardiac Surgery, University of Alberta, Edmonton, AB T6G 2B7, Canada.

Background: Mesenchymal stromal cells (MSCs) are the most prominent cell type used in clinical regenerative medicine and stem cell research. MSCs are commonly harvested from bone marrow that has been aspirated from patients' iliac crest. However, the ethical challenges of finding consenting patients and obtaining fresh autologous cells via invasive extraction methods remain to be barriers to MSC research.

Methods: Techniques of harvesting sternal bone marrow, isolating and culturing MSCs, MSC surface phenotyping, and MSC differentiation are described. Samples from 50 patients undergoing a sternotomy were collected, and the time taken to reach 80% confluency and cell count at the second splitting of MSC were measured.

Results: MSC isolated from the sternal bone marrow of patients undergoing cardiac surgery demonstrated successful MSC surface phenotyping and MSC differentiation. The mean cell count at the time of the second split was 1,628,025, and the mean time taken to reach the second split was 24.8 days.

Conclusion: Herein, we describe the first reported technique of harvesting sternal bone marrow from patients already undergoing open-chest cardiac surgery to reduce the invasiveness of bone marrow harvesting, as well as the methods of isolating, culturing, and identifying MSCs for the clinical application of constructing autologous MSC-derived biomaterials.
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http://dx.doi.org/10.3390/mi12080897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397946PMC
July 2021

The effects of body mass index on long-term outcomes and cardiac remodeling following mitral valve repair surgery.

Int J Obes (Lond) 2021 Aug 9. Epub 2021 Aug 9.

Division of Cardiac Surgery, Department of Surgery, University of Alberta, Edmonton, AB, Canada.

Background: Previous literature has demonstrated equivalent or improved survival post mitral valve (MV) surgery amongst patients with obesity when compared to their normal-weight counterparts. This relationship is poorly understood and the impact of body mass index (BMI) on cardiac remodeling has not been established.

Methods: In this retrospective, single-center study, we sought to identify the impact that BMI may have on long-term outcomes and cardiac remodeling post-MV repair. Outcomes were compared between patients of varying BMI undergoing MV repair between 2004 and 2018. The primary outcome was mortality and secondary outcomes included stroke, myocardial infarction, reoperation of the MV, rehospitalization, and cardiac remodeling.

Results: A total of 32 underweight, 249 normal weight, 249 overweight, 121 obese, and 50 morbidly obese patients were included in this study. Underweight patients had increased mortality at longest follow-up. Patients with morbid obesity were found to have higher rates of readmission for heart failure. Only underweight patients did not demonstrate a significant reduction in LVEF. Patients with normal weight and overweight had a significant reduction in left atrial size, and patients with obesity had a significant reduction in MV area.

Conclusions: An obesity paradox has been identified in cardiac surgery. While patients with obesity have higher rates of comorbidities preoperatively, their rates of mortality are equivalent or even superior to those with lower BMI. The results of our study confirm this finding with patients of high BMI undergoing MV repair demonstrating equivalent rates of morbidity to their normal BMI counterparts. While the obesity paradox has been relatively consistent in the literature, the understanding of its cause and long-term impacts are not well understood. Further focused investigation is necessary to elucidate the cause of this relationship.
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http://dx.doi.org/10.1038/s41366-021-00933-zDOI Listing
August 2021

Paracorporeal Support in Pediatric Patients: The Role of the Patient-Device Interaction.

Ann Thorac Surg 2021 Jul 28. Epub 2021 Jul 28.

Department of Pediatric Cardiology University of Alberta, Edmonton AB, Canada; Division of Pediatric Cardiology, Stollery Children's Hospital, Edmonton AB, Canada. Electronic address:

Background: Ventricular assist devices (VADs) are important in the treatment of pediatric heart failure. While paracorporeal pulsatile (PP) devices have historically been used, there has been increased use of paracorporeal continuous (PC) devices. We sought to compare the outcomes of children supported with a PP, PC, or combination of devices.

Methods: Retrospective review (2005-19) of patients <19 years of age from a single center, who received a PC, PP or combination of devices. Patient characteristics were compared between device strategies and Kaplan-Meier survival analysis was performed.

Results: Sixty-six patients were included (62% male, 62% non-congenital heart disease, median age 0.9 years (IQR 0.2, 4.9), median weight 8.5 kg (IQR 4.3, 17.7). PC devices were used in 45% of patients, PP in 35% and a combination in 20%. Patients on PC devices had a lower median weight (p=.02), a higher proportion of CHD (p=.02) and more patients requiring pre-VAD dialysis (p=.01). There was no difference in pre-VAD ECMO (p=.15) use. There was a difference in survival between the three device strategies (p=.02) CONCLUSIONS: Differences in survival was evident, with those on PC support having worse outcomes. Transition from PC to a PP devices was associated with a survival advantage. These findings may be driven by differences in patient characteristics across device strategies. Further studies are required to confirm these findings and to better understand the interaction between patient characteristics and device options.
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http://dx.doi.org/10.1016/j.athoracsur.2021.06.062DOI Listing
July 2021

Lung Transplantation, Pulmonary Endothelial Inflammation, and Ex-Situ Lung Perfusion: A Review.

Cells 2021 Jun 7;10(6). Epub 2021 Jun 7.

Division of Cardiac Surgery, Department of Surgery, University of Alberta, Edmonton, AB T6G 2B7, Canada.

Lung transplantation (LTx) is the gold standard treatment for end-stage lung disease; however, waitlist mortality remains high due to a shortage of suitable donor lungs. Organ quality can be compromised by lung ischemic reperfusion injury (LIRI). LIRI causes pulmonary endothelial inflammation and may lead to primary graft dysfunction (PGD). PGD is a significant cause of morbidity and mortality post-LTx. Research into preservation strategies that decrease the risk of LIRI and PGD is needed, and ex-situ lung perfusion (ESLP) is the foremost technological advancement in this field. This review addresses three major topics in the field of LTx: first, we review the clinical manifestation of LIRI post-LTx; second, we discuss the pathophysiology of LIRI that leads to pulmonary endothelial inflammation and PGD; and third, we present the role of ESLP as a therapeutic vehicle to mitigate this physiologic insult, increase the rates of donor organ utilization, and improve patient outcomes.
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http://dx.doi.org/10.3390/cells10061417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229792PMC
June 2021

The Position of the Heart During Normothermic Ex Situ Heart Perfusion is an Important Factor in Preservation and Recovery of Myocardial Function.

ASAIO J 2021 Mar 17. Epub 2021 Mar 17.

From the Department of Surgery, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada Alberta Transplant Institute, Edmonton, Alberta, Canada Department of surgery, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada Department of Laboratory Medicine and Pathology, Faculty of Medicine, Canada Canadian Donation and Transplantation Research Program, Canada Department of Chemical and Materials Engineering Faculty of Engineering, University of Alberta, Edmonton, Alberta, Canada Department of Mechanical Engineering, Faculty of Engineering, University of Alberta, Edmonton, Alberta, Canada Department of Physiology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada Department of Biomedical Engineering, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada.

Ex situ heart perfusion (ESHP) is being investigated as a method for the continuous preservation of the myocardium in a semiphysiologic state for subsequent transplantation. Most methods of ESHP position the isolated heart in a hanging (H) state, representing a considerable departure from the in vivo anatomical positioning of the heart and may negatively affect the functional preservation of the heart. In the current study, cardiac functional and metabolic parameters were assessed in healthy pig hearts, perfused for 12 hours, in either an H, or supported (S) position, either in nonworking mode (NWM) or working mode (WM). The cardiac function was best preserved in the S position hearts in WM (median 11 hour cardiac index (CI)/1 hour CI%: working mode perfusion in supported position = 94.77% versus nonworking mode perfusion in supported position = 62.80%, working mode perfusion in H position = 36.18%, nonworking mode perfusion in H position = 9.75%; p < 0.001). Delivery of pyruvate bolus significantly improved the function in S groups, however, only partially reversed myocardial dysfunction in the H heart groups. The hearts perfused ex situ in a semianatomical S position and in physiologic WM had better functional preservation and recovery than the H hearts in non-S position. Optimizing the positional support for the ex situ-perfused hearts may improve myocardial preservation during ESHP.
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http://dx.doi.org/10.1097/MAT.0000000000001386DOI Listing
March 2021

Heart donation and transplantation after circulatory determination of death: expert guidance from a Canadian consensus building process.

Can J Anaesth 2021 May 5;68(5):661-671. Epub 2021 Feb 5.

Donation, Trillium Gift of Life Network, Toronto, Canada.

Controlled donation after circulatory determination of death (DCD), where death is determined after cardiac arrest, has been responsible for the largest quantitative increase in Canadian organ donation and transplants, but not for heart transplants. Innovative international advances in DCD heart transplantation include direct procurement and perfusion (DPP) and normothermic regional perfusion (NRP). After death is determined, DPP involves removal and reanimation of the arrested heart on an ex situ organ perfusion system. Normothermic regional perfusion involves surgically interrupting (ligating the aortic arch vessels) brain blood flow after death determination, followed by restarting the heart and circulation in situ using extracorporeal membrane oxygenation. The objectives of this Canadian consensus building process by a multidisciplinary group of Canadian stakeholders were to review current evidence and international DCD heart experience, comparatively evaluate international protocols with existing Canadian medical, legal, and ethical practices, and to discuss implementation barriers. Review of current evidence and international experience of DCD heart donation (DPP and NRP) determined that DCD heart donation could be used to provide opportunities for more heart transplants in Canada, saving additional lives. Although candid discussion identified a number of potential barriers and challenges for implementing DCD heart donation in Canada, it was determined that DPP implementation is feasible (pending regulatory approval for the use of an ex situ perfusion device in humans) and in alignment with current medical guidelines for DCD. Nevertheless, further work is required to evaluate the consistency of NRP with current Canadian death determination policy and to ensure the absence of brain perfusion during this process.
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http://dx.doi.org/10.1007/s12630-021-01926-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035095PMC
May 2021

Resveratrol attenuates stimulated T-cell activation and proliferation: potential therapy against cellular rejection in organ transplantation.

Am J Clin Exp Immunol 2020 15;9(5):81-90. Epub 2020 Dec 15.

Department of Surgery, Division of Cardiac Surgery, University of Alberta Edmonton, AB, Canada.

Background: Pharmaceuticals to inhibit mammalian target of rapamycin (mTOR) protein, which plays an integral role in T cell survival and function, have been used to prevent complications associated with organ transplantation. Although studies have individually shown that resveratrol can inhibit mTOR and that inhibiting mTOR leads to attenuated immune function, no studies to date have examined these two functions conjointly under one study. Therefore, we hypothesize that resveratrol will decrease mTOR activation and expression as well as attenuate stimulated T cell activation and proliferation in peripheral blood mononuclear cells (PBMC).

Methods And Materials: Human PBMC were isolated and cultured. The cells were pre-treated with resveratrol (50 μM) overnight (18 hrs) before stimulation. The cells were collected for subsequent biochemical analysis after 1, 3, and 5 days. Additionally, the cells were stained with proliferation dye and cultured for 24 hours in PMA/Ionomycin with resveratrol for flow cytometry analysis.

Results: Resveratrol treated stimulated PBMCs displayed a significant decrease in activated phosphorylation of mTOR at days 1, 3, and 5 (P < 0.0329). Markers of T cell activation, tumour necrosis factor-alpha (TNF-α) and interferon-gamma (INF-γ), were also significantly reduced along with T cell proliferation following stimulated PBMC resveratrol treatment when compared to vehicle-treated controls (P < 0.01).

Conclusion: Taken together, our data suggest that resveratrol can decrease the immune response of stimulated T-cells and inhibit the expression and activation of mTOR mediated cellular signalling under the same study setting. Therefore, resveratrol proposes a possible adjunctive therapy option for patients undergoing organ transplantation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811925PMC
December 2020

A review of the immune response stimulated by xenogenic tissue heart valves.

Scand J Immunol 2021 Apr 7;93(4):e13018. Epub 2021 Jan 7.

Department of Surgery, Division of Cardiac Surgery, University of Alberta, Edmonton, AB, Canada.

Valvular heart disease continues to afflict millions of people around the world. In many cases, the only corrective treatment for valvular heart disease is valve replacement. Valve replacement options are currently limited, and the most common construct utilized are xenogenic tissue heart valves. The main limitation with the use of this valve type is the development of valvular deterioration. Valve deterioration results in intrinsic permanent changes in the valve structure, often leading to hemodynamic compromise and clinical symptoms of valve re-stenosis. A significant amount of research has been performed regarding the incidence of valve deterioration and determination of significant risk factors for its development. As a result, many believe that the underlying driver of valve deterioration is a chronic immune-mediated rejection process of the foreign xenogenic-derived tissue. The underlying mechanisms of how this occurs are an area of ongoing research and active debate. In this review, we provide an overview of the important components of the immune system and how they respond to xenografts. A review of the proposed mechanisms of xenogenic heart valve deterioration is provided including the immune response to xenografts. Finally, we discuss the role of strategies to combat valve degeneration such as preservation protocols, epitope modification and decellularization.
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http://dx.doi.org/10.1111/sji.13018DOI Listing
April 2021

Impact of sex on cardiac remodeling and long-term outcomes, following mitral valve replacement.

J Card Surg 2021 Feb 22;36(2):565-572. Epub 2020 Dec 22.

Division of Cardiac Surgery, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.

Background: Differences in cardiac remodeling after mitral valve (MV) surgery between the sexes is poorly understood. Inferior outcomes for females undergoing MV surgery compared with males have been suggested in the literature, although causative factors behind this discrepancy have not been identified. MATERIALS AND METHODS: In this propensity-matched, retrospective, single-center study, we sought to identify the impact that sex may have on cardiac remodeling and long-term outcomes to better inform clinical decision-making in MV surgical intervention. Outcomes were compared between males and females undergoing MV replacement (MVR) between 2004 and 2018. The primary outcome was cardiac remodeling 1 year postoperatively. Secondary outcomes included mortality, stroke, myocardial infarction (MI), reoperation of the MV, and rehospitalization.

Results: A total of 311 males and 311 females were included after propensity matching. Both groups demonstrated significant improvement in left atrial remodeling, although only males demonstrated a significant degree of improved left ventricular remodeling while their female counterparts did not. Mortality rates were relatively equivalent between the two groups, although males were more likely to develop sepsis and require rehospitalization due to MI.

Conclusions: There has been little research exploring the differences in cardiac remodeling between the sexes after MVR. The results of this study have suggested that MVR is equally safe for both sexes and has demonstrated a difference in the heart's ability to remodel after MVR. The significance of this difference has the potential to result in largely different clinical outcomes for males and females. Further study is necessary to fully elucidate this relationship.
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http://dx.doi.org/10.1111/jocs.15264DOI Listing
February 2021

Clinical transplantation using negative pressure ventilation ex situ lung perfusion with extended criteria donor lungs.

Nat Commun 2020 11 13;11(1):5765. Epub 2020 Nov 13.

Division of Cardiac Surgery, Department of Surgery, University of Alberta, Edmonton, AB, Canada.

Lung transplantation remains the best treatment option for end-stage lung disease; however, is limited by a shortage of donor grafts. Ex situ lung perfusion, also known as ex vivo lung perfusion, has been shown to allow for the safe evaluation and reconditioning of extended criteria donor lungs, increasing donor utilization. Negative pressure ventilation ex situ lung perfusion has been shown, preclinically, to result in less ventilator-induced lung injury than positive pressure ventilation. Here we demonstrate that, in a single-arm interventional study (ClinicalTrials.gov number NCT03293043) of 12 extended criteria donor human lungs, negative pressure ventilation ex situ lung perfusion allows for preservation and evaluation of donor lungs with all grafts and patients surviving to 30 days and recovered to discharge from hospital. This trial also demonstrates that ex situ lung perfusion is safe and feasible with no patients demonstrating primary graft dysfunction scores grade 3 at 72 h or requiring post-operative extracorporeal membrane oxygenation.
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http://dx.doi.org/10.1038/s41467-020-19581-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666579PMC
November 2020

The Human Explanted Heart Program: A translational bridge for cardiovascular medicine.

Biochim Biophys Acta Mol Basis Dis 2021 01 22;1867(1):165995. Epub 2020 Oct 22.

Division of Cardiology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

The progression of cardiovascular research is often impeded by the lack of reliable disease models that fully recapitulate the pathogenesis in humans. These limitations apply to both in vitro models such as cell-based cultures and in vivo animal models which invariably are limited to simulate the complexity of cardiovascular disease in humans. Implementing human heart tissue in cardiovascular research complements our research strategy using preclinical models. We established the Human Explanted Heart Program (HELP) which integrates clinical, tissue and molecular phenotyping thereby providing a comprehensive evaluation into human heart disease. Our collection and storage of biospecimens allow them to retain key pathogenic findings while providing novel insights into human heart failure. The use of human non-failing control explanted hearts provides a valuable comparison group for the diseased explanted hearts. Using HELP we have been able to create a tissue repository which have been used for genetic, molecular, cellular, and histological studies. This review describes the process of collection and use of explanted human heart specimens encompassing a spectrum of pediatric and adult heart diseases, while highlighting the role of these invaluable specimens in translational research. Furthermore, we highlight the efficient procurement and bio-preservation approaches ensuring analytical quality of heart specimens acquired in the context of heart donation and transplantation.
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http://dx.doi.org/10.1016/j.bbadis.2020.165995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581399PMC
January 2021

Structural Valve Deterioration Is Linked to Increased Immune Infiltrate and Chemokine Expression.

J Cardiovasc Transl Res 2021 Jun 21;14(3):503-512. Epub 2020 Oct 21.

Division of Cardiac Surgery, Department of Surgery, University of Alberta, Edmonton, AB, T6G 2R3, Canada.

We aim to investigate whether structural valve deterioration (SVD) of bioprosthetic xenogenic tissue heart valves (XTHVs) is associated with increased immune cell infiltration and whether co-expression of several chemokines correlates with this increase in immune infiltrate. Explanted XTHVs from patients undergoing redo valve replacement for SVD were obtained. Immunohistochemical, microscopic, and gene expression analysis approaches were used. XTHVs (n = 37) were obtained from 32 patients (mean 67.7 years) after a mean time of 11.6 years post-implantation. Significantly increased immune cellular infiltration was observed in the explanted SVD valves for all immune cell types examined, including T cells, macrophages, B cells, neutrophils, and plasma cells, compared to non-SVD controls. Furthermore, a significantly increased chemokine gradient in explanted SVD valves accompanied immune cell infiltration. These data suggest the development of SVD is associated with a significantly increased burden of immune cellular infiltrate correlated to the induction of a chemokine gradient around the XHTV, representing chronic immune rejection.Graphical abstract Proposed interaction between innate and adaptive immunity leading to the development of structural valve deterioration in xenogenic tissue heart valves.
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http://dx.doi.org/10.1007/s12265-020-10080-xDOI Listing
June 2021

Experimental investigation into the effect of compliance of a mock aorta on cardiac performance.

PLoS One 2020 12;15(10):e0239604. Epub 2020 Oct 12.

Department of Mechanical Engineering, University of Alberta, Edmonton, Canada.

Demand for heart transplants far exceeds supply of donated organs. This is attributed to the high percentage of donor hearts that are discarded and to the narrow six-hour time window currently available for transplantation. Ex-vivo heart perfusion (EVHP) provides the opportunity for resuscitation of damaged organs and extended transplantation time window by enabling functional assessment of the hearts in a near-physiologic state. Present work investigates the fluid mechanics of the ex-vivo flow loop and corresponding impact on cardiac performance. A mechanical flow loop is developed that is analogous to the region of the EVHP system that mimics in-vivo systemic circulation, including the body's largest and most compliant artery, the aorta. This investigation is focused on determining the effect of mock aortic tubing compliance on pump performance. A custom-made silicone mock aorta was developed to simulate a range of in-vivo conditions and a physiological flow was generated using a commercial ventricular assist device (VAD). Monitored parameters, including pressure, tube distension and downstream velocity, acquired using time-resolved particle imaging velocimetry (PIV), were applied to an unsteady Bernoulli analysis of the flow in a novel way to evaluate pump performance as a proxy for cardiac workload. When compared to the rigid case, the compliant mock aorta case demonstrated healthier physiologic pressure waveforms, steadier downstream flow and reduced energetic demands on the pump. These results provide experimental verification of Windkessel theory and support the need for a compliant mock aorta in the EVHP system.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239604PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549783PMC
November 2020

A Novel Right Ventricular Volume and Pressure Loaded Piglet Heart Model for the Study of Tricuspid Valve Function.

J Vis Exp 2020 07 28(161). Epub 2020 Jul 28.

Division of Pediatric Cardiology, Department of Pediatrics, University of Alberta.

Heart conditions in which the tricuspid valve (TV) faces either increased volume or pressure stressors are associated with premature valve failure. Mechanistic studies to improve our understanding of the underlying pathophysiology responsible for the development of premature TV failure are lacking. Due to the inability to conduct these studies in humans, an animal model is required. In this manuscript, we describe the protocols for a novel chronic recovery infant piglet heart model for the study of changes in the TV when placed under combined volume and pressure stress. In this model, volume loading of the right ventricle and the TV is achieved through the disruption of the pulmonary valve. Then pressure loading is accomplished through the placement of a pulmonary artery band. The success of this model is assessed at four weeks post intervention surgery through echocardiography, intracardiac pressure measurement, and pathologic examination of the heart specimens.
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http://dx.doi.org/10.3791/61251DOI Listing
July 2020

Discharge and Readmission to the Pediatric Cardiac ICU in Pediatric Patients With Durable Ventricular Assist Devices.

Pediatr Crit Care Med 2020 09;21(9):e810-e818

Department of Pediatric Cardiology, University of Alberta, Edmonton, AB, Canada.

Objectives: Pediatric patients implanted with a durable ventricular assist device are initially managed in the pediatric cardiac ICU but are eligible for discharge to the ward. Our objectives were to characterize discharge and readmission of ventricular assist device patients to the pediatric cardiac ICU, identify risk factors for readmission, and determine whether discharge or readmission is associated with mortality.

Design: Retrospective study.

Setting: Stollery Children's Hospital.

Patients: Patients implanted with a durable ventricular assist device at less than 18 years old between 2005 and 2016.

Interventions: None.

Measurements And Main Results: There were 44 patients who underwent ventricular assist device implantation at a median age of 3.7 years (interquartile range, 0.6-9.0 yr), with the most common etiology being noncongenital heart disease (76.7%). Median time of total ventricular assist device support was 110.0 days (interquartile range, 42.3-212.3 d) with the median index pediatric cardiac ICU stay being 34.0 days (interquartile range, 19.8-81.0 d). Thirty patients (68.0%) were discharged to the ward with 18 (60.0%) having at least one readmission. The median time to first readmission was 18.0 days (interquartile range, 14.8-109.8 d) with a median of two readmissions per patient (interquartile range, 1.0-3.0). The most common reason for readmission was pump thrombosis (30.4%), followed by neurologic dysfunction (23.9%). There were no statistically significant pre- or post-implant factors associated with readmission, and readmission was not associated with mortality (p = 0.600). Univariate Kaplan-Meier survival analysis indicated that use of pre-implant extracorporeal membrane oxygenation, post-implant continuous renal replacement therapy, as well as failure to be discharged from the index pediatric cardiac ICU stay were associated with mortality.

Conclusions: Readmissions to the pediatric cardiac ICU occurred in 60.0% of pediatric patients on durable ventricular assist devices with the first readmission occurring within a month of discharge from the index pediatric cardiac ICU stay. While readmission was not associated with mortality, lack of discharge from index pediatric cardiac ICU stay was likely due to a worse pre-implant clinical status.
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http://dx.doi.org/10.1097/PCC.0000000000002456DOI Listing
September 2020

End-Stage Liver Disease Models and Outcomes in Pediatric Patients Supported With Short-Term Continuous-Flow Ventricular Assist Devices.

ASAIO J 2020 08;66(8):933-938

Division of Pediatric Cardiology, University of Alberta, Alberta, Canada.

Short-term continuous-flow ventricular assist devices (STCF-VADs) are increasingly being utilized in pediatrics. End-stage liver disease (ELD) models have been associated with outcomes in adult patients on mechanical circulatory support. We sought to determine the relationship between outcomes in children on STCF-VADs and three ELD models: model for end-stage liver disease-excluding international normalized ratio (MELD-XI; all) and MELD-XI (> 1 year), PELD, and a novel score, PedMELD-XI. All patients (< 19 years) supported with STCF-VADs, between June 2009 and December 2016 were included. The MELD-XI, PELD, and PedMELD-XI scores were calculated and their association with adverse events and a composite measure of death, major bleeding, and neurologic dysfunction was analyzed. Of 32 patients, median age was 0.57 years (interquartile range [IQR], 0.10-4.43), median weight was 7.15 kg (IQR, 3.68-16.53), 53.1% had congenital heart disease, and 53.1% were male. In total, 78.1% patients experienced an adverse event (78.1% a major bleed, 25.0% neurologic dysfunction, and 15.6% death). The median MELD-XI score was 11.17 (IQR, 9.44-30.01), MELD-XI (>1 year) 9.44 (IQR, 9.44-24.33), PELD 6.00 (IQR, 4.00-13.75), and PedMELD-XI -14.91 (IQR, -18.85 to -12.25). A higher MELD-XI for all ages (13.80 vs. 9.44, p = 0.037) and less negative PedMELD-XI (-14.16 vs. -19.34, p = 0.028) scores were significantly associated with bleeding and the composite outcome. PedMELD-XI was significantly associated with death (-12.87 vs. -16.84, p = 0.041) while a trend was seen for increased MELD-XI in all ages being associated with death (31.52 vs. 10.11, p = 0.051). Last, there was no association with the models and neurologic events. MELD-XI and PedMELD-XI were significantly associated with major bleeding and the composite endpoints with PedMELD-XI also being associated with death. These results suggest that ELD models can be used to predict outcomes in this specific patient population, however, further analysis in a larger population is required.
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http://dx.doi.org/10.1097/MAT.0000000000001078DOI Listing
August 2020

A Low-Cost Perfusate Alternative for Ex Vivo Lung Perfusion.

Transplant Proc 2020 Dec 2;52(10):2941-2946. Epub 2020 Jul 2.

Division of Cardiac Surgery, Department of Surgery, University of Alberta, Edmonton, AB, Canada; Mazankowski Alberta Heart Institute, Edmonton, AB, Canada; Alberta Transplant Institute, Edmonton, AB, Canada; Canadian National Transplant Research Program, Edmonton, AB, Canada. Electronic address:

Background: Normothermic ex vivo lung perfusion (EVLP) has been used successfully to evaluate and recondition marginal donor lungs; however, multiple barriers continue to prevent its widespread adoption. We sought to develop a common hospital ingredient-derived perfusate (CHIP) with equivalent functional and inflammatory characteristics to a standard Krebs-Henseleit buffer with 8% serum albumin-derived perfusate (KHB-Alb) to improve access and reduce costs of ex vivo organ perfusion.

Methods: Sixteen porcine lungs were perfused using negative pressure ventilation (NPV) EVLP for 12 hours in a normothermic state and were allocated equally to 2 groups: KHB-Alb vs CHIP. Physiological parameters, cytokine profiles, and edema formation were compared between treatment groups.

Results: Perfused lungs in both groups demonstrated equivalent oxygenation (partial pressure of arterial oxygen/fraction of inspired oxygen ratio >350 mm Hg) and physiological parameters. There was equivalent generation of tumor necrosis factor-α and IL-6, irrespective of perfusate solution used, when comparing CHIP vs KHB-Alb. Pig lungs developed equivalent edema formation between groups (CHIP: 15.8 ± 4.8%, KHB-Alb 19.5 ± 4.4%, P > .05).

Conclusion: A perfusate derived of common hospital ingredients provides equivalent results to a standard Krebs-Henseleit buffer with 8% serum albumin-based perfusate in NPV-EVLP.
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http://dx.doi.org/10.1016/j.transproceed.2020.05.007DOI Listing
December 2020

Immunity and Stress Responses Are Induced During Ex Situ Heart Perfusion.

Circ Heart Fail 2020 06 5;13(6):e006552. Epub 2020 Jun 5.

Departments of Surgery (S. Hatami, X.Q., M.B., M.O., A.K., S. Himmat, J.N., D.H.F.), University of Alberta, Edmonton, Canada.

Background: Ex situ heart perfusion (ESHP) preserves the donated heart in a perfused, beating condition preventing cold storage-related ischemia and provides a platform to evaluate myocardial viability during preservation. However, myocardial function declines gradually during ESHP. Extracorporeal circulation systems are associated with the induction of systemic inflammatory and stress responses. Our aim was to evaluate the incidence of inflammation and induction of endoplasmic reticulum stress responses during an extended period of ESHP.

Methods: Cardiac function, myocardial tissue injury, markers of inflammation, oxidative stress, and endoplasmic reticulum stress were assessed in healthy pig hearts, perfused for 12 hours either in nonworking mode (non-WM=7) or working mode (WM, n=6).

Results: Cardiac function declined during ESHP but was significantly better preserved in the hearts perfused in WM (median 11-hour cardiac index/1-hour cardiac index: WM=27% versus non-WM=9.5%, =0.022). Myocardial markers of endoplasmic reticulum stress were expressed higher in ESHP hearts compared with in vivo samples. The proinflammatory cytokines and oxidized low-density lipoprotein significantly increased in the perfusate throughout the perfusion in both perfusion groups. The left ventricular expression of the cytokines and malondialdehyde was induced in non-WM, whereas it was not different between WM and in vivo.

Conclusions: Myocardial function declines during ESHP regardless of perfusion mode. However, ESHP in WM may lead to superior preservation of myocardial function and viability. Both inflammation and endoplasmic reticulum stress responses are significantly induced during ESHP and may contribute to the myocardial functional decline, representing a potential therapeutic target to improve the clinical donor heart preservation.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006552DOI Listing
June 2020

The effects of body mass index on outcomes for patients undergoing surgical aortic valve replacement.

BMC Cardiovasc Disord 2020 05 29;20(1):255. Epub 2020 May 29.

Division of Cardiac Surgery, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.

Background: Most of the studies of obesity and postoperative outcome have looked predominantly at coronary artery bypass grafting with fewer focused on valvular disease. The purpose of this study was to compare the outcomes of patients undergoing aortic valve replacement stratified by body mass index (BMI, kg/m^2).

Methods: The Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry captured 4780 aortic valve replacements in Alberta, Canada from January 2004 to December 2018. All recipients were stratified by BMI into five groups (BMI: < 20, 20-24.9, 25-29.9, 30-34.9, and > = 35). Log-rank test and Cox regression were used to examine the crude and adjusted survival differences.

Results: Intra-operative clamp time and pump time were similar among the five groups. Significant statistical differences between groups existed for the incidence of isolated AVR, AVR and CABG, hemorrhage, septic infection, and deep sternal infection (p < 0.05). While there was no significant statistical difference in the mortality rate across the BMI groups, the underweight AVR patients (BMI < 20) were associated with increased hazard ratio (1.519; 95% confidence interval: 1.028-2.245) with regards to all-cause mortality at the longest follow-up compared with normal weight patients.

Conclusion: Overweight and obese patients should be considered as readily for AVR as normal BMI patients.
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http://dx.doi.org/10.1186/s12872-020-01528-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256925PMC
May 2020

Current techniques and the future of lung preservation.

Cryobiology 2020 06 29;94:1-8. Epub 2020 Apr 29.

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, T6G 2R3, Canada; Centre for Innovation, Canadian Blood Services, 8249 114th Street, Edmonton, AB, T6G 2R8, Canada. Electronic address:

Although lung transplant remains the only option for patients suffering from end-stage lung failure, donor supply is insufficient to meet demand. Static cold preservation is the most common method to preserve lungs in transport to the recipient; however, this method does not improve lung quality and only allows for 8 h of storage. This results in lungs which become available for donation but cannot be used due to failure to meet physiologic criteria or an inability to store them for a sufficient time to find a suitable recipient. Therefore, lungs lost due to failure to meet physiological or compatibility criteria may be mitigated through preservation methods which improve lung function and storage durations. Ex situ lung perfusion (ESLP) is a recently developed method which allows for longer storage times and has been demonstrated to improve lung function such that rejected lungs can be accepted for donation. Although greater use of ESLP will help to improve donor lung utilization, the ability to cryopreserve lungs would allow for organ banking to better utilize donor lungs. However, lung cryopreservation research remains underrepresented in the literature despite its unique advantages for cryopreservation over other organs. Therefore, this review will discuss the current techniques for lung preservation, static cold preservation and ESLP, and provide a review of the cryopreservation challenges and advantages unique to lungs.
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http://dx.doi.org/10.1016/j.cryobiol.2020.04.009DOI Listing
June 2020

Addressing organ shortages: progress in donation after circulatory death for liver transplantation

Can J Surg 2020 03 20;63(2):E135-E141. Epub 2020 Mar 20.

From the Department of Surgery, Division of General Surgery, University of Alberta Hospital, Edmonton, Alta. (Nostedt, Shapiro, Bigam); the Department of Physiology, University of Alberta, Edmonton, Alta. (Freed); and the Department of Surgery, Division of Cardiac Surgery, University of Alberta, Alberta Heart Institute, Edmonton, Alta. (Freed).

Reducing wait list mortality among patients awaiting liver transplantation remains a substantial challenge because of organ shortage. In efforts to expand the donor pool there has been a trend toward increased use of donation after circulatory death (DCD) liver grafts. However, these marginal grafts are prone to higher complication rates, particularly biliary complications. In addition, many procured DCD livers are then deemed unsuitable for transplant. Despite these limitations, DCD grafts represent an important resource to address the current organ shortage, and as such there are research efforts directed toward improving the use of and outcomes for transplantation of these grafts. We review the current progress in DCD liver transplantation.
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http://dx.doi.org/10.1503/cjs.005519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828961PMC
March 2020

Maintaining the permanence principle for death during in situ normothermic regional perfusion for donation after circulatory death organ recovery: A United Kingdom and Canadian proposal.

Am J Transplant 2020 08 27;20(8):2017-2025. Epub 2020 Jan 27.

Department of Surgery, University of Cambridge, Cambridge, UK.

There is international variability in the determination of death. Death in donation after circulatory death (DCD) can be defined by the permanent cessation of brain circulation. Post-mortem interventions that restore brain perfusion should be prohibited as they invalidate the diagnosis of death. Retrieval teams should develop protocols that ensure the continued absence of brain perfusion during DCD organ recovery. In situ normothermic regional perfusion (NRP) or restarting the heart in the donor's body may interrupt the permanent cessation of brain perfusion because, theoretically, collateral circulations may restore it. We propose refinements to current protocols to monitor and exclude brain reperfusion during in situ NRP. In abdominal NRP, complete occlusion of the descending aorta prevents brain perfusion in most cases. Inserting a cannula in the ascending aorta identifies inadequate occlusion of the descending aorta or any collateral flow and diverts flow away from the brain. In thoracoabdominal NRP opening the aortic arch vessels to atmosphere allows collateral flow to be diverted away from the brain, maintaining the permanence standard for death and respecting the dead donor rule. We propose that these hypotheses are correct when using techniques that simultaneously occlude the descending aorta and open the aortic arch vessels to atmosphere.
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http://dx.doi.org/10.1111/ajt.15775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540256PMC
August 2020

Cryopreservation timing is a critical process parameter in a thymic regulatory T-cell therapy manufacturing protocol.

Cytotherapy 2019 12 3;21(12):1216-1233. Epub 2019 Dec 3.

School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada; BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Regulatory T cells (Tregs) are a promising therapy for several immune-mediated conditions but manufacturing a homogeneous and consistent product, especially one that includes cryopreservation, has been challenging. Discarded pediatric thymuses are an excellent source of therapeutic Tregs with advantages including cell quantity, homogeneity and stability. Here we report systematic testing of activation reagents, cell culture media, restimulation timing and cryopreservation to develop a Good Manufacturing Practice (GMP)-compatible method to expand and cryopreserve Tregs. By comparing activation reagents, including soluble antibody tetramers, antibody-conjugated beads and artificial antigen-presenting cells (aAPCs) and different media, we found that the combination of Dynabeads Treg Xpander and ImmunoCult-XF medium preserved FOXP3 expression and suppressive function and resulted in expansion that was comparable with a single stimulation with aAPCs. Cryopreservation tests revealed a critical timing effect: only cells cryopreserved 1-3 days, but not >3 days, after restimulation maintained high viability and FOXP3 expression upon thawing. Restimulation timing was a less critical process parameter than the time between restimulation and cryopreservation. This systematic testing of key variables provides increased certainty regarding methods for in vitro expansion and cryopreservation of Tregs. The ability to cryopreserve expanded Tregs will have broad-ranging applications including enabling centralized manufacturing and long-term storage of cell products.
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http://dx.doi.org/10.1016/j.jcyt.2019.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474528PMC
December 2019

Outcomes following bioprosthetic valve replacement in prior non-cardiac transplant recipients.

Clin Transplant 2019 11 13;33(11):e13720. Epub 2019 Oct 13.

Division of Cardiac Surgery, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.

Background: We report on overall survival and valve-related outcomes after bioprosthetic valve replacement in prior transplant recipients.

Methods: From January 2004 to December 2018, 20 consecutive patients (mean age 65.7-years, 90% male) with prior non-cardiac transplantation underwent bioprosthetic aortic (n = 18) or combined aortic and mitral (n = 2) valve replacement. Patients consisted of kidney (n = 14), lung (n = 2), liver (n = 3), and bone-marrow (n = 2) transplants with the most common indication for valve replacement being calcific degeneration (n = 12). Outcomes were measured over a 12-year span, with a median follow-up duration of 3.9 years.

Results: Overall survival at 30 days was 100% and at median follow-up was 60%. Acute kidney injury occurred in 50% (n = 10) with temporary dialysis required in 5% (n = 1) and 15% (n = 3) suffered respiratory failure. No patients experienced major bleeding, heart failure, or sternal wound infection. No patients required redo valve replacement during the study period.

Conclusions: Our results provide contemporary data demonstrating that patients with prior transplant can undergo bioprosthetic valve replacement with acceptable inhospital mortality rates and long-term survival, with a low rate of major morbidity. Furthermore, bioprosthetic valve replacement is a viable option in this group of patients with no redo valve replacement and acceptable long-term hemodynamic valvular function.
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http://dx.doi.org/10.1111/ctr.13720DOI Listing
November 2019

Mimicking "J-Shaped" and Anisotropic Stress-Strain Behavior of Human and Porcine Aorta by Fabric-Reinforced Elastomer Composites.

ACS Appl Mater Interfaces 2019 Sep 29;11(36):33323-33335. Epub 2019 Aug 29.

Department of Surgery , University of Alberta , Edmonton , Alberta T6G 2E1 , Canada.

An ex vivo heart perfusion device preserves the donor heart in a warm beating state during transfer between extraction and implantation surgeries. One of the current challenges includes the use of rigid and noncompliant plastic tubes, which causes injuries to the heart at the junction between the tissue and the tube. The compliant and rapidly strain-stiffening mechanical property that generates a "J-shaped" stress-strain behavior is necessary for producing the Windkessel effect, which ensures continuous flow of blood through the aorta. In this study, we mimic the J-shaped and anisotropic stress-strain behavior of human aorta in synthetic elastomers to replace the problematic noncompliant plastic tube. First, we assess the mechanical properties of human ( = 1) and porcine aorta ( = 14) to quantify the nonlinear and anisotropic behavior under uniaxial tensile stress from five different regions of the aorta. Second, fabric-reinforced elastomer composites were prepared by reinforcing silicone elastomers with embedded fabrics in a trilayer geometry. The knitted structures of the fabric provide strain-stiffening as well as anisotropic mechanical properties of the resulting composite in a deterministic manner. By optimizing the combination between different elastomers and fabrics, the resulting composites matched the J-shaped and anisotropic stress-strain behavior of natural human and porcine aorta. Finally, improved analytical constitutive models based on Gent's and Mooney-Rivlin's constitutive model (to describe the elastomer matrix) combined with Holzapfel-Gasser-Ogden's model (to represent the stiffer fabrics) were developed to describe the J-shaped behavior of the natural aortas and the fabric-reinforced composites. We anticipate that the suggested fabric-reinforced silicone elastomer composite design concept can be used to develop complex soft biomaterials, as well as in emerging engineering fields such as soft robotics and microfluidics, where the Windkessel effect can be useful in regulating the flow of fluids.
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http://dx.doi.org/10.1021/acsami.9b10524DOI Listing
September 2019

Total parenteral nutrition in ex vivo lung perfusion: Addressing metabolism improves both inflammation and oxygenation.

Am J Transplant 2019 12 11;19(12):3390-3397. Epub 2019 Sep 11.

Division of Cardiac Surgery, Department of Surgery, University of Alberta, Edmonton, AB, Canada.

Ex vivo lung perfusion (EVLP) protocols generally limit metabolic supplementation to insulin and glucose. We sought to determine whether the addition of total parenteral nutrition (TPN) would improve lung function in EVLP. Ten porcine lungs were perfused using EVLP for 24 hours and supplemented with insulin and glucose. In the treatment group (n = 5), the perfusate was also supplemented with a continuous infusion of TPN containing lipids, amino acids, essential vitamins, and cofactors. Physiologic parameters and perfusate electrolytes were continuously evaluated. Perfusate lactate, lipid and branch chain amino acid (BCAA) concentrations were also analyzed to elucidate how substrates were being utilized over time. Lungs in the TPN group exhibited significantly better oxygenation. Perfusate sodium was more stable in the TPN group. In the control group, free fatty acids (FFA) were quickly depleted, reaching negligible levels early in the perfusion. Alternatively, BCAA in the control group rose continually over the perfusion demonstrating a shift toward proteolysis for energy substrate. In the TPN group, both FFA and BCAA concentrations remained stable at in vivo levels after initial stabilization. TNF-α concentrations were lower in the TPN group. The addition of TPN in EVLP allows for better electrolyte composition, decreased inflammation, and improved graft performance.
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http://dx.doi.org/10.1111/ajt.15572DOI Listing
December 2019

Avoiding initial hypothermia does not improve liver graft quality in a porcine donation after circulatory death (DCD) model of normothermic perfusion.

PLoS One 2019 6;14(8):e0220786. Epub 2019 Aug 6.

Department of Surgery, Division of General Surgery, University of Alberta, Edmonton AB, Canada.

Background: Normothermic machine perfusion (NMP) of liver grafts donated after circulatory death (DCD) has shown promise in large animal and clinical trials. Following procurement, initial flush with a cold preservation solution is the standard of care. There is concern that initial cooling followed by warming may exacerbate liver injury, and the optimal initial flush temperature has yet to be identified. We hypothesize that avoidance of the initial cold flush will yield better quality liver grafts.

Methods: Twenty-four anaesthetized pigs were withdrawn from mechanical ventilation and allowed to arrest. After 60-minutes of warm ischemia to simulate a DCD procurement, livers were flushed with histidine-tryptophan-ketoglutarate (HTK) at 4°C, 25°C or 35°C (n = 4 per group). For comparison, an adenosine-lidocaine crystalloid solution (AD), shown to have benefit at warm temperatures in heart perfusions, was also used (n = 4 per group). During 12-hours of NMP, adenosine triphosphate (ATP), lactate, transaminase levels, and histological injury were determined. Bile production and hemodynamics were monitored continuously.

Results: ATP levels recovered substantially following 1-hour of NMP reaching pre-ischemic levels by the end of NMP with no difference between groups. There was no difference in peak aspartate aminotransferase (AST) or in lactate dehydrogenase (LDH). Portal vein resistance was lowest in the 4°C group reaching significance after 2 hours (0.13 CI -0.01,0.277, p = 0.025). Lactate levels recovered promptly with no difference between groups. Comparison to AD groups showed no statistical difference in the abovementioned parameters. On electron microscopy the HTK4°C group had the least edema with mean cell thickness of 2.92μm (p = 0.41) while also having the least sinusoidal dilatation with a mean diameter of 5.36μm (p = 0.04). For AD, the 25°C group had the lowest mean cell thickness at 3.14μm (p = 0.09).

Conclusions: Avoidance of the initial cold flush failed to demonstrate added benefit over standard 4°C HTK in this DCD model of liver perfusion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220786PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684160PMC
March 2020

Continuous Hemodialysis Does Not Improve Graft Function During Ex Vivo Lung Perfusion Over 24 Hours.

Transplant Proc 2019 Jul - Aug;51(6):2022-2028. Epub 2019 Jul 11.

Division of Cardiac Surgery, Department of Surgery, University of Alberta, Edmonton, AB, Canada; Mazankowski Alberta Heart Institute, Edmonton, AB, Canada; Alberta Transplant Institute, Edmonton, AB, Canada; Canadian National Transplant Research Program, Edmonton, AB, Canada. Electronic address:

Background: Extended periods of ex vivo lung perfusion (EVLP) lead to several inadvertent consequences including accumulation of lactate and increasing electrolyte concentrations in the perfusate. We sought to determine whether continuous hemodialysis (CHD) of the perfusate would be a suitable modality for improving ionic homeostasis in extended EVLP without compromising functional outcomes.

Methods: Twelve porcine lungs were perfused using EVLP for 24 hours. All lungs were ventilated with negative pressure ventilation. Lungs in the treatment group (n = 6) underwent continuous hemodialysis of the perfusate. Functional parameters, edema formation, and histopathologic analysis were used to assess graft function. Electrolyte and lactate profiles were also followed to assess the efficiency of hemodialysis.

Results: Lungs in both treatment and control groups demonstrated stable and acceptable oxygenation to 24 hours. Lungs demonstrated a decrease in compliance over time. There was no difference in oxygenation and compliance between groups. CHD-EVLP lungs had higher pulmonary vascular resistance and pulmonary artery pressures. Despite increased perfusion pressures, weight gain at both 11 and 23 hours was not different between groups. Perfusate sodium and lactate concentrations were significantly lower in the CHD-EVLP group.

Conclusion: The addition of continuous hemodialysis to EVLP did not improve graft function up to 24 hours despite improved maintenance of perfusate composition.
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http://dx.doi.org/10.1016/j.transproceed.2019.03.042DOI Listing
November 2019

Valve-Sparing Aortic Root Replacement 3 Decades After Repair of Aortico-Left Ventricular Tunnel.

Ann Thorac Surg 2020 01 19;109(1):e37-e39. Epub 2019 Jun 19.

Division of Cardiac Surgery, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Northern Alberta Adult Congenital Heart Program, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

Aortico-left ventricular tunnel is a rare congenital anomaly requiring surgical repair early in childhood. After corrective surgery, such patients are at risk of developing aortic insufficiency and aortic root dilatation. Herein, we describe a valve-sparing aortic root replacement 3 decades after the repair of aortico-left ventricular tunnel.
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http://dx.doi.org/10.1016/j.athoracsur.2019.04.092DOI Listing
January 2020

Clearance of transaminases during normothermic ex situ liver perfusion.

PLoS One 2019 24;14(4):e0215619. Epub 2019 Apr 24.

Department of Surgery, University of Alberta, Edmonton, Canada.

Background: One of the most promising applications of liver normothermic machine perfusion (NMP) is the potential to directly assess graft viability and injury. In most NMP studies, perfusate transaminases are utilized as markers of graft injury. Our aim was to further elucidate the metabolism of transaminases by healthy porcine livers during NMP, specifically whether such livers could clear circuit perfusate transaminases.

Methods: A highly concentrated transaminase solution was prepared from homogenized liver, with an aspartate aminotransferase (AST) level of 107,427 U/L. Three livers in the treatment group were compared to three controls, during 48 hours of NMP. In the treatment group, the circuit perfusate was injected with the transaminase solution to artificially raise the AST level to a target of 7,500 U/L. Perfusate samples were taken at two-hour intervals and analyzed for biochemistry until NMP end. Graft oxygen consumption and vascular parameters were monitored.

Results: Compared to controls, treated perfusions demonstrated abrupt elevations in transaminase levels (p>0.0001) and lactate dehydrogenase (LDH) (p>0.0001), which decreased over time, but never to control baseline. Liver function, as demonstrated by lactate clearance and oxygen consumption was not different between groups. The treatment group demonstrated a higher portal vein resistance (p = 0.0003), however hepatic artery resistance was similar. Treated livers had higher bile production overall (p<0.0001).

Conclusions: Addition of high levels of transaminases and LDH to a healthy porcine liver during ex situ perfusion results in progressive clearance of these enzymes, suggesting preserved liver metabolism. Such tolerance tests may provide valuable indicators of prospective graft function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215619PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481840PMC
January 2020
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