pre-clinical-model-of-cardiac-donation-after-circulatory-death

Pre-clinical Model of Cardiac Donation after Circulatory Death

Cardiac transplantation demand is on the rise; nevertheless, organ availability is limited due to a paucity of suitable donors. Organ donation after ...

large-animal-model-donation-after-circulatory-death-normothermic

Large-Animal Model of Donation after Circulatory Death and Normothermic Regional Perfusion for Cardiac Assessment

The increase in demand for cardiac transplantation throughout the years has fueled interest in donation after circulatory death (DCD) to expand the organ ...

Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)

Université de Montréal

With limited resources, cardiac surgery is frequently cancelled due to lack of ICU beds. Immediate postoperative extubation (UFT) is performed in our hospital setting. The aim of the present study is to report patients undergoing off-pump aortocoronary bypass grafting (OPCABG) with immediate extubation and no ICU stay. Eighty-five patients undergoing OPCABG were included. UFT analgesia consisted of high thoracic epidural analgesia (n=65), or PCA morphine (n=20). Discharge criteria from PACU to cardiac ward were: alert, cooperative patient, respiratory rate <25/min, PaO(2)>80 mmHg and PaCO(2)<45 mmHg, temperature >36 degrees C, hemodynamic stability, no bleeding, no ischemia, and sufficient analgesia. More males (71/14) were included. Mean age was 63.4 years, NYHA class III, ejection fraction 59.4. Three grafts were performed in 119 min. Patients were extubated 12+/-2 min after closure. After 428 min in PACU, four patients did not meet ward criteria; three bradycardia requiring pacing, one elevated CK-MB. Two patients returned to the ICU, one for hypertension, and one for hypovolemia. Cardiac complications were: atrial fibrillation (29%), MI=2, bradycardia=3. During the same period, 304 OR-extubated patients spent 21+/-6 h in the ICU. The cost from leaving the OR until the patient reached the cardiac ward was 1265$ for ICU bypass patients vs. 6405$ for ICU patients, the difference representing 5140$ per patient. ICU bypass after OPCABG is safe. By avoiding ICU, this protocol reduces costs, improves resource utilization and may reduce OR cancellation due to ICU bed shortages.

Do patients after off-pump coronary artery bypass grafting need the intensive care unit? A prospective audit of 85 patients.

Images in cardiology. Acute chest pain due to ruptured giant aortocoronary saphenous vein graft aneurysm.

Because lung transplantation is the only effective therapy for terminal respiratory failure, the demand for donor lungs has increased steadily. However, the number of donors has remained fairly constant over the years, which results in an increasing duration of waiting for lung transplantation. To overcome the lack of organs, various strategies have been developed by transplant centers including use of marginal donors. To increase the lung utilization rate in multiorgan donors, we implemented a simple lung recruitment protocol involving a brief period of controlled sustained inflation. In 2005, the lung utilization rate in the transplant program at our institution was only 20% in multiorgan donors. With the lung recruitment protocol, the rate of lung utilization for transplantation increased to 33%, in 2006, 24% in 2007, and 24% in 2008. Following the lung recruitment protocol, the arterial oxygen tension/fraction of inspired oxygen ratio increased to greater than 15% in more than 40% of donors. We were able to improve gas exchange sufficiently that as many as two-thirds of the lungs were suitable for transplantation. During the protocol, no complications were reported, and no patient became hemodynamically unstable, precluding organ procurement. We believe that optimization of multiorgan donor management with simple interventions may improve oxygenation, reducing the number of inadequate donor lungs and increasing the overall donor pool and organ availability.

Pulmonary recruitment protocol for organ donors: a new strategy to improve the rate of lung utilization.

Principal limitation of cell therapy is cell loss after transplantation because of the interplay between ischemia, inflammation, and apoptosis. We investigated the mechanism of preconditioning of mesenchymal stem cells (MSCs) with oxytocin (OT), which has been proposed as a novel strategy for enhancing therapeutic potential of these cells in ischemic heart. In this study, we demonstrate that rat MSCs express binding sites for OT receptor and OT receptor transcript and protein as detected by RT-PCR and immunofluorescence, respectively. In response to OT (10(-10) to 10(-6) M) treatment, MSCs respond with rapid calcium mobilization and up-regulation of the protective protein kinase B (PKB or Akt) and phospho-ERK1/2 proteins. In OT-stimulated cells, phospho-Akt accumulates intracellularly close to the mitochondrial marker cytochrome c oxidase subunit 4. Functional analyses reveal the involvement of Akt/ERK1/2 pathways in cell proliferation, migration, and protection against the cytotoxic and apoptotic effects of hypoxia and serum deprivation. In addition, OT preconditioning increases MSC glucose uptake. Genes with angiogenic, antiapoptotic, and cardiac antiremodeling properties, such as heat shock proteins (hsps) HSP27, HSP32, HSP70, vascular endothelial growth factor, thrombospondin, tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, TIMP-3, and matrix metalloproteinase-2, were also up-regulated upon OT exposure. Moreover, coculture with OT-preconditioned MSC reduces apoptosis, as measured using terminal transferase dUTP nick end labeling assay in newborn rat cardiomyocytes exposed to hypoxia and reoxygenation. In conclusion, these results indicate that OT treatment evokes MSC protection through both intrinsic pathways and secretion of cytoprotective factors. Ex vivo cellular treatment with OT represents an attractive strategy aimed to maximize the biological and functional properties of effector cells.

Preconditioning of stem cells by oxytocin to improve their therapeutic potential.

Multidetector computed tomography (MDCT) scanners with current equipment allow for a rapid and robust noninvasive assessment of coronary artery bypass graft (CABG) anatomy and patency. With both appropriate expertise in MDCT techniques and knowledge in CABG imaging interpretation, radiologists should play an important and active role in the postoperative care of patients with bypass grafts. In this pictorial essay, we review the MDCT techniques and anatomy relevant to CABG imaging, interpretation pitfalls, some basic and advanced surgical designs, as well as postoperative graft complications in patients with CABG, with clinical illustrations from our local experience. 

Coronary artery bypass graft imaging with 256-slice MDCT: surgical concepts, current techniques, and interpretation.

Reply to Lobo Filho et al.

Stem cell (SC) therapy improves left ventricular function and dimensions in ischemic heart disease. Few small-scale trials have studied the effects of SC therapy on nonischemic cardiomyopathy (CMP), the leading cause of heart transplantation in the adults. The objectives were to gain a better insight into the effects of SC therapy for nonischemic CMP by conducting a systematic review of the literature and meta-analysis of randomized controlled trials.

Stem cell therapy for the treatment of nonischemic cardiomyopathy: a systematic review of the literature and meta-analysis of randomized controlled trials.

After ischemic injury, the endogenous repair mechanisms of the human heart are insufficient for meaningful tissue regeneration, so muscle lost is replaced by noncontractile scar tissue. Current treatments for ischemic cardiomyopathy improve quality of life and increase life expectancy, but cannot cure the underlying disease of cardiomyocyte loss. Cellular transplantation is emerging as a valuable therapeutic approach to heal the ischemic heart. Adult bone marrow stem cells are capable of differentiation, regeneration of infarcted myocardium, and induction of myogenesis and angiogenesis, ultimately leading to improved contractility. Positive results from animal studies have prompted several clinical trials to ascertain the safety and feasibility of cell therapy. However, despite all the excitement in stem cell research resulting from initial experimental data and preliminary clinical trials, the mixed results observed have raised many unanswered questions. A major obstacle to the identification of the optimal cell therapy is that the fate of the implanted cells and the nature of their beneficial effects are ill-defined. A better understanding is fundamental for the development of new therapeutic agents, and to optimize stem cell applications. Well-designed and powered double-blinded randomized studies are clearly needed to confirm promising findings from early studies. With several ongoing randomized trials directed toward evaluation of stem cell therapies in patients with acute or chronic ischemic cardiomyopathy, the Canadian initiative represents a milestone. 

The current state of stem cell therapeutics: Canadian approaches in the international context.

The use of cardiopulmonary bypass (CPB) during coronary artery bypass graft surgery (CABG) is associated with a systemic inflammatory response, resulting in altered microcirculation. The aim of this study was to evaluate whether beating heart surgery can preserve the microcirculation.

Microcirculatory response during on-pump versus off-pump coronary artery bypass graft surgery.

The heart which has limited renewal and regenerative capacity is a prime target for cellular therapy. Stem cell transplantation has emerged as a promising therapeutic strategy to improve healing of the ischemic heart, repopulate the injured myocardium, and restore cardiac function. However, clinical usefulness is impacted by the quality and quantity of delivered cells, the suboptimal manipulations prior to transplantation, and the general poor viability of the cells transferred particularly to an ischemic microenvironment. Focus is now on developing new ways to enhance stem cell renewal and survival capacity before transplant. This can be done by physical, chemical, pharmacological, or genetic manipulation of cells followed by accurate evaluation of conditioning methods by validated tests.This chapter covers the proper handling of mesenchymal stem cells (human and rat lines) and methodologies to evaluate efficacy and the translational potential of conditioning methods. Specifically, we will cover stem cell culture methods, preconditioning protocols, viability assessment in hypoxic and oxidative challenges as encountered in an ischemic microenvironment, and the proliferative capacity of cells.

Optimization of Mesenchymal Stem Cells to Increase Their Therapeutic Potential.

The IMPACT-CABG trial is the first North American multicenter phase II randomized study of intramyocardial delivery of autologous CD133 stem cells in patients with chronic ischemic cardiomyopathy undergoing coronary artery bypass grafting. The primary objective was to demonstrate safety, including freedom from major adverse cardiac events. The secondary objective was to evaluate feasibility of same-day autologous cell preparation. Although the trial was not powered to evaluate LV function, exploratory data were collected.

The IMPACT-CABG trial: A multicenter, randomized clinical trial of CD133 stem cell therapy during coronary artery bypass grafting for ischemic cardiomyopathy.

Organ donation after circulatory death (DCD) is a potential solution for the shortage of suitable organs for transplant. Heart transplantation using DCD donors is not frequently performed due to the potential myocardial damage following warm ischemia. Heat shock protein (HSP) 90 has recently been investigated as a novel target to reduce ischemia/reperfusion injury. The objective of this study is to evaluate an innovative HSP90 inhibitor (HSP90i) as a cardioprotective agent in a model of DCD heart.

Novel heat shock protein 90 inhibitor improves cardiac recovery in a rodent model of donation after circulatory death.

Ischemia-reperfusion associated with prolonged warm ischemia during donation after circulatory death (DCD) induces acute lung injury. The objective of this study was to combine ex vivo lung perfusion (EVLP) and a heat shock protein-90 inhibitor (HSP90i) to recondition DCD organs and prevent primary graft dysfunction.

ArticleTotal : 2	Year
Publication title Cited by 4	2019
Publication title Cited by 6	2022

Article	Year
Do patients after off-pump coronary artery bypass grafting need the intensive care unit? A prospective audit of 85 patients. Interactive cardiovascular and thoracic surgery\| PubMed ID: 18024492	2008
Images in cardiology. Acute chest pain due to ruptured giant aortocoronary saphenous vein graft aneurysm. The Canadian journal of cardiology\| PubMed ID: 19214290	2009
Pulmonary recruitment protocol for organ donors: a new strategy to improve the rate of lung utilization. Transplantation proceedings\| PubMed ID: 19857731	2009
Preconditioning of stem cells by oxytocin to improve their therapeutic potential. Endocrinology\| PubMed ID: 23024264	2012
Coronary artery bypass graft imaging with 256-slice MDCT: surgical concepts, current techniques, and interpretation. Clinical imaging\| PubMed ID: 24976306	2014
Reply to Lobo Filho et al. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery\| PubMed ID: 25035413	2015
Stem cell therapy for the treatment of nonischemic cardiomyopathy: a systematic review of the literature and meta-analysis of randomized controlled trials. The Canadian journal of cardiology\| PubMed ID: 25138483	2014
The current state of stem cell therapeutics: Canadian approaches in the international context. The Canadian journal of cardiology\| PubMed ID: 25249498	2014
Microcirculatory response during on-pump versus off-pump coronary artery bypass graft surgery. Perfusion\| PubMed ID: 26091812	2016
Optimization of Mesenchymal Stem Cells to Increase Their Therapeutic Potential. Methods in molecular biology (Clifton, N.J.)\| PubMed ID: 27236678	2016
The IMPACT-CABG trial: A multicenter, randomized clinical trial of CD133 stem cell therapy during coronary artery bypass grafting for ischemic cardiomyopathy. The Journal of thoracic and cardiovascular surgery\| PubMed ID: 27665225	2016
Novel heat shock protein 90 inhibitor improves cardiac recovery in a rodent model of donation after circulatory death. The Journal of thoracic and cardiovascular surgery\| PubMed ID: 32354629	2022
HSP90 Inhibitor Improves Lung Protection in Porcine Model of Donation After Circulatory Arrest. The Annals of thoracic surgery\| PubMed ID: 32652069	2020

Nicolas Noiseux

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