Donor Heart Procurement Research Articles

Revolutionizing Donor Heart Procurement: Innovations and Future Directions for Enhanced Transplantation Outcomes.

Heart failure persists as a critical public health challenge, with heart transplantation esteemed as the optimal treatment for patients with end-stage heart failure. However, the limited availability of donor hearts presents a major obstacle to meeting patient needs. In recent years, the most groundbreaking progress in heart transplantation has been in donor heart procurement, significantly expanding the donor pool and enhancing clinical outcomes. This review comprehensively examines these advancements, including the resurgence of heart donation after circulatory death and innovative recovery and evaluation technologies such as normothermic machine perfusion and thoraco-abdominal normothermic regional perfusion. Additionally, novel preservation methods, including controlled hypothermic preservation and hypothermic oxygenated perfusion, are evaluated. The review also explores the use of extended-criteria donors, post-cardiopulmonary resuscitation donors, and high-risk donors, all contributing to increased donor availability without compromising outcomes. Future directions, such as xenotransplantation, biomarkers, and artificial intelligence in donor heart evaluation and procurement, are discussed. These innovations promise to address current limitations and optimize donor heart utilization, ultimately enhancing transplantation success. By identifying recent advancements and proposing future research directions, this review aims to provide insights into advancing heart transplantation and improving patient outcomes.

Donor circadian clock influences the long-term survival of heart transplantation by immunoregulation.

Circadian clocks play important role in immunoregulation. We aimed to investigate cardiac circadian clock specific pathways and compare cardiac grafts procured at different timing on survival after transplantation to explore novel criteria for donor selection. In primate heart, phase set enrichment analysis (PSEA) showed rhythmic transcripts were enriched in antigen processing and presentation during activation of circadian rhythm. Digital sorting of immune cell composition and single-sample gene set enrichment analysis (ssGSEA) in unused donor transcriptomes showed the pathway, positive regulation of circadian rhythm significantly correlates with allograft rejection and antigen presentation pathways as well as with increased compositions of matured dendritic cell, CD4+ T cell, and naive B cell. Single-centre retrospective cohort of 390 adult heart transplants between 1 January 2015 and 31 December 2020 was used to generate a propensity score matching (PSM) cohort. Survival curve differed significantly showing inferior long-term survival when donor hearts were procured at activation group (12 pm to 12 am) compared to repression group (12 am to 12 pm) (6-year survival: 64.2% vs. 75.8%, P = 0.0065). Activation group was also associated with significantly higher rates of in-hospital death, cardiopulmonary resuscitation, and usage of mechanical circulatory support after heart transplantation compared to repression group. Furthermore, tendency for post-transplant free of rejection rates was higher in repression group compared to activation group (acute rejection, Gehan-Breslow P = 0.11 and 0.04; chronic rejection, Log rank P = 0.077 and 0.15, in full and PSM cohorts, respectively). Adjusted Cox regression analysis showed that activation group was associated with 2.20 times increased hazard of death (hazard ratio: 2.20; 95% confidence interval: 1.23-3.95; P = 0.008) compared to repression group. Circadian immunity may represent donor-related risk factors for cardiac allograft rejection through activating genes related to antigen presentation pathway and immune cells oscillation at specific time of day. Molecular circadian clock should be considered during retrieval of cardiac allografts in order to maximize graft durability.

Long-distance donor heart procurement using an innovative cold static storage system.

The global lack of donor shortage poses a major limitation for heart transplantation. New concepts with expanded donor inclusion criteria comprise extended transport distances and prolonged ischemic times with the aim of reaching a larger number of potential donors. Recent developments in cold storage solutions may allow more donor hearts with prolonged ischemic times to be use for transplantation in the future. We present our experience during a long-distance donor heart procurement with the longest reported transport distance and transport time in the current literature. This was made possible through the use of SherpaPak™, an innovative cold storage system which allows for controlled temperatures during transportation.

Ex Vivo Heart Perfusion for Cardiac Transplantation Allowing for Prolonged Perfusion Time and Extension of Distance Traveled for Procurement of Donor Hearts: An Initial Experience in the United States.

We retrospectively reviewed consecutive patients who received HT at our institution in the post-Food and Drug Administration approval period from May 1 to October 15, 2022. Patients were divided into 2 groups: OCS versus conventional technique. Baseline characteristics and outcomes were compared. A total of 21 patients received HT during this period, 8 using OCS and 13 conventional techniques. All hearts were from donation after brain death donors. The indication for OCS was an expected ischemic time of >4 h. Baseline characteristics in the 2 groups were comparable. The mean distance traveled for heart recovery was significantly higher in the OCS group (OCS, 845 ± 337, versus conventional, 186 ± 188 mi; P < 0.001), as was the mean total preservation time (6.5 ± 0.7 versus 2.5 ± 0.7 h; P < 0.001). The mean OCS time was 5.1 ± 0.7 h. In-hospital survival in the OCS group was 100% compared with 92.3% in the conventional group (P = 0.32). Primary graft dysfunction was similar in both groups (OCS 12.5% versus conventional 15.4%; P = 0.85). No patient in the OCS group required venoarterial extracorporeal membrane oxygenation support after transplant compared with 1 in the conventional group (0% versus 7.7%; P = 0.32). The mean intensive care unit length of stay after transplant was comparable. OCS allowed utilization of donors from extended distances that otherwise would not be considered because ischemic time would be prohibitive by conventional technique.

Keep Your Cool! One Year Outcomes with Use of a Hypothermic Preservation System Compared to Standard Storage with Ice During Heart Procurement

<h3>Purpose</h3> Traditionally, after procurement, donor hearts are cooled with ice during transport to the transplant center. However, this can lead to uneven cooling and can result in tissue injury, which may affect subsequent allograft function. The utilization of a hypothermic preservation system (SherpaPak, Paragonix) results in controlled and uniform cooling. This approach may enable longer-distance procurements and may result in better allograft function after transplant. <h3>Methods</h3> A single center study of heart transplantation using donor hearts transported on ice from 1/1/19-07/16/20 compared to a hypothermic preservation system (Sherpa) from 7/17/20-6/13/21. Patients were assessed for primary graft dysfunction (PGD), defined as requiring any mechanical circulatory support, length of stay (LOS) after transplant, graft function and one year survival. <h3>Results</h3> There were a total of 115 patients, 56 (49%) transported with Ice and 59 (51%) with Sherpa. There were no differences in recipient's baseline demographics: mean age (54 years), male (79%), and nonischemic (61%), but a higher use of LVAD in the Ice v Sherpa (18% v. 5%, p=0.03). Donor characteristics were similar: age (35 years), male (68%), white (59%), and cause of death (anoxia 38%, head trauma 41%, stroke 17%). The median post-transplant LOS was 20 days and not different between groups. Despite a longer ischemic time for the Sherpa v Ice transport (255 v. 230 minutes, p=0.021), there were no differences in incidence of PGD (17% v. 14%, p=0.69); median ejection fraction at 6 months (61%) and 12 months (61%); and 1 year patient survival (91% v. 95%, p=0.45), Figure 1a/b. <h3>Conclusion</h3> The use of a hypothermic preservation system results in similar one year patient survival and graft function, incidence of PGD, and hospital LOS, despite longer ischemic times. Use of this system safely enables more distant donor heart procurement.

Rethinking the Impact of Donor eGFR on Heart Transplant Outcomes

<h3>Purpose</h3> With limited evidence regarding the effect of donor renal function on outcomes post-cardiac transplant, this study sought to determine if donor eGFR has an impact on post-transplant outcomes in patients undergoing heart transplantation. <h3>Methods</h3> The UNOS Registry was queried for all cardiac transplant recipients and stratified into two groups by donor eGFR: eGFR >60 (high) or eGFR <60 (low). Baseline characteristics were compared via standard statistical analysis. Survival analysis was censored at 5-years using Kaplan-Meier analysis, and Cox proportional regression analysis was adjusted for age, sex, diabetes, race, ischemic time, dialysis, life support, waiting time, and HLA mismatch. <h3>Results</h3> 37205 subjects were grouped to high eGFR and 14892 subjects to low eGFR. Donors with low eGFR were more likely to be older (31.3 vs 32.9, p< 0.001). Recipients were more likely to be older (54.7 years vs 52.4, p<0.001) and male (77.2% vs 74.3% p<0.001). Compared to the high eGFR group, heart transplant recipients from donors in the low eGFR group showed no significant difference in mortality (p= 0.30) or causes of death (p= 0.054). Unadjusted analysis showed a hazard ratio of 0.978 (0.938-1.019 95% CI). Following adjustment, HR was 0.992 (0.948-1.039 95% CI). <h3>Conclusion</h3> Our study presents preliminary data to demonstrate cardiac donors with low eGFR have similar outcomes and life expectancy up to 60 months as compared to donors with high eGFR. With further research, there is an opportunity to expand the eligibility requirements for donor heart procurement and thereby increase the potential donor pool.

Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury.

Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular and extracellular pH, which can reach as low as 6.0 to 6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly affects cardiac function. We used genetic and pharmacologic methods to investigate the role of acid-sensing ion channel 1a (ASIC1a) in cardiac IRI at the cellular and whole-organ level. Human induced pluripotent stem cell-derived cardiomyocytes as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and postconditioning therapeutic agents. Analysis of human complex trait genetics indicates that variants in the ASIC1 genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using human induced pluripotent stem cell-derived cardiomyocytes in vitro and murine ex vivo heart models, we demonstrate that genetic ablation of ASIC1a improves cardiomyocyte viability after acute IRI. Therapeutic blockade of ASIC1a using specific and potent pharmacologic inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction and 2 models of ex vivo donor heart procurement and storage as clinical models to show that ASIC1a inhibition improves post-IRI cardiac viability. Use of ASIC1a inhibitors as preconditioning or postconditioning agents provided equivalent cardioprotection to benchmark drugs, including the sodium-hydrogen exchange inhibitor zoniporide. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors has no effect on cardiac ion channels regulating baseline electromechanical coupling and physiologic performance. Our data provide compelling evidence for a novel pharmacologic strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.

Effect of Donor Heart Preservation Temperature Monitoring Technology on Primary Graft Dysfunction and Outcomes in Heart Transplantation

<h3>Introduction</h3> Cardiac tissue preservation is an essential component of heart transplantation (HTx). Recently, The International Society for Heart and Lung Transplantation 2020 consensus statement on donor heart procurement recommended heart preservation at a temperature greater than 4°C, ideally between 5-10°C, to avoid freezing and subsequent irreversible myocardial cell damage. Paragonix Technologies Inc. SherpaPak (SP) (Boston, MA, USA) is a novel cardiac transport system with continuous, real-time temperature monitoring which allows for users to keep the recommended temperature for the duration of transport. The effect of SP technology has not been well described in the literature. We reviewed a series of cases at our single center to analyze the impact on primary graft dysfunction (PGD) and HTx outcomes. <h3>Case Report</h3> A review of 30 HTx cases at a single center since the first use of SP (November 2019 to October 2020) was conducted. Cases numbers of SP and ice in standard cooler box were 13 (43.3 %) and 17 (56.7%), respectively. There were no significant differences in pre-HTx donor and recipient characteristics except for donor heart ischemic time (SP 217.8 ± 14.7 vs. Ice 187.9 ± 44.0 minutes, p=0.03) (Table 1). There were no significant differences in PGD rates and length of stay metrics post-HTx. <h3>Summary</h3> In our case series, although mean donor ischemic time was 30 minutes longer on SP, post HTx outcomes including PGD rates were similar compared to traditional preservation methods. Further, larger studies are warranted to understand the potential benefits of this new technology.

Fiftieth anniversary of the first heart transplantation in Switzerland in the context of the worldwide history of heart transplantation.

On 3 December 1967, Christiaan Barnard performed the first heart transplantation in the world at Groote Schuur Hospital in Cape Town, South Africa. In the succeeding months, heart transplantations in the USA, Asia and Europe followed. On 14 April 1969, &Aring;ke Senning successfully accomplished the first heart transplantation in Switzerland at the former Cantonal Hospital in Zurich. In the summer of 1969, he undertook a second heart transplantation. Although the surgical procedure went well technically, both patients died within weeks to months after transplantation. Causes of death were infection in the first and rejection in the second patient. Senning&rsquo;s colleagues around the world had similar experiences. Survival after heart transplantation was unacceptably low. The heart transplant community recognised the lack of knowledge about immunological processes and appropriate immunosuppressive regimens as underlying reason for the early deaths. Most transplant centres decided to refrain from heart transplantation until sufficient immunological insight became available. After the introduction of the new immunosuppressive drug ciclosporin into the clinic and the availability of tools to monitor rejection in the early 1980s, heart transplant programmes were restarted all over the world. The legal recognition of brain death allowed procurement of donor hearts without exposure to warm ischaemia, and the principle of cold storage enabled prolongation of ischaemia time and acceptance of donors in distant hospitals, resulting in enlargement of the donor pool. In Switzerland, Marko Turina resumed heart transplantation in 1985 at Senning&rsquo;s former workplace in Zurich. The number of heart transplants in Switzerland and in the world grew rapidly because the outcome markedly improved. Particularly over the long-term, survival in Zurich surpassed the outcome worldwide. Zurich created internationally recognised milestones such as transplantation of patients with grown-up congenital heart disease, the implementation of the bicaval instead of the right atrial anastomosis during the transplant procedure and the dual transplantation of one heart. Since the middle of the 1990s, however, the number of heart transplants has plateaued, mainly because of donor shortage. The current era is characterised by efforts to increase the number of donors. The utilisation of marginal donors, the change from informed to presumed consent for organ donation and donation after cardiocirculatory-determined death have been proposed to augment the donor pool.

Does duration of donor brain injury impact heart transplantation outcomes?

We aimed to study the implications of pre-transplantation time intervals on HT outcomes. Brain injury time (BIT) was defined as the period from the donor brain injury to brain death declaration. Brain death interval (BDI) was defined as the period from brain death to application of an aortic cross-clamp during donor heart procurement. Allograft ischemia was defined as the time from donor aortic cross-clamp to aortic unclamping. End points included mortality and rejections. Between 1997 and 2017, we assessed 173 patients. Kaplan-Meier analyses showed that prolonged donor BIT, BDI, allograft ischemia, and total injury time had no significant effect on mortality and rejections. Patients were subdivided into short BIT (<97hours, n=87) and long BIT (≥97hours, n=86) groups. No differences in rejection scores nor in time to first rejection were noted. Kaplan-Meier analysis showed a similar long-term survival in the two groups. Sub-analysis of both groups according to their median BDI (12hours) revealed no differences in mortality or time to rejection. Pre-transplantation time intervals do not affect mortality or rejection. Our findings have important clinical implications regarding HT allocation and organ availability.

Extended distance cardiac allograft can successfully be utilized without impacting long-term survival

Despite the severe shortage of donor cardiac allografts, the general belief in worse outcomes with donors from prolonged distances has resulted in many centers greatly limiting the acceptable geographic distance of acceptable donors. However, with improvements in allograft preservation, it is likely that distance may be extended without compromising graft integrity. We hypothesized that recipients of appropriately selected allografts from greater distances would have equivalent long-term survival compared with recipients from closer geographic regions. We retrospectively analyzed the United Network for Organ Sharing (UNOS) adult heart transplant data from January 2000 to December 2013. Recipients were stratified by donor distance. Demographic and outcomes data were analyzed, with a primary end-point of survival. During the study period, 25,996 isolated orthotopic heart transplantations (OHTs) were performed. Patients were stratified by distance: 0 to 500 miles (n = 24,645); 501 to 1,000 miles (n = 1,201); 1,001 to 1,500 miles (n = 134); and 1,501+ miles (n = 16). Increased donor allograft distance correlated with significantly longer ischemic times (3.1 miles for 0 to 500 miles vs 7.5 hours for 1,501+ miles, p = 0.0001). One- and 5-year survival was similar in all cohorts, using Kaplan-Meier survival analysis (log rank, p = 0.8025). There was no difference in rate of stroke (p = 0.82), dialysis (p = 0.60) or reoperation (p = 0.28). Length of stay was equivalent across cohorts (p = 0.11). Appropriately selected allografts from donors at a greater distance should be considered to increase organ availability. Donor heart procurement from increased distance may not directly increase morbidity and mortality post-heart transplant.

Operative technique and pitfalls in donor heart procurement.

We describe a simple and reproducible donor heart procurement technique in sequential steps. A detailed understanding of procurement and organ preservation techniques should be an essential part of a heart transplant training program.

Donor pretreatment with adenosine monophosphate-activated protein kinase activator protects cardiac grafts from cold ischaemia/reperfusion injury.

Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy metabolism and has been shown to be protective in ischaemia/reperfusion injury (IRI). We hypothesized that preactivation of AMPK with an activator before donor heart procurement could protect heart grafts from cold IRI. Donor Sprague-Dawley rats were injected intravenously with AMPK activator 5-amino-imidazole-4-carboxamide ribonucleotide (AICAR) or vehicle 30 min before heart procurement. Heart grafts were then preserved in histidine-tryptophan-ketoglutarate (HTK) solution at 4°C for 8 h. After preservation, grafts were immediately mounted on the Langendorff perfusion system and perfused with Krebs-Henseleit buffer at 37°C for 1 h. Adenosine triphosphate (ATP) and malondialdehyde (MDA) content in graft tissue were quantified post-preservation and post-reperfusion. After reperfusion, isolated heart function was assessed using a pressure transducer; cumulative release of creatine kinase (CK) and lactate dehydrogenase (LDH) into the perfusate was measured to assess cardiomyocyte necrosis; ultrastructural changes in the mitochondria of the grafts were examined using transmission electron microscopy (TEM). After preservation, myocardial ATP content in the pretreated hearts was significantly higher than in the control hearts (3.247 ± 0.3034 vs 1.817 ± 0.2533 µmol/g protein; P < 0.05). AICAR-pretreated heart grafts exhibited significantly higher coronary flow (9.667 ± 0.3159 vs 8.033 ± 0.2459 ml/min; P < 0.05) and left ventricular developing pressure (58.67 ± 2.894 vs 42.67 ± 3.333 mmHg; P < 0.05) than the vehicle treated after reperfusion. Cumulative release of CK (300.0 ± 25.30 vs 431.7 ± 42.39 U/l; P < 0.05) and LDH (228.0 ± 16.68 vs 366.8 ± 57.41 U/l; P < 0.05) in the perfusate was significantly lower in the AICAR-pretreated group than that in the control group. Myocardial MDA content was also reduced in the pretreated group (0.5167 ± 0.1046 vs 0.9333 ± 0.1333 nmol/mg protein; P < 0.05). TEM suggested that the mitochondrial structure of AICAR-pretreated hearts was much better preserved. Moreover, AICAR-pretreated hearts significantly diminished cytosolic cytochrome c release after reperfusion. This study demonstrates that pretreatment with AMPK activator AICAR significantly protects heart grafts from extended cold IRI. This novel protocol may be useful and feasible in clinical heart transplantation.

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. Nonetheless, the heart is able to withstand limited periods of warm ischaemia, which could provide a window of opportunity for DCDD. Development of clinical approaches specifically for DCDD is critical for the exploitation of these organs, because current practices for donor heart procurement, evaluation, and storage have been optimized for conventional donation after brain death, without consideration of warm ischaemia before organ procurement. Establishment of clinical protocols and ethical and legal frameworks for DCDD of other organs is underway. This Review provides a timely evaluation of the potential for DCDD in heart transplantation.

The hurdles of providing mechanical circulatory support to children with congenital heart disease

We are now facing an increasing population of previously operated patients with congenital heart disease waiting for heart transplantation. Because of the shortage of donor organs, it is likely that the number of those requiring long-term VAD support will increase. In this perspective, reports such as the one from the team of Newcastle are essential to deepen our understanding of the best strategies to implement in this complex subset of patients [1]. The team is responsible for a large part of the UK population and has accumulated a large experience in this field. As such, we should pay great attention to their experience. They report an apparent success with bridge to heart transplantation with extracorporeal membrane oxygenator (ECMO). One should be aware that the excellence of the UK organization in the field of heart transplantation ensures a rapid procurement of donor hearts for those placed on urgent listing, a situation that cannot be matched everywhere. It has now been recognized that mortality of patients bridged to heart transplantation with ECMO is higher than the mortality of patients bridged with VAD [2, 3]. It has, therefore, now been recommended that patients waiting for transplantation on ECMO should be transitioned early to VAD, at the latest within 2 weeks of the initiation of the support [4, 5]. Their conclusion that patients with congenital heart disease can be successfully bridged to transplantation with mechanical support is in accordance with the recent statements of those sharing similar experience. However, the poor outcomes described in their patients with single-ventricle physiology do not seem to justify this conclusion. All of their patients supported for more than 8 days with VAD died and none of those supported for more than 15 days survived, which may be interpreted as a failure of this strategy. I believe that lessons can be taken from the Newcastle experience. A high proportion of their patients were supported from cardiac arrest, signing the severity of the clinical status of the patients at the time of support. The supported patients with single-ventricle physiology were young a likely sign that these patients had a primary failure of their univentricular circulation and one can suspect that a high proportion of them were supported as a rescue strategy from a failed procedure. We know that the use of VAD as a rescue strategy is associated with an extremely high mortality [6]. This high mortality should not prevent us from pursuing this strategy, but push us to implement support very early after a failed intervention, and probably only in selected patients. In our experience from Melbourne, the only patients to survive a VAD support after a failed surgery were supported within 3 days of their operation. Similarly, patients should be supported before cardiac arrest especially when they are bound to a univentricular circulation, as resuscitation will be less efficient in this instance. The poor outcomes encountered in supported patients with single ventricle should encourage us to support these patients earlier. We have been able to support 2 patients with failing Fontan circulation for one year and 6 months respectively and others have reported similar experience [7]. The report of Newcastle demonstrates that the support of patients with single ventricle is fraught with enormous difficulties, and highlights the fact that we have not identified yet the optimal management of these patients. We should, however, keep in mind that this goal can be achieved. It is certain that circulatory support will be the only option for an increasing number of these patients and it is our duty to make all attempts to improve their outcomes.

Criteria for Procurement of Donor Hearts: What Counts in Daily Practice of Coordinators?

Criteria for Procurement of Donor Hearts: What Counts in Daily Practice of Coordinators?

Abstract 255: A Normokalemic Nondepolarizing Cardioplegia Minimizes Myocardial Injury and Improves Cardiac Function in a Large Animal Model of Donation After Cardiocirculatory Death

Background: Procurement of donor hearts is typically preceded by delivery of a cold hyperkalemic cardioplegia (CP) that achieves arrest by depolarization of the membrane potential. This method has no intrinsic cardioprotective properties and may exacerbate ischemia-reperfusion (IR) injury. A tepid adenosine-lidocaine (AL) non-depolarizing CP has been shown to limit IR injury and improve myocardial functional recovery in a small animal model of orthotopic heart transplantation. We sought to determine the impact of AL CP on myocardial injury and function, in a porcine model of donation after cardio-circulatory death (DCD). Methods: Female Yorkshire pigs (60 kg) were subjected to a hypoxic cardiac arrest. Following a 15-minute standoff period donor hearts were procured, resuscitated ex-vivo, and transplanted into a recipient animal. Hearts in group 1 (N=7) were protected with a cold blood-Plegisol CP, perfused with a blood-crystalloid solution during ex-vivo assessment, and arrested with a cold blood-Plegisol CP prior to transplantation. Hearts in group 2 (N=5) were protected with a tepid AL-STEEN CP and perfused with a blood-STEEN solution in a continuous fashion during ex-vivo assessment and transplantation. Results: Animals in group 2 had a significantly longer ex-vivo perfusion time compared to those in group 1 (174±29 vs. 135±45 min, p&lt;0.05), yet they demonstrated significantly less weight gain (14±4 vs. 25±8 grams/hour, p&lt;0.05). Further, animals in group 2 exhibited less troponin I release during ex-vivo perfusion and had significantly better diastolic function following wean from cardiopulmonary bypass (left ventricular end-diastolic pressure volume relationship 0.115±0.052 vs. 0.508±0.223, p&lt;0.05). However, there was no significant difference in level of calpain activity between groups (171.3±68.6 vs. 140.12±50.6, p=0.36). Conclusion: A tepid non-depolarizing AL CP results in less myocardial edema during ex-vivo perfusion, minimizes myocardial injury, and improves diastolic function following transplantation of DCD hearts, but fails to eliminate the activation of calcium-dependent proteases. Further studies should investigate if a calpain inhibitor delivered at reperfusion could further minimize IR injury in DCD hearts.

Intermittent antegrade cardioplegia: isolated heart preservation with the Asporto heart preservation device

A major problem in procurement of donor hearts is the limited time a donor heart remains viable. After cardiectomy, ischemic hypoxia is the main cause of donor heart degradation. The global myocardial ischemia causes a cascade of oxygen radical formation that cumulates in an elevation in hydrogen ions (decrease in pH), irreversible cellular injury, and potential microvascular changes in perfusion. To determine the changes of prolonged storage times on donor heart microvasculature and the effects of intermittent antegrade perfusion. Using porcine hearts flushed with a Ribosol-based cardioplegic solution, we examined how storage time affects microvascular myocardial perfusion by using contrast-enhanced magnetic resonance imaging at a mean (SD) of 6.1 (0.6) hours (n = 13) or 15.6 (0.6) hours (n = 11) after cardiectomy. Finally, to determine if administration of cardioplegic solution affects pH and microvascular perfusion, isolated hearts (group 1, n = 9) given a single antegrade dose, were compared with hearts (group 2, n = 8) given intermittent antegrade cardioplegia (150 mL, every 30 min, 150 mL/min) by a heart preservation device. Khuri pH probes in left and right ventricular tissue continuously measured hydrogen ion levels, and perfusion intensity on magnetic resonance images was plotted against time. Myocardial perfusion measured via magnetic resonance imaging at 6.1 hours was significantly greater than at 15.6 hours (67% vs 30%, P = .00008). In group 1 hearts, the mean (SD) for pH at the end of 6 hours decreased to 6.2 (0.2). In group 2, hearts that received intermittent antegrade cardioplegia, pH at the end of 6 hours was higher at 6.7 (0.3) (P = .0005). Magnetic resonance imaging showed no significant differences between the 2 groups in contrast enhancement (group 1, 62%; group 2, 40%) or in the wet/dry weight ratio. Intermittent perfusion maintains a significantly higher myocardial pH than does a conventional single antegrade dose. This difference may translate into an improved quality of donor hearts procured for transplantation, allowing longer distance procurement, tissue matching, improved outcomes for transplant recipients, and ideally a decrease in transplant-related costs.

Intermittent Antegrade Cardioplegia: Isolated Heart Preservation with the Asporto Heart Preservation Device

A major problem in procurement of donor hearts is the limited time a donor heart remains viable. After cardiectomy, ischemic hypoxia is the main cause of donor heart degradation. The global myocardial ischemia causes a cascade of oxygen radical formation that cumulates in an elevation in hydrogen ions (decrease in pH), irreversible cellular injury, and potential microvascular changes in perfusion. To determine the changes of prolonged storage times on donor heart microvasculature and the effects of intermittent antegrade perfusion. Using porcine hearts flushed with a Ribosol-based cardioplegic solution, we examined how storage time affects microvascular myocardial perfusion by using contrast-enhanced magnetic resonance imaging at a mean (SD) of 6.1 (0.6) hours (n = 13) or 15.6 (0.6) hours (n = 11) after cardiectomy. Finally, to determine if administration of cardioplegic solution affects pH and microvascular perfusion, isolated hearts (group 1, n = 9) given a single antegrade dose, were compared with hearts (group 2, n = 8) given intermittent antegrade cardioplegia (150 mL, every 30 min, 150 mL/min) by a heart preservation device. Khuri pH probes in left and right ventricular tissue continuously measured hydrogen ion levels, and perfusion intensity on magnetic resonance images was plotted against time. Myocardial perfusion measured via magnetic resonance imaging at 6.1 hours was significantly greater than at 15.6 hours (67% vs 30%, P = .00008). In group 1 hearts, the mean (SD) for pH at the end of 6 hours decreased to 6.2 (0.2). In group 2, hearts that received intermittent antegrade cardioplegia, pH at the end of 6 hours was higher at 6.7 (0.3) (P = .0005). Magnetic resonance imaging showed no significant differences between the 2 groups in contrast enhancement (group 1, 62%; group 2, 40%) or in the wet/dry weight ratio. Intermittent perfusion maintains a significantly higher myocardial pH than does a conventional single antegrade dose. This difference may translate into an improved quality of donor hearts procured for transplantation, allowing longer distance procurement, tissue matching, improved outcomes for transplant recipients, and ideally a decrease in transplant-related costs.

Improved Poststorage Cardiac Function by Poly (ADP-ribose) Polymerase Inhibition: Role of Phosphatidylinositol 3-Kinase Akt Pathway

Inhibition of poly(ADP-ribose) polymerase 1 (PARP) has been shown to be effective in minimizing cardiac ischemia reperfusion injury. We investigated the cardioprotective effect of the PARP inhibitor, INO-1153, in isolated working rat hearts after 6 hr of hypothermic storage in Celsior. Hearts were treated with 1 muM INO-1153 before hypothermic storage, at cardioplegia and storage or after hypothermic storage. Hearts not exposed to INO-1153 served as controls. Another group was pretreated with the phosphatidylinositol 3-kinase inhibitor Wortmannin (0.1 muM) before storage in INO-1153-supplemented Celsior. After baseline measurement of aortic flow, heart rate, coronary flow, and cardiac output were obtained, hearts were arrested and stored in Celsior at 2-3 degrees C for 6 hr. After storage, hearts were reperfused for 15 min before performing work for a further 30 min, at which time poststorage indices of cardiac function were remeasured then heart tissue was stored at -80 degrees C for Western blot analysis. The presence of INO-1153 during prestorage perfusion or during cardioplegia and storage significantly improved poststorage cardiac function. Functional improvements produced by INO-1153 were completely abolished by Wortmnanin pretreatment. Western blots showed a significant increase in phospho-Akt in presence of INO-1153, which was inhibited by Wortmannin. Activation of the prosurvival phosphatidylinositol 3-kinase-Akt pathway was involved in the protective action of PARP inhibition in this model of donor heart procurement and hypothermic storage. Importantly for the logistics of clinical organ procurement, maximum protection is observed when the PARP inhibitor is included in the cardioplegic storage solution.