BACKGROUND:Heart transplantation (HT) from donation after circulatory death (DCD) donors has successfully expanded the donor pool with excellent short-term survival outcomes, but there is uncertainty regarding long-term outcomes. OBJECTIVES:This study compared 10-year patient survival and freedom from cardiac allograft vasculopathy (CAV) in recipients of DCD hearts with a contemporary cohort of recipients of hearts from donation after brain death (DBD) donors. METHODS:The study included consecutive heart transplant recipients at St Vincent's Hospital Sydney (Darlinghurst, New South Wales, Australia) from the commencement of the DCD heart transplant program in July 2014 until December 2024. Outcomes for recipients of DCD hearts (n = 118) vs DBD hearts (n = 385) were compared. DCD hearts were retrieved using a direct procurement protocol with normothermic machine perfusion. DBD hearts were retrieved with either static cold storage (n = 336) or hypothermic machine perfusion (n = 49). RESULTS:There were no significant differences in short- or long-term survival between DCD and DBD heart transplant recipients (1-year survival: 94% vs 88%; 10-year survival: 67% vs 64%, respectively; HR: 0.9 [95% CI: 0.5-1.4]; P = 0.5). The 10-year freedom from CAV was 61% and 41% for the DCD and DBD recipient groups, respectively (P = 0.5). There was no significant difference in the incidence of severe primary graft dysfunction when comparing DCD recipients with DBD recipients (14% vs 14%, respectively). Asystolic warm ischemic time was found to be the only retrieval-specific independent risk factor for severe primary graft dysfunction in DCD HT (OR: 1.4 [95% CI: 1.1-2.0]; P = 0.03). CONCLUSIONS:Heart transplant recipients from DCD donors have similar survival and freedom from CAV at 10 years post HT when compared with a contemporary cohort of recipients from DBD donors. These findings establish the long-term safety and efficacy of DCD HT.

Purpose: Heart transplantation from donation after circulatory death (DCD) donors has expanded the donor pool. Global experience with older DCD donor hearts is limited. In January 2018 our unit increased the DCD donor heart age limit from 40yrs to 55yrs. In this study we review the outcomes of heart transplants (HTs) from younger (age <40 yrs) versus older DCD heart donors (age >40yrs).

Purpose: The TransMedics OCS (Andover, MA, USA) normothermic machine perfusion (NMP) device has facilitated the procurement of donation after circulatory death (DCD) donor hearts, as well as marginal brain dead donor (BDD) hearts in our unit since 2014. The XVIVO Heart Box (Gothenburg, Sweden) hypothermic machine perfusion (HMP) was introduced to our unit in 2021 with the aim of overcoming prolonged BDD donor ischemic times (DIT). Australia is a geographically dispersed country and the use of machine perfusion enabled distant procurement.

Mitral annular calcification (MAC) is a major complicating factor in cardiac valve surgery, leading to increased difficulty and complexity in valve replacement. Utilisation of the Cavitron Ultrasonic Surgical Aspirator (CUSA) for annular decalcification has facilitated successful surgical intervention in the setting of severe calcific valve disease in patients who may have otherwise been deemed inoperable or had unsatisfactory surgical outcomes.

Heart transplantation from donation after circulatory death (DCD) donors has the potential to substantially increase overall heart transplant activity. The aim of this report is to review the first 8 y of our clinical heart transplant program at St Vincent’s Hospital Sydney, to describe how our program has evolved and to report the impact that changes to our retrieval protocols have had on posttransplant outcomes. Since 2014, we have performed 74 DCD heart transplants from DCD donors utilizing a direct procurement protocol followed by normothermic machine perfusion. Changes to our retrieval protocol have resulted in a higher retrieval rate from DCD donors and fewer rejections of DCD hearts during normothermic machine perfusion. Compared with our previously reported early experience in the first 23 transplants, we have observed a significant reduction in the incidence of severe primary graft dysfunction from 35% (8/23) to 8% (4/51) in the subsequent 51 transplant recipients (P < 0.01). The only withdrawal time interval significantly associated with severe primary graft dysfunction was the asystolic warm ischemic time: 15 (12–17) versus 13 (11–14) min (P < 0.05). One- and 5-y survival of DCD heart transplant recipients was 94% and 88%, comparable to that of a contemporary cohort of donation after brain death recipients: 87 and 81% (P-value was not significant). In conclusion, heart transplantation from DCD donors has become a major contributor to our overall transplant activity accounting for almost 30% of all transplants performed by our program in the last 2 y, with similar DCD and donation after brain death outcomes.

Donation after circulatory death is a technique utilising the heart from donors after withdrawal of life support and requires sustained circulatory cessation prior to organ retrieval. This unit was the first to perform heart transplants utilising distantly procured hearts from donation after circulatory death (DCD) donors in 2014.

Organ donation can take place after patient death, which is medically and legally defined in 1 of 2 manners: (1) irre-versible cessation of all brain function or (2) permanent cessation of circulation. Brain death is conventionally es-tablished by repeated neurological examinations demon-strating the absence of brain stem reflexes or absence of brain perfusion. Circulatory death is defined by the absence of a pulse determined by physical examination or by intra-arterial pressure monitoring. The first cardiac transplanta-tion was performed in 1967 by Christiaan Barnard in Cape Town, South Africa.1 Although this first transplant was performed using a DCD donor, after establishment of brain death criteria, the use of DCD hearts ceased because of the concerns regarding ischemic injury associated with circulatory death. Until recently, adult cardiac transplanta-tion has entirely used "heart beating" donation after brain death (DBD) donors. In this article, we describe recent re-newed application of DCD for cardiac transplantation, focusing on what has been learned and what areas warrant further investigation. The United States accounts for approximately half of the overall world heart transplant volume.2 Heart transplant volume in the United States using DBD donors has progres-sively increased over the last 5 years.3 This is partly due to the increased use of advanced age, hepatitis C positive, or otherwise marginal donors. In addition, the increased num-ber of heart transplants may result from greater availability of donors who die related to drug overdose. Likewise, the world heart transplant volume appears to be increasing pre-dominantly due to DBD donors.4 The Global Observatory on Donation and Transplantation reports 8722 transplants performed worldwide in 2019, a 5% increase in total numbers versus 2018.4 Waitlist mortality in the United States has progressively decreased over the last 5 years;

OBJECTIVES:To determine safety and feasibility of ex-situ coronary angiography.BACKGROUND:To cater for the perpetually growing demand for heart donors, interest in donation following circulatory death (DCD) has been rekindled. Further pursuit of donor pool expansion has led to eligibility extension to "marginal" donors who are at higher risk of coronary artery disease (CAD). Excluding CAD in potentially eligible DCD donors, for whom ante-mortem angiography is commonly not permitted, is therefore challenging. Ex-situ coronary angiography serves as an ethical and feasible diagnostic tool to assess for preclusive CAD.METHODS:We undertook a systematic review of the published literature and institutional retrospective review of case experience with ex-situ coronary angiography of donor hearts, supported by a portable organ care system.RESULTS:Combined literature and institutional case review yielded nine total cases of ex-situ coronary angiography of donor human hearts plus one experimental porcine model. Of the eight cases of ex-situ coronary angiography performed at our institute, all were conducted without complication or injury to the allograft. Two thirds of reported human cases have proceeded to successful transplantation.CONCLUSIONS:Diagnostic coronary angiography of the ex-situ beating donor heart is safe, feasible, and demonstrates novel clinical utility in mitigating subsequent transplantation of unsuitable allografts. In the setting of suspected coronary atherosclerosis of the donor heart, which may preclude favorable transplantation outcomes, ex-situ coronary angiography should be considered at eligible transplant centers.

Donation after circulatory death (DCD) is a technique utilising the heart from donors after withdrawal of life support and requires the donor to sustain circulatory cessation prior to organ retrieval. Our unit was the first to perform heart transplants utilising distantly procured hearts from DCD donors in 2014. We report the experience at our institution and lessons learnt throughout this period.The TransMedics™ organ care system (OCS) facilitated transportation of DCD hearts back to our hospital. The OCS allows for normothermic reperfusion, assessment and optimisation of the donor hearts. Donors were under 55 years of age, with no known history of cardiac disease. Originally, the time from withdrawal of life support to delivery of preservation fluid was mandated to be less than 30 minutes. In 2018 this was revised to commence once systolic arterial pressure is <90 mmHg. Evaluation of organ suitability for transplantation is determined by metabolic assessment of lactate extraction and reduction in the overall value over time, as well as visual assessment of the heart en route. To date our unit has retrieved 101 hearts and performed 73 DCD heart transplants. The average donor age was 32.5 ± 10.4 years (61 males and 12 females) with LVEF at referral 62 ± 5%. The average recipient age was 53.5 ± 12.8 years (61 males and 12 females) with LVEF 23 ± 10%. Median ICU stay was 5 (2-10) days and hospital stay 17.5 (11-27.6) days. The average time on the OCS was 279.4 ± 57.2 minutes. The 30 day survival was 97.2% and 6 month survival was 95.5%, with one early death secondary to complications from severe primary graft dysfunction.The application of ex-vivo perfusion to donor heart procurement has transformed cardiac transplantation by facilitating the use of a previously non-utilised source of donors and has contributed to an annual increase of 25% in heart transplant activity at our institution. To date our DCD heart procurement is safe and reproducible with early and mid-term outcomes comparable to those of traditional brain dead donors with 91% (86%) and 87% (81%) 1 and 5 year survival respectively.

Total arterial revascularization (TAR) is adopted to overcome late vein graft atherosclerosis, and occlusion. Uptake of TAR remains low despite reports suggesting superior survival. Previous studies primarily involved single sites and short-term follow-up. We report the influence of TAR on long-term survival in a large multicenter patient cohort.We reviewed 63,592 cases from an audited collaborative multicenter database. Of those, 34,181 consecutive patients undergoing first-time isolated coronary artery bypass (CABG) from 2001 to 2012 were studied. The data were linked to the National Death Index. We compared outcomes in patients who underwent TAR (n = 12,271) with outcomes in those who did not (n = 21,910). The influence of TAR on 10-year all-cause late mortality was assessed by propensity score analyses in 6,232 matched pairs.The 30-day mortality was 0.8% (96/12,271) for TAR patients and 1.8% (398/21,910) for non-TAR patients (p < 0.001). Late mortality was 7.5% (918/12,271) for TAR patients and 8.9% (1,952/21,910) for non-TAR patiets (p < 0.001). The mean follow-up time was 4.9 years. In the propensity-matched cohort, the perioperative mortality was 0.9% (53/6,232) for TAR patients versus 1.2% (76/6,232) for non-TAR patients (p < 0.001). Kaplan-Meier survival in the matched cohort at 1, 5, and 10 years was 97.2%, 91.3%, and 85.4% for TAR patients and 96.5%, 90.1%, and 81.2% for non-TAR patients (p < 0.001). Late mortality was 8.0% (n = 500) for TAR patients and 10.0% (n = 622) for non-TAR patients (p < 0.001). Stratified Cox proportional hazards models showed lower risk for all-cause late mortality in the TAR group (TAR:HR 0.80, 95% confidence interval 0.71 to 0.90, p < 0.001).TAR is associated with low perioperative mortality and, importantly, improved long-term survival and could be used more liberally.

Ischaemia-reperfusion injury (IRI) results in myocardial cell death and compromised cardiac function making it a leading risk factor for heart failure.

Background. Hearts from older donors or procured via donation after circulatory death (DCD) can alleviate transplant waitlist; however, these hearts are particularly vulnerable to injury caused by warm ischemic times (WITs) inherent to DCD. This study investigates how the combination of increasing donor age and pharmacologic supplementation affects the ischemic tolerance and functional recovery of DCD hearts and how age impacts cardiac mitochondrial respiratory capacity and oxidative phosphorylation. Methods. Wistar rats (12-, 18-, and 24-mo-old) were subjected to DCD with 20-min fixed WIT. Hearts were procured, instrumented onto a Langendorff perfusion circuit, flushed with Celsior preservation solution with or without supplementation (glyceryl trinitrate [GTN]/erythropoietin [EPO]/zoniporide [Z]) and perfused (Krebs-Henseleit buffer, 37°C Langendorff 30-min, working 30-min). Cardiac functional recovery of aortic flow (AF), coronary flow (CF), cardiac output (CO), and lactate dehydrogenase release were measured. Native heart tissue (3-, 12-, and 24-mo) were assessed for mitochondrial respiratory capacity. Results. Unsupplemented 18- and 24-month DCD hearts showed a 6-fold decrease in AF recovery relative to unsupplemented 12-month DCD hearts. GTN/EPO/Z supplementation significantly increased AF and CO recovery of 18-month DCD hearts to levels comparable to supplemented 12-month hearts; however, GTN/EPO/Z did not improve 24-month DCD heart recovery. Compared to 12-month heart tissue, 24-month hearts exhibited significantly impaired mitochondrial oxygen flux at complex I, II, and uncoupled maximal respiration stage. Conclusions. Reduced ischemic tolerance after DCD was associated with increasing age. Pharmacologic supplementation improves functional recovery of rat DCD hearts but only up to age 18 months, possibly attributed to a decline in mitochondrial respiratory capacity with increasing age.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Purpose: Primary Graft Dysfunction (PGD) is a leading cause of shortterm mortality after heart transplantation (HT).Available registries lack data to identify PGD based on post-HT hemodynamics and mechanical circulatory support (MCS).Herein, we describe the development of a multicenter International Consortium on PGD: a registry designed to quantify the incidence, risk factors, and impact of PGD, in order to develop contemporary risk prediction models.Methods: We are currently collecting data from 10 participating sites in Europe and North America which will include clinical data from an estimated 3,826 HT recipients (Table 1).We defined PGD using the ISHLT 2014 consensus criteria.Our complete consortium will include data on baseline donors and recipients demographics, pre and post-HT hemodynamics, and the type and duration of MCS after HT.We will use regression models and supervised machine learning (ML) algorithms to develop risk prediction models that reflect the contemporary landscape of HT.Endpoints: To date, we have collected preliminary data on 2,178 single-organ HT recipients between 2010 -2020 (57% of the anticipated final sample size).Our consortium cohort consists of patients with age of 54 § 12 years, of whom 24.7% (n=537) are female.Pre-transplant MCS included IABP in 3.6% (n=80), ECMO in 1.4% (n=30), and durable LVAD in 8.3% (n=181).Donor age was 37 § 13 years and ischemic time was 3.4 § 1.0 hours.A total of 167 (7.7%) recipients met criteria for severe PGD and 76 (6.5%) for moderate PGD.Oneyear survival was 67% (95% CI 59 -74%) and 93% (95% CI 92 -94%) in patients with and without severe PGD, respectively.We aim to develop contemporary tools for risk stratification of HT recipients for incident PGD.Our multicenter, international consortium allows for comprehensive phenotyping of HT recipients based upon a standardized definition of PGD to accurately understand PGD incidence, risk factors, and outcomes in the era of MCS.Interim Results: To date, we have collected 106 variables on 2,476 single-organ HT recipients from 2010 to 2020 (Figure 1A).Mean age of cohort is 53.9 ± 12.3 years; 25% female, 330 recipients from Canada, 518 from Europe, and 1628 from the US.Pre-transplant MCS included IABP in 8.4% (n=207), ECMO in 1.3% (n=33), and durable LVAD in 32.1% (n=795) (Figure 1B).Average donor age was 36.4 ± 13.0 years with mean ischemic time 3.4 ± 1.1 hours.A total of 214 (8.6%) of recipients met criteria for severe PGD, requiring VA-ECMO (n=186), RVAD (n=28), or both (n=3).Among 1811 patients with adequate follow up data, 1-year survival was 78% (95% CI 72% -83%) in patients with severe PGD, and 95% (95% CI 94% -96%) in those without severe PGD (Figure 1C).The previously-published RADIAL PGD risk score performed poorly in our cohort, with an AUC of 0.50 for severe PGD(Figure 1D).

Heart transplantation from donation after circulatory death (DCD) donors is a rapidly expanding practice. In this review, we describe the history and challenges of DCD heart transplantation and overview the procurement protocols and methods of limiting ischemic injury, current outcomes, and future directions. There are now at least three protocols that permit resuscitation and viability assessment of the DCD heart either in situ or ex situ. While the retrieval protocol for hearts from DCD donors will depend on local regulations, the outcomes of DCD heart transplant recipients reported to date are excellent regardless of the retrieval protocol and are comparable to the outcomes of heart transplant recipients from donation after brain death (DBD) donors. In the two centers with the largest published experience, DCD heart transplantation now accounts for one third of their heart transplant activity. With international trends indicating that there is an increasing utilisation of the DCD pathway, it is expected that DCD donors will become a major source of heart donation worldwide. J Heart Lung Transplant 2021;40:882-889 (c) 2021 International Society for Heart and Lung Transplantation. All rights reserved.

The persistent scarcity of donor allografts for transplantation has led to the acceptance of donors deemed 'marginal', due to factors such as older age, or indeed donor pathway. Ex situ organ perfusion or machine perfusion has evolved in the last decade as the primary technique utilised to facilitate the safe transplantation of such organs, traditionally often associated with higher rates of primary graft dysfunction, and subsequently, poor recipient outcomes. As well as having been demonstrated to permit the use of marginal brain dead donors with non-inferior outcomes, machine perfusion has also played a critical role in the development of heart transplant programs utilising donation after circulatory death donors. This represents a rapidly evolving area in heart transplantation, with over a decade of rigorous basic science research now translating into an increased quantity and quality of donor hearts for transplantation. Regardless of where future advances are made, current clinical experience and outcomes with marginal brain dead and donation after circulatory death donors has established ex situ perfusion and resuscitation of cardiac allografts as an invaluable tool in heart transplantation.

Supplementation of cardiac preservation solution with 10µM Empa yields significantly improved functional recovery after prolonged cold storage, with similar cardioprotective efficacy to the NHEI zoniporide. Given the approved clinical use of Empa, this study highlights its potential as a suitable alternative for NHEI in donor heart preservation.