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Experience in donation after circulatory-determined death (DCD) heart transplantation (HTx) is expanding. There is limited information on the functional outcomes of DCD HTx recipients. We sought to evaluate functional outcomes in our cohort of DCD recipients. We performed a single-center, retrospective, observational cohort study comparing outcomes in consecutive DCD and donation after brain death (DBD) HTx recipients between 2015 and 2019. Primary outcome was allograft function by echocardiography at 12 and 24 months. Secondary outcomes included incidence of cardiac allograft vasculopathy, treated rejection, renal function, and survival. Seventy-seven DCD and 153 DBD recipients were included. There was no difference in left ventricular ejection fraction at 12 months (59% vs 59%, P = .57) and 24 months (58% vs 58%, P = .87). There was no significant difference in right ventricular function at 12 and 24 months. Unadjusted survival between DCD and DBD recipients at 5 years (85.7% DCD and 81% DBD recipients; P = .45) was similar. There were no significant differences in incidence of cardiac allograft vasculopathy (odds ratio 1.59, P = .21, 95% confidence interval 0.77-3.3) or treated rejection (odds ratio 0.60, P = .12, 95% confidence interval 0.32-1.15) between DBD and DCD recipients. Post-transplant renal function was similar at 1 and 2 years. In conclusion, cardiac allografts from DCD donors perform similarly to a contemporary population of DBD allografts in the medium term., Competing Interests: Disclosure The authors of this manuscript have conflicts of interest to disclose, as described by the American Journal of Transplantation. S. Messer and S.R. Large have applied for a patent for organ perfusion system and methods. S.R. Large has a patent awarded for apparatus for testing, assessment and maintenance of procured hearts for transplantation. Remaining authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The United Kingdom (UK) was one of the first countries to pioneer heart transplantation from donation after circulatory death (DCD) donors. To facilitate equity of access to DCD hearts by all UK heart transplant centers and expand the retrieval zone nationwide, a Joint Innovation Fund (JIF) pilot was provided by NHS Blood and Transplant (NHSBT) and NHS England (NHSE). The activity and outcomes of this national DCD heart pilot program are reported., Methods: This is a national multi-center, retrospective cohort study examining early outcomes of DCD heart transplants performed across 7 heart transplant centers, adult and pediatric, throughout the UK. Hearts were retrieved using the direct procurement and perfusion (DPP) technique by 3 specialist retrieval teams trained in ex-situ normothermic machine perfusion. Outcomes were compared against DCD heart transplants before the national pilot era and against contemporaneous donation after brain death (DBD) heart transplants, and analyzed using Kaplan-Meier analysis, chi-square test, and Wilcoxon's rank-sum., Results: From September 7, 2020 to February 28, 2022, 215 potential DCD hearts were offered of which 98 (46%) were accepted and attended. There were 77 potential donors (36%) which proceeded to death within 2 hours, with 57 (27%) donor hearts successfully retrieved and perfused ex situ and 50 (23%) DCD hearts going on to be transplanted. During this same period, 179 DBD hearts were transplanted. Overall, there was no difference in the 30-day survival rate between DCD and DBD (94% vs 93%) or 90 day survival (90% vs 90%) respectively. There was a higher rate of ECMO use post-DCD heart transplants compared to DBD (40% vs 16%, p = 0.0006), and DCD hearts in the pre pilot era, (17%, p = 0.002). There was no difference in length of ICU stay (9 DCD vs 8 days DBD, p = 0.13) nor hospital stay (28 DCD vs 27 DBD days, p = 0.46)., Conclusion: During this pilot study, 3 specialist retrieval teams were able to retrieve DCD hearts nationally for all 7 UK heart transplant centers. DCD donors increased overall heart transplantation in the UK by 28% with equivalent early posttransplant survival compared with DBD donors., Competing Interests: Disclosure The authors have no conflicts of interest to declare. This research was funded by the National Health Service Blood and Transplant and National Health Service England., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Background: In an effort to address the increasing demand for heart transplantation within the United Kingdom (UK), we established a clinical program of heart transplantation from donation after circulatory-determined death (DCD) donors in 2015. After 5 years, we report the clinical early outcomes and impact of the program., Methods: This is a single-center, retrospective, matched, observational cohort study comparing outcomes of hearts transplanted from DCD donors from March 1, 2015 to February 29, 2020 with those from matched donation after brain death (DBD) donors at Royal Papworth Hospital (RPH) (Cambridge, UK). DCD hearts were either retrieved using thoracoabdominal normothermic regional perfusion or the direct procurement and perfusion technique. All DBD hearts were procured using standard cold static storage. The primary outcomes were recipient 30-day and 1-year survival., Results: During the 5-year study, DCD heart donation increased overall heart transplant activity by 48% (79 for DCD and 164 for DBD). There was no difference in survival at 30 days (97% for DCD vs 99% for DBD, p = 1.00) or 1 year (91% for DCD vs 89% for DBD, p = 0.72). There was no difference in the length of stay in the intensive care unit (7 for DCD vs 6 for DBD days, p = 0.24) or in the hospital (24 for DCD vs 25 for DBD days, p = 0.84)., Conclusions: DCD heart donation increased overall heart transplant activity at RPH by 48%, with no difference in 30-day or 1-year survival in comparison with conventional DBD heart transplantations. DCD heart donation is set to make a dramatic difference in the number of patients who can benefit from heart transplantation., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Patients waitlisted for and recipients of solid organ transplants (SOT) are perceived to have a higher risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and death; however, definitive epidemiological evidence is lacking. In a comprehensive national cohort study enabled by linkage of the UK transplant registry and Public Health England and NHS Digital Tracing services, we examined the incidence of laboratory-confirmed SARS-CoV-2 infection and subsequent mortality in patients on the active waiting list for a deceased donor SOT and recipients with a functioning SOT as of February 1, 2020 with follow-up to May 20, 2020. Univariate and multivariable techniques were used to compare differences between groups and to control for case-mix. One hundred ninety-seven (3.8%) of the 5184 waitlisted patients and 597 (1.3%) of the 46 789 SOT recipients tested positive for SARS-CoV-2. Mortality after testing positive for SARS-CoV-2 was 10.2% (20/197) for waitlisted patients and 25.8% (154/597) for SOT recipients. Increasing recipient age was the only variable independently associated with death after positive SARS-CoV-2 test. Of the 1004 transplants performed in 2020, 41 (4.1%) recipients have tested positive for SARS-CoV-2 with 8 (0.8%) deaths reported by May 20. These data provide evidence to support decisions on the risks and benefits of SOT during the coronavirus disease 2019 pandemic., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: In response to a growing number of patients on the UK urgent heart transplant waiting list, the UK donor heart allocation scheme was revised in October 2016 with the introduction of a new super-urgent category. Patients with temporary mechanical circulatory support (tMCS) became eligible for super-urgent registration. The aim of this study was to compare activity, indications, and outcomes before and after the change., Methods: Data on adult (aged ≥16 years) heart transplant registrations and recipients in the 2 years before (Era 1: July 1, 2014-June 30, 2016) and after (Era 2: January 2017-December 2018) the introduction of the new scheme were extracted from the UK Transplant Registry and analyzed using competing risks analysis, Kaplan-Meier analysis, and Cox proportional-hazards regression., Results: There were 525 waiting-list registrations in Era 1 and 594 in Era 2, including 14% super-urgent registrations, with 90% having some form of tMCS. Median waiting time to transplant was 41 days for all urgent registrations in Era 1 compared with 17 days for super-urgent registrations and 71 days for urgent registrations in Era 2. Numbers of non-urgent transplants were not affected. Deaths on the waiting list significantly decreased from 5% to 2% at 6 months between Era 1 and Era 2 (adjusted hazard ratio = 0.29, 95% CI = 0.13-0.62). In addition, total number of patients with tMCS were not different between both eras, suggesting no significant change in this area of clinical decision making. Post-transplant survival at 1 year for super-urgent recipients was not significantly different from post-transplant survival at 1 year for other categories., Conclusions: The Introduction of a super-urgent heart allocation scheme in the UK reduces waiting time to transplant for the sickest patients, with comparable post-transplant survival while reducing deaths on the waiting list., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Despite the successes from refined peri-operative management techniques and immunosuppressive therapies, antibodies remain a serious cause of morbidity and mortality for patients both before and after heart transplantation. Patients awaiting transplant who possess antibodies against human leukocyte antigen are disadvantaged by having to wait longer to receive an organ from a suitably matched donor. The number of pre-sensitized patients has been increasing, a trend that is likely due to the increased use of mechanical circulatory support devices. Even patients who are not pre-sensitized can go on to produce donor-specific antibodies after transplant, which are associated with worse outcomes. The difficulty in managing antibodies is uncertainty over which antibodies are of clinical relevance, which patients to treat, and which treatments are most effective and safe. There is a distinct lack of data from prospective trials. An international consensus conference was organized and attended by 103 participants from 75 centers to debate contentious issues, determine the best practices, and formulate ideas for future research on antibodies. Prominent experts presented state-of-the-art talks on antibodies, which were followed by group discussions, and then, finally, a reconvened session to establish consensus where possible. Herein we address the discussion, consensus points, and research ideas., (Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Acute cellular rejection (ACR) is a common complication in the first year after heart transplantation (HT). Routine surveillance for ACR is undertaken by endomyocardial biopsy (EMB). Measurement of cardiac troponins (cTn) in serum is an established diagnostic test of cardiac myocyte injury. This systematic review aimed to determine whether cTn measurement could be used to diagnose or exclude ACR., Methods: PubMed, Google Scholar and the JHLT archive were searched for studies reporting the result of a cTn assay and a paired surveillance EMB. Significant ACR was defined as International Society for Heart and Lung Transplantataion (ISHLT) Grade ≥3a/≥2R. Considerable heterogeneity between studies precluded quantitative meta-analysis. Individual study sensitivity and specificity data were examined and used to construct a pooled hierarchical summary receiver-operator characteristic (ROC) curve., Results: Twelve studies including 993 patients and 3,803 EMBs, of which 3,729 were paired with cTn levels, had adequate data available for inclusion. The overall rate of significant ACR was 12%. There was wide variation in diagnostic performance. cTn assays demonstrated sensitivity of 8% to 100% and specificity of 13% to 88% for detection of ACR. The positive predictive value (PPV) was low but the negative predictive value (NPV) was relatively high (79% to 100%). High-sensitivity cTn assays had greater sensitivity and NPV than conventional cTn assays for detection of ACR (sensitivity: 82% to 100% vs 8% to 77%; NPV: 97% to 100% vs 81% to 95%, respectively)., Conclusions: cTn assays do not have sufficient specificity to diagnose ACR in place of EMB. However, hs-cTn assays may have sufficient sensitivity and negative predictive value to exclude ACR and limit the need for surveillance EMB. Further research is required to assess this strategy., (Copyright © 2018 International Society for the Heart and Lung Transplantation. All rights reserved.)

Background: The requirement for heart transplantation is increasing, vastly outgrowing the supply of hearts available from donation after brain death (DBD) donors. Transplanting hearts after donation after circulatory-determined death (DCD) may be a viable additive alternative to DBD donors. This study compared outcomes from the largest single-center experience of DCD heart transplantation against matched DBD heart transplants., Methods: DCD hearts were retrieved using normothermic regional perfusion (NRP) or direct procurement and perfusion (DPP). During NRP, perfusion was restored to the arrested heart within the donor with the exclusion of the cerebral circulation, whereas DPP hearts were removed directly. All hearts were maintained on machine perfusion during transportation. A retrospective cohort of DBD heart transplants, matched for donor and recipient characteristics, was used as a comparison group. The primary outcome measure of this study (set by the United Kingdom regulatory body) was 90-day survival., Results: There were 28 DCD heart transplants performed during the 25-month study period. Survival at 90 days was not significantly different between DCD and matched DBD transplant recipients (DCD, 92%; DBD, 96%; p = 1.0). Hospital length of stay, treated rejection episodes, allograft function, and 1-year survival (DCD, 86%; DBD, 88%; p = 0.98) were comparable between groups. The method of retrieval (NRP or DPP) was not associated with a difference in outcome., Conclusions: These results suggest that heart transplantation from DCD heart donation provides comparable short-term outcomes to traditional DBD heart transplants and can serve to increase heart transplant activity in well-selected patients., (Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: After a severe shortage of brain-dead donors, the demand for heart transplantation has never been greater. In an attempt to increase organ supply, abdominal and lung transplant programs have turned to the donation after circulatory-determined death (DCD) donor. However, because heart function cannot be assessed after circulatory death, DCD heart transplantation was deemed high risk and never adopted routinely. We report a novel method of functional assessment of the DCD heart resulting in a successful clinical program., Methods: Normothermic regional perfusion (NRP) was used to restore function to the arrested DCD heart within the donor after exclusion of the cerebral circulation. After weaning from support, DCD hearts underwent functional assessment with cardiac-output studies, echocardiography, and pressure-volume loops. In the feasibility phase, hearts were transported perfused before evaluation of function in modified working mode extracorporeally. After the establishment of a reliable assessment technique, hearts with demonstrable good function were then selected for clinical transplantation., Results: NRP was instituted in 13 adult DCD donors, median age of 33 years (interquartile range [IQR], 28-38 years), after a median ischemic time from withdrawal to perfusion of 24 minutes (IQR, 21-29; range, 17-146 minutes). Two of 4 hearts in the feasibility phase were unsuitable for transplantation after functional assessment. Nine DCD hearts were transplanted in the clinical phase, with 100% survival. The median intensive care duration was 5 days (IQR, 4-5 days), with 2 patients requiring mechanical support. There were no episodes of rejection (total, 1,436 patient-days; range, 48-297). During the same period, we performed 20 standard heart transplants using brain-dead donors., Conclusions: NRP allows rapid reperfusion and functional assessment of the DCD donor heart, ensuring only viable hearts are selected for transplantation. This technique minimizes the risk of primary graft dysfunction and maximizes confidence in DCD heart transplantation, realizing a 45% increase in our heart transplant activity., (Copyright © 2016. Published by Elsevier Inc.)

Sirolimus is a potent immunosuppressant agent that has utility in solid-organ transplantation (SOT), particularly for its renal-sparing effects. However, lung toxicity can be a significant issue and a variety of different lung injury patterns have been described. We report an unrecognized association of sirolimus with lung cavitation in patients who have undergone cardiothoracic transplantation. Between 1996 and 2010, lung and heart transplant patients received sirolimus-based immunosuppression as a second-line agent after initial therapy with calcineurin inhibitors. All cases of sirolimus-induced lung cavities were recorded and a retrospective review of the case notes of these patients was undertaken. A total of 9 patients were identified. Clinical symptoms, time to first cavity and mean levels were variable. Some patients showed complete resolution, whereas others had persistent cavitatory lung lesions. Patients who developed persistent lung cavities had a worse outcome than those who did not have cavitation., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Although the world of advanced heart failure has intensely focused its spotlight on mechanical circulatory support, the field of heart transplantation has continued to evolve. We highlight the latest clinical and laboratory research that have affected the field of adult heart transplantation. Major scientific and clinical advances in the field of heart transplantation have focused on expanding the donor pool, refining the use of immunosuppression, and monitoring the effects of therapy., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Most deaths in the first 30 days after cardiac transplantation are due to failure of the donor heart, often with the clinical picture of right ventricular failure. Indeed, there is a significant reduction in contractility of the human donor heart and loss of contractile reserve before and soon after transplantation. This myocardial insult appears in association with brain death in the donor and follows a "catecholamine storm" associated with a rapidly rising intracranial pressure. Microscopy of the myocardium in organ donors shows a picture typical of catecholamine-induced injury and similar to changes found in endomyocardial specimens of stress cardiomyopathy (catecholamine-induced cardiomyopathy, or Takotsubo cardiomyopathy). There are 3 common features between stress cardiomyopathy and the heart of a brain-dead donor: exposure of the heart to unusually high catecholamine levels, ventricular dysfunction, and prompt recovery. Stress cardiomyopathy is a temporary myocardial dysfunction that has been described after sub-arachnoid hemorrhage, traumatic head injury, pheochromocytoma, acute emotional distress, exogenous administration of catecholamines, and non-related surgery. Given the common features of this catecholamine-mediated myocardial insult, we ask if brain-dead donor heart dysfunction is an extreme variant of stress cardiomyopathy? And, if so is it, like stress cardiomyopathy, reversible? Can we therefore expect recovery of the dysfunctional donor heart over time, thereby permitting increased use of hearts offered for transplantation?, (Copyright 2010 International Society for Heart and Lung Transplantation. All rights reserved.)

Tumor necrosis factor (TNF) utilizes two receptors, TNFR1 and 2, to initiate target cell responses. We assessed expression of TNF, TNFRs and downstream kinases in cardiac allografts, and compared TNF responses in heart organ cultures from wild-type ((WT)C57BL/6), TNFR1-knockout ((KO)), TNFR2(KO), TNFR1/2(KO) mice. In nonrejecting human heart TNFR1 was strongly expressed coincidentally with inactive apoptosis signal-regulating kinase-1 (ASK1) in cardiomyocytes (CM) and vascular endothelial cells (VEC). TNFR2 was expressed only in VEC. Low levels of TNF localized to microvessels. Rejecting cardiac allografts showed increased TNF in microvessels, diminished TNFR1, activation of ASK1, upregulated TNFR2 co-expressed with activated endothelial/epithelial tyrosine kinase (Etk), increased apoptosis and cell cycle entry in CM. Neither TNFR was expressed significantly by cardiac fibroblasts. In (WT)C57BL/6 myocardium, TNF activated both ASK1 and Etk, and increased both apoptosis and cell cycle entry. TNF-treated TNFR1(KO) myocardium showed little ASK1 activation and apoptosis but increased Etk activation and cell cycle entry, while TNFR2(KO) myocardium showed little Etk activation and cell cycle entry but increased ASK1 activation and apoptosis. These observations demonstrate independent regulation and differential functions of TNFRs in myocardium, consistent with TNFR1-mediated cell death and TNFR2-mediated repair.

Background: The pre-transplant serum level of soluble CD30 (sCD30), a proteolytic derivative of the lymphocyte surface receptor CD30, has been suggested as a biomarker for immunologic risk after organ transplantation., Methods: Pre-transplant serum sCD30 levels were determined in 200 consecutive adult heart transplant recipients undertaken at a single center. Transplant outcome (acute rejection in the first 12 months and patient survival up to 5 years post-transplant) was determined., Results: Patients treated with a left ventricular assist device (LVAD) prior to transplantation (n = 28) had higher levels of sCD30 (median 64 U/ml, range 12 to 112 U/ml) than those (n = 172) with no LVAD (median 36 U/ml, range 1 to 158 U/ml, p < 0.0001). Recipients were categorized according to whether sCD30 levels were "low" (lower quartile, <24 U/ml, n = 50), "intermediate" (24 to 58 U/ml, n = 100) or "high" (upper quartile, >58 U/ml, n = 50). Neither acute rejection nor recipient survival differed according to sCD30 level, with values (mean +/- SEM) of 0.30 +/- 0.04, 0.23 +/- 0.03 and 0.30 +/- 0.05 acute rejection episodes per 100 days in the low, intermediate and high groups, respectively, with recipient survival rates at 1 year of 77.7%, 84.9% and 86% and at 5 years of 73.6%, 67.9% and 75.8%, respectively., Conclusions: Pre-transplant serum sCD30 level does not predict acute allograft rejection or recipient survival after heart transplantation, although sCD30 levels are increased by LVAD, possibly as a result of biomaterial-host immune interaction.

Objectives: The Levitronix CentriMag ventricular assist device (VAD) is a centrifugal pump designed for short-term extracorporeal support in cardiogenic shock. The aim of this study is to report our clinical experience with the Levitronix CentriMag for uni- and biventricular support., Methods: Between July 2004 and December 2006, 27 patients were supported using the Levitronix CentriMag device. Nineteen were male. Mean age was 47.9 (range 19 to 72) years. Indications for support at implantation were cardiogenic shock that included: end-stage heart failure and too ill to undergo transplantation, with questionable neurologic status (9 subjects); right ventricular failure after left VAD (LVAD) implantation (5 subjects); post-cardiotomy status (7 subjects); and acute donor graft failure after heart transplantation (6 subjects)., Results: Post-VAD 30-day survival was 30% (8 patients). Mean support time was 11 days for all patients (range 1 to 51 days). Mean support time for 14 Levitronix biventricular VADs was 11 (range 1 to 51) days. Mean support time for 7 Levitronix LVADs was 13.7 (range 1 to 30) days. The highest survival rates after Levitronix support were after donor graft failure (50%) and after cardiotomy (42%). Levitronix right VAD (RVAD) support after long-term LVAD insertion incurred 100% hospital mortality. Of those who survived, 8 patients were discharged home after VAD support and remain alive to date. Two patients were bridged to primary and another bridged to repeat heart transplantation. Five patients were weaned to recovery. Re-operation for bleeding occurred in 8 patients, clinical evidence of cerebral thromboembolism in 3, overwhelming sepsis in 1, and aortic thrombus formation in 1. Clot formation in the tubing was observed in 1 patient, necessitating emergent replacement at bedside, which was successful., Conclusions: The Levitronix CentriMag system is a reliable and facile temporary circulatory support system as a bridge to decision in patients with refractory acute cardiogenic shock.

Background: Everolimus is an immunosuppressive agent that reduces cardiac allograft vasculopathy. This report presents the 24-month results of a multicenter trial of everolimus vs azathioprine in heart transplantation., Methods: A total of 634 patients were randomized to receive 1.5 mg everolimus, 3 mg everolimus or azathioprine, with cyclosporine and steroids. A 12-month, double-blind, double-dummy period was followed by a 12-month open-label period., Results: At 24 months, the percentage of patients reaching the composite efficacy end-points was significantly lower with everolimus (1.5 mg: 45.9%, p = 0.016; 3 mg: 36.0%, p < 0.001) than with azathioprine (57.5%). The change in maximal intimal thickness from baseline to 24 months was significantly smaller with everolimus 1.5 mg (0.07 mm, p = 0.014) and 3 mg (0.06 mm, p = 0.004) compared with azathioprine (0.15 mm). The 24-month incidence of vasculopathy was 33.3% with everolimus 1.5 mg, 45.5% with everolimus 3 mg and 58.3% with azathioprine (p = 0.017 vs everolimus 1.5 mg). Incidence of cytomegalovirus infection was 3-fold lower in patients receiving everolimus compared with azathioprine (7.2% and 7.1% in the 1.5-mg and 3-mg everolimus cohorts, respectively, and 21% in the azathioprine group; p < 0.0001). Median serum creatinine levels at 24 months were higher with everolimus than with azathioprine, but decreased when cyclosporine exposure was reduced (everolimus 1.5 mg: baseline 167 micromol, after 6 months 157.5 micromol; everolimus 3 mg: baseline 185.6 micromol, after 6 months 160 micromol; azathioprine: baseline 123.3 micromol, after 6 months 127 micromol)., Conclusions: Everolimus significantly reduced acute rejection and limited the progression of allograft vasculopathy at 24 months compared with azathioprine. Although graft and patient survival was comparable at 24 months, everolimus therapy may improve longer-term outcomes after heart transplantation.

Background: We examined waiting time for adult heart transplantation in the UK and sought to determine whether recipients with particular ABO blood groups were disadvantaged., Methods: Data were obtained from the National Transplant Database. Registration outcome data were analyzed for 622 new, non-urgent, adult, heart-only registrations from April 1, 1999 to March 31, 2003. Unadjusted waiting times of the 618 first registrations were summarized using Kaplan-Meier estimates., Results: Death rates were relatively low, with no significant difference in the proportions of patients among the different blood groups who died while waiting. A smaller proportion of blood group O patients were transplanted at 1 year after registration, with a significant difference in waiting time to transplant between blood groups (p < 0.0001). Blood group A and AB patients were generally transplanted sooner than O and B patients, with median waiting times of 81 days (95% CI: 67 to 114) and 76 days (95% CI: 52 to 178) vs 214 days (95% CI: 162 to 308) and 174 days (95% CI: 78 to 249), respectively., Conclusions: Although no particular blood group was disadvantaged in terms of mortality on the heart transplant list, blood group O and B patients waited significantly longer for transplantation. The difference was at least partly due to a large proportion of blood group O hearts being used for non-O patients. To address this imbalance, the UK Transplant Cardiothoracic Advisory Group (CTAG) changed the allocation protocol, so that "out-of-zone" offers of blood group O donors for non-urgent patients are now restricted to O and B recipients.

Background: Acute rejection increases the inflammatory burden of the transplanted organ and predisposes to cardiac allograft vasculopathy (CAV). In this study we aim to determine the magnitude of the association, and to differentiate between the effects of mild vs severe rejection episodes., Methods: Between 1988 and 2003, 489 1-year survivors of heart transplantation underwent 1,435 angiograms. These patients were classified as having no CAV (0% stenosis), mild/moderate CAV (<70%) or severe CAV (>70%). Acute rejection was considered either mild (Grades 1A, 1B and 2 untreated) or moderate/severe (Grade 2 treated on a clinical basis and Grades 3A, 3B and 4). We used multi-state Markov models to examine risk factors for the onset of CAV., Results: Expressed as relative risk, the onset of CAV was significantly increased by donor age (1.26 per 10 years, 95% confidence interval [CI] 1.12 to 1.42), male recipient (1.72, 95% CI 1.01 to 2.94), pre-transplant recipient ischemic disease (1.53, 95% CI 1.14 to 2.06) and cumulative number of moderate/severe rejections (1.10 per episode, 95% CI 1.03 to 1.18). Human leukocyte antigen (HLA) and cytomegalovirus (CMV) matching, donor gender, recipient age, smoking, cumulative CMV infections and mild rejections were not significant risk factors. Estimated annual onset rate of CAV was 11.3% for patients with no moderate/severe rejection, rising to 13.6% for those with two and 18.0% for those with five such rejections., Conclusions: Acute moderate/severe cellular rejection has a cumulative impact on CAV onset, whereas mild, untreated rejection is not associated with CAV.

Background: Over 50,000 heart transplants have been performed in the last 3 decades. The global shortage of donor organs and the relaxation of candidate selection criteria over time has resulted in recent controversy about the benefits of heart transplantation for some risk groups. We assessed the survival benefit acquired in the Papworth Hospital heart transplant population overall, taking into account resuscitated marginal donors and high-risk recipients., Methods: All heart transplant patients listed between 1979 and June 2002 were analyzed (n = 1,212). Of these, 931 cardiac transplantations were done, including the use of 126 marginal donors. High-risk recipients (n = 163) were defined as patients being in the hospital, on intravenous inotropic drugs, and/or with a high transpulmonary gradient (>15 mm Hg). Using Cox regression with transplantation as a time-dependent covariate, we assessed the survival benefit of transplantation. In our model we assumed that after transplantation the initial risk of death is high relative to continued waiting, followed by an exponential decline in risk. The crossover point (COP) is the time at which the risk of death after transplantation is equal to that of continued waiting (i.e., the relative risk is 1). The equity point (EP) determines the time at which the early post-operative risk is offset by the later period of lower risk and, therefore, the time at which transplantation has a survival advantage., Results: Overall, the COP was at 54 days and EP at 141 days. In the marginal donor sub-group, COP was achieved at 32 days with EP at 72 days, indicating a survival benefit. The difference in the COP and EP between the borderline donor and normal donor sub-groups was not statistically significant. Post-transplant survival was not significantly different from recipients of normal cardiac allografts (p = .43). Likewise, for the high-risk recipient group, the COP and EP were at 72 and 203 days. Although post-op survival was significantly shorter than the normal-risk group, both groups achieved survival benefits., Conclusion: Heart transplantation provides survival benefit in these risk groups of recipients in our population. This is a reflection of our active donor management protocol and rigorous donor and recipient selection process.

Background: To ascertain survival of ischemic advanced heart failure patients by treatment allocation, we examined the outcome of transplant assessment patients allocated to medical therapy, high-risk conventional surgery, or transplantation., Methods: Patients were identified from the Papworth transplant database and excluded if primary etiology was not ischemic. Grouping was undertaken according to treatment allocation at initial assessment, and analysis was performed by intention to treat. Survival was computed from the time of assessment and Cox regression used to stratify patients according risk with the Heart Failure Survival Score., Results: From May 1993 to September 2001, a total of 755 patients were admitted for transplant assessment, with 348 (46.1%) identified as having heart failure of ischemic origin. Variables required for calculation of the Heart Failure Survival Score was available in 273 patients (78.4%), and 20 patients (7.3%) were lost to follow-up. Of the remaining 253 patients, 89 (35.2%) were allocated to medical therapy, 32 (12.6%) to surgery, and 132 (52.2%) to transplantation. The relative risk (95% confidence limit) of death compared with medical therapy was 0.62 (0.28, 1.40) for surgery and 0.38 (0.24, 0.61) for transplantation in medium- to high-risk patients. For low-risk patients, the relative risks for death compared with medical therapy were 1.87 (0.63, 5.60) for surgery and 1.97 (0.79, 4.96) for transplantation., Conclusions: Transplantation improved survival of medium- and high-risk patients compared with medical therapy. In the low-risk group, this was not evident. However, repeated assessment of risk is required because the hazard for death rises steadily after the third year in these patients.

Background: According to International Society for Heart and Lung Transplantation (ISHLT) data, the 30-day survival after heart transplantation has continually improved from 84% (1979-85) to 91% (1996-2001). This has probably been achieved by better donor/recipient selection, along with improved surgical technique and immunosuppressive therapy. On the other hand, the data concerning the early causes of death after cardiac transplantation is incomplete, because in 25% of cases, an unknown cause is listed. This study investigated the incidence and causes of 30-day mortality (determined by postmortem studies) after cardiac transplantation and assessed the possibility of improvements., Methods: A retrospective study of all patients who underwent heart transplantation at Papworth Hospital from 1979 to June 2001 (n = 879) and who died within 30 days of surgery was carried out. Postmortem examination data were available for all patients., Results: The mean (standard deviation) recipient and donor ages were 46 (12) and 31 (12) years, respectively. Overall, the 30-day mortality was 8.5% (n = 75), 12.1% for the 1979 to 1985 period and 6.9% for the 1996 to 2001 period. The primary causes of death were graft failure (30.7%), acute rejection (22.7%) (1.3% for the 1996-2001 era), sepsis (18.7%) gastrointestinal problems (bowel infarction and pancreatitis; (9.3%), postoperative bleeding (6.7%), and other (12%)., Conclusions: Our 30-day mortality compares favorably with the data from the ISHLT registry, with great improvement in the early mortality. Acute rejection is no longer a major cause of early mortality. Further reduction may be achieved by a better protection of the donor heart against the effects of brainstem death and ischemic injuries. However, the quest to improve early outcome should not be at the expense of needy patients by being overselective.

Background: The deleterious effects of brainstem death (BSD) on donor cardiac function and endothelial integrity have been documented previously. Domino cardiac donation (heart of a heart-lung recipient transplanted into another recipient) is a way to avoid the effects of brainstem death and may confer both short- and long-term benefits to allograft recipients., Methods: This study evaluates short- and long-term outcome in heart recipients of BSD donors (cadaveric) as compared with domino hearts explanted from patients who underwent heart-lung transplantation., Results: Patients having undergone cardiac transplantation between April 1989 and August 2001 at Papworth Hospital were included (n = 571). Domino donor hearts were used in 81 (14%) of these cases. The pre-operative transpulmonary gradient was not significantly different between the two groups (p = 0.7). There was no significant difference in 30-day mortality (4.9% for domino vs 8.6% for BSD, p = 0.38) or in actuarial survival (p = 0.72). Ischemic time was significantly longer in the BSD group (p < 0.001). Acute rejection and infection episodes were not significantly different (p = 0.24 vs: 0.08). Relative to the BSD group, the risk (95% confidence interval) of acute rejection in the domino group was 0.89 (0.73 to 1.08). Similarly, the relative risk of infection was 0.78 (0.59 to 1.03). The 5-year actuarial survival rates (95% confidence interval) were 78% (69% to 87%) and 69% (65% to 73%) in the domino and BSD groups respectively. Angiography data at 2 years were available in 50 (62%) and 254 (52%) patients in the domino and BSD groups, respectively. The rates for 2-year freedom from cardiac allograft vasculopathy (CAV) were 96% (91% to 100%) and 93% (90% to 96%), respectively., Conclusion: Despite the lack of endothelial cell activation after brainstem death and a shorter ischemic time, the performance of domino donor hearts was similar to that of BSD donor hearts. This may indicate a similar pathology (i.e., endothelial cell activation) in the domino donors.

Peripheral blood eosinophil counts (EOS) are undetectable in 40% blood samples sent for routine haematology at Papworth Hospital during the first 3 months after heart transplantation (HTx). Increases in EOS usually precede the development of allograft rejection by a median of 4 days. We compared the effects of cyclosporin (dose and total blood concentration), prednisolone (dose and both total and unbound plasma concentrations) and azathioprine, as well as plasma concentrations of the CCR-3 chemokines, eotaxin and RANTES, on changes in EOS in 47 consecutive HTx recipients, with a median follow-up of 90 (IQR 85-95) days. Multivariate analysis confirmed the independent association between both prednisolone dose (P<0.0001) and eotaxin (P<0.0001) and changes in EOS. The plasma eotaxin concentration was, in turn, most closely associated with the cyclosporin dose (P<0.001) and plasma prednisolone concentration (P=0.022). The blood cyclosporin concentration (P=0.028), EOS (P=0.012) and prednisolone dose (P=0.015) were all independently associated with the risk of treated acute rejection. When prednisolone pharmacokinetic parameters were substituted for the prednisolone dose in this multivariate model, only the pharmacokinetic parameter retained a significant association with the risk of rejection. Changes in EOS preceding cardiac allograft rejection are directly associated with plasma eotaxin concentrations and indirectly with prednisolone dosage. Cyclosporin may also indirectly influence these changes by inhibiting eotaxin production. EOS, prednisolone dose and blood cyclosporin concentrations were independently associated with the risk of acute rejection. The total and unbound fractions of prednisolone in plasma appear to be even more closely related to rejection but are difficult to measure. Monitoring EOS, as a surrogate measure of prednisolone immunosuppression, may be more cost-effective for controlling rejection than conventional cyclosporin monitoring in the first 6 weeks after HTx.

Coexisting end-stage heart and kidney failure can be treated by combined cardiac and renal transplantation. This study reviews the short- and long-term outcomes after such a procedure over a 16-year period at a single institution. All patients who underwent single-donor simultaneous heart and kidney transplantation during the period of March 1986 to April 2002 (including heart retransplantation) were included (n = 13). They were listed for combined heart and kidney transplantation as they fulfilled our criteria for irreversible end-stage organ failure. Retrospective review of patient data from the transplant database, patient case notes and post-mortem reports were carried out. The mean (SD) recipient age was 45 (12) years and there were 2 females. The mean pre-operative creatinine level was 724 (415) micromol/liter with 9 patients (69.2%) on continuous ambulatory peritoneal dialysis and 2 patients (15.4%) on hemodialysis prior to transplantation. The 30-day mortality rate was 15.4% (2 of 13). For surviving patients the mean creatinine level at hospital discharge was 158 (93) micromol/liter. The mean number of acute cardiac rejection episodes per 100 patient-days was significantly lower (p = 0.01) than that for the heart-only transplant group (n = 760) during the same period. The median (interquartile range) post-operative survival was 1,969 (620 to 3,468) days. The actuarial survival rates (95% confidence interval) at 1 and 10 years were 77% (54% to 100%) and 67% (40% to 94%), respectively, and were not significantly different from the isolated heart transplant population (p = 0.68). Only 1 episode of acute renal rejection was diagnosed on clinical grounds, which was treated accordingly. There was no renal allograft loss in the long-term survivors. Combined cardiac and renal transplantation with allografts from the same donor has acceptable short- and long-term outcomes for patients with coexisting end-stage cardiac and renal failure. This group of patients may also experience fewer acute rejection episodes post-operatively.

Background: The effect of cytomegalovirus (CMV) status on acute rejection in heart transplantation is not well understood. Furthermore, there is some evidence to suggest that CMV antibody positivity is associated with cardiac allograft vasculopathy (CAV)., Methods: This study compared the effect of CMV antibody status in heart transplant donors (D) and recipients (R) on acute and chronic rejection episodes during the ganciclovir prophylaxis era., Results: All heart transplant recipients at Papworth Hospital during the ganciclovir prophylaxis era were included (n = 374). They were grouped according to recipients and their respective donor CMV serology: R(-)/D(-) (n = 82); R(+)/D(-) (n = 114); R(-)/D(+) (n = 73); and R(+)/D(+) (n = 105). Ganciclovir prophylaxis was administered to the R(-)/D(+) group. The mean (SD) recipient and donor ages were 46 (11), 51 (9), 47 (11) and 52 (8) years (p < 0.001), and 32 (11), 33 (14), 36 (12) and 38 (14) years (p = 0.01), respectively, for the CMV groups. The mean number of acute rejection episodes (as confirmed by cardiac biopsy) per 100 patient-days was 0.13 (0.36), 0.11 (0.34), 0.12 (0.34) and 0.12 (0.34), respectively (p > 0.05) There was no statistical difference in the development of CAV as assessed by angiography (p = 0.92). At 2 years, the "freedom from CAV" rates were 96%, 97%, 97% and 98%, respectively. The 5-year post-operative survival rates were 83%, 79%, 67% and 73% (p = 0.08 overall)., Conclusions: CMV status of heart transplant recipients and their respective donors does not influence acute or chronic rejection in terms of cardiac allograft vasculopathy.

Background: Predictions of the incidence of renal failure within a heart transplant population are based on the early experiences of cyclosporine (CsA)-based immunosuppression. We report a single-center experience of end-stage renal failure (ESRF) during a 17-year period encompassing current lower dose CsA regimens., Method: Prospectively collected data were analyzed on all patients who underwent first heart transplants between April 1982 and February 1999 (n = 697). We further categorized patients by the date of transplantation into a higher and lower dosage maintenance CsA group., Results: End-stage renal failure developed in 44 patients. The median time to dialysis was 87 months after transplantation and was independent of the initial CsA regimens used (p = 0.798). In the ESRF group, 14 underwent hemodialysis, 28 underwent peritoneal dialysis, and 9 underwent renal transplantation. One- and 5-year survival rates after dialysis were 82% and 62% respectively. The incidence of ESRF at our institution was 5.8%. It increased with post-operative survival and was independent of the initial CsA regimen used. We found no difference in pre-transplant age, sex, diagnosis, immediate post-operative creatinine, or the development of diabetes between the ESRF group and controls. The ESRF group received higher dosages of CsA within the first post-transplant year, although this did not reach significance (CsA dosage, 5.9 microg/kg/day vs 5.1 microg/kg/day, respectively p = 0.075)., Conclusions: Lower dosage CsA regimes have not altered the incidence of ESRF at our institution, suggesting an individual predisposition to nephropathy. Therefore, reduction in the future incidence of ESRF may rely on extremely low-dose or calcineurin-free immunosuppression regimes.

Background: The success of intrathoracic organ transplantation has lead to a growing imbalance between the demand and supply of donor organs. Accordingly, there has been an expansion in the use of organs from nonconventional donors such as those who died from carbon monoxide poisoning. We describe our experience with 7 patients who were transplanted using organs after fatal carbon monoxide poisoning., Methods: A retrospective study of the 1,312 intrathoracic organ transplants between January 1979 and February 2000 was completed. Seven of these transplants (0.5%) were fulfilled with organs retrieved from donors after fatal carbon monoxide poisoning. There were six heart transplants and one single lung transplant. The history of carbon monoxide inhalation was obtained in all of these donors., Results: Five of 6 patients with heart transplant are alive and well with survival ranging from 68 to 1,879 days (mean, 969 +/- 823 days). One patient (a 29-year-old male) died 12 hours posttransplant caused by donor organ failure. The patient who had a right single lung transplant did well initially after the transplant, but died after 8 months caused by Pneumocystis carinii pneumonia. All those recipients who were transplanted from carbon monoxide poisoned donors and ventilated for more than 36 hours, survived for more than 30 days. Moreover, these donors were assessed and optimized by the Papworth donor management protocol., Conclusions: Carbon monoxide poisoned organs can be considered for intrathoracic transplantation. In view of the significant risk of donor organ failure, a cautious approach is still warranted. Ideally, the donor should be hemodynamically stable for at least 36 hours from the time of poisoning and on minimal support. A formal approach of invasive monitoring and active management further improves the chances of successful outcome.

Background: The standard technique of ventricular transplantation with atrioplasty (SOHT) distorts atrial anatomy. This may compromise diastolic ventricular function, impair atrioventricular valve competence and elevate resting ANP secretion. In contrast, complete atrioventricular anastomosis (CAVT) preserves atrial geometry., Methods: We evaluated long term outcome in a prospective randomized trial of CAVT vs. SOHT. The primary outcome measures were peak oxygen uptake, atrioventricular valve regurgitation and ANP secretion., Results: 58 recipients (median age 49 years; range 21-64) were consecutively randomized (29 CAVT; 29 SOHT). There were no differences in total ischaemic time, cardiopulmonary bypass time, postoperative bleeding or immunosuppression. Cardiopulmonary exercise tolerance testing was performed by 29 recipients at 742 to 1825 days. Pulmonary function was equivalent. Peak oxygen consumption expressed as a percentage of predicted maximum was 53.5% with CAVT and 63.8% with SOHT (p = 0.14). Echocardiography was performed on 41 recipients at 944 to 1665 days. There was less tricuspid regurgitation with CAVT (3/22 [13.6%] CAVT vs. 10/19 [52.6%] SOHT; p = 0.019). The incidence of mitral regurgitation was similar (5/22 [22.7%] CAVT vs. 4/19 [21.1%] SOHT; p = 0.803). Resting ANP secretion was assessed in 17 recipients at 1013 to 1812 days. All were hemodynamically stable and none had concurrent rejection. Resting ANP secretion was less with CAVT (CAVT: 283 pg/ml; SOHT: 521.4; p = 0.041)., Conclusions: Peak oxygen consumption was not influenced by implantation technique. However, CAVT reduced the incidence of tricuspid regurgitation and attenuated the elevation in resting ANP secretion.

Despite the advances in the medical management of heart failure over the last 20 years it remains a major cause of morbidity and mortality. While cardiac transplantation has evolved into an established mode of therapy, the number of patients with severe heart failure who could benefit from cardiac transplantation far exceeds the supply of donor organs. The development of an implantable left ventricular assist device (LVAD) began in the early 1970s in centres such as the Texas Heart Institute and was funded by the National Heart, Lung, and Blood Institute. Clinical trials of these devices began in the mid 1980s and several hundred patients have now been supported with one or other of these devices. Most patients have had an LVAD implanted as a bridge to cardiac transplantation. Recently there has also been interest in the use of an LVAD for (a) permanent ventricular support and (b) as a bridge to recovery in patients with potentially reversible causes of heart failure.

Background: A retrospective serologic study was made of 67 heart-lung and 295 heart transplant recipients (with transplantations at Papworth Hospital, Cambridge, England) to determine the incidence and clinical impact of Epstein-Barr virus infection., Methods: Epstein-Barr virus capsid antigen immunofluorescence tests were performed, and the antibody avidity was determined by modifying the washing procedure to include a mild reducing agent (8M urea)., Results: This testing showed that 6.0% of the patients had primary Epstein-Barr virus infections, whereas 17.4% had the reactivation of a past infection. Primary infections were only detected in patients who were Epstein-Barr virus antibody-negative before transplantation, who had received an organ from an Epstein-Barr virus antibody-positive donor. Of the patients with serologically proven Epstein-Barr virus infections, 52.9% had symptoms. Although these were generally mild, five heart and two heart-lung transplant recipients had malignant lymphoma and one heart and one heart-lung transplant recipient had lymphoproliferative disease after Epstein-Barr virus infection. Additional four heart transplant recipients had lymphoma after transplantation. None of these four patients had evidence of active Epstein-Barr virus infection; one was Epstein-Barr virus antibody-negative during the study period and three had stable Epstein-Barr virus virus capsid antigen immunoglobulin G titers throughout., Conclusions: Epstein-Barr virus infection in organ transplant recipients may lead on to life-threatening lymphoproliferative disease or lymphoma. For this reason it may be beneficial to monitor patients after transplantation for evidence of Epstein-Barr virus infection and to follow the progress of those affected.

Background: This study aims to identify characteristics that increase the chance of death of potential cardiac transplant recipients before donor organs become available., Methods: Between June 1, 1988, and May 31, 1993, 332 patients were accepted for heart transplantation; 235 underwent surgery. Ninety-seven patients had not received transplants; of these, 71 died, 13 were transferred to other lists, and 13 were awaiting organs at the close of the study. Median waiting time for those patients who received organs was 109 days, whereas patients who did not receive organs spent a median of 94 days on the list. Recipients are matched to donor organs according to blood group, size (height), and, recently, preoperative transpulmonary pressure gradient. Recently cytomegalovirus antibody mismatches (positive donor to negative recipient) have been avoided where possible. These factors, together with age, gender, underlying diagnosis, previous heart surgery, and Toxoplasma antibody status were studied to assess their influence on waiting time and survival., Results: No characteristics were found significantly to influence survival after acceptance, so that the chance of death while the patient was waiting for heart transplantation is mainly affected by the severity of disease and the length of time a patient waits. In multivariate analyses the following were independently significantly associated with shorter waiting times: small patients (< 1.7 m tall; p = 0.005), patients with blood types B and AB (p = 0.003), and patients with cardiomyopathy (p < 0.001)., Conclusions: These results can be used by cardiologists to help assess the time at which a patient should be referred for transplantation.

This study employed a second-generation anti-HCV ELISA, and a second-generation recombinant immunoblot assay and hepatitis C virus RNA detection by polymerase chain reaction to investigate the anti-HCV prevalence in 554 British organ donors and the transmission of hepatitis C virus to heart, liver and kidney recipients between 1984 and 1991. Serum samples from six (1.08%) donors were reactive in the second-generation anti-HCV ELISA and four (67%) of these gave positive or indeterminate results in the recombinant immunoblot assay-2. Of the 15 recipients of these organs from hepatitis C virus-confirmed positive/indeterminate donors, 14 (93%) acquired hepatitis C virus infection and seven (47%) had evidence of hepatitis C virus-related liver disease after transplantation and no evidence of blood transfusion-related transmission. Only six of the 15 (40%) recipients had detectable anti-HCV after transplantation, while 12 of 14 (86%) patients tested had hepatitis C virus RNA in their serum detectable by "nested" polymerase chain reaction. These data indicate a very high rate of transmission with a major risk of the development of liver disease. We believe our study supports the testing of all British organ donors for anti-HCV and that organs from anti-HCV-positive patients should not be transplanted unless the recipient has life-threatening disease and there is a donor shortage, when their use may be justified. Since there are time constraints on organ donor testing, which may frequently be done on call during unsocial hours, we would recommend second-generation ELISA as the current screening test of choice.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Beta blockers and calcium antagonists are widely used in the management of angina pectoris in the belief that the combination is more efficacious than either drug alone., Methods: This double blind randomised crossover placebo controlled study compares the effects of nicardipine, atenolol and their combination in 30 patients with chronic stable angina. Each treatment period lasted 6 weeks with dose titration after 3 weeks. Symptom limited treadmill exercise testing and radionuclide ventriculography at rest was carried out at the end of each treatment period., Results: Total exercise duration and time to 1-mm ST-segment depression was significantly prolonged by nicardipine and atenolol when compared to placebo, the combination offered no additional benefit. Time to onset of angina was significantly prolonged by nicardipine and the combination but not by atenolol. Indices of left ventricular function were not significantly affected by any treatment other than an increase in left ventricular end diastolic volume on atenolol and the combination., Conclusions: Nicardipine and atenolol are equally effective in prolonging exercise duration and time to onset of ischemia in patients with chronic stable angina while the combination appeared to offer no additional benefit. Nicardipine prolonged the time to onset of angina significantly; again there was no further improvement with the combination. Neither drug appears to have an important effect on the parameters of diastolic function studied in patients with chronic stable angina.

Captopril alone as therapy for mild heart failure was compared with a combination of frusemide and amiloride in a double-blind randomised crossover trial in 14 patients who had previously been treated with diuretics. Although 10 patients remained stable on captopril alone, 4 patients deteriorated, with the development of pulmonary oedema of breathlessness. All 4 patients had had pulmonary oedema previously, unlike the patients who remained stable. Angiotensin converting enzyme inhibition alone is not sufficient treatment for patients with mild heart failure and a history of overt pulmonary oedema.