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Background: Acute cellular rejection (ACR) is common in the first year after cardiac transplantation, and regular surveillance endomyocardial biopsy (EMB) is required. An inexpensive, simple noninvasive diagnostic test would be useful. Prior studies suggest cardiac troponin (cTn) has potential as a "rule-out" test to minimize the use of EMB. Our aim was to determine whether a new high-sensitivity cardiac troponin I (hs-cTnI) assay would have utility as a "rule-out" test for ACR after heart transplantation., Methods: Blood samples at patient follow-up visits were collected and stored over a period of 5 y. Serum cTnI concentrations were measured using the ARCHITECTSTAT hs-cTnI assay and compared with an EMB performed on the same day. Receiver-operator curve analysis based on mixed-effects logistic regression models that account for repeated measurements in individuals was performed to determine a serum troponin level below which ACR could be reliably excluded., Results: One hundred seventy patients had 883 serum hs-cTnI results paired to a routine surveillance EMB. Fifty-one (6%) EMB showed significant ACR (grade ≥2R). Receiver-operator curve analysis approximated the null hypothesis area under the curve 0.509 (95% CI, 0.428-0.591). Sub-analysis including repeated hs-cTnI levels in a single individual, and early (<3 mo) EMB also showed no diagnostic utility of hs-cTnI measurement (area under the curve 0.512)., Conclusions: In the largest published study to date, we found no association between hs-cTnI concentration and the presence of significant ACR on surveillance EMB. Measurement of hs-cTnI may not be a useful technique for diagnosis or exclusion of ACR after heart transplantation., Competing Interests: K.K.L. has received an honorarium unrelated to this research from Abbotts Diagnostics and N.L.M. has received honorarium and grants unrelated to this research, from Abbots Diagnostics, Roche Diagnostics, and Siemens Healthcare. The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) improve sensitivity of cardiac allograft vasculopathy (CAV) detection compared to invasive coronary angiography (ICA), but their ability to predict clinical events is unknown. We determined whether severe CAV detected with ICA, IVUS, or OCT correlates with graft function., Methods: Comparison of specific vessel parameters between IVUS and OCT on 20 patients attending for angiography 12-24 months post-orthotopic heart transplant. Serial left ventricular ejection fraction (EF) was recorded prospectively., Results: Analyzing 55 coronary arteries, OCT and IVUS correlated well for vessel CAV characteristics. A mean intimal thickness (MIT) OCT  > .25 mm had a sensitivity of 86.7% and specificity of 74.3% at detecting Stanford grade 4 CAV. Those with angiographically evident CAV had significant reduction in graft EF over 7.3 years follow-up (median ΔEF -2% vs +1.5%, P = .03). Patients with MIT OCT  > .25 mm in at least one vessel had a lower median EF at time of surveillance (57% vs 62%, P = .014). Two MACEs were noted., Conclusion: Imaging with OCT correlates well with IVUS for CAV detection. Combined angiography and OCT to screen for CAV within 12-24 months of transplant predicts concurrent and future deterioration in graft function., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Competing Interests: Competing interests: None declared.

Background: We aim to evaluate practice and understand the impact of the first wave of the SARS-CoV-2 pandemic on heart transplantation in the UK., Methods: A retrospective review of the UK Transplant Registry (UKTR) and a national survey of UK heart transplant centers have been performed. The early pandemic period is defined here as 1 March to 31 May 2020., Results: There was geographic variation in the prevalence of COVID-19 across the UK. All centers reported adaptations to maintain the safety of their staff, candidate, and recipient populations. The number of donors fell by 31% during the early pandemic period. Heart utilization increased to 35%, compared to 26% during the same period of 2019. The number of heart transplants was well maintained, across all centers, with 38 performed, compared to 41 during the same period of 2019, with no change in 30-day survival. Twenty-seven heart transplant recipients with confirmed COVID-19 infection were reported during the study period., Conclusion: All UK heart transplant centers have successfully adapted their programs to overcome the challenges of staff redeployment and ICU and hospital resource limitation, associated with the pandemic, whilst continuing heart transplant activity. On-going evaluation of practice changes, with sharing of lessons learned, is required as the pandemic continues., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Predicted heart mass (PHM) equations have been proposed as an alternative method for size matching in heart transplantation. We assessed association between donor-recipient size mismatch, defined using PHM equations, and survival post-heart transplant in the United Kingdom. Data from all adult patients who received a heart transplant between 1995 and 2017 were obtained from the United Kingdom Transplant Registry. PHM was calculated using published equations. Primary outcome was 1-year survival post-heart transplantation. Recipients of undersized organs had reduced 1-year survival (HR 1.31, 95% CI 1.03-1.67, p = .03). Oversizing had no impact on survival (HR 0.99, 95% CI 0.78-1.26, p = .96). Gender mismatching had no impact on survival in the cohort matched by PHM (HR 1.12, 95% CI 0.86-1.47, p = .4). In recipients without pulmonary hypertension, undersizing by PHM had no impact on 1-year survival (HR 0.95, 95% CI 0.61-1.49, p = .83). In recipients with pulmonary hypertension, oversizing donor RV by using PHM RV equation (PHM RV ) results in improved survival at 1 year (HR 0.65, 95% CI 0.5-0.83, p = .001). In conclusion, receiving an organ undersized by PHM was associated with decreased 1-year survival. Subgroup analyses demonstrated that undersizing only impacted survival in recipients with pulmonary hypertension and that these recipients had improved outcomes if they received an organ with an RV oversized by >10% by PHM RV ., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.)

For a carefully selected group of patients with advanced heart failure where prognosis and quality of life remain poor, cardiac transplantation is the treatment of choice. Long-term survival and quality of life are now excellent in most patients post-transplantation, but important short- and long-term complications remain a significant concern. The mainstay of early and longer term post-transplant care is the surveillance for and treatment of these complications. This review article provides an overview of the contemporary outcomes after heart transplant, the more commonly encountered problems and their management in the early and late stages., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© Indian Association of Cardiovascular-Thoracic Surgeons 2019.)

Background: Vasoplegia has been associated with inferior outcomes following heart transplantation (HTx). This observational study was designed to investigate outcomes in recipients with vasoplegia following left ventricular assist device (LVAD) explant HTx., Methods: Patients undergoing LVAD explant followed by HTx from 01/2013-12/2018 at our centre were included. Vasoplegia was defined as the requirement for high dose vasopressor [noradrenaline (>0.5 μg/kg/min) and vasopressin (>1 U/h)] over the first 24 hours following HTx. Demographic and outcome data were retrieved from the transplant unit database., Results: During the study period 24 patients underwent LVAD explant HTx. Of these, 13 (54.2%) developed vasoplegia. Both groups had similar duration of LVAD support (median 684 vs. 620 days P=0.62). There was a higher incidence of driveline infection in patients developing vasoplegia (69.2% vs. 18.2% P=0.02). HTx following donation after circulatory death (DCD) occurred in 9 (37.5%) patients and was not associated with a higher incidence of vasoplegia (P=0.21). Vasoplegia developed early following reperfusion and intensive care unit admission vasopressor-inotrope scores were significantly higher in patients with vasoplegia (P=0.002). Patients developing vasoplegia had similar ICU (P=0.79) and hospital (P=0.93) lengths of stay. Survival was equivalent both at 30-day (92.3% vs. 100% P=0.99) and 1-year (67.7% vs. 74.7% P=0.70). Our overall HTx 1-year survival was 89.3% over this period., Conclusions: Vasoplegia is seen with a high incidence in HTx recipients bridged with an LVAD. This appears to be associated with the presence of driveline infections. Early aggressive management is advocated, resulting in equivalent 1-year survival to those patients not developing vasoplegia., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd.2020.03.53). JMA serves as an unpaid editorial board member of Journal of Thoracic Disease from Oct 2019 to Sep 2021. The other authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

Objectives: The authors describe the experience of patient transfer on veno-arterial extracorporeal membrane oxygenation (VA-ECMO) used as a salvage therapy for refractory cardiogenic shock, examining feasibility and long-term outcomes., Design: A retrospective case series., Setting: A tertiary referral cardiothoracic transplantation center., Participants and Interventions: Since 2012, the authors' multidisciplinary team has traveled to the referring center of 15 patients referred with refractory cardiogenic shock. Of these, 13 were instituted on VA ECMO support (8 peripheral and 5 central) and subsequently transferred to the authors' center. A further 11 patients were transferred to the authors' institution by the referring team, already having been placed on VA-ECMO (8 peripheral and 3 central)., Measurements and Main Results: All patients were safely transferred. The distance travelled ranged from 16 to 341 miles. The median duration of support on VA-ECMO was 4 days, ranging from 1 to 24 days. The VA-ECMO support was weaned, or the patient underwent a definitive surgical management (including 4 undergoing cardiac transplantation and 3 pulmonary endarterectomy) in 15 (62.5%) patients. The median intensive care unit stay was 15 days (range 1-109). Overall 30-day survival for this patient cohort was 69.6% with 1-year survival of 59.8%. For patients who were weaned from VA-ECMO, the 30-day survival was 100% and 1-year survival 92.9%., Conclusions: The authors' experience demonstrates the feasibility and survival benefit of a salvage VA-ECMO retrieval service for carefully selected patients with refractory cardiogenic shock. The authors suggest that a system based on the model of nationally commissioned severe respiratory failure services could be organized to support the transfer of these patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Left ventricular assist devices are funded in the UK exclusively as a bridge to transplant (BTT). However, patients who potentially could receive a transplant may develop reversible contraindications to transplant. Bridge to candidacy (BTC) has sometimes been controversial, given the uncertain clinical efficacy of BTC and the risk that reimbursement could be denied. We analysed the UK ventricular assist device database to understand how common BTC was and to assess patient survival rates and incidences of transplants., Methods: We identified BTC implants in patients with pulmonary hypertension, chronic kidney disease and obesity using the UK guidelines for heart transplants., Results: A total of 306 of 540 patients had complete data and 157 were identified as BTC (51%). Overall, there was no difference in survival rates between patients designated as BTC and those designated at BTT (71.9 vs 72.9% at 1 year, respectively; P = 0.82). However, the survival rate was lower at all time points in those with an estimated glomerular filtration rate (eGFR) <40 and in patients with a body mass index (BMI) >32 up to 1-year postimplant. There were no significant differences in the incidence of transplant between patients who were BTC and BTT or for any subgroup up to 5 years. However, we noted a diverging trend towards a lower cumulative incidence of transplant for patients with a BMI >32., Conclusions: BTC is common in the UK and appears clinically effective, given that the survival rates and the incidence of transplants were comparable with those for BTT. Patients with a high BMI have a worse survival rate through to 1 year and a trend for a lower incidence of a transplant. Patients with a low eGFR also have a worse survival rate, but a similar proportion received transplants., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Competing Interests: Competing interests: None declared.

Objective: To study the survival and patient outcome in a population of UK patients supported by an implantable left ventricular assist device (LVAD) as a bridge to heart transplantation., Methods: Data on all adult patients (n=342) who received a HeartMate II or HVAD as a first long-term LVAD between January 2007 and 31 December 2013 were extracted from the UK Ventricular Assist Device (VAD) Database in November 2015. Outcomes analysed include survival on a LVAD, time to urgent listing, heart transplantation and complications including those needing a pump exchange., Results: 112 patients were supported with the Thoratec HeartMate II and 230 were supported with the HeartWare HVAD. Median duration of support was 534 days. During the study period, 81 patients required moving to the UK urgent waiting list for heart transplantation. Of the 342 patients, 85 (24.8%) received a heart transplant, this included 63 on the urgent list. Thirty-day survival was 88.9%, while overall patient survival at 3 years from LVAD implant was 49.6%. 156 patients (46%) died during LVAD support; the most common cause of death on a VAD was a cerebrovascular accident. There was no significant difference between the two devices used in any outcome., Conclusions: In a population of patients with advanced heart failure, who have a very poor prognosis, support with an implantable LVAD allowed a quarter to receive a heart transplant in a 3-year period. Overall survival of the cohort was about 50%. With improvement in technology and in post-LVAD management, it is likely that outcomes will improve further., Competing Interests: Competing interests: ST: Proctor and Investigator for Medtronic (HeartWare); RV: Proctor and Consultant for Abbott (Thoratec), SSh: Proctor and Consultant for Medtronic (HeartWare), AS: Consultant for Medtronic (HeartWare), SSc: Consultant for Abbott (Thoratec)., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Cardiovascular-safety studies assessing glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have provided inconsistent data on the risk for developing heart failure. Animal studies have shown that GLP-1 is a vasodilator; if confirmed in humans, this may ameliorate heart failure symptoms., Methods: In a single-center, observational pilot study, we recruited 10 patients with advanced heart failure undergoing right heart catheterization, and we recorded pulmonary hemodynamic measures, including cardiac output calculated by thermodilution and the indirect Fick method before and after a 15-minute continuous infusion of native GLP-1 (7-36) NH 2 ., Findings: There was a neutral effect of GLP-1 on all pressure and hemodynamics indices as derived by cardiac output calculated by thermodilution. However, there was a small but consistent reduction in cardiac output as calculated by the indirect Fick method after GLP-1 infusion (baseline, 4.0 [1.1] L/min vs GLP-1, 3.6 [0.9] L/min; P = 0.003), driven by a consistent reduction in mixed venous oxygen saturation after GLP-1 infusion (baseline, 62.2% [7.0%] vs GLP-1, 59.3% [6.8%]; P < 0.001), whereas arterial saturation remained constant (baseline, 96.8% [3.3%] vs GLP-1, 97.0% [3.2%]; P = 0.34). This resulted in an increase in systemic vascular resistance by Fick (baseline, 1285 [228] dyn · s/cm 5 vs GLP-1, 1562 [247] dyn · s/cm 5 ; P = 0.001)., Implications: Acute infusion of GLP-1 has a neutral hemodynamic effect, when assessed by thermodilution, in patients with heart failure. However, GLP-1 reduces mixed venous oxygen saturation. ClinicalTrials.gov identifier: NCT02129179., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: Many patients have a cardiac implantable electronic device (CIED) extracted at the time of heart transplantation. CIED components may be retained after heart transplantation, but their frequency, nature, and clinical significance is uncertain., Methods and Results: Consecutive patients that underwent heart transplantation over 10 years from 1 January 2007 until 1 January 2017 were identified from the unit database. Pre- and post-operative chest radiographs were reviewed by two independent observers for the presence of CIED components. Adverse events relating to any retained CIED component were recorded. Two hundred and six patients had a CIED removed at the time of transplantation. Retained CIED components were present in 86 (42%) patients. The most common retained CIED components were suture sleeves and superior vena cava (SVC) coils of dual coil implantable cardioverter-defibrillator (ICD) leads. An SVC coil was retained in 25% of patients that had a dual coil ICD lead. Seven adverse events were associated with CIED removal or retained CIED components, including one fatal event. However, retained CIED components were not associated with reduced long-term survival after heart transplantation., Conclusion: Retained CIED components were seen in 42% of patients that had a CIED prior to transplantation, may be associated with serious adverse events but are not associated with reduced long-term survival. Cardiac surgeons should be aware of all CIED system components and be familiar with techniques for their complete removal at the time of transplantation.

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.)

Objective: Cardiac allograft vasculopathy (CAV) can be detected early with intravascular ultrasound (IVUS), but there is limited information on the most efficient imaging protocol., Methods: Coronary angiography and IVUS of the three coronary arteries were performed. Volumetric IVUS analysis was performed, and a Stanford grade determined for each vessel., Results: Eighteen patients were included 18 (range 12-24) months after transplantation. Angiographic CAV severity ranged from none (CAV0) to mild (CAV1), whereas IVUS CAV severity ranged from none (Stanford grade I) to severe (grade IV). Maximal intimal thickness measured with IVUS was significantly greater in the LAD (0.84 ± 0.48 mm) than in the LCX (0.46 ± 0.32 mm) or the RCA (0.53 ± 0.41 mm, P = .005). Diagnostic accuracy of IVUS in the left anterior descending artery was 100% (18 of 18 Stanford grades matched the patient's highest overall Stanford grade), 66% in the right coronary artery (12 of 18), and 56% in the left circumflex artery (11 of 18). The minimal required length of left anterior descending artery pullbacks to attain 100% accuracy was 36 mm (range 3-36 mm) distal from the guide catheter ostium., Conclusions: These data suggest that focal IVUS imaging of the proximal LAD followed by volumetric analysis may suffice when screening for transplant vasculopathy., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.)

Advances in left ventricular assist device (LVAD) therapy have resulted in increasing numbers of adult LVAD recipients in the community. However, device failure, stroke, bleeding, LVAD thrombosis and systemic infection can be life-threatening emergencies. Currently, four LVAD systems are implanted in six UK transplant centres, each of which provides device-specific information to local emergency services. This has resulted in inconsistent availability and content of information with the risks of delayed or inappropriate decision-making. In order to improve patient safety, a consortium of UK healthcare professionals with expertise in LVADs developed universally applicable prehospital emergency algorithms. Guidance was framed as closely as possible on the standard ABCDE approach to the assessment of critically ill patients., Competing Interests: Competing interests: RH and AS have had remunerated consultancy agreements with Medtronic which provided funding for this initiative., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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.)

Aims: A non-invasive gene-expression profiling (GEP) test for rejection surveillance of heart transplant recipients originated in the USA. A European-based study, Cardiac Allograft Rejection Gene Expression Observational II Study (CARGO II), was conducted to further clinically validate the GEP test performance., Methods and Results: Blood samples for GEP testing (AlloMap(®), CareDx, Brisbane, CA, USA) were collected during post-transplant surveillance. The reference standard for rejection status was based on histopathology grading of tissue from endomyocardial biopsy. The area under the receiver operating characteristic curve (AUC-ROC), negative (NPVs), and positive predictive values (PPVs) for the GEP scores (range 0-39) were computed. Considering the GEP score of 34 as a cut-off (>6 months post-transplantation), 95.5% (381/399) of GEP tests were true negatives, 4.5% (18/399) were false negatives, 10.2% (6/59) were true positives, and 89.8% (53/59) were false positives. Based on 938 paired biopsies, the GEP test score AUC-ROC for distinguishing ≥3A rejection was 0.70 and 0.69 for ≥2-6 and >6 months post-transplantation, respectively. Depending on the chosen threshold score, the NPV and PPV range from 98.1 to 100% and 2.0 to 4.7%, respectively., Conclusion: For ≥2-6 and >6 months post-transplantation, CARGO II GEP score performance (AUC-ROC = 0.70 and 0.69) is similar to the CARGO study results (AUC-ROC = 0.71 and 0.67). The low prevalence of ACR contributes to the high NPV and limited PPV of GEP testing. The choice of threshold score for practical use of GEP testing should consider overall clinical assessment of the patient's baseline risk for rejection., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Right heart catheterisation (RHC) may be performed through a mechanical valve prosthesis in the tricuspid position using a partially inflated pulmonary artery flotation catheter. Preprocedural preparation should include an ex vivo trial with an identical valve prosthesis and the type of catheter to be used for the procedure. The operator should expect immediate unloading of the right ventricle due to catheter-associated tricuspid regurgitation, but it is possible to estimate pulmonary vascular resistance using the Fick principle. The risk of catheter entrapment or damage to the prosthetic leaflets during the procedure is likely to be low. This risk may be acceptable to the clinician and the patient if pulmonary vascular resistance must be measured in order to determine eligibility for heart transplantation., (2016 BMJ Publishing Group Ltd.)

Background: A single non-invasive gene expression profiling (GEP) test (AlloMap®) is often used to discriminate if a heart transplant recipient is at a low risk of acute cellular rejection at time of testing. In a randomized trial, use of the test (a GEP score from 0-40) has been shown to be non-inferior to a routine endomyocardial biopsy for surveillance after heart transplantation in selected low-risk patients with respect to clinical outcomes. Recently, it was suggested that the within-patient variability of consecutive GEP scores may be used to independently predict future clinical events; however, future studies were recommended. Here we performed an analysis of an independent patient population to determine the prognostic utility of within-patient variability of GEP scores in predicting future clinical events., Methods: We defined the GEP score variability as the standard deviation of four GEP scores collected ≥315 days post-transplantation. Of the 737 patients from the Cardiac Allograft Rejection Gene Expression Observational (CARGO) II trial, 36 were assigned to the composite event group (death, re-transplantation or graft failure ≥315 days post-transplantation and within 3 years of the final GEP test) and 55 were assigned to the control group (non-event patients). In this case-controlled study, the performance of GEP score variability to predict future events was evaluated by the area under the receiver operator characteristics curve (AUC ROC). The negative predictive values (NPV) and positive predictive values (PPV) including 95 % confidence intervals (CI) of GEP score variability were calculated., Results: The estimated prevalence of events was 17 %. Events occurred at a median of 391 (inter-quartile range 376) days after the final GEP test. The GEP variability AUC ROC for the prediction of a composite event was 0.72 (95 % CI 0.6-0.8). The NPV for GEP score variability of 0.6 was 97 % (95 % CI 91.4-100.0); the PPV for GEP score variability of 1.5 was 35.4 % (95 % CI 13.5-75.8)., Conclusion: In heart transplant recipients, a GEP score variability may be used to predict the probability that a composite event will occur within 3 years after the last GEP score., Trial Registration: Clinicaltrials.gov identifier NCT00761787.

Background: Selected patients with cardiac sarcoidosis undergo heart transplantation, but outcomes may be adversely affected by recurrent cardiac sarcoidosis or progressive extra-cardiac sarcoidosis., Objectives: We present our single-center experience of patients with cardiac sarcoidosis who underwent heart transplantation., Methods: Consecutive patients that underwent heart transplantation between 1990 and 2012 were assessed. Cardiac sarcoidosis was defined by the presence of multiple non-caseating epithelioid cell granulomata in the explanted heart. Baseline characteristics and clinical outcomes were compared with a control group without cardiac sarcoidosis that underwent heart transplantation during this period., Results: 901 patients underwent heart transplantation during the study period, of whom 4 patients had a pre-transplant diagnosis of cardiac sarcoidosis and 8 patients had sarcoidosis identified in the explanted heart. Patients with cardiac sarcoidosis had excellent post-transplant outcomes with survival of 92% at one year and 83% at five years. Survival was similar to patients that underwent heart transplantation for an alternate diagnosis. We did not encounter recurrent cardiac sarcoidosis or progressive extra-cardiac sarcoidosis during 1001 months of follow-up., Conclusions: Carefully selected patients with advanced heart failure due to cardiac sarcoidosis have an acceptable outcome after transplantation. Cardiologists should be aware that reported experience of transplantation for cardiac sarcoidosis mostly represents isolated cardiac sarcoidosis that was only diagnosed at pathological examination of the explanted heart.

Advanced heart failure is a rare but important complication of hypertrophic cardiomyopathy (HCM). The only definitive treatment is heart transplantation and the role of ventricular assist devices remains uncertain. We describe the use of implantable biventricular assist devices in the treatment of a patient with 'end-stage' non-dilated HCM., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aims: Heart transplantation (HTx) is limited by the scarcity of suitable donor hearts. Consequently, more patients with advanced heart failure require a ventricular assist device (VAD). We report U.K. activity, trends, and outcome for long-term VAD support as a bridging therapy to HTx., Methods and Results: Patients were grouped into three eras: E1, February 2004-March 2006; E2, April 2006-March 2009; and E3, April 2009-March 2011. Exclusions were patients who received isolated short-term support or extracorporeal membrane oxygenation without prior or subsequent long-term VAD support. A total of 247 patients received VAD support; 202 left ventricular (LVAD) support alone and 45 both left and right ventricular support. Activity increased over time, from 36 patients implanted in E1 to 123 in E3. Overall, 46 patients received a first-generation device, 80 a second-generation device, and 121 a third-generation device. Use of third-generation devices increased from <6% in E1 to 78% in E3. Median duration of LVAD support increased from 141 days in E1 to 578 days in E3 (P < 0.001). Overall survival to 1 year after LVAD implant rose from 58.3% [95% confidence interval (CI) 40.7-72.4%] in E1 to 72.5% (95% CI 63.3-79.8%) in E3 (P = 0.21), and improved significantly with device generation; at 1 year, 50% of patients with first-generation devices were alive compared with 68.1% and 76.9% of patients with second- and third-generation devices, respectively (P = 0.002). These differences remained after risk adjustment. HTx following LVAD implant reduced over time (P < 0.001)., Conclusion: VAD activity and duration of support have increased. There has been a shift from first- and second- to third-generation devices, and an associated improvement in survival.

Objectives: Raised pulmonary artery pressure (PAP), trans-pulmonary gradient (TPG) and pulmonary vascular resistance (PVR) are risk factors for poor outcomes after heart transplant in patients with secondary pulmonary hypertension (PH) and may contraindicate transplant. Unloading of the left ventricle with an implantable left ventricular assist device (LVAD) may reverse these pulmonary vascular changes. We studied the effect of implanting centrifugal LVADs in a cohort of patients with secondary PH as a bridge to candidacy., Methods: Pulmonary haemodynamics on patients implanted with centrifugal LVADs at a single unit between May 2005 and December 2010 were retrospectively reviewed., Results: Twenty-nine patients were implanted with centrifugal LVADs (eight HeartWare ventricular assist device (HVAD), HeartWare International, USA and 21 VentrAssist, Ventracor Ltd., Australia). Seventeen were ineligible for transplant by virtue of high TPG/PVR. All the patients were optimized with inotrope/balloon pump followed by LVAD insertion. Four required temporary right VAD support. Thirty-day mortality post-LVAD was 3.4% (1 of 29) with a 1-year survival of 85.7% (24 of 28). Thirteen patients have been transplanted to date: 30-day mortality was 7.7% (1 of 13) and 1-year survival was 91% (10 of 11). Baseline and post-VAD pulmonary haemodynamics were significantly improved: systolic PAP (mmHg), mean PAP, TPG (mmHg) of 57 ± 9.5, 42 ± 4.4 and 14 ± 3.9 reduced to 32 ± 7.5, 18 ± 5.5 and 9 ± 3.3, respectively. PVR reduced from 5 ± 1.5 to 2.1 ± 0.5 Wood units (P < 0.05)., Conclusions: In selected heart failure patients with secondary PH, use of centrifugal LVAD results in significant reductions in PAP, TPG and PVR, which are observed within 1 month, reaching a nadir by 3 months. Such patients bridged to candidacy have post-transplant survival comparable with those having a heart transplant as primary treatment.

Background: There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading scheme for heart graft endomyocardial biopsy specimens (EMBs)., Methods: We evaluated agreement within the CARGO II pathology panel and between the panel (acting by majority) and the collaborating centers (treated as a single entity), regarding the ISHLT grades of 937 EMBs (with all grades ≥2R merged because of small numbers)., Results: Overall all-grade agreement was almost 71% both within the panel and between the panel and the collaborating centers but, in both cases, was largely because of agreement on grade 0: for the average pair of pathologists, fewer than a third of the EMBs assigned grade ≥2R by at least one were assigned this grade by both., Conclusion: The 2004 revision has done little to improve agreement on the higher ISHLT grades. An EMB grade ≥2R is not by itself sufficient as a basis for clinical decisions or as a research criterion. Steps should be taken toward greater uniformity in EMB grading, and efforts should be made to replace the ISHLT classification with diagnostic criteria--EMB based or otherwise--that correspond better with the pathophysiology of the transplanted heart.

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.)

Objective: Primary graft failure is the most common cause of mortality early after heart transplantation. The availability of relatively low-cost short-term mechanical support devices has altered the management of primary graft failure but there are few data on clinical outcome. Here, we describe the UK experience with Levitronix CentriMag support following heart transplantation across multiple centres., Methods: Data for all adult heart transplants and all CentriMag devices used within 30 days of heart transplantation in the UK between November 2003 and July 2008 were collected. Transplant characteristics were compared for those who did and did not receive CentriMag support, and device outcomes and survival rates were summarised., Results: A total of 572 heart transplants were performed in this period. As many as 38 patients (6.6%) were implanted with CentriMag devices for primary graft failure. Four patients received extracorporeal membrane oxygenation concurrently and were excluded from further analysis. There were no significant differences in transplant characteristics between the patients who received CentriMag support and those who did not. Twelve patients were explanted; nine survived but three died shortly afterwards. Five underwent acute retransplantation; two survived and three died. Seventeen patients died on support. The 30-day and 1-year survival rates were 50% (95% confidence interval (CI) 32-65%) and 32% (95% CI 18-48%), respectively. Patients who previously had a bridge-to-transplant ventricular assist device (VAD) had significantly better survival than those who did not (1-year survival 71% vs 22%, p = 0.029)., Conclusions: Primary graft failure remains an important early complication of heart transplantation. Levitronix CentriMag support led to the salvage of 32% of patients with severe allograft failure., (Copyright © 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. 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.)

Background: Intravenous prostacyclin (iv PGI) and inhaled Iloprost (inh ilo) are established therapies in pulmonary arterial hypertension (PAH), however comparative data are lacking., Methods and Patients: We performed a long-term open label comparison trial of iv PGI or high dose inh ilo in 24 patients with severe PAH: 12 patients (9 female, 40 +/- 14 years, 10 idiopathic PAH, 2 PAH in connective tissue disease CTD) received iv PGI, whereas 12 patients (7 female, 43 +/- 12 years, 5 IPAH, 6 CTD, 1 porto-pulmonary hypertension) were commenced on inh ilo with a median dose of 120 μg/24 h. Haemodynamic parameters and 6 min walking distance (6MWD) at baseline did not differ between both groups., Results: After 3 months therapy, patients on iv PGI showed a significant increase in 6MWD from 220 to 280 m (p < 0.01), whereas patients on high dose inh ilo increased 6MWD from 200 to 275 m (p < 0.05). The event free follow up was 23 [1-76] months in the iv PGI2I group, and 16 [7-38] months in the high dose inh ilo group (p < 0.05). Patients with a 6MWD ≥ 300 m after 3 months therapy had a significantly longer event free follow up [16 vs. 35 months; p < 0.004]., Conclusion: In this patient population with severe pulmonary hypertension of different etiologies, event free follow up on treatment with iv PGI is significantly longer compared to high dose inh ilo. The 6MWD after 3 months treatment might be predictive for long term outcome., (Copyright © 2010 Elsevier Ltd. 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.)

A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Transplantation Society (BTS) has reviewed the available literature and made recommendations for the diagnosis and management of post-transplant lymphoproliferative disorder (PTLD) in adult recipients of solid organ transplants. This review details the risk factors predisposing to development, initial features and diagnosis. It is important that the risk of developing PTLD is considered when using post transplant immunosuppression and that the appropriate investigations are carried out when there are suspicions of the diagnosis. These must include tissue for histology and computed tomography scan to assess the extent of disease. These recommendations have been made primarily for adult patients, there have been some comments made with regard to paediatric practice.

A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Transplantation Society (BTS) has reviewed the available literature and made recommendations for the diagnosis and management of post-transplant lymphoproliferative disorder in adult recipients of solid organ transplants. This review details the therapeutic options recommended including reduction in immunosuppression (RIS), transplant organ resection, radiotherapy and chemotherapy. Effective therapy should be instituted before progressive disease results in declining performance status and multi-organ dysfunction. The goal of treatment should be a durable complete remission with retention of transplanted organ function with minimal toxicity.

Objective: The Thoratec (Thoratec Corp, Pleasanton, Calif) implantable ventricular assist device (IVAD) can be used for univentricular or biventricular support. The objective of this study is to review the 5-year experience of bridging patients to heart transplantation with this device in a single center. Surgical aspects, including hybrid pump pocket, double tunneling of driveline, and optimal cannulae placement, are discussed., Methods: This is a retrospective review of 24 patients treated between January 2002 and December 2007. Nineteen patients (79.1%) received a single implantable ventricular assist device as left ventricular assist devices, and 5 patients (21.9%) received 2 implantable ventricular assist devices as biventricular assist devices. The devices were implanted in pre-peritoneal/posterior rectus hybrid pump pockets. The driveline was passed through a 2-stage double-tunnel to exit onto the lateral chest wall. Patients were anticoagulated with Warfarin aiming for an international normalized ratio of 2.0 to 3.0., Results: Twenty male and 4 female patients with a mean age of 39.8 years (17-57 years) and a body surface area of 1.87 m(2) (1.63-2.2 m(2)) were supported for a total of 2308 patient-days. Mean duration of support was 96 days (10-301 days). The cause of heart failure was dilated cardiomyopathy in 18 patients and ischemic cardiomyopathy in 6 patients. Preoperatively, 23 patients were receiving inotropes, 12 patients required intra-aortic balloon pump support, 5 patients were intubated and mechanically ventilated, and 3 patients required continuous venovenous hemofiltration for renal support. Eleven patients (45.8%) were discharged with ventricular assist device support (1015 home patient-days). Complications observed were a) neurologic: stroke in 3 patients, transient ischemic attacks in 4 patients; and b) infection: driveline infection in 3 patients and pump pocket infection in 1 patient. There was no mechanical device failure. Support to transplantation was achieved in 17 patients (70.8%): 3 of 5 biventricular assist devices (60%) and 14 of 19 left ventricular assist devices (73.7%)., Conclusion: The Thoratec IVAD is a versatile and reliable ventricular assist device. It can provide univentricular or biventricular support for bridging patients to heart transplantation with acceptable complication rates. The portable Thoratec TLC-II console facilitated discharge while patients waited for a suitable donor heart., (Crown Copyright 2010. Published by Mosby, Inc. 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.

Background: Malignancy is an important complication after heart transplantation. The incidence, spectrum, risk factors, and clinical impact of posttransplant malignancy were investigated in a cohort of patients with long-term follow-up at a single center., Methods: Data for 835 patients who underwent heart transplantation between 1979 and 2002 and survived beyond one month were retrospectively evaluated for posttransplant skin cancer, solid organ tumors, and lymphoma., Results: One hundred thirty-nine malignancies developed in 126 patients (15.1%). Skin cancer, solid organ tumors, and lymphoma represented 49%, 27%, and 24% of the malignancies, respectively. Mean patient age at transplantation for patients developing skin cancer, solid organ tumor, and lymphoma were 50 years, 51 years, and 46 years, respectively (p = 0.024). Risk factors for skin cancer were: age greater than 40 at transplantation, number of treated rejection episodes in the first year after transplantation, and smoking history. Variables associated with solid organ malignancy development were age and smoking history. There was no variable related to the development of posttransplant lymphoma. Median survival after diagnosis of skin cancer, solid organ tumor, and lymphoma were 5.0 years, 0.3 years, and 0.7 years, respectively (p < 0.001)., Conclusions: Posttransplant malignancies have different risk factors and variable clinical impact. Older age at transplantation, smoking history, and more episodes of treated rejection were related to increased incidence of nonlymphoid malignancy incidence after heart transplantation, whereas no variable was associated with lymphoid malignancy. Skin cancers have a benign course, while solid organ malignancies and lymphomas carry an unfavorable prognosis.

Purpose of Review: Anaesthetizing a patient who benefited from a heart transplant will undoubtedly fascinate any anaesthetist. Basic principles need to be adhered to in order to ensure that no unnecessary harm is caused to these patients. Furthermore, the conscientious anaesthetist will want to remain abreast of the advances in the understanding of physiological changes occurring over the years after transplantation and the continuous innovations in the field of immunosuppression., Recent Findings: Understanding of the mechanisms surrounding cardiac allograft vasculopathy and insight into the possibility of reinnervation are continuously evolving; but changes in therapeutic regimens in an attempt to lower side effects have probably a greater impact on day-to-day clinical practice., Conclusion: Understanding how to administer fluids adequately to a transplant patient; how to use direct vasoactive agents; how to manage the infectious risk; and the need to be aware of the multiple side effects of immunosuppressive regimens are essential to recognize, prevent or treat possible perioperative complications.

Aims: Heart transplant assessment includes cardiac output calculation by right heart catheterisation. Real-time 3D echocardiography (RT-3DE), unlike 2D echocardiography, can measure stroke volume without inaccurate geometrical assumptions. The purpose of this study was to assess the feasibility and accuracy of non-invasive RT-3DE cardiac output calculation., Methods and Results: Forty consecutive patients referred for transplant assessment underwent transthoracic RT-3DE. Full volume 3DE data sets were acquired from apical views with the iE33 ultrasound system (Philips Ultrasound, Bothell, USA). Four patients were excluded due to poor image quality. The remaining 36 patients had end-diastolic (LVEDV) and end-systolic (LVESV) left ventricular volumes manually traced, using endocardial detection software. Cardiac output was subsequently calculated: [(LVEDV - LVESV) x heart rate]. Thermodilution derived cardiac outputs, under the same haemodynamic conditions, were used as reference for comparison. There was close correlation between RT-3DE and catheter derived cardiac outputs (r = 0.91, y = 0.86x + 0.45, SEE 0.39 L/min, mean difference from reference -0.06 L/min, SD 0.40 L/min). RT-3DE data analysis took 3 min per case., Conclusion: This study shows RT-3DE is an accurate method for calculating cardiac output. In patients requiring serial evaluation of cardiac function, this non-invasive test may be preferable to invasive right heart catheterisation.

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.

Subtraction hybridization applied to a 'differentiation therapy' model of cancer employing human melanoma cells resulted in the cloning of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24). Initial studies confirm an inverse correlation between mda-7 expression and melanoma development and progression. Forced expression of mda-7 by means of a plasmid or via a replication incompetent adenovirus (Ad.mda-7) promotes growth suppression and induces apoptosis in a broad array of human cancers. In contrast, mda-7 does not induce growth suppressive or toxic effects in normal cells. Based on structure (containing an IL-10 signature motif), secretion by cells (including subsets of T-cells) and location on chromosome 1q (in an area containing IL-10-family genes), mda-7 has now been renamed mda-7/IL-24. Studies by several laboratories have uncovered many of mda-7/IL-24's unique properties, including cancer-specific apoptosis-induction, cell cycle regulation, an ability to inhibit angiogenesis, potent 'bystander antitumor activity' and a capacity to enhance the sensitivity of tumor cells to radiation, chemotherapy and monoclonal antibody therapy. Moreover, based on its profound cancer tropism, substantiated by in vivo human xenograft studies in nude mice, mda-7/IL-24 (administered as Ad.mda-7) was evaluated in a phase I clinical trial in patients with melanomas and solid cancers. These studies document that mda-7/IL-24 is well tolerated and demonstrates evidence of significant clinical activity. In these contexts, mda-7/IL-24 represents a unique cytokine gene with potential for therapy of human cancers. The present review focuses on three unique properties of mda-7/IL-24, namely its potent 'bystander antitumor activity', ability to sensitize tumor cells to radiation, and its antiangiogenesis properties. Additionally, an overview of the phase I clinical trial is provided. These studies affirm that mda-7/IL-24 has promise for the management of diverse cancers.

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.

Objective: Cardiac arrest in the organ donor raises concerns about the possibility of ischemic cardiac damage. We evaluated the outcome of heart transplantation in patients receiving an organ from donors who had suffered a period of cardiac arrest., Methods: Demographics, operative details and outcome data were obtained retrospectively. Actuarial survival was reported using Kaplan-Meier analysis and compared with the log rank test. Cox proportional hazards regression was used to model risk adjusted survival., Results: Between 1 January 1991 and 1 November 2004 38 patients were transplanted with hearts from multiorgan donors who were resuscitated after a cardiac arrest. The mean (standard deviation) duration of cardiac arrest was 15 (8)min. The interval between donor cardiac arrest and organ excision was 69 (5)h. The 30-day mortality was 2.6% (1/38). In the same interim 566 patients underwent cardiac transplantation with hearts from organ donors without a cardiac arrest. Median time to follow up was 61 months (IQR 15-166). One and 5-year survival comparing the arrest and non-arrest groups was 94.2% versus 83.6% and 79.8% versus 74.5%, respectively, p=0.35. Donor cardiac arrest was not an adverse predictor of mortality on multivariate analysis, the adjusted odds ratio was 0.86 (95% CI 0.60-1.25, p=0.42)., Conclusions: With careful case selection, there was no evidence that survival after cardiac transplantation was worse following a period of cardiac arrest in the organ donor. A history of cardiac arrest in the organ donor should not exclude an organ from being considered for transplantation.