Prioritising transplantation for adult congenital heart disease, UK national data.

OBJECTIVE: There are no multi-centre data on the outcomes of transplant for adult congenital heart disease (ACHD) outside of North America. The literature has identified a number of concerns for this population such as increased wait-list and early post-operative mortality. We investigated outcomes in a national cohort to see if these problems are replicated outside of America. METHODS: Adults (aged ≥16 years) undergoing primary heart transplantation 1995-2014 were identified in the UK Registry and registration, operative and post-transplantation related clinical factors were compared to non ACHD recipients. RESULTS: Of 3026 adults who underwent primary heart transplantation, 134 (4.4%) had ACHD (median age 30 years; 40.3% female). For the ACHD patients listed as urgent status, the time to transplant was not significantly different to non ACHD patients and ACHD were not more likely to die or be removed from the wait list. Despite ACHD recipients having longer hospital stays (27 vs. 22 days; p = 0.003) and worse 90-day survival (79.5% vs. 86.6%; p = 0.02), long-term post-transplantation survival was not significantly different. Creatinine clearance was significantly better in ACHD patients at follow-up. In the last 10 years of our study period, all single ventricle transplants have been restricted to experienced ACHD teams, one year survival for Fontan patients was 89.5%. CONCLUSIONS: The use of urgent listing appears to have benefited the ACHD group by allowing equal access to transplantation, and recent concentration of expertise for single ventricle transplants has been associated with excellent early survival.

Heart or heart-lung transplantation for patients with congenital heart disease in England.

BACKGROUND: Increased longevity in patients with congenital heart disease (CHD) is associated with late complications, mainly heart failure, which may not be amenable to redo surgery and become refractory to medical therapy and so, trigger referral for transplantation. We assessed the current role and future prospects of heart and heart-lung transplantation for patients with CHD in England. METHODS: We performed a retrospective analysis of hospital episodes for England for 1997-2015, identifying patients with a CHD code (ICD-10 'Q2xx.x'), who underwent heart or heart-lung transplantation. RESULTS: In total, 469 transplants (82.2% heart and 17.8% heart-lung) were performed in 444 patients. Half of patients transplanted had mild or moderate CHD complexity, this percentage increased with time (p=0.001). While overall, more transplantations were performed over the years, the proportion of heart-lung transplants declined (p<0.0001), whereas the proportion of transplants performed in adults remained static. Mortality was high during the first year, especially after heart-lung transplantation, but remained relatively low thereafter. Older age and heart-lung transplantation were strong predictors of death. While an increase in CHD transplants is anticipated, actual numbers in England seem to lag behind the increase in CHD patients with advanced heart failure. CONCLUSIONS: The current and future predicted increase in the numbers of CHD transplants does not appear to parallel the expansion of the CHD population, especially in adults. Further investment and changes in policy should be made to enhance the number of donors and increase CHD transplant capacity to address the increasing numbers of potential CHD recipients and optimise transplantation outcomes in this growing population.

ISHLT Primary Graft Dysfunction Incidence, Risk Factors, and Outcome: A UK National Study.

BACKGROUND: Heart transplantation (HTx) remains the most effective long-term treatment for advanced heart failure. Primary graft dysfunction (PGD) continues to be a potentially life-threatening early complication. In 2014, a consensus statement released by International Society for Heart and Lung Transplantation (ISHLT) established diagnostic criteria for PGD. We studied the incidence of PGD across the United Kingdom. METHODS: We analyzed the medical records of all adult patients who underwent HTx between October 2012 and October 2015 in the 6 UK heart transplant centers Preoperative donor and recipient characteristics, intraoperative details, and posttransplant complications were compared between the PGD and non-PGD groups using the ISHLT definition. Multivariable analysis was performed using logistic regression. RESULTS: The incidence of ISHLT PGD was 36%. Thirty-day all-cause mortality in those with and without PGD was 31 (19%) versus 13 (4.5%) (P = 0.0001). Donor, recipient, and operative factors associated with PGD were recipient diabetes mellitus (P = 0.031), recipient preoperative bilateral ventricular assist device (P < 0.001), and preoperative extracorporeal membranous oxygenation (P = 0.023), female donor to male recipient sex mismatch (P = 0.007), older donor age (P = 0.010), and intracerebral haemorrhage/thrombosis in donor (P = 0.023). Intraoperatively, implant time (P = 0.017) and bypass time (P < 0.001) were significantly longer in the PGD cohort. Perioperatively, patients with PGD received more blood products (P < 0.001). Risk factors identified by multivariable logistic regression were donor age (P = 0.014), implant time (P = 0.038), female: male mismatch (P = 0.033), recipient diabetes (P = 0.051) and preoperative ventricular assist device/extracorporeal membranous oxygenation support (P = 0.012). CONCLUSIONS: This is the first national study to examine the incidence and significance of PGD after HTx using the ISHLT definition. PGD remains a frequent early complication of HTx and is associated with increased mortality.

Right atrial and ventricular echocardiographic strain analysis predicts requirement for right ventricular support after left ventricular assist device implantation.

Aims: The need for right ventricular assist device (RVAD) support after left ventricular assist device (LVAD) therapy is associated with increased morbidity and mortality. We used 2D echocardiographic strain analysis to assess right atrial (RA) and right ventricular (RV) mechanics and predict the need for RV mechanical support after LVAD implantation. Methods and results: Seventy advanced chronic heart failure (ACHF) patients [59 male, age 47 ± 12 years, 79% dilated cardiomyopathy, left ventricular ejection fraction 23 ± 10%] received continuous-flow LVAD as a bridge to transplantation over an 18 month period. A retrospective analysis of RV and RA strain and right heart dyssynchrony was performed comparing those requiring RVAD (20%, n = 14) with those who did not (non-RVAD 80%, n = 56). One-year survival was significantly lower in the RVAD group (50% vs. 79%; P < 0.03). Independent predictors of RVAD support were: low peak RA longitudinal strain (RALS) [odds ratio (OR) 2.5, 95% confidence interval (95% CI) 1.37-2.0; P = 0.03], low RV free-wall longitudinal strain (RVFWLS) (OR 1.3, 95% CI 1.03-2.3; P = 0.04), and degree of intra-RV dyssynchrony (DRVFW-IVS, OR 1.3, 95% CI 1.02-1.3; P = 0.04). Conclusion: In LVAD recipients needing RVAD support, there was lower RALS and RVFWLS in addition to greater RV free-wall mechanical delay. We conclude that RA and RV strain and dyssynchrony analysis have the potential to add incremental value to the pre-VAD-implantation assessment made using conventional echo measurements.

Patient survival and therapeutic outcome in the UK bridge to transplant left ventricular assist device population.

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.

Durable left ventricular assist device support as a bridge to heart transplant candidacy†.

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 interval between brainstem death and cardiac assessment influences the retrieval of hearts for transplantation.

OBJECTIVES: The optimum time after brainstem death (BSD) at which to assess the function of donor hearts is unknown. We hypothesized that a longer interval may be associated with a higher transplantation rate due to improved function. METHODS: Data were obtained from the UK Transplant Registry for the period between April 2010 and March 2015. The time when fixed dilated pupils were first noted in the donor was considered as the time of BSD. Retrieval was defined as the time when the abdominal organs were surgically perfused. RESULTS: BSD to retrieval duration was available for 1947 donors, of which 458 (24%) donated their heart. In the univariable analysis (not adjusting other donor risk factors), evidence was available to suggest that the BSD to cardiac assessment duration had a non-linear association with heart utilization (P < 0.0001). Adjusting for donor risk factors, the relationship remained with longer intervals being associated with increased transplantation (P = 0.0056). The modelled probability of heart utilization had a similar pattern to the observed rate of heart utilization. However, the probability of heart donation began to plateau after approximately 48 h. The analysis of the subset of donors attended by a cardiothoracic retrieval team showed a similar pattern. CONCLUSIONS: These data suggest that time interval from BSD to organ retrieval influences the heart retrieval rate. When the sole reason for declining a donor heart is poor function, a period of further observation and optimization up to 2 days should be considered.

Cardiac transplantation in a 20-year-old woman with scleroderma.

Purpose: To describe cardiac transplantation in a young woman with juvenile onset diffuse scleroderma and cardiac involvement. Methods: Case report. Results: A young White girl developed anti-topoisomerase-1 positive diffuse scleroderma aged 14 years with myositis. Pulmonary function tests were normal. Skin disease was treated with mycophenolate mofetil 1 g twice daily, methotrexate 7.5 mg weekly and periodic intravenous prostacyclin. When aged 17 years, she developed raised troponin T of 0.207 mcg/L (normal range <0.03) and NTproBNP (155 pmol/L); 6-min walking distance was 341 m, and she had episodes of presyncope with effort. The next year she developed symptomatic ventricular tachycardias and dual-chamber implantable cardioverter-defibrillator was inserted, with further episodes of ventricular tachycardia and one shock delivered. By age 19 years, 6-min walking distance was 125 m. Echocardiography showed ejection fraction of 15%-20% with dilated left ventricle and pericardial effusion. She was treated with intravenous Rituximab. She became breathless while dressing and managed only 118 m in 6 min. She experienced increasing orthopnoea and peripheral oedema and was found to be in a low cardiac output state, requiring treatment with intravenous milrinone to maintain renal function. She underwent orthotopic cardiac transplantation, making an excellent post-operative recovery, and was discharged 16 days later with tacrolimus, mycophenolate mofetil and prednisolone. After 1 year, she was in New York Heart Association functional class I and with normal cardiac function on echocardiography. Conclusion: This case illustrates the severe cardiac involvement that can occur in juvenile onset diffuse cutaneous systemic sclerosis, in which cardiac involvement is the leading cause of death.

Acute fulminant necrotizing eosinophilic myocarditis: early diagnosis and treatment.

Necrotizing eosinophilic myocarditis is a rare but potentially fatal condition that requires prompt recognition and treatment. We describe a case of a young athlete presenting with chest pain and breathlessness, with evidence of rapidly deteriorating cardiac function. The condition was successfully treated with corticosteroids, with no evidence of residual myocardial damage. This is the first reported case to demonstrate the utility of cardiac magnetic resonance imaging for diagnosis and monitoring response to treatment. It also highlights the value of endomyocardial biopsy in establishing a tissue diagnosis in cases of fulminant myocarditis, in order to direct treatment appropriately.

Algorithms to guide ambulance clinicians in the management of emergencies in patients with implanted rotary left ventricular assist devices.

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.

Quality of life of advanced chronic heart failure: medical care, mechanical circulatory support and transplantation.

OBJECTIVES: Advanced chronic heart failure (ACHF) is progressive with poor prognosis and quality of life (QoL). Heart transplantation (HTx) is an effective treatment for ACHF, but is limited by scarcity of donor hearts. Left ventricular assist device (LVAD) support is a useful bridging therapy, and short- and medium-term outcomes have improved. We investigated QoL in patients assessed for HTx, awaiting HTx and after HTx. METHODS: We carried out a cross-sectional survey across four groups: Group 1-patients assessed for HTx, Group 2-patients listed for HTx on medical therapy, Group 3-patients supported with LVAD and Group 4-patients after HTx. Two questionnaires, the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the EuroQol dimensions (EQ-5D), were administered in all adult HTx centres in the UK. Scores calculated for the KCCQ and EQ-5D were compared. RESULTS: Three hundred and eighty-six patients completed questionnaires: 194 in Group 1, 28 in Group 2, 82 in Group 3 and 82 in Group 4. Patients after HTx reported the best QoL [KCCQ overall summary score: mean 73.0 (SD 27.2)]; patients with LVAD reported better QoL than those being assessed for HTx and those listed for HTx on medical therapy [overall summary score; LVAD: 52.6 (22.0), Listed on medical therapy: 33.3 (21.1), ASSESSMENT: 35.5 (21.5)]. Similarly, EQ-5D scores were highest in patients after HTx [HTx: mean 0.74 (0.27); LVAD: 0.58 (0.26), Listed on medical therapy: 0.44 (0.27), ASSESSMENT: 0.50 (SD 0.30)]. CONCLUSIONS: Patients supported with LVAD had a significantly better QoL than those awaiting HTx without LVAD support, although HTx patients reported the best QoL.

Investigation of the Characteristics of HeartWare HVAD and Thoratec HeartMate II Under Steady and Pulsatile Flow Conditions.

The aim of this study was to elucidate the dynamic characteristics of the Thoratec HeartMate II (HMII) and the HeartWare HVAD (HVAD) left ventricular assist devices (LVADs) under clinically representative in vitro operating conditions. The performance of the two LVADs were compared in a normothermic, human blood-filled mock circulation model under conditions of steady (nonpulsatile) flow and under simulated physiologic conditions. These experiments were repeated using 5% dextrose in order to determine its suitability as a blood analog. Under steady flow conditions, for the HMII, approximately linear inverse LVAD differential pressure (H) versus flow (Q) relationships were observed with good correspondence between the results of blood and 5% dextrose under all conditions except at a pump speed of 9000 rpm. For the HVAD, the corresponding relationships were inverse curvilinear and with good correspondence between the blood-derived and 5% dextrose-derived relationships in the flow rate range of 2-6 L/min and at pump speeds up to 3000 rpm. Under pulsatile operating conditions, for each LVAD operating at a particular pump speed, an counterclockwise loop was inscribed in the HQ domain during a simulated cardiac cycle (HQ loop); this showed that there was a variable phase relationship between LVAD differential pressure and LVAD flow. For both the HMII and HVAD, increasing pump speed was associated with a right-hand and upward shift of the HQ loop and simulation of impairment of left ventricular function was associated with a decrease in loop area. During clinical use, not only does the pressure differential across the LVAD and its flow rate vary continuously, but their phase relationship is variable. This behavior is inadequately described by the widely accepted representation of a plot of pressure differential versus flow derived under steady conditions. We conclude that the dynamic HQ loop is a more meaningful representation of clinical operating conditions than the widely accepted steady flow HQ curve.

Does postoperative blood pressure influence development of aortic regurgitation following continuous-flow left ventricular assist device implantation?†.

OBJECTIVES: The true impact of postoperative blood pressure (BP) control on development of aortic regurgitation (AR) following continuous-flow left ventricular assist device (CF-LVAD) implantation remains uncertain. This study examines the influence of BP in patients with de novo AR following CF-LVAD implantation. METHODS: All patients with no or

Preoperative predictors and outcomes of right ventricular assist device implantation after continuous-flow left ventricular assist device implantation.

OBJECTIVE: The outcomes of ventricular assist device therapy remain limited by right ventricular failure. We sought to define the predictors and evaluate the outcomes of right ventricular failure requiring right ventricular assist device support after long-term continuous-flow left ventricular assist device implantation. METHODS: Records of all continuous-flow left ventricular assist device recipients for the last 10 years were analyzed, including patients on preoperative intra-aortic balloon pump, extracorporeal membrane oxygenation, and short-term ventricular assist device support. Perioperative clinical, echocardiographic, hemodynamic, and laboratory data of continuous-flow left ventricular assist device recipients requiring right ventricular assist device support (right ventricular assist device group) were compared with the rest of the patient cohort (control group). RESULTS: Between July 2003 and June 2013, 152 patients underwent continuous-flow left ventricular assist device implantation as a bridge to transplantation. The overall postoperative incidence of right ventricular assist device support was 23.02% (n = 35). Right ventricular assist device implantation did not significantly affect eventual transplantation (P = .784) or longer-term survival (P = .870). Preoperative right ventricular diameter (P < .001), tricuspid annular plane systolic excursion (P < .001), previous sternotomy (P = .002), preoperative short-term mechanical support (P = .005), left atrial diameter (P = .014), female gender (P = .020), age (P = .027), and preoperative bilirubin levels (P = .031) were univariate predictors of right ventricular assist device implantation. Multivariate analysis revealed lesser tricuspid annular plane systolic excursion (P = .013; odds ratio, 0.613; 95% confidence interval, 0.417-0.901) and smaller left atrial diameter (P = .007; odds ratio, 0.818; 95% confidence interval, 0.707-0.947) as independent predictors of right ventricular assist device implantation. Receiver operating characteristic curve of tricuspid annular plane systolic excursion yielded an area under the curve of 0.85 (95% confidence interval, 0.781-0.923), with cutoff tricuspid annular plane systolic excursion less than 12.5 mm having 84% sensitivity and 75% specificity. CONCLUSIONS: Lesser tricuspid annular plane systolic excursion and smaller left atrial diameter are independent predictors of the need for right ventricular assist device support after continuous-flow left ventricular assist device implantation. Right ventricular assist device implantation does not adversely affect eventual transplantation or survival after continuous-flow left ventricular assist device implantation.

Usefulness of Rabbit Anti-thymocyte Globulin in Patients With Giant Cell Myocarditis.

Giant cell myocarditis (GCM) is an aggressive inflammatory myocardial disease. Immunosuppression is an effective treatment for some cases. However, the duration of action of agents such as muromonab CD3 is short and others such as the calcineurin inhibitors may lead to renal failure. Here we describe the outcome of a novel approach to treatment using rabbit anti-thymocyte globulin (RATG). A retrospective analysis of 6 patients treated with RATG for GCM was performed. Diagnosis was confirmed by endomyocardial biopsy, and RATG was administered with a high dose of corticosteroids. None of the patients had cytokine release syndrome or leukopenia, and 5 had thrombocytopenia (2 of them severe). Only 1 had a serious bleeding event that occurred after implantation of mechanical circulatory support. None developed impaired renal function after the treatment. Five were successfully discharged home with an increase in global left ventricular ejection fraction of 29%. Four are currently alive without recurrent disease, 1 of them after heart transplantation, with a mean follow-up of 970 days (423 to 1,875 days), left ventricular ejection fraction of 53%, and all in current New York Heart Association Classification class ≤II. Only 1 case had GCM recurrence. There were 2 deaths: one because of intracranial bleeding after mechanical circulatory support implantation and the other caused by primary graft dysfunction. In conclusion, patients with GCM can be successfully immunosuppressed with RATG and corticosteroids, thereby avoiding renal impairment. Early thrombocytopenia is the main adverse event. Larger cohorts of patients are necessary to compare the different immunosuppressant strategies available for GCM in a randomized fashion.

Acute sirolimus overdose: a multicenter case series.

BACKGROUND: There are few data relating to sirolimus overdose in the medical literature. Our objectives were to describe all cases of overdose with sirolimus reported to Swiss, German and Austrian Poisons Centres between 2002-2013. METHODS: An observational case-series analysis was performed to determine circumstances, magnitude, management and outcome of sirolimus overdose. RESULTS: Five cases of acute sirolimus overdose were reported--three in young children and two in adults. Four were accidental and one was with suicidal intent. Two patients developed symptoms probably related to sirolimus overdose: mild elevation of alkaline phosphatase, fever and gastroenteritis in a 2.5-year-old male who ingested 3 mg, and mild changes in total cholesterol in an 18-year-old female after ingestion of 103 mg. None of these events were life-threatening. Serial blood concentration measurements were performed starting 24 h after ingestion of 103 mg in a single case, and these followed a similar pharmacokinetic time-course to measurements taken after dosing in the therapeutic range. CONCLUSIONS: Acute sirolimus overdose occurred accidentally in the majority of cases. Even large overdoses appeared to be well-tolerated, however children might be at greater risk of developing complications. Further study of sirolimus overdose is needed.

The Current and Future Landscape of SERCA Gene Therapy for Heart Failure: A Clinical Perspective.

Gene therapy has been applied to cardiovascular disease for over 20 years but it is the application to heart failure that has generated recent interest in clinical trials. There is laboratory and early clinical evidence that delivery of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy is beneficial for heart failure and this therapy could become the first positive inotrope with anti-arrhythmic properties. In this review we will discuss the rationale for SERCA2a gene therapy as a viable strategy in heart failure, review the published data, and discuss the ongoing clinical trials, before concluding with comments on the future challenges and potential for this therapy.