Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial.

BACKGROUND: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is an established treatment for heart failure (HF) with reduced left ventricular ejection fraction. It has not been rigorously compared with angiotensin-converting enzyme inhibitors in children. PANORAMA-HF (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF) is a randomized, double-blind trial that evaluated the pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy of sacubitril/valsartan versus enalapril in children 1 month to <18 years of age with HF attributable to systemic left ventricular systolic dysfunction (LVSD). METHODS: Children with HF attributable to LVSD were randomized to sacubitril/valsartan versus enalapril to assess the efficacy and safety of sacubitril/valsartan at 52 weeks of follow-up. The primary end point of the study was to determine whether sacubitril/valsartan was superior to enalapril for the treatment of pediatric patients with HF attributable to systemic LVSD, assessed using a primary global rank end point consisting of ranking patients from worst to best on the basis of clinical events such as death, listing for urgent heart transplant, mechanical life support requirement, worsening HF, New York Heart Association (NYHA)/Ross class, Patient Global Impression of Severity (PGIS), and Pediatric Quality of Life Inventory physical functioning domain. The change from baseline to 52 weeks in NT-proBNP (N-terminal pro-B-type natriuretic peptide) was an exploratory end point. RESULTS: A total of 375 children (mean age, 8.1±5.6 years; 52% female) were randomized to sacubitril/valsartan (n=187) or enalapril (n=188). At week 52, no significant difference was observed between the 2 treatment arms in the global rank end point (Mann-Whitney probability, 0.52 [95% CI, 0.47-0.58]; Mann-Whitney odds, 0.91 [95% CI, 0.72-1.14]; P=0.42). At week 52, clinically meaningful reductions were observed in both treatment arms in NYHA/Ross, PGIS, Patient Global Impression of Change, and NT-proBNP, without significant differences between groups. Adverse events were similar between treatment arms (incidence: sacubitril/valsartan, 88.8%; enalapril, 87.8%), and the safety profile of sacubitril/valsartan was acceptable in children. CONCLUSIONS: In this study, sacubitril/valsartan did not show superiority over enalapril in the treatment of children with HF attributable to systemic LVSD using the prespecified global rank end point. However, both treatment arms showed clinically meaningful improvements over 52 weeks. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02678312.

Rapid desensitization through immunoadsorption during cardiopulmonary bypass. A novel method to facilitate human leukocyte antigen incompatible heart transplantation.

BACKGROUND: Anti-human leukocyte antigen (HLA)-antibody production represents a major barrier to heart transplantation, limiting recipient compatibility with potential donors and increasing the risk of complications with poor waiting-list outcomes. Currently there is no consensus to when desensitization should take place, and through what mechanism, meaning that sensitized patients must wait for a compatible donor for many months, if not years. We aimed to determine if intraoperative immunoadsorption could provide a potential desensitization methodology. METHODS: Anti-HLA antibody-containing whole blood was added to a Cardiopulmonary bypass (CPB) circuit set up to mimic a 20 kg patient undergoing heart transplantation. Plasma was separated and diverted to a standalone, secondary immunoadsorption system, with antibody-depleted plasma returned to the CPB circuit. Samples for anti-HLA antibody definition were taken at baseline, when combined with the CPB prime (on bypass), and then every 20 min for the duration of treatment (total 180 min). RESULTS: A reduction in individual allele median fluorescence intensity (MFI) to below clinically relevant levels (<1000 MFI), and in the majority of cases below the lower positive detection limit (<500 MFI), even in alleles with a baseline MFI >4000 was demonstrated. Reduction occurred in all cases within 120 min, demonstrating efficacy in a time period usual for heart transplantation. Flowcytometric crossmatching of suitable pseudo-donor lymphocytes demonstrated a change from T cell and B cell positive channel shifts to negative, demonstrating a reduction in binding capacity. CONCLUSIONS: Intraoperative immunoadsorption in an ex vivo setting demonstrates clinically relevant reductions in anti-HLA antibodies within the normal timeframe for heart transplantation. This method represents a potential desensitization technique that could enable sensitized children to accept a donor organ earlier, even in the presence of donor-specific anti-HLA antibodies.

Isolation and expansion of thymus-derived regulatory T cells for use in pediatric heart transplant patients.

Regulatory T-cells (Tregs) are a subset of T cells generated in the thymus with intrinsic immunosuppressive properties. Phase I clinical trials have shown safety and feasibility of Treg infusion to promote immune tolerance and new studies are ongoing to evaluate their efficacy. During heart transplantation, thymic tissue is routinely discarded providing an attractive source of Tregs. In this study, we developed a GMP-compatible protocol for expanding sorted thymus-derived CD3+ CD4+ CD25+ CD127- (Tregs) as well as CD3+ CD4+ CD25+ CD127- CD45RA+ (RA+ Tregs) cells. We aimed to understand whether thymic RA+ Tregs can be isolated and expanded offering an advantage in terms of stability as it has been previously shown for circulating adult CD45RA+ Tregs. We show that both Tregs and RA+ Tregs could be expanded in large numbers and the presence of rapamycin is essential to inhibit the growth of IFN-γ producing cells. High levels of FOXP3, CTLA4, and CD25 expression, demethylation of the FOXP3 promoter, and high suppressive ability were found with no differences between Tregs and RA+ Tregs. After freezing and thawing, all Treg preparations maintained their suppressive ability, stability, as well as CD25 and FOXP3 expression. The number of thymic Tregs that could be isolated with our protocol, their fold expansion, and functional characteristics allow the clinical application of this cell population to promote tolerance in pediatric heart transplant patients.

T cell phenotype in paediatric heart transplant recipients.

Paediatric heart transplantation recipients suffer an increased incidence of infectious, autoimmune and allergic problems. The relative roles of thymus excision and immunosuppressive treatments in contributing to these sequelae are not clear. We compared the immunological phenotypes of 25 heart transplant recipients (Tx), 10 children who underwent thymus excision during non-transplantation cardiac surgery (TE) and 25 age range-matched controls, in two age bands: 1-9 and 10-16 years. Significant differences from controls were seen mainly in the younger age band with Tx showing lower CD3 and CD4 cell counts whilst TE showed lower CD8 cell counts. Naïve T cell and recent thymic emigrant proportions and counts were significantly lower than controls in both groups in the lower age band. T cell recombination excision circle (TREC) levels were lower than controls in both groups in both age bands. There were no differences in regulatory T cells, but in those undergoing thymus excision in infancy, their proportions were higher in TE than Tx, a possible direct effect of immunosuppression. T cell receptor V beta spectratyping showed fewer peaks in both groups than in controls (predominantly in the older age band). Thymus excision in infancy was associated with lower CD8 cell counts and higher proportions of Tregs in TE compared to Tx. These data are consistent with thymus excision, particularly in infancy, being the most important influence on immunological phenotype after heart transplantation.

The complication rate of intravascular ultrasound (IVUS) in a multicenter pediatric heart transplant population: A study of the international pediatric IVUS consortium.

BACKGROUND: Our purpose was to determine the complication rate from intravascular ultrasound (IVUS) in a large, multicenter cohort of pediatric heart transplant (PHT) patients. METHODS: We retrospectively reviewed all PHT who underwent IVUS at 5 institutions (2006-2014). Rates of major and minor complications were calculated. All adverse events (AE) were graded from 1 to 5 using a previously published AE severity scale. RESULTS: There were 1380 catheterizations in 505 patients and 32 AE (2.3%); 9 major (0.6%) and 23 AE (1.7%). The major AE attributed to IVUS were all coronary artery vasospasm (7). Major and minor AE rates directly related to IVUS were 0.5% and 0.7%, respectively. Minor AE possibly attributable to IVUS included excessive fluoroscopy (3) and transient ST segment changes (7). Of AE related to IVUS, only 3 were of moderate severity. The rest were ≤ minor in severity. There were no reports of coronary artery dissection or death. CONCLUSION: Most AE during routine PHT coronary evaluation with IVUS were minor and not directly related to the use of IVUS. The number of coronary related AE was similar to a registry-based report of coronary angiography alone. Efforts to minimize IVUS-related complications should be focused on preventing coronary artery vasospasm.

Transplanted human thymus slices induce and support T-cell development in mice after cryopreservation.

Nude mouse human thymus transplant model: Fresh or cryopreserved and thawed human thymus slices were transplanted subcutaneously into recipient nude mice. Nude mice subsequently produced mouse CD3+ CD4+ T-cells.

Permanent pacemaker implantation after pediatric heart transplantation: Risk factors, indications, and outcomes.

BACKGROUND: Permanent pacemaker (PPM) placement in adults following orthotopic heart transplantation (OHT) has been well documented. However, studies concerning the need for PPM implantation in pediatric heart transplant recipients are less common. METHODS: Institutional transplant and pacing databases as well as patient medical records were reviewed for all pediatric patients undergoing OHT (n = 314; all with bicaval connection) at our institution between January 2000 and March 2018. RESULTS: A total of 16 patients (5.1%) were implanted with a pacemaker after transplantation. Donor age was the only significant risk factor for post-transplant PPM implantation, with a median age of 28.5 years (7.0-49.0) in the pacing group vs 15.5 years (0.4-56.0) in the non-pacing group (P = 0.009). Indication for pacemaker insertion was more often complete heart block (CHB) (12/16, 75%) than sinus node dysfunction (SND) (4/16, 25%). There was no significant difference in mortality between recipients who received a PPM and those who did not (log-rank test; P = 0.345). CONCLUSIONS: Increasing donor age is associated with increased PPM placement following pediatric heart transplantation. Interestingly, a high proportion of CHB patients recovered sinus rhythm, and long-term outcomes for paced patients are similar to other heart transplant recipients.

Pediatric heart transplantation in the current era.

PURPOSE OF REVIEW: To provide an international perspective and current review of pediatric heart transplantation (PHTx). RECENT FINDINGS: Waitlist survival and long-term outcomes in PHTx continue to improve. Strategies to maximize donor pool utilization include ABO incompatible listing for infants and expanded donor-to-recipient weight ranges. However, there is a high degree of practice variation internationally, from listing strategies and donor acceptance practices to chronic immunosuppression regimens, long-term graft surveillance, and consideration for retransplantation. SUMMARY: Common indications for PHTx include end-stage congenital heart disease and cardiomyopathy. Current median graft survival among PHTx recipients ranges from 13 to 22 years. Common morbidities include infection, rejection, renal dysfunction, coronary allograft vasculopathy, and posttransplant lymphoproliferative disease. International registry data, collaborative initiatives to standardize management, and multicenter studies continue to improve knowledge and advancement of the field.

The importance of qualitative and quantitative regional wall motion abnormality assessment at rest in pediatric coronary allograft vasculopathy.

CAV remains one of the main limiting factors for survival in children after heart transplantation. In this study, we explored the incremental value of routine CMR for evaluation and detection of CAV using qualitative and quantitative analysis of regional and global myocardial function and strain. This was a prospective imaging biomarker validation trial. Twenty-two patients (11 male), aged between 10 and 17 years (median 14 years) post-heart transplantation, were prospectively enrolled and underwent CMR in addition to their biennial review workup with Echo, angiography, and IVUS. Nine healthy control patients were enrolled to undergo CMR alone. Echo was used to analyze WMAs and systolic function. CMR images were analyzed qualitatively for RWMA and quantitatively for volumetric analysis, S and SR. All results were compared to IVUS and angiography assessments. Qualitatively, CMR detected RWMA corresponding to angiographic disease in 3 patients that were not detected on Echo. However, quantitative strain analysis suggested RWMA in an extra 9 patients. Detection of regional wall motion abnormality using quantitative strain analysis was associated with a higher mean stenosis grade (P=.04) and reduced graft survival (P=.04) compared to those with no quantitative wall motion abnormality. Overall, only longitudinal stain was abnormal in patients compared with controls, but there was no correlation between any of the global indices of S or SR and IVUS measurements. CMR is more sensitive than Echo for the visual detection of significant WMAs. Quantitative CMR strain analysis at rest may give additional information to discriminate those at greatest risk.

Systematic Literature Review on the Incidence and Prevalence of Heart Failure in Children and Adolescents.

While the epidemiology of adult heart failure has been extensively researched, this systematic review addresses the less well characterized incidence and prevalence of pediatric HF. The search strategy used Cochrane methodology and identified 83 unique studies for inclusion. Studies were categorized according to whether the HF diagnosis was reported as primary (n = 10); associated with other cardiovascular diseases (CVDs) (n = 49); or associated with non-CVDs (n = 24). A narrative synthesis of the evidence is presented. For primary HF, the incidence ranged from 0.87/100,000 (UK and Ireland) to 7.4/100,000 (Taiwan). A prevalence of 83.3/100,000 was reported in one large population-based study from Spain. HF etiology varied across regions with lower respiratory tract infections and severe anemia predominating in lower income countries, and cardiomyopathies and congenital heart disease major causes in higher income countries. Key findings for the other categories included a prevalence of HF associated with cardiomyopathies ranging from 36.1% (Japan) to 79% (US); associated with congenital heart disease from 8% (Norway) to 82.2% (Nigeria); associated with rheumatic heart diseases from 1.5% (Turkey) to 74% (Zimbabwe); associated with renal disorders from 3.8% (India) to 24.1% (Nigeria); and associated with HIV from 1% (US) to 29.3% (Brazil). To our knowledge, this is the first systematic review of the topic and strengthens current knowledge of pediatric HF epidemiology. Although a large body of research was identified, heterogeneity in study design and diagnostic criteria limited the ability to compare regional data. Standardized definitions of pediatric HF are required to facilitate cross-regional comparisons of epidemiological data.

Recommendations from the Association for European Paediatric and Congenital Cardiology for clinical training in paediatric heart failure and transplantation.

Advanced medical and surgical treatment of heart failure and management of patients following heart transplantation is an emerging area. Treatment options at various levels are becoming available in an increasing number of countries. This rapidly evolving field involves a complex multi-disciplinary approach with a number of complementary medical and surgical strategies, including pharmacotherapy, structural cardiac interventions, electrophysiological optimisation, mechanical circulatory support, and heart transplantation. Furthermore, the importance of psycho-social support and care of patients and their families cannot be overstated. The aforementioned challenges and dynamics of new developments require guidance for core and advanced medical training in heart failure and transplantation. The Association for European Paediatric and Congenital Cardiology working group "pulmonary hypertension, heart failure and transplantation" has produced this document as an expert consensus statement; however, all recommendations must be considered and applied in the context of the local and national infrastructure and legal regulations.

Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study).

BACKGROUND: Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor approved for the treatment of adult heart failure (HF); however, the benefit of sacubitril/valsartan in pediatric HF patients is unknown. STUDY DESIGN: This global multi-center study will use an adaptive, seamless two-part design. Part 1 will assess the pharmacokinetics/pharmacodynamics of single ascending doses of sacubitril/valsartan in pediatric (1 month to <18 years) HF patients with systemic left ventricle and reduced left ventricular systolic function stratified into 3 age groups (Group 1: 6 to <18 years; Group 2: 1 to <6 years; Group 3: 1 month to <1 year). Part 2 is a 52-week, efficacy and safety study where 360 eligible patients will be randomized to sacubitril/valsartan or enalapril. A novel global rank primary endpoint derived by ranking patients (worst-to-best outcome) based on clinical events such as death, initiation of mechanical life support, listing for urgent heart transplant, worsening HF, measures of functional capacity (NYHA/Ross scores), and patient-reported HF symptoms will be used to assess efficacy. CONCLUSION: The PANORAMA-HF study, which will be the largest prospective pediatric HF trial conducted to date and the first to use a global rank primary endpoint, will determine whether sacubitril/valsartan is superior to enalapril for treatment of pediatric HF patients with reduced systemic left ventricular systolic function.

Changes in health in England, with analysis by English regions and areas of deprivation, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

BACKGROUND: In the Global Burden of Disease Study 2013 (GBD 2013), knowledge about health and its determinants has been integrated into a comparable framework to inform health policy. Outputs of this analysis are relevant to current policy questions in England and elsewhere, particularly on health inequalities. We use GBD 2013 data on mortality and causes of death, and disease and injury incidence and prevalence to analyse the burden of disease and injury in England as a whole, in English regions, and within each English region by deprivation quintile. We also assess disease and injury burden in England attributable to potentially preventable risk factors. England and the English regions are compared with the remaining constituent countries of the UK and with comparable countries in the European Union (EU) and beyond. METHODS: We extracted data from the GBD 2013 to compare mortality, causes of death, years of life lost (YLLs), years lived with a disability (YLDs), and disability-adjusted life-years (DALYs) in England, the UK, and 18 other countries (the first 15 EU members [apart from the UK] and Australia, Canada, Norway, and the USA [EU15+]). We extended elements of the analysis to English regions, and subregional areas defined by deprivation quintile (deprivation areas). We used data split by the nine English regions (corresponding to the European boundaries of the Nomenclature for Territorial Statistics level 1 [NUTS 1] regions), and by quintile groups within each English region according to deprivation, thereby making 45 regional deprivation areas. Deprivation quintiles were defined by area of residence ranked at national level by Index of Multiple Deprivation score, 2010. Burden due to various risk factors is described for England using new GBD methodology to estimate independent and overlapping attributable risk for five tiers of behavioural, metabolic, and environmental risk factors. We present results for 306 causes and 2337 sequelae, and 79 risks or risk clusters. FINDINGS: Between 1990 and 2013, life expectancy from birth in England increased by 5·4 years (95% uncertainty interval 5·0-5·8) from 75·9 years (75·9-76·0) to 81·3 years (80·9-81·7); gains were greater for men than for women. Rates of age-standardised YLLs reduced by 41·1% (38·3-43·6), whereas DALYs were reduced by 23·8% (20·9-27·1), and YLDs by 1·4% (0·1-2·8). For these measures, England ranked better than the UK and the EU15+ means. Between 1990 and 2013, the range in life expectancy among 45 regional deprivation areas remained 8·2 years for men and decreased from 7·2 years in 1990 to 6·9 years in 2013 for women. In 2013, the leading cause of YLLs was ischaemic heart disease, and the leading cause of DALYs was low back and neck pain. Known risk factors accounted for 39·6% (37·7-41·7) of DALYs; leading behavioural risk factors were suboptimal diet (10·8% [9·1-12·7]) and tobacco (10·7% [9·4-12·0]). INTERPRETATION: Health in England is improving although substantial opportunities exist for further reductions in the burden of preventable disease. The gap in mortality rates between men and women has reduced, but marked health inequalities between the least deprived and most deprived areas remain. Declines in mortality have not been matched by similar declines in morbidity, resulting in people living longer with diseases. Health policies must therefore address the causes of ill health as well as those of premature mortality. Systematic action locally and nationally is needed to reduce risk exposures, support healthy behaviours, alleviate the severity of chronic disabling disorders, and mitigate the effects of socioeconomic deprivation. FUNDING: Bill & Melinda Gates Foundation and Public Health England.

Exposure of Microcystis aeruginosa to Hydrogen Peroxide under Light: Kinetic Modeling of Cell Rupture and Simultaneous Microcystin Degradation.

The effect of hydrogen peroxide on the cell integrity of a cyanobacterium, Microcystis aeruginosa, and on the release and degradation of microcystins (MCs) under simulated sunlight was investigated. The cyanobacterium was exposed to H2O2 in the range of 0-60 mg·L(-1) for 3.5 h. Production of OH radical in the solution was estimated by a chemical probe method. More than 99% (2 log) of the M. aeruginosa cells were ruptured or damaged by 3 h for all the treatments. Loss of cell integrity over time revealed two distinct phases. Cells retained their integrity during the initial lag phase and rapidly ruptured following first-order reaction afterward. A linear relationship was found between the duration of the lag phase and the steady-state concentration of OH radical. Release of MCs was closely correlated with the loss of cell integrity. Sequential reaction models were developed to simulate the release and degradation of MCs. These models were able to quantitatively describe the kinetics of all reactions under different H2O2 doses and extended exposure time. In particular, the models successfully predicted the concentration change of MCs using independently measured parameters. These models provide a simple and quantitative means to estimate the interaction of oxidants and cells and the consequent release of metabolites during oxidation treatment of cyanobacterium-laden waters.

Peri-operative kidney injury and long-term chronic kidney disease following orthotopic heart transplantation in children.

Significant advances in cardiac intensive care including extracorporeal life support have enabled children with complex congenital heart disease and end-stage heart failure to be supported while awaiting transplantation. With an increasing number of survivors after heart transplantation in children, the complications from long-term immunosuppression, including renal insufficiency, are becoming more apparent. Severe renal dysfunction after heart transplant is defined by a serum creatinine level >2.5 mg/dL (221 µmol/L), and/or need for dialysis or renal transplant. The degree of renal dysfunction is variable and is progressive over time. About 3-10 % of heart transplant recipients will go on to develop severe renal dysfunction within the first 10 years post-transplantation. Multiple risk factors for chronic kidney disease post-transplant have been identified, which include pre-transplant worsening renal function, recipient demographics and morbidity, peri-transplant haemodynamics and long-term exposure to calcineurin inhibitors. Renal insufficiency increases the risk of post-transplant morbidity and mortality. Hence, screening for renal dysfunction pre-, peri- and post-transplantation is important. Early and timely detection of renal insufficiency may help minimize renal insults, and allow prompt implementation of renoprotective strategies. Close monitoring and pre-emptive management of renal dysfunction is an integral aspect of peri-transplant and subsequent post-transplant long-term care.

The anteromedial tibial rim sign: an indicator of patellotibial impaction in acute anterior cruciate ligament tears.

OBJECTIVE: We have encountered unexplained anteromedial tibial rim edema in acute anterior cruciate ligament (ACL) tears. Our goal was to determine the incidence, internal derangements, and mechanism of injury in patients with anteromedial tibial rim edema (rim sign). MATERIALS AND METHODS: A retrospective review of ACL tears diagnosed by magnetic resonance imaging over 7 years was performed. Patients were dichotomized into those with and without a rim sign. RESULTS: There were 132 acute ACL tears. Individuals with a rim sign (31, 23%) had more contusions, fractures, ligament tears (P < 0.001), posterolateral corner injuries (P = 0.001), and posterior horn lateral meniscus tears (P = 0.042) than those without. Five individuals demonstrated edema in the inferior patella, consistent with patellotibial impaction. CONCLUSIONS: The rim sign is common in ACL tears, indicating greater internal derangement. The rim sign represents patellotibial impaction with edema rarely present in the patella.

Cysts of the anterior horn lateral meniscus and the ACL: is there a relationship?

OBJECTIVE: Parameniscal cysts have a very high association with meniscal tears in all locations except the anterior horn lateral meniscus (AHLM). The common insertion of the anterior cruciate ligament (ACL) and the AHLM root may provide a pathway for disease. The purpose of our study was to determine if cysts of the ACL are the origin of cysts adjacent to the AHLM. MATERIALS AND METHODS: Radiology reports of all magnetic resonance (MR) examinations of the knee over a 7-year period were searched for "cyst", "ganglion", and "ganglia". Two fellowship-trained musculoskeletal radiologists independently reviewed those MR examinations reported to have a possible cyst of the AHLM and/or the ACL. The study group consisted of those patients with a cyst located adjacent to the AHLM but no meniscal tear of the adjacent meniscus. The ACL in each of these patients was evaluated for the presence of a cyst. Comparison with age- and gender-matched controls was performed. RESULTS: Of 708 cases that contained the word "cyst", "ganglion", or "ganglia", 121 reports indicated a possible cyst of the ACL or AHLM. Twelve individuals had a cyst located adjacent to the AHLM with no meniscal tear. Six (50%) of these individuals had a cyst of the ACL; no ACL cysts were identified in the control group (p = 0.014). Interreader agreement for AHLM parameniscal cysts and AHLM tears was substantial. CONCLUSIONS: Our results suggest that cysts adjacent to the AHLM may in part be explained by cysts or ganglia of the ACL.

Impairment of heart rate recovery after peak exercise predicts poor outcome after pediatric heart transplantation.

BACKGROUND: A blunted heart rate recovery (HRR) from peak exercise is associated with adverse outcome in adults with ischemic heart disease. We assessed HRR after pediatric heart transplantation (HTx) and its prognostic use. METHODS AND RESULTS: Between 2004 and 2010 we performed 360 maximal exercise tests (median, 2 tests/patient; range, 1-7) in 128 children (66 men; age at test, 14 ± 3 years) who received HTx (age, 8.5 ± 5.1 years) because of cardiomyopathy (66%) or congenital heart defects (34%). The change in heart rate from peak exercise to 1 minute of recovery was measured as HRR and was expressed as Z score calculated from reference data obtained in 160 healthy children. HRR was impaired soon after HTx (average in first 2 years Z=-1.9 ± 3.5) but improved afterward (Z=+0.52/y), such that HRR Z score normalized in most patients by 6 years after HTx (average, 0.6 ± 1.8). A subsequent decline in HRR Z score was noted from 6 years after HTx (rate of Z=-0.11/y). After 27 ± 15 months from the most recent exercise test, 19 patients died or were re-heart transplantation. For the follow-up after 6 years, HRR Z score was the only predictor of death/re-heart transplantation (P=0.003). Patients in the lowest quartile of HRR Z score had a much higher 5-year event rate (event-free rate, 29% versus 84%; hazard ratio, 7.0; P=0.0013). CONCLUSIONS: HRR is blunted soon after HTx but normalizes at ≈ 6 years, potentially as a result of parasympathetic reinnervation of the graft, but then declines. This late decline in HRR Z score is associated with worse outcome.

Restriction and dependence to autonomy and freedom: transformation in adolescent heart transplant recipients.

The process of heart transplantation poses numerous challenges and adaptive tasks for paediatric patients and their families. Few studies have examined how the experience of transplant interacts with developmental transitions such as adolescence, a period of significant change, and adjustment in itself. We explored adolescent heart transplant recipients' and their parents' experience of transplant from the point at which their heart condition was diagnosed to several months after transplantation. We adopted a developmental focus, to consider how participants negotiated the tasks of adolescence in the context of their transplant experiences. A qualitative approach was used to interview five adolescent-parent dyads, who reported few post-transplant complications, and the data were analysed according to the principles of IPA. Our findings revealed transplant to be a transformative experience, with two themes marking a contrast between pre- and post-transplant states: "Restriction and Dependence" and "Autonomy and Freedom." The themes are considered in relation to adolescent development. We propose that clinicians working with paediatric heart transplant recipients and their families need to consider the particular developmental challenges faced by adolescent patients and view the attainment of developmental milestones alongside physical and psychological markers of successful adjustment.