Role of CAMK2D in neurodevelopment and associated conditions.

The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family consists of four different isozymes, encoded by four different genes-CAMK2A, CAMK2B, CAMK2G, and CAMK2D-of which the first three have been associated recently with neurodevelopmental disorders. CAMK2D is one of the major CAMK2 proteins expressed in the heart and has been associated with cardiac anomalies. Although this CAMK2 isoform is also known to be one of the major CAMK2 subtypes expressed during early brain development, it has never been linked with neurodevelopmental disorders until now. Here we show that CAMK2D plays an important role in neurodevelopment not only in mice but also in humans. We identified eight individuals harboring heterozygous variants in CAMK2D who display symptoms of intellectual disability, delayed speech, behavioral problems, and dilated cardiomyopathy. The majority of the variants tested lead to a gain of function (GoF), which appears to cause both neurological problems and dilated cardiomyopathy. In contrast, loss-of-function (LoF) variants appear to induce only neurological symptoms. Together, we describe a cohort of individuals with neurodevelopmental disorders and cardiac anomalies, harboring pathogenic variants in CAMK2D, confirming an important role for the CAMK2D isozyme in both heart and brain function.

Evaluation and Management of Chronic Heart Failure in Children and Adolescents With Congenital Heart Disease: A Scientific Statement From the American Heart Association.

With continued medical and surgical advancements, most children and adolescents with congenital heart disease are expected to survive to adulthood. Chronic heart failure is increasingly being recognized as a major contributor to ongoing morbidity and mortality in this population as it ages, and treatment strategies to prevent and treat heart failure in the pediatric population are needed. In addition to primary myocardial dysfunction, anatomical and pathophysiological abnormalities specific to various congenital heart disease lesions contribute to the development of heart failure and affect potential strategies commonly used to treat adult patients with heart failure. This scientific statement highlights the significant knowledge gaps in understanding the epidemiology, pathophysiology, staging, and outcomes of chronic heart failure in children and adolescents with congenital heart disease not amenable to catheter-based or surgical interventions. Efforts to harmonize the definitions, staging, follow-up, and approach to heart failure in children with congenital heart disease are critical to enable the conduct of rigorous scientific studies to advance our understanding of the actual burden of heart failure in this population and to allow the development of evidence-based heart failure therapies that can improve outcomes for this high-risk cohort.

Waitlist Outcomes for Pediatric Heart Transplantation in the Current Era: An Analysis of the Pediatric Heart Transplant Society Database.

BACKGROUND: Waitlist mortality (WM) remains elevated in pediatric heart transplantation. Allocation policy is a potential tool to help improve WM. This study aims to identify patients at highest risk for WM to potentially inform future allocation policy changes. METHODS: The Pediatric Heart Transplant Society database was queried for patients <18 years of age indicated for heart transplantation between January 1, 2010 to December 31, 2021. Waitlist mortality was defined as death while awaiting transplant or removal from the waitlist due to clinical deterioration. Because WM is low after the first year, analysis was limited to the first 12 months on the heart transplant list. Kaplan-Meier analysis and log-rank testing was conducted to compare unadjusted survival between groups. Cox proportional hazard models were created to determine risk factors for WM. Subgroup analysis was performed for status 1A patients based on body surface area (BSA) at time of listing, cardiac diagnosis, and presence of mechanical circulatory support. RESULTS: In total 5974 children met study criteria of which 3928 were status 1A, 1012 were status 1B, 963 were listed status 2, and 65 were listed status 7. Because of the significant burden of WM experienced by 1A patients, further analysis was performed in only patients indicated as 1A. Within that group of patients, those with smaller size and lower eGFR had higher WM, whereas those patients without congenital heart disease or support from a ventricular assist device (VAD) at time of listing had decreased WM. In the smallest size cohort, cardiac diagnoses other than dilated cardiomyopathy were risk factors for WM. Previous cardiac surgery was a risk factor in the 0.3 to 0.7 m2 and >0.7 m2 BSA groups. VAD support was associated with lower WM other than in the single ventricle cohort, where VAD was associated with higher WM. Extracorporeal membrane oxygenation and mechanical ventilation were associated with increased risk of WM in all cohorts. CONCLUSIONS: There is significant variability in WM among status-1A patients. Potential refinements to current allocation system should factor in the increased WM risk we identified in patients supported by extracorporeal membrane oxygenation or mechanical ventilation, single ventricle congenital heart disease on VAD support and small children with congenital heart disease, restrictive cardiomyopathy, or hypertrophic cardiomyopathy.

The Prevalence and Association of Exercise Test Abnormalities With Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) can be associated with an abnormal exercise response. In adults with HCM, abnormal results on exercise stress testing are predictive of heart failure outcomes. Our goal was to determine whether an abnormal exercise response is associated with adverse outcomes in pediatric patients with HCM. METHODS: In an international cohort study including 20 centers, phenotype-positive patients with primary HCM who were <18 years of age at diagnosis were included. Abnormal exercise response was defined as a blunted blood pressure response and new or worsened ST- or T-wave segment changes or complex ventricular ectopy. Sudden cardiac death (SCD) events were defined as a composite of SCD and aborted sudden cardiac arrest. Using Kaplan-Meier survival, competing outcomes, and Cox regression analyses, we analyzed the association of abnormal exercise test results with transplant and SCD event-free survival. RESULTS: Of 724 eligible patients, 630 underwent at least 1 exercise test. There were no major differences in clinical characteristics between those with or without an exercise test. The median age at exercise testing was 13.8 years (interquartile range, 4.7 years); 78% were male and 39% were receiving beta-blockers. A total of 175 (28%) had abnormal test results. Patients with abnormal test results had more severe septal hypertrophy, higher left atrial diameter z scores, higher resting left ventricular outflow tract gradient, and higher frequency of myectomy compared with participants with normal test results (P<0.05). Compared with normal test results, abnormal test results were independently associated with lower 5-year transplant-free survival (97% versus 88%, respectively; P=0.005). Patients with exercise-induced ischemia were most likely to experience all-cause death or transplant (hazard ratio, 4.86 [95% CI, 1.69-13.99]), followed by those with an abnormal blood pressure response (hazard ratio, 3.19 [95% CI, 1.32-7.71]). Exercise-induced ischemia was also independently associated with lower SCD event-free survival (hazard ratio, 3.32 [95% CI, 1.27-8.70]). Exercise-induced ectopy was not associated with survival. CONCLUSIONS: Exercise abnormalities are common in childhood HCM. An abnormal exercise test result was independently associated with lower transplant-free survival, especially in those with an ischemic or abnormal blood pressure response with exercise. Exercise-induced ischemia was also independently associated with SCD events. These findings argue for routine exercise testing in childhood HCM as part of ongoing risk assessment.

Research Gaps in Pediatric Heart Failure: Defining the Gaps and Then Closing Them Over the Next Decade.

Given the numerous opportunities and the wide knowledge gaps in pediatric heart failure, an international group of pediatric heart failure experts with diverse backgrounds were invited and tasked with identifying research gaps in each pediatric heart failure domain that scientists and funding agencies need to focus on over the next decade.

Three decades of collaboration through the Pediatric Heart Transplant Society Registry: A journey through registry data with a highlight on children with single ventricle anatomy.

BACKGROUND: The Pediatric Heart Transplant Society (PHTS) Registry was founded 30 years ago as a collaborative effort among like-minded providers of this novel life-saving technique for children with end-stage heart failure. In the intervening decades, the data from the Registry have provided invaluable knowledge to the field of pediatric heart transplantation. This report of the PHTS Registry provides a comprehensive look at the data, highlighting both the longevity of the registry and one unique aspect of the PHTS registry, allowing for exploration into children with single ventricle anatomy. METHODS: The PHTS database was queried from January 1, 1993 to December 31, 2019 to include pediatric (age < 18 years) patients listed for HT. For our analysis, we primarily analyzed patients by era. The early era was defined as children listed for HT from January 1, 1993 to December 31, 2004; middle era January 1, 2005 to December 31, 2009; and recent era January 1, 2010 to December 31, 2019. Outcomes after listing and transplant, including mortality and morbidities, are presented as unadjusted for risk, but compared across eras. RESULTS: Since 1993, 11 995 children were listed for heart transplant and entered into the PHTS Registry with 9755 listed during the study period. The majority of listings occurred within the most recent era. Waitlist survival improved over the decades as did posttransplant survival. Other notable changes over time include fewer patients experiencing allograft rejection or infection after transplant. Waitlist and posttransplant survival have changed dramatically in patients with single ventricle physiology and significantly differ by stage of single ventricle palliation. SUMMARY: Key points from this PHTS Registry summary and focus on patients with single ventricle congenital heart disease in particular, include the changing landscape of candidates and recipients awaiting heart transplant. There is clear improvement in waitlist and transplant outcomes for children with both cardiomyopathy and congenital heart disease alike.

Nutritional status and cannula infections in pediatric patients on ventricular assist device support.

BACKGROUND: Ventricular assist devices (VADs) are used to bridge pediatric patients to heart transplantation. Paracorporeal VADs require the placement of cannulas, which can create an environment for infections. We examined cannula infections in pediatric VAD patients and the role of nutritional status. METHODS: This retrospective study (2005-2021) included patients <20 years old on VAD support using Berlin Heart EXCOR® cannulas. Cannula infections were defined by a positive culture and need for antibiotic therapy. Malnutrition was defined using the American Society of Parenteral and Enteral Nutrition guidelines as well as the Michigan MTool. RESULTS: There were 76 patients with a median age at implant of 0.9 years (IQR 0.4, 3.6), 50% male, with 73.7% having non-congenital heart disease. More than one-quarter (26.3%) of patients developed a cannula infection. Higher pre-implant weight (OR = 1.93, p = 0.05), creatinine (OR = 1.02, p = 0.044), and pre-albumin (OR = 15.79, p = 0.025), as well as duration of VAD support (OR = 1.01; p = 0.003) were associated with increased odds of developing a cannula infection. There was no difference in the malnutrition parameters between those with and without an infection. CONCLUSIONS: Further exploration in a larger cohort is needed to see whether these associations remain and if the incorporation of objective measures of nutritional status at the time of infection are predictive.

Use of a Postoperative Care Management Pathway Reduces the Incidence of Chylothorax Post-Fontan Palliation.

Pleural effusions and chylothorax are challenging morbidities post-Fontan palliation. We sought to evaluate the efficacy of our Fontan Care Pathway (FCP) in reducing the incidence of post-operative chylothorax and Time to Chest Tube Removal (TTCTR), and to determine risk factors associated with longer TTCTR. Between 2016 and 2022 our institutional approach to post-Fontan care fell into three categories: Group 1 (n = 36): no standardized approach; Group 2 (n = 30): a prophylactic chylothorax diet (fat content < 5%); Group 3 (n = 57): the FCP (a chylothorax diet, fluid restriction, supplemental O2 and aggressive diuresis). The incidence of chylothorax and TTCTR was compared between groups. Predictors of TTCTR were analyzed using linear regression modelling, adjusting for covariates. Chylothorax rate decreased in Group 3 compared to Groups 1 and 2 (9% vs. 28% and 33% respectively, p = 0.011), without alteration in TTCTR. Univariate factors associated with median TTCTR included chylothorax (+ 13.7 days, p = 0.001), additional procedures at time of Fontan (+ 2.4 days per procedure p = 0.017), Fontan revision or takedown (+ 11.7 days, p = 0.018) and minor/major complications (+ 5.1, p = 0.01 and + 15.8, p < 0.001, respectively). On multivariable analysis, chylothorax (+ 6.5 days, p = 0.005) and major complications (+ 15.8 days, p = 0.001) were associated with increased TTCTR. When chylothorax was excluded from multivariable analysis, the FCP showed a significant decrease in TTCTR (- 3.3 days, p = 0.034). A bundled therapy approach was associated with reduced laboratory confirmed chylothorax post-Fontan, whereas diet change alone was not. Additional studies in this area, with larger sample sizes are warranted.

Successful implementation of telehealth visits in the paediatric heart failure and heart transplant population.

The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) and Pediatric Heart Transplant Society (PHTS) convened a working group at the beginning of 2020 during the COVID-19 pandemic, with the aim of using telehealth as an alternative medium to provide quality care to a high-acuity paediatric population receiving advanced cardiac therapies. An algorithm was developed to determine appropriateness, educational handouts were developed for both patients and providers, and post-visit surveys were collected. Telehealth was found to be a viable modality for health care delivery in the paediatric heart failure and transplant population and has promising application in the continuity of follow-up, medication titration, and patient education/counselling domains.

Family perspectives of ex situ heart perfusion.

BACKGROUND: Pediatric patients awaiting a heart transplant have high waitlist mortality. Several strategies have been utilized to decrease waiting times, but a mortality risk still exists. New medical technologies may improve waiting times and associated mortality. Ex situ heart perfusion (ESHP) is one such technology, which can decrease the impact of cold ischemia on the donor heart and allow for a longer out-of-body time. Adoption of such technology in pediatric heart transplantation will require support from end users, including patient and families. The aim of this qualitative study was to report the perspectives of families with experience related to pediatric HTx toward ESHP. METHODS: Semistructured interviews were conducted with 12 parents or guardians of children who were awaiting or received heart transplantation. Interviews were transcribed, and data were analyzed using qualitative content analysis. RESULTS: Participants expressed varied awareness and knowledge of ESHP. Independent of their understanding of ESHP, all purported that ESHP was an excellent idea and that this technology should be implemented in the pediatric population. They did not identify fundamentally different ethical issues or concerns for ESHP being used relative to other medical technologies. Overall, most participants described consent processes for ESHP should be like any other procedure. All agreed that the surgeon should continue to describe the overall health of the donor heart, provide their medical recommendations, and allow families to have the final say. CONCLUSIONS: The concepts described by the parents and guardians are important in moving this novel technology forward. This information will serve the basis for knowledge translation that will provide educational resources to broaden the understanding and reach of ESHP.

Barriers and misconceptions of ex situ heart perfusion in pediatric donation.

BACKGROUND: Despite efforts, pediatric HTx candidates continue to have high waitlist mortality due to limited donor availability. However, there is a significant number of offered hearts not used due to concerns of viability. ESHP is a method for continuous perfusion of the donor heart that allows assessment and extended out-of-body time. It is imperative to understand healthcare stakeholders' perspectives on ESHP for implementation. Therefore, the aims of this qualitative study were to: (1) Explore pediatric stakeholders' perspectives toward ESHP; and (2) Identify barriers to widespread adoption of this technology. METHODS: Virtual focus groups were completed with pediatric HTx healthcare professional stakeholders. Following transcription of audio-recordings, the material was analyzed using content analysis. RESULTS: Four focus groups were completed with 17 participants, representing 12 institutions and three countries. Focus groups revealed varied understanding of both current and potential uses of ESHP. Participants did see the potential benefits of extending out-of-body time for and the ability to evaluate donor heart quality. However, concerns were expressed relating to patient selection, wait-list times, post-HTx outcomes, adverse events, and technical issues. These were felt to be important to understand in order to justify the costs of ESHP and impact on the healthcare system. CONCLUSIONS: This project represents the first qualitative formative evaluation of ESHP in pediatrics. The knowledge gained from stakeholders will form the basis for education initiatives, clinical trial design, and roll-out of new ESHP technologies designed for pediatrics.

Successful ABO incompatible heart transplantation after desensitization therapy in an older child.

BACKGROUND: ABO-incompatible heart transplantation (HTx) has become a standard procedure for children below 2 years of age due to an immunologically immature immune system and associated low isohemagglutinin titers. METHODS: We report a case of an ABO-incompatible HTx (recipient blood group O, donor blood group A) at the age of 5 years and 11 months with a fully matured immune system and previously high isohemagglutinin titers that diminished as a result of human leucocyte antigen (HLA) desensitization therapy with rituximab and immunoglobulins. RESULTS: The anti-A titer at the time of HTx was 1:16 with post-transplant isoagglutinin titers never exceeding 1:4 without any signs of rejection with now 3 years of post-HTx follow-up. CONCLUSIONS: ABO isohemagglutinin titers should be routinely assessed in children undergoing desensitization therapy since ABOi transplantation can be considered in selected cases to expand the donor pool with the option of crossing the ABO barrier to find a better-matched allograft.

Ex situ heart perfusion for optimization of pediatric donor organ utilization: Attitudes and perceptions.

BACKGROUND: Children with heart failure have the highest mortality while awaiting transplantation. Ex situ heart perfusion (ESHP), a method for continuous perfusion of the donor heart, has the potential to improve access to transplant by increasing travel distance between donor and recipient. An adult ESHP device is currently available, but as of yet there is no pediatric device. The aim of this study was to evaluate current knowledge of ESHP among pediatric heart transplant practitioners, define potential barriers, and identify uses of this novel technology. METHODS: An electronic survey was developed to assess perspectives of international pediatric heart transplant stakeholders (n = 68) on ESHP. Select questions were analyzed to evaluate for associations between groups of respondents and patterns of response. RESULTS: Most respondents were familiar but <10% had clinically utilized ESHP. There was optimism that ESHP could decrease waitlist mortality. Respondents were concerned about potential device malfunction and lack of long-term outcomes. There were no differences found in terms of ESHP familiarity among age groups, practitioner center volume, country of work, or discipline. CONCLUSIONS: ESHP has the potential to expand the pediatric heart donor pool and decrease waitlist mortality. More education on outcomes and risks/benefits is needed in order to promote widespread adoption.

Predicting outcomes following short-term ventricular assist device implant with the MELD-XI score.

BACKGROUND: Short-term continuous flow (STCF) ventricular assist devices (VADs) are utilized in adults with cardiogenic shock; however, mortality remains high. Previous studies have found that high pre-operative MELD-XI scores in durable VAD patients are associated with mortality. The use of the MELD-XI score to predict outcomes in STCF-VAD patients has not been explored. We sought to determine the relationship between MELD-XI and outcomes in adults with STCF-VADs. METHODS: This was a retrospective review of adults implanted with STCF-VADs between 2009 and 2019. Receiver operating characteristic (ROC) analysis was performed to predict outcomes and Kaplan-Meier analysis was done to assess survival. RESULTS: Seventy-nine patients were included with a median MELD-XI score of 21.2 (IQR 13.5, 27.0). Patients with an unsuccessful wean from support (p < 0.001) or major post-operative bleeding (p = 0.03) had significantly higher pre-implant MELD-XI scores. The optimal MELD-XI cut-point for mortality was 24.9 with 27.8 for major bleeding. Survival was worse among patients in the high-risk MELD-XI group, however, not statistically significant (p = 0.09). Prior ECMO support, but not MELD-XI, was an independent predictor of unsuccessful wean (p = 0.03). CONCLUSIONS: Pre-operative MELD-XI score was a moderate predictor of unsuccessful wean with limited utility in predicting bleeding in patients on STCF-VAD support. This scoring system may be useful in the clinical setting for pre-implant risk stratification and counseling among patients and outcomes.

Percutaneous Treatment of Ascending Aortic Obstruction in a Young Child After Orthotopic Heart Transplantation.

We report a case of a 14-month-old child with ascending aortic obstruction (AAO) post cardiac transplantation, who underwent successful percutaneous ascending aortic stent angioplasty. Congenital or acquired AAO is typically treated with surgical augmentation. The experience with percutaneous techniques is limited and often avoided due to challenges with equipment stability and proximity to coronary arteries and aortic valve leaflets. This case highlights that a percutaneous approach to relief of AAO is a feasible alternative even in small children utilizing a newer pre-mounted stent.

Outcomes after initial heart failure consultation in Fontan patients.

BACKGROUND: Patients with Fontan failure are high-risk candidates for heart transplantation and other advanced therapies. Understanding the outcomes following initial heart failure consultation can help define appropriate timing of referral for advanced heart failure care. METHODS: This is a survey study of heart failure providers seeing any Fontan patient for initial heart failure care. Part 1 of the survey captured data on clinical characteristics at the time of heart failure consultation, and Part 2, completed 30 days later, captured outcomes (death, transplant evaluation outcome, and other interventions). Patients were classified as "too late" (death or declined for transplant due to being too sick) and/or "care escalation" (ventricular assist device implanted, inotrope initiated, and/or listed for transplant), within 30 days. "Late referral" was defined as those referred too late and/or had care escalation. RESULTS: Between 7/2020 and 7/2022, 77 Fontan patients (52% inpatient) had an initial heart failure consultation. Ten per cent were referred too late (6 were too sick for heart transplantation with one subsequent death, and two others died without heart transplantation evaluation, within 30 days), and 36% had care escalation (21 listed ± 5 ventricular assist device implanted ± 6 inotrope initiated). Overall, 42% were late referrals. Heart failure consultation < 1 year after Fontan surgery was strongly associated with late referral (OR 6.2, 95% CI 1.8-21.5, p=0.004). CONCLUSIONS: Over 40% of Fontan patients seen for an initial heart failure consultation were late referrals, with 10% dying or being declined for transplant within a month of consultation. Earlier referral, particularly for those with heart failure soon after Fontan surgery, should be encouraged.

Learning from each other: The hidden benefit of practice variation.

It has long been recognized that there is significant variation in the way that centers approach clinical management and problems within pediatric transplantation. This has recently been highlighted in two publications by the PHTS showing practice variation in both surveillance for cardiac allograft vasculopathy and diagnosis of acute rejection. These differences in practice are important to recognize and serve as the foundation for collaborative learning, developing research questions, and implementing quality improvement initiatives. To further understand the practice variation within the society, and to begin the process of learning from each other, the society has developed a Clinical Approach Working Group, whose task is to tackle issues seen in transplant and integrate current literature with clinical protocols and experience from the individual sites. The early work of this group has results in the series of Clinical approach articles presented in this issue of Pediatric Transplantation.

Clinical approach to mechanical circulatory support in the transplant patient from the Pediatric Heart Transplant Society.

The use of mechanical circulatory support (MCS) for pediatric patients who have undergone heart transplant has grown rapidly in the past decade. This includes support in the immediate post-transplant period and "rescue" therapy for patient later in their transplant course. Extracorporeal membrane oxygenation (ECMO) remains a standard modality of support for intraoperative concerns and for acute decompensation in the immediate post-transplant period. However, both pulsatile and continuous flow ventricular assist devices (VADs) have been used with increasing success in transplant patients for longer durations of support. Centers participating in the Pediatric Heart Transplant Society (PHTS) were queried to provide their internal protocols and rationale for mechanical circulatory support following heart transplant. These protocols coupled with evidence-based literature were used to provide the following description of clinical approaches to MCS in the transplant patient highlighting areas of both broad consensus and significant practice variation.

Ventricular assist device support following pediatric heart transplantation.

BACKGROUND: VAD support for early graft failure after HTx is a rare event in pediatrics. METHODS: We retrospectively describe our single-center experience with post-HTx VAD support in a cohort of patients transplanted between 01/05 and 12/20. RESULTS: Nine patients underwent VAD insertion in the early post-HTx period [median age 6.1 years (Range 0.3-20.3), median weight 17.6 kg (Range 3.5-65.0), and congenital heart disease (67%)]. Of the nine patients with early graft failure, almost half (44%) were implanted after 2015 and all of these patients had a pre-HTx plan for possible post-transplant VAD insertion. Time to VAD implant was a median of 0 day (Range 0-11). Total time on VAD support was a median of 12 days (Range 3.0-478.0). Two-thirds (n = 6; 67%) of the patients were weaned from support, retransplanted (11%) and two patients died (22%). In all of the patients where post-HTx VAD was anticipated there was 100% survival. CONCLUSIONS: In this small patient series, post-HTx VAD was a useful measure in selected patients especially with pre-HTx planning. However, more shared experiences to verify these findings are needed.

Clinical approach to vasoplegia in the transplant patient from the Pediatric Heart Transplant Society.

This manuscript outlines a clinical approach to vasoplegia incorporating the current state of knowledge regarding vasoplegia in pediatric patients immediately post-transplant and to identify modifiable factors both pre- and post-transplant that may reduce post-operative morbidity, end-organ dysfunction, and mortality. Centers participating in the Pediatric Heart Transplant Society (PHTS) were asked to provide their internal protocols and rationale for vasoplegia management, and applicable adult and pediatric data were reviewed. The authors synthesized the above protocols and literature into the following description of clinical approaches to vasoplegia highlighting areas of both broad consensus and of significant practice variation.