Dapagliflozin Use in Children with Advanced Heart Failure Undergoing Heart Transplantation: A Matched Case-Control Study.

Dapagliflozin has been associated with euglycemic ketoacidosis in adults with diabetes contributing to poor outcomes when continued prior to surgery. It is unknown if preoperative use of dapagliflozin may lead to adverse events (AE) in nondiabetic children with advanced heart failure (HF) undergoing heart transplantation (HTx). We performed a single-center, matched case-control analysis of nondiabetic primary pediatric HTx recipients < 21 years-old who underwent HTx and followed through postoperative day (POD) 3. Cases who received dapagliflozin leading up to HTx (n = 22) were matched by age and cardiac diagnosis to two historical controls who did not receive dapagliflozin (n = 44). Median age at HTx was 13.8 years (range 0.36-20.7) and 48% were female. Cardiac diagnoses included cardiomyopathy (45%), Fontan failure (41%), and single ventricle status post stage I palliation (14%). Cases received median dapagliflozin dose of 0.17 mg/kg once daily; therapy was stopped one day prior to HTx. There were no significant differences in blood glucose nadirs, arterial blood gas indices including nadirs of pH, bicarbonate, or peaks of arterial blood lactic acid POD0-3. Vasopressor, inotrope, and insulin infusion usage were not different. No patients were treated for severe hypoglycemia, euglycemic ketoacidosis, or urinary tract infections. There were no deaths. Length of stay in ICU and time from HTx to hospital discharge did not differ between cohorts. Use of dapagliflozin in children with advanced HF until HTx is not associated with AE in the immediate postoperative period nor increased length of hospitalization post-HTx. Potential cardiovascular benefits of dapagliflozin in patients awaiting HTx should be prioritized.

Prevalence of iron deficiency and anemia in pediatric heart transplant recipients.

INTRODUCTION: The prevalence of iron deficiency and anemia in the setting of modern-day maintenance immunosuppression in pediatric heart transplant (HTx) recipients is unclear. The primary aim was to determine the prevalence of iron deficiency (serum ferritin < 30 ng/mL ± transferrin saturation < 20%) and anemia per World Health Organization diagnostic criteria and associated risk factors. METHODS: Single-center, cross-sectional analysis of 200 consecutive pediatric HTx recipients (<21 years old) from 2005 to 2021. Data were collected at 1-year post-HTx at the time of annual protocol biopsy. RESULTS: Median age at transplant was 3 years (IQR .5-12.2). The median ferritin level was 32 ng/mL with 46% having ferritin < 30 ng/mL. Median transferrin saturation (TSAT) was 22% with 47% having TSAT < 20%. Median hemoglobin was 11 g/dL with 54% having anemia. Multivariable analysis revealed lower absolute lymphocyte count, TSAT < 20%, and estimated glomerular filtration rate <75 mL/min/1.73 m2 were independently associated with anemia. Ferritin < 30 ng/mL in isolation was not associated with anemia. Ferritin < 30 ng/mL may aid in detecting absolute iron deficiency while TSAT < 20% may be useful in identifying patients with functional iron deficiency ± anemia in pediatric HTx recipients. CONCLUSION: Iron deficiency and anemia are highly prevalent in pediatric HTx recipients. Future studies are needed to assess the impact of iron deficiency, whether with or without anemia, on clinical outcomes in pediatric HTx recipients.

A Review of Pediatric Cardiomyopathy.

Though pediatric cardiomyopathy is rare in children, there is significant associated morbidity and mortality. Etiology varies from inborn errors of metabolism to familial genetic mutations and myocyte injury. Major classes include dilated, hypertrophic, restrictive, and non-compaction. Diagnosis generally involves a combination of clinical history and echocardiography. The use of cross-sectional imaging is gaining popularity. Management varies between subtype and may involve a combination of medical and surgical interventions depending on clinical status.

Mortality After Major Cardiovascular Events in Survivors of Childhood Cancer.

BACKGROUND: Adult survivors of childhood cancer are at risk for cardiovascular events. OBJECTIVES: In this study, we sought to determine the risk for mortality after a major cardiovascular event among childhood cancer survivors compared with noncancer populations. METHODS: All-cause and cardiovascular cause-specific mortality risks after heart failure (HF), coronary artery disease (CAD), or stroke were compared among survivors and siblings in the Childhood Cancer Survivor Study (CCSS) and participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Cox proportional hazard regression models were used to estimate HRs and 95% CIs between groups, adjusted for demographic and clinical factors. RESULTS: Among 25,658 childhood cancer survivors (median age at diagnosis 7 years, median age at follow-up or death 38 years) and 5,051 siblings, 1,780 survivors and 91 siblings had a cardiovascular event. After HF, CAD, and stroke, 10-year all-cause mortalities were 30% (95% CI: 26%-33%), 36% (95% CI: 31%-40%), and 29% (95% CI: 24%-33%), respectively, among survivors vs 14% (95% CI: 0%-25%), 14% (95% CI: 2%-25%), and 4% (95% CI: 0%-11%) among siblings. All-cause mortality risks among childhood cancer survivors were increased after HF (HR: 7.32; 95% CI: 2.56-20.89), CAD (HR: 5.54; 95% CI: 2.37-12.93), and stroke (HR: 3.57; 95% CI: 1.12-11.37). CAD-specific mortality risk was increased (HR: 3.70; 95% CI: 1.05-13.02). Among 5,114 CARDIA participants, 345 had a major event. Although CARDIA participants were on average decades older at events (median age 57 years vs 31 years), mortality risks were similar, except that all-cause mortality after CAD was significantly increased among childhood cancer survivors (HR: 1.85; 95% CI: 1.16-2.95). CONCLUSIONS: Survivors of childhood cancer represent a population at high risk for mortality after major cardiovascular events.

External assessment and refinement of a population pharmacokinetic model to guide tacrolimus dosing in pediatric heart transplant.

STUDY OBJECTIVE: The immunosuppressant tacrolimus is a first-line agent to prevent graft rejection following pediatric heart transplant; however, it suffers from extensive inter-patient variability and a narrow therapeutic window. Personalized tacrolimus dosing may improve transplant outcomes by more efficiently achieving and maintaining therapeutic tacrolimus concentrations. We sought to externally validate a previously published population pharmacokinetic (PK) model that was constructed with data from a single site. DATA SOURCE: Data were collected from Seattle, Texas, and Boston Children's Hospitals, and assessed using standard population PK modeling techniques in NONMEMv7.2. MAIN RESULTS: While the model was not successfully validated for use with external data, further covariate searching identified weight (p < 0.0001 on both volume and elimination rate) as a model-significant covariate. This refined model acceptably predicted future tacrolimus concentrations when guided by as few as three concentrations (median prediction error = 7%; median absolute prediction error = 27%). CONCLUSION: These findings support the potential clinical utility of a population PK model to provide personalized tacrolimus dosing guidance.

Treating Pediatric Myocarditis with High Dose Steroids and Immunoglobulin.

There is considerable variability in practice among pediatric centers for treatment of myocarditis. We report outcomes using high dose steroids in conjunction with IVIG. This is a single center retrospective study of children < 21 years of age diagnosed with myocarditis and treated with high dose steroids and IVIG from January 2004-April 2021. Diagnostic criteria for myocarditis included positive endomyocardial biopsy, cardiac magnetic resonance (CMR) imaging meeting Lake Louise criteria, or strictly defined clinical diagnosis. Forty patients met inclusion criteria. Median age at diagnosis was 11.6 years (0.7-14.6). Diagnosis was made clinically in 70% of cases (N = 28), by CMR in 12.5% (N = 5) and by biopsy in 17.5% (N = 7). Median ejection fraction (EF) at diagnosis was 35% (IQR 24-48). Median duration of IV steroids was 7 days (IQR 4-12) followed by an oral taper. Median cumulative dose of IV immunoglobulin (IVIG) was 2 g/kg. There were no serious secondary bacterial infections after steroid initiation. Ten patients (25%) required mechanical circulatory support. Overall transplant free survival was 92.5% with median follow-up of 1 year (IQR 0-6 years). Six patients required re-admission for cardiovascular reasons. By 3 months from diagnosis, 70% of patients regained normal left ventricular function. High dose steroids in conjunction with IVIG to treat acute myocarditis can be safe without significant infections or long-term side effects. Our cohort had excellent recovery of ventricular function and survival without transplant. Prospective comparison of a combination of high dose steroids with IVIG versus other therapies is needed.

A fatal case of bortezomib-induced lung toxicity in a young adult heart transplant recipient.

Bortezomib is approved for the treatment of multiple myeloma but increasingly used in heart transplant (HTx) recipients with antibody-mediated rejection (AMR). Severe pulmonary toxicity is a rare complication in multiple myeloma patients treated with bortezomib, but has not been described in a solid organ transplant recipient. A 20-year-old man 7 years post-HTx presented with acute rejection with hemodynamic compromise. Endomyocardial biopsy showed mixed rejection (ISHLT grade 2R-3R acute cellular rejection (ACR) and pAMR 1 (I+) with diffuse C4d staining). Two new high MFI circulating MHC class-II donor-specific antibodies (DSA) were detected. Treatment included corticosteroids, antithymocyte globulin, plasmapheresis, IVIG, rituximab, and bortezomib (1.3 mg/m2 ). Due to rebound in DSA, a second course of bortezomib was started. Thrombocytopenia and peripheral neuropathy prompted a 50% dose reduction during the 2nd course. Shortly after the 3rd reduced dose, the patient developed hypoxemic respiratory failure. Bronchoscopy revealed pulmonary hemorrhage with negative infectious studies. Chest CT showed bilateral parenchymal disease with bronchiectasis and alveolar bleeding. Despite treatment with high-dose steroids, severe ARDS ensued with multisystem organ failure. The patient expired 23 days after the final dose of bortezomib. Post-mortem lung histology revealed diffuse alveolar damage, pulmonary fibrosis, and hemorrhage. Cardiac histology showed resolving/residual ACR 1R and pAMR 1 (I+). While rare, bortezomib-induced lung toxicity (BILT) can occur in HTx recipients and can carry a high risk of mortality. Drug reaction and immediate drug withdrawal should be considered in patients who develop respiratory symptoms, though optimal management of BILT is unclear.

Assessment of rejection risk following subtherapeutic calcineurin inhibitor levels after pediatric heart transplantation.

CNIs are the mainstay of immunosuppressive therapy after pediatric HTx. While regular laboratory surveillance is performed to ensure blood levels are within targeted range, the risk of acute rejection associated with subtherapeutic CNI levels has never been quantified. This is a retrospective single-center review of 8413 CNI trough levels in 138 pediatric HTx recipients who survived >1 year after HTx. Subtherapeutic CNI levels were defined as <50% of the lower limit of target range. The risk of acute, late (>12 months post-transplant) rejection following recipients' subtherapeutic CNI levels was assessed using time-varying multivariable Cox proportional hazards analysis. We found that 79 of 138 recipients (57%) had at least one subtherapeutic CNI level on routine surveillance laboratories during a mean follow-up of 5.5 ± 3.6 years. Following an episode of subtherapeutic levels, 17 recipients (22%) had biopsy-proven rejection within the next 3 months; the majority (9/17) within the first 2 weeks. After presenting with subtherapeutic CNI levels, recipients incurred a 6.1 times increased risk of acute rejection in the following 3 months (HR = 6.11 [2.41, 15.51], P = <.001). Age at HTx, HLA sensitization, or positive crossmatch were not associated with acute late rejection, but rejection in the first post-transplant year was (HR 2.61 [1.27, 5.35], P = .009). Thus, maintaining therapeutic CNI levels is the most important factor in preventing acute rejection in recipients who are >12 months after pediatric HTx. Recipients who present with subtherapeutic CNI levels on surveillance monitoring are 6.1 times more likely to develop rejection in the following 3 months.

Outcomes of low-intensity biopsy surveillance for rejection in paediatric cardiac transplantation.

BACKGROUND: Significant inter-centre variability in the intensity of endomyocardial biopsy surveillance for rejection following paediatric cardiac transplantation has been reported. Our aim was to determine if low-intensity biopsy surveillance with two scheduled biopsies in the first year would produce outcomes similar to published registry outcomes. METHODS: A retrospective study of paediatric recipients transplanted between 2008 and 2014 using a low-intensity biopsy protocol consisting of two surveillance biopsies at 3 and 12-13 months in the first post-transplant year, then annually thereafter. Additional biopsies were performed based on echocardiographic and clinical surveillance. Excluded were recipients that were re-transplanted or multi-organ transplanted or were followed at another institution. RESULTS: A total of 81 recipients in the first 13 months after transplant underwent an average of 2 (SD ± 1.3) biopsies, 24 ± 6.8 echocardiograms, and 17 ± 4.4 clinic visits per recipient. During the 13-month period, 19 recipients had 24 treated rejection episodes, with the first at an average of 2.8 months post-transplant. The 3-, 12-, 36-, and 60-month conditional on discharge graft survival were 100%, 98.8%, 98.8%, and 90.4%, respectively, comparable to reported figures in major paediatric registries. At a mean follow-up of 4.7 ± 2.1 years, four patients (4.9%) developed cardiac allograft vasculopathy, three (3.7%) developed a malignancy, and seven (8.6%) suffered graft loss. CONCLUSION: Rejection surveillance with a low-intensity biopsy protocol demonstrated similar intermediate-term outcomes and safety measures as international registries up to 5 years post-transplant.

Paediatric cardio-oncology: epidemiology, screening, prevention, and treatment.

With 5-year survival of children with cancer exceeding 80% in developed countries, premature cardiovascular disease is now a major cause of early morbidity and mortality. In addition to the acute and chronic cardiotoxic effects of anthracyclines, related chemotherapeutics, and radiation, a growing number of new molecular targeted agents may also have detrimental effects on the cardiovascular system. Survivors of childhood cancer also may have earlier development of conventional cardiovascular risk factors such as hypertension, dyslipidaemia, and diabetes, which further increase their risk of serious cardiovascular disease. This review will examine the epidemiology of acute and chronic cardiotoxicity relevant to paediatric cancer patients, including genetic risk factors. We will also provide an overview of current screening recommendations, including the evidence regarding both imaging (e.g. echocardiography and magnetic resonance imaging) and blood-based biomarkers. Various primary and secondary prevention strategies will also be discussed, primarily in relation to anthracycline-related cardiomyopathy. Finally, we review the available evidence related to the management of systolic and diastolic dysfunction in paediatric cancer patients and childhood cancer survivors.

Iron Laboratory Studies in Pediatric Patients With Heart Failure from Dilated Cardiomyopathy.

Iron deficiency (FeD), with or without anemia, in adults with heart failure (HF) is associated with poor outcomes, which can be improved with replacement therapy. A similar therapeutic opportunity may exist for children; however, iron laboratory measurements and FeD have not been described in pediatric patients with HF. A single-center, retrospective study was conducted on 28 patients <21 years old with a diagnosis of dilated cardiomyopathy and HF who had iron laboratories (serum iron, iron saturation, and ferritin) performed. The mean (standard deviation) age at time of laboratory collection was 10.3 (5.5) years. Twenty-seven patients (96.4%) met the criteria for FeD. Serum iron and iron saturation were significantly associated with inpatient hospitalization, being on inotropic medications, or having stage D HF. Low-serum iron was associated with a higher left ventricular end-diastolic dimension and left ventricular end-systolic dimension z-score by echocardiography ((ß -2.58, 95% confidence interval [CI] -4.76, -0.40, p = 0.02) and (ß -2.43, 95% CI -4.70, -0.17, p = 0.04)), respectively. Low ferritin was associated with higher mortality (relative risk 0.29, 95% CI 0.12, 0.70, p = 0.006). In conclusion, FeD was common in this pediatric cohort with more advanced HF. Iron profile abnormalities were associated with worse HF severity and outcomes including mortality.

Cardio-oncology Related to Heart Failure: Pediatric Considerations for Cardiac Dysfunction.

Although tremendous advances in pediatric cancer treatment have improved the survival of many children, these patients remain at increased risk of early morbidity and mortality with cardiovascular disease as a leading cause of death. Heightened awareness in providers with increased surveillance and improvement in cardiovascular imaging modalities have led to earlier detection of cardiac dysfunction, but the outcomes remain poor once this has dysfunction developed. A great deal of work remains to be done to refine screening and identify high-risk patients more precisely, and to develop more evidence-based strategies for effective primary and secondary cardioprotection and treatment.

Impact of preoperative risk factors on outcomes after Norwood palliation for hypoplastic left heart syndrome.

BACKGROUND: Infants with hypoplastic left heart syndrome (HLHS) are susceptible to pre-Norwood comorbidities (PCs) and complications. This study aimed to describe the effect of PCs on timing and survival of Norwood palliation (NP). METHODS: A single-center, retrospective review of infants with HLHS who underwent initial NP between 2003 and 2010 was performed. PCs included intact atrial septum, ≥ moderate atrioventricular regurgitation (AVVR), no antenatal diagnosis, mitral stenosis/aortic atresia subtype, genetic abnormality, and prematurity. Complications included pre-NP mechanical ventilation, inotropic support, infection, arrhythmia, and end-organ injury. The primary outcome measure was survival after NP. RESULTS: 113 patients were included with 78 (69%) patients having at least one PC and 61 (78%) of those patients having at least one complication. Patients with PCs underwent NP later than those without PCs (7 vs 6 days, P = .036) as well as when associated with a complication (8 vs 5 days, P < .001). Patients with PCs had similar post-Norwood hospital length of stay (P = .116) except when the PC occurred in conjunction with a complication (28 vs 21 days; P = .015). In-hospital mortality post-NP was 10% and interstage mortality was 15%. On multivariable analysis, ≥ moderate AVVR was associated with increased overall mortality (OR 2.8, 95% CI 1.3-6.2). Age at NP was not associated with mortality (P = .638). CONCLUSIONS: Although PCs are common in infants with HLHS, only ≥ moderate AVVR was associated with increased mortality in this single-center experience. Older age at NP was not a significant risk factor for interstage mortality.

Impact of postoperative nutrition on weight gain in infants with hypoplastic left heart syndrome.

OBJECTIVE: The study objective was to evaluate risk factors for poor weight gain in infants with hypoplastic left heart syndrome after stage 1 palliation. METHODS: We reviewed all term infants with hypoplastic left heart syndrome who had stage 1 palliation and stage 2 palliation at Texas Children's Hospital between 2000 and 2011 (n = 120). Predictor variables included age at stage 1 palliation, intensive care unit factors, calories delivered, and echocardiographic findings. Outcome variables included weight for age Z scores at hospital discharge, stage 2 palliation, and change in weight for age Z scores between stage 1 palliation and hospital discharge. RESULTS: Complete nutritional data were available for 47 of 120 patients. Median total parenteral nutrition duration was 6 days (range, 1-43 days), and median intensive care unit calories delivered was 53.9 kcal/kg/d (range, 22.3-119.6 kcal/kg/d). Before hospital discharge, the median caloric intake was 106.7 kcal/kg/d (range, 70.0-152.0 kcal/kg/d). Median weight for age Z scores was -0.59 (range, -3.6 to 0.5) at stage 1 palliation, -1.62 (range, -4.5 to -0.1) at intensive care unit transfer, and -1.81 (range, -4.9 to -0.5) at hospital discharge. A total of 46 of 47 patients had a negative change in weight for age Z scores between stage 1 palliation and hospital discharge, with a median change of -1.14 (range, -2.3 to 0.6). Change in weight for age Z scores from stage 1 palliation to discharge was directly associated with calories delivered and indirectly associated with hospital length of stay and moderate tricuspid regurgitation (P < .001). CONCLUSIONS: Postoperative nutrition fails to meet the needs of infants with hypoplastic left heart syndrome despite increased focus on nutritional support. Modifiable factors (eg, nutritional intake) and hemodynamic factors (eg, tricuspid regurgitation) may play roles in the poor weight gain of these infants.

Bcl-2-mediated potentiation of neocarzinostatin-induced apoptosis: requirement for caspase-3, sulfhydryl groups, and cleavable Bcl-2.

Overexpression of antiapoptotic Bcl-2 family members is thought to contribute to chemotherapeutic resistance of neural crest tumors. Paradoxical potentiation by Bcl-2 of apoptosis induced by the antineoplastic prodrug, neocarzinostatin (NCS), has been observed in PC12 pheochromocytoma cells. Prior studies have indicated that the cleavage of Bcl-2 to its proapoptotic counterpart mediated by caspase-3 is responsible for this potentiation of apoptosis. This has led to the hypothesis that induction of caspase-3 expression in bcl-2-transfected, caspase-3-deficient MCF-7 cells, will result in Bcl-2 cleavage and Bcl-2-dependent potentiation of NCS-induced apoptosis. These studies have further led to the hypothesis that both cleavable Bcl-2 and sulfhydryl groups are required for the activity of caspase-3 in this regard. As hypothesized, co-transfection of bcl-2-transfected MCF-7 cells with a caspase-3 expression construct results in cleavage of Bcl-2 and potentiation of dose-dependent, NCS-mediated cell death. Furthermore, PC12 cells transfected with an expression construct for cleavage-resistant Bcl-2 demonstrated attenuated potentiation of apoptosis relative to their counterparts transfected with wild-type bcl-2. Finally, irreversible oxidative titration of sulfhydryl groups resulted in concentration-dependent attenuation of apoptosis in PC12 cells, along with prevention of caspase-3 activation and Bcl-2 cleavage. These results definitively demonstrate the requirement for caspase-3, cleavable Bcl-2, and available sulfhydryl groups (separate from those required for NCS activation) in potentiation of NCS-induced apoptosis by Bcl-2.