Background Children hospitalized with acute decompensated heart failure (ADHF) frequently require intravenous vasoactive (IVV) support drugs and are at risk for adverse cardiovascular (ACV) outcomes. ...We wished to assess whether serial changes in B‐type natriuretic peptide (BNP) levels are associated with successful weaning off IVV support and/or prespecified ACV outcomes in children hospitalized with ADHF. Methods and Results Children hospitalized with ADHF from 2005 to 2021 at our institution were assessed for serial changes in BNP, weaning off of IVV support, and ACV outcomes. Changes in BNP level were evaluated using linear mixed‐effects modeling. Bonferroni correction was used to adjust for multiple hypothesis testing. In 131 hospitalizations of children with ADHF, the median age was 4.8 years, with 74% receiving IVV support. ACV outcomes occurred in 62 children. IVV support was associated with lower admission left ventricular ejection fraction (26.7% versus 32%, P =0.002), more severe left ventricular dilation (left ventricular internal diastolic dimension Z score 5.9 versus 3.1, P =0.021) moderate or more mitral regurgitation (41.3% versus 20.6%, P =0.038), and qualitative right ventricular systolic dysfunction (in 45.4% versus 11.8%, P <0.001). Decline in BNP levels was more rapid in patients who were successfully weaned from IVV support (−0.20 versus –0.03 2log pg/mL per day, P <0.001) and in the non‐ACV group (−0.17 versus –0.03 2log pg/mL per day, P <0.001). Right ventricular systolic dysfunction was an independent risk factor for ACV (odds ratio, 2.49; P =0.045). Conclusions The declining rate of serial BNP levels was associated with weaning from IVV support and no ACV outcomes in children hospitalized with ADHF. Right ventricular systolic dysfunction was associated with ACV outcomes.
Digital PCR (dPCR) is a powerful tool for research and diagnostic applications that require absolute quantification of target molecules or detection of rare events, but the number of nucleic acid ...targets that can be distinguished within an assay has limited its usefulness. For most dPCR systems, one target is detected per optical channel and the total number of targets is limited by the number of optical channels on the platform. Higher-order multiplexing has the potential to dramatically increase the usefulness of dPCR, especially in scenarios with limited sample. Other potential benefits of multiplexing include lower cost, additional information generated by more probes, and higher throughput. To address this unmet need, we developed a novel melt-based hairpin probe design to provide a robust option for multiplexing digital PCR. A prototype multiplex digital PCR (mdPCR) assay using three melt-based hairpin probes per optical channel in a 16-well microfluidic digital PCR platform accurately distinguished and quantified 12 nucleic acid targets per well. For samples with 10,000 human genome equivalents, the probe-specific ranges for limit of blank were 0.00%–0.13%, and those for analytical limit of detection were 0.00%–0.20%. Inter-laboratory reproducibility was excellent (
r
2
= 0.997). Importantly, this novel melt-based hairpin probe design has potential to achieve multiplexing beyond the 12 targets/well of this prototype assay. This easy-to-use mdPCR technology with excellent performance characteristics has the potential to revolutionize the use of digital PCR in research and diagnostic settings.
In solid-organ transplantation, human leukocyte antigen (HLA) donor-specific antibodies (DSA) are strongly associated with graft rejection, graft loss, and patient death. The predominant tests used ...for detecting HLA DSA before and after solid-organ transplantation are HLA single antigen bead (SAB) assays. However, SAB assays may not detect antibodies directed against HLA epitopes that are not represented in the SAB. The prevalence and potential impact of unrepresented HLA epitopes are expected to vary by ethnicity, but have not been thoroughly investigated. To address this knowledge gap, HLA allele frequencies from seven ethnic populations were compared with HLA proteins present in SAB products from two manufacturers to determine unrepresented HLA proteins.
Allele frequencies were obtained from the Common, Intermediate, and Well Documented HLA catalog v3.0, and frequencies of unrepresented HLA types were calculated. Next-generation sequencing was used to determine HLA types of 60 deceased solid-organ donors, and results were used to determine if their HLA-A, -B, -C, and -DRB1 proteins were not present in SAB reagents from two vendors. Unrepresented HLA proteins were compared with the most similar protein in SAB assays from either vendor and then visualized using modeling software to assess potential HLA epitopes.
For the seven ethnic populations, 0.5% to 11.8% of each population had HLA proteins not included in SAB assays from one vendor. Non-European populations had greater numbers of unrepresented alleles. Among the deceased donors, 26.7% (16/60) had at least one unrepresented HLA-A, -B, -C, or -DRB1 protein. Structural modeling demonstrated that a subset of these had potential HLA epitopes that are solvent accessible amino acid mismatches and are likely to be accessible to B cell receptors.
In conclusion, SAB assays cannot completely rule out the presence of HLA DSA. HLA epitopes not represented in those assays vary by ethnicity and should not be overlooked, especially in non-European populations. Allele-level HLA typing can help determine the potential for HLA antibodies that could evade detection.
Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disease manifested by progressive pulmonary vascular remodeling, compromised pulmonary blood flow and right heart failure. Most ...studies have explored how pulmonary endothelial function modulates disease pathogenesis. We hypothesize that IPAH is a progressive panvasculopathy, affecting both pulmonary and systemic vascular beds, and that systemic endothelial dysfunction correlates with disease severity. Recent studies have demonstrated systemic endothelial dysfunction in adults with pulmonary hypertension; however, adults often have additional comorbidities affecting endothelial function. Systemic endothelial function has not been explored in children with IPAH.
In this single-center, prospective, cross-sectional study we examined brachial artery flow-mediated dilation (FMD), a nitric oxide-mediated, endothelial-dependent response, in children with IPAH and matched controls. FMD measurements were compared with clinical and echocardiographic measures of IPAH severity.
Thirteen patients and 13 controls were studied, ranging in age from 6 to 20 years. FMD was decreased in IPAH subjects compared with controls (5.1 ± 2.1% vs 9.7 ± 2.0%; p < 0.0001). In IPAH subjects, FMD correlated directly with cardiac index (R(2) = 0.34, p = 0.035), and inversely with tricuspid regurgitation velocity (R(2) = 0.57, p = 0.019) and right ventricular myocardial performance index (R(2) = 0.44, p = 0.028).
The presence of systemic endothelial dysfunction in children with IPAH and its strong association with IPAH severity demonstrate that IPAH is a global vasculopathy. Although morbidity in IPAH is typically associated with pulmonary vascular disease, systemic vascular changes may also relate to disease pathogenesis and progression. Further study into shared mechanisms of systemic and pulmonary endothelial dysfunction may contribute to future therapies for IPAH.
Ventricular assist devices (VAD) are associated with the formation of antibodies to anti-human leukocyte antigens (HLA) or sensitization. The incidence and effects of VAD-associated anti-HLA ...sensitization have not been well studied in the pediatric population.
A retrospective review of all patients undergoing VAD implant at our institution from 1998 to 2008 was performed. Panel reactive antibody (PRA) results before VAD implant, after VAD implant, and after orthotopic heart transplantation (OHT) were recorded. Patients who became sensitized (PRA for class I and/or II immunoglobulin G antibodies >or= 10%) on VAD support were compared with non-sensitized patients with regard to demographics, diagnosis, device type, and blood product exposure on VAD support. Outcomes after OHT were also compared between groups.
VAD support was initiated in 20 patients (median age, 14.4 years), with 75% survival to OHT or recovery. PRA data before and after VAD implant were available for 17 patients. VAD-associated sensitization developed in 35% of recipients. There were no differences between those sensitized in association with VAD support and non-sensitized patients with regard to age, gender, diagnosis, device type, extracorporeal membrane oxygenation use, or blood product exposure on VAD support. Black race predicted sensitization on VAD (p = 0.02). There were no differences in survival or rejection between groups.
VAD therapy was associated with the development of anti-HLA sensitization in 35% of recipients. Black race predicted sensitization, but there were no differences in overall survival or outcomes after OHT.
Some pediatric patients referred for heart transplant (HTx) are sub-optimal candidates. Their outcomes without HTx are presumed to be dismal, but have not been well described. Knowledge about their ...outcomes is critical when weighing the risks between a high-risk transplant and "terminal" palliation.
We retrospectively reviewed all HTx referrals from January 2005 to July 2013. We excluded those who were listed for HTx, or who were denied HTx due to being "too well," seeking only those who were in need of but not suitable for HTx. End-points included mortality and length of survival.
Of 212 referrals, 39 (19%) (age 0 to 19 years, median 3.5 years) were denied HTx for reasons other than being too well. Twenty-eight (72%) had palliated congenital heart disease. Overall mortality during the follow-up period was 38% (n = 15) with a median follow-up time of 195 days (8 to 2,832 days). Ten patients received subsequent cardiac surgery with 1 death (10%) and median follow-up of 2.6 years. Mortality risk was not influenced by age, weight, growth failure, congenital heart disease or single-ventricle physiology. Mechanical ventilation (hazard ratio 6.31, p = 0.001) and inotrope dependence (hazard ratio 4.79, p = 0.006) were associated with the highest risk of mortality. Quality of life was measured with the PedsQL cardiac module and completed by 11 of 16 eligible patients with an overall average score of 70.2 ± 23.9.
An advanced heart failure program can achieve satisfactory results for pediatric patients who are not suitable candidates for HTx. For some children, high-risk palliative surgery can result in better outcome than high-risk HTx. Mortality was related to the degree of heart failure at presentation rather than underlying heart disease.
The objective of this study was to determine the efficacy of balloon angioplasty (BA) by comparing the immediate and long-term outcomes of patients with and without re-coarctation after a Norwood ...procedure.
Although BA has become the standard means for treating recurrent coarctation following a Norwood operation, it has been suggested that re-coarctation remains a significant cause of morbidity and mortality.
Patients who survived a Norwood operation from December 1986 through June 2001 were studied. Differences between groups were evaluated by ttest and logistic regression. Survival differences were tested by log-rank tests using Kaplan-Meier survival curves.
Fifty-eight of 633 patients underwent treatment for re-coarctation (9.2%). Thirty-five patients underwent BA (before 1988, 23 had surgery). Median age at catheterization was 6.6 months (1.9 to 35.6 months). Balloon angioplasty was successful (gradient <10 mm Hg) in 32 of 35 patients (92%). There were no BA-related deaths or neurologic complications. Recurrent obstruction after BA occurred in seven patients (20%); five underwent re-dilation. Kaplan-Meier estimates of freedom from recurrent obstruction after initial BA were 97% at one month, 79% at one year, and 79% at five years. There were no differences in survival between patients with re-coarctation treated by BA and patients who did not undergo treatment for re-coarctation.
We found that 9.2% of patients underwent treatment for re-coarctation following a Norwood operation. Balloon angioplasty is effective, with low morbidity, no early mortality, and no difference in long-term survival when compared with patients who did not have re-coarctation. Recurrent coarctation following BA occurred in 17% of patients, usually within the first year after BA.
Abstract
INTRODUCTION: MEK inhibitors (MEKi) have shown efficacy in pediatric low-grade glioma, among other tumors, but have been associated with acute cardiac dysfunction in adults. Cardiac ...consequences in children are unknown. MATERIAL AND METHODS: We performed a single center retrospective cohort study evaluating cardiac function by echocardiography (echo) in children and young adults <21 years old receiving MEKi at Children’s Hospital Los Angeles between October 2013 and May 2018. Blinded assessment of left ventricular function by fractional shortening (FS) and ejection fraction (EF) was performed on all available echocardiograms obtained before, during, and following therapy, as well as after re-initiation of therapy. RESULTS: Twenty-six patients underwent MEKi therapy with echo follow-up during the study period. Twenty-four of these had complete echo data. Median follow-up was 12 months. Borderline EF (EF 53-57.9%) occurred in 12 (50%) patients; and 3 (12.5%) progressed to abnormal EF (EF <53%). Cardiac dysfunction, when it occurred, was mild (lowest documented EF was 45%, and lowest FS was 24.4%). EF abnormalities typically fluctuated during therapy, resolved off therapy, and recurred with MEKi re-initiation. No clinical or demographic differences were detected between those who maintained normal cardiac function and those who developed borderline or overt cardiac dysfunction. Symptomatic heart failure did not occur. CONCLUSION: In this cohort of children and young adults, MEKi use was associated with a relatively high incidence of borderline decrease in left ventricular function, often of uncertain clinical significance. There was no evidence of permanent cardiac dysfunction. Further evaluation in larger prospective trials is needed.
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