Because of remarkable surgical and medical advances over the past several decades, there are growing numbers of infants and children living with single ventricle congenital heart disease (SV), where ...there is only one functional cardiac pumping chamber. Nevertheless, cardiac dysfunction (and ultimately heart failure) is a common complication in the SV population, and pharmacological heart failure therapies have largely been ineffective in mitigating the need for heart transplantation. Given that there are several inherent risk factors for ventricular dysfunction in the setting of SV in addition to probable differences in molecular adaptations to heart failure between children and adults, it is perhaps not surprising that extrapolated adult heart failure medications have had limited benefit in children with SV heart failure. Further investigations into the molecular mechanisms involved in pediatric SV heart failure may assist with risk stratification as well as development of targeted, efficacious therapies specific to this patient population. In this review, we present a brief overview of SV anatomy and physiology, with a focus on patients with a single morphological right ventricle requiring staged surgical palliation. Additionally, we discuss outcomes in the current era, risk factors associated with the progression to heart failure, present state of knowledge regarding molecular alterations in end-stage SV heart failure, and current therapeutic interventions. Potential avenues for improving SV outcomes, including identification of biomarkers of heart failure progression, implications of personalized medicine and stem cell-derived therapies, and applications of novel models of SV disease, are proposed as future directions.
Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric ...hypertrophic cardiomyopathy to guide SCD prevention strategies.
In an international multicenter observational cohort study, phenotype-positive patients with isolated hypertrophic cardiomyopathy <18 years of age at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest, and aborted SCD, that is, appropriate shock following primary prevention implantable cardioverter defibrillators. Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD. The cause-specific regression model was implemented using boosting, and tuned with 10 repeated 4-fold cross-validations. The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized by using the c-statistic for competing risk models. The final model was validated in an independent external cohort (SHaRe Sarcomeric Human Cardiomyopathy Registry, n=285).
Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up. The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated sudden cardiac arrests, and 14 aborted SCD). Risk predictors included age at diagnosis, documented nonsustained ventricular tachycardia, unexplained syncope, septal diameter
-score, left ventricular posterior wall diameter
score, left atrial diameter
score, peak left ventricular outflow tract gradient, and presence of a pathogenic variant. Unlike in adults, left ventricular outflow tract gradient had an inverse association, and family history of SCD had no association with SCD. Clinical and clinical/genetic models were developed to predict 5-year freedom from SCD. Both models adequately discriminated between patients with and without SCD events with a c-statistic of 0.75 and 0.76, respectively, and demonstrated good agreement between predicted and observed events in the primary and validation cohorts (validation c-statistic 0.71 and 0.72, respectively).
Our study provides a validated SCD risk prediction model with >70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. An individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for implantable cardioverter defibrillator insertion. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0403679.
The phosphodiesterase 3A (PDE3A) gene encodes a PDE that regulates cardiac myocyte cyclic adenosine monophosphate (cAMP) levels and myocardial contractile function. PDE3 inhibitors (PDE3i) are used ...for short-term treatment of refractory heart failure (HF), but do not produce uniform long-term benefit.
The authors tested the hypothesis that drug target genetic variation could explain clinical response heterogeneity to PDE3i in HF.
PDE3A promoter studies were performed in a cloned luciferase construct. In human left ventricular (LV) preparations, mRNA expression was measured by reverse transcription polymerase chain reaction, and PDE3 enzyme activity by cAMP-hydrolysis.
The authors identified a 29-nucleotide (nt) insertion (INS)/deletion (DEL) polymorphism in the human PDE3A gene promoter beginning 2,214 nt upstream from the PDE3A1 translation start site. Transcription factor ATF3 binds to the INS and represses cAMP-dependent promoter activity. In explanted failing LVs that were homozygous for PDE3A DEL and had been treated with PDE3i pre-cardiac transplantation, PDE3A1 mRNA abundance and microsomal PDE3 enzyme activity were increased by 1.7-fold to 1.8-fold (p < 0.05) compared with DEL homozygotes not receiving PDE3i. The basis for the selective up-regulation in PDE3A gene expression in DEL homozygotes treated with PDE3i was a cAMP response element enhancer 61 nt downstream from the INS, which was repressed by INS. The DEL homozygous genotype frequency was also enriched in patients with HF.
A 29-nt INS/DEL polymorphism in the PDE3A promoter regulates cAMP-induced PDE3A gene expression in patients treated with PDE3i. This molecular mechanism may explain response heterogeneity to this drug class, and may inform a pharmacogenetic strategy for a more effective use of PDE3i in HF.
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Abstract Background Pediatric heart failure (HF) patients have a suboptimal response to traditional HF medications, although phosphodiesterase 3 inhibition (PDE3i) has been used with greater success ...than in the adult HF population. We hypothesize that molecular alterations specific to children with HF and HF etiology may impact response to treatment. Methods and Results Adenylyl cyclase (AC) and phosphodiesterase (PDE) isoforms were quantified using qRT-PCR in explanted myocardium from adults with dilated cardiomyopathy (DCM), children with DCM, and children with single ventricle congenital heart disease of right ventricular morphology (SRV). AC and PDE expression profiles are uniquely regulated in each subject group and demonstrate distinct changes in response to chronic PDE3i. There is unique upregulation of: AC5 in adult DCM with PDE3i (fold-change 2.415, p=0.043), AC2 in pediatric DCM (fold-change 2.396, p=0.0067), and PDE1C in pediatric SRV (fold-change 1.836, p=0.032). Remarkably, PDE5A expression is consistently increased across all age and disease groups. Conclusions Unique regulation of AC and PDE isoforms supports a differential molecular adaptation to HF in children compared with adults, and may help identify mechanisms specific to the pathogenesis of pediatric HF. Greater understanding of these differences will help optimize medical therapies based on age and disease process.
Objectives Empiric treatment with milrinone, a phosphodiesterase (PDE) 3 inhibitor, has become increasingly common in patients with single ventricle heart disease of right ventricular (RV) morphology ...(SRV); our objective was to characterize the myocardial response to PDE3 inhibition (PDE3i) in the pediatric population with SRV. Study design Cyclic adenosine monophosphate levels, PDE activity, and phosphorylated phospholamban (PLN) were determined in explanted human ventricular myocardium from nonfailing pediatric donors (n = 10) and pediatric patients transplanted secondary to SRV. Subjects with SRV were further classified by PDE3i treatment (n = 13 with PDE3i and n = 12 without PDE3i). Results In comparison with nonfailing RV myocardium (n = 8), cyclic adenosine monophosphate levels are lower in patients with SRV treated with PDE3i (n = 12, P = .021). Chronic PDE3i does not alter total PDE or PDE3 activity in SRV myocardium. Compared with nonfailing RV myocardium, SRV myocardium (both with and without PDE3i) demonstrates equivalent phosphorylated PLN at the protein kinase A phosphorylation site. Conclusions As evidenced by preserved phosphorylated PLN, the molecular adaptation associated with SRV differs significantly from that demonstrated in pediatric heart failure because of dilated cardiomyopathy. These alterations support a pathophysiologically distinct mechanism of heart failure in pediatric patients with SRV, which has direct implications regarding the presumed response to PDE3i treatment in this population.
Cardiac allograft vasculopathy (CAV) is a leading cause of retransplantation and death in pediatric heart transplant recipients. Our aim was to evaluate the association between serum vascular ...endothelial growth factor-A (VEGF) and CAV development in the pediatric heart transplant population.
In this retrospective study performed at a university hospital, VEGF concentrations were measured by enzyme-linked immunosorbent assay in banked serum from pediatric heart transplant recipients undergoing routine cardiac catheterization. In subjects with CAV (n = 29), samples were obtained at 2 time-points: before CAV diagnosis (pre-CAV) and at the time of initial CAV diagnosis (CAV). In subjects without CAV (no-CAV, n = 16), only 1 time-point was used. VEGF concentrations (n = 74) were assayed in duplicate.
Serum VEGF is elevated in pediatric heart transplant recipients before catheter-based diagnosis of CAV (no-CAV mean: 144.0 ± 89.05 pg/ml; pre-CAV mean: 316.2 ± 118.3 pg/ml; p = 0.0002). Receiver-operating characteristic curve analysis of pre-CAV VEGF levels demonstrated an area under the curve of 87.7% (p = 0.0002), with a VEGF level of 226.3 pg/ml predicting CAV development with 77.8% sensitivity and 91.7% specificity. VEGF is similarly elevated in subjects with angiographically diagnosed CAV and in those with normal angiography but intravascular ultrasound (IVUS) evidence of CAV.
The increase in serum VEGF before onset of detectable CAV is fundamental to its utility as a predictive biomarker and suggests further investigations of VEGF in the pathogenesis of CAV are warranted in the pediatric heart transplant population.
The GNAS gene (OMIM#139320), located on chromosome 20q13.2, encodes for the alpha‐subunit of the stimulatory signaling protein, Gsα protein. GNAS variants with inactivating properties are associated ...with Albright's hereditary osteodystrophy (AHO) and when maternally inherited, pseudohypoparathyroidism 1a (OMIM#103580), which includes multiple hormone resistance. In this clinical report we describe a novel GNAS variant, c.159A>G, p.K53N, in an individual with features consistent with AHO and pseudohypoparathyroidism 1a and its segregation through multiple maternal relatives, including two genotype positive maternal first cousins who also display features classic for AHO. The proband developed unique features including cardiomyopathy which required a heart transplant at 5 years old and immune dysregulation resulting in multisystem organ failure and ultimately, death at the age of 18 years. Additional investigations exploring alternative explanations for the proband's presentation were pursued including whole genome sequencing which was negative. We postulate that the atypical features seen in the proband may have resulted from dysregulated Gsα signaling in cardiac tissue. Future studies are needed to explore the properties of the K53N GNAS variant and this proposed mechanism.
The scope of this review is to discuss aspects of general pediatric care which significantly impact the outcome of children after heart transplant. The general practitioner (GP) often serves as the ...frontline for prevention and early detection of common problems after heart transplant.
Multiple studies in the literature show the negative impact of preventable illness in immune compromised patients, including the appropriateness of vaccine administration. Except for live vaccines, pediatric heart transplant recipients generally follow standard childhood vaccine schedules. In addition, diagnosis of cardiac and noncardiac conditions by the practitioner can lead to earlier treatment by subspecialists. While rejection and infection are such conditions the practitioner may identify, psychological and neurocognitive conditions are common and impact both adherence to medications and quality of life.
These issues are addressed in this review of the recent literature. Through knowledge, detection, and collaboration of care, the practitioner can greatly improve the well being of pediatric heart transplant recipients.
Genetic defects in the RAS/mitogen-activated protein kinase pathway are an important cause of hypertrophic cardiomyopathy (RAS-HCM). Unlike primary HCM (P-HCM), the risk of sudden cardiac death (SCD) ...and long-term survival in RAS-HCM are poorly understood.
The study's objective was to compare transplant-free survival, incidence of SCD, and implantable cardioverter-defibrillator (ICD) use between RAS-HCM and P-HCM patients.
In an international, 21-center cohort study, we analyzed phenotype-positive pediatric RAS-HCM (n = 188) and P-HCM (n = 567) patients. The between-group differences in cumulative incidence of all outcomes from first evaluation were compared using Gray’s tests, and age-related hazard of all-cause mortality was determined.
RAS-HCM patients had a lower median age at diagnosis compared to P-HCM (0.9 years IQR: 0.2-5.0 years vs 9.8 years IQR: 2.0-13.9 years, respectively) (P < 0.001). The 10-year cumulative incidence of SCD from first evaluation was not different between RAS-HCM and P-HCM (4.7% vs 4.2%, respectively; P = 0.59). The 10-year cumulative incidence of nonarrhythmic deaths or transplant was higher in RAS-HCM compared with P-HCM (11.0% vs 5.4%, respectively; P = 0.011). The 10-year cumulative incidence of ICD insertions, however, was 5-fold lower in RAS-HCM compared with P-HCM (6.9% vs 36.6%; P < 0.001). Nonarrhythmic deaths occurred primarily in infancy and SCD primarily in adolescence.
RAS-HCM was associated with a higher incidence of nonarrhythmic death or transplant but similar incidence of SCD as P-HCM. However, ICDs were used less frequently in RAS-HCM compared to P-HCM. In addition to monitoring for heart failure and timely consideration of advanced heart failure therapies, better risk stratification is needed to guide ICD practices in RAS-HCM.
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