Pediatric Cardiomyopathy Research Articles

Septal Myectomy Outcomes in Children and Adolescents With Obstructive Hypertrophic Cardiomyopathy

BackgroundLittle data exist regarding characteristics and outcomes of pediatric patients undergoing septal myectomy. We evaluated this in a large referral population. MethodsSeptal myectomy was performed in 199 consecutive patients aged ≤18 years with obstructive hypertrophic cardiomyopathy from January 1, 1976, to June 30, 2021. ResultsMedian age was 13 years (interquartile range [IQR], 8-15 years). Left ventricular myectomy approaches included transaortic (163 of 198 [82%]), transapical (16 of 198 [8%]), and combined (19 of 198 [10%]). Right ventricular interventions included myectomy (13 of 199 [7%]) and patch reconstruction of the outflow tract (15 of 199 [8%]). Maximum left ventricular outflow tract gradients decreased after myectomy (prebypass: 50 mm Hg [IQR, 31-73 mm Hg] vs postbypass: 4 mm Hg [IQR, 0-9 mm Hg], P < .001), and this was sustained long-term (5 mm Hg [IQR, 5-10 mm Hg] at 10 years). Iatrogenic aortic and mitral valve injuries occurred in 13 of 199 (7%) and 1 of 199 (1%), respectively; however, all were successfully repaired. Operative mortality was 2 of 199 (1%). The cumulative incidence of redo myectomy was low, at 5.8% at 5 and 8.3% at 10 years. Redo myectomy patients had higher maximum left ventricular outflow tract gradients on echocardiography at predischarge and 1 year and were younger at the index operation (8 years [IQR, 2.5-10 years] vs 13 years [IQR, 9-16 years], P < .001). Overall survival at 10 years was 90%, relative to 47% in a previously reported pediatric nonoperative cohort. ConclusionsPediatric septal myectomy provides safe, effective, and durable relief of ventricular outflow tract obstruction. Iatrogenic valve injury remains a low but nonnegligible risk. Recurrent obstruction requiring redo myectomy is infrequent and can be identified early. Long-term survival in this pediatric septal myectomy cohort appears to fare better than pediatric hypertrophic cardiomyopathy cohorts managed nonoperatively.

Generation of a human induced pluripotent stem cell line from a pediatric heart failure patient with de novo DNM1L mutation

We generated a new iPSC line (LCHi003-A) from the pediatric dilated cardiomyopathy patient carrying the de novo mutation on DNM1L gene. The new iPSC line expressed high pluripotent markers and were capable to differentiate into trilineage.

(1118) Administrative Databases: Friend or Foe in Pediatric Cardiomyopathy

(1118) Administrative Databases: Friend or Foe in Pediatric Cardiomyopathy

Rare Case of Pediatric Hypertrophic Obstructive Cardiomyopathy (HOCM) in A 6-year-old Boy: How to Recognize, Assess, and Manage the Risk?

Highlights: It discusses pediatric HCM which is usually caused by autosomal dominant traits caused by mutation in cardiac sarcomere protein genes. It explains how to recognize the cardiac risk Abstract: Hypertrophic Obstructive Cardiomyopathy (HOCM) is a disease characterized by increased left ventricular (LV) wall thickness and accompanied by obstructive physiology measured by increased LV outflow tract gradient. It is mainly inherited in autosomal dominant traits caused by a mutation in cardiac sarcomere protein genes. In pediatrics, HOCM is rare and comprises a different diagnosis and management approach compared to adults. The risk of sudden cardiac death (SCD) is also higher in the pediatric population. Case Summary. This report is about a case of HOCM found incidentally in a 6-year-old boy and a discussion based on the latest literature review. The patient first came for evaluation for cardiac murmur and abnormality in ECG and chest x-ray. Diagnosis of HOCM was made through echocardiography assessment. Discussion. ICD implantation for primary prevention of SCD was considered based on individualized 5-year SCD risk assessment which is around 7%. Optimal pharmacological therapy with beta-blocker, careful planning of ICD implantation with balanced benefit and risk, and septal reduction surgery when indicated should extend the life expectancy and quality of life of pediatric HOCM. It is both essential and interesting to recognize pediatric HOCM diagnostic findings and to pursue further research about therapies of this rare disease.

Narrative review of pediatric heart failure in the age of precision medicine.

Improvement in the affordability and convenience of genetic testing has rapidly expanded the understanding of the mechanistic causes of various pediatric cardiomyopathies. Concurrently, new therapies are being developed to better-target specific pathologies as opposed to classic therapies that treat the maladaptive processes of chronic heart failure. This review will discuss the advances in genetic testing and specific therapies that have been shown to benefit or potentially benefit genetically distinct subsets of the pediatric population with heart failure or at risk of developing heart failure. We undertook a comprehensive database search (January 2000-August 2022) of PubMed, utilizing terms 'pediatric', 'cardiomyopathy', 'heart failure', 'genetics', and 'precision medicine'. Additional notable studies were obtained from ClinicalTrials.gov. Studies published in English that examine genetic basis and treatment modalities of pediatric heart failure. New and investigational therapies for hypertrophic cardiomyopathies associated with obstruction or Noonan syndrome, Fabry cardiomyopathy, Barth syndrome, Duchenne muscular dystrophy, single ventricle failure, and heart failure in specific demographics are discussed. The rapid expansion of the genetic understanding of cardiomyopathy and heart failure as well as tailored therapies to specific molecular causes holds great promise for the future of pediatric heart failure treatment. Whereas conventional heart failure therapies target the maladaptive remodeling response that leads to worsening of heart failure, these therapies target the molecular causes of cardiomyopathy and heart failure in certain populations allowing for a potential to more significantly impact the clinical trajectory of pediatric heart failure.

Cardiomyocyte deoxyribonucleic acid damage and cardiac recovery in paediatric dilated cardiomyopathy.

The goal of this study was to identify the clinical significance of the deoxyribonucleic acid (DNA) damage response marker, phosphorylated H2A histone variant X, on the bridge to recovery in low-weight paediatric patients with dilated cardiomyopathy (DCM) after having a Berlin Heart EXCOR implanted. Consecutive paediatric patients with DCM who had an EXCOR implanted for DCM at our hospital between 2013 and 2021 were reviewed. Patients were classified into 2 groups according to the degree of DNA damage in the left ventricular cardiomyocytes-the low DNA damage group and the high DNA damage group-using the median value as the threshold. We examined and compared the preoperative factors and histologic findings associated with cardiac functional recovery following the explant procedure in the 2 groups. Competing outcome analysis of 18 patients (median body weight, 6.1 kg) showed that the incidence of an EXCOR explant was 40% at 1 year after the implant procedure. Serial echocardiography revealed significant left ventricular functional recovery in the low DNA damage group 3 months after the implant. The univariable Cox proportional hazards model revealed that the percentage of phosphorylated H2A histone variant X-positive cardiomyocytes was the significant factor associated with cardiac recovery and the EXCOR explant (hazard ratio, 0.16; 95% confidence interval, 0.027-0.51; P = 0.0096). The degree of DNA damage response to the EXCOR implant may aid in predicting the bridge to recovery with EXCOR among low-weight paediatric patients with DCM.

Clinical-Epidemiological Profile of Congenital And Acquired Heart Diseases Admitted To A Private Hospital

Objectives To characterize the clinical-epidemiological profile of children with heart diseases (congenital, acquired and arrhythmias), conducted by the pediatric cardio group of a private general hospital, from January 2016 to March 2020. Method Retrospective longitudinal observational interference study, with quantitative design, carried out in a private hospital. A total of 502 patients were selected according to the following inclusion criteria: patients who had congenital heart disease, acquired heart disease and arrhythmia, all managed by the pediatric cardiomyopathy group. Descriptive analysis of absolute and relative frequencies were represented through tables and graphs. Results Of the 502 patients included in the study, 86.5% had congenital heart disease, 7.7% acquired heart disease and 5.8% arrhythmias. 50.2% were female, 49.6% male and 0.2% were not defined so far. Prematurity occurred in 19.3% of cases, presence of syndromes in 31.2 % and associated comorbidities in 34.7%. In total, 530 procedures were performed, of which 77% were surgeries, 18.5% hemodynamic procedures and 4.5% hybrid procedures. A risk score called RACHS-1 (adjusted risk for surgery and congenital heart disease) was used to categorize the surgeries. There was a predominance of category 3 (38.4%), followed by category 2 (28.6%), category 1 (18.2%), category 4 (9.6%) and category 6 (5.2%). Conclusions The complexity of the profile of the found heart diseases reiterates that measures are needed for an integrated approach of different specialties and professionals for the treatment of these patients.

P209: Diagnostic yield and clinical utility of whole exome sequencing in pediatric cardiomyopathy*

P209: Diagnostic yield and clinical utility of whole exome sequencing in pediatric cardiomyopathy*

Pediatric restrictive cardiomyopathy with nephrotic syndrome: A novel genetic association

Pediatric restrictive cardiomyopathy with nephrotic syndrome: A novel genetic association

P279: Evaluating the utility of a new pathogenicity predictor for pediatric cardiomyopathy

P279: Evaluating the utility of a new pathogenicity predictor for pediatric cardiomyopathy

263 GENETIC CAUSES OF CARDIOMYOPATHIES IN CHILDREN

Abstract Background The genetic background of paediatric cardiomyopathies is only partially resolved, because of their rarity and heterogeneity. However, the assessment of aetiology is of paramount importance in order to define prognosis and therapeutic choices. Moreover, the recognition of genetic causes is the basis for cascade screening in the family. Aims This study aimed to identify the genetic causes of cardiomyopathies in children evaluated and followed at our paediatric hospital. Methods A validated Next Generation Sequencing (NGS) target panel was performed in a cohort of 76 paediatric patients: 36 Hypertrophic Cardiomyopathy, (HCM), 24 Dilated Cardiomyopathy (DCM), 3 Restrictive Cardiomyopathy (RCM), 2 Left Ventricular Non Compaction (LVNC), 10 Arrhythmogenic Cardiomyopathy (AC) and one with a cardiac arrest. Genetic counselling was offered to parents. Furthermore, 9 patients with negative genes panel were selected for Whole Exome Sequencing (WES). Results By target genes panel analysis we identified a pathogenic or likely pathogenic variant in 32/76 patients (42%). Most genotyped patients had a sarcomeric aetiology and MYH7 (11/32, 34%), MYBPC3 (7/32, 22%) and thin-filaments genes (9/32, 28%) resulted the most mutated genes. 11/32 (34%) patients had a complex genotype. In one patient we found the rare coexistence of two independent monogenic diseases (Osteogenesis Imperfecta and HCM) due respectively to COL1A1 and MYH7 variants. Moreover, we identified five syndromic cases (5/32, 16%): three patients with Noonan Syndrome (one with SOS1 variant and two with PTPN11 variants), one boy with Danon Disease (with LAMP2 variant) and a newborn with Alström Syndrome (due to ALMS1 variants). By WES we identified a de novo variant in FLNC gene in a 7 years old child RCM, a Noonan Syndrome due to biallelic LZTR1 variants in a 9 years old child, two PLEC1 variants in a newborn with DCM and Epidermolysis bullosa, and a de novo NKX2-5 variant in a child with RCM. Conclusions A definitive molecular diagnosis could be obtained in a substantial proportion of children (42%). The genetic test results had direct implications for clinical management, to suggest therapeutic interventions. Moreover, predictive genetic testing in family members resulted very important for clinical follow-up and to establish the recurrence risk for subsequent pregnancies.

Heart rate reduction as a marker to optimize carvedilol treatment and enhance myocardial recovery in pediatric dilated cardiomyopathy.

Introduction: An elevated heart rate is associated with an increased risk of death or cardiac transplant in children with dilated cardiomyopathy (DCM). Whether heart rate is a clinical marker to address therapy, is poorly investigated in children. Aim: To investigate the relationship between heart rate reduction (HRR) and left ventricular ejection fraction (LVEF) in DCM, treated with carvedilol. Methods: This is a multi center retrospective analysis conducted on all children with DCM (aged <18years) between 2013 and 2020, with LVEF <40% and treated with carvedilol. Carvedilol was up titrated to the maximal tolerated dose or to 1mg/kg/day. Echocardiographic data on left ventricular function and dimension were collected. The relationship between HRR and LVEF, left ventricular end-diastolic (LVEDd) and end-systolic diameter (LVESd) was assessed before and after HRR with carvedilol, using regression analysis. Results: 100 patients were enrolled (M: 51%; age 7 ± 8years). The mean LVEF was 30.2 ± 10% before treatment and 43.7 ± 9.6% after treatment, at the maximum therapeutic dose (p < 0.0001). There was a positive relationship between HRR and increase in LVEF (R 2 = 0.06, p = 0.014). A HRR of >20% correlated with an improvement in LVEF >13%. At 3years follow up, HRR demonstrated a significant reduction of LVESd (R2 = 0.1, p = 0.003) LVEDd (R2 = 0.07, p = 0.008) and LVEF recovery up to 15% (p < 0.0001). No deaths or heart transplant occurred during follow-up. Conclusion: This study demonstrates that HRR is safe and improvement in LVEF is related to the degree of HRR. The magnitude of LVEF improvement was enhanced by a major reduction in HR. It provides evidence that HRR could be used as a clinical marker to treat HF in children.

Serum from pediatric dilated cardiomyopathy patients promotes dysregulation of cardiolipin biosynthesis and mitochondrial dysfunction in primary cardiomyocytes

Pediatric dilated cardiomyopathy (DCM) is a devastating and poorly understood disease with most clinical treatment paradigms extrapolated from the adult population. Our studies showed that aspects of metabolism and mitochondrial function are dysregulated in pediatric hearts. Cardiolipin (CL), a unique phospholipid in the inner mitochondrial membrane, is essential for optimal mitochondrial function and was shown to be dysregulated in failing adult and pediatric human heart.

Abstract 14006: Circulating microRNAs Predict Recovery in Pediatric Dilated Cardiomyopathy Patients

Introduction: microRNAs (miRs) are small single stranded RNAs capable of targeting expression of several genes. Circulating miRs are stable and can be important biomarkers of disease progression and diagnosis. Hypothesis: We hypothesized circulating miRs could be a reliable prognostic biomarker of recovery for pediatric dilated cardiomyopathy (DCM). Methods: TaqMan Open Array miR panel (ThermoFisher Scientific) was used to investigate expression of 381 circulating miRs. Samples originated from the Pediatric Cardiomyopathy Registry (PCMR) and were collected within 3 months of a new diagnosis of DCM. Inclusion criteria included &lt;18 years of age at diagnosis of idiopathic or familial DCM (EF&lt;50% or left ventricular end-diastolic dimension [LVEDd] z-score ≥+2). Patients with DCM secondary to musculoskeletal diseases or anthracycline toxicity were excluded. Primary outcomes, occurring within 1 year of enrollment, were defined as: [1] Death, transplant (tx) listing or initiation of mechanical circulatory support; [2] Recovered- normalization of ventricular size and function (EF≥50% and LVEDd z-score &lt;+2) or [3] Stable- persistent DCM with EF&lt;50% or LVEDd z-score ≥+2. Statistical analysis included random forest, hierarchical clustering and area under the receiver operator curve (AUC). Results: N=10 subjects were included in Group 1, of which 70% were female, 6 were white, 2 Hispanic and 3 of other/unknown races, median age 9.5y. N=5 samples were included in Group 2, of which 60% were female, 3 were white, 1 black and 1 native American, median age 1.9y. N=20 samples were included in Group 3, of which 40% were female, 10 were white, 5 black, 1 Pacific islander, 2 Hispanic and 4 of other/unknown races, median age 2.1y. The top 3 miRs differentiating Group 2 (Recovered) from Group 1 (Death/Tx) (AUC of 0.92) were hsa-miR-655, -410 and -636. The top 3 miRs differentiating Group 2 (Recovered) from Group 3 (Stable) were hsa-miR-17, -410 and -345 (AUC of 0.76). Conclusions: These results indicate circulating miRs can predict recovery in the pediatric DCM population. A unique biomarker signature of miRs specific to patients who have the potential to recover would improve risk stratification of this population.

Primary cardiomyopathies in childhood: clinical and diagnostic features (literature review)

Primary cardiomyopathies in childhood are a rare but serious disease that is a common cause of heart failure and the most common reason for heart transplantation in children over one year of age. Over the past decades, the diagnosis of cardiomyopathy has advanced from traditional clinical imaging methods to new genetic and imaging techniques. The article presents a review of the literature data on the modern classification of primary pediatric cardiomyopathies and the features of the clinical course and imaging, which is an integral part of the diagnosis based on the primary morphofunctional phenotype.

Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy

Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism.

Cardiopulmonary Exercise Testing in Pediatric Patients With Hypertrophic Cardiomyopathy

BackgroundExercise stress testing (EST) in pediatric hypertrophic cardiomyopathy (HCM) patients has not well described in a large heterogenous cohort. ObjectivesThe objective of the study was to determine the clinical utility of EST in pediatric HCM. MethodsThis was a retrospective single-center analysis of HCM patients younger than 21 years who had EST between January 1, 2000, and January 1, 2019. Clinical, demographic characteristics, and EST data were analyzed, using the last EST during the study or prior to the event in subjects with a primary outcome. The primary composite endpoint included cardiac death, transplant, or arrhythmia requiring implantable cardioverter-defibrillator placement. Outcome analysis was performed using Cox proportional hazard modeling. ResultsThe study cohort included 140 patients, 52% with a recognized genetic variant. There were 2 tests aborted due to safety concerns (ST-segment changes, ventricular ectopy). The median age at first EST was 13.6 years. Ninety percent of patients were tested using cycle ergometry, and 44% were on a beta-blocker. The median peak oxygen consumption was 37.1 mL/kg/min (IQR: 12.5 mL/kg/min) or 81.2% predicted, the mean anaerobic threshold was 21.8 Ml (IQR: 8.3 mL), and the median peak power was 2.6 ± 1.1 W/kg or 73.7% predicted. Ectopy during EST was seen in 44% of patients, and 8% had an abnormal blood pressure response to exercise. The endpoint was reached in 12 patients. The presence of any degree of ectopy was a predictor of the composite endpoint (hazard ratio: 5.8; 95% CI: 1.3-26.7). ConclusionsEST is clinically useful in select pediatric patients with HCM. Ectopy on EST is a risk factor for cardiac death, cardiac transplant, and arrhythmias requiring implantable cardioverter-defibrillator.

Effect of β-Blocker Therapy on the Level of Soluble ST2 Protein in Pediatric Dilated Cardiomyopathy.

Background and Objectives: A prognosis for kids with pediatric dilated cardiomyopathy (PDCM) is urgently needed to identify high-risk patients. This study aimed to determine the association of levels and soluble suppression of tumorigenicity 2 (sST2) and medical therapy of β-blocker inhibitors with the risk of adverse events in PDCM. Materials and Methods: A total of 124 patients with PDCM were enrolled after admission from 2 centers in China and followed up for adverse events (death, cardiac transplantation, and heart-failure-related rehospitalization). Based on a median sST2 level and the usage of β-blocker inhibitors, patients were divided into four groups. The Cox proportional hazard model was used to assess the risk of incident adverse events. Results: The median level of sST2 was 23.77 ng/mL, and 53 (42.7%) patients received β-blocker treatment. Over a median follow-up of 678 days, 37 (29.8%) adverse events occurred. Compared with patients with sST2 < median and without β-blocker, patients with sST2 ≥ median and without β-blocker (HR: 7.01; 95% CI: 1.21–40.45), followed by those with sST2 ≥ median and use of β-blocker had the highest risk of adverse events (hazard ratio (HR): 5.51; 95% confidence interval (CI): 1.17–25.84). However, a significant association was not observed in patients with sST2 < median and use of β-blocker. These associations were consistent across different subgroups. Conclusions: A higher level of sST2 was associated with a higher risk of adverse events in patients with PDCM, and β-blocker treatment for children with high levels of sST2 can effectively avoid adverse events.

Clinical profile and outcome of cardiomyopathies in infants and children seen at a tertiary centre

IntroductionDue to their rare prevalence and marked heterogeneity, pediatric cardiomyopathies (CMPs) are little known and scarcely reported. We report the etiology, clinical profile and outcome of a consecutive cohort of children diagnosed with CMP and followed at Meyer Children's Hospital over a decade. Patients and methodsWe retrospectively reviewed patients consecutively referred from May 2008 to May 2019 for pediatric onset CMP (<18 years). Heart disease caused by arrhythmic disorders, toxic agents, rheumatic conditions and maternal disease were excluded. ResultsWe enrolled 110 patients (65 males), diagnosed at a median age of 27 [4–134] months; 35% had an infant onset (<1 year of age). A positive family history was more often associated with childhood-onset (38.8%). Hypertrophic cardiomyopathy (HCM; 48 patients) was the most frequent phenotype, followed by dilated cardiomyopathy (DCM; 35 patients). While metabolic and idiopathic etiologies were preponderant in infants, metabolic and sarcomeric diseases were most frequent in the childhood-onset group. Major adverse cardiac events (MACE) occurred in 31.8% of patients, including hospitalization for acute heart failure in 25.5% of patients, most commonly due to DCM. Overall, the most severe outcomes were documented in patients with metabolic diseases. ConclusionsIn a consecutive cohort of pediatric patients with CMP, those with infantile onset and with a metabolic etiology had the worst prognosis. Overall, MACE occurred in 41% of the entire population, most commonly associated with DCM, inborn errors of metabolism and genetic syndromes. Systematic NGS genetic testing was critical for etiological diagnosis and management.

Genetic profile and genotype-phenotype correlations in hypertrophic cardiomyopathy presenting during childhood

Genetic cardiomyopathy (CM) is a rare disease in childhood. Risk factors for outcomes remain poorly described. Our study aimed to analyse clinical and genetical aspects in a pediatric hypertrophic cardiomyopathy (HMC) population and to establish genotype-phenotype correlations. A retrospective study of all patients with “idiopathic” HCM diagnosed in southeast France, before the age of 18 years was performed. All data (clinic, echocardiography, genetic testing) were retrospectively collected. Patients who did not have complete genetic testing according to current scientific development had another DNA blood sample during the study to complete the testing. Genetic tests were considered positive if the variant found was classified as pathogenic, likely pathogenic or variant of uncertain significance. Thirty-three patients were diagnosed with “idiopathic” HCM. Median age at diagnosis was 6.8 years old [0.3–12.1]. Genetic testing was positive in 21 cases (63.6%). Patients with an identified mutation had more visceral impact (38% vs. 8%, P = 0.009), a higher rate of implantable cardiac defibrillator (24% vs. none, P = 0.025) and more frequent heart transplant (19% vs. none, P = 0.025). In our population with paediatric HCM, a positive genetic testing is associated with a worse clinical course. Those data have to be corroborated with larger-scale studies.