Cardiac biomarkers in pediatric cardiomyopathy: Study design and recruitment results from the Pediatric Cardiomyopathy Registry

Background: Cardiomyopathies are a rare cause of pediatric heart disease, but they are one of the leading causes of heart failure admissions, sudden death, and need for heart transplant in childhood. Reports from the Pediatric Cardiomyopathy Registry (PCMR) have shown that almost 40% of children presenting with symptomatic cardiomyopathy either die or undergo heart transplant within 2 years of presentation. Little is known regarding circulating biomarkers as predictors of outcome in pediatric cardiomyopathy. Study Design: The Cardiac Biomarkers in Pediatric Cardiomyopathy (PCM Biomarkers) study is a multi-center prospective study conducted by the PCMR investigators to identify serum biomarkers for predicting outcome in children with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Patients less than 21 years of age with either DCM or HCM were eligible. Those with DCM were enrolled into cohorts based on time from cardiomyopathy diagnosis: categorized as new onset or chronic. Clinical endpoints included sudden death and progressive heart failure. Results: There were 288 children diagnosed at a mean age of 7.2±6.3 years who enrolled in the PCM Biomarkers Study at a median time from diagnosis to enrollment of 1.9 years. There were 80 children enrolled in the new onset DCM cohort, defined as diagnosis at or 12 months prior to enrollment. The median age at diagnosis for the new onset DCM was 1.7 years and median time from diagnosis to enrollment was 0.1 years. There were 141 children enrolled with either chronic DCM or chronic HCM, defined as children ≥2 years from diagnosis to enrollment. Among children with chronic cardiomyopathy, median age at diagnosis was 3.4 years and median time from diagnosis to enrollment was 4.8 years. Conclusion: The PCM Biomarkers study is evaluating the predictive value of serum biomarkers to aid in the prognosis and management of children with DCM and HCM. The results will provide valuable information where data are lacking in children. Clinical Trial Registration: NCT01873976 https://clinicaltrials.gov/ct2/show/NCT01873976?term=PCM+Biomarker&rank=

Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study

Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (P=0.005 and P=0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first-degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy

Metabolic syndrome and cardiovascular mortality among participants of the hypertension detection and follow-up program

Metabolic Syndrome (MetS) is a clustering of cardiovascular (CV) risk factors that includes obesity, dyslipidemia, hyperglycemia, and elevated blood pressure. Applying the criteria for MetS can serve as a clinically feasible tool for identifying patients at high risk for CV morbidity and mortality, particularly those who do not fall into traditional risk categories. The objective of this study was to examine the association between MetS and CV mortality among 10,940 American hypertensive adults, ages 30-69 years, participating in a large randomized controlled trial of hypertension treatment (HDFP 1973-1983). MetS was defined as the presence of hypertension and at least two of the following risk factors: obesity, dyslipidemia, or hyperglycemia. Of the 10,763 individuals with sufficient data available for analysis, 33.2% met criteria for MetS at baseline. The baseline prevalence of MetS was significantly higher among women (46%) than men (22%) and among non-blacks (37%) versus blacks (30%). All-cause and CV mortality was assessed for 10,763 individuals. Over a median follow-up of 7.8 years, 1,425 deaths were observed. Approximately 53% of these deaths were attributed to CV causes. Compared to individuals without MetS at baseline, those with MetS had higher rates of all-cause mortality (14.5% v. 12.6%) and CV mortality (8.2% versus 6.4%). The unadjusted risk of CV mortality among those with MetS was 1.31 (95% confidence interval [CI], 1.12-1.52) times that for those without MetS at baseline. After multiple adjustment for traditional risk factors of age, race, gender, history of cardiovascular disease (CVD), and smoking status, individuals with MetS, compared to those without MetS, were 1.42 (95% CI, 1.20-1.67) times more likely to die of CV causes. Of the individual components of MetS, hyperglycemia/diabetes conferred the strongest risk of CV mortality (OR 1.73; 95% CI, 1.39-2.15). Results of the present study suggest MetS defined as the presence of hypertension and 2 additional cardiometabolic risk factors (obesity, dyslipidemia, or hyperglycemia/diabetes) can be used with some success to predict CV mortality in middle-aged hypertensive adults. Ongoing and future prospective studies are vital to examine the association between MetS and cardiovascular morbidity and mortality in select high-risk subpopulations, and to continue evaluating the public health impact of aggressive, targeted screening, prevention, and treatment efforts to prevent future cardiovascular disability and death

Survival Without Cardiac Transplantation Among Children With Dilated Cardiomyopathy

Studies of children with dilated cardiomyopathy (DCM) have suggested that improved survival has been primarily due to utilization of heart transplantation. This study sought to determine transplant-free survival for these children over 20 years and identify the clinical characteristics at diagnosis that predicted death. Children <18 years of age with some type of DCM enrolled in the Pediatric Cardiomyopathy Registry were divided by year of diagnosis into an early cohort (1990 to 1999) and a late cohort (2000 to 2009). Competing risks and multivariable modeling were used to estimate the cumulative incidence of death, transplant, and echocardiographic normalization by cohort and to identify the factors associated with death. Of 1,953 children, 1,199 were in the early cohort and 754 were in the late cohort. Most children in both cohorts had idiopathic DCM (64% vs. 63%, respectively). Median age (1.6 vs. 1.7 years), left ventricular end-diastolic z-scores (+4.2 vs. +4.2), and left ventricular fractional shortening (16% vs. 17%) at diagnosis were similar between cohorts. Although the rates of echocardiographic normalization (30% and 27%) and heart transplantation (24% and 24%) were similar, the death rate was higher in the early cohort than in the late cohort (18% vs. 9%; p = 0.04). Being in the early cohort (hazard ratio: 1.4; 95% confidence interval: 1.04 to 1.9; p = 0.03) independently predicted death. Children with DCM have improved survival in the more recent era. This appears to be associated with factors other than heart transplantation, which was equally prevalent in both eras. (Pediatric Cardiomyopathy Registry [PCMR]; NCT00005391) [Display omitted

Abstract 16468: Results of Research Genetic Testing in Pediatric Cardiomyopathy Patients Justify Broader Clinical Genetic Testing

Introduction: Pediatric cardiomyopathies are genetically heterogeneous diseases with high risk of death or cardiac transplant. Despite progress in identifying causes, the majority of cases remain idiopathic. Currrently, genetic testing is not performed in all children with cardiomyopathy. Gene identification leads to better individual risk stratification and has the potential to stimulate the development of therapies based on the underlying mutation. The aim of this study is to identify genetic mutations in pediatric cardiomyopathy patients using whole exome sequencing. Hypothesis: Sarcomeric mutations are under-diagnosed causes of all forms of cardiomyopathy in children. Methods: Probands with cardiomyopathy were recruited from 11 institutions. Results of clinical genetic testing prior to enrollment were collected. Whole exome sequencing was performed and mutations were identified in 35 genes currently available on clinical genetic testing panels. Results: The initial 154 probands subjected to exome included 78 patients with DCM, 43 with HCM, 14 with RCM, and 19 with LVNC, mixed, or unknown types. Familial disease was present in 38% and the remainder were idiopathic. Twenty-seven percent had positive clinical genetic testing prior to enrollment. Exome testing identified mutations in 38 subjects who had not had clinical testing, increasing the cohort positive testing rate to 55% (DCM, 34.6%; HCM, 74.4%; RCM, 71.4%). Forty-five percent of subjects with no family history of disease had an identifiable mutation. Conclusions: Pediatric cardiomyopathy patients have a high incidence of mutations that can be identified by clinically available genetic testing. Lack of a family history of cardiomyopathy was not predictive of normal genetic testing. These results support the broader use of genetic testing in pediatric patients with all functional phenotypes of cardiomyopathy to identify disease causation allowing better family risk stratification

Comparing presenting clinical features of 48 children with microscopic polyangiitis (MPA) against 183 having granulomatosis with polyangiitis (GPA)

Objectives: To uniquely classify children with MPA, describe their demographics, presenting features, initial treatments, and compare with GPA patients. Methods: The European Medicines Agency (EMA) classification algorithm, applied by computation to categorical data of patients recruited to A Registry for Childhood Vasculitis, censored to November 2015, uniquely distinguished MPA from GPA patients who were classified with adult and pediatric-specific criteria. Descriptive statistics were used for comparisons. Results: 231 (64% female) of 440 patients fulfilled classification criteria for either MPA (n=48) or GPA (n=183); respectively median time-to-diagnosis was 1.6 and 2.1 months, range to 39 and 73 months. Comparing MPA versus GPA patients respectively they were significantly younger (median 11 versus 14 years); constitutional features were equally common; pulmonary manifestations (44% versus 74%) were less frequent and less severe (hemorrhage, oxygen-requiring, pulmonary failure); renal features (76% versus 83%) were similarly frequent but tended towards greater severity (nephrotic-range proteinuria, dialysis-requirement, end-stage disease). Airway/eye involvement was absent among MPA patients as these GPA-defining features preclude an MPA diagnosis within the EMA algorithm. MPA and GPA patients respectively received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%) plus plasmapheresis (19% and 22%). Other treatments in decreasing frequencies from 13% to 3% were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. Conclusion: Younger onset age, and perhaps both gastrointestinal manifestations and worse kidney disease seem to characterize children with MPA versus GPA. Delay in diagnosis suggests suboptimal recognition. Compared to adults, initial treatments are comparable, but the complete reversal of female to male prevalence ratios is provocative.Medicine, Faculty ofNon UBCMedicine, Department ofRheumatology, Division ofPediatrics, Department ofReviewedFacultyOthe

Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

Background Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes