Survival Without Cardiac Transplantation Among Children With Dilated Cardiomyopathy.

2017

2663-2673

2017 Nov 28

1558-3597

BACKGROUND: Studies of children with dilated cardiomyopathy (DCM) have suggested that improved survival has been primarily due to utilization of heart transplantation.

OBJECTIVES: This study sought to determine transplant-free survival for these children over 20 years and identify the clinical characteristics at diagnosis that predicted death.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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).

10.1016/j.jacc.2017.09.1089

J. Am. Coll. Cardiol.

29169474

The genetic architecture of pediatric cardiomyopathy.

2022

2022 Jan 10

1537-6605

<p>To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants &lt; 1 year were less likely to have a molecular diagnosis (p &lt; 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p &lt; 0.001) and SPARK parental controls (p &lt; 1&nbsp;× 10). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.</p>

10.1016/j.ajhg.2021.12.006

Am J Hum Genet

35026164

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

2021

e017731

2021 Apr 28

2047-9980

<p>Background 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 (=0.005 and =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. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01873963.</p>

10.1161/JAHA.120.017731

J Am Heart Assoc

33906374

Cardiac Biomarkers in Pediatric Cardiomyopathy: Study Design and Recruitment Results from the Pediatric Cardiomyopathy Registry.

2019

1-10

2019 Jun

1058-9813

<p><strong>Background: </strong>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.</p>

<p><strong>Study Design: </strong>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.</p>

<p><strong>Results: </strong>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.</p>

<p><strong>Conclusion: </strong>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.</p>

<p><strong>Clinical Trial Registration NCT01873976: </strong>https://clinicaltrials.gov/ct2/show/NCT01873976?term=PCM+Biomarker&amp;…;

10.1016/j.ppedcard.2019.02.004

Prog. Pediatr. Cardiol.

31745384

Cardiac transplantation in children with Down syndrome, Turner syndrome, and other chromosomal anomalies: A multi-institutional outcomes analysis.

2018

749-754

2018 Jun

1557-3117

<p><strong>BACKGROUND: </strong>The purpose of this study was to describe the prevalence, characteristics, and outcomes in pediatric patients with chromosomal anomalies (CA) undergoing orthotopic heart transplantation (OHT).</p>

<p><strong>METHODS: </strong>A query of the database of the Pediatric Health Information System, a large administrative and billing database of 43 tertiary children's hospitals, was performed for the Years 2004 to 2016. Pediatric patients who received OHT were analyzed based on presence and type of CA. CA analyzed included: Down syndrome (DS); Turner syndrome (TS)/gonadal dysgenesis; conditions due to anomaly of unspecified chromosome; autosomal deletion; microdeletion; and autosomal anomaly. Healthcare-associated charge analysis during hospitalization for OHT and survival after OHT were assessed.</p>

<p><strong>RESULTS: </strong>A total of 3,080 hospitalizations were identified in which OHTs were performed. Of these OHTs, 64 (2.1%) were performed in patients with a concomitant diagnosis of CA. The presence of CA did not confer a higher risk of in-hospital mortality after OHT (odds ratio 1.2 [0.5 to 3.2], p = 0.651). Differences in in-hospital mortality between different types of CA, including DS and TS, did not reach statistical significance. Survival at 1-year post-OHT was similar in patients with CA compared to those without CA (p = 0.248). Length of stay after OHT was longer in patients with CA: 76 (interquartile range [IQR] 76 to 142 days vs 49 [IQR 21 to 98] days) (p &lt; 0.001), respectively. Overall adjusted hospital charges were significantly higher in the CA group: $1.2 million (IQR $740,000 to $2.2 million) vs $792,000 (IQR $425,000 to $1.5 million] (p &lt; 0.001), respectively.</p>

<p><strong>CONCLUSIONS: </strong>CA is present in ~2% of pediatric patients undergoing OHT. The presence of CA was not associated with increased mortality in pediatric patients undergoing OHT. Limitations of this study include the small number of patients available for analysis and a likely highly selective cohort of patients with CA.</p>

10.1016/j.healun.2018.01.1296

29449075

No Obesity Paradox in Pediatric Patients With Dilated Cardiomyopathy.

2018

222-230

2018 Mar

2213-1787

<p><strong>OBJECTIVES: </strong>This study aimed to examine the role of nutrition in pediatric dilated cardiomyopathy (DCM).</p>

<p><strong>BACKGROUND: </strong>In adults with DCM, malnutrition is associated with mortality, whereas obesity is associated with survival.</p>

<p><strong>METHODS: </strong>The National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry was used to identify patients with DCM and categorized by anthropometric measurements: malnourished (MN) (body mass index [BMI]&nbsp;&lt;5% for&nbsp;≥2 years or weight-for-length&nbsp;&lt;5% for&nbsp;&lt;2 years), obesity (BMI &gt;95% for age&nbsp;≥2 years or weight-for-length &gt;95% for&nbsp;&lt;2 years), or normal bodyweight (NB). Of 904 patients with DCM, 23.7% (214) were MN, 13.3% (120) were obese, and 63.1% (570) were NB.</p>

<p><strong>RESULTS: </strong>Obese patients were older (9.0 vs. 5.7 years for NB; p&nbsp;&lt; 0.001) and more likely to have a family history of DCM (36.1% vs. 23.5% for NB; p&nbsp;= 0.023). MN patients were younger (2.7 years vs. 5.7 years for NB; p&nbsp;&lt; 0.001) and more likely to have heart failure (79.9% vs. 69.7% for NB; p&nbsp;= 0.012), cardiac dimension z-scores &gt;2, and higher ventricular mass compared with NB. In multivariable analysis, MN was associated with increased risk of death (hazard&nbsp;ratio [HR]: 2.06; 95% confidence interval [CI]: 1.66 to 3.65; p&nbsp;&lt; 0.001); whereas obesity was not (HR: 1.49; 95% CI: 0.72 to 3.08). Competing outcomes analysis demonstrated increased risk of mortality for MN compared with NB (p&nbsp;=&nbsp;0.03), but no difference in transplant rate (p&nbsp;= 0.159).</p>

<p><strong>CONCLUSIONS: </strong>Malnutrition is associated with increased mortality and other unfavorable echocardiographic and clinical&nbsp;outcomes compared with those of NB. The same effect of obesity on survival was not observed. Further studies are needed investigating the long-term impact of abnormal anthropometric measurements on outcomes in pediatric DCM. (Pediatric&nbsp;Cardiomyopathy Registry; NCT00005391).</p>

10.1016/j.jchf.2017.11.015

JACC Heart Fail

29428438

Pediatric Cardiomyopathies.

2017

855-873

2017 Sep 15

1524-4571

<p>Pediatric cardiomyopathies are rare diseases with an annual incidence of 1.1 to 1.5 per 100 000. Dilated and hypertrophic cardiomyopathies are the most common; restrictive, noncompaction, and mixed cardiomyopathies occur infrequently; and arrhythmogenic right ventricular cardiomyopathy is rare. Pediatric cardiomyopathies can result from coronary artery abnormalities, tachyarrhythmias, exposure to infection or toxins, or secondary to other underlying disorders. Increasingly, the importance of genetic mutations in the pathogenesis of isolated or syndromic pediatric cardiomyopathies is becoming apparent. Pediatric cardiomyopathies often occur in the absence of comorbidities, such as atherosclerosis, hypertension, renal dysfunction, and diabetes mellitus; as a result, they offer insights into the primary pathogenesis of myocardial dysfunction. Large international registries have characterized the epidemiology, cause, and outcomes of pediatric cardiomyopathies. Although adult and pediatric cardiomyopathies have similar morphological and clinical manifestations, their outcomes differ significantly. Within 2 years of presentation, normalization of function occurs in 20% of children with dilated cardiomyopathy, and 40% die or undergo transplantation. Infants with hypertrophic cardiomyopathy have a 2-year mortality of 30%, whereas death is rare in older children. Sudden death is rare. Molecular evidence indicates that gene expression differs between adult and pediatric cardiomyopathies, suggesting that treatment response may differ as well. Clinical trials to support evidence-based treatments and the development of disease-specific therapies for pediatric cardiomyopathies are in their infancy. This compendium summarizes current knowledge of the genetic and molecular origins, clinical course, and outcomes of the most common phenotypic presentations of pediatric cardiomyopathies and highlights key areas where additional research is required.</p>

<p><strong>CLINICAL TRIAL REGISTRATION: </strong>URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02549664 and NCT01912534.</p>

10.1161/CIRCRESAHA.116.309386

Circ. Res.

28912187

Prevalence, predictors, and outcomes of cardiorenal syndrome in children with dilated cardiomyopathy: a report from the Pediatric Cardiomyopathy Registry.

2015

2177-88

2015 Dec

1432-198X

<p><strong>BACKGROUND: </strong>The association of cardiorenal syndrome (CRS) with mortality in children with dilated cardiomyopathy (DCM) is unknown.</p>

<p><strong>METHODS: </strong>With a modified Schwartz formula, we estimated glomerular filtration rates (eGFR) for children ≥1 year of age with DCM enrolled in the Pediatric Cardiomyopathy Registry at the time of DCM diagnosis and annually thereafter. CRS was defined as an eGFR of &lt;90 mL/min/1.73 m(2). Children with and without CRS were compared on survival and serum creatinine concentrations (SCr). The association between eGFR and echocardiographic measures was assessed with linear mixed-effects regression models.</p>

<p><strong>RESULTS: </strong>Of 285 eligible children with DCM diagnosed at ≥1 year of age, 93 were evaluable. CRS was identified in 57 of these 93 children (61.3%). Mean (standard deviation) eGFR was 62.0 (22.6) mL/min/1.73 m(2) for children with CRS and 108.0 (14.0) for those without (P &lt; 0.001); median SCr concentrations were 0.9 and 0.5 mg/dL, respectively (P &lt; 0.001). The mortality hazard ratio of children with CRS versus those with no CRS was 2.4 (95% confidence interval 0.8-7.4). eGFR was positively correlated with measures of left ventricular function and negatively correlated with age.</p>

<p><strong>CONCLUSIONS: </strong>CRS in children newly diagnosed with DCM may be associated with higher 5-year mortality. Children with DCM, especially those with impaired left ventricular function, should be monitored for renal disease.</p>

10.1007/s00467-015-3165-8

Pediatr. Nephrol.

26210985