Genetic Evaluation of A Nation-Wide Dutch Pediatric DCM Cohort: The Use of Genetic Testing in Risk Stratification.

BACKGROUND: This study aimed to describe the current practice and results of genetic evaluation in Dutch children with dilated cardiomyopathy and to evaluate genotype-phenotype correlations that may guide prognosis. METHODS: We performed a multicenter observational study in children diagnosed with dilated cardiomyopathy, from 2010 to 2017. RESULTS: One hundred forty-four children were included. Initial diagnostic categories were idiopathic dilated cardiomyopathy in 67 children (47%), myocarditis in 23 (16%), neuromuscular in 7 (5%), familial in 18 (13%), inborn error of metabolism in 4 (3%), malformation syndrome in 2 (1%), and "other" in 23 (16%). Median follow-up time was 2.1 years [IQR 1.0-4.3]. Hundred-seven patients (74%) underwent genetic testing. We found a likely pathogenic or pathogenic variant in 38 children (36%), most often in MYH7 (n = 8). In 1 patient initially diagnosed with myocarditis, a pathogenic LMNA variant was found. During the study, 39 patients (27%) reached study endpoint (SE: all-cause death or heart transplantation). Patients with a likely pathogenic or pathogenic variant were more likely to reach SE compared with those without (hazard ratio 2.8; 95% CI 1.3-5.8, P = 0.007), while transplant-free survival was significantly lower (P = 0.006). Clinical characteristics at diagnosis did not differ between the 2 groups. CONCLUSIONS: Genetic testing is a valuable tool for predicting prognosis in children with dilated cardiomyopathy, with carriers of a likely pathogenic or pathogenic variant having a worse prognosis overall. Genetic testing should be incorporated in clinical work-up of all children with dilated cardiomyopathy regardless of presumed disease pathogenesis.

Predicting outcome in children with dilated cardiomyopathy: the use of repeated measurements of risk factors for outcome.

AIMS: We aimed to determine whether in children with dilated cardiomyopathy repeated measurement of known risk factors for death or heart transplantation (HTx) during disease progression can identify children at the highest risk for adverse outcome. METHODS AND RESULTS: Of 137 children we included in a prospective cohort, 36 (26%) reached the study endpoint (SE: all-cause death or HTx), 15 (11%) died at a median of 0.09 years [inter-quartile range (IQR) 0.03-0.7] after diagnosis, and 21 (15%) underwent HTx at a median of 2.9 years [IQR 0.8-6.1] after diagnosis. Median follow-up was 2.1 years [IQR 0.8-4.3]. Twenty-three children recovered at a median of 0.6 years [IQR 0.5-1.4] after diagnosis, and 78 children had ongoing disease at the end of the study. Children who reached the SE could be distinguished from those who did not, based on the temporal evolution of four risk factors: stunting of length growth (-0.42 vs. -0.02 length Z-score per year, P < 0.001), less decrease in N-terminal pro-B-type natriuretic peptide (NT-proBNP) (-0.26 vs. -1.06 2log pg/mL/year, P < 0.01), no decrease in left ventricular internal diastolic dimension (LVIDd; 0.24 vs. -0.60 Boston Z-score per year, P < 0.01), and increase in New York University Pediatric Heart Failure Index (NYU PHFI; 0.49 vs. -1.16 per year, P < 0.001). When we compared children who reached the SE with those with ongoing disease (leaving out the children who recovered), we found similar results, although the effects were smaller. In univariate analysis, NT-proBNP, length Z-score, LVIDd Z-score, global longitudinal strain (%), NYU PHFI, and age >6 years at presentation (all P < 0.001) were predictive of adverse outcome. In multivariate analysis, NT-proBNP appeared the only independent predictor for adverse outcome, a two-fold higher NT-proBNP was associated with a 2.8 times higher risk of the SE (hazard ratio 2.78, 95% confidence interval 1.81-3.94, P < 0.001). CONCLUSIONS: The evolution over time of NT-proBNP, LVIDd, length growth, and NYU PHFI identified a subgroup of children with dilated cardiomyopathy at high risk for adverse outcome. In this sample, with a limited number of endpoints, NT-proBNP was the strongest independent predictor for adverse outcome.

Emotional and behavioral problems in children with dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) in children is an important cause of severe heart failure and carries a poor prognosis. Adults with heart failure are at increased risk of anxiety and depression and such symptoms predict adverse clinical outcomes such as mortality. In children with DCM, studies examining these associations are scarce. AIMS: We studied whether in children with DCM: (1) the level of emotional and behavioral problems was increased as compared to normative data, and (2) depressive and anxiety problems were associated with the combined risk of death or cardiac transplantation. METHODS: To assess emotional and behavioral problems in children with DCM, parents of 68 children, aged 1.5-18 years (6.9±5.7 years), completed the Child Behavior Checklist. RESULTS: Compared to normative data, more young children (1.5-5 years) with DCM had somatic complaints (24.3% vs. 8.0%; p < .001), but fewer had externalizing problems (5.4% vs. 17.0%; p = .049). Overall internalizing problems did not reach significance. Compared to normative data, more older children (6-18 years) showed internalizing problems (38.7% vs. 17.0%; p = .001), including depressive (29.0% vs. 8.0%; p < .001) and anxiety problems (19.4% vs. 8.0%; p = .023), and somatic complaints (29.0% vs. 8.0%; p < .001). Anxiety and depressive problems, corrected for heart failure severity, did not predict the risk of death or cardiac transplantation. CONCLUSION: Children of 6 years and older showed more depressive and anxiety problems than the normative population. Moreover, in both age groups, somatic problems were common. No association with outcome could be demonstrated.

Distribution of strain patterns in children with dilated cardiomyopathy.

OBJECTIVES: This study aimed to evaluate the predicting value of quantitative and qualitative dyssynchrony parameters as assessed by two-dimensional speckle tracking echocardiography (STE) on outcome in children with dilated cardiomyopathy (DCM). Furthermore, the reproducibility of these parameters was investigated. BACKGROUND: In previous studies in adults with heart failure, several dyssynchrony parameters have been shown to be a valuable predictor of clinical outcome. METHODS: This multicenter, prospective study included 75 children with DCM and 75 healthy age-matched controls. Using STE, quantitative (time to global peak strain and parameters describing intraventricular time differences) and qualitative dyssynchrony parameters (pattern analysis) of the apical four-chamber, three-chamber, two-chamber views, and the short axis of the left ventricle were assessed. Cox regression was used to identify risk factors for the primary endpoints of death or heart transplantation. Inter-observer and intra-observer variability were described. RESULTS: During a median of 21 months follow-up, 10 patients (13%) reached an endpoint. Although quantitative dyssynchrony measures were higher in patients as compared to controls, the inter-observer and intra-observer variability were high. Pattern analysis showed mainly reduced strain, instead of dyssynchronous patterns. CONCLUSIONS: In this study, quantitative dyssynchrony parameters were not reproducible, precluding their use in children. Qualitative pattern analysis showed predominantly reduced strain, suggesting that in children with DCM dyssynchrony may be a minor problem.

Parent reports of health-related quality of life and heart failure severity score independently predict outcome in children with dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy in children causes heart failure and has a poor prognosis. Health-related quality of life in this patient group is unknown. Moreover, results may provide detailed information of parents' sense of their child's functioning. We hypothesised that health-related quality of life, as rated by parents, and the paediatric heart failure score, as assessed by physicians, have both predictive value on outcome. Methods and results In this prospective study, health-related quality of life was assessed by parent reports: the Infant Toddler Quality of Life questionnaire (0-4 years) or Child Health Questionnaire-Parent Form 50 (4-18 years) at 3-6-month intervals. We included 90 children (median age 3.8 years, interquartile range (IQR) 0.9-12.3) whose parents completed 515 questionnaires. At the same visit, physicians completed the New York University Pediatric Heart Failure Index. Compared with Dutch normative data, quality of life was severely impaired at diagnosis (0-4 years: 7/10 subscales and 4-18 years: 8/11 subscales) and ⩾1 year after diagnosis (3/10 and 6/11 subscales). Older children were more impaired (p<0.05). After a median follow-up of 3 years (IQR 2-4), 15 patients underwent transplantation. Using multivariable time-dependent Cox regression, "physical functioning" subscale and the Heart Failure Index were independently predictive of the risk of death and heart transplantation (hazard ratio 1.24 per 10% decrease of predicted, 95% confidence interval (CI) 1.06-1.47 and hazard ratio 1.38 per unit, 95% CI 1.19-1.61, respectively). CONCLUSION: Physical impairment rated by parents and heart failure severity assessed by physicians independently predicted the risk of death or heart transplantation in children with dilated cardiomyopathy.

Six-Minute Walk Test as a Predictor for Outcome in Children with Dilated Cardiomyopathy and Chronic Stable Heart Failure.

Cardiopulmonary exercise testing is an important tool to predict prognosis in children and adults with heart failure. A much less sophisticated exercise test is the 6 min walk test, which has been shown an independent predictor for morbidity and mortality in adults with heart failure. Therefore, we hypothesized that the 6 min walk test could be predictive for outcome in children with dilated cardiomyopathy. We prospectively included 49 children with dilated cardiomyopathy ≥6 years who performed a 6 min walk test. Median age was 11.9 years (interquartile range [IQR] 7.4-15.1), median time after diagnosis was 3.6 years (IQR 0.6-7.4). The 6 min walk distance was transformed to a percentage of predicted, using age- and gender-specific norm values (6MWD%). For all patients, mean 6MWD% was 70 ± 21%. Median follow-up was 33 months (IQR 14-50). Ten patients reached the combined endpoint of death or heart transplantation. Using univariable Cox regression, a higher 6MWD% resulted in a lower risk of death or transplantation (hazard ratio 0.95 per percentage increase, p = 0.006). A receiver operating characteristic curve was generated to define the optimal threshold to identify patients at highest risk for an endpoint. Patients with a 6MWD% < 63% had a 2 year transplant-free survival of 73%, in contrast to a transplant-free survival of 92% in patients with a 6MWD% ≥ 63% (p = 0.003). In children with dilated cardiomyopathy, the 6 min walk test is a simple and feasible tool to identify children with a higher risk of death or heart transplantation.

Usefulness of Serial N-terminal Pro-B-type Natriuretic Peptide Measurements to Predict Cardiac Death in Acute and Chronic Dilated Cardiomyopathy in Children.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is an important predictor of outcome in adults with heart failure. In children with heart failure secondary to dilated cardiomyopathy (DC) markers that reliably predict disease progression and outcome during follow-up are scarce. We investigated whether serial NT-proBNP measurements were predictive for outcome in children with DC. All available NT-proBNP measurements in children with DC were analyzed. Linear mixed-effect models and Cox regression were used to analyze the predictive value of NT-proBNP on the end point of cardiac death (death, heart transplantation, or mechanical circulatory support). During 7 years, 115 patients were included. At diagnosis, median NT-proBNP was high and not predictive for outcome. At any time during follow-up, a twofold higher NT-proBNP resulted in a 2.9 times higher risk in the first year (p <0.001) and a 1.8 times higher risk thereafter (p <0.001). Furthermore, at any time, the slope of log10(NT-proBNP) was significantly predictive for the risk of an end point (0 to 30 days hazard ratio [HR] 3.5, >30 days HR 2.9; >1 year HR 6.4). In patients with idiopathic DC (IDC) at 30 days after diagnosis, NT-proBNP ≥7,990 pg/ml showed a 1- and 2-year event-free survival of 79% and 71% and >1 year after diagnosis NT-proBNP ≥924 pg/ml showed a 2- and 5-year event-free survival of 50% and 40%, whereas below both thresholds event-free survival was 100%. In non-IDC, these thresholds were not predictive for outcome. In conclusion, NT-proBNP at any time during follow-up and its change over time were significantly predictive for the risk of cardiac death in children with DC. In children with IDC >1 year after diagnosis, NT-proBNP >924 pg/ml identified a subgroup with a poor outcome.

Prospective Evaluation of Sleep Apnea as Manifestation of Heart Failure in Children.

In adults with heart failure, central sleep apnea (CSA), often manifested as Cheyne-Stokes respiration, is common, and has been associated with adverse outcome. Heart failure in children is commonly caused by dilated cardiomyopathy (DCM). It is unknown whether children with heart failure secondary to DCM have CSA, and whether CSA is related to the severity of heart failure. In this prospective observational study, 37 patients (<18 year) with heart failure secondary to DCM were included. They underwent polysomnography, clinical and laboratory evaluation and echocardiographic assessment. After a median follow-up time of 2 years, eight patients underwent heart transplantation. CSA (apnea-hypopnea index [AHI] ≥1) was found in 19 % of the patients. AHI ranged from 1.2 to 4.5/h. The occurrence of CSA was not related to the severity of heart failure. Three older patients showed a breathing pattern mimicking Cheyne-Stokes respiration, two of whom required heart transplantation. CSA was found in 19 % of the children with heart failure secondary to DCM. No relation was found with the severity of heart failure. In a small subset of children with severe DCM, a pattern mimicking Cheyne-Stokes respiration was registered.

Management of children with dilated cardiomyopathy in The Netherlands: Implications of a low early transplantation rate.

BACKGROUND: The policy for listing and transplant for children with dilated cardiomyopathy (DCM) in The Netherlands has been conservative because of low donor availability. The effects of this policy on outcome are reported. METHODS: This was a multicenter, nationwide study performed in 148 children with DCM. The primary outcome was death or heart transplant. RESULTS: Overall, 43 patients (29%) died or were transplanted. Within 1 year of diagnosis, 21 patients died, and only 4 underwent transplantation (3 on mechanical circulatory support). The 1-year survival was 85% (95% confidence interval [CI] = 79-91), and 5-year survival was 84% (95% CI = 78-90). Transplantation-free survival at 1 year was 82% (95% CI = 75-88) and at 5 years was 72% (95% CI = 64-80). Within 1 year of diagnosis, with death as the main end-point (21 of 25, 84%), intensive care unit admission (hazard ratio = 2.6, p = 0.05) and mechanical circulatory support (hazard ratio = 3.2, p = 0.03) were risk factors (multivariable Cox analysis); inotropic support was longer in patients reaching an end-point. At >1 year after diagnosis, with transplantation as the main end-point (15 of 18, 83%), age >6 years (hazard ratio = 6.1, p = 0.02) was a risk factor. There were 56 (38%) children who recovered, 50% within 1 year of diagnosis. Recovery was associated with younger age; was similar in patients with myocarditis (43%) and idiopathic disease (41%); and was similar in patients initially admitted to the intensive care unit, admitted to the ward, or treated as outpatients. CONCLUSIONS: The transplantation rate in our cohort in the first year was low, with 1-year and 5-year survival rates similar to other cohorts. Our results suggest that a conservative approach to list children for transplantation early after presentation may be justifiable except for patients with prolonged intensive care unit or mechanical circulatory support.

Feeding and drinking skills in preterm and low birth weight infants compared to full term infants at a corrected age of nine months.

Feeding and drinking skills were registered in 47 preterm (<32 weeks) and/or low birth weight (<1500 g) infants and compared to 52 healthy full term infants at a (corrected) age of nine months. In the preterm and/or SGA infants a delay was found for sufficient postural balance, drinking independently from a bottle, eating skills and accepting teeth brushing at a corrected age of nine months compared to healthy controls. For tongue position and movement, and choking during drinking no difference was found between both groups.