Abstract Background Multicenter longitudinal objective data for survival into adulthood of patients who have undergone Fontan procedures are lacking. Objectives This study sought to describe ...transplant-free survival and explore relationships between laboratory measures of ventricular performance and functional status over time. Methods Exercise testing, echocardiography, B-type natriuretic peptide, functional health assessment, and medical history abstraction were repeated 9.4 ± 0.4 years after the Fontan Cross-Sectional Study (Fontan 1) and compared with previous values. Cox regression analysis explored risk factors for interim death or cardiac transplantation. Results From the original cohort of 546 subjects, 466 were contacted again, and 373 (80%) were enrolled at 21.2 ± 3.5 years of age. Among subjects with paired testing, the percent predicted maximum oxygen uptake decreased (69 ± 14% vs. 61 ± 16%; p < 0.001; n = 95), ejection fraction decreased (58 ± 11% vs. 55 ± 10%; p < 0.001; n = 259), and B-type natriuretic peptide increased (median interquartile range 13 7 to 25 pg/mol vs. 18 9 to 36 pg/mol; p < 0.001; n = 340). At latest follow-up, a lower Pediatric Quality of Life Inventory physical summary score was associated with poorer exercise performance (R2 adjusted = 0.20; p < 0.001; n = 274). Cumulative complications since the Fontan procedure included additional cardiac surgery (32%), catheter intervention (62%), arrhythmia treatment (32%), thrombosis (12%), and protein-losing enteropathy (8%). Since Fontan 1, 54 subjects (10%) have received a heart transplant (n = 23) or died without transplantation (n = 31). The interval risk of death or/cardiac transplantation was associated with poorer ventricular performance and functional health status assessed at Fontan 1, but it was not associated with ventricular morphology, the subject’s age, or the type of Fontan connection. Conclusions Interim transplant-free survival over 12 years in this Fontan cohort was 90% and was independent of ventricular morphology. Exercise performance decreased and was associated with worse functional health status. Future interventions might focus on preserving exercise capacity. (Relationship Between Functional Health Status and Ventricular Performance After Fontan—Pediatric Heart Network; NCT00132782 )
A Cross-Sectional Study of Exercise Performance During the First 2 Decades of Life After the Fontan Operation Stephen M. Paridon, Paul D. Mitchell, Steven D. Colan, Richard V. Williams, Andrew ...Blaufox, Jennifer S. Li, Renee Margossian, Seema Mital, Jennifer Russell, Jonathan Rhodes, for the Pediatric Heart Network Investigators Exercise testing in a large group of Fontan survivors was performed, and clinical factors influencing exercise performance were assessed. Ramp cycle ergometry with metabolic cart measurements was performed on 411 subjects (mean age 12.4 ± 3.2 years). Peak oxygen consumption (VO2 ) was decreased at 65% of predicted for age and gender. Peak VO2 at ventilatory anaerobic threshold was better preserved at 78% of predicted than peak VO2 . Higher O2 pulse was associated with better exercise performance.
Objectives This study sought to determine the incidence and predictors of recovery of normal echocardiographic function among children with idiopathic dilated cardiomyopathy (DCM). Background Most ...children with idiopathic DCM have poor outcomes; however, some improve. Methods We studied children <18 years of age from the Pediatric Cardiomyopathy Registry who had both depressed left ventricular (LV) function (fractional shortening or ejection fraction z- score <–2) and LV dilation (end-diastolic dimension LVEDD z- score >2) at diagnosis and who had at least 1 follow-up echocardiogram 30 days to 2 years from the initial echocardiogram. We estimated the cumulative incidence and predictors of normalization. Results Among 868 children who met the inclusion criteria, 741 (85%) had both echocardiograms. At 2 years, 22% had recovered normal LV function and size; 51% had died or undergone heart transplantation (median, 3.2 months), and 27% had persistently abnormal echocardiograms. Younger age (hazard ratio HR: 0.92; 95% confidence interval CI: 0.88 to 0.97) and lower LVEDD z- score (HR: 0.78; 95% CI: 0.70 to 0.87) independently predicted normalization. Nine children (9%) with normal LV function and size within 2 years of diagnosis later underwent heart transplantation or died. Conclusions Despite marked LV dilation and depressed function initially, children with idiopathic DCM can recover normal LV size and function, particularly those younger and with less LV dilation at diagnosis. Investigations related to predictors of recovery, such as genetic associations, serum markers, and the impact of medical therapy or ventricular unloading with assist devices are important next steps. Longer follow-up after normalization is warranted as cardiac failure can recur. (Pediatric Cardiomyopathy Registry; NCT00005391 )
Patients with functional single ventricles after the Fontan procedure have abnormal cardiac mechanics. The aims of this study were to determine factors that influence diastolic function and to ...describe associations of diastolic function with current clinical status.
Echocardiograms were obtained as part of the Pediatric Heart Network Fontan Cross-Sectional Study. Diastolic function grade (DFG) was assessed as normal (grade 0), impaired relaxation (grade 1), pseudonymization (grade 2), or restrictive (grade 3). Studies were also classified dichotomously (restrictive pattern present or absent). Relationships between DFG and pre-Fontan variables (e.g., ventricular morphology, age at Fontan, history of volume-unloading surgery) and current status (e.g., systolic function, valvar regurgitation, exercise performance) were explored.
DFG was calculable in 326 of 546 subjects (60%) (mean age, 11.7 ± 3.3 years). Overall, 32% of patients had grade 0, 9% grade 1, 37% grade 2, and 22% grade 3 diastolic function. Although there was no association between ventricular morphology and DFG, there was an association between ventricular morphology and E', which was lowest in those with right ventricular morphology (P < .001); this association remained significant when using Z scores adjusted for age (P < .001). DFG was associated with achieving maximal effort on exercise testing (P = .004); the majority (64%) of those not achieving maximal effort had DFG 2 or 3. No additional significant associations of DFG with laboratory or clinical measures were identified.
Assessment of diastolic function by current algorithms results in a high percentage of patients with abnormal DFG, but few clinically or statistically significant associations were found. This may imply a lack of impact of abnormal diastolic function on clinical outcomes in this cohort, or it may indicate that the methodology may not be applicable to pediatric patients with functional single ventricles.
Assessment of the size and function of a functional single ventricle (FSV) is a key element in the management of patients after the Fontan procedure. Measurement variability of ventricular mass, ...volume, and ejection fraction (EF) among observers by echocardiography and cardiac magnetic resonance imaging (CMR) and their reproducibility among readers in these patients have not been described. From the 546 patients enrolled in the Pediatric Heart Network Fontan Cross-Sectional Study (mean age 11.9 ± 3.4 years), 100 echocardiograms and 50 CMR studies were assessed for measurement reproducibility; 124 subjects with paired studies were selected for comparison between modalities. Interobserver agreement for qualitative grading of ventricular function by echocardiography was modest for left ventricular (LV) morphology (κ = 0.42) and weak for right ventricular (RV) morphology (κ = 0.12). For quantitative assessment, high intraclass correlation coefficients were found for echocardiographic interobserver agreement (LV 0.87 to 0.92, RV 0.82 to 0.85) of systolic and diastolic volumes, respectively. In contrast, intraclass correlation coefficients for LV and RV mass were moderate (LV 0.78, RV 0.72). The corresponding intraclass correlation coefficients by CMR were high (LV 0.96, RV 0.85). Volumes by echocardiography averaged 70% of CMR values. Interobserver reproducibility for the EF was similar for the 2 modalities. Although the absolute mean difference between modalities for the EF was small (<2%), 95% limits of agreement were wide. In conclusion, agreement between observers of qualitative FSV function by echocardiography is modest. Measurements of FSV volume by 2-dimensional echocardiography underestimate CMR measurements, but their reproducibility is high. Echocardiographic and CMR measurements of FSV EF demonstrate similar interobserver reproducibility, whereas measurements of FSV mass and LV diastolic volume are more reproducible by CMR.
Objectives To assess self-reported quality of life (QOL) in a large multicenter cohort of adolescent and young adults surviving Fontan. Study design Cross-sectional. The Pediatric Quality of Life ...Inventory (PedsQL) was administered to 408 survivors of Fontan ages 13-25 years enrolled in the Pediatric Heart Network Fontan Follow-up Study. Subjects also completed either the Child Health Questionnaire (age <19 years) or Short Form Health Survey (age ≥19 years). PedsQL data were compared with matched controls without a chronic health condition. Correlations between the measures were examined. Results Mean PedsQL scores for subjects receiving Fontan were significantly lower than those for the control group for physical and psychosocial QOL ( P < .001). Overall, 45% of subjects receiving Fontan had scores in the clinically significant impaired range for physical QOL with 30% in the impaired range for psychosocial QOL. For each 1 year increase in age, the physical functioning score decreased by an average of 0.76 points ( P = .004) and the emotional functioning score decreased by an average of 0.64 points ( P = .03). Among subjects ≥19 years of age, the physical functioning score decreased by an average of 2 points for each year increase in age ( P = .02). PedsQL scale scores were significantly correlated with conceptually related Child Health Questionnaire ( P < .001) and Short Form Health Survey scores ( P < .001). Conclusions Survivors of Fontan are at risk for significantly impaired QOL which may decline with advancing age. Routine assessment of QOL is essential to inform interventions to improve health outcomes. The PedsQL allowed QOL assessment from pediatrics to young adulthood. Trial registration ClinicalTrials.gov : NCT00132782.
Objectives We explored the association of noncoronary cardiac abnormalities with coronary artery dilation and with laboratory inflammatory markers early after Kawasaki disease (KD) diagnosis. ...Background Left ventricular (LV) dysfunction, mitral regurgitation (MR), and aortic root dilation occur early after diagnosis; their associations with coronary artery dilation and inflammatory markers have not been well-described. Methods Centrally interpreted echocardiograms were obtained at KD diagnosis and 1 and 5 weeks after diagnosis on 198 subjects in the National Institutes of Health-sponsored Pediatric Heart Network KD pulsed steroid trial. Regression models were constructed to investigate the relationships among early LV dysfunction, MR, and aortic root dilation with coronary artery dilation and laboratory inflammatory markers. Results At diagnosis, LV systolic dysfunction was present in 20% of subjects and was associated with coronary artery dilation, seen in 29% (p = 0.004). Although LV dysfunction improved rapidly, LV dysfunction at diagnosis predicted greater odds of coronary artery dilation at 1 and 5 weeks after diagnosis (5-week odds ratio: 2.7, 95% confidence interval: 1.2 to 6.3). At diagnosis, MR was present in 27% of subjects and aortic root dilation was present in 8%; each was associated with larger coronary artery size at diagnosis. Left ventricular dysfunction was associated with higher erythrocyte sedimentation rate and, at diagnosis only, lower serum albumin; MR was associated with higher erythrocyte sedimentation rate and lower albumin at all times. Aortic root size had little association with inflammatory markers. Conclusions Noncoronary cardiac abnormalities are associated with coronary artery dilation and laboratory evidence of inflammation in the first 5 weeks after KD, suggesting a shared inflammatory mechanism. (Trial of Pulse Steroid Therapy in Kawasaki Disease A Trial Conducted by the Pediatric Heart Network; NCT00132080 )
Objectives To describe growth patterns in infants with single ventricle physiology and determine factors influencing growth. Study design Data from 230 subjects enrolled in the Pediatric Heart ...Network Infant Single Ventricle Enalapril Trial were used to assess factors influencing change in weight-for-age z-score (∆z) from study enrollment (0.7 ± 0.4 months) to pre-superior cavopulmonary connection (SCPC; 5.1 ± 1.8 months, period 1) and pre-SCPC to final study visit (14.1 ± 0.9 months, period 2). Predictor variables included patient characteristics, feeding regimen, clinical center, and medical factors during neonatal (period 1) and SCPC hospitalizations (period 2). Univariate regression analysis was performed, followed by backward stepwise regression and bootstrapping reliability to inform a final multivariable model. Results Weights were available for 197 of 230 subjects for period 1 and 173 of 197 subjects for period 2. For period 1, greater gestational age, younger age at study enrollment, tube feeding at neonatal hospitalization discharge, and clinical center were associated with a greater negative ∆z (poorer growth) in multivariable modeling (adjusted R2 = 0.39, P < .001). For period 2, younger age at SCPC and greater daily caloric intake were associated with greater positive ∆z (better growth; R2 = 0.10, P = .002). Conclusions Aggressive nutritional support and earlier SCPC are modifiable factors associated with a favorable change in weight-for-age z-score.
Objectives This study was undertaken to determine the effects of creating a systemic-to-pulmonary venous atrial-level communication (fenestration) at the time of the Fontan procedure on late ...outcomes. Background Fenestrations are frequently performed during Fontan procedures, but late consequences are not well described. Methods Patient characteristics were compared between those with and without surgical fenestration among 536 subjects (mean age 11.9 years) enrolled in the Pediatric Heart Network Fontan Cross-Sectional Study. The status of the fenestration and the association of a currently patent fenestration with health status and measures of ventricular performance were investigated. Results Fenestration was performed in 361 patients (67%), and frequency differed by year and center (p < 0.001 for each). After adjustment for center, age at Fontan, year of Fontan, and prior superior cavopulmonary surgery, the fenestrated group had shorter length of Fontan hospital stay. At the time of cross-sectional testing 8 ± 3 years after Fontan, the fenestration remained open in 19% of subjects. Among those with confirmed fenestration closure, 59% were by catheter intervention and 1% by surgical intervention, and 40% had apparent spontaneous closure. Compared with those without evidence of a fenestration, subjects with a current fenestration were taking more medications (p = 0.02) and had lower resting oxygen saturation (median 89% vs. 95%, p < 0.001). Functional health status, exercise performance, echocardiographic variables, prevalence of post-Fontan stroke or thrombosis, and growth did not differ by current fenestration status. Conclusions Surgical fenestration is associated with well-demonstrated early post-operative benefits. This cross-sectional study found few associations between a persistent fenestration and deleterious later outcomes.
Clinical trials often rely on echocardiographic measures of left ventricular size and function as surrogate end points. However, the quantitative impact of factors that affect the reproducibility of ...these measures is unknown. To address this issue, the National Heart, Lung, and Blood Institute-funded Pediatric Heart Network designed a longitudinal observational study of children with known or suspected dilated cardiomyopathy aged 0 to 22 years from eight pediatric clinical centers.
Clinical data were collected together with 150 echocardiographic indices of left ventricular size and function. Separate observers performed duplicate echocardiographic imaging. Multiple observers performed measurements from three cardiac cycles to enable assessment of intraobserver and interobserver variability. The impacts of beat averaging (BA), observer type (local vs core), and variable type (areas, calculations, dimensions, slopes, time intervals, and velocities) on measurement reproducibility were studied. The outcome measure was percentage error (100 × difference/mean).
Of 173 enrolled subjects, 131 met criteria for dilated cardiomyopathy. BA, variable type and observer type all influenced percentage error (P < .0001). Core interobserver percentage error (medians, 11.4%, 10.2%, and 9.3% for BA using one, two, and three beats, respectively) was approximately twice the intraobserver percentage error (medians, 6.3%, 4.9%, and 4.2% for BA using one, two, and three beats, respectively). Slopes and calculated variables exhibited high percentage error despite BA. Chamber dimensions, areas, velocities, and time intervals exhibited low percentage error.
This comprehensive evaluation of quantitative echocardiographic methods will provide a valuable resource for the design of future pediatric studies. BA and a single core lab observer improve the reproducibility of echocardiographic measurements in children with dilated cardiomyopathy. Certain measurements are highly reproducible, while others, despite BA, are poorly reproducible.
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