Cardiac Remodeling in Subclinical Hypertrophic Cardiomyopathy: The VANISH Randomized Clinical Trial.

Importance: Valsartan has shown promise in attenuating cardiac remodeling in patients with early-stage sarcomeric hypertrophic cardiomyopathy (HCM). Genetic testing can identify individuals at risk of HCM in a subclinical stage who could benefit from therapies that prevent disease progression. Objective: To explore the potential for valsartan to modify disease development, and to characterize short-term phenotypic progression in subclinical HCM. Design, Setting, and Participants: The multicenter, double-blind, placebo-controlled Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) randomized clinical trial was conducted from April 2014 to July 2019 at 17 sites in 4 countries (Brazil, Canada, Denmark, and the US), with 2 years of follow-up. The prespecified exploratory VANISH cohort studied here included sarcomere variant carriers with subclinical HCM and early phenotypic manifestations (reduced E' velocity, electrocardiographic abnormalities, or an increased left ventricular [LV] wall thickness [LVWT] to cavity diameter ratio) but no LV hypertrophy (LVH). Data were analyzed between March and December 2022. Interventions: Treatment with placebo or valsartan (80 mg/d for children weighing <35 kg, 160 mg/d for children weighing ≥35 kg, or 320 mg/d for adults aged ≥18 years). Main Outcomes and Measures: The primary outcome was a composite z score incorporating changes in 9 parameters of cardiac remodeling (LV cavity volume, LVWT, and LV mass; left atrial [LA] volume; E' velocity and S' velocity; and serum troponin and N-terminal prohormone of brain natriuretic peptide levels). Results: This study included 34 participants, with a mean (SD) age of 16 (5) years (all were White). A total of 18 participants (8 female [44%] and 10 male [56%]) were randomized to valsartan and 16 (9 female [56%] and 7 male [44%]) were randomized to placebo. No statistically significant effects of valsartan on cardiac remodeling were detected (mean change in composite z score compared with placebo: -0.01 [95% CI, -0.29 to 0.26]; P = .92). Overall, 2-year phenotypic progression was modest, with only a mild increase in LA volume detected (increased by 3.5 mL/m2 [95% CI, 1.4-6.0 mL/m2]; P = .002). Nine participants (26%) had increased LVWT, including 6 (18%) who developed clinically overt HCM. Baseline LA volume index (LAVI; 35 vs 28 mL/m2; P = .01) and average interventricular septum thickness (8.5 vs 7.0 mm; P = .009) were higher in participants who developed HCM. Conclusions and Relevance: In this exploratory cohort, valsartan was not proven to slow progression of subclinical HCM. Minimal changes in markers of cardiac remodeling were observed, although nearly one-fifth of patients developed clinically overt HCM. Transition to disease was associated with greater baseline interventricular septum thickness and LAVI. These findings highlight the importance of following sarcomere variant carriers longitudinally and the critical need to improve understanding of factors that drive disease penetrance and progression. Trial Registration: ClinicalTrials.gov Identifier: NCT01912534.

Delphi Panel Consensus Recommendations for Screening and Managing Childhood Cancer Survivors at Risk for Cardiomyopathy.

Background: Cardiomyopathy is a leading cause of late morbidity and mortality in childhood cancer survivors (CCS). Evidence-based guidelines recommend risk-stratified screening for cardiomyopathy, but the management approach for abnormalities detected when screening asymptomatic young adult CCS is poorly defined. Objectives: The aims of this study were to build upon existing guidelines by describing the expert consensus-based cardiomyopathy screening practices, management approach, and clinical rationale for the management of young adult CCS with screening-detected abnormalities and to identify areas of controversy in practice. Methods: A multispecialty Delphi panel of 40 physicians with expertise in cancer survivorship completed 3 iterative rounds of semi-open-ended questionnaires regarding their approaches to the management of asymptomatic young adult CCS at risk for cardiomyopathy (screening practices, referrals, cardiac testing, laboratory studies, medications). Consensus was defined as ≥90% panelist agreement with recommendation. Results: The response rate was 100% for all 3 rounds. Panelists reached consensus on the timing and frequency of echocardiographic screening for anthracycline-associated cardiomyopathy, monitoring during pregnancy, laboratory testing for modifiable cardiac risk factors, and referral to cardiology for ejection fraction ≤50% or preserved ejection fraction with diastolic dysfunction. Controversial areas (<75% agreement) included chest radiation dose threshold to merit screening, indications for advanced cardiac imaging and cardiac serum biomarkers for follow-up of abnormal echocardiographic findings, and medical management of asymptomatic left ventricular systolic dysfunction. Conclusions: Expert practice is largely consistent with existing risk-based screening guidelines. Some recommendations for managing abnormalities detected on screening echocardiography remain controversial. The rationale offered by experts for divergent approaches may help guide clinical decisions in the absence of guidelines specific to young adult CCS.

Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.

Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80-160 mg daily in children) or placebo for 2 years ( NCT01912534 ). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.

Exercise Capacity and Predictors of Performance After Fontan: Results from the Pediatric Heart Network Fontan 3 Study.

Impaired exercise following Fontan is a surrogate of morbidity. Single-center longitudinal data exist, but there is a lack of contemporary multi-center data. Ramp cycle ergometry was re-performed in consented participants who had originally participated in the Pediatric Heart Network's Fontan cross-sectional study. Annualized change was evaluated at maximal and submaximal exercise. Associations between these outcomes and patient characteristics were analyzed. There were 336 participants in Fontan 3, mean age 23.2 years. Paired measurements of peak oxygen consumption (peak VO2) were available for 95; peak exercise data at Fontan 3 were available for 275. Percent-predicted peak VO2 declined by 0.8 ± 1.7% per year (p < 0.001). At Fontan 3, the lowest performing peak VO2 tertile had the highest rate of overweight and obesity (p < 0.001). Female gender was more prevalent in the highest performing tertile (p = 0.004). Paired data at the ventilatory anaerobic threshold (VO2 at VAT) were available for 196; VAT data at Fontan 3 were available for 311. Percent-predicted VO2 at VAT decreased by 0.8 ± 2.6% per year (p < 0.001). At Fontan 3, VO2 at VAT was better preserved than peak VO2 across all tertiles, with higher rates of overweight and obesity in the lower performing group (p = 0.001). Female gender (p < 0.001) and left ventricular morphology (p = 0.03) were associated with better performance. Submaximal exercise is better preserved than maximal in the Fontan population, but declined at the same rate over the study period. The overall longitudinal rate of decline in exercise performance is slower than what has been described previously.

Value of Exercise Stress Echocardiography in Children with Hypertrophic Cardiomyopathy.

BACKGROUND: Exercise stress echocardiography (ESE) is a valuable diagnostic and prognostic tool in adults with hypertrophic cardiomyopathy (HCM). Inducible and resting left ventricular outflow tract gradients are important predictors of heart failure. However, there are minimal data on the utility of this modality in children. METHODS: Retrospective review of all pediatric HCM patients who underwent ESE at Boston Children's Hospital (January 2007-June 2018) was carried out. Patients were assigned to one of three categories based on left ventricular outflow tract gradients: group 1: <30 mm Hg at rest and exercise; group 2: <30 mm Hg at rest and ≥30 mm Hg with exercise; and group 3: ≥ 30 mm Hg at rest and exercise. Records were reviewed for earliest occurrence of composite endpoint of any one of the following: cardiac syncope, chest pain, nonsustained and sustained ventricular tachycardia, aborted cardiac arrest, heart failure class ≥ II, or HCM-related death/transplantation. RESULTS: A total of 91 children (67% males) with median age 12 years (6-24 years) at first ESE and median left ventricle wall thickness of 20 mm formed the cohort. Median follow-up duration was 3 years. During ESE, only one child experienced an event and was resuscitated. Of the 91 children, 25 were classified as group 1, 40 as group 2, and 26 as group 3. Twenty-six patients met the composite endpoint, including two heart transplant, one aborted cardiac arrest, and one sudden cardiac death. Group 3 patients had a 5 times higher risk of developing symptoms and/or serious clinical outcome at any age (hazard ratio = 5.18; 95% CI, [1.39-19.2]; P = .014). During our short follow-up time, group 2 patients had a higher risk of outcome, but this did not achieve statistical significance (hazard ratio = 1.95; 95% CI, [0.5-7.6]; P = .33). CONCLUSIONS: In this large series of pediatric patients with HCM, ESE can be performed safely and served as an effective tool to identify the lowest risk patients for cardiac outcome.

Baseline Characteristics of the VANISH Cohort.

BACKGROUND: The VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) targeted young sarcomeric gene mutation carriers with early-stage hypertrophic cardiomyopathy (HCM) to test whether valsartan can modify disease progression. We describe the baseline characteristics of the VANISH cohort and compare to previous trials evaluating angiotensin receptor blockers. METHODS: Applying a randomized, double-blinded, placebo-controlled design, 178 participants with nonobstructive HCM (age, 23.3±10.1 years; 61% men) were randomized in the primary cohort and 34 (age, 16.5±4.9 years; 50% men) in the exploratory cohort of sarcomeric mutation carriers without left ventricular hypertrophy. RESULTS: In the primary cohort, maximal left ventricular wall thickness was 17±4 mm for adults and Z score 7.0±4.5 for children. Nineteen percent had late gadolinium enhancement on cardiac magnetic resonance. Mean peak oxygen consumption was 33 mL/kg per minute, and 92% of participants were New York Heart Association functional class I. New York Heart Association class II was associated with older age, MYH7 variants, and more prominent imaging abnormalities. Six previous trials of angiotensin receptor blockers in HCM enrolled a median of 24 patients (range, 19-133) with mean age of 51.2 years; 42% of patients were in New York Heart Association class ≥II, and sarcomeric mutations were not required. CONCLUSIONS: The VANISH cohort is much larger, younger, less heterogeneous, and has less advanced disease than prior angiotensin receptor blocker trials in HCM. Participants had relatively normal functional capacity and mild HCM features. New York Heart Association functional class II symptoms were associated with older age, more prominent imaging abnormalities, and MYH7 variants, suggesting both phenotype and genotype contribute to disease manifestations. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01912534.

Comparison of echocardiographic measurements to invasive measurements of diastolic function in infants with single ventricle physiology: a report from the Pediatric Heart Network Infant Single Ventricle Trial.

BACKGROUND: While echocardiographic parameters are used to quantify ventricular function in infants with single ventricle physiology, there are few data comparing these to invasive measurements. This study correlates echocardiographic measures of diastolic function with ventricular end-diastolic pressure in infants with single ventricle physiology prior to superior cavopulmonary anastomosis. METHODS: Data from 173 patients enrolled in the Pediatric Heart Network Infant Single Ventricle enalapril trial were analysed. Those with mixed ventricular types (n = 17) and one outlier (end-diastolic pressure = 32 mmHg) were excluded from the analysis, leaving a total sample size of 155 patients. Echocardiographic measurements were correlated to end-diastolic pressure using Spearman's test. RESULTS: Median age at echocardiogram was 4.6 (range 2.5-7.4) months. Median ventricular end-diastolic pressure was 7 (range 3-19) mmHg. Median time difference between the echocardiogram and catheterisation was 0 days (range -35 to 59 days). Examining the entire cohort of 155 patients, no echocardiographic diastolic function variable correlated with ventricular end-diastolic pressure. When the analysis was limited to the 86 patients who had similar sedation for both studies, the systolic:diastolic duration ratio had a significant but weak negative correlation with end-diastolic pressure (r = -0.3, p = 0.004). The remaining echocardiographic variables did not correlate with ventricular end-diastolic pressure. CONCLUSION: In this cohort of infants with single ventricle physiology prior to superior cavopulmonary anastomosis, most conventional echocardiographic measures of diastolic function did not correlate with ventricular end-diastolic pressure at cardiac catheterisation. These limitations should be factored into the interpretation of quantitative echo data in this patient population.

Regional practice norms for the care of childhood cancer survivors at risk for cardiomyopathy: A Delphi study.

BACKGROUND: Treatment-associated cardiomyopathy is a leading cause of morbidity and mortality for childhood cancer survivors (CCS). As evidence is not available to guide the management of CCS at risk for cardiomyopathy, we aim to describe the collective opinion of regional experts for the care of these patients using a consensus-based Delphi methodology. PROCEDURE: Nineteen physicians from the New England region who care for CCS treated with cardiotoxic therapy (anthracyclines, thoracic radiation) participated in a Delphi panel querying their management approach, using three rounds of anonymous questionnaires formatted as five clinical scenarios. Consensus ≥ 89% agreement. RESULTS: The response rate was 100% for the first round and 95% for subsequent rounds. Panelists reached consensus on screening asymptomatic CCS with serial echocardiograms (94%) and electrocardiograms (89%), with some disagreement on frequency during pregnancy (83%). All panelists agreed with exercise promotion, with no restrictions on weight training. Consensus was reached on indications for referrals; cardiology for asymptomatic left ventricular dysfunction (ALVD) (100%) and maternal-fetal medicine for pregnancy (94%). In the scenario of ALVD, there was disagreement on the benefit of additional cardiac testing (50% cardiologists recommended cardiac MRI), and although all panelists endorsed treating with angiotension-converting enzyme (ACE) inhibitors, most adult cardiologists (75%) also recommended therapy with beta blockers, compared with none of the pediatric cardiologists or primary-care physicians. CONCLUSIONS: Despite a lack of evidence to guide the management of CCS at risk for cardiomyopathy, a panel of regional physicians reached consensus on managing most clinical scenarios. A controversial area requiring further study is the medical management of ALVD.

Markers of Bone Mineral Metabolism and Cardiac Structure and Function in Perinatally HIV-Infected and HIV-Exposed but Uninfected Children and Adolescents.

BACKGROUND: Disordered bone mineral metabolism and low vitamin D concentrations are associated with cardiovascular abnormalities; few studies have evaluated this relationship in HIV-infected youth. SETTING: The Adolescent Master Protocol is a Pediatric HIV/AIDS Cohort Study network study conducted across 14 US sites. METHODS: Among perinatally HIV-infected (PHIV) and perinatally HIV-exposed but uninfected (PHEU) youth enrolled in the Adolescent Master Protocol, we evaluated associations of vitamin D [measured as 25-hydroxy-vitamin D (25-OHD)], parathyroid hormone (PTH), calcium, phosphate, and fibroblast growth factor-23 (FGF-23) concentrations with echocardiographic measures of left ventricular (LV) structure, function, and concentrations of NT-proBNP, a biomarker of cardiac damage. RESULTS: Among 485 participants (305 PHIV and 180 PHEU) with echocardiograms and bone mineralization measures, low 25-OHD (<20 ng/mL) was common among all participants (48% PHIV and 44% PHEU), but elevated PTH (>65 pg/mL) was identified more often among PHIV participants than PHEU participants (9% vs 3%, P = 0.02). After adjusting for HIV status and demographic covariates, both low 25-OHD and elevated PTH were associated with lower mean LV mass z-scores, whereas elevated PTH was associated with higher mean fractional shortening z-scores. Participants with low 25-OHD also had slightly higher mean LV end-systolic wall stress z-scores, but differences were more pronounced in PHEU participants than in PHIV participants. FGF-23 was inversely related to end-diastolic septal thickness, both overall and among PHIV participants. CONCLUSIONS: In this cohort of PHIV and PHEU youth, we observed associations of 25-OHD, PTH, and FGF-23 with both structural and functional cardiac parameters, supporting links between bone mineral metabolism and cardiac status.

Cardiac and inflammatory biomarkers in perinatally HIV-infected and HIV-exposed uninfected children.

OBJECTIVES: To compare distributions of serum cardiac and inflammatory biomarkers between perinatally HIV-infected (PHIV) and perinatally HIV-exposed uninfected (PHEU) children, to evaluate their associations with echocardiographic measures, and among PHIV youth, with antiretroviral therapy (ART) and HIV disease severity measures. DESIGN: Cross-sectional analysis of temporally paired serum samples for biomarkers and echocardiograms in a prospective multicenter cohort study of PHIV and PHEU youth. METHODS: Serum samples were analyzed among 402 youth in the PHACS Adolescent Master Protocol (AMP) for high-sensitivity cardiac troponin-T (hs-cTnT, a cardiomyocyte injury marker), N-terminal-pro-brain natriuretic peptide (NT-proBNP, a myocardial stress marker), and inflammatory markers [high-sensitivity C-reactive protein, interleukin (IL)-1, IL-6, IL-8, IL-10, IL-18, tumor necrosis factor-α (TNF-α), and soluble TNF receptor II (sTNF-RII)]. Echocardiograms were centrally measured and parameters converted to z cores to account for differences in age and body size. RESULTS: Compared with PHEU (N = 156), PHIV youth (N = 246) more often had detectable hs-cTnT and higher levels of sTNF-RII and IL-18. Higher inflammatory biomarkers were generally associated with higher left ventricular (LV) wall stress and lower LV function and LV mass in the two groups. Among PHIV youth, the biomarkers were more strongly associated with current rather than historical immunologic and virologic status. CONCLUSION: PHEU and PHIV have modest, significant differences in serum levels of specific inflammatory and active myocardial injury biomarkers. Higher biomarker levels were associated with lower LV mass and shifts in LV structure. Further study is warranted on the longitudinal role of cardiac and inflammatory biomarkers for targeting interventions among PHIV and PHEU youth.

Longitudinal Outcomes of Patients With Single Ventricle After the Fontan Procedure.

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).

The Effect of the Superior Cavopulmonary Anastomosis on Ventricular Remodeling in Infants with Single Ventricle.

BACKGROUND: Infants with single ventricular physiology have volume and pressure overload that adversely affect ventricular mechanics. The impact of superior cavopulmonary anastomosis (SCPA) on single left ventricles versus single right ventricles is not known. METHODS: As part of the Pediatric Heart Network placebo-controlled trial of enalapril in infants with single ventricular physiology, echocardiograms were obtained before SCPA and at 14 months and analyzed in a core laboratory. Retrospective analysis of the following measurements included single ventricular end-diastolic volume (EDV), end-systolic volume (ESV), mass, mass-to-volume ratio (mass/volume), and ejection fraction. Qualitative assessment of atrioventricular valve regurgitation and assessment of diastolic function were also performed. RESULTS: A total of 156 participants underwent echocardiography at both time points. Before SCPA, mean ESV and mass Z scores were elevated (3.4 ± 3.7 and 4.2 ± 2.9, respectively) as were mean EDV and mass/volume Z scores (2.1 ± 2.5 and 2.0 ± 2.9, respectively). EDV, ESV, and mass decreased after SCPA, but mass/volume and the degree of atrioventricular valve regurgitation did not change. Subjects with morphologic left ventricles demonstrated greater reductions in ventricular volumes and mass than those with right ventricles (mean change in Z score: left ventricular [LV] EDV, -1.9 ± 2.1; right ventricular EDV, -0.7 ± 2.5; LV ESV, -2.3 ± 2.9; right ventricular ESV, -0.9 ± 4.6; LV mass, -2.5 ± 2.8; right ventricular mass, -1.3 ± 2.6; P ≤ .03 for all). Approximately one third of patients whose diastolic function could be assessed had abnormalities at each time point. CONCLUSIONS: Decreases in ventricular size and mass occur in patients with single ventricle after SCPA, and the effect is greater in those with LV morphology. The remodeling process resulted in commensurate changes in ventricular mass and volume such that the mass/volume did not change significantly in response to the volume-unloading surgery.

Assessment of Diastolic Function in Single-Ventricle Patients After the Fontan Procedure.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Systolic-diastolic functional coupling in healthy children and in those with dilated cardiomyopathy.

Systolic and diastolic function affect dilated cardiomyopathy (DCM) outcomes. However, systolic-diastolic coupling, as a distinct characteristic, may itself affect function but is poorly characterized. We hypothesized that echocardiographic left ventricular (LV) longitudinal systolic tissue velocities (S') correlate with diastolic longitudinal velocities (E') and that their relationship is associated with ventricular function and that this relationship is impaired in pediatric DCM. We analyzed data from the Pediatric Heart Network Ventricular Volume Variability study, using linear regression and generalized additive modeling to assess relationships between S' and E' at the lateral and septal mitral annulus. We explored relationships between the systolic:diastolic (S:D) coupling ratio (S':E' relative to age) and ventricular function. Up to 4 echocardiograms from 130 DCM patients (mean age: 9.3 ± 6.1 yr) and 1 echocardiogram from each of 591 healthy controls were analyzed. S' and E' were linearly related in controls (r = 0.64, P < 0.001) and DCM (r = 0.83, P < 0.001). In DCM, the magnitude of association between S' and E' was reduced with progressive ventricular remodeling. The S:D ratio was more strongly associated with LV function in controls vs. DCM. The septal S:D ratio was higher (presumed worse) in DCM vs. controls (0.69 ± 0.13 vs. 0.62 ± 0.12, P = 0.001). A higher septal S:D ratio was associated with worse LV dimensions (parameter estimate: 0.0061, P = 0.004), mass (parameter estimate: 0.0074, P = 0.002), ejection fraction (parameter estimate: -0.0303, P = 0.024), and inflow propagation (parameter estimate: -0.3538, P < .001). S:D coupling becomes weaker in DCM with LV remodeling and dysfunction. The S:D coupling ratio may be useful to assess coupling, warranting study in relation to patient outcomes.

Assessment of Quality of Life in Young Patients with Single Ventricle after the Fontan Operation.

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.

The reproducibility and absolute values of echocardiographic measurements of left ventricular size and function in children are algorithm dependent.

BACKGROUND: Several quantification algorithms for measuring left ventricular (LV) size and function are used in clinical and research settings. The aims of this study were to investigate the effects of measurement algorithm and beat averaging on the reproducibility of measurements of the left ventricle and to assess the magnitude of agreement among the algorithms in children with dilated cardiomyopathy. METHODS: Echocardiograms were obtained in 169 children from eight clinical centers. Inter- and intrareader reproducibility was assessed on measurements of LV volumes using the biplane Simpson, modified Simpson, and 5/6 × area × length (5/6AL) algorithms. Percentage error was calculated as inter- or intrareader difference/mean × 100. Single-beat measurements and the three-beat average (3BA) were compared. Intraclass correlation coefficients were calculated to assess agreement. RESULTS: Single-beat interreader reproducibility was lowest (percentage error was highest) using biplane Simpson; 5/6AL and modified Simpson were similar but significantly better than biplane Simpson (P < .05). Single-beat intrareader reproducibility was highest using 5/6AL (P < .05). The 3BA improved reproducibility for almost all measures (P < .05). Reproducibility in both single-beat and 3BA values fell with greater LV dilation and systolic dysfunction (P < .05). Intraclass correlation coefficients were >0.95 across measures, although absolute volume and mass values were systematically lower for biplane Simpson compared with modified Simpson and 5/6AL. CONCLUSIONS: The reproducibility of LV size and functional measurements in children with dilated cardiomyopathy is highest using the 5/6AL algorithm and can be further improved by using the 3BA. However, values derived from different algorithms are not interchangeable.

Survival data and predictors of functional outcome an average of 15 years after the Fontan procedure: the pediatric heart network Fontan cohort.

OBJECTIVE: Multicenter longitudinal outcome data for Fontan patients surviving into adulthood are lacking. The aim of this study was to better understand contemporary outcomes in Fontan survivors by collecting follow-up data in a previously well-characterized cohort. DESIGN: Baseline data from the Fontan Cross-Sectional Study (Fontan 1) were previously obtained in 546 Fontan survivors aged 11.9 ± 3.4 years. We assessed current transplant-free survival status in all subjects 6.8 ± 0.4 years after the Fontan 1 study. Anatomic, clinical, and surgical data were collected along with socioeconomic status and access to health care. RESULTS: Thirty subjects (5%) died or underwent transplantation since Fontan 1. Subjects with both an elevated (>21 pg/mL) brain natriuretic peptide and a low Child Health Questionnaire physical summary score (<44) measured at Fontan 1 were significantly more likely to die or undergo transplant than the remainder, with a hazard ratio of 6.2 (2.9-13.5). Among 516 Fontan survivors, 427 (83%) enrolled in this follow-up study (Fontan 2) at 18.4 ± 3.4 years of age. Although mean scores on functional health status questionnaires were lower than the general population, individual scores were within the normal range in 78% and 88% of subjects for the Child Health Questionnaire physical and psychosocial summary score, and 97% and 91% for the SF-36 physical and mental aggregate score, respectively. Since Fontan surgery, 119 (28%) had additional cardiac surgery; 55% of these (n = 66) in the interim between Fontan 1 and Fontan 2. A catheter intervention occurred in 242 (57%); 32% of these (n = 78) after Fontan 1. Arrhythmia requiring treatment developed in 118 (28%) after Fontan surgery; 58% of these (n = 68) since Fontan 1. CONCLUSIONS: We found 95% interim transplant-free survival for Fontan survivors over an average of 7 years of follow-up. Continued longitudinal investigation into adulthood is necessary to better understand the determinants of long-term outcomes and to improve functional health status.

Factors associated with serum B-type natriuretic peptide in infants with single ventricles.

Data regarding the value of B-type natriuretic peptide (BNP) measurements in infants with a single-ventricle (SV) physiology are lacking. This analysis aimed to describe the BNP level changes in infants with an SV physiology before and after superior cavopulmonary connection (SCPC) surgery. Levels of BNP were measured by a core laboratory before SCPC (at 5.0 ± 1.6 months) and at the age of 14 months during a multicenter trial of angiotensin-converting enzyme inhibition therapy for infants with SV. Multivariable longitudinal analysis was used to model the associations between BNP levels and three sets of grouped variables (echocardiography, catheterization, growth). Multivariable analysis was performed to assess associations with patient characteristics at both visits. Associations between BNP levels and neurodevelopmental variables were investigated at the 14 month visit because neurodevelopmental assessment was performed only at this visit. The BNP level was significantly higher before SCPC (n = 173) than at the age of 14 months (n = 134). The respective median levels were 80.8 pg/ml (interquartile range [IQR], 35-187 pg/ml) and 34.5 pg/ml (IQR, 17-67 pg/ml) (p < 0.01). A BNP level higher than 100 pg/ml was present in 72 subjects (42 %) before SCPC and in 21 subjects (16 %) at the age of 14 months. In the 117 patients who had BNP measurements at both visits, the median BNP level decreased 32 pg/ml (IQR, 1-79 pg/ml) (p < 0.01). In the longitudinal multivariable analysis, higher BNP levels were associated with a higher end-systolic volume z-score (p = 0.01), a greater degree of atrioventricular (AV) valve regurgitation (p < 0.01), a lower weight z-score (p < 0.01), and a lower length z-score (p = 0.02). In multivariable analyses, a higher BNP level at the age of 14 months was associated with arrhythmia after SCPC surgery (p < 0.01), a prior Norwood procedure (p < 0.01), a longer hospital stay after SCPC surgery (p = 0.04), and a lower Bayley psychomotor developmental index (p = 0.02). The levels of BNP decreases in infants with SV from the pre-SCPC visit to the age of 14 months. A higher BNP level is associated with increased ventricular dilation in systole, increased AV valve regurgitation, impaired growth, and poorer neurodevelopmental outcomes. Therefore, BNP level may be a useful seromarker for identifying infants with SV at risk for worse outcomes.

Recovery of echocardiographic function in children with idiopathic dilated cardiomyopathy: results from the pediatric cardiomyopathy registry.

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).

Functional health status in children and adolescents after Fontan: comparison of generic and disease-specific assessments.

PURPOSE: The aim of this study was to compare associations between generic versus disease-specific functional health status assessments and patient and clinical characteristics for patients with severe congenital heart disease. METHODS: This was a cross-sectional observational study involving 325 single ventricle patients, aged 10-18 years, after Fontan procedure. Enrolled patients underwent a medical history review, laboratory testing, and assessment of the functional health status by completion of the generic Child Report Child Health Questionnaire and the disease-specific Congenital Heart Adolescent and Teenage questionnaire. Correlated conceptually equivalent domains from both questionnaires were identified and their associations with patient and clinical variables were compared. RESULTS: From the generic assessment, patients perceived marginally lower physical functioning (p = 0.05) but greater freedom from bodily pain compared with a normal population (p < 0.001). The equivalent physical functioning/limitations domain of the generic instrument, compared with the disease-specific instrument, had similar associations (higher multi-variable model R²) with medical history variables (R² = 0.14 versus R² = 0.12, respectively) and stronger associations with exercise testing variables (R² = 0.22 versus R² = 0.06). Similarly, the corresponding freedom from bodily pain/symptoms domains from both questionnaires showed a greater association for the generic instrument with medical history variables (R² = 0.15 versus R² = 0.09, respectively) and non-cardiac conditions (R² = 0.13 versus R² = 0.06). The associations of each questionnaire with echocardiographic results, cardiac magnetic resonance imaging results, and serum brain natriuretic peptide levels were uniformly weak (R² range <0.01 to 0.04). CONCLUSIONS: Assessment of the physical functional health status using generic and disease-specific instruments yields few differences with regard to associations between conceptually similar domains and patient and clinical characteristics for adolescents after Fontan procedure.