Extracardiac Manifestations Fail to Predict the Severity of Cardiac Phenotype in Children and Young Adults with Marfan Syndrome.

We performed a secondary analysis of the Pediatric Heart Network (PHN) Marfan Trial public-use database to evaluate associations between extracardiac features and cardiac and aortic phenotypes in study participants. Aortic aneurysm phenotype was defined as aortic root Z-score ≥4.5, aortic root growth rate ≥75th percentile, aortic dissection, and aortic surgery. Severe cardiac phenotype was defined as aortic dissection, aortic Z-score ≥4.5, aortic valve surgery, at least moderate mitral regurgitation, mitral valve surgery, left ventricular dysfunction, or death. Extracardiac manifestations were characterized by specific organ system involvement and by a novel aggregate extracardiac score (AES) that was created for this study based on the original Ghent nosology. Mixed effects logistic regression analysis compared AES and systems involvement to outcomes. Of 608 participants (60% male), the median age at enrollment was 10.8 years (interquartile range: 6, 15.4). Aortic aneurysm phenotype was observed in 71% of participants and 64% had severe cardiac phenotype. On univariable analysis, skeletal (OR: 1.95, 95% CI: 1.01, 3.72; p = 0.05), skin manifestation (OR: 1.62, 95% CI: 1.13, 2.34; p = 0.01) and AES (OR: 1.17, 95% CI: 1.02, 1.34; p = 0.02) were associated with aortic aneurysm phenotype but were not significant in multivariable analysis. There was no association between extracardiac manifestations and severe cardiac phenotype. Thus, the severity of cardiac manifestations in Marfan syndrome (MFS) was independent of extracardiac phenotype and AES. Severity of extracardiac involvement did not appear to be a useful clinical marker for cardiovascular risk-stratification in this cohort of children and young adults with MFS.

Extracardiac Manifestations Fail to Predict the Severity of Cardiac Phenotype in Children and Young Adults with Marfan Syndrome.

We performed a secondary analysis of the Pediatric Heart Network Marfan Trial public-use database to evaluate associations between extracardiac features and cardiac and aortic phenotypes in study participants. Aortic aneurysm phenotype was defined as aortic root Z-score ≥ 4.5, aortic root growth rate ≥ 75th percentile, aortic dissection, and aortic surgery. Severe cardiac phenotype was defined as aortic dissection, aortic Z-score ≥4.5, aortic valve surgery, at least moderate mitral regurgitation, mitral valve surgery, left ventricular dysfunction, or death. Extracardiac manifestations were characterized by specific organ system involvement and by a novel aggregate extracardiac score that was created for this study based on the original Ghent nosology. Logistic regression analysis compared aggregate extracardiac score and systems involvement to outcomes. Of 608 participants (60% male), the median age at enrollment was 10.8 years (interquartile range: 6, 15.4). Aortic aneurysm phenotype was observed in 71% of participants and 64% had severe cardiac phenotype. On univariate analysis, skeletal (OR: 1.95, 95% CI: 1.01, 3.72; p = 0.05), skin manifestation (OR: 1.62, 95% CI: 1.13, 2.34; p = 0.01) and aggregate extracardiac score (OR: 1.17, 95% CI: 1.02, 1.34; p = 0.02) were associated with aortic aneurysm phenotype but were not significant in multivariate analysis. There was no association between extracardiac manifestations and severe cardiac phenotype. Thus, the severity of cardiac manifestations in Marfan syndrome was independent of extracardiac phenotype and aggregate extracardiac score. Severity of extracardiac involvement did not appear to be a useful clinical marker for cardiovascular risk-stratification in this cohort of children and young adults with Marfan syndrome.

Cardiac Magnetic Resonance Imaging to Determine Single Ventricle Function in a Pediatric Population is Feasible in a Large Trial Setting: Experience from the Single Ventricle Reconstruction Trial Longitudinal Follow up.

The Single Ventricle Reconstruction (SVR) Trial was a randomized prospective trial designed to determine survival advantage of the modified Blalock-Taussig-Thomas shunt (BTTS) vs the right ventricle to pulmonary artery conduit (RVPAS) for patients with hypoplastic left heart syndrome. The primary aim of the long-term follow-up (SVRIII) was to determine the impact of shunt type on RV function. In this work, we describe the use of CMR in a large cohort follow up from the SVR Trial as a focused study of single ventricle function. The SVRIII protocol included short axis steady-state free precession imaging to assess single ventricle systolic function and flow quantification. There were 313 eligible SVRIII participants and 237 enrolled, ages ranging from 10 to 12.5 years. 177/237 (75%) participants underwent CMR. The most common reasons for not undergoing CMR exam were requirement for anesthesia (n = 14) or ICD/pacemaker (n = 11). A total of 168/177 (94%) CMR studies were diagnostic for RVEF. Median exam time was 54 [IQR 40-74] minutes, cine function exam time 20 [IQR 14-27] minutes, and flow quantification time 18 [IQR 12-25] minutes. There were 69/177 (39%) studies noted to have intra-thoracic artifacts, most common being susceptibility artifact from intra-thoracic metal. Not all artifacts resulted in non-diagnostic exams. These data describe the use and limitations of CMR for the assessment of cardiac function in a prospective trial setting in a grade-school-aged pediatric population with congenital heart disease. Many of the limitations are expected to decrease with the continued advancement of CMR technology.

Coronary artery dilation associated with bicuspid and unicuspid aortic valve disease in children: a series of 17 patients.

INTRODUCTION: Coronary artery dilation associated with bicuspid/unicuspid aortic valves is described in adults with limited data in children. We aimed to describe the clinical course of children with bicuspid/unicuspid aortic valves and coronary dilation including coronary Z-score changes over time, association of coronary changes with aortic valve anatomy/function, and complications. MATERIALS AND METHODS: Institutional databases were searched for children ≤18 years with both bicuspid/unicuspid aortic valves and coronary dilation (1/2006-6/2021). Kawasaki disease and isolated supra-/subvalvar aortic stenosis were excluded. Statistics were descriptive with associations measured by Fisher's exact test and overlapping 83.7% confidence intervals. RESULTS: Of 17 children, bicuspid/unicuspid aortic valve was diagnosed at birth in 14 (82%). Median age at coronary dilation diagnosis was 6.4 years (range: 0-17.0). Aortic stenosis was present in 14 (82%) [2 (14%) moderate, 8 (57%) severe]; 10 (59%) had aortic regurgitation; 8 (47%) had aortic dilation. The right coronary was dilated in 15 (88%), left main in 6 (35%), and left anterior descending in 1 (6%) with no relationship between leaflet fusion pattern or severity of aortic regurgitation/stenosis on coronary Z-score. Follow-up evaluations were available for 11 (mean 9.3 years, range 1.1-14.8) with coronary Z-scores increasing in 9/11 (82%). Aspirin was used in 10 (59%). There were no deaths or coronary artery thrombosis. DISCUSSION: In children with bicuspid/unicuspid aortic valves and coronary dilation, the right coronary artery was most frequently involved. Coronary dilation was observed in early childhood and frequently progressed. Antiplatelet medication use was inconsistent, but no child died nor developed thrombosis.

Intramyocardial cell-based therapy with Lomecel-B during bidirectional cavopulmonary anastomosis for hypoplastic left heart syndrome: the ELPIS phase I trial.

Aims: Hypoplastic left heart syndrome (HLHS) survival relies on surgical reconstruction of the right ventricle (RV) to provide systemic circulation. This substantially increases the RV load, wall stress, maladaptive remodelling, and dysfunction, which in turn increases the risk of death or transplantation. Methods and results: We conducted a phase 1 open-label multicentre trial to assess the safety and feasibility of Lomecel-B as an adjunct to second-stage HLHS surgical palliation. Lomecel-B, an investigational cell therapy consisting of allogeneic medicinal signalling cells (MSCs), was delivered via intramyocardial injections. The primary endpoint was safety, and measures of RV function for potential efficacy were obtained. Ten patients were treated. None experienced major adverse cardiac events. All were alive and transplant-free at 1-year post-treatment, and experienced growth comparable to healthy historical data. Cardiac magnetic resonance imaging (CMR) suggested improved tricuspid regurgitant fraction (TR RF) via qualitative rater assessment, and via significant quantitative improvements from baseline at 6 and 12 months post-treatment (P < 0.05). Global longitudinal strain (GLS) and RV ejection fraction (EF) showed no declines. To understand potential mechanisms of action, circulating exosomes from intramyocardially transplanted MSCs were examined. Computational modelling identified 54 MSC-specific exosome ribonucleic acids (RNAs) corresponding to changes in TR RF, including miR-215-3p, miR-374b-3p, and RNAs related to cell metabolism and MAPK signalling. Conclusion: Intramyocardially delivered Lomecel-B appears safe in HLHS patients and may favourably affect RV performance. Circulating exosomes of transplanted MSC-specific provide novel insight into bioactivity. Conduct of a controlled phase trial is warranted and is underway.Trial registration number NCT03525418.

Impact of Udenafil on Echocardiographic Indices of Single Ventricle Size and Function in FUEL Study Participants.

BACKGROUND: The FUEL trial (Fontan Udenafil Exercise Longitudinal) demonstrated statistical improvements in exercise capacity following 6 months of treatment with udenafil (87.5 mg po BID). The effect of udenafil on echocardiographic measures of single ventricle function in this cohort has not been studied. METHODS: The 400 enrolled participants were randomized 1:1 to udenafil or placebo. Protocol echocardiograms were obtained at baseline and 26 weeks after initiation of udenafil/placebo. Linear regression compared change from baseline indices of single ventricle systolic, diastolic and global function, atrioventricular valve regurgitation, and mean Fontan fenestration gradient in the udenafil cohort versus placebo, controlling for ventricular morphology (left ventricle versus right ventricle/other) and baseline value. RESULTS: The udenafil participants (n=191) had significantly improved between baseline and 26 weeks visits compared to placebo participants (n=195) in myocardial performance index (P=0.03, adjusted mean difference [SE] of changes between groups -0.03[0.01]), atrioventricular valve inflow peak E (P=0.009, 3.95 [1.50]), and A velocities (P=0.034, 3.46 [1.62]), and annular Doppler tissue imaging-derived peak e' velocity (P=0.008, 0.60[0.23]). There were no significant differences in change in single ventricle size, systolic function, atrioventricular valve regurgitation severity, or mean fenestration gradient. Participants with a dominant left ventricle had significantly more favorable baseline values of indices of single ventricle size and function (lower volumes and areas, E/e' ratio, systolic:diastolic time and atrioventricular valve regurgitation, and higher annular s' and e' velocity). CONCLUSIONS: FUEL participants who received udenafil demonstrated a statistically significant improvement in some global and diastolic echo indices. Although small, the changes in diastolic function suggest improvement in pulmonary venous return and/or augmented ventricular compliance, which may help explain improved exercise performance in that cohort. REGISTRATION: URL: https://clinicaltrials.gov; Unique Identifier: NCT02741115.

Traumatic Left Ventricular Aneurysm and Ventricular Septal Defect in a Child.

Cardiac injuries following blunt trauma are rare but potentially lethal in children. We present a 23-month-old child who sustained an aneurysm of the left ventricle free wall and ventricular septum with associated ventricular septal defect following blunt trauma. She underwent successful surgical repair 6 weeks following her date of injury. Surgical decision-making surrounding this case is discussed.

Usefulness of Left Ventricular Myocardial Deformation in Children Hospitalized for Acute Myocarditis who Develop Arrhythmias.

Cardiac arrhythmias occur in 3-40% of patients with acute myocarditis and cause significant morbidity and mortality. Myocardial injury also results in abnormal myocardial deformation. The relationship between left ventricular (LV) deformation, measured by two-dimensional speckle tracking echocardiography (2D-STE), and arrhythmia in pediatric myocarditis is unknown. We evaluated the association between 2D-STE and arrhythmias in children hospitalized with acute myocarditis. We reviewed patients ≤ 18 years hospitalized for acute myocarditis from 2008 to 2018. Arrhythmias were defined as 1) non-sustained or sustained ventricular tachycardia or ventricular fibrillation, 2) sustained supraventricular tachycardia (SVT), 3) high-grade or complete heart block, and 4) any arrhythmia treated with an antiarrhythmic medication. Systolic LV strain values (including LV global longitudinal strain (GLS), global circumferential strain (GCS), and six segments of LV regional long axis strain) were obtained from initial echocardiograms during hospitalization. Of 66 patients hospitalized, 23 (35%) had arrhythmias. SVT was the predominant arrhythmia (74%). Global and regional strain indices were reduced in the arrhythmia group: LV GLS [-8.9 (IQR -13.6, -6.1) vs. -13.7 (IQR -16.9, -9.7), p = 0.038]; basal inferior/septal [-10.7 (IQR -15.5, -7.8) vs. -16.4 (IQR -18, -11.8), p = 0.009]; basal anterior/lateral [-7.1 (IQR -12.8, -4.7) vs. -9.4 (IQR -16.7, -7.4), p = 0.025]; and mid inferior/septal segments [-9 (IQR -13, -7.7) vs. -14.1 (IQR -22.5, -10.7), p = 0.007]. After controlling for age, reductions in GLS and segmental strain in the two basal and two mid-segments were associated with increased arrhythmia occurrence (p <0.05). Our findings suggest that echocardiographic LV deformation by 2D-STE may be useful in identifying pediatric patients with acute myocarditis at risk for arrhythmias.

Expanding the phenotype of CACNA1C mutation disorders.

BACKGROUND: Pathogenic variants in the L-type Ca2+ channel gene CACNA1C cause a multi-system disorder that includes severe long QT syndrome (LQTS), congenital heart disease, dysmorphic facial features, syndactyly, abnormal immune function, and neuropsychiatric disorders, collectively known as Timothy syndrome. In 2015, a variant in CACNA1C (p.R518C) was reported to cause cardiac-only Timothy syndrome, a genetic disorder with a mixed phenotype of congenital heart disease, hypertrophic cardiomyopathy (HCM), and LQTS that lacked extra-cardiac features. We have identified a family harboring the p.R518C pathogenic variant with a wider spectrum of clinical manifestations. METHODS: A four-generation family harboring the p.R518C pathogenic variant was reviewed in detail. The proband and his paternal great-uncle underwent comprehensive cardiac gene panel testing, and his remaining family members underwent cascade testing for the p.R518C pathogenic variant. RESULTS: In addition to displaying cardinal features of CACNA1C disorders including LQTS, congenital heart disease, HCM, and sudden cardiac death, family members manifested atrial fibrillation and sick sinus syndrome. CONCLUSION: Our report expands the cardiac phenotype of CACNA1C variants and reflects the variable expressivity of mutations in the L-type Ca2+ channel.

Longitudinal study of anthropometry in Fontan survivors: Pediatric Heart Network Fontan study.

BACKGROUND: Growth abnormalities in single-ventricle survivors may reduce quality of life (QoL) and exercise capacity. METHODS: This multicenter, longitudinal analysis evaluated changes in height and body mass index (BMI) compared to population norms and their relationship to mortality, ventricular morphology, QoL, and exercise capacity in the Pediatric Heart Network Fontan studies. RESULTS: Fontan 1 (F1) included 546 participants (12 ±â€¯3.4 years); Fontan 2 (F2), 427 (19 ±â€¯3.4 years); and Fontan 3 (F3), 362 (21 ±â€¯3.5 years), with ~60% male at each time point. Height z-score was -0.67 ±â€¯-1.27, -0.60 ±â€¯1.34, and- 0.43 ±â€¯1.14 at F1-F3, lower compared to norms at all time points (P ≤ .001). BMI z-score was similar to population norms. Compared to survivors, participants who died had lower height z-score (P ≤ .001). Participants with dominant right ventricle (n = 112) had lower height z-score (P ≤ .004) compared to dominant left (n = 186) or mixed (n = 64) ventricular morphologies. Higher height z-score was associated with higher Pediatric Quality of Life Inventory for the total score (slope = 2.82 ±â€¯0.52; P ≤ .001). Increase in height z-score (F1 to F3) was associated with increased oxygen consumption (slope = 2.61 ±â€¯1.08; P = .02), whereas, for participants >20 years old, an increase in BMI (F1 to F3) was associated with a decrease in oxygen consumption (slope = -1.25 ±â€¯0.33; P ≤ .001). CONCLUSIONS: Fontan survivors, especially those with right ventricular morphology, are shorter when compared to the normal population but have similar BMI. Shorter stature was associated with worse survival. An increase in height z-score over the course of the study was associated with better QoL and exercise capacity; an increase in BMI was associated with worse exercise capacity.

Thrombotic microangiopathy following heart transplant in pediatric Danon disease.

This case describes an uncommon acute complication of diffuse thrombotic angiopathy and associated aHUS/TTP in an 11-year-old girl with Danon disease who underwent orthotopic heart transplant. Shortly after transplant, despite an uncomplicated operative course, the patient developed severe kidney injury and progressive altered mental status, culminating in cerebral edema, brain herniation, and death. She had received a single dose of tacrolimus (FK506) and a single dose of antithymocyte globulin. Sources of progressive somnolence, including oversedation from impaired renal clearance of opiates, and severe myopathy as has been previously described in Danon disease, were ruled out, and the patient continued to decline. Initial brain CT scan early after transplant showed no signs of cerebral edema, but repeat CT indicated severe cerebral edema. Based on autopsy, diffuse thrombotic angiopathy, with signs of hemolytic anemia with schistocytes, was likely responsible for her deterioration in the broader condition of aHUS/TTP.

The Bayley-III scale may underestimate neurodevelopmental disability after cardiac surgery in infants.

OBJECTIVES: Neurodevelopmental disability is the most common complication among congenital heart surgery survivors. The Bayley scales are standardized instruments to assess neurodevelopment. The most recent edition (Bayley Scales of Infant and Toddler Development 3rd Edition, Bayley-III) yields better-than-expected scores in typically developing and high-risk infants than the second edition (Bayley Scales of Infant Development 2nd Edition, BSID-II). We compared BSID-II and Bayley-III scores in infants undergoing cardiac surgery. METHODS: We evaluated 2198 infants who underwent operations with cardiopulmonary bypass between 1996 and 2009 at 26 institutions. We used propensity score matching to limit confounding by indication in a subset of patients (n = 705). RESULTS: Overall, unadjusted Bayley-III motor scores were higher than BSID-II Psychomotor Development Index scores (90.7 ± 17.2 vs 77.6 ± 18.8, P < 0.001), and unadjusted Bayley-III composite cognitive and language scores were higher than BSID-II Mental Development Index scores (92.0 ± 15.4 vs 88.2 ± 16.7, P < 0.001). In the propensity-matched analysis, Bayley-III motor scores were higher than BSID-II Psychomotor Development Index scores [absolute difference 14.1, 95% confidence interval (CI) 11.7-17.6; P < 0.001] and the Bayley-III classified fewer children as having severe [odds ratio (OR) 0.24; 95% CI 0.14-0.42] or mild-to-moderate impairment (OR 0.21; 95% CI 0.14-0.32). The composite of Bayley-III cognitive and language scores was higher than BSID-II Mental Development Index scores (absolute difference 4.0, 95% CI 1.4-6.7; P = 0.003), but there was no difference between Bayley editions in the proportion of children classified as having severe cognitive and language impairment. CONCLUSIONS: The Bayley-III yielded higher scores than the BSID-II and classified fewer children as severely impaired. The systematic bias towards higher scores with the Bayley-III precludes valid comparisons between early and contemporary cardiac surgery cohorts.

Results of the FUEL Trial.

BACKGROUND: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. METHODS: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. RESULTS: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. CONCLUSIONS: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.

Surveillance Testing and Preventive Care After Fontan Operation: A Multi-Institutional Survey.

More children with single ventricle heart disease are surviving after Fontan surgery. This circulation has pervasive effects on multiple organ systems and has unique modes of failure. Many centers have created multidisciplinary programs to care for these patients. Our aim was to survey such programs to better understand current approaches to care. We hypothesized that significant variability in surveillance testing strategy would be present. Eleven academic institutions with established Fontan care programs performing a combined estimated 300 Fontan surgeries per year, with a total population of 1500-2000 Fontan patients, were surveyed using a REDCap survey regarding surveillance testing and basic practice philosophies. Fontan care programs were structured both as consultative services (64%) and as the primary clinical team (9%). Electrocardiograms (73%) and echocardiograms (64%) were most commonly obtained annually. Serum studies, including complete blood count (73%), complete metabolic panel (73%), and Brain-type natriuretic peptide (54%), were most commonly obtained annually. Hepatic testing consisted of liver ultrasound in most centers, obtained biennially (45%) or > every 2 years (45%). Liver biopsy was not routinely recommended (54%). Neurodevelopmental outcomes were assessed at most institutions (54%), with a median frequency of every 3-4 years. There is considerable variability in the surveillance testing regimen and management strategy after a Fontan procedure at surveyed programs. There is an urgent need for surveillance guidelines to reduce variability, define quality metrics, streamline collaborative practice, and prospective research to better understand the complex adaptations of the body to Fontan physiology.

Respiratory Testing and Hospital Outcomes in Asymptomatic Infants Undergoing Heart Surgery.

Respiratory viral infections in infants undergoing congenital heart surgery lead to prolonged intubation time, hospital (HLOS) and cardiac intensive care unit length of stay (CICU LOS). The objective of this study was to evaluate the prevalence of respiratory viruses using molecular testing in otherwise healthy infants presenting for low complexity heart surgery, and to evaluate the impact of a positive viral screen and study questionnaire on post-surgical HLOS, CICU LOS, intubation time, respiratory complications, and oxygen therapy at home discharge. Sixty-nine infants (1 month to 1 year) undergoing cardiac surgery from November to May of the years 2012 to 2014 were prospectively enrolled, surveyed and tested. We compared the outcomes of positive molecular testing and positive study questionnaire to test negative subjects. We also evaluated the predictive value of study questionnaire in identification of viruses by molecular testing. Of the 69 enrolled infants, 58 had complete information available for analysis. 17 (30%) infants tested positive by molecular testing for respiratory pathogens. 38 (65%) had a "positive" questionnaire. Among the 20 viruses detected, Human Rhinovirus was the most common 12 (60%). Seven (12%) of the 58 patients developed respiratory symptoms following surgery prompting molecular testing. Four of these tested positive for a respiratory virus post-surgically. Neither positive molecular testing nor a positive questionnaire prior to surgery was associated with greater post-operative HLOS, CICU LOS, intubation time, respiratory complications, or use of oxygen at discharge compared to negative testing. The questionnaire poorly predicted positive molecular testing. Routine screening for respiratory viruses in asymptomatic infants may not be an effective strategy to predict infants at risk of post-operative complications.

Mortality and Resource Use Following Cardiac Interventions in Children with Trisomy 13 and Trisomy 18 and Congenital Heart Disease.

We sought to evaluate the mortality, risk factors for mortality, and resource utilization following cardiac interventions in trisomy 13 (T13) and 18 (T18) children. All T13 and T18 children who underwent a cardiac intervention from January 1999 to March 2015 were identified from the Pediatric Health Information System database. Data collected included demographics, type of congenital heart disease (CHD), cardiac interventions, comorbidities, length of stay (LOS), hospital charges, and deaths (within 30 days). Logistic regression analysis was used to determine factors associated with mortality. There were 49 (47% females) T13 and 140 (67% females) T18 subjects. The two cohorts were similar in distribution for race, geographic region, insurance type, and median household income. The most common CHD in both groups was a shunt lesion followed by conotruncal defects. Compared to T18, the T13 cohort had higher mortality (29% vs. 12%), tracheostomies (12% vs. 4%), gastrostomies (18% vs. 6%), and overall resource use (P < 0.05 for all). White race (OR 0.23, 95% CI 0.06-0.81) in T13 and older age (in weeks) at surgery in T18 (OR 0.75, 95% CI 0.64-0.86) were associated with lower mortality. A select group of T13 and T18 CHD patients can undergo successful cardiac interventions, albeit with a higher mortality and resource use. T13 patients have higher mortality and resource use compared to T18. In T13 and T18 patients, interventions for CHD may be an acceptable and ethical option following a careful individualized selection and counseling by a team of experts.

Life-Threatening Event Risk in Children With Wolff-Parkinson-White Syndrome: A Multicenter International Study.

OBJECTIVES: This study sought to characterize risk in children with Wolff-Parkinson-White (WPW) syndrome by comparing those who had experienced a life-threatening event (LTE) with a control population. BACKGROUND: Children with WPW syndrome are at risk of sudden death. METHODS: This retrospective multicenter pediatric study identified 912 subjects ≤21 years of age with WPW syndrome, using electrophysiology (EPS) studies. Case subjects had a history of LTE: sudden death, aborted sudden death, or atrial fibrillation (shortest pre-excited RR interval in atrial fibrillation [SPERRI] of ≤250 ms or with hemodynamic compromise); whereas subjects did not. We compared clinical and EPS data between cases and subjects. RESULTS: Case subjects (n = 96) were older and less likely than subjects (n = 816) to have symptoms or documented tachycardia. Mean age at LTE was 14.1 ± 3.9 years of age. The LTE was the sentinel symptom in 65%, consisting of rapidly conducted pre-excited atrial fibrillation (49%), aborted sudden death (45%), and sudden death (6%). Three risk components were considered at EPS: SPERRI, accessory pathway effective refractory period (APERP), and shortest paced cycle length with pre-excitation during atrial pacing (SPPCL), and all were shorter in cases than in control subjects. In multivariate analysis, risk factors for LTE included male sex, Ebstein malformation, rapid anterograde conduction (APERP, SPERRI, or SPPCL ≤250 ms), multiple pathways, and inducible atrial fibrillation. Of case subjects, 60 of 86 (69%) had ≥2 EPS risk stratification components performed; 22 of 60 (37%) did not have EPS-determined high-risk characteristics, and 15 of 60 (25%) had neither concerning pathway characteristics nor inducible atrioventricular reciprocating tachycardia. CONCLUSIONS: Young patients may experience LTE from WPW syndrome without prior symptoms or markers of high-risk on EPS.

Design and rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) trial.

The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double-blind, placebo-controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co, Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation.

Predictors of Rapid Aortic Root Dilation and Referral for Aortic Surgery in Marfan Syndrome.

Few data exist regarding predictors of rapid aortic root dilation and referral for aortic surgery in Marfan syndrome (MFS). To identify independent predictors of the rate of aortic root (AoR) dilation and referral for aortic surgery, we investigated the data from the Pediatric Heart Network randomized trial of atenolol versus losartan in young patients with MFS. Data were analyzed from the echocardiograms at 0, 12, 24, and 36 months read in the core laboratory of 608 trial subjects, aged 6 months to 25 years, who met original Ghent criteria and had an AoR z-score (AoRz) > 3. Repeated measures linear and logistic regressions were used to determine multivariable predictors of AoR dilation. Receiver operator characteristic curves were used to determine cut-points in AoR dilation predicting referral for aortic surgery. Multivariable analysis showed rapid AoR dilation as defined by change in AoRz/year > 90th percentile was associated with older age, higher sinotubular junction z-score, and atenolol use (R2 = 0.01) or by change in AoR diameter (AoRd)/year > 90th percentile with higher sinotubular junction z-score and non-white race (R2 = 0.02). Referral for aortic root surgery was associated with higher AoRd, higher ascending aorta z-score, and higher sinotubular junction diameter:ascending aorta diameter ratio (R2 = 0.17). Change in AoRz of 0.72 SD units/year had 42% sensitivity and 92% specificity and change in AoRd of 0.34 cm/year had 38% sensitivity and 95% specificity for predicting referral for aortic surgery. In this cohort of young patients with MFS, no new robust predictors of rapid AoR dilation or referral for aortic root surgery were identified. Further investigation may determine whether generalized proximal aortic dilation and effacement of the sinotubular junction will allow for better risk stratification. Rate of AoR dilation cut-points had high specificity, but low sensitivity for predicting referral for aortic surgery, limiting their clinical use. Clinical Trial Number ClinicalTrials.gov number, NCT00429364.

Digoxin Use in Infants with Single Ventricle Physiology: Secondary Analysis of the Pediatric Heart Network Infant Single Ventricle Trial Public Use Dataset.

Digoxin has been associated with reduced interstage mortality after Norwood procedure. We sought to determine its association with survival and change in weight-for-age Z-score (WAZ) before the superior cavopulmonary connection (SCPC) surgery and at 14 months in a heterogeneous group of single ventricle infants. We performed a post-hoc analysis of the Pediatric Heart Network Infant Single Ventricle public use dataset to determine associations between digoxin and survival, transplant-free survival, and change in WAZ pre-SCPC and at 14 months. Sub-analyses of survival and transplant-free survival were performed for subjects who underwent Damus-Kaye-Stansel (DKS)/Norwood. Propensity score weighting was used in Cox hazard-proportion models. Of 229 subjects, 82 (36%) received digoxin and 147 (64%) received no digoxin. Pre-SCPC and 14-month survival and transplant-free survival were not significantly different between the digoxin and no digoxin groups for the main cohort and DKS/Norwood sub-group. However, in DKS/Norwood subjects there was a trend towards improved interstage transplant-free survival in the digoxin group (95.7 vs. 89.6%, p = 0.08). Digoxin was associated with a greater decrease in WAZ from birth to pre-SCPC (- 1.96 ± 0.19 vs. - 1.31 ± 0.18, p < 0.001) and birth to 14 months (- 0.64 ± 0.15 vs. - 0.19 ± 0.15, p = 0.03). Digoxin was not associated with improved survival during the interstage or at 14 months in a mixed single ventricle cohort, but there was a trend towards improved interstage transplant-free survival in post-Norwood infants. As digoxin was associated with poorer weight gain, further research is needed to identify the risks/benefits for anatomic subtypes of infants with single ventricles.