Seema Mital

Comparison of shunt types in the Norwood procedure for single-ventricle lesions.

BACKGROUND The Norwood procedure with a modified Blalock-Taussig (MBT) shunt, the first palliative stage for single-ventricle lesions with systemic outflow obstruction, is associated with high mortality. The right ventricle-pulmonary artery (RVPA) shunt may improve coronary flow but requires a ventriculotomy. We compared the two shunts in infants with hypoplastic heart syndrome or related anomalies. METHODS Infants undergoing the Norwood procedure were randomly assigned to the MBT shunt (275 infants) or the RVPA shunt (274 infants) at 15 North American centers. The primary outcome was death or cardiac transplantation 12 months after randomization. Secondary outcomes included unintended cardiovascular interventions and right ventricular size and function at 14 months and transplantation-free survival until the last subject reached 14 months of age. RESULTS Transplantation-free survival 12 months after randomization was higher with the RVPA shunt than with the MBT shunt (74% vs. 64%, P=0.01). However, the RVPA shunt group had more unintended interventions (P=0.003) and complications (P=0.002). Right ventricular size and function at the age of 14 months and the rate of nonfatal serious adverse events at the age of 12 months were similar in the two groups. Data collected over a mean (+/-SD) follow-up period of 32+/-11 months showed a nonsignificant difference in transplantation-free survival between the two groups (P=0.06). On nonproportional-hazards analysis, the size of the treatment effect differed before and after 12 months (P=0.02). CONCLUSIONS In children undergoing the Norwood procedure, transplantation-free survival at 12 months was better with the RVPA shunt than with the MBT shunt. After 12 months, available data showed no significant difference in transplantation-free survival between the two groups. (ClinicalTrials.gov number, NCT00115934.)

A Cross-Sectional Study of Exercise Performance During the First 2 Decades of Life After the Fontan Operation

OBJECTIVES The aim of this study was to describe exercise performance during the first 2 decades of life in Fontan survivors by a cross-sectional study and to identify factors that influence exercise performance. BACKGROUND Exercise performance after the Fontan procedure is reduced relative to performance in healthy subjects. Data on pre-adolescents are limited, and the patterns of exercise performance in different ages are unexplored. METHODS Ramp cycle ergometry was performed with expired gas. Data were analyzed for the entire study population and for subpopulations that did and did not achieve a maximal aerobic capacity. RESULTS Of 411 subjects tested (12.4 +/- 3.2 years of age), 166 achieved a maximal aerobic capacity. Peak oxygen consumption (VO(2)) was 26.3 ml/kg/min (65% of predicted for age and gender [% predicted]) for the entire population and was lower in the submaximal capacity subgroup compared with the maximal capacity subgroup (63% predicted and 67% predicted, respectively; p = 0.02). Oxygen consumption at ventilatory anaerobic threshold (VAT) was better preserved (78% predicted for the total population) than peak VO(2). Higher % predicted O(2) pulse at peak exercise was associated with greater % predicted peak VO(2), work rate, and VAT. Adolescence and male gender were associated with decreased % predicted peak VO(2). The relationship between echocardiographic indexes of ventricular function and exercise function was surprisingly weak. CONCLUSIONS In Fontan patients, maximal aerobic capacity is reduced compared with healthy subjects, with better preservation of submaximal performance. Higher O(2) pulse is associated with better exercise performance, whereas adolescence and male gender are associated with decreased performance compared with healthy subjects.

Enalapril in Infants With Single Ventricle Results of a Multicenter Randomized Trial

Background— Angiotensin-converting enzyme inhibitor therapy improves clinical outcome and ventricular function in adults with heart failure. Infants with single-ventricle physiology have poor growth and are at risk for abnormalities in ventricular systolic and diastolic function. The ability of angiotensin-converting enzyme inhibitor therapy to preserve ventricular function and improve somatic growth and outcomes in these infants is unknown. Methods and Results— The Pediatric Heart Network conducted a double-blind trial involving 230 infants with single-ventricle physiology randomized to receive enalapril (target dose 0.4 mg · kg−1 · d−1) or placebo who were followed up until 14 months of age. The primary end point was weight-for-age z score at 14 months. The primary analysis was intention to treat. A total of 185 infants completed the study. There were 24 and 21 withdrawals or deaths in the enalapril and placebo groups, respectively (P=0.74). Weight-for-age z score was not different between the enalapril and placebo groups (mean±SE −0.62±0.13 versus −0.42±0.13, P=0.28). There were no significant group differences in height-for-age z score, Ross heart failure class, brain natriuretic peptide concentration, Bayley scores of infant development, or ventricular ejection fraction. The incidence of death or transplantation was 13% and did not differ between groups. Serious adverse events occurred in 88 patients in the enalapril group and 87 in the placebo group. Conclusions— Administration of enalapril to infants with single-ventricle physiology in the first year of life did not improve somatic growth, ventricular function, or heart failure severity. The results of this randomized trial do not support the routine use of enalapril in this population. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00113087.

De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies

Putting both heart and brain at risk For reasons that are unclear, newborns with congenital heart disease (CHD) have a high risk of neurodevelopmental disabilities. Homsy et al. performed exome sequence analysis of 1200 CHD patients and their parents to identify spontaneously arising (de novo) mutations. Patients with both CHD and neurodevelopmental disorders had a much higher burden of damaging de novo mutations, particularly in genes with likely roles in both heart and brain development. Thus, clinical genotyping of patients with CHD may help to identify those at greatest risk of neurodevelopmental disabilities, allowing surveillance and early intervention. Science, this issue p. 1262 Genotyping of children with congenital heart disease may identify those at high risk of neurodevelopmental disorders. Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.

Early Developmental Outcome in Children With Hypoplastic Left Heart Syndrome and Related Anomalies The Single Ventricle Reconstruction Trial

Background— Survivors of the Norwood procedure may experience neurodevelopmental impairment. Clinical trials to improve outcomes have focused primarily on methods of vital organ support during cardiopulmonary bypass. Methods and Results— In the Single Ventricle Reconstruction trial of the Norwood procedure with modified Blalock-Taussig shunt versus right-ventricle-to-pulmonary-artery shunt, 14-month neurodevelopmental outcome was assessed by use of the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development-II. We used multivariable regression to identify risk factors for adverse outcome. Among 373 transplant-free survivors, 321 (86%) returned at age 14.3±1.1 (mean±SD) months. Mean PDI (74±19) and MDI (89±18) scores were lower than normative means (each P<0.001). Neither PDI nor MDI score was associated with type of Norwood shunt. Independent predictors of lower PDI score (R2=26%) were clinical center (P=0.003), birth weight <2.5 kg (P=0.023), longer Norwood hospitalization (P<0.001), and more complications between Norwood procedure discharge and age 12 months (P<0.001). Independent risk factors for lower MDI score (R2=34%) included center (P<0.001), birth weight <2.5 kg (P=0.04), genetic syndrome/anomalies (P=0.04), lower maternal education (P=0.04), longer mechanical ventilation after the Norwood procedure (P<0.001), and more complications after Norwood discharge to age 12 months (P<0.001). We found no significant relationship of PDI or MDI score to perfusion type, other aspects of vital organ support (eg, hematocrit, pH strategy), or cardiac anatomy. Conclusions— Neurodevelopmental impairment in Norwood survivors is more highly associated with innate patient factors and overall morbidity in the first year than with intraoperative management strategies. Improved outcomes are likely to require interventions that occur outside the operating room. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00115934.

Endorsement of Health and Human Services Recommendation for Pulse Oximetry Screening for Critical Congenital Heart Disease

Incorporation of pulse oximetry to the assessment of the newborn infant can enhance detection of critical congenital heart disease (CCHD). Recently, the Secretary of Health and Human Services (HHS) recommended that screening for CCHD be added to the uniform screening panel. The American Academy of Pediatrics (AAP) has been a strong advocate of early detection of CCHD and fully supports the decision of the Secretary of HHS. The AAP has published strategies for the implementation of pulse oximetry screening, which addressed critical issues such as necessary equipment, personnel, and training, and also provided specific recommendations for assessment of saturation by using pulse oximetry as well as appropriate management of a positive screening result. The AAP is committed to the safe and effective implementation of pulse oximetry screening and is working with other advocacy groups and governmental agencies to promote pulse oximetry and to support widespread surveillance for CCHD. Going forward, AAP chapters will partner with state health departments to implement the new screening strategy for CCHD and will work to ensure that there is an adequate system for referral for echocardiographic/pediatric cardiac evaluation after a positive screening result. It is imperative that AAP members engage their respective policy makers in adopting and funding the recommendations made by the Secretary of HHS.

Comparative Left Ventricular Function Following Atrial, Septal, and Apical Single Chamber Heart Pacing in the Young

Ventricular pacing, typically initiated from a RV apical electrode, inherently causes abnormal biventricular activation, decreases LV function, and causes histopathological changes. Since pacing initiated in childhood can he expected to have a more protracted course compared with the adult, the consequences of this alteration in LV hemodynamics gain added significance among the young pacemaker recipient. The purpose of this study was to evaluate the potential of improving paced LV function by a septal electrode implant site. Acute alterations in cardiac index, LV pressure, and contraction indices, including dP/dt, Vmax. and Vpm, were compared among 22 patients (median age 10 years) with normal cardiac anatomy during intracardiac electrophysiological studies. LV hemodynamics were measured during intrinsic rhythms and following 15 minutes of atrial, HV apical, and septal pacing at an appropriate exercise rate for age of 150 ppm. Results showed a significant decrease in LV dP/dt, Vmax, and Vpm, and increase in LV end‐diastolic pressure only with apical pacing. Septal pacing, in spite of loss of any atrial contribution to ventricular filling, maintained comparable indices with intrinsic and atrial paced rhythms. This study demonstrates that normalized LV function is maintained by septal and deteriorates with apical pacing acutely among young, nonischemic hearts. Continued evaluation of appropriate pacing electrode designs to permit septal implant is needed to ensure optimal chronically paced LV function.

Transplantation-Free Survival and Interventions at 3 Years in the Single Ventricle Reconstruction Trial

Background— In the Single Ventricle Reconstruction (SVR) trial, 1-year transplantation-free survival was better for the Norwood procedure with right ventricle–to–pulmonary artery shunt (RVPAS) compared with a modified Blalock-Taussig shunt (MBTS). At 3 years, we compared transplantation-free survival, echocardiographic right ventricular ejection fraction, and unplanned interventions in the treatment groups. Methods and Results— Vital status and medical history were ascertained from annual medical records, death indexes, and phone interviews. The cohort included 549 patients randomized and treated in the SVR trial. Transplantation-free survival for the RVPAS versus MBTS groups did not differ at 3 years (67% versus 61%; P=0.15) or with all available follow-up of 4.8±1.1 years (log-rank P=0.14). Pre-Fontan right ventricular ejection fraction was lower in the RVPAS group than in the MBTS group (41.7±5.1% versus 44.7±6.0%; P=0.007), and right ventricular ejection fraction deteriorated in RVPAS (P=0.004) but not MBTS (P=0.40) subjects (pre-Fontan minus 14-month mean, −3.25±8.24% versus 0.99±8.80%; P=0.009). The RVPAS versus MBTS treatment effect had nonproportional hazards (P=0.004); the hazard ratio favored the RVPAS before 5 months (hazard ratio=0.63; 95% confidence interval, 0.45–0.88) but the MBTS beyond 1 year (hazard ratio=2.22; 95% confidence interval, 1.07–4.62). By 3 years, RVPAS subjects had a higher incidence of catheter interventions (P<0.001) with an increasing HR over time (P=0.005): <5 months, 1.14 (95% confidence interval, 0.81–1.60); from 5 months to 1 year, 1.94 (95% confidence interval, 1.02–3.69); and >1 year, 2.48 (95% confidence interval, 1.28–4.80). Conclusions— By 3 years, the Norwood procedure with RVPAS compared with MBTS was no longer associated with superior transplantation-free survival. Moreover, RVPAS subjects had slightly worse right ventricular ejection fraction and underwent more catheter interventions with increasing hazard ratio over time. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00115934.

Physical activity levels in children and adolescents are reduced after the Fontan procedure, independent of exercise capacity, and are associated with lower perceived general health

Objectives: To determine physical activity levels in paediatric patients who underwent the Fontan procedure, and their relationship to functional status and exercise capacity. Study Design: We studied 147 patients (ages 7–18 years) at a median of 8.1 years after Fontan, as part of the Pediatric Heart Network cross-sectional study of Fontan survivors. Assessment included medical history, self-reported physical activity, parent-completed Child Health Questionnaire (CHQ), cardiopulmonary exercise testing and physical activity level measured by accelerometry (MTI Actigraph). Results: Measured time spent in moderate and vigorous activity was markedly below normal at all ages, particularly in females, and was not significantly related to self-reported activity levels, or to maximum Vo2, Vo2 at anaerobic threshold or maximum work rate on exercise testing. Lower measured activity levels were significantly related to lower perceived general health but not to self-esteem, physical functioning, social impact of physical limitations or overall physical or psychosocial health summary scores. Reduced exercise capacity was more strongly related than measured activity levels to lower scores in general health, self-esteem and physical functioning. Conclusions: Physical activity levels are reduced after Fontan, independent of exercise capacity, and are associated with lower perceived general health but not other aspects of functional status.

Nitric Oxide Modulates Mitochondrial Respiration in Failing Human Heart

Background-Our objective for this study was to investigate whether nitric oxide (NO) modulates tissue respiration in the failing human myocardium. Methods and Results-Left ventricular free wall and right ventricular tissue samples were taken from 14 failing explanted human hearts at the time of transplantation. Tissue oxygen consumption was measured with a Clark-type oxygen electrode in an airtight stirred bath containing Krebs solution buffered with HEPES at 37 degrees C (pH 7.4). Rate of decrease in oxygen concentration was expressed as a percentage of the baseline, and results of the highest dose are indicated. Bradykinin (10(-4) mol/L, -21+/-5%), amlodipine (10(-5) mol/L, -14+/-5%), the ACE inhibitor ramiprilat (10(-4) mol/L, -21+/-2%), and the neutral endopeptidase inhibitor thiorphan (10(-4) mol/L, -16+/-5%) all caused concentration-dependent decreases in tissue oxygen consumption. Responses to bradykinin (-2+/-6%), amlodipine (-2+/-4%), ramiprilat (-5+/-6%), and thiorphan (-4+/-7%) were significantly attenuated after NO synthase blockade with N-nitro-L-arginine methyl ester (10(-4) mol/L; all P<0.05). NO-releasing compounds S-nitroso-N-acetyl-penicillamine (10(-4) mol/L, -34+/-5%) and nitroglycerin (10(-4) mol/L, -21+/-5%), also decreased tissue oxygen consumption in a concentration-dependent manner. However, the reduction in tissue oxygen consumption in response to S-nitroso-N-acetyl-penicillamine (-35+/-7%) or nitroglycerin (-16+/-5%) was not significantly affected by N-nitro-L-arginine methyl ester. Conclusions-These results indicate that the modulation of oxygen consumption by both endogenous and exogenous NO is preserved in the failing human myocardium and that the inhibition of kinin degradation plays an important role in the regulation of mitochondrial respiration.