William L. Border

Modifiable risk factors and major cardiac events among adult survivors of childhood cancer.

PURPOSE To evaluate the relative contribution of modifiable cardiovascular risk factors on the development of major cardiac events in aging adult survivors of childhood cancer. PATIENTS AND METHODS Among 10,724 5-year survivors (median age, 33.7 years) and 3,159 siblings in the Childhood Cancer Survivor Study, the prevalence of hypertension, diabetes mellitus, dyslipidemia, and obesity was determined, along with the incidence and severity of major cardiac events such as coronary artery disease, heart failure, valvular disease, and arrhythmia. On longitudinal follow-up, rate ratios (RRs) of subsequent cardiac events associated with cardiovascular risk factors and cardiotoxic therapy were assessed in multivariable Poisson regression models. RESULTS Among survivors, the cumulative incidence of coronary artery disease, heart failure, valvular disease, and arrhythmia by 45 years of age was 5.3%, 4.8%, 1.5%, and 1.3%, respectively. Two or more cardiovascular risk factors were reported by 10.3% of survivors and 7.9% of siblings. The risk for each cardiac event increased with increasing number of cardiovascular risk factors (all P(trend) < .001). Hypertension significantly increased risk for coronary artery disease (RR, 6.1), heart failure (RR, 19.4), valvular disease (RR, 13.6), and arrhythmia (RR, 6.0; all P values < .01). The combined effect of chest-directed radiotherapy plus hypertension resulted in potentiation of risk for each of the major cardiac events beyond that anticipated on the basis of an additive expectation. Hypertension was independently associated with risk of cardiac death (RR, 5.6; 95% CI, 3.2 to 9.7). CONCLUSION Modifiable cardiovascular risk factors, particularly hypertension, potentiate therapy-associated risk for major cardiac events in this population and should be the focus of future interventional studies.

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.

Early manifestations and spectrum of recipient twin cardiomyopathy in twin–twin transfusion syndrome: relation to Quintero stage

To examine cardiac structural and functional changes in twin–twin transfusion syndrome (TTTS), relative to Quintero stage, as a means of evaluating the spectrum of cardiomyopathy in TTTS.

Lower weight-for-age z score adversely affects hospital length of stay after the bidirectional Glenn procedure in 100 infants with a single ventricle

OBJECTIVE Poor growth has been described in infants with a single ventricle; however, little is known regarding its effect on surgical outcomes. We sought to assess the effect of nutritional status at the time of the bidirectional Glenn procedure on short-term outcomes. METHODS We performed a retrospective case series of children who underwent the bidirectional Glenn procedure at our institution between January 2001 and December 2007. Anthropometric measurements were recorded at the time of neonatal admission and the bidirectional Glenn procedure. Data from preoperative echocardiograms and cardiac catheterization were recorded. The primary outcome variable was length of hospital stay. RESULTS Data on 100 infants were included for analysis. Age at the time of the bidirectional Glenn procedure was 5.1 months (range, 2.4-10 months). The median weight-for-age z score at birth was -0.4 (range, -2.6 to 3.2), and by the time of the bidirectional Glenn procedure, it had decreased to -1.3 (range, -3.9 to 0.6). In multivariable modeling longer postoperative hospital stays were predicted by lower weight-for-age z score (P = .02), younger age (P < .001), being fed through a gastrostomy tube (P = .01), and undergoing concomitant aortic arch reconstruction (P < .001) at the time of the bidirectional Glenn procedure. CONCLUSIONS There is suboptimal weight gain between neonatal discharge and the bidirectional Glenn procedure. A lower weight-for-age z score and younger age at the time of the bidirectional Glenn procedure affects length of hospital stay independent of hemodynamic or echocardiographic variables.

Color M-Mode and Doppler Tissue Evaluation of Diastolic Function in Children: Simultaneous Correlation with Invasive Indices

OBJECTIVE The purpose of this study was to explore the validity of diastolic indices derived from color M-mode Doppler and Doppler tissue imaging in a heterogeneous group of pediatric patients by comparing them with simultaneously obtained invasive indices of diastolic function. METHODS A total of 20 children undergoing left heart catheterization had echocardiographic images recorded simultaneously with high-fidelity left ventricular (LV) pressure tracings. Transmitral Doppler, pulmonary vein Doppler, Doppler tissue imaging, and color M-mode Doppler flow propagation velocity were recorded. LV peak negative dP/dt, the time constant of isovolumic relaxation, and LV end-diastolic pressure were compared with the echocardiographic indices. RESULTS The ratio of peak E-wave mitral velocity/propagation velocity correlated significantly with LV end-diastolic pressure (r = 0.71; P <.001). Propagation velocity correlated with the time constant of isovolumic relaxation (r = -0.56; P =.01) and peak negative dP/dt (r = 0.50; P <.03). Septal mitral annular myocardial velocity correlated significantly with the time constant of isovolumic relaxation (r = -0.58, P =.01). CONCLUSION The newer diastolic indices derived from color M-mode Doppler and Doppler tissue imaging appear to be a helpful adjunct in the noninvasive assessment of diastolic function in children.

Individual Prediction of Heart Failure Among Childhood Cancer Survivors

PURPOSE To create clinically useful models that incorporate readily available demographic and cancer treatment characteristics to predict individual risk of heart failure among 5-year survivors of childhood cancer. PATIENTS AND METHODS Survivors in the Childhood Cancer Survivor Study (CCSS) free of significant cardiovascular disease 5 years after cancer diagnosis (n = 13,060) were observed through age 40 years for the development of heart failure (ie, requiring medications or heart transplantation or leading to death). Siblings (n = 4,023) established the baseline population risk. An additional 3,421 survivors from Emma Childrens Hospital (Amsterdam, the Netherlands), the National Wilms Tumor Study, and the St Jude Lifetime Cohort Study were used to validate the CCSS prediction models. RESULTS Heart failure occurred in 285 CCSS participants. Risk scores based on selected exposures (sex, age at cancer diagnosis, and anthracycline and chest radiotherapy doses) achieved an area under the curve of 0.74 and concordance statistic of 0.76 at or through age 40 years. Validation cohort estimates ranged from 0.68 to 0.82. Risk scores were collapsed to form statistically distinct low-, moderate-, and high-risk groups, corresponding to cumulative incidences of heart failure at age 40 years of 0.5% (95% CI, 0.2% to 0.8%), 2.4% (95% CI, 1.8% to 3.0%), and 11.7% (95% CI, 8.8% to 14.5%), respectively. In comparison, siblings had a cumulative incidence of 0.3% (95% CI, 0.1% to 0.5%). CONCLUSION Using information available to clinicians soon after completion of childhood cancer therapy, individual risk for subsequent heart failure can be predicted with reasonable accuracy and discrimination. These validated models provide a framework on which to base future screening strategies and interventions.

Persistent Diastolic Flow Reversal in Abdominal Aortic Doppler-Flow Profiles Is Associated With an Increased Risk of Necrotizing Enterocolitis in Term Infants With Congenital Heart Disease

OBJECTIVE. Diastolic runoff in the abdominal aorta, with subsequent circulatory mesenteric insufficiency, has been postulated as a cause of necrotizing enterocolitis in term infants with congenital heart disease. With this study we sought to determine whether Doppler-flow characteristics in the abdominal aorta can predict which infants are at specific risk, independent of gestational age and type of congenital heart disease. PATIENTS AND METHODS. We conducted a case-control study of term infants with congenital heart disease and proven necrotizing enterocolitis (n = 18) compared with gestational age–matched and diagnosis-matched control subjects (n = 20). Abdominal aortic Doppler velocities, time intervals, and reversals were analyzed. Groups were compared, and independent risk factors for necrotizing enterocolitis were determined. RESULTS. The groups were similar with regard to weight, pulse pressure, use of prostaglandins or inotropes, presence of a patent ductus arteriosus, and systolic function. However, 47% of the case subjects with necrotizing enterocolitis had persistent retrograde diastolic flow in the abdominal aorta compared with 15% of the control subjects. When adjusting for multiple risk factors, persistent diastolic flow reversal remained the only factor significantly associated with necrotizing enterocolitis. CONCLUSION. Persistent diastolic flow reversal in the abdominal aortic Doppler profile is associated with an increased risk of necrotizing enterocolitis in term infants with congenital heart disease irrespective of gestational age or anatomic type of congenital heart disease.

Slide Tracheoplasty in Infants and Children: Risk Factors for Prolonged Postoperative Ventilatory Support

BACKGROUND A single-institution experience with slide tracheoplasty for management of tracheal stenosis in children with emphasis on identifying predictors of prolonged postoperative mechanical ventilation is reviewed. METHODS Patient characteristics, hospital course, and outcomes for children undergoing slide tracheoplasty were recorded. Univariate and multivariate analysis was performed to identify factors leading to prolonged mechanical ventilation (>48 hours postoperatively). RESULTS Since April 2001, 40 children underwent slide tracheoplasty utilizing cardiopulmonary bypass (CPB) support at a median age of 6.2 months (range, 7 days to 15 years), and median weight of 6.1 kg (range, 1.9 to 57 kg). Thirteen patients had undergone prior operations. Thirteen patients (32.5%) were mechanically ventilated before operation. Thirteen patients underwent additional procedures at the time of the slide tracheoplasty. Mean CBP support time was 123 minutes. Seven patients required aortic cross-clamping (mean, 69 minutes). There were 2 early and 2 late deaths, none related to the tracheoplasty. One patient required repair of a recurrent tracheal stenosis, 4 patients required tracheotomy, and 3 required temporary stent placement. Twenty-one patients (52.5%) were extubated within 48 hours after tracheoplasty. Univariate and multivariate analysis revealed only preoperative mechanical ventilatory support (odds ratio 28.4, p = 0.015) and duration of CPB support (odds ratio 1.06, p = 0.007) to be significant predictors of the need for prolonged intubation. CONCLUSIONS Slide tracheoplasty utilizing CPB support is a versatile and effective treatment for tracheal stenosis in children even when combined with repair of congenital cardiac anomalies. Most children can be successfully weaned from mechanical ventilatory support early after repair.

Low-weight infants are at increased mortality risk after palliative or corrective cardiac surgery.

BACKGROUND Low weight is an established risk factor for mortality after congenital cardiac surgery. Given the advances in the care of neonates and infants after surgery, we sought to examine the effect of low weight on outcomes in the current era. METHODS From 2002 to 2012, 2051 infants aged 90 days or less underwent cardiac surgery including 534 (26.0%) with single-ventricle pathology. Regression models examined the effect of low weight (≤ 2.5 kg; n = 274, 13.4%) on early and late outcomes. RESULTS Overall, the incidence of prematurity, associated chromosomal/extracardiac abnormalities was higher in infants who weighed 2.5 kg or less than in those who weighed more than 2.5 kg; the incidence of single-ventricle pathology was comparable between the 2 groups. In addition, infants who weighed 2.5 kg or less underwent more palliation and had a higher proportion of STAT (Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery) risk category 4 and 5 procedures. Adjusted regression models showed that low weight (≤ 2.5 kg) did not increase unplanned reoperation (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.48-1.67; P = .73) or extracorporeal membrane oxygenation requirement (OR, 1.23; 95% CI, 0.68-2.22; P = .49), however it was associated with significant increase in hospital mortality (OR, 2.15; 95% CI, 1.33-3.50; P = .002). In addition, there was a significant association between low weight and increased duration of postoperative mechanical ventilation and intensive care unit and hospital stays. Adjusted hazard analysis showed that weight equal to or less than 2.5 kg was associated with diminished late survival (hazard ratio, 1.89; 95% CI, 1.39-2.55; P < .001) and that was evident in all patients subgroups (P < .001 for all). CONCLUSIONS In a large single-center series, low weight continues to be associated with increased early mortality risk and resource utilization after palliative and corrective cardiac surgery. The hazard of death in low-weight patients continues beyond the perioperative period for at least 1 year before normalizing. Strategies to improve outcomes for this high-risk population must address perioperative care, outpatient surveillance, and management.

Birth Weight and Prematurity in Infants with Single Ventricle Physiology: Pediatric Heart Network Infant Single Ventricle Trial Screened Population

OBJECTIVES Although congenital heart disease is associated with low birth weight and prematurity, there is little information about these birth outcomes in infants with single ventricle physiology. We describe the birth outcomes (i.e., gestational age and birth weight) in neonates with single ventricle physiology screened for enrollment in the Pediatric Heart Networks Infant Single Ventricle Trial, compare these outcomes with US norms, and examine the association of birth outcomes with anatomic diagnosis and race. PATIENTS AND METHODS All neonates with single ventricle physiology presenting to Infant Single Ventricle Trial centers were screened for enrollment. Demographic data and anatomic diagnoses were obtained from medical records. RESULTS A total of 1245 neonates with single ventricle physiology were screened at 10 centers (63 to 266 per center). Diagnoses included hypoplastic left heart syndrome in 49%, unbalanced atrioventricular septal defect in 12%, and tricuspid atresia in 9%. Preterm birth occurred in 16% of neonates with single ventricle physiology vs. 12% in normal neonates (P < .001), low birth weight (<2.5 kg) in 18% vs. 8% in normals (P < .001), and small for gestational age (<10th percentile by definition) in 22% vs. 10% in normals (P < .001). A genetic syndrome was reported in 8%. The percentage of preterm birth, low birth weight, and small for gestational age was similar between screened neonates with and without hypoplastic left heart syndrome. CONCLUSIONS In this large, contemporary cohort of neonates with single ventricle physiology, rates of preterm birth, low birth weight, and small for gestational age were higher than in the general population, but similar between screened neonates with and without hypoplastic left heart syndrome.