Karen Altmann

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.

Two-dimensional echocardiographic assessment of right ventricular function as a predictor of outcome in hypoplastic left heart syndrome

This study was undertaken to assess the importance of right ventricular function at the time of initial presentation on early and intermediate outcome in patients with hypoplastic left heart syndrome (HLHS). Several studies have attempted to define physiologic risk factors for poor early outcome following the Norwood palliation for HLHS. No clinical or hemodynamic factors including right ventricular function have been found to reliably predict Norwood I operative survival. The relation between initial ventricular function and later survival has not been investigated. To assess the importance of right ventricular (RV) function at the time of initial presentation on outcome in patients with HLHS, systolic function was determined by qualitative and quantitative methods in 60 consecutive patients before surgical intervention. The effects on stage I operative survival, survival to stage II, and overall survival were analyzed. Initial RV function did not impact on stage I survival. However, analysis of later outcome of the stage I survivors showed that those with prestage I RV dysfunction had significantly greater mortality before stage II. Actuarial survival 18 months after Norwood surgery was 93% for patients with initially normal RV function compared with 47% for those with abnormal function (p = <0.005). The relative risk for later mortality was approximately 11 times greater for patients with initial RV dysfunction. Thus, RV dysfunction identifiable soon after initial presentation does not impact on early survival after Norwood I operation for HLHS. Intermediate and overall survival, however, is significantly decreased in patients with initially diminished RV function.

Comparison of three-dimensional echocardiographic assessment of volume, mass, and function in children with functionally single left ventricles with two-dimensional echocardiography and magnetic resonance imaging

Diminished systolic function or inappropriate hypertrophy are considered risk factors for outcome following the Fontan procedure. These parameters are difficult to assess in univentricular hearts that do not conform to the uniform shapes prescribed by conventional 2-dimensional imaging volume algorithms. Three-dimensional echocardiography requires no geometric assumptions and has been validated in both normal and distorted left ventricles. To assess the feasibility and accuracy of this technique in patients with univentricular hearts, we compared 2- and 3-dimensional echocardiographic estimates of ventricular volume, ejection fraction, and mass in patients with functionally single left ventricles with results obtained by magnetic resonance imaging (MRI). Twelve patients with functionally single left ventricles (6 months to 22 years) underwent examination by all 3 modalities. Correlation and agreement with MRI were calculated for volumes, ejection fraction, and mass. Three-dimensional echocardiographic comparison with MRI yielded a bias of 3.4 +/- 5.5 ml and 14.2 +/- 8.3 ml for systolic and diastolic volumes, respectively. Agreement analysis for mass showed a bias of 5.8 +/- 8.4 grams. Two-dimensional echocardiography showed less agreement for both volumes and mass (bias of -2.9 +/- 8.1, 2.9 +/- 10.4 ml and -8.3 +/- 12.0 g for volume and mass, respectively, p >0.05). Ejection fraction by 3-dimensional echocardiography showed significantly closer agreement with MRI (bias of 4.4 +/- 5.3%) than 2-dimensional echocardiography (bias of 8.5 +/- 10.3%, p = 0.04). Thus, 3-dimensional echocardiography provides estimates of ventricular volumes, ejection fraction, and mass that are comparable to MRI in this select group of patients with single ventricles of left ventricular morphology.

The ventricular volume variability study of the Pediatric Heart Network: study design and impact of beat averaging and variable type on the reproducibility of echocardiographic measurements in children with chronic dilated cardiomyopathy.

BACKGROUND Clinical trials often rely on echocardiographic measures of left ventricular size and function as surrogate end points. However, the quantitative impact of factors that affect the reproducibility of these measures is unknown. To address this issue, the National Heart, Lung, and Blood Institute-funded Pediatric Heart Network designed a longitudinal observational study of children with known or suspected dilated cardiomyopathy aged 0 to 22 years from eight pediatric clinical centers. METHODS Clinical data were collected together with 150 echocardiographic indices of left ventricular size and function. Separate observers performed duplicate echocardiographic imaging. Multiple observers performed measurements from three cardiac cycles to enable assessment of intraobserver and interobserver variability. The impacts of beat averaging (BA), observer type (local vs core), and variable type (areas, calculations, dimensions, slopes, time intervals, and velocities) on measurement reproducibility were studied. The outcome measure was percentage error (100 × difference/mean). RESULTS Of 173 enrolled subjects, 131 met criteria for dilated cardiomyopathy. BA, variable type and observer type all influenced percentage error (P < .0001). Core interobserver percentage error (medians, 11.4%, 10.2%, and 9.3% for BA using one, two, and three beats, respectively) was approximately twice the intraobserver percentage error (medians, 6.3%, 4.9%, and 4.2% for BA using one, two, and three beats, respectively). Slopes and calculated variables exhibited high percentage error despite BA. Chamber dimensions, areas, velocities, and time intervals exhibited low percentage error. CONCLUSIONS This comprehensive evaluation of quantitative echocardiographic methods will provide a valuable resource for the design of future pediatric studies. BA and a single core lab observer improve the reproducibility of echocardiographic measurements in children with dilated cardiomyopathy. Certain measurements are highly reproducible, while others, despite BA, are poorly reproducible.

Factors affecting growth in infants with single ventricle physiology: a report from the Pediatric Heart Network Infant Single Ventricle Trial.

OBJECTIVES To describe growth patterns in infants with single ventricle physiology and determine factors influencing growth. STUDY DESIGN Data from 230 subjects enrolled in the Pediatric Heart Network Infant Single Ventricle Enalapril Trial were used to assess factors influencing change in weight-for-age z-score (z) from study enrollment (0.7 ± 0.4 months) to pre-superior cavopulmonary connection (SCPC; 5.1 ± 1.8 months, period 1) and pre-SCPC to final study visit (14.1 ± 0.9 months, period 2). Predictor variables included patient characteristics, feeding regimen, clinical center, and medical factors during neonatal (period 1) and SCPC hospitalizations (period 2). Univariate regression analysis was performed, followed by backward stepwise regression and bootstrapping reliability to inform a final multivariable model. RESULTS Weights were available for 197 of 230 subjects for period 1 and 173 of 197 subjects for period 2. For period 1, greater gestational age, younger age at study enrollment, tube feeding at neonatal hospitalization discharge, and clinical center were associated with a greater negative z (poorer growth) in multivariable modeling (adjusted R(2) = 0.39, P < .001). For period 2, younger age at SCPC and greater daily caloric intake were associated with greater positive z (better growth; R(2) = 0.10, P = .002). CONCLUSIONS Aggressive nutritional support and earlier SCPC are modifiable factors associated with a favorable change in weight-for-age z-score.

Predictors of Disease Progression in Pediatric Dilated Cardiomyopathy

Background—Despite medical advances, children with dilated cardiomyopathy (DCM) remain at high risk of death or need for cardiac transplantation. We sought to identify predictors of disease progression in pediatric DCM. Methods and Results—The Pediatric Heart Network evaluated chronic DCM patients with prospective echocardiographic and clinical data collection during an 18-month follow-up. Inclusion criteria were age <22 years and DCM disease duration >2 months. Patients requiring intravenous inotropic/mechanical support or listed status 1A/1B for transplant were excluded. Disease progression was defined as an increase in transplant listing status, hospitalization for heart failure, intravenous inotropes, mechanical support, or death. Predictors of disease progression were identified using Cox proportional hazards modeling and classification and regression tree analysis. Of the 127 patients, 28 (22%) had disease progression during the 18-month follow-up. Multivariable analysis identified older age at diagnosis (hazard ratio=1.14 per year; P<0.001), larger left ventricular (LV) end-diastolic M-mode dimension z-score (hazard ratio=1.49; P<0.001), and lower septal peak systolic tissue Doppler velocity z-score (hazard ratio=0.81; P=0.01) as independent predictors of disease progression. Classification and regression tree analysis stratified patients at risk of disease progression with 89% sensitivity and 94% specificity based on LV end-diastolic M-mode dimension z-score ≥7.7, LV ejection fraction <39%, LV inflow propagation velocity (color M-mode) z-score <−0.28, and age at diagnosis ≥8.5 months. Conclusions—In children with chronic stable DCM, a combination of diagnosis after late infancy and echocardiographic parameters of larger LV size and systolic and diastolic function predicted disease progression. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00123071.

Methods for noninvasive measurement of tissue iron in Cooley's anemia

Abstract: To examine the relationship between myocardial storage iron and body iron burden, as assessed by hepatic storage iron measurements, we studied 22 patients with transfusion‐dependent thalassemia syndromes, all being treated with subcutaneous deferoxamine, and 6 healthy subjects. Study participants were examined with a Philips 1.5‐T Intera scanner using three multiecho spin echo sequences with electrocardiographic triggering and respiratory navigator gating. Myocardial and hepatic storage iron concentrations were determined using a new magnetic resonance method that estimates total tissue iron stores by separately measuring the two principal forms of storage iron, ferritin and hemosiderin. In a subset of 10 patients with β‐thalassemia major, the hepatic storage iron concentration had been monitored repeatedly for 12‐14 years by chemical analysis of tissue obtained by liver biopsy and by magnetic susceptometry. In this subset, we examine the relationship between hepatic iron concentration over time and our current magnetic resonance estimates of myocardial iron stores. No significant relationship was found between simultaneous estimates of myocardial and hepatic storage iron concentrations. By contrast, in the subset of 10 patients with β‐thalassemia major, the correlation between the 5‐year average of hepatic iron concentration and the current myocardial storage iron was significant (R= .67, P= .03). In these patients, myocardial storage iron concentrations seem to reflect the control of body iron over a period of years. Magnetic resonance methods promise to provide more effective monitoring of iron deposition in vulnerable tissues, including the liver, heart, and endocrine organs, and could contribute to the development of iron‐chelating regimens that more effectively prevent iron toxicity.

Bulboventricular Foramen Resection: Hemodynamic and Electrophysiologic Results

BACKGROUND The two major surgical approaches to the relief of bulboventricular foramen (BVF) obstruction in patients with single left ventricle (LV) are the Damus-Kaye-Stansel (DKS) procedure or direct BVF resection. Theoretical advantages of the DKS include better out-flow gradient relief, lower potential incidences of postoperative heart block and lower incidences of reoperation. Potential disadvantages of this approach include increased semilunar valvar insufficiency, lack of feasibility when attempting septation-type operations for univentricular hearts, and a technically more difficult operation. We report the results of direct surgical BVF resection. METHODS From June 1990 to June 1999, 9 patients had direct BVF resection performed at our institution. The median age at surgery was 16.5 years (range 1 month to 27 years). Diagnoses in these patients were [S,L,L] single LV (n = 8) and [S,D,D] single LV tricuspid atresia (n = 1). Eight of 9 patients had pulmonary artery bands placed either before BVF resection or at the same time as this procedure. Three patients required reoperation for reobstruction at the BVF (12 total operations in 9 patients). RESULTS Median preoperative peak systolic gradient across the BVF measured at cardiac catheterization was 47 mm Hg (range 10 to 63 mm Hg). The median peak gradient measured by Doppler echocardiography was 44 mm Hg (range 5 to 125 mm Hg). Eight of 9 patients survived the operation to discharge from the hospital and 7 of 9 are alive at follow-up. At a median follow-up of 22 months (range 5 to 76 months), 8 of 8 surviving patients had an unobstructed BVF as determined by qualitative two-dimensional echocardiography and Doppler color flow imaging. There was one perioperative and one late death 5 months postoperatively (secondary to fungal sepsis). No patient developed new or worsened aortic insufficiency after BVF resection. Eight of 9 patients had no change in AV nodal conduction after surgery. One patient developed Mobitz II heart block requiring postoperative implantation of a pacemaker. CONCLUSIONS Direct resection of an obstructive BVF can be performed with total relief of obstruction although reoperation may be required. Atrioventricular nodal function can be preserved in most patients with this operative approach, including those with [S,L,L] segmental anatomy.

Incidence of Aortic Root Dilatation in Pectus Excavatum and Its Association With Marfan Syndrome

OBJECTIVE To investigate the incidence of aortic root dilatation in pectus excavatum. DESIGN Retrospective medical record review and echocardiographic reanalysis. SETTING Morgan Stanley Childrens Hospital of New York-Presbyterian. PARTICIPANTS Surgical candidates with pectus excavatum (n = 37) and age-matched controls (n = 44) referred for an echocardiogram from 1994 to 2002. INTERVENTIONS Two-dimensional and color Doppler transthoracic echocardiograms. OUTCOME MEASURES The aortic annulus and root were measured and z scores were calculated and compared. Medical records were reviewed for genetic evaluation. RESULTS Patients with pectus excavatum and age-matched controls were reanalyzed. There was no difference in age, weight, height, or body surface area between patients and controls. There were no differences in the mean aortic annulus diameter, mean aortic annulus z score, or mean aortic root measurements. However, the aortic root z score was significantly higher in the pectus excavatum group compared with the controls: 0.9 (SD, 1.06) vs 0.0 (SD, 1.25) (P = .001). There were more patients with an aortic root z score of 2 or greater in the pectus excavatum group (9 of 37 patients) than in the control group (0 of 43 controls), with a calculated odds ratio of 29.7 (95% confidence interval, 1.10-1.59). Genetic evaluation was performed in 5 patients with a pectus excavatum and dilated aortic root; 2 of them received diagnoses of Marfan syndrome. CONCLUSIONS Aortic root dilatation is more common in patients with pectus excavatum than in a control population. Echocardiographic screening may be useful in the identification of aortic root dilatation in patients with isolated pectus excavatum.

Coronary Artery Fistulas: A Review of the Literature and Presentation of Two Cases of Coronary Fistulas with Drainage into the Left Atrium

We report 2 cases of infants presenting with a murmur shortly after birth and diagnosed with coronary artery fistulas with drainage into the left atrium. The first infant had a fistulous communication between the left main coronary artery and the left atrial appendage and presented with signs and symptoms of heart failure. The infant was repaired surgically in the first week of life. The second infant was asymptomatic and had a fistulous communication between the right coronary artery and the left atrium. The infant will have the fistula closed in the cardiac catheterization laboratory when the child is older. The literature on coronary artery fistulas is reviewed, and the diagnosis and management of coronary artery fistulas is discussed.