Jami C. Levine

Atenolol versus Losartan in Children and Young Adults With Marfan's Syndrome

BACKGROUND Aortic-root dissection is the leading cause of death in Marfans syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers. METHODS We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfans syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events. RESULTS From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [±SD] age, 11.5±6.5 years in the atenolol group and 11.0±6.2 years in the losartan group), who had an aortic-root z score greater than 3.0. The baseline-adjusted rate of change in the mean (±SE) aortic-root z score did not differ significantly between the atenolol group and the losartan group (-0.139±0.013 and -0.107±0.013 standard-deviation units per year, respectively; P=0.08). Both slopes were significantly less than zero, indicating a decrease in the aortic-root diameter relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups. CONCLUSIONS Among children and young adults with Marfans syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aortic-root dilatation between the two treatment groups over a 3-year period. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00429364.).

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.

Results of in utero atrial septoplasty in fetuses with hypoplastic left heart syndrome

Neonates with hypoplastic left heart syndrome and intact or highly restrictive atrial septum have a high rate of mortality. We sought to assess the effect of prenatal intervention intended to create atrial septal defects in fetuses with this diagnosis.

Absent right superior vena cava in visceroatrial situs solitus.

Absence of the right superior vena cava (SVC) in visceroatrial situs solitus is rare (0.07% to 0.13% of congenital cardiovascular malformations), and little is known about the type and frequency of additional heart defects and arrhythmias. We reviewed previous publications and present 9 new cases. Based on 121 known cases, we found that this anomaly is typically characterized by: (1) persistence of the left SVC draining into the right atrium by way of the coronary sinus, and (2) left-sided azygos vein draining into the left SVC. Less constant features were: (3) additional cardiovascular malformations (46%), and (4) rhythm abnormalities (36%) that usually appeared related to the complications of old age. Since absence of the right SVC is clinically silent, its status should be assessed echocardiographically prior to invasive medical or surgical procedures. This is important to avoid various management difficulties during the following procedures: (1) implantation of a transvenous pacemaker, (2) placement of a pulmonary artery catheter for intraoperative or intensive care unit monitoring without fluoroscopy, (3) systemic venous cannulation for extracorporeal membrane oxygenation, (4) systemic venous cannulation for cardiopulmonary bypass, (5) partial or total cavopulmonary anastomoses; and (6) orthotopic heart transplantation and endomyocardial biopsies.

Changes in left heart hemodynamics after technically successful in-utero aortic valvuloplasty.

Severe aortic stenosis in the mid‐gestation fetus can progress to hypoplastic left heart syndrome (HLHS). @ In‐utero aortic valvuloplasty is an innovative therapy to promote left ventricular growth and function and potentially to prevent HLHS. This study evaluated the effects of mid‐gestation fetal balloon aortic valvuloplasty on subsequent fetal left ventricular function and left heart Doppler characteristics.

Radiofrequency ablation of accessory pathways associated with congenital heart disease including heterotaxy syndrome

Congenital heart disease complicates the management of most accessory pathway-mediated tachycardias and also increases the challenge of radiofrequency ablation. Since 1990, radiofrequency ablation of accessory atrioventricular (AV) pathways has been attempted in 10 patients (age range 3.5 months to 30 years) with congenital heart disease: Ebsteins anomaly (n = 5), heterotaxy with AV discordance (n = 3), tetralogy of Fallot (n = 1) and total anomalous pulmonary venous return (n = 1). Eight patients had manifest Wolff-Parkinson-White syndrome and 2 had concealed pathways. Five patients had multiple pathways including 4 of the 5 with Ebsteins anomaly. Of 16 pathways total, 15 were associated with the tricuspid valve including all pathways in the patients with Ebsteins anomaly and heterotaxy. The His bundle area was identified in all patients and involved an anterior AV node in 2 of 3 with heterotaxy. Ablation was performed on the atrial side of the AV ring in all cases. No instance of AV block was encountered. Complete success was achieved in 6 patients including the 3 with heterotaxy. In 2 patients, manifest preexcitation was eliminated and clinical symptoms were greatly modified. The procedure was transiently successful in 1 patient who later had surgical interruption of the accessory pathway during tetralogy of Fallot repair. Ablation was unsuccessful in 1 patient. Thus, the overall success was 80%.

Coronary Artery Dilation Among Patients Presenting With Systemic-Onset Juvenile Idiopathic Arthritis

Objective. To evaluate coronary artery diameters among patients presenting with systemic-onset juvenile idiopathic arthritis (SoJIA). Methods. Fifty cases of SoJIA were reviewed. At the time of initial presentation with fever, 12 patients had echocardiograms that included a complete evaluation of the coronary arteries. A single reviewer measured the diameters of the left main, proximal left anterior descending, and proximal right coronary arteries. Body surface area-adjusted z scores were calculated with respect to a normative population. Results. Coronary artery dilation (z score: >2) was observed for 5 of the 12 patients with SoJIA who had echocardiograms performed at the time of presentation with fever. No patient developed a coronary artery aneurysm, and all of the coronary artery z scores normalized within 4 months. Only 2 of the 5 patients with coronary artery z scores of >2 fulfilled the clinical criteria for Kawasaki disease, the most commonly recognized cause of coronary artery dilation among children. Conclusions. Children presenting with SoJIA may have coronary artery dilation similar to that observed for children with Kawasaki disease. These data suggest that the presence of coronary artery dilation on initial echocardiograms for patients with fever does not exclude the diagnosis of SoJIA.

Sodium channel abnormalities are infrequent in patients with long QT Syndrome: Identification of two novel SCN5A mutations

Long QT syndrome (LQTS) is a heterogeneous disorder caused by mutations of at least five different loci. Three of these, LQT1, LQT2, and LQT5, encode potassium channel subunits. LQT3 encodes the cardiac-specific sodium channel, SCN5A. Previously reported LQTS-associated mutations of SCN5A include a recurring three amino acid deletion (DeltaKPQ1505-1507) in four different families, and four different missense mutations. We have examined the SCN5A gene in 88 index cases with LQTS, including four with Jervell and Lange-Nielsen syndrome and the remainder with Romano-Ward syndrome. Screening portions of DIII-DIV, where mutations have previously been found, showed that none of these patients has the three amino acid deletion, DeltaKPQ1505-1507, or the other four known mutations. We identified a novel missense mutation, T1645M, in the DIV; S4 voltage sensor immediately adjacent to the previously reported mutation R1644H. We also examined all of the additional pore-forming regions and voltage-sensing regions and discovered another novel mutation, T1304M, at the voltage-sensing region DIII; S4. Neither T1645M nor T1304M were seen in a panel of unaffected control individuals. Five of six T1304M gene carriers were symptomatic. In contrast to previous studies, QT(onset-c) was not a sensitive indicator of SCN5A-associated LQTS, at least in this family. These data suggest that mutations of SCN5A are responsible for only a small proportion of LQTS cases.

Does Initial Shunt Type for the Norwood Procedure Affect Echocardiographic Measures of Cardiac Size and Function During Infancy? The Single Ventricle Reconstruction Trial

Background— The Pediatric Heart Network trial comparing outcomes in 549 infants with single right ventricle undergoing a Norwood procedure randomized to modified Blalock-Taussig shunt or right ventricle–pulmonary artery shunt (RVPAS) found better 1-year transplant-free survival in those who received RVPAS. We sought to compare the impact of shunt type on echocardiographic indices of cardiac size and function up to 14 months of age. Methods and Results— A core laboratory measured indices of cardiac size and function from protocol exams: early after Norwood procedure (age 22.5±13.4 days), before stage II procedure (age 4.8±1.8 months), and at 14 months (age 14.3±1.2 months). Mean right ventricular ejection fraction was <50% at all intervals for both groups and was higher in the RVPAS group after Norwood procedure (49±7% versus 44±8%; P<0.001) but was similar by 14 months. Tricuspid and neoaortic regurgitation, diastolic function, and pulmonary artery and arch dimensions were similar in the 2 groups at all intervals. Neoaortic annulus area (4.2±1.2 versus 4.9±1.2 cm2/m2), systolic ejection times (214.0±29.4 versus 231.3±28.6 ms), neoaortic flow (6.2±2.4 versus 9.4±3.4 L/min per square meter), and peak arch velocity (1.9±0.7 versus 2.2±0.7 m/s) were lower at both interstage examinations in the RVPAS compared with the modified Blalock-Taussig shunt group (P<0.001 for all), but all were similar at 14 months. Conclusions— Indices of cardiac size and function after the Norwood procedure are similar for modified Blalock-Taussig shunt and RVPAS by 14 months of age. Interstage differences between shunt types can likely be explained by the physiology created when the shunts are in place rather than by intrinsic differences in cardiac function. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00115934.

Renin-Angiotensin-Aldosterone Genotype Influences Ventricular Remodeling in Infants With Single Ventricle

Background— We investigated the effect of polymorphisms in the renin-angiotensin-aldosterone system (RAAS) genes on ventricular remodeling, growth, renal function, and response to enalapril in infants with single ventricle. Methods and Results— Single ventricle infants enrolled in a randomized trial of enalapril were genotyped for polymorphisms in 5 genes: angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 receptor, aldosterone synthase, and chymase. Alleles associated with renin-angiotensin-aldosterone system upregulation were classified as risk alleles. Ventricular mass, volume, somatic growth, renal function using estimated glomerular filtration rate, and response to enalapril were compared between patients with ≥2 homozygous risk genotypes (high risk), and those with <2 homozygous risk genotypes (low risk) at 2 time points: before the superior cavopulmonary connection (pre-SCPC) and at age 14 months. Of 230 trial subjects, 154 were genotyped: Thirty-eight were high risk, and 116 were low risk. Ventricular mass and volume were elevated in both groups pre-SCPC. Ventricular mass and volume decreased and estimated glomerular filtration rate increased after SCPC in the low-risk (P<0.05), but not the high-risk group. These responses were independent of enalapril treatment. Weight and height z-scores were lower at baseline, and height remained lower in the high-risk group at 14 months, especially in those receiving enalapril (P<0.05). Conclusions— Renin-angiotensin-aldosterone system–upregulation genotypes were associated with failure of reverse remodeling after SCPC surgery, less improvement in renal function, and impaired somatic growth, the latter especially in patients receiving enalapril. Renin-angiotensin-aldosterone system genotype may identify a high-risk subgroup of single ventricle patients who fail to fully benefit from volume-unloading surgery. Follow-up is warranted to assess long-term impact. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00113087.