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.

Echocardiographic image collection and evaluation in infants with CHD: lessons learned from the imaging core lab for the Residual Lesion Score study.

Many factors affect patient outcome after congenital heart surgery, including the complexity of the heart disease, pre-operative status, patient specific factors (prematurity, nutritional status and/or presence of comorbid conditions or genetic syndromes), and post-operative residual lesions. The Residual Lesion Score is a novel tool for assessing whether specific residual cardiac lesions after surgery have a measurable impact on outcome. The goal is to understand which residual lesions can be tolerated and which should be addressed prior to leaving the operating room. The Residual Lesion Score study is a large multicentre prospective study designed to evaluate the association of Residual Lesion Score to outcomes in infants undergoing surgery for CHD. This Pediatric Heart Network and National Heart, Lung, and Blood Institute-funded study prospectively enrolled 1,149 infants undergoing 5 different congenital cardiac surgical repairs at 17 surgical centres. Given the contribution of echocardiographic measurements in assigning the Residual Lesion Score, the Residual Lesion Score study made use of a centralised core lab in addition to site review of all data. The data collection plan was designed with the added goal of collecting image quality information in a way that would permit us to improve our understanding of the reproducibility, variability, and feasibility of the echocardiographic measurements being made. There were significant challenges along the way, including the coordination, de-identification, storage, and interpretation of very large quantities of imaging data. This necessitated the development of new infrastructure and technology, as well as use of novel statistical methods. The study was successfully completed, but the size and complexity of the population being studied and the data being extracted required more technologic and human resources than expected which impacted the length and cost of conducting the study. This paper outlines the process of designing and executing this complex protocol, some of the barriers to implementation and lessons to be considered in the design of future studies.

Bicuspid aortic valve and its ascending aortopathy.

PURPOSE OF REVIEW: To synthesize and critically assess recent clinical and research advancements in pediatric bicuspid aortic valve (BAV) and its associated aortopathy. RECENT FINDINGS: In pediatric patients with BAV, progressive aortic dilation (i.e. bicuspid aortopathy) is commonly present and associated with increased risk for aortic aneurysm, dissection, and surgery in adulthood. Ongoing research explores the cause, incidence, and progression of bicuspid aortopathy to promote earlier diagnosis and improve preventive management. Recent findings include: high familial incidence and need for improved familial screening; safety of recreational physical activity in most affected children; potential for medical management to slow aortic growth; feasibility of pediatric registries to evaluate longitudinal outcomes; and potential genetic and hemodynamic biomarkers for disease risk stratification. SUMMARY: Pediatric bicuspid aortopathy is an important area for investigation and preventive management to improve long-term cardiovascular outcomes. Recent literature promotes familial screening, recreational exercise, medical prophylaxis, registry-based longitudinal evaluation, and continued scientific inquiry.

Angiotensin receptor blockers and ß blockers in Marfan syndrome: an individual patient data meta-analysis of randomised trials.

BACKGROUND: Angiotensin receptor blockers (ARBs) and ß blockers are widely used in the treatment of Marfan syndrome to try to reduce the rate of progressive aortic root enlargement characteristic of this condition, but their separate and joint effects are uncertain. We aimed to determine these effects in a collaborative individual patient data meta-analysis of randomised trials of these treatments. METHODS: In this meta-analysis, we identified relevant trials of patients with Marfan syndrome by systematically searching MEDLINE, Embase, and CENTRAL from database inception to Nov 2, 2021. Trials were eligible if they involved a randomised comparison of an ARB versus control or an ARB versus ß blocker. We used individual patient data from patients with no prior aortic surgery to estimate the effects of: ARB versus control (placebo or open control); ARB versus ß blocker; and indirectly, ß blocker versus control. The primary endpoint was the annual rate of change of body surface area-adjusted aortic root dimension Z score, measured at the sinuses of Valsalva. FINDINGS: We identified ten potentially eligible trials including 1836 patients from our search, from which seven trials and 1442 patients were eligible for inclusion in our main analyses. Four trials involving 676 eligible participants compared ARB with control. During a median follow-up of 3 years, allocation to ARB approximately halved the annual rate of change in the aortic root Z score (mean annual increase 0·07 [SE 0·02] ARB vs 0·13 [SE 0·02] control; absolute difference -0·07 [95% CI -0·12 to -0·01]; p=0·012). Prespecified secondary subgroup analyses showed that the effects of ARB were particularly large in those with pathogenic variants in fibrillin-1, compared with those without such variants (heterogeneity p=0·0050), and there was no evidence to suggest that the effect of ARB varied with ß-blocker use (heterogeneity p=0·54). Three trials involving 766 eligible participants compared ARBs with ß blockers. During a median follow-up of 3 years, the annual change in the aortic root Z score was similar in the two groups (annual increase -0·08 [SE 0·03] in ARB groups vs -0·11 [SE 0·02] in ß-blocker groups; absolute difference 0·03 [95% CI -0·05 to 0·10]; p=0·48). Thus, indirectly, the difference in the annual change in the aortic root Z score between ß blockers and control was -0·09 (95% CI -0·18 to 0·00; p=0·042). INTERPRETATION: In people with Marfan syndrome and no previous aortic surgery, ARBs reduced the rate of increase of the aortic root Z score by about one half, including among those taking a ß blocker. The effects of ß blockers were similar to those of ARBs. Assuming additivity, combination therapy with both ARBs and ß blockers from the time of diagnosis would provide even greater reductions in the rate of aortic enlargement than either treatment alone, which, if maintained over a number of years, would be expected to lead to a delay in the need for aortic surgery. FUNDING: Marfan Foundation, the Oxford British Heart Foundation Centre for Research Excellence, and the UK Medical Research Council.

Molecular characterization and investigation of the role of genetic variation in phenotypic variability and response to treatment in a large pediatric Marfan syndrome cohort.

PURPOSE: In a large cohort of 373 pediatric patients with Marfan syndrome (MFS) with a severe cardiovascular phenotype, we explored the proportion of patients with MFS with a pathogenic FBN1 variant and analyzed whether the type/location of FBN1 variants was associated with specific clinical characteristics and response to treatment. Patients were recruited on the basis of the following criteria: aortic root z-score > 3, age 6 months to 25 years, no prior or planned surgery, and aortic root diameter < 5 cm. METHODS: Targeted resequencing and deletion/duplication testing of FBN1 and related genes were performed. RESULTS: We identified (likely) pathogenic FBN1 variants in 91% of patients. Ectopia lentis was more frequent in patients with dominant-negative (DN) variants (61%) than in those with haploinsufficient variants (27%). For DN FBN1 variants, the prevalence of ectopia lentis was highest in the N-terminal region (84%) and lowest in the C-terminal region (17%). The association with a more severe cardiovascular phenotype was not restricted to DN variants in the neonatal FBN1 region (exon 25-33) but was also seen in the variants in exons 26 to 49. No difference in the therapeutic response was detected between genotypes. CONCLUSION: Important novel genotype-phenotype associations involving both cardiovascular and extra-cardiovascular manifestations were identified, and existing ones were confirmed. These findings have implications for prognostic counseling of families with MFS.

Frequency of Ventricular Arrhythmias and Other Rhythm Abnormalities in Children and Young Adults With the Marfan Syndrome.

Patients with the Marfan syndrome (MFS) are at risk for sudden death. The contribution of arrhythmias is unclear. This study examines the prevalence of arrhythmias in children with the MFS and their relation to clinical and/or echocardiographic factors. Data from the Pediatric Heart Network randomized trial of atenolol versus losartan in MFS were analyzed (6 months to 25 years old, aortic root diameter z-score > 3.0, no previous aortic surgery and/or dissection). Baseline 24-hour ambulatory electrocardiographic monitoring was performed. Significant ventricular ectopy (VE) and supraventricular ectopy (SVE) were defined as ≥10 VE or SVE/hour, or the presence of high-grade ectopy. Three-year composite clinical outcome of death, aortic dissection, or aortic root replacement was analyzed. There were 274 analyzable monitors on unique patients from 11 centers. Twenty subjects (7%) had significant VE, 13 (5%) significant SVE; of these, 2 (1%) had both. None had sustained ventricular or supraventricular tachycardia. VE was independently associated with increasing number of major Ghent criteria (odds ratio [OR] = 2.13/each additional criterion, p = 0.03) and greater left ventricular end-diastolic dimension z-score (OR = 1.47/each 1 unit increase in z-score, p = 0.01). SVE was independently associated with greater aortic sinotubular junction diameter z-score (OR = 1.56/each 1 unit increase in z-score, p = 0.03). The composite clinical outcome (14 events) was not related to VE or SVE (p ≥ 0.3), but was independently related to heart rate variability (higher triangular index). In conclusion, in this cohort, VE and SVE were rare. VE was related to larger BSA-adjusted left ventricular size. Routine ambulatory electrocardiographic monitoring may be useful for risk stratification in select MFS patients.

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.

Influence of Aortic Stiffness on Aortic-Root Growth Rate and Outcome in Patients With the Marfan Syndrome.

The Pediatric Heart Network randomized trial of atenolol versus losartan in the Marfan syndrome showed no treatment differences in the rates of aortic-root growth or clinical outcomes. In this report we present treatment effects on aortic stiffness and determine whether baseline aortic stiffness predicts aortic-root growth and clinical outcomes. Echocardiograms at 0, 6, 12, 24, and 36 months from 608 subjects (6 months to 25 years) who met original Ghent criteria and had a maximum aortic-root z-score (ARz) >3 were centrally reviewed. Stiffness index (SI) and elastic modulus (EM) were calculated for aortic root and ascending aorta. Data were analyzed using multivariable mixed effects modeling and Cox regression. Heart rate-corrected aortic-root SI over 3 years decreased with atenolol but did not change with losartan (-0.298 ± 0.139 vs 0.141 ± 0.139/year, p = 0.01). In the entire cohort, above-median aortic-root SI (>9.1) and EM (>618 mm Hg) predicted a smaller annual decrease in ARz (p ≤0.001). Upper-quartile aortic-root EM (>914 mm Hg) predicted the composite outcome of aortic-root surgery, dissection, or death (hazard ratio 2.17, 95% confidence interval 1.02 to 4.63, p = 0.04). Crude 3-year event rates were 10.4% versus 3.2% for higher versus lower EM groups. In conclusion, atenolol was associated with a decrease in aortic-root SI, whereas losartan was not. Higher baseline aortic-root SI and EM were associated with a smaller decrease in ARz and increased risk for clinical outcomes. These data suggest that noninvasive aortic stiffness measures may identify patients at higher risk of progressive aortic enlargement and adverse clinical outcomes, potentially allowing for closer monitoring and more aggressive therapy.

MATR3 disruption in human and mouse associated with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus.

Cardiac left ventricular outflow tract (LVOT) defects represent a common but heterogeneous subset of congenital heart disease for which gene identification has been difficult. We describe a 46,XY,t(1;5)(p36.11;q31.2)dn translocation carrier with pervasive developmental delay who also exhibited LVOT defects, including bicuspid aortic valve (BAV), coarctation of the aorta (CoA) and patent ductus arteriosus (PDA). The 1p breakpoint disrupts the 5' UTR of AHDC1, which encodes AT-hook DNA-binding motif containing-1 protein, and AHDC1-truncating mutations have recently been described in a syndrome that includes developmental delay, but not congenital heart disease [Xia, F., Bainbridge, M.N., Tan, T.Y., Wangler, M.F., Scheuerle, A.E., Zackai, E.H., Harr, M.H., Sutton, V.R., Nalam, R.L., Zhu, W. et al. (2014) De Novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea. Am. J. Hum. Genet., 94, 784-789]. On the other hand, the 5q translocation breakpoint disrupts the 3' UTR of MATR3, which encodes the nuclear matrix protein Matrin 3, and mouse Matr3 is strongly expressed in neural crest, developing heart and great vessels, whereas Ahdc1 is not. To further establish MATR3 3' UTR disruption as the cause of the proband's LVOT defects, we prepared a mouse Matr3(Gt-ex13) gene trap allele that disrupted the 3' portion of the gene. Matr3(Gt-ex13) homozygotes are early embryo lethal, but Matr3(Gt-ex13) heterozygotes exhibit incompletely penetrant BAV, CoA and PDA phenotypes similar to those in the human proband, as well as ventricular septal defect (VSD) and double-outlet right ventricle (DORV). Both the human MATR3 translocation breakpoint and the mouse Matr3(Gt-ex13) gene trap insertion disturb the polyadenylation of MATR3 transcripts and alter Matrin 3 protein expression, quantitatively or qualitatively. Thus, subtle perturbations in Matrin 3 expression appear to cause similar LVOT defects in human and mouse.

Atenolol versus losartan in children and young adults with Marfan's syndrome.

BACKGROUND: Aortic-root dissection is the leading cause of death in Marfan's 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 Marfan's 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 Marfan's 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.).

Outcomes after primary transcatheter therapy in infants and young children with severe bilateral peripheral pulmonary artery stenosis.

BACKGROUND: Angioplasty and stent implantation have become accepted therapies for isolated peripheral pulmonary stenosis, and have been shown to increase vessel diameter and reduce right ventricular (RV) pressure acutely in patients with pulmonary artery (PA) stenosis. The purpose of this study was to assess long-term outcomes after primary transcatheter therapy for peripheral pulmonary stenosis. METHODS AND RESULTS: We studied 69 patients who underwent primary transcatheter intervention for severe isolated peripheral pulmonary stenosis at ≤ 5 years of age. Genetic/syndromic diagnoses included Williams syndrome (n=23), non-Williams familial arteriopathy (n=12), and Alagille syndrome (n=3). At the initial PA intervention, median RV:aortic pressure ratio decreased from 1.00 to 0.88 (median decrease, 0.18; P<0.001). Patients with a higher preintervention RV:aortic pressure ratio had a greater reduction (P<0.001). During follow-up (median, 8.5 years), 10 patients died, 5 from complications of PA catheterization (all before 1998). Thirteen patients underwent surgical PA intervention, most within 1 year and along with repair of supravalvar aortic stenosis. Freedom from any PA reintervention was 38 ± 6% at 1 year and 22 ± 6% at 5 years. The median RV:aortic pressure ratio decreased from 1.0 at baseline to 0.53 at the most recent catheterization (P<0.001), and 82% of patients with available clinical follow-up were asymptomatic. CONCLUSIONS: Transcatheter therapy for infants with severe peripheral pulmonary stenosis has become safer, regardless of genetic condition. Coupled with reintervention and surgical relief in selected cases, RV:aortic pressure ratios decrease substantially and most patients are asymptomatic at late follow-up.

Characteristics of children and young adults with Marfan syndrome and aortic root dilation in a randomized trial comparing atenolol and losartan therapy.

BACKGROUND: The Pediatric Heart Network designed a clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in children and young adults with Marfan syndrome randomized to receive atenolol or losartan. We report here the characteristics of the screened population and enrolled subjects. METHODS AND RESULTS: Between 2007 and 2011, 21 clinical sites randomized 608 subjects, aged 6 months to 25 years who met the original Ghent criteria and had a body surface area-adjusted aortic root diameter z-score >3.0. The mean age at study entry was 11.2 years, 60% were male, and 25% were older teenagers and young adults. The median aortic root diameter z-score was 4.0. Aortic root diameter z-score did not vary with age. Mitral valve prolapse and mitral regurgitation were more common in females. Among those with a positive family history, 56% had a family member with aortic surgery, and 32% had a family member with a history of aortic dissection. CONCLUSIONS: Baseline demographic, clinical, and anthropometric characteristics of the randomized cohort are representative of patients in this population with moderate to severe aortic root dilation. The high percentage of young subjects with relatives who have had aortic dissection or surgery illustrates the need for more definitive therapy; we expect that the results of the study and the wealth of systematic data collected will make an important contribution to the management of individuals with Marfan syndrome.

Thoracic aortic disease in two patients with juvenile polyposis syndrome and SMAD4 mutations.

Dilation or aneurysm of the ascending aorta can progress to acute aortic dissection (Thoracic Aortic Aneurysms and Aortic Dissections, TAAD). Mutations in genes encoding TGF-ß-related proteins (TGFBR1, TGFBR2, FBN1, and SMAD3) cause syndromic and inherited TAAD. SMAD4 mutations are associated with juvenile polyposis syndrome (JPS) and a combined JPS-hereditary hemorrhagic telangiectasia (HHT) known as JPS-HHT. A family with JPS-HHT was reported to have aortic root dilation and mitral valve abnormalities. We report on two patients with JPS-HHT with SMAD4 mutations associated with thoracic aortic disease. The first patient, an 11-year-old boy without Marfan syndrome features, had JPS and an apparently de novo SMAD4 mutation (c.1340_1367dup28). Echocardiography showed mild dilation of the aortic annulus and aortic root, and mild dilation of the sinotubular junction and ascending aorta. Computed tomography confirmed aortic dilation and showed small pulmonary arteriovenous malformations (PAVM). The second patient, a 34-year-old woman with colonic polyposis, HHT, and features of Marfan syndrome, had a SMAD4 mutation (c.1245_1248delCAGA). Echocardiography showed mild aortic root dilation. She also had PAVM and hepatic focal nodular hyperplasia. Her family history was significant for polyposis, HHT, thoracic aortic aneurysm, and dissection and skeletal features of Marfan syndrome in her father. These two cases confirm the association of thoracic aortic disease with JPS-HHT resulting from SMAD4 mutations. We propose that the thoracic aorta should be screened in patients with SMAD4 mutations to prevent untimely death from dissection. This report also confirms that SMAD4 mutations predispose to TAAD.

Surgical interventions for atrioventricular septal defect subtypes: the pediatric heart network experience.

BACKGROUND: The influence of atrioventricular septal defect (AVSD) subtype on outcomes after repair is poorly understood. METHODS: Demographic, procedural, and outcome data were obtained 1 and 6 months after AVSD repair in an observational study conducted at 7 North American centers. RESULTS: The 215 AVSD patients were subtyped as 60 partial, 27 transitional, 120 complete, and 8 with canal-type VSD. Preoperatively, transitional patients had the highest prevalence of moderate or severe left atrioventricular valve regurgitation (LAVVR, p = 0.01). At repair, complete AVSD and canal-type VSD patients, both with the highest prevalence of trisomy 21 (p < 0.001), were younger (p < 0.001), had lower weight-for-age z scores (p = 0.005), and had more associated cardiac defects (p < 0.001). Annuloplasty was similar among subtypes (p = 0.91), with longer duration of ventilation and hospitalization for complete AVSD (p < 0.001). Independent predictors of moderate or severe LAVVR at the 6-month follow-up were older log(age) at repair (p = 0.02) but not annuloplasty, subtype, or center (p > 0.4). Weight-for-age z scores improved in all subtypes at the 6-month follow-up, and improvement was similar among subtypes (p = 0.17). CONCLUSIONS: AVSD subtype was significantly associated with patient characteristics and clinical status before repair and influenced age at repair. Significant postoperative LAVVR is the most common sequela, with a similar prevalence across centers 6 months after the intervention. Annuloplasty failed to decrease the postoperative prevalence of moderate or severe LAVVR at 6 months. After accounting for age at repair, AVSD subtype was not associated with postoperative LAVVR severity or growth failure at 6 months. Further investigation is needed to determine if interventional strategies specific to AVSD subtype improve surgical outcomes.

Increased vertebral artery tortuosity index is associated with adverse outcomes in children and young adults with connective tissue disorders.

BACKGROUND: Arterial tortuosity is described as a common and distinctive feature of Loeys-Dietz syndrome (LDS), yet reports on arterial tortuosity are based on qualitative observations and none have investigated an association between tortuosity and cardiovascular outcomes in LDS or other connective tissue disorders. METHODS AND RESULTS: We performed a retrospective analysis of 90 patients ≤50 years of age with Marfan syndrome, LDS, Ehlers-Danlos syndrome, or nonspecific connective tissue disorder who underwent thoracic contrast-enhanced magnetic resonance angiography. Controls (n=30) underwent magnetic resonance imaging to exclude arrhythmogenic right ventricular dysplasia. Using a volume-rendered angiogram, vertebral arteries were measured along the curvature of the vessel (actual length) and linearly (straight length), and distance factor was calculated: [(actual/straight length-1)×100]. Each subject's maximum distance factor was designated the Vertebral Tortuosity Index (VTI). The VTI was compared among diagnostic groups and among patients with cardiac surgery, dissection, and death. Median age at magnetic resonance imaging was 19.6 years (range 0.2 to 50.1). VTI interrater reliability was excellent (intraclass correlation coefficient =0.987). The VTI was higher in Marfan syndrome (n=57, median 26; interquartile range 10 to 49) and LDS (n=13, median 58; interquartile range 18 to 92) compared with controls (median 4.5; interquartile range 3 to 6; P<0.001 for both). Higher VTI was associated with younger age at surgery even when controlling for root size (adjusted P=0.002). Vertebral tortuosity index ≥50 was associated with earlier age at dissection and death compared with VTI <50 (P=0.001 versus P<0.001). We found no difference in age at surgery, dissection, or death in Marfan syndrome compared with LDS. CONCLUSION: Arterial tortuosity measured by magnetic resonance angiography is a reproducible marker of adverse cardiovascular outcomes in connective tissue disorders.

Surgical management of complete atrioventricular septal defect: associations with surgical technique, age, and trisomy 21.

OBJECTIVES: We sought to evaluate the contemporary results after repair of a complete atrioventricular septal defect and to determine the factors associated with suboptimal outcomes. METHODS: The demographic, procedural, and outcome data were obtained within 1 and 6 months after repair of a complete atrioventricular septal defect in 120 children in a multicenter observational study from June 2004 to 2006. RESULTS: The median age at surgery was 3.7 months (range, 9 days to 1.1 years). The type of surgical repair was a single patch (18%), double patch (72%), and a single atrial septal defect patch with primary ventricular septal defect closure (10%). The incidence of residual septal defects and the degree of left atrioventricular valve regurgitation (LAVVR) did not differ by repair type. The median interval of intensive care stay were 4 days, ventilation use 2 days, and total hospitalization 8 days. All were independent of the presence of trisomy 21 (80% of the cohort). The in-hospital mortality rate was 2.5% (3/120). The overall 6-month mortality rate was 4% (5/120). The presence of associated anomalies and younger age at surgery were independently associated with a longer hospital stay. The age at repair was not associated with residual ventricular septal defect or moderate or greater LAVVR at 6 months. Moderate or greater LAVVR occurred in 22% at 6 months, and the strongest predictor for this was moderate or greater LAVVR at 1 month (odds ratio, 6.9; 95% confidence interval, 2.2-21.7; P < .001). CONCLUSIONS: The outcomes after repair of complete atrioventricular septal defect did not differ by repair type or the presence of trisomy 21. An earlier age at surgery was associated with increased resource use but had no association with the incidence of residual ventricular septal defect or significant LAVVR.

Partial and transitional atrioventricular septal defect outcomes.

BACKGROUND: Surgical and perioperative improvements permit earlier repair of partial and transitional atrioventricular septal defects (AVSD). We sought to describe contemporary outcomes in a multicenter cohort. METHODS: We studied 87 patients undergoing primary biventricular repair of partial or transitional AVSD between June 2004 and February 2006 across seven North American centers. One-month and 6-month postoperative data included weight-for-age z-scores, left atrioventricular valve regurgitation (LAVVR) grade, residual shunts, and left ventricular ejection fraction. Paired methods were used to assess 6-month change. RESULTS: Median age at surgery was 1.8 years; median weight z-score was -0.88. Median days for ventilation were 1, intensive care 2, and hospitalization 5, all independent of age, with 1 in-hospital death. At 1 month, 27% (16 of 73) had ejection fraction less than 55%; 20% (17 of 87) had significant LAVVR; 2 had residual shunts; 1 each had subaortic stenosis and LAVV stenosis. At 6 months (n = 60), there were no interim deaths, reinterventions, or new development of subaortic or LAVV stenosis. Weight z-score improved by a median 0.4 units (p < 0.001), especially for underweight children less than 18 months old. Left atrioventricular valve regurgitation occurred in 31% (change from baseline, p = 0.13), occurring more frequently in patients repaired at 4 to 7 years (p = 0.01). Three patients had ejection fraction less than 55%, and 1 had a residual atrial shunt. CONCLUSIONS: Surgical repair for partial/transitional AVSD is associated with low morbidity and mortality, short hospital stays, and catch-up growth, particularly in underweight children repaired between 3 and 18 months of age. Left atrioventricular valve regurgitation remains the most common residual defect, occurring more frequently in children repaired after 4 years of age.

Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era.

BACKGROUND: Although abnormal pulmonary vascular structure and function in preterm infants with bronchopulmonary dysplasia may predispose infants to pulmonary artery hypertension, little is known about the characteristics and outcomes of bronchopulmonary dysplasia-associated pulmonary artery hypertension in the surfactant era. METHODS: We studied 42 premature infants (< 32 weeks of gestation) with bronchopulmonary dysplasia who were diagnosed as having pulmonary artery hypertension > or = 2 months after birth, between 1998 and 2006, at a median age of 4.8 months. Pulmonary artery hypertension was graded through echocardiography for all patients; 13 patients also underwent cardiac catheterization. RESULTS: Eighteen (43%) of 42 patients had severe pulmonary artery hypertension (systemic or suprasystemic right ventricular pressure). Among 13 patients who underwent catheterization, the mean pulmonary artery pressure was 43 +/- 8 mmHg and the pulmonary vascular resistance index was 9.9 +/- 2.8 Wood units. In 12 patients, pulmonary artery pressure and pulmonary vascular resistance improved with 100% oxygen and 80 ppm inhaled nitric oxide but remained elevated. The pulmonary vascular resistance index decreased to 7.9 +/- 3.8 Wood units in 100% oxygen and to 6.4 +/- 3.1 Wood units with the addition of nitric oxide. Sixteen patients (38%) died during the follow-up period. Estimated survival rates were 64% +/- 8% at 6 months and 53% +/- 11% at 2 years after diagnosis of pulmonary artery hypertension. In multivariate analyses, severe pulmonary artery hypertension and small birth weight for gestational age were associated with worse survival rates. Among 26 survivors (median follow-up period: 9.8 months), pulmonary artery hypertension was improved, relative to its most severe level, in 24 patients (89%). CONCLUSION: Premature infants with bronchopulmonary dysplasia and severe pulmonary artery hypertension are at high risk of death, particularly during the first 6 months after diagnosis of pulmonary artery hypertension.

Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome.

BACKGROUND: Cardiovascular disease, including aortic root dilation, dissection, and rupture, is the leading cause of mortality in patients with Marfan syndrome (MFS). The maximal aortic root diameter at the sinuses of Valsalva is considered the best predictor of adverse cardiovascular outcome. Although advances in therapy have improved life expectancy, affected individuals continue to suffer cardiovascular morbidity and mortality. Recent studies in an FBN1-targeted mouse model of MFS with aortic disease similar to that seen in humans showed that treatment with losartan normalized aortic root growth and aortic wall architecture. METHODS: The Pediatric Heart Network designed a randomized clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in subjects with MFS receiving atenolol or losartan. Individuals 6 months to 25 years of age with a body surface area-adjusted aortic root z score >3.0 will be eligible for inclusion. The primary aim is to compare the effect of atenolol therapy with that of losartan therapy on the rate of aortic root growth over 3 years. Secondary end points include progression of aortic regurgitation; incidence of aortic dissection, aortic root surgery, and death; progression of mitral regurgitation; left ventricular size and function; echocardiographically derived measures of central aortic stiffness; skeletal and somatic growth; and incidence of adverse drug reactions. CONCLUSION: This randomized trial should make a substantial contribution to the management of individuals with MFS and expand our understanding of the mechanisms responsible for the aortic manifestations of this disorder.