Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome.

OBJECTIVE: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. STUDY DESIGN: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. RESULTS: Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. CONCLUSIONS: In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.

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.

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.).

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.

The Academic Learning Health System: A Framework for Integrating the Multiple Missions of Academic Medical Centers.

The learning health system (LHS) has emerged over the past 15 years as a concept for improving health care delivery. Core aspects of the LHS concept include: promoting improved patient care through organizational learning, innovation, and continuous quality improvement; identifying, critically assessing, and translating knowledge and evidence into improved practices; building new knowledge and evidence around how to improve health care and health outcomes; analyzing clinical data to support learning, knowledge generation, and improved patient care; and engaging clinicians, patients, and other stakeholders in processes of learning, knowledge generation, and translation. However, the literature has paid less attention to how these LHS aspects may integrate with the multiple missions of academic medical centers (AMCs). The authors define an academic learning health system (aLHS) as an LHS built around a robust academic community and central academic mission, and they propose 6 features that emphasize how an aLHS differs from an LHS. An aLHS capitalizes on embedded academic expertise in health system sciences; engages the full spectrum of translational investigation from mechanistic basic sciences to population health; builds pipelines of experts in LHS sciences and clinicians with fluency in practicing in an LHS; applies core LHS principles to the development of curricula and clinical rotations for medical students, housestaff, and other learners; disseminates knowledge more broadly to advance the evidence for clinical practice and health systems science methods; and addresses social determinants of health, creating community partnerships to mitigate disparities and improve health equity. As AMCs evolve, the authors expect that additional differentiating features and ways to operationalize the aLHS will be identified and hope this article stimulates further discussion around the intersection of the LHS concept and AMCs.

Decreased exercise performance with age in children with hypoplastic left heart syndrome.

OBJECTIVE: Children born with hypoplastic left heart syndrome (HLHS) may experience cardiac dysfunction after staged surgery or transplantation, which may worsen with age. We examined the hypothesis that exercise testing can address cardiovascular capacity and suggest interventions to improve quality of life. STUDY DESIGN: Children with HLHS > or = 8 years old performed treadmill or bicycle ergometric testing at 4 centers. Results were compared with norms for age and sex. RESULTS: Of the 42 participants, the mean age was 12.9 years (range, 8.5-17.0 years), 64% were boys, 20 had staged surgery, and 34 completed metabolic assessment. The percent of predicted maximal oxygen uptake (mVO2) was higher in younger children. Children aged 8 to 12 years achieved 70% of predicted mVO2; children aged 13 to 17 years achieved 60% of predicted mVO2 (P = .02). The percent of predicted peak heart rate trended higher in younger patients (83% versus 75%, P = .07). Electrocardiographic changes were more common in older children. In treadmill testing, patients who had a transplant had better exercise performance than patients who underwent staged surgery in percent of predicted exercise time (82% versus 54%, P < .0001) and peak rate-pressure product (241 x 10(3) versus 195 x 10(3), P = .02). The percent of predicted mVO2 did not differ between patients who had a transplant (66%) and patients who underwent staged surgery (61%, P = .25). CONCLUSION: Children with HLHS showed considerable age-related decline in exercise performance, regardless of surgical strategy.

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.

The reproducibility and absolute values of echocardiographic measurements of left ventricular size and function in children are algorithm dependent.

BACKGROUND: Several quantification algorithms for measuring left ventricular (LV) size and function are used in clinical and research settings. The aims of this study were to investigate the effects of measurement algorithm and beat averaging on the reproducibility of measurements of the left ventricle and to assess the magnitude of agreement among the algorithms in children with dilated cardiomyopathy. METHODS: Echocardiograms were obtained in 169 children from eight clinical centers. Inter- and intrareader reproducibility was assessed on measurements of LV volumes using the biplane Simpson, modified Simpson, and 5/6 × area × length (5/6AL) algorithms. Percentage error was calculated as inter- or intrareader difference/mean × 100. Single-beat measurements and the three-beat average (3BA) were compared. Intraclass correlation coefficients were calculated to assess agreement. RESULTS: Single-beat interreader reproducibility was lowest (percentage error was highest) using biplane Simpson; 5/6AL and modified Simpson were similar but significantly better than biplane Simpson (P < .05). Single-beat intrareader reproducibility was highest using 5/6AL (P < .05). The 3BA improved reproducibility for almost all measures (P < .05). Reproducibility in both single-beat and 3BA values fell with greater LV dilation and systolic dysfunction (P < .05). Intraclass correlation coefficients were >0.95 across measures, although absolute volume and mass values were systematically lower for biplane Simpson compared with modified Simpson and 5/6AL. CONCLUSIONS: The reproducibility of LV size and functional measurements in children with dilated cardiomyopathy is highest using the 5/6AL algorithm and can be further improved by using the 3BA. However, values derived from different algorithms are not interchangeable.

Multi-detector row computed tomographic angiography in pediatric heart transplant recipients: Initial observations.

BACKGROUND: The purpose of this study was to assess the feasibility and limitation of multi-detector row computed tomographic (MDCT) imaging for evaluating coronary arteries in pediatric heart transplant patients. METHODS: Coronary MDCT angiography was performed in eight pediatric heart transplant recipients. The presence of coronary calcification was evaluated. Luminal changes of the visualized coronary segments on MDCT images were compared with catheter angiographic findings and intravascular ultrasound. RESULTS: Coronary calcification was present in one patient who had severe coronary arteriopathy documented by intravascular ultrasound. In 48 coronary segments visualized on MDCT images, 33, 7, and 4 segments each had normal, luminal irregularities, and moderate stenoses, respectively, which were confirmed by catheter angiography. Twelve coronary segments could not be assessed because of severe motion artifacts. Image quality degradation was more pronounced in patients with higher heart rates. CONCLUSIONS: Noninvasive MDCT angiography is promising but requires further technical improvement to evaluate coronary arteries in pediatric heart transplant patients.

Echocardiographic methods, quality review, and measurement accuracy in a randomized multicenter clinical trial of Marfan syndrome.

BACKGROUND: The Pediatric Heart Network is conducting a large international randomized trial to compare aortic root growth and other cardiovascular outcomes in 608 subjects with Marfan syndrome randomized to receive atenolol or losartan for 3 years. The authors report here the echocardiographic methods and baseline echocardiographic characteristics of the randomized subjects, describe the interobserver agreement of aortic measurements, and identify factors influencing agreement. METHODS: Individuals aged 6 months to 25 years who met the original Ghent criteria and had body surface area-adjusted maximum aortic root diameter (ROOTmax) Z scores > 3 were eligible for inclusion. The primary outcome measure for the trial is the change over time in ROOTmaxZ score. A detailed echocardiographic protocol was established and implemented across 22 centers, with an extensive training and quality review process. RESULTS: Interobserver agreement for the aortic measurements was excellent, with intraclass correlation coefficients ranging from 0.921 to 0.989. Lower interobserver percentage error in ROOTmax measurements was independently associated (model R(2) = 0.15) with better image quality (P = .002) and later study reading date (P < .001). Echocardiographic characteristics of the randomized subjects did not differ by treatment arm. Subjects with ROOTmaxZ scores ≥ 4.5 (36%) were more likely to have mitral valve prolapse and dilation of the main pulmonary artery and left ventricle, but there were no differences in aortic regurgitation, aortic stiffness indices, mitral regurgitation, or left ventricular function compared with subjects with ROOTmaxZ scores < 4.5. CONCLUSIONS: The echocardiographic methodology, training, and quality review process resulted in a robust evaluation of aortic root dimensions, with excellent reproducibility.

Tetralogy of Fallot: anatomic variants and their impact on surgical management.

Tetralogy of Fallot is the most common form of cyanotic congenital heart disease. In this condition, episodic worsening of hypoxemia results from dynamic shifts in physiology, so-called "Tet spells." The relative frequency of this lesion and the risks of exacerbating "Tet spells" make anesthetic management of this patient population challenging. The conduct of palliative and reparative cardiac surgery is determined in large part by the anatomic variations within the spectrum of this disorder, most notably the severity of right ventricular outflow tract obstruction. This review will address the impact that the anatomic substrate has on the perioperative management of this interesting patient population.

Getting beyond "Good job": how to give effective feedback.

This article is the fourth in a series by the Council on Medical Student Education in Pediatrics (COMSEP) reviewing the critical attributes and skills of superb clinical teachers. The previous article in this series reviewed the vital importance of direct observation of students.(1) The purpose of this article is to describe how to use the information gained from the direct observation, namely the role of feedback. Although too often used interchangeably, encouragement, evaluation, and feedback are quite distinct. Encouragement (eg, "good job!") is supportive but does nothing to improve the learner's skills. Evaluation is summative and is the final judgment of the learner's performance. Feedback, however, is designed to improve future performance. This article focuses on feedback-what it is, why it is important, some of the barriers to effective feedback, and how to give helpful feedback.

Myocardial velocity, strain, and strain rate abnormalities in healthy obese children.

Childhood obesity is a major health care issue in the United States. This epidemic has important cardiovascular implications. Newer imaging modalities in obese adults have demonstrated abnormal systolic and diastolic cardiac function. The authors proposed to determine whether these abnormalities are present in obese children. A total of 168 children were identified from our echocardiographic database. Body mass index for age was calculated. Echocardiographic clips were analyzed using imaging technology to determine myocardial motion, strain, and strain rate. Patients at risk for obesity and those meeting criteria for obesity had increased late diastolic myocardial motion compared with normal-weight children. Obese patients had decreased systolic strain compared with normal-weight children. As with adults, obese children have significant differences in diastolic function and strain. These abnormalities may be subtle markers for the emergence of future cardiac disease.

The state of undergraduate pediatric medical education in North America: The COMSEP survey.

BACKGROUND/PURPOSE: One mission of all academic medical centers is the education of medical students. The resources allocated to the oversight of this mission vary. The status of pediatric undergraduate medical education and the role of the pediatric clerkship director (PCD) was published in 1995. We sought to provide an updated description by surveying current North American PCDs. METHODS: A survey was designed by members of the Council on Medical Student Education in Pediatrics and administered via the Internet. RESULTS: Eighty-four percent of U.S. PCDs (110/131) and 50% of Canadian PCDs (8/16) completed the survey. Significant differences compared with 1995 include (a) more clerkship directors are assistant professors, women, and generalists; (b) clerkship directors have more time for clerkship activities but less than they perceive that they need; and (c) traditional scholarship is even more difficult to accomplish than in the past. CONCLUSION: The position of PCD is perceived to be a legitimate career track, but most PCDs hold lower academic rank and have less traditional scholarly activity than PCDs did 10 years ago. Although PCDs have more time (40% now vs. 28% in 1995), they still feel that it is not adequate, needing almost 50% of their total time to adequately do their job.

Cardiovascular management of marfan syndrome in the young.

Marfan syndrome is an autosomal-dominant disorder of connective tissue resulting from a mutation in the fibrillin gene. Manifestations of the disorder primarily affect the skeletal, cardiovascular, and ocular systems. The phenotypic manifestations of this disorder can be quite variable. The major cause of morbidity and mortality in this patient population is the cardiovascular manifestations of the disorder: aortic root dilation and dissection. Individuals with this disorder are at risk for catastrophic cardiovascular events, most often as a result of aortic dissection. Although the incidence of dissection in childhood is exceedingly low, the background of a progressively dilating aortic root appears to be the major factor contributing to this risk in adulthood. Therefore, it is beneficial to identify affected individuals as early as possible to institute lifestyle changes and medical therapy in an effort to enhance their long-term outcome. Familial screening, once a case has been identified, and consideration of genetic screening of an affected family may also be helpful. Medical therapy with beta blockers, calcium channel blockers, and/or angiotensin inhibitors has been shown to be somewhat effective in slowing the rate of growth of the aorta. Exciting new data suggest that angiotensin II receptor antagonists may provide an even greater degree of protection from aortic dilatation in this population. Despite medical therapy, patients with Marfan syndrome do have progressive dilatation of their aortic root. The risk of aortic dissection increases with increasing size of the aorta. Prophylactic surgical techniques have been successful in reducing the morbidity and mortality associated with aortic dissection, resulting in a longer average life span in this patient population.

Mapping students' clinical experiences to pediatric clerkship goals.

In anticipation of new LCME accreditation requirements, our third year clerkship students began tracking pediatric clinical experiences using a hand-held Electronic Student Encounter Log (ESEL) in June 2005. ESEL was tailored to support rapid documentation of diseases seen at a pediatric tertiary care hospital, while retaining access to primary care diagnoses. We matched encounters that 37 students documented to experiences that fulfill the pediatric clerkship's 19 educational goals. We discovered omissions in both ESEL and the goal definitions. No student documented meeting all goals, and no goal was met by all students. Handheld encounter logs are useful for tracking clinical experiences. Logs, logging instructions, and goals require regular compatibility checks.

Relationship of surgical approach to neurodevelopmental outcomes in hypoplastic left heart syndrome.

OBJECTIVE: Two strategies for surgical management are used for infants with hypoplastic left heart syndrome (HLHS), primary heart transplantation and the Norwood procedure. We sought to determine how these 2 surgical approaches influence neurodevelopmental outcomes at school age. METHODS: A multicenter, cross-sectional study of neurodevelopmental outcomes among school-aged children (>8 years of age) with HLHS was undertaken between July 2003 and September 2004. Four centers enrolled 48 subjects, of whom 47 completed neuropsychologic testing. Twenty-six subjects (55%) had undergone the Norwood procedure and 21 (45%) had undergone transplantation, with an intention-to-treat analysis. The mean age at testing was 12.4 +/- 2.5 years. Evaluations included the Wechsler Abbreviated Scale of Intelligence, Clinical Evaluation of Language Fundamentals, Wechsler Individual Achievement Test, and Beery-Buktenica Developmental Test of Visual-Motor Integration. RESULTS: The mean neurocognitive test results were significantly below population normative values. The mean full-scale IQ for the entire cohort was 86 +/- 14. In a multivariate model, there was no association of surgical strategy with any measure of developmental outcome. A longer hospital stay, however, was associated significantly with lower verbal, performance, and full-scale IQ scores. Aortic valve atresia was associated with lower math achievement test scores. CONCLUSIONS: Neurodevelopmental deficits are prevalent among school-aged children with HLHS, regardless of surgical approach. Complications that result in prolonged hospitalization at the time of the initial operation are associated with neurodevelopmental status at school age.

Novel use of the Amplatzer duct occluder to close perivalvar leak involving a prosthetic mitral valve.

Perivalvar leak following atrioventricular valve replacement can result in heart failure or hemolytic anemia. These patients may be poor surgical candidates given a complex clinical condition. We describe transcatheter closure of a perivalvar leak in a 3-month infant who had undergone left atrioventricular valve replacement with a St. Jude's prosthesis.

Transcatheter occlusion of baffle leaks following atrial switch procedures for transposition of the great vessels (d-TGV).

Baffle-related complications following atrial switch procedures for transposition are relatively common. Transcatheter treatment of baffle stenosis has an established role as a therapeutic modality. However, transcatheter device closure of atrial baffles leaks has rarely been reported. We report four patients who underwent device closure of baffle leaks using the Amplatzer septal occluder following atrial switch procedures in order to demonstrate the safety and utility of this method of treatment and to establish its role as a suitable alternative to surgical closure.