Whole-exome sequencing uncovers the genetic complexity of bicuspid aortic valve in families with early-onset complications.

Bicuspid aortic valve (BAV) is the most common congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that specific gene variants predispose to early-onset complications of BAV (EBAV). We analyzed whole-exome sequences (WESs) to identify rare coding variants that contribute to BAV disease in 215 EBAV-affected families. Predicted damaging variants in candidate genes with moderate or strong supportive evidence to cause developmental cardiac phenotypes were present in 107 EBAV-affected families (50% of total), including genes that cause BAV (9%) or heritable thoracic aortic disease (HTAD, 19%). After appropriate filtration, we also identified 129 variants in 54 candidate genes that are associated with autosomal-dominant congenital heart phenotypes, including recurrent deleterious variation of FBN2, MYH6, channelopathy genes, and type 1 and 5 collagen genes. These findings confirm our hypothesis that unique rare genetic variants drive early-onset presentations of BAV disease.

Cardiovascular Management of Aortopathy in Children: A Scientific Statement From the American Heart Association.

Aortopathy encompasses a spectrum of conditions predisposing to dilation, aneurysm, dissection, or rupture of the aorta and other blood vessels. Aortopathy is diagnosed commonly in children, from infancy through adolescence, primarily affecting the thoracic aorta, with variable involvement of the peripheral vasculature. Pathogeneses include connective tissue disorders, smooth muscle contraction disorders, and congenital heart disease, including bicuspid aortic valve, among others. The American Heart Association has published guidelines for diagnosis and management of thoracic aortic disease. However, these guidelines are predominantly focused on adults and cannot be applied adeptly to growing children with emerging features, growth and developmental changes, including puberty, and different risk profiles compared with adults. Management to reduce risk of progressive aortic dilation and dissection or rupture in children is complex and involves genetic testing, cardiovascular imaging, medical therapy, lifestyle modifications, and surgical guidance that differ in many ways from adult management. Pediatric practice varies widely, likely because aortopathy is pathogenically heterogeneous, including genetic and nongenetic conditions, and there is limited published evidence to guide care in children. To optimize care and reduce variation in management, experts in pediatric aortopathy convened to generate this scientific statement regarding the cardiovascular care of children with aortopathy. Available evidence and expert consensus were combined to create this scientific statement. The most common causes of pediatric aortopathy are reviewed. This document provides a general framework for cardiovascular management of aortopathy in children, while allowing for modification based on the personal and familial characteristics of each child and family.

Bullous Lung Disease in Turner Syndrome: An Underrecognized Comorbidity?

Congenital pulmonary anomalies in Turner syndrome (TS) are rarely reported. Herein, we describe a female with TS who presented with emphysema in infancy and developed pulmonary hypertension in adulthood. A 4-month-old patient presented with recurrent emesis and failure to thrive. Diagnostic testing indicated cardiomegaly and echocardiogram revealed abnormalities including left aortic arch with aberrant right subclavian artery, aortic coarctation, and left ventricular (LV) dysfunction. At 19-months, she underwent surgical intervention through a lateral thoracotomy which exposed numerous small air-filled blebs over the left lung. She had persistent LV dysfunction postoperatively. At 12-years-old, genetic testing revealed 45,X/46,Xidic(Y)(q11.22) and she subsequently received routine treatment for Turner syndrome. At 23-years-old, this patient presented to the emergency department with dyspnea, worsening cough, and edema. Echocardiogram demonstrated a reduced LVEF, aortic valve insufficiency, and pulmonary artery (PA) hypertension. CT chest showed multiple apical blebs and cardiac catheterization demonstrated pulmonary hypertension. She was treated with intravenous diuresis and cessation of Humira, which normalized LVEF and reduced PA pressure. Repeat cardiac catheterization 6 months later indicated elevated LVEDP, pulmonary vascular resistance, and mean PA pressures. Altered lymphatic drainage in utero of patients with TS may lead to emphysematous changes in the lungs. These changes may not raise concern in infancy but can possibly contribute to cardiopulmonary pathology in the future. We recommend ongoing routine care to monitor for acquired cardiopulmonary co-morbidities. Bullous lung disease may occur due to altered lymphatic drainage in patients with TS and may be a risk factor for developing or contributing to pulmonary hypertension.

Prevalence of hepatic steatosis and fibrosis in Turner syndrome: A prospective case-control study.

BACKGROUND AND AIMS: Abnormal liver chemistries are common in Turner syndrome (TS). Guidelines suggest that TS patients undergo annual screening of liver enzymes, but the role of non-invasive screening for steatosis and fibrosis is not clearly defined. We compared the prevalence of hepatic steatosis and fibrosis among TS patients to healthy controls using ultrasound with shear-wave elastography (SWE) and assessed for risk factors associated with steatosis and fibrosis in TS. METHODS: Prospective case-control study of TS versus control patients from 2019 to 2021. All patients underwent abdominal ultrasound with doppler and SWE to assess hepatic fibrosis and steatosis. Risk factors were compared between TS and controls, as well as within the TS group. RESULTS: A total of 55 TS and 50 control patients were included. Mean age was 23.6 years vs. 24.6 years in the control group (p = .75). TS patients had significantly more steatosis (65% vs. 12%, stage 1 vs. 0, p < .0001) and fibrosis (39% vs. 2%, average Metavir F2 vs. F0, p < .00001) than controls. These findings remained significant after adjusting for body mass index (BMI) (p < .01). GGT is more sensitive than AST or ALT in identifying these changes. CONCLUSION: TS is associated with an increased prevalence of hepatic steatosis and fibrosis compared to healthy controls. Our findings suggest that serum GGT and ultrasound with SWE may help identify TS patients with liver disease. Early risk factor mitigation including timely oestrogen replacement, weight control, normalization of lipids and promoting multidisciplinary collaboration should be encouraged.

Siblings with profound connective tissue disease: First report of biallelic TGFBR1-related Loeys-Dietz syndrome.

Heterozygous missense variants in TGFBR1, encoding one subunit of the transforming growth factor-beta receptor, are a well-established cause of Loeys-Dietz syndrome (LDS)-an autosomal dominant disorder with variable phenotypic expression. Patients with LDS have compromised connective tissues that can result in life-threatening arterial aneurysms, craniosynostosis, characteristic craniofacial and skeletal anomalies, skin translucency, and abnormal wound healing. We report a full sibship with a biallelic type of TGFBR1-related disease. Each born at 38 weeks had aortic root dilation, congenital diaphragmatic hernia (CDH), skin translucency, and profound joint laxity at birth. Both had progressive dilation of the aorta and recurrence of a diaphragmatic defect after plication early in infancy. Patient 1 died at 66 days of age and Patient 2 is alive at 4 years and 4 months of age with multiple morbidities including cystic lung disease complicated by recurrent pneumothoraces and ventilator dependence, craniosynostosis, cervical spine instability, progressive dilation of the aorta, worsening pectus excavatum, large lateral abdominal wall hernia, and diffuse aortic ectasia. Fibroblasts cultured from Patient 2 showed decreased TGF-ß responsiveness when compared to control fibroblasts, consistent with previous observations in cells from individuals with autosomal dominant LDS. Whole genome copy number evaluation and sequencing for both patients including their parents as reference revealed compound heterozygous variants of uncertain clinical significance in exon 2 of TGFBR1 (c.239G>A; p.Arg80Gln paternal and c.313C>G; p.His105Asp maternal) in both siblings in trans. Each parent with their respective variant has no apparent medical issues and specifically no LDS characteristics. Neither of these variants have been previously reported. Thousands of patients have been diagnosed with LDS-an established autosomal dominant disease. These siblings represent the first reports of biallelic TGFBR1-related LDS and expand the differential diagnosis of CDH.

Derivation and Validation of a General Predictive Model for Long Term Risks for Mortality and Invasive Interventions in Congenital and Acquired Cardiac Conditions Encountered in the Young.

Accurate prognostic assessment is a key driver of clinical decision making in heart disease in the young (HDY). This investigation aims to derive, validate, and calibrate multivariable predictive models for time to surgical or catheter-mediated intervention (INT) and for time to death in HDY. 4108 unique subjects were prospectively and consecutively enrolled, and randomized to derivation and validation cohorts. Total follow-up was 26,578 patient-years, with 102 deaths and 868 INTs. Accelerated failure time multivariable predictive models for the outcomes, based on primary and secondary diagnoses, pathophysiologic severity, age, sex, genetic comorbidities, and prior interventional history, were derived using piecewise exponential methodology. Model predictions were validated, calibrated, and evaluated for sensitivity to changes in the independent variables. Model validity was excellent for predicting mortality and INT at 4 months, 1, 5, 10, and 22 years (areas under receiver operating characteristic curves 0.813-0.915). Model calibration was better for INT than for mortality. Age, sex, and genetic comorbidities were significant independent factors, but predicted outcomes were most sensitive to variations in composite predictors incorporating primary diagnosis, pathophysiologic severity, secondary diagnosis, and prior intervention. Despite 22 years of data acquisition, no significant cohort effects were identified in which predicted mortality and intervention varied by study entry date. A piecewise exponential model predicting survival and freedom from INT is derived which demonstrates excellent validity, and performs well on a clinical sample of HDY outpatients. Objective model-based predictions could educate both patient and provider, and inform clinical decision making in HDY.

The Fontan Udenafil Exercise Longitudinal Trial: Subgroup Analysis.

The Pediatric Heart Network's Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.5 mg twice daily). In this post hoc analysis, we evaluate whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. The effect of udenafil on exercise was evaluated within subgroups defined by baseline characteristics, including peak oxygen consumption (VO2), serum brain-type natriuretic peptide level, weight, race, gender, and ventricular morphology. Differences among subgroups were evaluated using ANCOVA modeling with fixed factors for treatment arm and subgroup and the interaction between treatment arm and subgroup. Within-subgroup analyses demonstrated trends toward quantitative improvements in peak VO2, work rate at the ventilatory anaerobic threshold (VAT), VO2 at VAT, and ventilatory efficiency (VE/VCO2) for those randomized to udenafil compared to placebo in nearly all subgroups. There was no identified differential response to udenafil based on baseline peak VO2, baseline BNP level, weight, race and ethnicity, gender, or ventricular morphology, although participants in the lowest tertile of baseline peak VO2 trended toward larger improvements. The absence of a differential response across subgroups in response to treatment with udenafil suggests that the treatment benefit may not be restricted to specific sub-populations. Further work is warranted to confirm the potential benefit of udenafil and to evaluate the long-term tolerability and safety of treatment and to determine the impact of udenafil on the development of other morbidities related to the Fontan circulation.Trial Registration NCT0274115.

Assessment of Hypertension, Guideline-Directed Counseling, and Outcomes in the ACHD Population.

Guidelines for the diagnosis and treatment of hypertension were published by the American Heart Association (AHA) in 2017. The prevalence of hypertension in adults with congenital heart disease (ACHD) under these guidelines has yet to be characterized. We sought to assess the prevalence, impact, and provider response to hypertension under current guidelines. Data were obtained retrospectively from records of routine clinic visits over a 10 year period. Potential hypertension-related adverse outcomes including stroke, myocardial infarction, surgical intervention for aortic aneurysm, aortic dissection, atrial fibrillation or flutter, cardiac transplantation and death were recorded. The 1070 patients who met inclusion criteria had a mean age of 30.8 ± 10.0 years. The prevalence of hypertension under the 2017 guidelines was 46.6%. Multivariate modeling identified cyanosis, male gender, older age, and overweight/obesity as independent risk factors for hypertension. Guideline-directed management of hypertension in ACHD patients occurred more frequently in ACHD and adult cardiology clinics than in pediatric cardiology clinics (44.1% and 45.1% vs. 24.0%, p < 0.01, respectively). Adverse outcomes were reported in 217 (20%) patients, the most prevalent of which was atrial fibrillation or flutter (11%). Multivariable modelling for any adverse outcome identified older age, hypertension, cyanosis, greater complexity ACHD, and obesity as risk factors. Modifiable risk factors for atherosclerotic cardiovascular disease are common and often under addressed in the ACHD population.

Oxygen Uptake Efficiency Slope Predicts Adverse Outcome Following Atrial Switch Procedure.

Prior to the 1990s, d-TGA was palliated with the atrial switch procedure resulting in a systemic right ventricle associated with significant long-term morbidity and mortality. Determining the optimal timing of heart transplantation (HT) in these patients has been difficult. While cardiopulmonary exercise testing (CPET) is commonly used to try and risk stratify these patients, traditional exercise parameters have lacked the sensitivity and specificity to assess long-term risk. We sought to assess changes in exercise parameters over time in order to determine if any CPET parameter or combination of parameters could reliably identify risk for adverse outcome in this patient group. A retrospective review of serial CPET for 40 patients over 17 years was completed. Patients with adverse event within 6 months prior to CPET were noted. CPET parameters were compared and linear mixed model regression with repeated measures was performed on serial tests for longitudinal assessment. The linear mixed model regression identified OUES indexed to BSA to be the most sensitive parameter in identifying patients at risk of adverse event and became a stronger predictor of adverse event when combined with peak heart rate. CPET is useful in identifying patients with atrial switch at increased risk of adverse outcome. Indexed OUES and peak heart rate are better prognostic indicators than VO2 and VE/VCO2.

Machine Learning-Enabled Fully Automated Assessment of Left Ventricular Volume, Ejection Fraction and Strain: Experience in Pediatric and Young Adult Echocardiography.

BACKGROUND: Left ventricular (LV) volumes, ejection fraction (EF), and myocardial strain have been shown to be predictive of clinical and subclinical heart disease. Automation of LV functional assessment overcomes difficult technical challenges and complexities. We sought to assess whether a fully automated assessment of LV function could be reliably used in children and young adults. METHODS: Fifty normal volunteers (22/28, female/male) were prospectively recruited for research echocardiography. LV volumes, EF, and strain were measured both manually and automatically. An experienced sonographer performed all the manual analysis and recorded the analysis timing. The fully automated analyses were accomplished by 5 groups of observers with different knowledge and medical background. AutoLV and AutoSTRAIN (TomTec) were employed for the fully automated LV analysis. The LV volumes, EF, strain, and analysis time were compared between manual and automated methods, and among the 5 groups of observers. RESULTS: Software-determined endocardial border detection was achievable in all subjects. The analysis times of the experienced sonographer were significantly shorter for AutoLV and AutoSTRAIN than manual analyses (both p < 0.001). Strong correlations were seen between conventional EF and AutoLV (r = 0.8373), and between conventional three view global longitudinal strain (GLS) and AutoSTRAIN (r = 0.9766). The volumes from AutoLV and three view GLS from AutoSTRAIN had strong correlations among different observers regardless of level of expertise. EF from AutoLV analysis had moderately strong correlations among different observers. CONCLUSION: Automated pediatric LV analysis is feasible in normal hearts. Machine learning-enabled image analysis saves time and produces results that are comparable to traditional methods.

Results of the FUEL Trial.

BACKGROUND: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. METHODS: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. RESULTS: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. CONCLUSIONS: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.

Comparison Between Currently Recommended Long-Term Medical Management of Coronary Artery Aneurysms After Kawasaki Disease and Actual Reported Management in the Last Two Decades.

In the 2017 American Heart Association (AHA) Kawasaki disease (KD) guidelines, risk levels (RLs) for long-term management are defined by both maximal and current coronary artery (CA) dimensions normalized as z-scores. We sought to determine the degree to which current recommended practice differs from past actual practice, highlighting areas for knowledge translation efforts. The International KD Registry (IKDR) included 1651 patients with CA aneurysms (z-score > 2.5) from 1999 to 2016. Patients were classified by AHA RL using maximum CA z-score (RL 3 = small, RL 4 = medium, RL 5 = large/giant) and subcategorized based on decreases over time. Medical management provided was compared to recommendations. Low-dose acetylsalicylic acid (ASA) use ranged from 86 (RL 3.1) to 95% (RL 5.1) for RLs where use was "indicated." Dual antiplatelet therapy (ASA + clopidogrel) use ranged from 16% for RL 5.2 to 9% for RL 5.4. Recommended anticoagulation (warfarin or low molecular weight heparin) use was 65% for RL 5.1, while 12% were on triple therapy (anticoagulation + dual antiplatelet). Optional statin use ranged from 2 to 8% depending on RL. Optional beta-blocker use was 2-25% for RL 5, and 0-5% for RLs 3 and 4 where it is not recommended. Generally, past practice was consistent with the latest AHA guidelines, taking into account the flexible wording of recommendations based on the limited evidence, as well as unmeasured patient-specific factors. In addition to strengthening the overall evidence base, knowledge translation efforts may be needed to address variation in thromboprophylaxis management.

Transition Readiness in Teens and Young Adults with Congenital Heart Disease: Can We Make a Difference?

OBJECTIVES: To examine changes in transition readiness (knowledge, self-efficacy, self-management) over time and explore factors associated with transition readiness, including psychosocial quality of life (QOL) and health service utilization in teens/young adults with congenital heart disease. STUDY DESIGN: In a multicenter prospective cohort study, 356 patients, age 14-27 years, completed transition readiness and QOL assessments at routine cardiology visits at baseline and 1-year follow-up. RESULTS: Median patient age was 19.8 years at 1.03 years (IQR 0.98-1.24) following baseline transition readiness assessment. Average knowledge deficit scores decreased at follow-up (P < .0001) and self-efficacy scores increased (P < .0001). Self-management scores increased (P < .0001), but remained low (mean 57.7, 100-point scale). Information was requested by 73% of patients at baseline and was associated with greater increase in knowledge at follow-up (P = .005). Increased knowledge (P = .003) and perceived self-efficacy (P = .01) were associated with improved psychosocial QOL, but not health service utilization at follow-up. Patients who preferred face-to-face information from healthcare providers (47%) vs other information sources were more likely to request information (P < .0001). In patients <18 years old, greater agreement between teen and parental perception of teen's knowledge was associated with greater increase in patient knowledge (P = .02) and self-efficacy (P = .003). CONCLUSION: Transition readiness assessment demonstrated improved knowledge, self-efficacy, and self-management at 1-year follow-up in teens/young adults with congenital heart disease. Improved knowledge and self-efficacy were associated with improved psychosocial QOL. Self-management remained low. Supplemental media for conveying information and greater involvement of parents may be needed to optimize transition readiness.

PIGQ glycosylphosphatidylinositol-anchored protein deficiency: Characterizing the phenotype.

PIGQ (OMIM *605754) encodes phosphatidylinositol glycan biosynthesis class Q (PIGQ) and is required for proper functioning of an N-acetylglucosamine transferase complex in a similar manner to the more established PIGA, PIGC, and PIGH. There are two previous patients reported with homozygous and apparently deleterious PIGQ mutations. Here, we provide the first detailed clinical report of a patient with heterozygous deleterious mutations associated with glycosylphosphatidylinositol-anchored protein (GPI-AP) biosynthesis deficiency. Our patient died at 10 months of age. The rare skeletal findings in this disorder expand the differential diagnosis of long bone radiolucent lesions and sphenoid wing dysplasia. This clinical report describes a new and rare disorder-PIGQ GPI-AP biosynthesis deficiency syndrome.

Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations.

PURPOSE: Smooth muscle dysfunction syndrome (SMDS) due to heterozygous ACTA2 arginine 179 alterations is characterized by patent ductus arteriosus, vasculopathy (aneurysm and occlusive lesions), pulmonary arterial hypertension, and other complications in smooth muscle-dependent organs. We sought to define the clinical history of SMDS to develop recommendations for evaluation and management. METHODS: Medical records of 33 patients with SMDS (median age 12 years) were abstracted and analyzed. RESULTS: All patients had congenital mydriasis and related pupillary abnormalities at birth and presented in infancy with a patent ductus arteriosus or aortopulmonary window. Patients had cerebrovascular disease characterized by small vessel disease (hyperintense periventricular white matter lesions; 95%), intracranial artery stenosis (77%), ischemic strokes (27%), and seizures (18%). Twelve (36%) patients had thoracic aortic aneurysm repair or dissection at median age of 14 years and aortic disease was fully penetrant by the age of 25 years. Three (9%) patients had axillary artery aneurysms complicated by thromboembolic episodes. Nine patients died between the ages of 0.5 and 32 years due to aortic, pulmonary, or stroke complications, or unknown causes. CONCLUSION: Based on these data, recommendations are provided for the surveillance and management of SMDS to help prevent early-onset life-threatening complications.

Newly described recessive MYH11 disorder with clinical overlap of Multisystemic smooth muscle dysfunction and Megacystis microcolon hypoperistalsis syndromes.

We describe a neonatal patient with fixed dilated pupils and pulmonary, bladder, and bowel dysfunction suspicious for the presence of ACTA2 R179 mediated multisystemic smooth muscle dysfunction syndrome. Whole exome sequencing revealed compound heterozygous mutations in MYH11 after ACTA2 specific testing revealed no abnormalities. The child lived until 18 months of age and represents the only reported case of an MYH11 compound heterozygote with widespread smooth muscle dysfunction.

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.).

Myhre syndrome: Clinical features and restrictive cardiopulmonary complications.

Myhre syndrome, a connective tissue disorder characterized by deafness, restricted joint movement, compact body habitus, and distinctive craniofacial and skeletal features, is caused by heterozygous mutations in SMAD4. Cardiac manifestations reported to date have included patent ductus arteriosus, septal defects, aortic coarctation and pericarditis. We present five previously unreported patients with Myhre syndrome. Despite varied clinical phenotypes all had significant cardiac and/or pulmonary pathology and abnormal wound healing. Included herein is the first report of cardiac transplantation in patients with Myhre syndrome. A progressive and markedly abnormal fibroproliferative response to surgical intervention is a newly delineated complication that occurred in all patients and contributes to our understanding of the natural history of this disorder. We recommend routine cardiopulmonary surveillance for patients with Myhre syndrome. Surgical intervention should be approached with extreme caution and with as little invasion as possible as the propensity to develop fibrosis/scar tissue is dramatic and can cause significant morbidity and mortality.

Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy.

Aortopathy can be defined as aortic dilation, aneurysm, dissection, and tortuosity. Familial aortopathy may occur secondary to fibrillin-1 (FBN1) mutations in the setting of Marfan syndrome, or may occur as a result of other genetic defects with different, but occasionally overlapping, phenotypes. Because of the phenotypic overlap and genetic heterogeneity of disorders featuring aortopathy, we developed a next generation sequencing (NGS) assay and comparative genomic hybridization (CGH) array to detect mutations in 10 genes that cause thoracic aortic aneurysms (TAAs). Here, we report on the clinical and molecular findings in 175 individuals submitted for aortopathy panel testing at ARUP laboratories. Ten genes associated with heritable aortopathies were targeted using hybridization capture prior to sequencing. NGS results were analyzed, and variants were confirmed using Sanger sequencing. Array CGH was used to detect copy-number variation. Of 175 individuals, 18 had a pathogenic mutation and 32 had a variant of uncertain significance (VUS). Most pathogenic mutations (72%) were identified in FBN1. A novel large SMAD3 duplication and FBN1 deletion were identified. Over half who had TAAs or other aortic involvement tested negative for a mutation, suggesting that additional aortopathy genes exist. We anticipate that the clinical sensitivity of at least 10.3% will rise with VUS reclassification and as additional genes are identified and included in the panel. The aortopathy NGS panel aids in the timely molecular diagnosis of individuals with disorders featuring aortopathy and guides proper treatment.

Lifetime cardiac reinterventions following the Fontan procedure.

Patients with single ventricle physiology face significant morbidity and mortality following the Fontan procedure resulting in the need for additional cardiac reinterventions. Online patient education resources provide limited information on the reinterventions performed in single ventricle patients following the Fontan procedure. We sought to determine cardiac surgical and percutaneous reintervention rates and factors affecting reinterventions following the Fontan procedure. Databases from a single tertiary care center were retrospectively reviewed for all patients who underwent a Fontan procedure between 1978 and 2002. The number and type of cardiac surgical and percutaneous interventions following the Fontan procedure were determined, and relationships between need for reintervention and clinical variables were sought. A total of 91 patients (55 males) underwent the Fontan procedure at a median age of 5.50 years (IQR: 3.33-9.50 years). Median age at last follow-up, death, or transplant was 21.89 years (IQR: 10.87-25.51 years). Following the Fontan procedure, 60 (66%) patients required an additional 144 median sternotomies and 61 (67%) required 139 percutaneous cardiac interventions. Pacemaker system placement/replacement was the most common intervention following the Fontan procedure. The median time to first cardiac surgery following the Fontan was 1.96 years (IQR: 0.06-8.42 years) while the median time to the first percutaneous intervention was 7.63 years (IQR: 0.65-15.89 years). Families of single ventricle patients should be counseled on the likelihood of requiring additional cardiac interventions following the Fontan procedure.