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.

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.

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.

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.

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.

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 adult congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that early onset complications of BAV (EBAV) are driven by specific impactful genetic variants. We analyzed whole exome sequences (WES) to identify rare coding variants that contribute to BAV disease in 215 EBAV families. Predicted pathogenic variants of causal genes were present in 111 EBAV families (51% of total), including genes that cause BAV (8%) or heritable thoracic aortic disease (HTAD, 17%). After appropriate filtration, we also identified 93 variants in 26 novel 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 contribute to early onset complications of BAV disease.

Bicuspid Aortic Valve Disease With Early Onset Complications: Characteristics And Aortic Outcomes.

Bicuspid aortic valve (BAV) is the most common congenital heart malformation in adults but can also cause childhood-onset complications. In multicenter study, we found that adults who experience significant complications of BAV disease before age 30 are distinguished from the majority of BAV cases that manifest after age 50 by a relatively severe clinical course, with higher rates of surgical interventions, more frequent second interventions, and a greater burden of congenital heart malformations. These observations highlight the need for prompt recognition, regular lifelong surveillance, and targeted interventions to address the significant health burdens of patients with early onset BAV complications.

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.

Impact of pregnancy on the cardiac health of women with prior surgeries for pulmonary valve anomalies.

OBJECTIVE: We assessed the impact of pregnancy on long-term cardiac outcomes in women with prior surgery for congenital pulmonary valve anomalies. STUDY DESIGN: Data on all reproductive age women with prior pulmonary valve repair or replacement, cared for at a tertiary institution over a 10-year period, were analyzed. Kaplan-Meier curves and proportional hazards models were estimated to assess the impact of pregnancy and multiparity on a composite long-term adverse outcome defined as death, heart failure, or unanticipated cardiac surgery. Peripartum cardiac complications were also assessed. RESULTS: Thirty-three parous and 20 nulliparous, nonpregnant controls with primary pulmonary valve replacement or repair were identified. Among the parous women, there were 95 pregnancies (median, 3.0; 1-10) resulting in 81 live births. Peripartum cardiac complications occurred in 28 (29.8%; 95% confidence interval, 20.4-39.2) of the pregnancies. A composite adverse long-term cardiac outcome occurred in 17 of 33 parous women, over 417 person-years (4 per 100 person-years) and 1 of 20 nulliparous women over 258 person-years (0.4 per 100 person-years); women with pregnancies were more likely at any point in time to have a composite long-term adverse cardiac outcome compared with nulliparous controls. Women with 2 or more pregnancies were more likely to have a composite adverse cardiac outcome than those with less than 2 pregnancies (hazard ratio, 8.8; 95% confidence interval, 1.5-50.3). CONCLUSION: Peripartum cardiac complications are common in women with prior pulmonary valve repair or replacement. Pregnancy appears to increase the risk of long-term adverse cardiac outcomes in these patients when compared with nulliparous controls.

Rare Genomic Copy Number Variants Implicate New Candidate Genes for Bicuspid Aortic Valve.

Bicuspid aortic valve (BAV), the most common congenital heart defect, is a major cause of aortic valve disease requiring valve interventions and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications (EBAV) to sporadic late onset disease. Rare genomic copy number variants (CNVs) have previously been implicated in the development of BAV and thoracic aortic aneurysms. We determined the frequency and gene content of rare CNVs in EBAV probands (n = 272) using genome-wide SNP microarray analysis and three complementary CNV detection algorithms (cnvPartition, PennCNV, and QuantiSNP). Unselected control genotypes from the Database of Genotypes and Phenotypes were analyzed using identical methods. We filtered the data to select large genic CNVs that were detected by multiple algorithms. Findings were replicated in cohorts with late onset sporadic disease (n = 5040). We identified 34 large and rare (< 1:1000 in controls) CNVs in EBAV probands. The burden of CNVs intersecting with genes known to cause BAV when mutated was increased in case-control analysis. CNVs intersecting with GATA4 and DSCAM were enriched in cases, recurrent in other datasets, and segregated with disease in families. In total, we identified potentially pathogenic CNVs in 8% of EBAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV.