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

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

Surgical management of pediatric renovascular hypertension and midaortic syndrome at a single-center multidisciplinary program.

OBJECTIVE: To evaluate the outcomes of various surgical approaches in the treatment of renovascular hypertension and midaortic syndrome (MAS) in children. METHODS: We performed a retrospective medical record review of patients who had undergone surgery for renovascular hypertension from 2010 to 2018 at our center under the care of a multidisciplinary team. The operative interventions included mesenteric artery growth improves circulation (MAGIC), tissue expander-stimulated lengthening of arteries (TESLA), aortic bypass using polytetrafluorethylene, renal artery reimplantation, and autotransplantation. The MAGIC procedure uses the meandering mesenteric artery as a free conduit for aortic bypass. The TESLA procedure is based on lengthening the normal distal aorta and iliac arteries by gradual filling of a retroaortic tissue expander for several weeks, followed by resection of the stenotic aorta and subsequent primary reconstruction. RESULTS: A total of 39 patients were identified, 10 with isolated renal artery stenosis, 26 with MAS, and 3 with systemic inflammatory vasculitis. The median age at presentation and surgery was 6.4 years (range, 0-16.3 years) and 9.3 years (range, 0-9.2 years), respectively. The MAS-associated syndromes included neurofibromatosis type 1 (15.4%) and Williams syndrome (5.1%), although most cases were idiopathic. At surgery, 33.3% had had stage 1 hypertension (HTN), 53.8% stage 2 HTN, and 12.8% normal blood pressure with a median of three antihypertensive medications. Follow-up of 37 patients at a median of 2.5 years demonstrated normal blood pressure in 86.1%, stage 1 HTN in 8.3%, and stage 2 HTN in 5.6%, with a median of one antihypertensive medication for the entire cohort. CONCLUSIONS: The patterns of vascular involvement leading to renovascular hypertension in children are variable and complex, requiring thoughtful multidisciplinary planning and surgical decision-making. The MAGIC and TESLA procedures provide feasible approaches for aortic bypass and reconstruction using autologous tissues and will result in normalization of blood pressure in 85% of children 2.5 years after surgery.

Intraperitoneal corticosteroids for recurrent ascites in patients with Fontan circulation: Initial clinical experience.

Individuals with single-ventricle congenital heart disease who are palliated to a Fontan circulation are at risk for heart failure and liver disease, with recurrent ascites being a potentially debilitating cause of late morbidity. Although ascites associated with heart failure or liver failure is usually characterized by a high serum-ascites albumin gradient (SAAG), we have observed multiple instances of ascites in Fontan patients with low SAAG, suggesting an inflammatory process. We present three cases in which recalcitrant ascites severely and adversely impacted the quality of life and describe our initial experience with intraperitoneal corticosteroids in this setting.

Planned vaginal delivery and cardiovascular morbidity in pregnant women with heart disease.

BACKGROUND: Although consensus guidelines on the management of cardiovascular disease in pregnancy reserve cesarean delivery for obstetric indications, there is a paucity of data to support this approach. OBJECTIVE: The objective of the study was to compare cardiovascular and obstetric morbidity in women with cardiovascular disease according to the plan for vaginal birth or cesarean delivery. STUDY DESIGN: We assembled a prospective cohort of women delivering at an academic tertiary care center with a protocolized multidisciplinary approach to management of cardiovascular disease between September 2011 and December 2016. Our practice is to encourage vaginal birth in women with cardiovascular disease unless there is an obstetric indication for cesarean delivery. We allow women attempting vaginal birth a trial of Valsalva in the second stage with the ability to provide operative vaginal delivery if pushing leads to changes in hemodynamics or symptoms. Women were classified according to planned mode of delivery: either vaginal birth or cesarean delivery. We then used univariate analysis to compare adverse outcomes according to planned mode of delivery. The primary composite cardiac outcome of interest included sustained arrhythmia, heart failure, cardiac arrest, cerebral vascular accident, need for cardiac surgery or intervention, or death. Secondary obstetric and neonatal outcomes were also considered. RESULTS: We included 276 consenting women with congenital heart disease (68.5%), arrhythmias (11.2%), connective tissue disease (9.1%), cardiomyopathy (8.0%), valvular disease (1.4%), or vascular heart disease (1.8%) at or beyond 24 weeks' gestation. Seventy-six percent (n = 210) planned vaginal birth and 24% (n = 66) planned cesarean delivery. Women planning vaginal birth had lower rates of left ventricular outflow tract obstruction, multiparity, and preterm delivery. All women attempting vaginal birth were allowed Valsalva. Among planned vaginal deliveries 86.2% (n = 181) were successful, with a 9.5% operative vaginal delivery rate. Five women underwent operative vaginal delivery for the indication of cardiovascular disease without another obstetric indication at the discretion of the delivering provider. Four of these patients tolerated trials of Valsalva ranging from 15 to 75 minutes prior to delivery. Adverse cardiac outcomes were similar between planned vaginal birth and cesarean delivery groups (4.3% vs 3.0%, P = 1.00). Rates of postpartum hemorrhage (1.9% vs 10.6%, P < .01) and transfusion (1.9% vs 9.1%, P = .01) were lower in the planned vaginal birth group. There were no differences in adverse cardiac, obstetric, or neonatal outcomes in the cohort overall or the subset of women with high-risk cardiovascular disease or a high burden of obstetric comorbidity. CONCLUSION: These findings suggest that cesarean delivery does not reduce adverse cardiovascular outcomes and lend support to a planned vaginal birth for the majority of women with cardiovascular disease including those with high-risk disease.

Creatinine versus cystatin C to estimate glomerular filtration rate in adults with congenital heart disease: Results of the Boston Adult Congenital Heart Disease Biobank.

BACKGROUND: Glomerular filtration rate is a key physiologic variable with a central role in clinical decision making and a strong association with prognosis in diverse populations. Reduced estimated glomerular filtration rate (eGFR) is common among adults with congenital heart disease (ACHD). METHODS: We conducted a prospective cohort study of outpatient ACHD ≥18 years old seen in 2012-2017. Creatinine and cystatin C were measured; eGFR was calculated using either the creatinine or cystatin C Chronic Kidney Disease-Epidemiology Collaboration equation (CKD-EPICr and CKD-EPICysC, respectively). Survival analysis was performed to define the relationship between eGFR and both all-cause mortality and a composite outcome of death or nonelective cardiovascular hospitalization. RESULTS: Our cohort included 911 ACHD (39 ±â€¯14 years old, 49% female). Mean CKD-EPICr and CKD-EPICysC were similar (101 ±â€¯20 vs 100 ±â€¯23 mL/min/1.73 m2), but CKD-EPICr estimates were higher for patients with a Fontan circulation (n = 131, +10 ±â€¯19 mL/min/1.73 m2). After mean follow-up of 659 days, 128 patients (14.1%) experienced the composite outcome and 31 (3.4%) died. CKD-EPICysC more strongly predicted all-cause mortality (eGFR <60 vs >90 mL/min/1.73 m2: CKD-EPICysC unadjusted HR = 20.2 [95% CI 7.6-53.1], C-statistic = 0.797; CKD-EPICr unadjusted HR = 4.6 [1.7-12.7], C-statistic = 0.620). CKD-EPICysC independently predicted the composite outcome, whereas CKD-EPICr did not (CKD-EPICysC adjusted HR = 3.0 [1.7-5.3]; CKD-EPICr adjusted HR = 1.5 [0.8-3.1]). Patients reclassified to a lower eGFR category by CKD-EPICysC, compared with CKD-EPICr, were at increased risk for the composite outcome (HR = 2.9 [2.0-4.3], P < .0001); those reclassified to a higher eGFR class were at lower risk (HR = 0.5 [0.3-0.9], P = .03). CONCLUSIONS: Cystatin C-based eGFR more strongly predicts clinical events than creatinine-based eGFR in ACHD. Creatinine-based methods appear particularly questionable in the Fontan circulation.

Three-generation family with novel contiguous gene deletion on chromosome 2p22 associated with thoracic aortic aneurysm syndrome.

Latent transforming growth factor binding proteins (LTBP) are a family of extracellular matrix glycoproteins that play an important role in the regulation of transforming growth factor beta (TGF-ß) activation. Dysregulation of the TGF-ß pathway has been implicated in the pathogenesis of inherited disorders predisposing to thoracic aortic aneurysms syndromes (TAAS) including Marfan syndrome (MFS; FBN1) and Loeys-Dietz syndrome (LDS; TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD2, SMAD3). While these syndromes have distinct clinical criteria, they share clinical features including aortic root dilation and musculoskeletal findings. LTBP1 is a component of the TGF-ß pathway that binds to fibrillin-1 in the extracellular matrix rendering TGF-ß inactive. We describe a three-generation family case series with a heterozygous ∼5.1 Mb novel contiguous gene deletion of chromosome 2p22.3-p22.2 involving 11 genes, including LTBP1. The deletion has been identified in the proband, father and grandfather, who all have a phenotype consistent with a TAAS. Findings include thoracic aortic dilation, ptosis, malar hypoplasia, high arched palate, retrognathia, pes planus, hindfoot deformity, obstructive sleep apnea, and low truncal tone during childhood with joint laxity that progressed to reduced joint mobility over time. While the three affected individuals did not meet criteria for either MFS or LDS, they shared features of both. Although the deletion includes 11 genes, given the relationship between LTBP1, TGF-ß, and fibrillin-1, LTBP1 stands out as one of the possible candidate genes for the clinical syndrome observed in this family. More studies are necessary to evaluate the potential role of LTBP1 in the pathophysiology of TAAS.

Segmental Aortic Stiffness in Children and Young Adults With Connective Tissue Disorders: Relationships With Age, Aortic Size, Rate of Dilation, and Surgical Root Replacement.

BACKGROUND: Aortic diameter is an imperfect predictor of aortic complications in connective tissue disorders (CTDs). Novel indicators of vascular phenotype severity such as aortic stiffness and vertebral tortuosity index have been proposed. We assessed the relation between aortic stiffness by cardiac MRI, surgical root replacement, and rates of aortic root dilation in children and young adults with CTDs. METHODS AND RESULTS: Retrospective analysis of cardiac MRI data on children and young adults with a CTD was performed to derive aortic stiffness measures (strain, distensibility, and ß-stiffness index) at the aortic root, ascending aorta, and descending aorta. Vertebral tortuosity index was calculated as previously described. Rate of aortic root dilation before cardiac MRI was calculated as change in echocardiographic aortic root diameter z score per year. In 83 CTD patients (median age, 24 years; range, 1-55; 17% <18 years of age; 60% male), ascending aorta distensibility was reduced in comparison with published normative values: median z score, -1.93 (range, -8.7 to 1.3; P<0.0001 versus normals). Over a median follow-up period of 2.7 years, there were no aortic dissections or deaths, but 16 of 83 (19%) patients underwent surgical aortic root replacement. In multivariable analysis, lower aortic root strain (P=0.05) and higher vertebral tortuosity index (P=0.01) were independently associated with aortic root replacement. Lower ascending aorta strain (P=0.02) was associated with a higher rate of aortic root dilation. CONCLUSIONS: Higher aortic stiffness is associated with higher rates of surgical aortic replacement and aortic root dilation in children and young adults with CTDs.

Distinct effects of losartan and atenolol on vascular stiffness in Marfan syndrome.

We conducted a randomized, double-blind trial of losartan (100 mg QD) versus atenolol (50 mg QD) for 6 months in adults with Marfan syndrome. Carotid-femoral pulse wave velocity (PWV), central augmentation index (AIx), aortic diameter and left ventricular (LV) function were assessed with arterial tonometry and echocardiography. Thirty-four subjects (18 female; median age 35 years, IQR 27, 45) were randomized. Central systolic and diastolic blood pressure decreased comparably with atenolol and losartan (p = 0.64 and 0.31, respectively); heart rate decreased with atenolol (p = 0.02), but not with losartan. PWV decreased in patients treated with atenolol (-1.15 ± 1.68 m/s; p = 0.01), but not in those treated with losartan (-0.22 ± 0.59 m/s; p = 0.15; between-group difference p = 0.04). In contrast, AIx decreased in the losartan group (-9.6 ± 8.6%; p < 0.001) but not in the atenolol group (0.9 ± 6.2%, p = 0.57; between-group difference p < 0.001). There was no significant change in aortic diameters or LV ejection fraction in either treatment group. In adults with Marfan syndrome, 6 months of treatment with atenolol improves PWV, whereas losartan reduces the AIx. By improving vascular stiffness via distinct mechanisms of action, there is physiologic value to considering the use of both medications in individuals with Marfan syndrome.

The Impact of Pregnancy in Patients with Thoracic Aortic Disease: Epidemiology, Risk Assessment, and Management Considerations.

Thoracic aortic disease (TAD) poses substantial risks during pregnancy, particularly for women with genetic conditions such as Marfan syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome. This review examines the epidemiology, risk assessment, and management of TAD in pregnancy. Preconception counseling is vital considering the hereditary nature of TAD and potential pregnancy-related complications. Genetic testing and imaging surveillance aid in risk assessment. Medical management, including beta-blockade and strict blood pressure control, is essential throughout pregnancy. Surgical interventions may be necessary in certain cases. A multidisciplinary approach involving cardiologists, obstetricians, cardiac surgeons, anesthesiologists, and other specialists with expertise in cardio-obstetrics is essential for optimal outcomes. Patient education and shared decision-making play vital roles in navigating the complexities of TAD in pregnancy and improving maternal and neonatal outcomes.

Genetic syndromes associated with congenital heart disease.

Congenital heart defects are the most common type of birth defect, affecting 1% of live births. The underlying cause of congenital heart disease is frequently unknown. However, advances in human genetics and genome technologies have helped expand congenital heart disease pathogenesis knowledge during the last few decades. When the cardiac defects are part of a genetic syndrome, they are associated with extracardiac conditions and require multidisciplinary care and surveillance. Some genetic syndromes can have subtle clinical findings and remain undiagnosed well into adulthood. Each syndrome is associated with specific congenital and acquired comorbidities and a particular clinical risk profile. A timely diagnosis is essential for risk stratification, surveillance of associated conditions and counselling, particularly during family planning. However, genetic testing and counselling indications can be challenging to identify in clinical practice. This document intends to provide an overview of the most clinically relevant syndromes to consider, focusing on the phenotype and genotype diagnosis, outcome data, clinical guidelines and implications for care.

Genetically Triggered Thoracic Aortic Disease: Who Should be Tested?

Up to 25% of patients with thoracic aortic disease have an underlying Mendelian pathogenic variant. This is a heterogeneous group of disorders known as heritable thoracic aortic diseases (HTAD). Diagnosing associated pathogenic gene variants and syndromes is critical, as the underlying genetics have an implication in medical management, surveillance, thresholds for surgical intervention, surgical risk, pregnancy risk, and risk of inheritance by the offspring. Recently released 2022 American College of Cardiology/American Heart Association guidelines for the diagnosis and management of aortic diseases provide specific recommendations to identify patients at risk for heritable conditions and who should undergo genetic testing.

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

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

Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease.

The vascular smooth muscle cell (SMC)-specific isoform of alpha-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including premature onset of coronary artery disease (CAD) and premature ischemic strokes (including Moyamoya disease [MMD]), as well as previously defined TAAD. Sequencing of DNA from patients with nonfamilial TAAD and from premature-onset CAD patients independently identified ACTA2 mutations in these patients and premature onset strokes in family members with ACTA2 mutations. Vascular pathology and analysis of explanted SMCs and myofibroblasts from patients harboring ACTA2 suggested that increased proliferation of SMCs contributed to occlusive diseases. These results indicate that heterozygous ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, including TAAD, premature CAD, ischemic strokes, and MMD. These data demonstrate that diffuse vascular diseases resulting from either occluded or enlarged arteries can be caused by mutations in a single gene and have direct implications for clinical management and research on familial vascular diseases.

Effect of Losartan or Atenolol on Children and Young Adults With Bicuspid Aortic Valve and Dilated Aorta.

Bicuspid aortic valve aortopathy is defined by dilation of the aortic root (AoRt) and/or ascending aorta (AsAo), and increases risk for aortic aneurysm and dissection. The effects of medical prophylaxis on aortic growth rates in moderate to severe bicuspid aortopathy have not yet been evaluated. This was a single-center retrospective study of young patients (1 day to 29 years) with bicuspid aortopathy (AoRt or AsAo z-score ≥ 4 SD, or absolute dimension ≥ 4 cm), treated with either losartan or atenolol. Maximal diameters and BSA-adjusted z-scores obtained from serial echocardiograms were utilized in a mixed linear effects regression model. The primary outcome was the annual rate of change in AoRt and AsAo z-scores during treatment, compared with before treatment. The mean ages (years) at treatment initiation were 14.2 ± 5.1 (losartan; n = 27) and 15.2 ± 4.9 (atenolol; n = 18). Median treatment duration (years) was 3.1 (IQR 2.4, 6.0) for losartan, and 3.7 (IQR 1.4, 6.6) for atenolol. Treatment was associated with decreases in AoRt and AsAo z-scores (SD/year), for both losartan and atenolol (pre- vs post-treatment): losartan/AoRt: +0.06 ± 0.02 vs -0.14 ± 0.03, p < 0.001; losartan/AsAo: +0.20 ± 0.03 vs -0.09 ± 0.05, p < 0.001; atenolol/AoRt: +0.07 ± 0.03 vs -0.02 ± 0.04, p = 0.04; atenolol/AsAo: +0.21 ± 0.04 vs -0.06 ± 0.06, p < 0.001. Treatment was also associated with decreases in absolute growth rates (cm/year) for all comparisons (p ≤ 0.02). Medical prophylaxis reduced proximal aortic growth rates in young patients with at least moderate and progressive bicuspid aortopathy.

Prevalence and Prognostic Association of a Clinical Diagnosis of Depression in Adult Congenital Heart Disease: Results of the Boston Adult Congenital Heart Disease Biobank.

Background In adults with acquired heart disease, depression is common and associated with adverse outcomes. Depression may also be important in adults with congenital heart disease (CHD). Methods and Results We conducted a cohort study of outpatients with CHD, aged ≥18 years, enrolled in a prospective biobank between 2012 and 2017. Clinical data were extracted from medical records. Survival analysis assessed the relationship between depression, defined by a history of clinical diagnosis of major depression, with all-cause mortality and a composite outcome of death or nonelective cardiovascular hospitalization. A total of 1146 patients were enrolled (age, 38.5±13.8 years; 49.6% women). Depression had been diagnosed in 219 (prevalence=19.1%), and these patients were more likely to have severely complex CHD (41.3% versus 33.7%; P=0.028), cyanosis (12.1% versus 5.7%; P=0.003), and worse functional class (≥II; 33.3% versus 20.4%; P<0.0001), and to be taking antidepressant medication at time of enrollment (68.5% versus 5.7%; P<0.0001). Depression was associated with biomarkers indicative of inflammation (hsCRP [high-sensitivity C-reactive protein], 1.71 [25th-75th percentile, 0.82-4.47] versus 1.10 [0.45-2.40]; P<0.0001) and heart failure (NT-proBNP [N-terminal pro-B-type natriuretic peptide], 190 [92-501] versus 111 [45-264]; P<0.0001). During follow-up of 605±547 days, 137 participants (12.0%) experienced the composite outcome, including 33 deaths (2.9%). Depression was associated with increased risk for both all-cause mortality (multivariable hazard ratio, 3.0; 95% CI, 1.4-6.4; P=0.005) and the composite outcome (multivariable hazard ratio, 1.6; 95% CI, 1.1-2.5; P=0.025), adjusting for age, sex, history of atrial arrhythmia, systolic ventricular function, CHD complexity, and corrected QT interval. Conclusions In adults with CHD, major depression is associated with impaired functional status, heart failure, systemic inflammation, and increased risk for adverse outcomes.

Early and Midterm Outcomes of Valve-Sparing Aortic Root Replacement-Reimplantation Technique.

BACKGROUND: Valve-sparing aortic root replacement (VSARR) is an increasingly popular alternative to traditional aortic root replacement for aortic root aneurysm disease with a normal aortic valve. We evaluated the early and midterm outcomes of VSARR-reimplantation technique (VSARR-RT) done at a single institution over a decade. MATERIALS AND METHODS: We performed a retrospective study of all patients who underwent VSARR-RT between January 2004 and July 2014. RESULTS: A total of 85 patients underwent VSARR-RT. Median time to latest echocardiographic follow-up was 4 years (range: 15-72 months). Total observation time was 491 patient years. Mean age was 44.6 ± 14.3 years, and 13 (15%) were women. Thirty-nine (46%) patients had a connective tissue disorder and 6 (7%) had a bicuspid aortic valve. Thirty-three (39%) patients underwent concomitant procedures, including coronary artery bypass grafting (n = 9, 11%), mitral valve repair (n = 8, 9%), and aortic hemi-arch replacement (n = 7, 8%). There were no operative deaths or in-house mortality and no postoperative strokes. Kaplan-Meier analysis demonstrated survival of 99% (95% confidence interval [CI]: 97-100%) at 2 years and 98% (95% CI: 97-100%) at 8 years. Freedom from reoperation was 95.8% (95% CI: 91.2-100%) at 8 years. Freedom from endocarditis was 100% at 8 years. At the last echocardiographic follow-up, 95% of patients were free of severe aortic regurgitation (AR) and 82% free of moderate AR. Of the four patients who had severe AR, three underwent reoperations and received prosthetic valves and one is being clinically monitored. CONCLUSION: This study reports early and midterm outcomes after VSARR-RT at our institution, including those patients who underwent a VSARR-RT procedure combined with other procedures. Further follow-up remains necessary to determine long-term outcomes.

Relationship of Red Cell Distribution Width to Adverse Outcomes in Adults With Congenital Heart Disease (from the Boston Adult Congenital Heart Biobank).

Red cell distribution width (RDW), a measure of variability in red cell size, predicts adverse outcomes in acquired causes of heart failure. We examined the relation of RDW and outcomes in adults with congenital heart disease. We performed a prospective cohort study on 696 ambulatory patients ≥18years old enrolled in the Boston Adult Congenital Heart Disease Biobank between 2012 and 2016 (mean age 38.7 ± 13.5 years; 49.9% women). The combined outcome was all-cause mortality or nonelective cardiovascular hospitalization. Most patients had moderately or severely complex congenital heart disease (42.5% and 38.5%, respectively). Mean RDW was 14.0 ± 1.3%. RDW >15% was present in 81 patients (11.6%). After median 767days of follow-up, 115 patients sustained the primary combined outcome, including 31 who died. Higher RDW predicted both the combined outcome (hazard ratio [HR] for RDW >15% = 4.5, 95% confidence interval [CI] 3.0 to 6.6; HR per + 1SD RDW = 1.8, 95% CI 1.6 to 2.0, both p <0.0001) and death alone (HR for RDW >15% = 7.1, 95% CI 3.5 to 14.4; HR per + 1SD RDW = 1.8, 95% CI 1.6 to 2.0, both p <0.0001). RDW remained an independent predictor of the combined outcome after adjusting for age, cyanosis, congenital heart disease complexity, ventricular systolic function, New York Heart Association functional class, hemoglobin concentration, mean corpuscular volume, high-sensitivity C-reactive protein and estimated glomerular filtration rate (HR per + 1SD RDW = 1.5, 95% CI 1.2 to 1.9, p <0.0001). RDW also remained an independent predictor of mortality alone after adjustment for age plus each variable individually. In conclusion, elevated RDW is an independent predictor of all-cause mortality or nonelective cardiovascular hospitalization in adults with congenital heart disease. This simple clinical biomarker identifies increased risk for adverse events even among patients with preserved functional status.

Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ≈43% of 35 Families With Midaortic Syndrome.

Midaortic syndrome (MAS) is a rare cause of severe childhood hypertension characterized by narrowing of the abdominal aorta in children and is associated with extensive vascular disease. It may occur as part of a genetic syndrome, such as neurofibromatosis, or as consequence of a pathological inflammatory disease. However, most cases are considered idiopathic. We hypothesized that in a high percentage of these patients, a monogenic cause of disease may be detected by evaluating whole exome sequencing data for mutations in 1 of 38 candidate genes previously described to cause vasculopathy. We studied a cohort of 36 individuals from 35 different families with MAS by exome sequencing. In 15 of 35 families (42.9%), we detected likely causal dominant mutations. In 15 of 35 (42.9%) families with MAS, whole exome sequencing revealed a mutation in one of the genes previously associated with vascular disease (NF1, JAG1, ELN, GATA6, and RNF213). Ten of the 15 mutations have not previously been reported. This is the first report of ELN, RNF213, or GATA6 mutations in individuals with MAS. Mutations were detected in NF1 (6/15 families), JAG1 (4/15 families), ELN (3/15 families), and one family each for GATA6 and RNF213 Eight individuals had syndromic disease and 7 individuals had isolated MAS. Whole exome sequencing can provide conclusive molecular genetic diagnosis in a high fraction of individuals with syndromic or isolated MAS. Establishing an etiologic diagnosis may reveal genotype/phenotype correlations for MAS in the future and should, therefore, be performed routinely in MAS.

Longitudinal Changes in Segmental Aortic Stiffness Determined by Cardiac Magnetic Resonance in Children and Young Adults With Connective Tissue Disorders (the Marfan, Loeys-Dietz, and Ehlers-Danlos Syndromes, and Nonspecific Connective Tissue Disorders).

Aortic stiffness measured by cardiac magnetic resonance (CMR) in connective tissue disorder (CTD) patients has been previously shown to be abnormal and to be associated with adverse aortic outcomes. The rate of increase in aortic stiffness with normal aging has been previously described. However, longitudinal changes in aortic stiffness have not been characterized in CTD patients. We examined longitudinal changes in CMR-derived aortic stiffness in children and young adults with CTDs. A retrospective analysis of 50 children and young adults (median age, 20 years; range, 0.2 to 49; 40% < 18 years old) with a CTD, and with at least 2 CMR examinations (total 152 examinations) over a median duration of 3.9 (1 to 13.2) years was performed. Aortic stiffness measures (strain, distensibility, and ß stiffness index) were calculated on each examination at the aortic root (AoR), ascending aorta, and descending aorta. Longitudinal changes in parameters were analyzed using linear mixed-effects models. Aortic strain and distensibility decreased with age, whereas the ß stiffness index increased at all aortic segments. The average rates of decline in distensibility (x10-3 mm Hg-1 per 10-year increase in age) were 0.7, 1.3, and 1 at the AoR, ascending aorta, and descending aorta, respectively. The rates of decline in distensibility were not associated with the rates of AoR dilation or surgical AoR replacement. In conclusion, on serial CMR measurements in children and young adults with CTDs, aortic stiffness progressively increased with age, with rates of change only slightly higher than those previously reported in healthy adults.