Matrisome and Immune Pathways Contribute to Extreme Vascular Outcomes in Williams-Beuren Syndrome.

BACKGROUND: Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability. METHODS AND RESULTS: We performed genome sequencing on 473 individuals with Williams-Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway-level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome-wide association studies. We show that SVAS severity in Williams-Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes (ACAN and LTBP4) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome-wide association studies for aneurysm, bicuspid aortic valve, or aortic size. CONCLUSIONS: Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta-focused genome-wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.

Long-term surgical outcomes of congenital supravalvular aortic stenosis: a systematic review, meta-analysis and microsimulation study.

OBJECTIVES: Congenital supravalvular aortic stenosis (SVAS) is a rare form of congenital outflow tract obstruction and long-term outcomes are scarcely reported. This study aims to provide an overview of outcomes after surgical repair for congenital SVAS. METHODS: A systematic review of published literature was conducted, including observational studies reporting long-term clinical outcome (>2 years) after SVAS repair in children or adults considering >20 patients. Early risks, late event rates and time-to-event data were pooled and entered into a microsimulation model to estimate 30-year outcomes. Life expectancy was compared to the age-, sex- and origin-matched general population. RESULTS: Twenty-three publications were included, encompassing a total of 1472 patients (13 125 patient-years; pooled mean follow-up: 9.0 (6.2) years; median follow-up: 6.3 years). Pooled mean age at surgical repair was 4.7 (5.8) years and the most commonly used surgical technique was the single-patch repair (43.6%). Pooled early mortality was 4.2% (95% confidence interval: 3.2-5.5%) and late mortality was 0.61% (95% CI: 0.45-0.83) per patient-year. Based on microsimulation, over a 30-year time horizon, it was estimated that an average patient with SVAS repair (mean age: 4.7 years) had an observed life expectancy that was 90.7% (95% credible interval: 90.0-91.6%) of expected life expectancy in the matched general population. The microsimulation-based 30-year risk of myocardial infarction was 8.1% (95% credible interval: 7.3-9.9%) and reintervention 31.3% (95% credible interval: 29.6-33.4%), of which 27.2% (95% credible interval: 25.8-29.1) due to repair dysfunction. CONCLUSIONS: After surgical repair for SVAS, 30-year survival is lower than the matched-general-population survival and the lifetime risk of reintervention is considerable. Therefore, lifelong monitoring of the cardiovascular system and in particular residual stenosis and coronary obstruction is recommended.

Lethal Fungal Aortitis In Surgically Corrected Supravalvular Aortic Stenosis In A Child With Williams Syndrome.

Williams syndrome (WS), is a multisystem disorder occurring in 1 in 10,000 live births with supravalvular aortic stenosis (SVAS) being the most common cardiovascular manifestation. We present the case of a 2.5 years old male, a known case of WS who presented with cognitive delay, a history of right-sided stroke and left hemiplegia. Echocardiography revealed severe SVAS with a gradient of 105 mmHg. The diameter of the Sino tubular junction was 4 mm. Computerized tomography angiogram showed diffuse stenosis of ascending aorta with intraluminal thrombus. At surgery, the ascending aorta was augmented with autologous pericardial patches and end-to-end anastomosis of the proximal and distal aorta completed the reconstruction. The patient was discharged in a stable condition. He presented 6 weeks post-op with a pulsating pseudoaneurysm through the sternal wound. Emergency surgery with the removal of fungal vegetation and reconstruction of the ascending aorta was performed. He expired due to fungal sepsis a week later.

Williams Syndrome: Supravalvar Aortic, Aortic Arch, Coronary and Pulmonary Arteries: Is Comprehensive Repair Advisable and Achievable?

Williams syndrome, and various elastin protein mediated arteriopathies, presents a clinical challenge to pediatric cardiovascular specialists. In the severest phenotypes, multilevel obstruction to the systemic and pulmonic arterial systems result in biventricular dysfunction which can be imminently life-threatening. As a longstanding, quaternary referral center for complex pulmonary arteriopathies and pediatric connective tissue disease, Stanford Medicine Children's Health has developed a sizeable experience managing these patients. This manuscript is a summary of our current strategies, with a focus on our surgical techniques, peri-procedural considerations on timing and staging of various interventions, and long-term results.

Long-term Surgical Outcomes of Supravalvar Aortic Stenosis: Modified Simple Sliding Aortoplasty.

This study investigated long-term outcomes and factors associated with reoperations in patients who underwent surgical repair of congenital supravalvar aortic stenosis (SVAS). A total of 39 consecutive patients who underwent congenital SVAS repair from 1999 through 2018 were included. Aortic root geometry was evaluated by measuring the ratio of the sinotubular junction diameter to the aortic annulus diameter (STJ/AVA) on echocardiography and proportion of intercommissural distance (ICD) of each sinus on computed tomography. The median age and weight at the time of operation were 4.3 years and 16.9 kg, respectively. Williams syndrome was associated in 25 patients (64.1%). Modified simple sliding aortoplasty (MSSA) was mostly used (n = 35, 89.7%). The median follow-up duration was 9.5 years. There were no early deaths and 1 late death. Overall survival rate was 97.0% at 15 years. There were 7 reoperations during follow-up. Freedom from reoperation for left ventricular outflow tract obstruction and all-cause reoperation were 91.9% and 80.4%, respectively. Age younger than 2 years at initial repair were associated with all-cause reoperation in the univariable analysis. In 35 patients who underwent MSSA, the degree of aortic regurgitation was equal to or less than mild in all patients during follow-up. Their median STJ/AVA on postoperative echocardiography was 0.95 (0.84-1.02). SVAS repair with MSSA provided excellent long-term survival with well-preserved aortic valve competence. Age younger than 2 years at initial repair might be associated with reoperation.

An infant with suspected missed diagnosis of Williams syndrome failed weaning off CPB after surgical correction of pulmonary stenosis: a case report and literature review.

Williams syndrome (WS) is a rare congenital developmental disorder caused by the deletion of between 26 and 28 genes on chromosome 7q11.23. For patients with WS, in view of the particularity of the supravalvular aortic stenosis, choosing appropriate arterial cannula, maintaining higher perfusion pressure as well as strengthening myocardial protection during cardiopulmonary bypass (CPB) is essential to the clinical outcome. Here, we report a child with pulmonary artery valvular stenosis who failed to wean off CPB because of malignant arrhythmias and cardiac insufficiency after surgical correction of pulmonary valvular stenosis. With the assistance of extracorporeal membrane oxygenation (ECMO), emergency cardiac catheterization revealed supravalvular aortic stenosis (SVAS), which suggests a suspected missed diagnosis of WS. Finally, under the support of ECMO, the cardiac function gradually returned to normal, and the child was discharged 23 days after surgery.

Surgical Repair of Supravalvar Aortic Stenosis in Association With Transverse and Proximal Descending Aortic Abnormalities.

BACKGROUND: Supravalvar aortic stenosis (SVAS) may be an isolated defect of the proximal ascending aorta. However, more severe cases have extension of the arteriopathy into the transverse and proximal descending aorta. The purpose of this study was to review our experience with SVAS with and without aortic arch arteriopathy. METHODS: This was a retrospective review of 58 patients who underwent surgical repair of SVAS. The median age at repair was 18 months. A total of 37 patients had Williams syndrome. A total of 31 (53%) patients had associated peripheral pulmonary artery stenosis and 23 (39%) had coronary artery ostial stenosis (CAOS). RESULTS: A total of 37 of 58 (64%) patients had surgical repair of SVAS without the need for arch intervention while 21 (36%) patients had repair of the distal aortic arch. There were 3 (5.2%) operative deaths, 2 of whom had aortic arch involvement and one without arch involvement. There were 2 deaths after discharge from the hospital. Patients who needed arch surgery were more likely to have severe arch gradients compared to those without arch involvement (71% vs 30%, P < .05), were more likely to undergo concomitant procedures for peripheral pulmonary artery stenosis or CAOS (90% vs 62%, P < .05), and to have Williams syndrome (86% vs 51%, P < .05). CONCLUSIONS: More than one-third of patients who had SVAS repair at our institution had procedures directed at the transverse or proximal descending aorta. Patients with arch involvement had more severe arch obstruction, required more concomitant procedures, and were more likely to have Williams syndrome.

A rare combination of cardiovascular anomaly: Aortic stenosis at sinotubular junction level and discontinuity of right coronary artery.

BACKGROUND: Supravalvular aortic stenosis (SVAS) and congenital discontinuity of right coronary artery are both rare congenital cardiovascular abnormalities. This is the first case report about SVAS that occurred with the congenital discontinuity of right coronary artery. MATERIALS & METHODS: A 3-month-old female infant presented with aortic stenosis at sinotubular level and congenital right coronary artery deficiency. According to cardiovascular CT results, Doty technique was adopted to restore the aortic root geometry under cardiopulmonary bypass. An angioplasty was performed to establish right coronary blood flow at the same time. The patient had no abnormal cardiac symptoms after surgery. The postoperative echocardiogram revealed a normal laminar flow of the right coronary artery into the right coronary sinus, normal aortic blood flow and normal myocardial functions. DISCUSSION: SVAS is characterized by the stenosis of the lumen of the ascending aorta above the aortic valve. Congenital discontinuity of RCA is probably related to dysplasia or congenital occlusion of the RCA during the development of embryo. This kind of malformation may lead to the deficiency of blood supply in sinoatrial and atrioventricular node, eventually causing their dysfunction, which usually leads to arrhythmias as the main manifestations. Angioplasty can improve blood supply of the heart without increasing the risk of major complications, and perioperative prognosis revealed good. This case image also suggested that cardiovascular CT can provide excellent visualization of complex vascular anatomies. CONCLUSIONS: We reported this rare combination of malformations consisted of SVAS and discontinuity of right coronary artery. We treated this patient with the Doty technique and angioplasty procedures.

Supravalvular aortic stenosis repair: surgical training of 2 repair techniques using 3D-printed models.

There are a number of techniques used in the surgical treatment of supravalvular aortic stenosis with excellent results; however, junior surgeons' experience may be limited due to its rare nature. Simulation with 3D-printed models provides a safe platform for surgeons to rehearse surgical techniques prior to patient application but must replicate all features of surgical anatomy. Here, we describe how software manipulation can be used to accurately reproduce the surgical anatomy in supravalvular aortic stenosis and be used to train surgeons in 2 different techniques.

Midterm Results and Predictors for the Postoperative Vascular Stenosis of Supravalvular Aortic Stenosis.

This study reviewed the midterm outcomes of supravalvular aortic stenosis (SVAS) repair and determined the risk factors associated with postoperative aortic or pulmonary stenosis. We retrospectively reviewed 225 patients who underwent surgical correction of SVAS from 2010 to 2019. A total of 178 (79.1%), 44 (19.6%) and 3 (1.3%) patients underwent McGoon, Doty, and Brom repair, respectively. The median age at surgery was 2.2 years (interquartile range, 1.2-4.4). The median follow-up time was 3.7 years (interquartile range, 1.9-5.7). Early and late mortality rates were 3.1% and 1.4%, respectively. The overall 5-year survival rate was 97.9%. Eleven patients received reintervention, including 6 (2.8%) reoperations and 5 (2.3%) balloon dilatations. Higher preoperative pressure gradient at the distal ascending aorta or aortic arch was a risk factor for reintervention (P = 0.04). Rates of mortality and complications were not related to the surgical technique. Eleven patients (5.2%) developed sinotubular junction (STJ) stenosis. Freedom from postoperative distal artery stenosis (DAS) of type II SVAS was significantly lower than that of type I (P < 0.01). Higher preoperative pressure gradient at the STJ (P < 0.01) and concomitant bilateral or peripheral pulmonary artery (PA) stenosis (P < 0.01) were risk factors for postoperative DAS. Postoperative PA stenosis occurred more frequently in patients who received bilateral pulmonary arterioplasty (P < 0.01). Postoperative prognosis of the aortic root after SVAS repair was satisfactory. DAS and PA stenosis were common. The results of bilateral pulmonary arterioplasty were unsatisfactory. The surgical timing and technique for PA stenosis should be carefully considered.

Influence of Surgical Methods on Hemodynamics in Supravalvular Aortic Stenosis: A Computational Hemodynamic Analysis.

We compared differences in the hemodynamic parameters of multiple surgical techniques for supravalvular aortic stenosis (SVAS). A three-dimensional model was reconstructed based on a patient's CT scan. Virtual McGoon, Doty, and Brom repairs were completed using computer-aided design (CAD). Hemodynamic parameters were calculated through computational fluid dynamics (CFD). The velocity profile and wall shear stress (WSS) showed the blood flow pattern. Energy loss (EL) and energy efficiency (EE) were calculated to estimate the cardiac workload. The perioperative blood flow ratio (BFR) of brachiocephalic vessels and coronary arteries was calculated. The preoperative flow velocity was abnormally high (> 5.0 m/s). High WSS was detected at the sinotubular junction (STJ), and its preoperative distribution in the aorta was uneven. High-speed flow disappeared after each of the three operations. The WSS distribution at the aortic root was consistent with the postoperative STJ structure of each operation. EL in the systolic phase decreased postoperatively (Original: 634 mW, McGoon: 218 mW, Doty: 278 mW, Brom: 255 mW). No significant difference in brachiocephalic BFR was detected among the different techniques. A slightly increased coronary BFR (Original: 7.56%, McGoon: 7.99%, Doty: 8.55%, Brom: 8.89%) was detected. McGoon, Doty, and Brom repair each effectively restored stable blood flow and greatly improved EE. The best WSS distribution and coronary blood supply were achieved after Brom repair due to its ability to reconstruct the symmetrical aortic root structure. CFD combined with a virtual operation is a promising method in surgical planning and optimization for SVAS.

Sliding Aortoplasty for Severe Supravalvular Aortic Stenosis After the Lecompte Procedure.

This report describes the case of a 3-year-old boy with supravalvular aortic stenosis after an arterial switch operation in whom the stenosis was successfully repaired using an ascending sliding arch aortoplasty without using a patch. Because patches were avoided, growth of the surgical site is expected. Ascending sliding arch aortoplasty and longitudinal expansion of the pulmonary bifurcation are useful for relieving stenosis and preventing supravalvular aortic stenosis recurrence after an arterial switch operation.

Surgical Techniques in Management of Supravalvular Aortic Stenosis in Children.

BACKGROUND: Multiple techniques exist for the repair of supravalvular aortic stenosis (SVAS), but given the lesion's rarity, analyses comparing the efficacy of each repair have been limited. METHODS: A retrospective review of all children at a single institution who underwent repair of SVAS from June 1995 to May 2019 was performed. Anatomic and physiologic measurements across time points were compared between 2 predominant surgical techniques. Time-to-event outcomes were compared using the log-rank test. RESULTS: SVAS was repaired in 89 patients, by using a single-patch in 31 (35%) and the Doty repair in 58 (65%). Median age at operation was 2.5 years (interquartile range [IQR], 1.0 to 6.8 years), with median follow-up of 5.8 years (IQR, 1.8 to 10.7 years). Reoperation was required in 8 (9%) patients at a median of 1.5 years postoperatively (IQR, 0.3 to 4.8 years). There was 1 death after multiple reinterventions. The change from the preoperative to the postoperative sinotubular junction z-score was greater for patients after Doty repair (median change +2.5; IQR, 1.5, 4.1) than for patients after single-patch repair (median change +0.8; IQR, -0.1, 2.1; P = .001). Freedom from reoperation was longer for patients after Doty repair than after the single-patch technique (P = .008). CONCLUSIONS: The Doty repair provides longer freedom from reoperation after supravalvular aortic stenosis repair compared with a single-patch technique, likely through a greater increase in the sinotubular junction at the time of initial operation.

Cardiovascular abnormalities in patient with Williams-Beuren syndrome.

We present a case of a 42-year-old male patient with severe supravalvular aortic stenosis associated with aortic and mitral valve stenosis as well as an anomalous origin of the right coronary ostium caused by deletion in the q11.23 region of the human chromosome 7 in a patient with Williams-Beuren syndrome.

Long-term Surgical Prognosis of Primary Supravalvular Aortic Stenosis Repair.

BACKGROUND: Supravalvular aortic stenosis (SVAS) represents a heterogeneous group, including Williams syndrome, familial elastin arteriopathy, sporadic cases, and others. This study sought to evaluate long-term outcomes of SVAS repair. METHODS: A total of 87 patients underwent surgical repair of congenital SVAS at Boston Children's Hospital in Boston, Massachusetts, between 1997 and 2017. A total of 41 patients had Williams syndrome, and 46 did not. Of the 46 patients who did not have Williams syndrome, 23 had sporadic SVAS, and 13 had familial elastin arteriopathy. Demographic data and outcomes were reviewed and analyzed from medical records. RESULTS: The median age at operation was 2.9 years. Mean z score of the sinotubular junction was -3.29 ± 1.42 and of the aortic root was -0.09 ± 1.19. A total of 26% (n = 22) patients had coronary ostium stenosis, and 41% (n = 9) of them required patch plasty. Survival rates at 5, 10, and 20 years were all 94.3%. Freedom from left ventricular outflow tract reoperation at 5, 10, and 20 years was 78.5%, 70.3%, and 70.3%, respectively. Freedom from aortic arch reintervention at 5, 10, and 20 years was 98.6%, 94.3%, 89.3%, respectively. In risk factors analysis, age younger than 1 year, z scores of the aortic valve and aortic root, and concomitant right ventricular outflow tract surgical repair were predictive of the need for reoperation and reintervention for left or right ventricular outflow tract obstruction. CONCLUSIONS: Excellent long-term survival rates can be achieved with surgical repair of SVAS. Age younger than 1 year, small aortic valve and aortic root z scores, and concomitant right ventricular outflow tract surgical repair were predictors of reoperation and reintervention.

Congenital combined atresia of the left main coronary with supravalvar aortic stenosis.

Congenital atresia of the left main coronary artery (LMCA) is an exceedingly rare phenomenon, and in the most of them, coronary artery bypass graft is required. We here describe a rare case of this anomaly that concomitantly was associated with supravalvar aortic stenosis and coronary-pulmonary fistula without the presence of conventional collateral circulation in a 16-year-old boy. The patient was admitted to our center with chest pain and dyspnea. Echocardiographic examinations showed supravalvar aortic stenosis with normal function of the aortic valve. Coronary angiography revealed atresia of LMCA with poorly developed left anterior descending coronary artery and well-developed circumflex coronary artery and diagonal artery that perfused by dominant and lengthy right coronary artery. The patient underwent coronary artery bypass grafting with repair of supravalvar aortic stenosis. The postoperative course was uneventful. The 6-month follow-up revealed normal diameter of the ascending aorta with symptomatic relief of preoperative chest complaint.

Combined cutting balloon and conventional balloon angioplasty in a dog with supravalvular pulmonary stenosis.

A 7-year-old Miniature Schnauzer presented with exercise intolerance and easy fatigability. Echocardiography revealed the presence of supravalvular pulmonary stenosis. The peak velocity through the stenosis was 6.4 m/sec, and the interventricular septum was flattened. Cutting balloon angioplasty was designed for the treatment of coronary artery stenosis, which was resistant to conventional balloon angioplasty. Accordingly, the dog underwent cutting balloon angioplasty and conventional balloon dilation. One month after treatment, it showed neither exercise intolerance nor easy fatigability. The ventricular septum flattening disappeared. Five months later, the dog showed an increase in activity. Two years later, the peak velocity through the stenosis decreased to 4.4 m/sec. Neither clinical symptoms nor restenosis was observed. Thus, supravalvular pulmonary stenosis was successfully treated using this combination method. The present case showed that combined cutting balloon and conventional balloon angioplasty is a useful and minimally invasive treatment for supravalvular pulmonary stenosis.