Human Genetics of Semilunar Valve and Aortic Arch Anomalies.

Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.

Strategies for the Surgical Management of Highly Aggressive Williams Syndrome Aortopathy: A Three Case Report.

Severe aortopathy in Williams syndrome can sometimes present with an initial ascending aortic pathology, followed in short order by more distal multilevel obstruction and recurrence requiring reintervention. In this series, an early, comprehensive surgical approach using a combination of various access and perfusion strategies yielded excellent long-term results.

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.

Sudden Cardiac Arrest During a Sedated Cardiac Magnetic Resonance Study in a Nonsyndromic Child with Evolving Supravalvar Aortic Stenosis Due to Familial ELN Mutation.

Supravalvar aortic stenosis (SVAS) is a less common but clinically important form of left ventricular outflow tract obstruction, and commonly associated with Williams syndrome (WS). SVAS outside of WS may also occur sporadically or in a familial form, often with identifiable mutations in the elastin (ELN) gene. While risk of sudden cardiac death in patients with SVAS has been extensively described in the context of WS, less is known about risk in patients with isolated SVAS. We report a case of a nonsyndromic two-year-old boy with evolving manifestations of SVAS who developed sudden cardiac arrest and death during a sedated cardiac magnetic resonance imaging study. A strong family history of SVAS was present and targeted genetic testing identified an ELN gene mutation in the boy's affected father and other paternal relatives. We review risk factors found in the literature for SCA in SVAS patients and utilize this case to raise awareness of the risk of cardiac events in these individuals even in the absence of WS or severe disease. This case also underscores the importance of genetic testing, including targeted panels specifically looking for ELN gene mutations, in all patients with SVAS even in the absence of phenotypic concerns for WS or other genetic syndromes.

Emerging mechanisms of elastin transcriptional regulation.

Elastin provides recoil to tissues that stretch such as the lung, blood vessels, and skin. It is deposited in a brief window starting in the prenatal period and extending to adolescence in vertebrates, and then slowly turns over. Elastin insufficiency is seen in conditions such as Williams-Beuren syndrome and elastin-related supravalvar aortic stenosis, which are associated with a range of vascular and connective tissue manifestations. Regulation of the elastin (ELN) gene occurs at multiple levels including promoter activation/inhibition, mRNA stability, interaction with microRNAs, and alternative splicing. However, these mechanisms are incompletely understood. Better understanding of the processes controlling ELN gene expression may improve medicine's ability to intervene in these rare conditions, as well as to replace age-associated losses by re-initiating elastin production. This review describes what is known about the ELN gene promoter structure, transcriptional regulation by cytokines and transcription factors, and posttranscriptional regulation via mRNA stability and micro-RNA and highlights new approaches that may influence regenerative medicine.

Anesthetic Considerations for Patients With Williams Syndrome.

Williams syndrome (WS) is a relatively rare congenital disorder which manifests across multiple organ systems with a wide spectrum of severity. Cardiovascular anomalies are the most common and concerning manifestations of WS, with supravalvar aortic stenosis present in up to 70% of patients with WS. Although a relatively rare disease, these patients frequently require sedation or anesthesia for a variety of medical procedures. The risk of sudden death in this population is 25 to 100 times that of the general population, with many documented deaths associated with sedation or anesthesia. This increased risk coupled with a disproportionately frequent need for anesthetic care renders it prudent for the anesthesiologist to have a firm understanding of the manifestations of WS. In the following review, the authors discuss pertinent clinical characteristics of WS along with particular anesthetic considerations for the anesthesiologist caring for patients with WS presenting for non-cardiac surgery.

Supravalvar aortic stenosis: Imaging characteristics and associations on multidetector computed tomography angiography.

AIM: To evaluate the imaging features and associations in patients with supravalvar aortic stenosis on multidetector computed tomography (CT) angiography. MATERIALS AND METHODS: We retrospectively reviewed all CT angiography studies performed for evaluation of congenital heart diseases at our institution through the period from January 2014 to June 2020. Cases with supravalvar aortic stenosis were identified and classified as syndromic and nonsyndromic based on history, physical examination, and relevant investigations. The type and extent of vascular involvement and associated cardiovascular abnormalities were characterized. RESULTS: Supravalvar aortic stenosis was identified in 26/3926 (0.66%) patients (22 males and 4 females; Age range: 2 months to 20 years). Discrete stenosis was seen in 14/26 (53.8%) patients, while diffuse involvement of the ascending aorta to varying degrees was seen in the remaining 12 (46.2%) patients. About 15/26 (57.7%) patients had pulmonary involvement at some level, namely, infundibular, valvar, supravalvar, or peripheral pulmonic stenosis while 15/26 (57.7%) patients had coronary arterial involvement either in the form of stenosis, occlusion, or ectasia. Aortic valvular abnormality including thickening, partial fusion, and adhesion of leaflet edges to the sinutubular junction causing reduced coronary inflow was seen in 15/26 (57.7%) patients. Associated ventricular septal defect, patent ductus arteriosus, and mitral valvular prolapse were seen in four (15.4%), five (19.2%), and two (7.7%) patients respectively. CONCLUSION: Supravalvar aortic stenosis is a rare abnormality showing associated pulmonary arterial involvement, coronary arterial involvement, aortic valvular abnormalities, and associated congenital cardiac defects in the majority of cases, which may influence surgical outcomes.

MRI detection of occult venous anomalies in a patient with Williams syndrome: a case report.

Williams syndrome is a multisystem, congenital disorder which is commonly associated with arterial stenoses: supravalvar aortic stenosis and peripheral pulmonary artery stenosis. Venous abnormalities have not been previously reported in children with Williams syndrome. We present a case of a 3-year-old girl with Williams syndrome and diffuse venous ectasia as detected by MRI.

Williams syndrome.

Williams syndrome affects approximately one in 10 000 people and is caused by the deletion of genes on chromosome 7q11.23 which code for elastin. The phenotypic appearance of people with Williams syndrome is well characterized, but there continues to be new genetic and therapeutic discoveries. Patients with Williams syndrome have increased morbidity and mortality under sedation and anesthesia, largely as a result of cardiovascular abnormalities. This review article focuses on new information about Williams syndrome and outlines a structured approach to patients with Williams syndrome in the perioperative period.

Fatal severe coronary artery stenosis in Williams syndrome: decision making using late gadolinium enhancement cardiovascular MRI.

Williams syndrome is a well-recognised congenital disorder characterised by cardiovascular, connective tissue, and central nervous system abnormalities. Coronary artery abnormalities are seen in patients with supravalvar aortic stenosis, but end-stage ischaemic heart disease is rare. We report a case of end-stage ischaemic heart disease due to severe coronary arterial stenosis, highlighting how cardiovascular MRI contributed to the management.

Perioperative morbidity in children with elastin arteriopathy.

BACKGROUND: Children with elastin arteriopathy (EA), the majority of whom have Williams-Beuren syndrome, are at high risk for sudden death. Case reports suggest that the risk of perioperative cardiac arrest and death is high, but none have reported the frequency or risk factors for morbidity and mortality in an entire cohort of children with EA undergoing anesthesia. AIM: The aim of this study was to present one institution's rate of morbidity and mortality in all children with EA undergoing anesthesia and to examine patient characteristics that pose the greatest risk. METHODS: We reviewed medical records of children with EA who underwent anesthesia or sedation for any procedure at our institution from 1990 to 2013. Cardiovascular hemodynamic indices from recent cardiac catheterization or echocardiography were tabulated for each child. The incidence, type, and associated factors of complications occurring intraoperatively through 48 h postoperatively were examined. RESULTS: Forty-eight patients with confirmed EA underwent a total of 141 anesthetics. There were seven cardiac arrests (15% of patients, 5% of anesthetics) and nine additional intraoperative cardiovascular complications (15% of patients, 6% of anesthetics). Extracorporeal life support was initiated in five cases. There were no perioperative deaths. All children having a cardiac arrest or complication were <3 years old and had biventricular outflow tract obstruction (BVOTO). Subgroup analysis demonstrated high rates of cardiac arrest in two groups: children with BVOTO (44%) and age <3 years old (21%). CONCLUSIONS: We have confirmed that the rate of cardiac arrest and complications is significantly elevated in children with EA undergoing anesthesia. Children <3 years old and with BVOTO were at the greatest risk in our population.

Assessment of the structure and function of the aorta by echocardiography.

Echocardiography is the primary modality for imaging the aorta for the diagnosis and serial evaluation of pathological conditions. In this article, we review the methodology for optimal echocardiographic imaging of the various segments of the aorta and discuss abnormalities of the aorta including stenosis, dilation including aortopathy and sinus of Valsalva aneurysms, and fistulous communications involving the ascending aorta including aortoventricular tunnel and ruptured sinus of Valsalva aneurysm. We review novel echocardiographic measurements of aortic functional properties of the aorta such as elasticity and stiffness, and review the literature on the potential additive value of such measurements for structural assessment alone. Finally, we discuss the limitations of echocardiography in the precise and optimal imaging of the aorta.

The Ross, Konno, and Ross-Konno operations for congenital left ventricular outflow tract abnormalities.

Operations for left ventricular outflow tract abnormalities are centred on hemodynamic conditions that relate to subvalvar stenosis, valvar stenosis/regurgitation, aortic annular hypoplasia, and supravalvar aortic stenosis. Operative interventions over the years have evolved because the intervening outcomes proved to be unsatisfactory. The resection for subvalvar aortic stenosis has progressed from a fibrous "membrane" resection to a more extensive fibromuscular resection. Operative solutions for valvar aortic stenosis and regurgitation have resulted in operative interventions that depend on simple commissurotomy, leaflet extensions, prosthetic mechanical valve replacement, biologic valve replacement, including the pulmonary autograft, and operations to treat aortic annular stenosis. Although there are enthusiastic proponents for all of these strategies, the fact remains that none have proven to be curative; patients can expect to undergo further procedures during their lifetimes. The short- and mid-term solutions to these left ventricular outflow tract abnormalities have improved based on operations that have been attended by increasing operative complexity. The purpose of this review is to chronicle the operative steps of the Ross operation, the Konno-Rastan operation, the modified Konno operation, the Ross-Konno operation, and the modified Ross-Konno operation.

Clinical Care for Cardiovascular Disease in Patients With Williams-Beuren Syndrome.

Williams-Beuren syndrome (WBS) is a congenital multisystem disorder affecting the cardiovascular, central nervous, and musculoskeletal systems. Cardiovascular abnormalities, which consist principally of vascular stenoses, occur in approximately 80% of people with WBS and are the predominant cause of early morbidity and mortality. Supravalvar aortic stenosis and peripheral pulmonary artery stenosis are the most common stenotic lesions in WBS, though other stenoses often occur, including stenoses of the coronary arteries. Approximately one-third of people with WBS undergo cardiovascular interventions. The risk of sudden cardiac death is markedly higher than the general population, with most events occurring in the periprocedural period. Because of the rarity of WBS and the often-complex nature of the cardiovascular abnormalities, most physicians, including cardiologists, have limited experience in caring for patients with WBS. Further, heretofore, clinical cardiovascular management guidelines based on international expert consensus have not been available. This state-of-the-art review provides a comprehensive synopsis of the cardiovascular abnormalities in WBS and presents clinical management guidelines based on the authors' expert consensus.

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 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.

Assessment of three types of surgical procedures for supravalvar aortic stenosis: A systematic review and meta-analysis.

Importance: The safety and efficacy of different surgical repairs of supravalvar aortic stenosis (SVAS) are inconsistent. Objective: To compare the prognosis of single-, two- and three-patch repair for patients with SVAS. Data sources: PubMed, EMBASE, Cochrane Library, Web of Science, and clinicaltrials.gov were searched until April 17, 2022. Study selection: Study reported SVAS patients treated with single-, two- or three-patch repair. Data extraction and synthesis: Two reviewers independently extracted the data of study characteristics and clinical outcomes. Multiple pairwise and frequentist network meta-analyses were conducted. And a fixed-effect model was used when no heterogeneity existed. Main outcomes and measures: Outcomes included the rate of reintervention, aortic insufficiency, early mortality and late mortality, cardiopulmonary bypass (CPB) time, cross-clamping (CCP) time, and postoperative/ follow-up pressure gradient. Binary variables were evaluated by odds ratio (OR) and its 95% confidence interval (CI), while continuous variables were assessed by standardized mean difference (SMD) and its 95% CI. Results: Twenty-seven retrospective cohort studies were included, comprising 1,162 patients, undergoing single-patch (46.6% of cases), two-patch (33.9%), and three-patch repair (19.4%). Two-patch method had a lower rate of reintervention compared with single-patch (OR = 0.47, 95 % CI 0.28-0.89), and three-patch (OR = 0.31, 95 % CI 0.15-0.64). This finding also applied to juvenile and non-Asian patients. Three-patch method had a lower rate of aortic insufficiency compared with single-patch (OR = 0.11, 95 % CI 0.01-0.63), and two-patch (OR = 0.11, 95 % CI 0.02-0.83). But this repair had the longest CCP time, which was significantly longer than that of single- (SMD = 0.76, 95 % CI 0.36-1.17) or two-patch repair (SMD = 0.61, 95 % CI 0.06-1.16). No significant difference was found in mortality and pressure gradient among three procedures. Conclusion and relevance: Two-patch repair has the lowest reintervention rate and relatively reasonable operation time. Complex and severe SVAS is suggested to be treated with two-patch repair. Further prospective studies of a reasonable sample size will be required with a special focus on the use of different patch materials and surgeons' unique working experience. Systematic review registration: http://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022328146.

Aortic Valve-Sparing Surgical Treatment of Supravalvar Aortic Stenosis in a 65-Year-Old Adult.

Supravalvar aortic stenosis (SVAS) is a rare congenital cardiac disease that usually co-occurs with Williams syndrome. In the adult population, a few SVAS cases have been reported in patients affected by homozygous familial hypercholesterolemia. However, because of the rarity of this disease entity, there is no standard surgical treatment for SVAS. Here, we present a case of successful surgical treatment using an autologous excised aortic patch in a 65-year-old patient with SVAS.

Three-Patch Aortic Root Reconstruction With Extended Left Main Coronary Artery Patch Augmentation in Neonates and Infants.

Left main coronary artery (LMCA) stenosis is present in approximately 5% of patients with congenital supravalvular aortic stenosis (SVAS) (Fig. 1)1 and is associated with an increased risk of sudden cardiac death.2 However, patients undergoing coronary artery intervention at the time of SVAS repair are at the highest risk of experiencing major adverse cardiac events.3 Literature reports of surgical techniques and outcomes of concomitant coronary artery repair in these high-risk patients are diverse and inconsistently described. We have recently adopted a standardized surgical technique for management of this complex pathology by combining extended LMCA patch augmentation with a 3-patch aortic root reconstruction (Brom's technique). In this report, we describe our contemporary surgical technique of 3-patch aortic root reconstruction with extended LMCA patch augmentation for patients with congenital SVAS with ostial LMCA stenosis and bilateral outflow tract obstruction. Institutional review board approval was obtained for retrospective review of patient charts.

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.