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.

BACKGROUND: Primary supravalvar aortic stenosis (SVAS) is a rare congenital cardiovascular condition that can coexist with Williams-Beuren syndrome, coronary artery involvement, aortic coarctation, and pulmonary artery stenosis. SVAS repair can be achieved with low perioperative mortality, but long-term survival remains less well understood. We used the Pediatric Cardiac Care Consortium, a multicenter United States-based registry for pediatric cardiac operations, to assess long-term outcomes after SVAS repair.
METHODS: We used Kaplan-Meier plots and Cox proportional hazards regression to examine factors associated with postdischarge deaths. These included sex, age-group, weight z-score, coexisting conditions (Williams-Beuren syndrome, coronary artery involvement, coarctation, and pulmonary artery stenosis), surgical techniques, and era, defined as early (1982-1995) or late (1996-2003). Survival was assessed by matching with the National Death Index through 2021.
RESULTS: Of 333 patients who met inclusion criteria, 313 (94.0%) survived to discharge and 188 (60.1%) had identifiers for National Death Index matching. Over a median follow-up of 25.2 years (interquartile range, 21.1-29.4 years), 17 deaths occurred. The 30-year survival after discharge from SVAS repair was 88.7% (95% CI, 82.9%-94.8%). Infantile surgery and non-Williams-Beuren syndrome were associated with decreased 30-year survival. From the various repairs, the 2-sinus technique had better outcomes compared with all other types, except the 3-sinus technique (nonsignificant difference). Adjusted analysis revealed infantile age and type of repair as associated with postdischarge probability of death.
CONCLUSIONS: These data demonstrate favorable long-term outcomes after SVAS repair, except for the infantile group that was associated with more diffuse arteriopathy. As techniques continue to evolve, future studies are warranted to investigate their long-term outcomes.

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.
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.

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, 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.

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.

UNASSIGNED: The safety and efficacy of different surgical repairs of supravalvar aortic stenosis (SVAS) are inconsistent.
UNASSIGNED: To compare the prognosis of single-, two- and three-patch repair for patients with SVAS.
UNASSIGNED: PubMed, EMBASE, Cochrane Library, Web of Science, and clinicaltrials.gov were searched until April 17, 2022.
UNASSIGNED: Study reported SVAS patients treated with single-, two- or three-patch repair.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: http://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022328146.

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.

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.

OBJECTIVE: To evaluate the imaging features and associations in patients with supravalvar aortic stenosis on multidetector computed tomography (CT) angiography.
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.
CONCLUSIONS: 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.