UNASSIGNED: A series of incurable cardiovascular disorders arise due to improper formation of elastin during development. Supravalvular aortic stenosis (SVAS), resulting from a haploinsufficiency of ELN, is caused by improper stress sensing by medial vascular smooth muscle cells, leading to progressive luminal occlusion and heart failure. SVAS remains incurable, as current therapies do not address the root issue of defective elastin.
UNASSIGNED: We use SVAS here as a model of vascular proliferative disease using both human induced pluripotent stem cell-derived vascular smooth muscle cells and developmental Eln+/- mouse models to establish de novo elastin assembly as a new therapeutic intervention.
UNASSIGNED: We demonstrate mitigation of vascular proliferative abnormalities following de novo extracellular elastin assembly through the addition of the polyphenol epigallocatechin gallate to SVAS human induced pluripotent stem cell-derived vascular smooth muscle cells and in utero to Eln+/- mice.
UNASSIGNED: We demonstrate de novo elastin deposition normalizes SVAS human induced pluripotent stem cell-derived vascular smooth muscle cell hyperproliferation and rescues hypertension and aortic mechanics in Eln+/- mice, providing critical preclinical findings for the future application of epigallocatechin gallate treatment in humans.

BACKGROUND: We aimed to describe the frequency and yield of genetic testing in supravalvar aortic stenosis (SVAS) following negative evaluation for Williams-Beuren syndrome (WS).
RESULTS: This retrospective cohort study included patients with SVAS at our institution who had a negative evaluation for WS from May 1991 to September 2021. SVAS was defined as (1) peak supravalvar velocity of ≥2 meters/second, (2) sinotubular junction or ascending aortic Z score <-2.0, or (3) sinotubular junction Z score <-1.5 with family history of SVAS. Patients with complex congenital heart disease, aortic valve disease as the primary condition, or only postoperative SVAS were excluded. Genetic testing and diagnoses were reported. Of 162 patients who were WS negative meeting inclusion criteria, 61 had genetic testing results available (38%). Chromosomal microarray had been performed in 44 of 61 and was nondiagnostic for non-WS causes of SVAS. Sequencing of 1 or more genes was performed in 47 of 61. Of these, 39 of 47 underwent ELN sequencing, 20 of 39 (51%) of whom had a diagnostic variant. Other diagnoses made by gene sequencing were Noonan syndrome (3 PTPN11, 1 RIT1), Alagille syndrome (3 JAG1), neurofibromatosis (1 NF1), and homozygous familial hypercholesterolemia (1 LDLR1). Overall, sequencing was diagnostic in 29 of 47 (62%).
CONCLUSIONS: When WS is excluded, gene sequencing for SVAS is high yield, with the highest yield for the ELN gene. Therefore, we recommend gene sequencing using a multigene panel or exome analysis. Hypercholesterolemia can also be considered in individuals bearing the stigmata of this disease.

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.

Elastin-driven genetic diseases are a group of complex diseases driven by elastin protein insufficiency and dominant-negative production of aberrant protein, including supravalvular aortic stenosis (SVAS) and autosomal dominant cutis laxa. Here, a Chinese boy with a novel nonsense mutation in the ELN gene is reported.
We report a 1-year-old boy who presented with exercise intolerance, weight growth restriction with age, a 1-year history of heart murmur, and inguinal hernia. Gene sequencing revealed a novel nonsense mutation in the ELN gene (c.757 C > T (p.Gln253Ter), NM_000501.4). Due to severe branch pulmonary artery stenosis, the reconstruction of the branch pulmonary artery with autologous pericardium was performed. The inguinal hernia repair was performed 3 months postoperatively. After six months of outpatient follow-up, the child recovered well, gained weight with age, and had no special clinical symptoms.
We identified a de novo nonsense mutation in the ELN gene leading to mild SVAS and severe branch pulmonary artery stenosis. A new phenotype of inguinal hernia was also needed to be considered for possible association with the ELN gene. Still, further confirmation will be necessary.

OBJECTIVE: 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.

Elastic fibers are extracellular macromolecules that provide resilience and elastic recoil to elastic tissues and organs in vertebrates. They are composed of an elastin core surrounded by a mantle of fibrillin-rich microfibrils and are essentially produced during a relatively short period around birth in mammals. Thus, elastic fibers have to resist many physical, chemical, and enzymatic constraints occurring throughout their lives, and their high stability can be attributed to the elastin protein. Various pathologies, called elastinopathies, are linked to an elastin deficiency, such as non-syndromic supravalvular aortic stenosis (SVAS), Williams-Beuren syndrome (WBS), and autosomal dominant cutis laxa (ADCL). To understand these diseases, as well as the aging process related to elastic fiber degradation, and to test potential therapeutic molecules in order to compensate for elastin impairments, different animal models have been proposed. Considering the many advantages of using zebrafish, we here characterize a zebrafish mutant for the elastin a paralog (elnasa12235) with a specific focus on the cardiovascular system and highlight premature heart valve defects at the adult stage.

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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.

To characterise the ocular manifestations of Williams-Beuren syndrome (WBS) and compare these to patients with isolated elastin mediated supravalvular aortic stenosis (SVAS).
Fifty-seven patients with a diagnosis of WBS and five with SVAS underwent comprehensive ophthalmic evaluation at the National Institutes of Health from 2017 to 2020, including best-corrected visual acuity, slit-lamp biomicroscopy, optical biometry, dilated fundus examination, optical coherence tomography and colour fundus imaging.
Mean age of the 57 WBS patients was 20.3 years (range 3-60 years). Best-corrected visual acuity ranged from 20/20 to 20/400 with mean spherical equivalent near plano OU. Twenty-four eyes (21.8%) had an axial length (AL) less than 20.5 mm and 38 eyes (34.5%) had an AL measuring 20.5-22.0 mm. Stellate iris and retinal arteriolar tortuosity were noted in 30 (52.6%) and 51 (89.5%) WBS patients, respectively. Novel retinal findings in WBS included small hypopigmented retinal deposits (OD 29/57, OS 27/57) and broad foveal pit contour (OD 44/55, OS 42/51). Of the five patients with SVAS, none had stellate iris or broad foveal pit contour while 2/5 had retinal arteriolar tortuosity.
WBS is a complex multisystem genetic disorder with diverse ophthalmic findings that differ from those seen in isolated elastin mediated SVAS. These results suggest other genes within the WBS critical region, aside from ELN, may be involved in observed ocular phenotypes and perhaps broader ocular development. Furthermore, retinal arteriolar tortuosity may provide future insight into systemic vascular findings in WBS.