Supravalvular Aortic Stenosis Research Articles

The long-term results of using 3-patch technique for supravalvular aortic stenosis

The objective of this study evaluated the results of using 3-patch technique for supravalvular aortic stenosis [1]
 Methods: This was a review of seri cases: using 3-path technique for supravalvular aortic stenosis from 1/2012 to 12/2018
 Results: There were 8 patients who underwent using 3-patch technique, include 5 males and 3 females. The mean of age was 12,4 years (range 4 to 32 year), 7 childrents and 1 adult. The left ventricular outflow tract gradient was 62 mmHg. The time of cardiopulmonary bypass, aortic clamping and ventilator were: 104 minutes; 72 minutes. 7 patients were used pericardium path and 1 patient was another graft. There was not intrahospital mortality. Echocardiography post -operation: left ventricular outflow tract gradient was 11,8 mmHg. During follow-up time 7,8 years after surgery, there was no late death; there were 3 patients who had to reoperation include 2 patient with stenotic distal anastomosis postoperation 5 years and 1 patient with severe aortic valve stenosis postoperation 8 years Conclusion: The long-term of using 3-patch technique for supravalvular aortic stenosis were satisfaction and longer follow-up was essential to find-out about risks of reoperation.

Upper partial sternal split for pediatric cardiac surgery

ObjectivesWe introduced the use of an upper partial sternal split for pediatric cardiac surgical procedures in our unit in 2016. We report the outcomes of our experience in 51 patients using this approach.MethodsFrom February 2016 to September 2022, 51 patients underwent congenital cardiac surgical procedures using an upper partial sternal split including vascular ring repair (n = 20), subaortic membrane (n = 12), ventricular septal defect closure with aortic valve resuspension (n = 9), aortic arch repair (n = 4), pulmonary artery band (n = 2), pulmonary artery sling (n = 1), supravalvular aortic stenosis (n = 1), aortic valve replacement (n = 1), and pulmonary artery plasty (n = 1). The surgical approach involved a midline skin incision, based on the manubrium, followed by an upper manubriotomy. No special surgical instrumentation was required. Median patient age was 2.9 years (IQR 1.3, 6.0); median body weight was 15 kg (IQR 9.8, 20).ResultsThere was no mortality and no patient required intraoperative conversion to full sternotomy. One patient required re-exploration for bleeding when the incision was converted to a full sternotomy. There were no wound complications in any patient. Twenty-one patients (41%) were extubated on the table and of the remaining 30 patients, 23 patients (76%) were extubated within 24 h of surgery. Eleven patients did not require intensive care unit (ICU) admission. Median ICU and hospital stay was 1 day (IQR 1, 1.25) and 5 days (IQR 4, 8) ,respectively.ConclusionAn upper partial sternal split approach is straightforward and can be performed safely with a preferable cosmetic result in selected pediatric cardiac operations.

Effectiveness and Safety of Different Patch Materials for Supravalvar Aortic Stenosis (Middle-Term Outcomes).

To determine the effectiveness and safety of different patch materials in the treatment of pediatric patients with congenital supravalvular aortic stenosis (SVAS). 218 consecutive SVAS patients (age 14 years) who underwent surgery from Beijing Fuwai and Yunnan Fuwai hospital between 2002 and 2020 were included. Patients were divided into the pericardium patch group (133 (61.0%)), modified patch group (43 (19.7%)) and artificial patch group (42 (19.3%)). The primary safety endpoint was patch-related adverse complications (post-operation patch hemorrhage or aortic sinus aneurysm at 2-year follow-up). The primary effectiveness outcome was the re-operation or restenosis at 2-year follow-up. Multivariable cox regression was used to obtain the hazard ratio (HR). The median age at operation was 43.5 months (IQR 24.0-73.0). Only three patients had patch-related adverse complications, and no difference existed among the three groups (p = 0.763). After a median follow-up of 24.0 months (IQR 6.0-48.0), patients with a pericardium patch had a lower re-operation or restenosis rate compared with the other two groups (pericardium patch vs modified patch, HR = 0.30, 95% CI 0.12-0.77; pericardium patch vs artificial patch, HR = 0.33, 95% CI 0.13-0.82), even in the main subgroup and sensitivity analysis. In pediatric patients, the safety of autologous pericardium patch is acceptable, along with lower rates of middle-term re-operation or restenosis. http://www.chictr.org.cn, number: ChiCTR2300067851.

Williams Syndrome: A Rare Case Report

We report a rare case of Williams Syndrome diagnosed at an age of two months based on subtle facial dysmorphism (elfin facies) and a pulmonary systolic murmur at birth. Echocardiogram revealed mild supravalvular aortic stenosis and mild supravalvular pulmonary stenosis extending into branch pulmonary arteries. Mild developmental delay, hypotonia, feeding problems, constipation and failure to thrive were present. In view of distinctive facial phenotype in combination with cardiac abnormalities, Williams Syndrome was strongly suspected. It was confirmed by fluorescence in situ hybridisation test demonstrating a deletion of elastin gene on chromosome 7. This case highlights the importance of pediatricians awareness about malformation syndromes which can help in early diagnosis, timely genetic counselling to the family and better patient outcomes.

Presenilin-1 in smooth muscle cells facilitates hypermuscularization in elastin aortopathy

Smooth muscle cell (SMC) accumulation is central to the pathogenesis of elastin-defective arterial diseases, including supravalvular aortic stenosis (SVAS). We previously demonstrated that elastin insufficiency activates Notch signaling in aortic SMCs. Activation of Notch is catalyzed by the enzyme gamma-secretase, but the role of catalytic subunits presenilin (PSEN)-1 or PSEN-2 in elastin aortopathy is not defined. Genetic approaches reveal that endothelial cell-specific Psen1 deletion does not improve elastin aortopathy whereas the deletion of either Psen1 in SMCs or Psen2 globally attenuates Notch pathway and SMC proliferation, mitigating aortic disease. With SMC-specific Psen1 deletion in elastin nulls, these rescue effects are more robust and in fact, survival is increased. SMC deletion of Psen1 also attenuates hypermuscularization in newborns heterozygous for the elastin null gene, which genetically mimics SVAS. Similarly, the pharmacological inhibition of PSEN-1 mitigates SMC accumulation in elastin aortopathy. These findings put forth SMC PSEN-1 as a potential therapeutic target in SVAS.

Blockade of Inflammatory Markers Attenuates Cardiac Remodeling and Fibrosis in Rats with Supravalvular Aortic Stenosis.

Since cardiac inflammation has been considered an important mechanism involved in heart failure, an anti-inflammatory treatment could control cardiac inflammation and mitigate the worsening of cardiac remodeling. This study evaluated the effects of dexamethasone (DEX) and ramipril treatment on inflammation and cardiac fibrosis in an experimental model of heart failure induced by supravalvular aortic stenosis. Wistar rats (21d) were submitted to an aortic stenosis (AS) protocol. After 21 weeks, an echocardiogram and a maximal exercise test were performed, and after 24 weeks, rats were treated with DEX, ramipril or saline for 14d. The left ventricle (LV) was removed for histological and inflammatory marker analyses. The AS group showed exercise intolerance (-32% vs. Sham), higher relative wall thickness (+63%), collagen deposition and capillary rarefaction, followed by cardiac disfunction. Both treatments were effective in reducing cardiac inflammation, but only DEX attenuated the increased relative wall thickness (-17%) and only ramipril reduced LV fibrosis. In conclusion, both DEX and ramipril decreased cardiac inflammatory markers, which probably contributed to the reduced cardiac fibrosis and relative wall thickness; however, treated AS rats did not show any improvement in cardiac function. Despite the complex pharmacological treatment of heart failure, treatment with an anti-inflammatory could delay the patient's poor prognosis.

Novel mutation in ELN gene causes cardiac abnormalities and inguinal hernia: case report

BackgroundElastin-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.Case presentationWe 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.ConclusionWe 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.

Electrocardiograms Do Not Detect Myocardial Ischemia in Patients With Williams Syndrome and Nonsyndromic Elastin Arteriopathy With Coronary Artery Stenosis

Coronary artery stenosis (CAS) may affect up to 27% of patients with Williams syndrome (WS), which may lead to myocardial ischemia. Patients with WS face a 25- to 100-fold greater risk of sudden cardiac death, frequently linked to anesthesia. Assessing CAS requires either imaging while under general anesthesia or intraoperative assessment, with the latter considered the gold standard. Our study aimed to identify electrocardiogram (ECG) markers of myocardial ischemia in patients with WS or nonsyndromic elastin arteriopathy and documented CAS. We retrospectively reviewed patients with WS/elastin arteriopathy who underwent supravalvar aortic stenosis surgery and CAS assessment from January 1, 2006 to April 30, 2021. A pediatric electrophysiologist, not aware of the patients' CAS status, reviewed their preoperative ECGs for markers of ischemia. We assessed associations of study parameters using Wilcoxon rank-sum and Fisher's exact tests. Of 34 patients, 62% were male, with a median age of 20 months (interquartile range: 8 to 34). CAS was present in 62% (21 of 34), 76% of whom (16 of 21) were male. There were no ECG indicators of myocardial ischemia in patients with CAS. In conclusion, CAS was present in >1/2 the children with WS/elastin arteriopathy who underwent repair of supravalvar aortic stenosis. CAS in WS/nonsyndromic elastin arteriopathy does not appear to exhibit typical ECG-detectable myocardial ischemia. ECGs are not a useful screening tool for CAS in WS/elastin arteriopathy. Given the high anesthesia-related cardiac arrest risk, other noninvasive indicators of CAS are needed.

Abstract 11680: Presenilin 1 Deletion in Smooth Muscle Cells Ameliorates Hypermuscularization and Stenosis in Elastin Aortopathy

Introduction: Smooth muscle cell (SMC) accumulation is central to the pathogenesis of elastin-defective arterial diseases, such as atherosclerosis, pulmonary hypertension and supravalvular aortic stenosis (SVAS). We previously demonstrated that elastin deficiency activates the Notch pathway in aortic SMCs, resulting in hypermuscularization and stenosis. Activation of Notch is catalyzed by the enzyme gamma-secretase, but the role of specific catalytic subunits presenilin (PSEN)-1 or PSEN-2 in elastin aortopathy is not defined. Psen1 (-/-) mice die shortly after birth with intracranial hemorrhage and bone abnormalities, while Psen2 (-/-) mice are viable. Methods: Western blot and qRT-PCR for PSEN-1 and -2 were performed on human aortic SMCs in culture and wildtype and elastin null aortas at postnatal day (P) 0.5. Genetic deletion of cell type-specific Psen1 and/or global Psen2 was performed on the elastin mutant background. For SMC- or endothelial cell (EC)-specific Psen1 deletion, pregnant dams were injected with tamoxifen at embryonic days 14.5 and 15.5, and elastin mutant pups carrying no Cre, Acta2-CreER T2 , or Cdh5-CreER T2 were analyzed at P0.5. Results: PSEN-1 and -2 are upregulated in aortic SMCs with elastin deficiency in human and mouse. Global Psen2 deletion partially attenuates Notch downstream gene expression and SMC proliferation, mitigating elastin aortopathy while Psen1 deletion in SMCs more significantly inhibits this aortopathy and improves survival of elastin null pups. In contrast, Psen1 deletion in ECs does not improve aortic disease. The combination of global Psen2 deletion and SMC-specific Psen1 deletion has additive rescue effects on elastin aortopathy. In addition, SMC-specific Psen1 deletion rescues hypermuscularization in newborns heterozygous for the elastin null gene, which genetically mimics human SVAS. Conclusions: Elastin insufficiency in SMCs leads to upregulation of PSEN-1 and -2, which induce Notch signaling and SMC proliferation. Among PSEN subunits and vascular cell types, SMC PSEN-1 plays the major role in elastin aortopathy. Selective inhibition of SMC PSEN-1 may be an attractive therapeutic strategy for SVAS to improve efficacy and mitigate off-target effects of gamma-secretase blockade.

Anesthetic considerations in supravalvular aortic stenosis: A case series

Supravalvular aortic stenosis (SVAS), characterized by elastin arteriopathy, presents either as a localized narrowing at the sinotubular junction or as a diffuse form with additional involvement of the ascending aorta, aortic arch, and its branches. Associated lesions of the aortic valve, coronary artery narrowing, and pulmonary artery stenosis can further complicate the disease process. These patients are inherently at risk for developing myocardial ischemia, particularly in the setting of anesthesia or sedation. The left ventricular hypertrophy, secondary to the obstruction, results in increased left ventricular wall tension and myocardial oxygen consumption. Associated anatomic factors in the coronary arteries can further impair coronary blood flow. Any anesthetic drug that further increases oxygen consumption or decreases the coronary blood flow will result in an imbalance and increase the risk of cardiac arrest. We present a series of three patients with SVAS who were operated at our institute and subsequently discharged with good outcomes. The hemodynamic goal during the perioperative should aim to balance the myocardial oxygen supply-demand ratio. Extreme vigilance and aggressive resuscitative measures are needed to prevent any adverse myocardial event that can happen immediately after anesthetic induction or during periods of intense sympathetic stimulation such as laryngoscopy, sternotomy, aortic cannulation, or during emergence from anesthesia.

1226 The Role of Extracorporeal Membrane Oxygenation in William’s Syndrome Following Cardiac Surgery: A Case Report

Abstract Williams-Beuren Syndrome (WS) is a genetic syndrome seen in childhood, characterised by intellectual disabilities, outgoing personalities, elfin-like faces and cardiovascular complications. We report the story of a girl with WS who underwent complex cardiac surgery requiring extracorporeal membrane oxygenation (ECMO), to raise awareness of the perioperative challenges with WS. At 2 years old, a cardiac murmur was incidentally discovered. Further investigations revealed WS with cardiac manifestations including peripheral pulmonary artery stenosis (PPAS) and supravalvular aortic stenosis (SVAS). Isolated SVAS repair was feasible, however the severity of pulmonary artery hypoplasia deemed her inoperable. Her care was redirected to palliation. 18 months later, she remained in good clinical condition which prompted the multidisciplinary team (MDT) to change their decision and proceed with complex SVAS repair surgery (Brom technique) at the age of 5. Postoperatively, 3 failed attempts to wean from cardiopulmonary bypass preceded veno-arterial ECMO, which lasted 7 days. She stayed in intensive care for 17 days, and in hospital for 28 days. Frequent MDT decision making was crucial during her complex care. The patient is currently 15 years old, in good clinical condition, albeit exercise restrictions. WS patients have a known increased risk of perioperative sudden cardiac death and increasing use of paediatric ECMO, hence great attention and thorough preparation is required. Clear perioperative care guidelines for WS are essential to secure good outcomes in this patient population. This case demonstrated that MDT involvement and regular communication with the patient were key to deliver the appropriate care throughout her life.

Characterization of the Zebrafish Elastin a (elnasa12235) Mutant: A New Model of Elastinopathy Leading to Heart Valve Defects.

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.

Heart Rate Variability Analysis May Identify Individuals With Williams-Beuren Syndrome at Risk of Sudden Death.

Williams-Beuren syndrome (WBS) (Online Mendelian Inheritance in Man #194050) is a rare genetic multisystem disorder resulting from a chromosomal microdeletion at 7q11.23. The condition is characterized by distinct facies, intellectual disability, and supravalvar aortic stenosis. Those with WBS have an increased risk of sudden death, but mechanisms underlying this phenotype are incompletely understood. The aim of this study was to quantify and compare autonomic activity as reflected by heart rate variability (HRV) measures in a cohort of individuals with WBS (n=18) and age- and sex-matched control subjects (n=18). We performed HRV analysis on 24-hour electrocardiography recordings using nonlinear, time and frequency domain analyses on a cohort of subjects with WBS and age- and sex-matched control subjects enrolled in a prospective cross-sectional study designed to characterize WBS disease natural history. WBS subjects demonstrated diminished HRV (reflected by the SD of the NN intervals [P = 0.0001], SD of the average NN interval for 5-minute intervals over 24 hours [P< 0.0001], average of the 5-minute SDs of NN intervals for 24 hours [P = 0.0002], root mean square of successive differences of NN intervals [P = 0.0004], short axis of the Poincaré plot (SD1) [P< 0.0001], and long axis of the Poincaré plot [P< 0.0001]) and indirect markers of parasympathetic activity (reflected by the percent of NN intervals different from previous by 50% or more of local average [P<0.0007], root mean square of successive differences of NN intervals [P = 0.0004], natural log high-frequency power [P = 0.0038], and SD1 [P< 0.0001]). Additional parameters were also significantly different, including natural log very low-frequency power (decreased; P = 0.0002), natural log low-frequency power (decreased; P = 0.0024), and SD1 divided by the long axis of the Poincaré plot (decreased; P< 0.0001). Individuals with WBS demonstrate significant HRV abnormalities consistent with diminished autonomicreserve. Future studies will be needed to determine the relationship between autonomic dysregulation observed and sudden death risk seen in these patients. (Impact of Elastin Mediated Vascular Stiffness on EndOrgans;NCT02840448).

A Large Turkish Cohort of Williams Syndrome: The Evaluation of Facial, Cardiovascular, and Neuropsychiatric Features.

Williams syndrome is caused by a microdeletion at 7q11.23 and is characterized by a distinctive face, cardiovascular disease, and intellectual disability with a specific cognitive and behavioral profile. This study aims to evaluate the clinical features and obtain important information that can guide early diagnoses and correct follow-up. The study included 78 patients whose diagnoses were confirmed by fluorescent in situ hybridization. Facial features, anthropometric measurements, and neurocognitive, endocrine, and urinary system evaluations were obtained from the medical records, and photographs of the patients were evaluated retrospectively. The most common complaints at admission were cardiovascular disease and atypical face. The mean age at admission was 39 ± 4.8 months. The mean age of patients presenting with atypical face was 41 ± 5.6 months, while it was 11 ± 3.1 months in patients presenting with cardiovascular disease. Short nose/bulbous nasal type with anteverted nares and periorbital fullness, which are diagnostic facial features, were present in all patients in the infantile/ early childhood period. 80% of the patients had cardiovascular disease; supravalvular aortic stenosis (53.8%) and peripheral pulmonary artery stenosis (41%) were the most common cardiac anomalies.Intel lectu al/de velop menta l disability was present in 75.6% of the patients. Behavioral disorders including autism spectrum disorder and attention deficit hyperactivity disorder were detected in 50% of our patients. Hypersensitivity to loud and/or sudden sounds was present in all patients. We highlighted that recognition of facial findings is important for early diagnosis, especially in patients without cardiovascular disease. The frequency of cardiovascular, endocrinological, renal anomalies, and intellectual disab ility /deve lopme ntal delay was described that provide valuable information in the follow-up of patients.

Clinical Results of a Modified Doty’s Technique for Supravalvular Aortic Stenosis

This study aimed to assess the early and mid-term results of the modified Doty's technique compared with the traditional Doty's technique in patients with congenital supravalvular aortic stenosis (SVAS). We retrospectively included 73 consecutive SVAS patients in Beijing and Yunnan Fuwai Hospitals between 2014 and 2021. Patients were divided into the modified technique (n = 9) and the traditional technique group (n = 64). The modified technique involves altering the right head of the symmetrical inverted pantaloon-shaped patch into an asymmetrical triangular form to prevent compression of the right coronary artery ostium. The primary safety outcome was in-hospital surgery-related complications and the primary effectiveness outcome was re-operation at follow-up. The Mann-Whitney U test and Fisher's exact test were used to test the group difference. The median age at operation was 50 months (IQR 27.0-96.0). Twenty-two (30.1%) of the patients were female. The median follow-up was 23.5 months (IQR 3.0-46.0). No in-hospital surgery-related complications and follow-up re-operation occurred in the modified technique group, but the traditional technique group had 14 (21.8%) surgery-related complications and 5 (7.9%) re-operation. Patients with the modified technique had a well-developed aortic root and no aortic regurgitation occurred. A modified technique could be considered for patients with poor aortic root development to reduce postoperative surgery-related complications.

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.

A new mouse model of elastin haploinsufficiency highlights the importance of elastin to vascular development and blood pressure regulation

Supravalvular aortic stenosis (SVAS) is an autosomal dominant disease resulting from elastin (ELN) haploinsufficiency. Individuals with SVAS typically develop a thickened arterial media with an increased number of elastic lamellae and smooth muscle cell (SMC) layers and stenosis superior to the aortic valve. A mouse model of SVAS (Eln+/−) was generated that recapitulates many aspects of the human disease, including increased medial SMC layers and elastic lamellae, large artery stiffness, and hypertension. The vascular changes in these mice were thought to be responsible for the hypertension phenotype. However, a renin gene (Ren) duplication in the original 129/Sv genetic background and carried through numerous strain backcrosses raised the possibility of renin-mediated effects on blood pressure. To exclude excess renin activity as a disease modifier, we utilized the Cre-LoxP system to rederive Eln hemizygous mice on a pure C57BL/6 background (Sox2-Cre;Elnf/f). Here we show that Sox2-Cre;Eln+/f mice, with a single Ren1 gene and normal renin levels, phenocopy the original global knockout line. Characteristic traits include an increased number of elastic lamellae and SMC layers, stiff elastic arteries, and systolic hypertension with widened pulse pressure. Importantly, small resistance arteries of Sox2-Cre;Eln+/f mice exhibit a significant change in endothelial cell function and hypercontractility to angiotensin II, findings that point to pathway-specific alterations in resistance arteries that contribute to the hypertensive phenotype. These data confirm that the cardiovascular changes, particularly systolic hypertension, seen in Eln+/− mice are due to Eln hemizygosity rather than Ren duplication.

The Combined Treatment of Curcumin with Verapamil Ameliorates the Cardiovascular Pathology in a Williams–Beuren Syndrome Mouse Model

Williams-Beuren syndrome (WBS) is a rare disorder caused by a recurrent microdeletion with hallmarks of cardiovascular manifestations, mainly supra-valvular aortic stenosis (SVAS). Unfortunately, there is currently no efficient treatment. We investigated the effect of chronic oral treatment with curcumin and verapamil on the cardiovascular phenotype of a murine model of WBS harbouring a similar deletion, CD (complete deletion) mice. We analysed systolic blood pressure in vivo and the histopathology of the ascending aorta and the left ventricular myocardium to determine the effects of treatments and their underlying mechanism. Molecular analysis showed significantly upregulated xanthine oxidoreductase (XOR) expression in the aorta and left ventricular myocardium of CD mice. This overexpression is concomitant with increased levels of nitrated proteins as a result of byproduct-mediated oxidative stress damage, indicating that XOR-generated oxidative stress impacts the pathophysiology of cardiovascular manifestations in WBS. Only the combined therapy of curcumin and verapamil resulted in a significant improvement of cardiovascular parameters via activation of the nuclear factor erythroid 2 (NRF2) and reduction of XOR and nitrated protein levels. Our data suggested that the inhibition of XOR and oxidative stress damage could help prevent the severe cardiovascular injuries of this disorder.

Hibridização in situ fluorescente (FISH) como ferramenta diagnóstica insubstituível para a síndrome de Williams-Beuren em países em desenvolvimento: uma revisão de literatura

ABSTRACT Objective: The aim of this study was to sum up and characterize all Williams-Beuren syndrome cases diagnosed by fluorescence in situ hybridization (FISH) since its implementation, as well as to discuss FISH as a cost-effective methodology in developing countries. Data source: From January 1986 to January 2022, articles were selected using the databases in PubMed (Medline) and SciELO. The following terms were used: Williams syndrome and In Situ Hybridization, Fluorescence. Inclusion criteria included Williams-Beuren syndrome cases diagnosed by FISH with a stratified phenotype of each patient. Only studies written in English, Spanish, and Portuguese were included. Studies with overlapping syndromes or genetic conditions were excluded. Data synthesis After screening, 64 articles were included. A total of 205 individuals with Williams-Beuren syndrome diagnosed by FISH were included and further analyzed. Cardiovascular malformations were the most frequent finding (85.4%). Supravalvular aortic stenosis (62.4%) and pulmonary stenosis (30.7%) were the main cardiac alterations described. Conclusions: Our literature review reinforces that cardiac features may be the key to early diagnosis in Williams-Beuren syndrome patients. In addition, FISH may be the best diagnostic tool for developing nations that have limited access to new technologic resources.

Supravalvular aortic stenosis with bicuspid aortic valve in a patient with cutis laxa syndrome.

Supravalvular aortic stenosis with bicuspid aortic valve in a patient with cutis laxa syndrome.