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BVES downregulation in non-syndromic tetralogy of fallot is associated with ventricular outflow tract stenosis.

ABSTRACT: BVES is a transmembrane protein, our previous work demonstrated that single nucleotide mutations of BVES in tetralogy of fallot (TOF) patients cause a downregulation of BVES transcription. However, the relationship between BVES and the pathogenesis of TOF has not been determined. Here we reported our research results about the relationship between BVES and the right ventricular outflow tract (RVOT) stenosis. BVES expression was significantly downregulated in most TOF samples compared with controls. The expression of the second heart field (SHF) regulatory network genes, including NKX2.5, GATA4 and HAND2, was also decreased in the TOF samples. In zebrafish, bves knockdown resulted in looping defects and ventricular outflow tract (VOT) stenosis, which was mostly rescued by injecting bves mRNA. bves knockdown in zebrafish also decreased the expression of SHF genes, such as nkx2.5, gata4 and hand2, consistent with the TOF samples` results. The dual-fluorescence reporter system analysis showed that BVES positively regulated the transcriptional activity of GATA4, NKX2.5 and HAND2 promoters. In zebrafish, nkx2.5 mRNA partially rescued VOT stenosis caused by bves knockdown. These results indicate that BVES downregulation may be associated with RVOT stenosis of non-syndromic TOF, and bves is probably involved in the development of VOT in zebrafish.

SUBMITTER: Shi Y

PROVIDER: S-EPMC7447802 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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BVES downregulation in non-syndromic tetralogy of fallot is associated with ventricular outflow tract stenosis.

Shi Yan Y Li Yongqing Y Wang Yuequn Y Zhu Ping P Chen Yu Y Wang Heng H Yue Shusheng S Xia Xiaohui X Chen Jimei J Jiang Zhigang Z Zhou Chengbin C Cai Wanwan W Yuan Haiyun H Wu Yueheng Y Wan Yongqi Y Li Xiaohong X Zhu Xiaolan X Zhou Zuoqiong Z Dai Guo G Li Fang F Mo Xiaoyang X Ye Xiangli X Fan Xiongwei X Zhuang Jian J Wu Xiushan X Yuan Wuzhou W

Scientific reports 20200825 1

BVES is a transmembrane protein, our previous work demonstrated that single nucleotide mutations of BVES in tetralogy of fallot (TOF) patients cause a downregulation of BVES transcription. However, the relationship between BVES and the pathogenesis of TOF has not been determined. Here we reported our research results about the relationship between BVES and the right ventricular outflow tract (RVOT) stenosis. BVES expression was significantly downregulated in most TOF samples compared with contro ...[more]

PMID: 32843646

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Project description:Background: Current observational studies may not have large samples to investigate the relationship between pulmonary valve (PV) morphology differences and outcomes after complete repair for tetralogy of Fallot (TOF) by right ventricular outflow tract (RVOT) incision. This study aimed to assess the impact of PV morphology differences on outcomes after complete repair for TOF. Methods: This is a retrospective cohort study. Consecutive patients who underwent TOF repair with RVOT incision at Fuwai Hospital from January 2012 to December 2017 were included and compared according to PV morphology differences (unicuspid or bicuspid was abnormal morphology, while the tricuspid valve was normal morphology). The primary outcome was defined as a composite of death, or reintervention, or significant annular peak gradient (APG), or significant pulmonary regurgitation (PR), whichever occurred first. Multivariable Cox model analysis was used to assess the relationships between PV morphology differences and outcomes. Subgroup analysis and Propensity-score analysis were performed as sensitivity analyses to assess the robustness of our results. Results: The cohort included a total of 1,861 patients with primary diagnosis of TOF, with 1,688 undergoing CR-TOF with RVOT incision. The median age was 318 days [interquartile range (IQR): 223-534 days], a median weight of 8.9 kg (IQR: 7.6-10.5 kg) and 60.0% (1,011) were male. Complete follow-up data were available for 1,673 CR-TOF patients with a median follow-up duration of 49 months. Adjusted risks for the primary outcome and significant APG were lower for patients with normal PV morphology at follow up [adjusted hazard ratio (HR): 0.68; 95% CI: 0.46-0.98; adjusted HR: 0.22; 95% CI: 0.07-0.71, respectively]. The trend for the primary outcome during follow-up remained unchanged, even in subgroups and propensity score matching analyses. Conclusions: In this analysis of data from a large TOF cohort, patients with normal tricuspid PVs were associated with a decreased risk of the primary outcome and a lower risk of significant APG, as compared with patients with abnormal unicuspid or bicuspid PVs.

Project description:Objective: The study aims to establish a new method in the Tetralogy of Fallot (ToF) called the pulmonary valve bi-orifice method (pulmonary annular sparing with an individualized autologous pericardial patch; thus, two orifices are formed at the level of the pulmonary valve annulus) to reconstruct the right ventricular outflow tract (RVOT). Methods: A retrospective analysis of 128 TOF patients from October 2009 to June 2018 with severe pulmonary valve dysplasia who underwent transvalvular annular patch (TAP) procedure (control group) or an individualized pulmonary valve bi-orifice procedure (observation group) were studied. The RVOT for each patient in the observation group was individually reconstructed per the patient's weight and the size of the autologous pulmonary valve using the bi-orifice method; however, increasing the cross-sectional area of the pulmonary valve annulus without destroying its integrity. The result was then compared to the control group, where TAP procedures were applied to evaluate the short to mid-term outcome(s). An in vitro simulation test was used to verify the anti-regurgitation mechanism of the new method. Results: The in vitro simulation test indicated that the anti-regurgitation mechanism was completed by the pericardial patch and the autologous pulmonary valve movement toward each other. Thus, for clinical applications, patients in both groups were compared. The results showed no significant differences in cardiopulmonary bypass and aortic cross-clamp time, mechanical ventilation, and ICU and post-operative residence between the two groups. During the follow-up period (3- to 12-years), 14 patients in the observation group had mild regurgitation after surgery (22.2%), while 10 patients had moderate pulmonary regurgitation (15.8%) with no right ventricular (RV) dilation. On the other hand, 22 patients (39.6%) had moderate to severe regurgitation in the control group, while left pulmonary artery stenosis occurred in one patient. In the control group, six patients (9.2%) with severe RV dilation were reoperated. Conclusion: Individualized pulmonary valve bi-orifice procedure is a safe and excellent method for reconstructing RVOT in ToF.

Project description:BackgroundIntra-cardiac repair for tetralogy of Fallot has some degree of residual right ventricular outflow tract (RVOT) obstruction. However, the measurement of this gradient intra-operatively might get affected by the depth of anesthesia which is important for the long-term outcome.AimsThe primary aim was to compare intraoperative RVOT gradient post repair under two different anesthetic depths of 1% and 2% end-tidal sevoflurane. The secondary objective was to follow up the changes in RVOT gradient till 1 month postoperatively. Design: Observational study. Setting : Advanced Cardiac Centre of PGIMER, Chandigarh.MethodsFollowing intracardiac repair, RVOT gradient was measured directly by placing needle into the right ventricle and pulmonary artery at sevoflurane 1%, and subsequently, at 2% end.tidal concentration while maintaining hemodynamic stability. These gradients were also measured using transesophageal echocardiography (TEE) (ClinicalTrials.gov NCT03234582).ResultsTwenty-one patients were included in this study that had intra-cardiac repair, of which pulmonary annulus was preserved for 15 cases. Mean RVOT gradients measured invasively and by TEE at end-tidal sevoflurane concentration of 1% and 2% were not significantly different (6.67 ± 4.16 mmHg vs. 6.76 ± 3.82 mmHg, P > 0.05 invasively and 13.01 ± 7.40 mmHg vs. 12.53 ± 7.11 mmHg, P > 0.05 by TEE, respectively). RVOT gradient measured by trans-thoracic echocardiography (TTE) postoperatively at the time of extubation and during follow-up at 1 month showed significant reduction (11.37 ± 6.00 mmHg, P < 0.05 and 9.23 ± 4.92 mmHg, P < 0.01 respectively). Six patients who underwent repair with transannular patch had significant pulmonary regurgitation (PR) following surgery, with no significant change in PR severity or RVOT gradient on increasing anesthetic depth.ConclusionsPostoperative RVOT gradient was not altered by changing depth of anesthesia provided systemic blood pressure was maintained. One month postrepair RVOT gradients were significantly reduced as compared to the intraoperative values.

Project description:ObjectiveEighty percent of patients with a diagnosis of tetralogy of Fallot (TOF) do not have a known genetic etiology or syndrome. We sought to identify key molecular pathways and biological processes that are enriched in non-syndromic TOF, the most common form of cyanotic congenital heart disease, rather than single driver genes to elucidate the pathogenesis of this disease.MethodsWe undertook exome sequencing of 362 probands with non-syndromic TOF and their parents within the Pediatric Cardiac Genomics Consortium (PCGC). We identified rare (minor allele frequency <1 × 10-4), de novo variants to ascertain pathways and processes affected in this population to better understand TOF pathogenesis. Pathways and biological processes enriched in the PCGC TOF cohort were compared to 317 controls without heart defects (and their parents) from the Simons Foundation Autism Research Initiative (SFARI).ResultsA total of 120 variants in 117 genes were identified as most likely to be deleterious, with CHD7, CLUH, UNC13C, and WASHC5 identified in two probands each. Gene ontology analyses of these variants using multiple bioinformatic tools demonstrated significant enrichment in processes including cell cycle progression, chromatin remodeling, myocyte contraction and calcium transport, and development of the ventricular septum and ventricle. There was also a significant enrichment of target genes of SOX9, which is critical in second heart field development and whose loss results in membranous ventricular septal defects related to disruption of the proximal outlet septum. None of these processes was significantly enriched in the SFARI control cohort.ConclusionInnate molecular defects in cardiac progenitor cells and genes related to their viability and contractile function appear central to non-syndromic TOF pathogenesis. Future research utilizing our results is likely to have significant implications in stratification of TOF patients and delivery of personalized clinical care.

Dataset Information

BVES downregulation in non-syndromic tetralogy of fallot is associated with ventricular outflow tract stenosis.

Publications

BVES downregulation in non-syndromic tetralogy of fallot is associated with ventricular outflow tract stenosis.

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