A novel de novo TBX5 mutation in a patient with Holt-Oram syndrome leading to a dramatically reduced biological function

BACKGROUND: The Holt-Oram syndrome (HOS) is an autosomal dominant disorder affecting 1/100.000 live births. It is defined by upper limb anomalies and congenital heart defects with variable severity. We describe a dramatic phenotype of a male, 15-month-old patient being investigated for strict diagnostic criteria of HOS. ----- METHODS AND RESULTS: Genetic analysis revealed a so far unpublished TBX5 mutation, which occurs de novo in the patient with healthy parents. TBX5 belongs to the large family of T-box transcription factors playing major roles in morphogenesis and cell-type specification. The mutation located in the DNA-binding domain at position 920 (C→A) leads to an amino acid change at position 85 (proline → threonine). Three-dimensional analysis of the protein structure predicted a cis to trans change in the respective peptide bond, thereby probably provoking major conformational and functional alterations of the protein. The p.Pro85Thr mutation showed a dramatically reduced activation (97%) of the NPPA promoter in luciferase assays and failed to induce NPPA expression in HEK 293 cells compared to wild-type TBX5 protein. The mutation did not interfere with the nuclear localization of the protein. ----- CONCLUSION: These results suggest that the dramatic functional alteration of the p.Pro85Thr mutation leads to the distinctive phenotype of the patient

The impact of gender bias in cardiothoracic surgery in Europe: a European Society of Thoracic Surgeons and European Association for Cardio-Thoracic Surgery survey

OBJECTIVES The European Society of Thoracic Surgeons and the European Association for Cardio-Thoracic Surgery designed a questionnaire to assess the impact of gender bias on a cardiothoracic surgery career. METHODS A 46-item survey investigating gender bias was designed using online survey software from December 2020 to January 2021. All European Society of Thoracic Surgeons and European Association for Cardio-Thoracic Surgery members and non-members included in the mailing lists were invited to complete an electronic survey. Descriptive statistics and a comparison between gender groups were performed. RESULTS Our overall response rate was 11.5% (1118/9764), of which 36.14% were women and 63.69% were men. Women were more likely to be younger than men (P < 0.0001). A total of 66% of the women reported having no children compared to only 19% of the men (P < 0.0001). Only 6% of women vs 22% of men were professors. More women (72%) also reported never having been a formal mentor themselves compared to men (38%, P < 0.0001). A total of 35% of female respondents considered leaving surgery because of episodes of discrimination compared to 13% of men; 67% of women said that they experienced being unfairly treated due to gender discrimination. Of the male surgeons, 31% reported that they were very satisfied with their career compared to only 17% of women (P < 0.0001). CONCLUSIONS Women in cardiothoracic surgery reported significantly high rates of experiences with bias that may prevent qualified women from advancing to positions of leadership. Efforts to mitigate bias and support the professional development of women are at the centre of newly formed European committees

Improvement in long-term survival after hospital discharge but not in freedom from reoperation after the change from atrial to arterial switch for transposition of the great arteries

ObjectiveTo compare survival, freedom from reoperation, and functional status between atrial switch and arterial switch operations for transposition of the great arteries.MethodsData from 88, 329, and 512 patients who underwent Mustard, Senning, and arterial switch operations between 1974 and 2006 were analyzed.ResultsIn-hospital mortalities were 8.0% for Mustard, 4.6% for Senning, and 6.4% for arterial switch. Presence of ventricular septal defect (hazard ratio 3.3, P < .001) was the only risk factor for in-hospital mortality in multivariate analysis. Follow-up for Mustard was 22.6 ± 8.1 years, for Senning was 18.2 ± 5.7 years, and for arterial switch was 9.5 ± 5.7 years. Highest survival at 20 years was after arterial switch (96.6% ± 1.3%), followed by Senning (92.6% ± 1.5%) and Mustard (82.4% ± 4.3%). Transposition with ventricular septal defect (hazard ratio 3.1, P < .001), transposition with ventricular septal defect and left ventricular outflow tract obstruction (hazard ratio 3.0, P = .029), and Mustard operation (hazard ratio 2.1, P = .011) emerged as risk factors for late death, with arterial switch a protective factor (hazard ratio 0.3, P = .010). Highest freedom from reoperation at 20 years was after Senning (88.7% ± 1.9%), followed by arterial switch (75.0% ± 6.4%) and Mustard (70.6% ± 5.4%). Presence of complex transposition (hazard ratio 2.1, P < .001), previous palliative operation (hazard ratio 1.8, P = .016), surgery between 1985 and 1995 (hazard ratio 2.6, P = .002), surgery after 1995 (hazard ratio 3.5, P < .001), and Mustard operation (hazard ratio 3.3, P < .001) emerged as risk factors for reoperation.ConclusionChange from atrial to arterial switch led to improved long-term survival after hospital discharge but not to lower incidence of reoperation. Survival and freedom from reoperation are determined by morphology

Diagnostic Yield of Non-Invasive Testing in Patients with Anomalous Aortic Origin of Coronary Arteries : A Multicentric Experience

Background: Anomalous aortic origin of a coronary artery (AAOCA) is a congenital heart disease with a 0.3%-0.5% prevalence. Diagnosis is challenging due to nonspecific clinical presentation. Risk stratification and treatment are currently based on expert consensus and single-center case series. Methods: Demographical and clinical data of AAOCA patients from 17 tertiary-care centers were analyzed. Diagnostic imaging studies (Bidimensional echocardiography, coronary computed tomography angiography [CCTA] were collected. Clinical correlations with anomalous coronary course and origin were evaluated. Results: Data from 239 patients (42% males, mean age 15 y) affected by AAOCA were collected; 154 had AAOCA involving the right coronary artery (AAORCA), 62 the left (AAOLCA), 23 other anomalies. 211 (88%) presented with an inter-arterial course. Basal electrocardiogram (ECG) was abnormal in 37 (16%). AAOCA was detected by transthoracic echocardiography and CCTA in 53% and 92% of patients, respectively. Half of the patients reported cardiac symptoms (119/239; 50%), mostly during exercise in 121/178 (68%). An ischemic response was demonstrated in 37/106 (35%) and 16/31 (52%) of patients undergoing ECG stress test and stress-rest single positron emission cardiac tomography. Compared with AAORCA, patients with AAOLCA presented more frequently with syncope (18% vs. 5%, P = 0.002), in particular when associated with inter-arterial course (22% vs. 5%, P < 0.001). Conclusion: Diagnosis of AAOCA is a clinical challenge due to nonspecific clinical presentations and low sensitivity of first-line cardiac screening exams. Syncope seems to be strictly correlated to AAOLCA with inter-arterial course.Peer reviewe

Congenital heart disease risk loci identified by genome-wide association study in European patients

Genetic factors undoubtedly affect the development of congenital heart disease (CHD) but still remain ill defined. We sought to identify genetic risk factors associated with CHD and to accomplish a functional analysis of SNP-carrying genes. We performed a genome-wide association study (GWAS) of 4034 White patients with CHD and 8486 healthy controls. One SNP on chromosome 5q22.2 reached genome-wide significance across all CHD phenotypes and was also indicative for septal defects. One region on chromosome 20p12.1 pointing to the MACROD2 locus identified 4 highly significant SNPs in patients with transposition of the great arteries (TGA). Three highly significant risk variants on chromosome 17q21.32 within the GOSR2 locus were detected in patients with anomalies of thoracic arteries and veins (ATAV). Genetic variants associated with ATAV are suggested to influence the expression of WNT3, and the variant rs870142 related to septal defects is proposed to influence the expression of MSX7. We analyzed the expression of all 4 genes during cardiac differentiation of human and murine induced pluripotent stem cells in vitro and by single-cell RNA-Seq analyses of developing murine and human hearts. Our data show that MACROD2, GOSR2, WNT3, and MSX7 play an essential functional role in heart development at the embryonic and newborn stages

Surgery for anomalous aortic origin of coronary arteries : a multicentre study from the European Congenital Heart Surgeons Association

OBJECTIVES: We sought to describe early and late outcomes in a large surgical series of patients with anomalous aortic origin of coronary arteries. METHODS: We performed a retrospective multicentre study including surgical patients with anomalous aortic origin of coronary arteries since 1991. Patients with isolated high coronary takeoff and associated major congenital heart disease were excluded. RESULTS: We collected 156 surgical patients (median age 39.5 years, interquartile range 15-53) affected by anomalous right (67.9%), anomalous left (22.4%) and other anatomical abnormalities (9.6%). An interarterial course occurred in 86.5%, an intramural course in 62.8% and symptoms in 85.9%. The operations included coronary unroofing (56.4%), reimplantation (19.2%), coronary bypass graft (15.4%) and other (9.0%). Two patients with preoperative cardiac failure died postoperatively (1.3%). All survivors were discharged home in good clinical condition. At a median follow-up of 2 years (interquartile range 1-5, 88.5% complete), there were 3 deaths (2.2%), 9 reinterventions in 8 patients (5 interventional, 3 surgical); 91.2% are in New York Heart Association functional class CONCLUSIONS: Surgical repair of anomalous aortic origin of coronary arteries is effective and has few complications. Unroofing and coronary reimplantation are safe and are the most common procedures. The occurrence of late adverse events is not negligible, and long-term surveillance is mandatory. Most young athletes can return to an unrestrained lifestyle.Peer reviewe

Anomalous aortic origin of coronary arteries : Early results on clinical management from an international multicenter study

Background: Anomalous aortic origin of coronary arteries (AAOCA) is a rare abnormality, whose optimal management is still undefined. We describe early outcomes in patients treated with different management strategies. Methods: This is a retrospective clinicalmulticenter study including patients with AAOCA, undergoing or not surgical treatment. Patients with isolated high coronary take off and associated major congenital heart disease were excluded. Preoperative, intraoperative, anatomical and postoperative data were retrieved from a common database. Results: Among 217 patients, 156 underwent Surgical repair (median age 39 years, IQR: 15-53), while 61 were Medical (median age 15 years, IQR: 8-52), inwhomAAOCA was incidentally diagnosed during screening or clinical evaluations. Surgical patients were more often symptomatic when compared to medical ones (87.2% vs 44.3%, p b 0.001). Coronary unroofing was the most frequent procedure (56.4%). Operative mortality was 1.3% (2 patients with preoperative severe heart failure). At a median follow up of 18 months (range 0.1-23 years), 89.9% of survivors are in NYHA Conclusions: Surgery for AAOCA is safe andwith low morbidity. When compared to Medical patients, who remain on exercise restriction and medical therapy, surgical patients have a benefit in terms of symptoms and return to normal life. Since the long term-risk of sudden cardiac death is still unknown, we currently recommend accurate long term surveillance in all patients with AAOCA. (C) 2019 The Authors. Published by Elsevier B.V.Peer reviewe

Gender representation among speaking and leader roles at European cardio-thoracic surgical annual meetings

OBJECTIVES: Our goal was to evaluate gender representation among session leaders and abstract presenters at European cardiothoracic surgical annual meetings. METHODS: We did a descriptive study of the gender distribution among session leaders and abstract presenters at 2 European cardiothoracic international meetings from 2017 to 2022. Data from publicly available programmes were used to generate a list of session leaders and abstract presenters. The primary outcome was to evaluate the proportion of female sessions leaders at the annual meetings. Descriptive analyses were performed including the Cochran-Armitage trend test for linear trend of proportions. RESULTS: A total of 1025 sessions of 11 annual meetings of the European Association for Cardio-Thoracic Surgery (EACTS) and the European Society of Thoracic Surgeons were examined. A total of 397 (13.2%) out of 3007 total session leaders and 955 (15.2%) out of 6251 abstract presenters were female. From 2017 to 2022, the proportions of both female session leaders and abstract presenters trended significantly [10.4% to 21.9% (P&lt;0.001) and 13.7% to 18.3% (P&lt;0.001), respectively]. The EACTS female members and female meeting attendees significantly increased from 2017 to 2022 [11.1% to 15.9% (P&lt;0.001) and 23.7% to 26.9% (P&lt;0.001)], respectively. Most of the women attendees at the EACTS and the European Society of Thoracic Surgeons meetings who were session leaders and speakers came from Germany, Italy, the United Kingdom and the United States. CONCLUSIONS: Women are under-represented compared to men in leadership and speaking roles at European cardio-thoracic surgical annual meetings. In the past few years, an encouraging positive trend over time for female leadership roles has been noted; as a result, the proportion of female society members is represented at the annual meetings.</p