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 MSX1. 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 MSX1 play an essential functional role in heart development at the embryonic and newborn stages.

Long-term results after the arterial switch operation have shown that patients may develop aortic insufficiency, and that some even require aortic valve replacement. A retrospective review of 479 hospital survivors after the arterial switch operation (ASO) was performed. Echocardiographic findings were reviewed and the incidence, as well as the progression, of aortic insufficiency (AI) was investigated. The combined end point of the study was defined as the first documented occurrence of moderate or more aortic insufficiency or the need for aortic valve replacement (AVR). Upon discharge from the hospital 15% of the patients showed an AI of at least grade I, progressing to 20.7% after 1 year. At a mean follow-up time of 9.3+/-6 years, 249 patients (53%) were free from AI, trivial AI was present 179 patients (38%), mild AI in 34 patients (7.2%) and moderate AI in 7 patients (1.5%). There is a progression of AI with time after ASO (r=0.26, p<0.001). A total of 18 patients reached the combined end point, out of which 11 underwent an AVR at a mean time of 11.2 years after ASO. Freedom from the end point was 99.7+/-0.3%, 97.5+/-1%, 91.9+/-2%, 84.6+/-6% at 5, 10, 15 and 20 years, respectively. The following risk factors were identified by univariate analysis: Taussig-Bing anomaly (p=0.01), ventricular septal defect (VSD) (p=0.006), prior pulmonary artery banding (p=0.004), age over 12 months at time of ASO (p=0.001) and a postoperative incidence of trivial AI (p<0.0001). Independent risk factors by multivariate analysis were the presence of a left ventricular outflow tract obstruction (p<0.0001) and at least a trivial AI at 1 year after the ASO (p<0.0001). The incidence of trivial or mild AI after the ASO is considerable and a progression over time is evident. However, severe AI and the need for AVR are rare. Patients with VSD or Taussig-Bing anomaly, and those with left ventricular outflow tract obstruction exhibit a higher risk of developing significant aortic insufficiency. Particularly patients who have developed an AI at 1 year after the ASO need to be under close observation.

Background: Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assumed to play a prominent role. Methods: To identify perturbations in gene programs controlling ventricular muscle lineage development in HLHS, we performed whole-exome sequencing of 87 HLHS parent–offspring trios, nuclear transcriptomics of cardiomyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart development, single cell RNA sequencing, and 3D modeling in induced pluripotent stem cells from 3 patients with HLHS and 3 controls. Results: Gene set enrichment and protein network analyses of damaging de novo mutations and dysregulated genes from ventricles of patients with HLHS suggested alterations in specific gene programs and cellular processes critical during fetal ventricular cardiogenesis, including cell cycle and cardiomyocyte maturation. Single-cell and 3D modeling with induced pluripotent stem cells demonstrated intrinsic defects in the cell cycle/unfolded protein response/autophagy hub resulting in disrupted differentiation of early cardiac progenitor lineages leading to defective cardiomyocyte subtype differentiation/maturation in HLHS. Premature cell cycle exit of ventricular cardiomyocytes from patients with HLHS prevented normal tissue responses to developmental signals for growth, leading to multinucleation/polyploidy, accumulation of DNA damage, and exacerbated apoptosis, all potential drivers of left ventricular hypoplasia in absence of hemodynamic cues. Conclusions: Our results highlight that despite genetic heterogeneity in HLHS, many mutations converge on sequential cellular processes primarily driving cardiac myogenesis, suggesting novel therapeutic approaches.

Reconstruction of the right ventricular outflow tract (RVOT) with a conduit in patients below 1 year of age remains a matter of concern due to limited availability and durability of conduits. We sought to analyse the freedom from conduit exchange in this subgroup of patients by comparing different conduits. Data of 145 consecutive patients below 1 year of age, requiring a conduit for RVOT reconstruction between 1994 and 2011 were reviewed. The endpoints of the study were defined as: ‘conduit exchange for any reason’, ‘at least moderate conduit stenosis’ and ‘at least moderate insufficiency’. Homografts, bovine jugular vein conduits (Contegra) and porcine-valved Dacron conduits (Hancock) were implanted in 62 (43%), 35 (24%) and 48 (33%) patients, respectively. The mean conduit diameter was 12.9 ± 1.3 mm. A conduit exchange was necessary in 72 patients (55%) at a median time of 5.9 years [1.1–10.8]. The rate of freedom from conduit exchange at 5 years was 69.4 ± 6.6, 59.4 ± 8.7 and 53.8 ± 7.4%, respectively (P = 0.4). The rate of freedom from at least moderate stenosis was 85.4 ± 5.6, 75.1 ± 9.1 69.1 ± 7.9% at 5 years and 59.2 ± 11.1, 35.8 ± 12.0, 49.7 ± 10.1% at 10 years, for homografts, Contegra and Hancock conduits, respectively. The rate of freedom from at least moderate conduit insufficiency was 91.7 ± 4, 74.6 ± 9.1, 86.9 ± 7.4% at 5 years and 64.8 ± 14.1, 44.2 ± 13.7, 52.1 ± 14.2% at 10 years, for homografts, Contegra and Hancock conduits, respectively. Patients with a Contegra conduit developed moderate conduit stenosis or insufficiency faster than patients with a homograft (P = 0.01). Age below 1 month and heterotopic implantation of the conduit emerged as risk factors for conduit exchange in the univariate analysis (P = 0.05, P = 0.02, respectively). There was no significant influence of the conduit type, conduit size, z-score or the body surface area. In the multivariate analysis, heterotopic implantation emerged as the only risk factor for conduit exchange (P = 0.02, hazard ratio = 1.6, 95% confidence interval = 1.0–2.7). Homografts, bovine jugular vein conduits and porcine-valved Dacron conduits exhibit equal durability after implantation in patients below 1 year of age independent of their size. Nonetheless, moderate conduit stenosis or insufficiency develops earlier in patients with a Contegra conduit. Conduit placement in the neonatal period and implantation in a heterotopic position shortens the durability.

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. 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. 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). 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.