Dagenais, François

BACKGROUND: Bicuspid aortic valve (BAV) is a frequent congenital heart defect with a high heritability. Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases. This study aimed to further understand the genetic architecture of BAV. METHODS: A genome-wide association study meta-analysis including 9631 cases among 65 677 participants was performed. Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves. The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified in zebrafish. A polygenic risk score was developed, its association with BAV was evaluated in an independent cohort, and its association with a wide range of phenotypes (n=976) was evaluated in UK Biobank (n=355 618 individuals). RESULTS: Thirty-six genomic loci were identified, including 32 that were not described previously. Among the prioritized genes, KANK2 and ERBB4 were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas PRDM6 and STRN were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively. Targeting 4 candidate genes ( WNT4 , LEF1 , STRN , and KANK2 ) in zebrafish led to disruption in cardiac development. A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90–2.25; P =5.43×10 -62 ) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank. CONCLUSIONS: This study supports a significant polygenic contribution to BAV, where the combination of multiple common variants in genes involved in heart morphogenesis disrupts aortic valve development.

Abstract OBJECTIVES Safety, efficacy and durability are important considerations when selecting a bioprosthesis for aortic valve replacement (AVR). This study assessed 7-year clinical outcomes and haemodynamic performance of the Avalus bioprosthesis. METHODS Patients indicated for surgical AVR were enrolled in this prospective, nonrandomized trial, conducted across 39 sites globally. The primary end-point of this analysis was freedom from surgical explant or percutaneous valve-in-valve reintervention due to structural valve deterioration (SVD) at 7 years of follow-up, determined using Kaplan–Meier (KM) analysis. We also evaluated a composite end-point of SVD and/or severe haemodynamic dysfunction requiring reintervention. Survival, valve-related safety events and haemodynamic performance were assessed. Deaths and safety events were adjudicated by an independent clinical events committee. RESULTS A total of 1132 patients underwent surgical AVR. Mean age was 70 years; 854 patients (75%) were men. The mean STS risk of mortality was 2.0 ± 1.4%, and 659 patients (58%) had a New York Heart Association classification of I/II. One or more concomitant procedures were performed in 577 patients (51%). At 7 years, the Kaplan–Meier rate of freedom from SVD/severe haemodynamic dysfunction requiring reintervention was 1.2% (0.5–2.5%) with no cases adjudicated as SVD. The survival rate was 82.6% (79.5–85.0%). The KM event rate was 5.7% (4.3–7.7%) for reintervention, 6.3% (4.9–8.3%) for endocarditis and 0.4% (0.1–1.1%) for valve thrombosis. Mean aortic gradient, dimensionless velocity index and effective orifice area were 13.8 ± 5.9 mmHg, 0.42 ± 0.09 and 1.99 ± 0.53 cm2, respectively. CONCLUSIONS This analysis demonstrated excellent durability of the Avalus valve with good clinical outcomes and stable haemodynamic performance through 7 years of follow-up.

Abstract OBJECTIVES The objective of this analysis was to assess the normal haemodynamic performance of contemporary surgical aortic valves at 1 year postimplant in patients undergoing surgical aortic valve replacement for significant valvular dysfunction. By pooling data from 4 multicentre studies, this study will contribute to a better understanding of the effectiveness of surgical aortic valve replacement procedures, aiding clinicians and researchers in making informed decisions regarding valve selection and patient management. METHODS Echocardiograms were assessed by a single core laboratory. Effective orifice area, dimensionless velocity index, mean aortic gradient, peak aortic velocity and stroke volume were evaluated. RESULTS The cohort included 2958 patients. Baseline age in the studies ranged from 70.1 ± 9.0 to 83.3 ± 6.4 years, and Society of Thoracic Surgeons risk of mortality was 1.9 ± 0.7 to 7.5 ± 3.4%. Twenty patients who had received a valve model implanted in fewer than 10 cases were excluded. Ten valve models (all tissue valves; n = 2938 patients) were analysed. At 1 year, population mean effective orifice area ranged from 1.46 ± 0.34 to 2.12 ± 0.59 cm2, and dimensionless velocity index, from 0.39 ± 0.07 to 0.56 ± 0.15. The mean gradient ranged from 8.6 ± 3.4 to 16.1 ± 6.2 mmHg with peak aortic velocity of 1.96 ± 0.39 to 2.65 ± 0.47 m/s. Stroke volume was 75.3 ± 19.6 to 89.8 ± 24.3 ml. CONCLUSIONS This pooled cohort is the largest to date of contemporary surgical aortic valves with echocardiograms analysed by a single core lab. Overall haemodynamic performance at 1 year ranged from good to excellent. These data can serve as a benchmark for other studies and may be useful to evaluate the performance of bioprosthetic surgical valves over time. Clinical trial registration number NCT02088554, NCT02701283, NCT01586910 and NCT01531374.