Valve hemodynamic performance and myocardial strain after implantation of a third-generation, balloon-expandable, transcatheter aortic valve

Background: Left ventricular (LV) mechanics are impaired in patients with severe aortic stenosis (AS); however, transcatheter aortic valve implantation (TAVI) may positively affect LV mechanics. Assessed herein is the performance of the SAPIEN 3 transcatheter heart valve (THV) and the effect of TAVI on LV function recovery, as assessed by global longitudinal strain (GLS). Methods: A subset of patients from the SOURCE 3 registry (n = 276) from 16 European centers received SAPIEN 3 balloon-expandable THV. Echocardiography was performed at baseline, postprocedure, and at 1 year, including assessment of GLS using standard two-dimensional images, and was analyzed in a core laboratory. Paired analyses between baseline and discharge, baseline and at 1 year were conducted. Results: Hemodynamic parameters were improved after TAVI and sustained to 1 year. At 1 year, the rate of moderate to severe paravalvular leaks (PVL), and moderate to severe mitral and tricuspid regurgitations were 1.8%, 1.7%, and 8.0%, respectively. The discharge GLS (–15.6 ± 5.1; p = 0.004; n = 149) improved significantly from baseline (–15.1 ± 4.8) following TAVI. This improvement was sustained at 1 year compared with baseline (–17.0 ± 4.6, p < 0.001; n = 100). Conversely, LV ejection fraction (LVEF) did not significantly change following TAVI (p = 0.47). Conclusions: Following TAVI with a third-generation THV, valve performances were good at 1 year with low PVL rate. The LV mechanics improved immediately after the procedure and were maintained at 1 year. These findings demonstrate the benefit of TAVI on LV mechanics, and suggests that GLS may be superior to LVEF in assessing this benefit. Clinicaltrial.gov number: NCT0269895

Long-term results of surgical treatment of secondary severe mitral regurgitation in patients with end-stage heart failure: Advantage of prosthesis insertion

International audienc

Le reste

Que reste-t-il, en ce début de siècle, des acquis de ta civilisation européenne qui soit susceptible d'être repris, réagencé, voire restauré ? Et qu'est-ce qui demeure intraitable, irreprésentable, persistant toutefois à hanter la réflexion et la création ? S'il est ce qui subsiste après une disparition, le reste est aussi ce qui a été exclu pour qu'un ensemble se constitue. Cependant, ce qui a été exclu subsiste, obligeant à reconsidérer les procédures qui ont produit cette part à la fois rétive et spectrale, invitant à repenser la constitution du tout dont le reste, selon une représentation courante, serait un fragment. Au-delà de l'inventaire et du bilan, de la nostalgie comme de la célébration, ce recueil voudrait offrir l'occasion d'une interrogation conceptuelle, y compris sur la pertinence même de la notion de reste. Les auteurs ici rassemblés tentent, dans les domaines littéraire, philosophique et artistique, d'identifier les formes du reste auxquelles ils ont affaire, d'en dégager un potentiel agissant capable de nous aider à penser le présent ; ils proposent de donner un contenu pratique - sinon praticable - à la pensée du reste

SCN5A Variants as Genetic Arrhythmias Triggers for Familial Bileaflet Mitral Valve Prolapse

International audienceMitral valve prolapse (MVP) is a common valvular heart defect with variable outcomes. Several studies reported MVP as an underestimated cause of life-threatening arrhythmias and sudden cardiac death (SCD), mostly in young adult women. Herein, we report a clinical and genetic investigation of a family with bileaflet MVP and a history of syncopes and resuscitated sudden cardiac death. Using family based whole exome sequencing, we identified two missense variants in the SCN5A gene. A rare variant SCN5A:p.Ala572Asp and the well-known functional SCN5A:p.His558Arg polymorphism. Both variants are shared between the mother and her daughter with a history of resuscitated SCD and syncopes, respectively. The second daughter with prodromal MVP as well as her healthy father and sister carried only the SCN5A:p.His558Arg polymorphism. Our study is highly suggestive of the contribution of SCN5A mutations as the potential genetic cause of the electric instability leading to ventricular arrhythmias in familial MVP cases with syncope and/or SCD history

Expanding the phenome and variome of the ROBO-SLIT pathway in congenital heart defects: toward improving the genetic testing yield of CHD

International audienceBackground Recent studies have shown the implication of the ROBO-SLIT pathway in heart development. Within this study, we aimed to further assess the implication of the ROBO and SLIT genes mainly in bicuspid aortic valve (BAV) and other human congenital heart defects (CHD). Methods We have analyzed a cohort of singleton exome sequencing data comprising 40 adult BAV patients, 20 pediatric BAV patients generated by the Pediatric Cardiac Genomics Consortium, 10 pediatric cases with tetralogy of Fallot (ToF), and one case with coarctation of the aorta. A gene-centered analysis of data was performed. To further advance the interpretation of the variants, we intended to combine more than 5 prediction tools comprising the assessment of protein structure and stability. Results A total of 24 variants were identified. Only 4 adult BAV patients (10%) had missense variants in the ROBO and SLIT genes. In contrast, 19 pediatric cases carried variants in ROBO or SLIT genes (61%). Three BAV patients with a severe phenotype were digenic. Segregation analysis was possible for two BAV patients. For the homozygous ROBO4 : p.(Arg776Cys) variant, family segregation was consistent with an autosomal recessive pattern of inheritance. The ROBO4 : c.3001 + 3G > A variant segregates with the affected family members. Interestingly, these variants were also found in two unrelated patients with ToF highlighting that the same variant in the ROBO4 gene may underlie different cardiac phenotypes affecting the outflow tract development. Conclusion Our results further reinforce the implication of the ROBO4 gene not only in BAV but also in ToF hence the importance of its inclusion in clinical genetic testing. The remaining ROBO and SLIT genes may be screened in patients with negative or inconclusive genetic tests

Clinical insights into a tertiary care center cohort of patients with bicuspid aortic valve

International audienceAlthough bicuspid aortic valve (BAV) is one of the most common congenital heart diseases, clinical data associated with valve dysfunction are still limited. We evaluated clinical characteristics and echocardiography of French patients with BAV associated with leaking and stenosis degeneration. We initiated a prospective registry from 2014 to 2018 at a tertiary center. A total of 223 patients (168 males [75%], age 53 ± 17 years) were enrolled. Among these patients 83% had left–right coronary cusps fusion, 80% Sievers type 1 BAV and 49% showed aortic dilatation. Twenty-four patients (11%) had normal valve function, 66 patients (31%) had aortic stenosis (AS), 91 patients (41%) had aortic regurgitation (AR) and 40 patients (17%) had AR and AS. BAV phenotype did not predict neither AS nor AR (all p > 0.1). By multivariable analysis, age > 50 (41.6[10.3–248.2], p < 0.001) and presence of raphe/fusion (12.8[2.4–87.4], p < 0.001) were significantly associated with AS, whereas male gender was associated with AR (5[1.6–16.4], p = 0.005). In addition, leaking degeneration was observed at a much younger age than stenosis (44 ± 14 years vs. 66 ± 10 years, p < 0.01) and among patients with valve dysfunction younger age was independently associated with AR (1.9[1.85–1.94], p < 0.001). In this study we confirmed high prevalence of valve dysfunction at first diagnosis of BAV in a referred population. The degenerative process differs according to type of dysfunction and is mainly dependent on age and gender

Variations in the poly-histidine repeat motif of HOXA1 predispose individuals to bicuspid aortic valve

Abstract Bicuspid aortic valve (BAV) is the most common cardiovascular malformation (0.5–1.2% of the population) and is often associated with premature aortic valve stenosis or insufficiency, aortic aneurysm and other congenital cardiac heart defects. Although highly heritable, few causal mutations have been identified in BAV patients. Here, we report the association of novel variants in the transcription factor HOXA1 with BAV in humans. Targeted sequencing of HOXA1 in a cohort of 333 BAV patients identified rare indel variants in the homopolymeric histidine tract of HOXA1. In vitro analysis revealed that disruption of the histidine repeat motif causes a significant reduction in the half-life of the protein, and that these variants are associated with a defective transcriptional activity of the HOXA1 protein. Targeting the zebrafish hoxa1a ortholog in vivo resulted in aortic valve defects that could be rescued by expressing the wild-type human HOXA1 . Furthermore, expression of HOXA1 Histidine variants in zebrafish also impacted aortic valve development indicating a dominant negative effect of these mutated proteins. Lastly, homozygous knockout mice for Hoxa1 develop a BAV phenotype, which is associated with a very small, rudimentary non-coronary leaflet. Genetic lineage analysis indicates that this defect is caused by a strong reduction of mesenchymal cells in the intercalated cushion due to a failure of neural crest cell migration toward the heart which is consistent with our transcriptomic analysis showing a down-regulation of premigratory and migratory neural crest markers in Hoxa1 −/− compared with control embryos. Together, these findings indicate that variants causing HOXA1 dysfunction play a significant role in the genetic cause of BAV in humans

Long-term mortality associated with left ventricular dysfunction in mitral regurgitation due to flail leaflets: a multicenter analysis.

Background- Ejection fraction (EF) as a marker of left ventricular (LV) dysfunction and the appropriate thresholds for diagnosing severe or mild/moderate LV dysfunction in mitral regurgitation are doubted and poorly followed in clinical practice. We aimed at assessing the role of EF in a large registry of organic mitral regurgitation to objectively establish thresholds for various degrees of LV dysfunction and to analyze whether mitral surgery remains beneficial in those subsets of patients. Methods and Results- We investigated the relation between EF and mortality in 1875 patients with mitral regurgitation due to flail leaflets in sinus rhythm (65±13 years; median EF, 66% [60%-71%]) enrolled in the Mitral Regurgitation International Database (MIDA) registry. With EF 60%. Above 60%, no EF threshold further determined survival. The benefit of surgery remained considerable in the groups with EF 60%, with EF dropping <60%, mortality increases precipitously and prompt surgical referral is critical to outcome