Transcatheter aortic valve implantation in patients with rheumatic aortic stenosis.

BACKGROUND Rheumatic heart disease (RHD) accounts for the highest number of deaths from valvular heart disease globally. Yet, rheumatic aortic stenosis (AS) was excluded from landmark studies investigating the safety and efficacy of transcatheter aortic valve implantation (TAVI). We aimed to describe the clinical and anatomical characteristics of patients with rheumatic AS undergoing TAVI, and to compare procedural and clinical outcomes with patients undergoing TAVI for degenerative AS. METHODS In a prospective TAVI registry, patients with rheumatic AS were identified based on International Classification of Diseases version 10 codes and/or a documented history of acute rheumatic fever and/or the World Heart Federation criteria for echocardiographic diagnosis of RHD, and were propensity score-matched in a 1:4 ratio to patients with degenerative AS. RESULTS Among 2329 patients undergoing TAVI, 105 (4.5%) had rheumatic AS. Compared with patients with degenerative AS, patients with rheumatic AS were more commonly female, older, had higher surgical risk and more commonly suffered from multivalvular heart disease. In the unmatched cohort, both technical success (85.7% vs 85.9%, p=0.887) and 1-year cardiovascular mortality (10.0% vs 8.6%; HR 1.16, 95% CI 0.61 to 2.18, p=0.656) were comparable between patients with rheumatic and degenerative AS. In contrast, patients with rheumatic AS had lower rates of 30-day and 1-year cardiovascular mortality compared with matched patients with degenerative AS (1.9% vs 8.9%, adjusted HR (HRadj) 0.18, 95% CI 0.04 to 0.80, p=0.024; and 10.0% vs 20.3%, HRadj 0.44, 95% CI 0.24 to 0.84, p=0.012, respectively). CONCLUSION TAVI may be a safe and effective treatment strategy for selected elderly patients with rheumatic AS. TRIAL REGISTRATION NUMBER NCT01368250

Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins, and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Utilizing exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with YnMyr chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), with ages ranging from 1 to 50 years old, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%), and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each), as well as hypertrophy of the clava (24%) were common neuroimaging findings. acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism, and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localisation and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-Myristoylation was similarly affected in acbd6-deficient zebrafish and Xenopus tropicalis models, including Fus, Marcks, and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders

Comparison of 3 différent cardiac T2-mapping techniques at 1.5 Tesla

Le T2 mapping est une technique d'imagerie en IRM cardiaque qui gagne de plus en plus d'importance dans le domaine de la cardiologie. En effet, cette technique est de plus en plus employée en clinique afin de mettre en évidence un œdème du myocarde lors d'inflammation ou d'atteintes ischémiques. La technique du T2 mapping est en phase de remplacer la technique d'imagerie en pondération T2. L'utilisation du T2 mapping nécessite souvent un compromis entre résolution spatiale et acquisition de coupes en apnées. Si une méthode de mesure fiable existait permettant de corriger l'acquisition des images tout en tenant compte de la respiration, cela nous permettrait d'atteindre une meilleure résolution spatiale ainsi que l'examen d'une plus grande partie du myocarde. Dans ce contexte, j'ai mené un travail de recherche prospectif en collaboration avec le centre d'imagerie cardiaque du CHUV à Lausanne (Prof. Juerg Schwitter, Directeur de thèse) afin de comparer la performance de 3 différentes techniques d'imagerie d'IRM cardiaque (apnée vs 2 techniques de mapping T2 : navigué sur le foie 2D, auto-navigation 3D). Ces acquisitions ont été effectuées sur 13 volontaires sains. Chaque cœur a été analysé selon un modèle de tranches elles même divisées en segments. En utilisant un logiciel de traitement d'image (Gyrotools), nous avons déterminé la valeur T2 de chaque segment. A des fins de comparaison entre les valeurs T2, la méthode d'acquisition des mesures répétées selon ANOVA et une correction selon Bonferroni ont été appliquées. Ces mesures ont ensuite été exprimées en coefficient de variation permettant une comparaison entre les différentes techniques d'acquisitions. Cette étude a mis en évidence une très bonne fiabilité de la technique d'imagerie en apnée avec un faible coefficient de variation entre ses valeurs T2. La technique naviguée sur le foie est une alternative intéressante chez des patients où l'acquisition d'images en apnées n'est pas envisageable. Concernant la technique auto-naviguée 3D, les valeurs T2 ont mis en évidence un large coefficient de variation. De ce fait, cette méthode d'acquisition manque de robustesse comparée aux deux autres techniques et n'est pas encore indiquée pour l'utilisation en clinique. D'autres travaux de recherche sont nécessaires afin de permettre le développement de la technique 3D qui à terme permettra l'analyse d'une plus grande partie du myocarde ainsi qu'une meilleure résolution spatiale