0195: Identification of patients (pts) with chronic myeloid leukemia (CML) at high risk of artery occlusive events (AOE) during treatment with the 2nd generation tyrosine kinase inhibitor (TKI) nilotinib

BackgroundNilotinib is approved for use in pts with CML after failure of imatinib and in newly diagnosed CP-CML. However, several studies report a nilotinib-associated risk of AOE (arterial occlusive event), especially in pts with preexisting risk factors for CVD. In this study, we aimed at determining whether CVD risk estimation using the 2012 ESC classification could be useful to identify patients at high risk of AOE during nilotinib therapy.MethodsPts (n=75) treated with nilotinib upfront or after failure of prior TKI at our institution were included provided that baseline CVD status could be retrospectively collected. Patients were categorized into 2 groups according to ESC 2012 classification: low/moderate (L/M) and high/very high (H/VH) CVD risk.ResultsAt nilotinib initiation, median age was 51 years (19-76), 41 pts (54.7%) were males. At baseline, medical history revealed H/VH risk category in 15 pts (20%) including established CVD in 6 pts (8%) (all diagnosed before CML), DM (diabete melitus) in 10 pts (13.3%), severe AH (arterial hypertension) in 1 pt (1.3%), familial dyslipidemia in 1 pt (1.3%) and a SCORE ≥5% in 2 pts (2.6%).AOE occurred in 12 pts with myocardial infarction (MI) or coronary heart disease (CHD) (n=3), cerebrovascular events (CeVD) (n=3) and peripheral artery disease (PAD) (n=6). Cumulative incidence of AOE by 48 months was 72.22% (95% CI: 47.46-100) in the H/VH group and only 12.13% (95% CI: 4.32-34.08) in the L/M group. Log Rank comparison of Kaplan Meier analysis of 48-month survival without AOE showed a significant difference between the 2 groups (27.78% (95% CI: 0-58.9) versus 84.38% (95% CI: 67.04-100) p=0.0001). Sensitivity of the ESC classification in nilotinib-treated patients was 67% and specificity 89%.ConclusionsIn our retrospective study, CVD risk estimation according to the 2012 ESC classification reveals that pts who belong to the H/VH risk group at baseline are at very high risk of AOE during nilotinib therapy. In this context, CVD risk should be reassessed throughout therapy and risk factors should be tightly controlled according to current guidelines

Aortic Wall Elastic Properties in Case of Bicuspid Aortic Valve

Purpose of the ReviewBicuspid aortic valve (BAV) is associated with a significant risk of development of aneurysm and dissection of the ascending thoracic aorta. Development of what is called BAV associated aortopathy is particularly heterogeneous with an uncertain prognosis and with no prognostic biomarkers except for the aortic diameter. This situation leads to an important variability of the therapeutic strategy of this aortopathy. By reviewing the literature on aortic stiffness in the case of BAV, we aimed at evaluating its potential prognostic role in the development of aortic dilatation.Recent FindingsStudies evaluating aortic stiffness, with ultrasound or magnetic resonance imaging, converge toward the description of an increased segmental aortic stiffness in BAV patients regardless of age, diameter or aortic level, from the root to the arch. Even though there is a lack of longitudinal studies evaluating the progression of aortic dilatation, new data have recently shown the potential prognostic role of the maximal rate of systolic distension of the aortic wall with magnetic resonance imaging.SummaryAlthough the use of aortic distensibility calculation is a simple evaluation of stiffness that could be easily transposed in daily practice, its interpretation remains uncertain. New arterial stiffening indicators seem more promising but need a stronger validation

0059 : Non invasive ultrasonic chordal cutting

ObjectiveChordal cutting targeting leaflet tethering has been described to improve the efficiency of annuloplasty during ischemic mitral regurgitation surgery. Histotripsy is an ultrasound based technique for tissue fragmentation through the cavitation generated by a very intense ultrasonic pulse. In this study we investigate the feasibility of using histotripsy for chordal cutting to avoid cardiopulmonary bypass and invasive surgery in infarcted heart.MethodsExperiments were performed in vitro in explanted sheep heart (N=10) and in vivo in sheep beating heart (N=5, 40+/-4kg). In vitro, the mitral valve basal chordae was removed, fixed on a holder in a water tank. The ultrasound pulses were emitted from the therapeutic device (1- MHz focused transducer, pulses of 8μs duration, peak negative pressure of 17 MPa, repetition frequency of 100Hz) placed at a distance of 64mm. In vivo, we performed sternotomy and the device was applied on the thorax cavity which was filled out with water. We analysed MV coaptation and chordae by real time 3D echocardiography. The animals were sacrificed at the end of the procedure, for postmortem anatomical exploration of the heart.ResultsIn vitro, all the basal chordae were completely cut. The mean procedure time was 5.5 (+/-1.7) minutes. The diameter of the chordae was the main criteria affecting the duration of procedure. In the sheep, central basal chordae of anterior leaflet were completely cut. The mean procedure time was 22 (+/-9) minutes. By echography, the sectioned chordae was visible and no mitral valve prolapse was found. All the postmortem anatomical exploration of hearts confirmed the section of the basal chordea. No additional lesions were objectified.ConclusionsNoninvasive ultrasound histotripsy succeed to cut mitral valve basal chordae in vitro and in vivo in beating heart. If positive, this will open the door of completely noninvasive technique for MV repair especially in case of ischemic or functional MR

Role of the advanced nurse practitioner within the vascular team: A qualitative study of vascular physicians and nurses

ObjectiveTo assess the perception of Advanced Nurse Practitioners (ANP) by physicians and nurses in vascular medicine. As the status of ANP in France was recently enacted by law in 2018, we aimed to investigate physicians and nurses working with patients suffering from Peripheral Artery Disease (PAD) to gather their opinions and draw the cooperation outlines these practitioners could have with an ANP.MethodsA qualitative study based on in-depth interviews was conducted among healthcare practitioners taking care of patients with PAD: 10 physicians working either in a private practice settings or hospital settings or both, and eight nurses working within a hospital inpatients vascular unit. Verbatim responses were extracted and coded according to a continuous thematization method.ResultsThree main features emerged from participants’ responses. Vascular medicine has a specific organization with a significant lack of time and staff to fulfill the mission regarding patients’ severity of illness. Second, the ANP is wanted to fill part of this gap. The expected benefits include a smoother care pathway and increased capacity for cardiovascular education and prevention, especially during consultations. Lastly, some clarification is required to integrate such new practitioners within vascular teams already in place.ConclusionAdvanced nurse practitioners could be the missing link in a “Vascular team” by creating a continuum in the care of patients with PAD, ensuring clinical assessment, nursing supervision, adverse event screening, and renewing drug prescriptions with the required adaptations while ensuring essential part of therapeutic education adapted to each patient

Novel Association of the NOTCH Pathway Regulator MIB1 Gene With the Development of Bicuspid Aortic Valve.

IMPORTANCE Nonsyndromic bicuspid aortic valve (nsBAV) is the most common congenital heart valve malformation. BAV has a heritable component, yet only a few causative genes have been identified; understanding BAV genetics is a key point in developing personalized medicine. OBJECTIVE To identify a new gene for nsBAV. DESIGN, SETTING, AND PARTICIPANTS This was a comprehensive, multicenter, genetic association study based on candidate gene prioritization in a familial cohort followed by rare and common association studies in replication cohorts. Further validation was done using in vivo mice models. Study data were analyzed from October 2019 to October 2022. Three cohorts of patients with BAV were included in the study: (1) the discovery cohort was a large cohort of inherited cases from 29 pedigrees of French and Israeli origin; (2) the replication cohort 1 for rare variants included unrelated sporadic cases from various European ancestries; and (3) replication cohort 2 was a second validation cohort for common variants in unrelated sporadic cases from Europe and the US. MAIN OUTCOMES AND MEASURES To identify a candidate gene for nsBAV through analysis of familial cases exome sequencing and gene prioritization tools. Replication cohort 1 was searched for rare and predicted deleterious variants and genetic association. Replication cohort 2 was used to investigate the association of common variants with BAV. RESULTS A total of 938 patients with BAV were included in this study: 69 (7.4%) in the discovery cohort, 417 (44.5%) in replication cohort 1, and 452 (48.2%) in replication cohort 2. A novel human nsBAV gene, MINDBOMB1 homologue MIB1, was identified. MINDBOMB1 homologue (MIB1) is an E3-ubiquitin ligase essential for NOTCH-signal activation during heart development. In approximately 2% of nsBAV index cases from the discovery and replication 1 cohorts, rare MIB1 variants were detected, predicted to be damaging, and were significantly enriched compared with population-based controls (2% cases vs 0.9% controls; P = .03). In replication cohort 2, MIB1 risk haplotypes significantly associated with nsBAV were identified (permutation test, 1000 repeats; P = .02). Two genetically modified mice models carrying Mib1 variants identified in our cohort showed BAV on a NOTCH1-sensitized genetic background. CONCLUSIONS AND RELEVANCE This genetic association study identified the MIB1 gene as associated with nsBAV. This underscores the crucial role of the NOTCH pathway in the pathophysiology of BAV and its potential as a target for future diagnostic and therapeutic intervention.This study was supported in part by grants PID2019-104776RB-I00 and CB16/ 11/00399 (Dr de la Pompa) from the Spanish Ministerio de Ciencia e Innovación (MCIN/ AEI/ 10.13039/501100011033/); a grant from Hadassah France Association (Drs Gilon and Tessler); a grant from the Center for Interdisciplinary Data Science Research of the Hebrew University of Jerusalem (Dr Tessler); grant R35 CA220340 from the National Institutes of Health (Dr Blacklow), and grants R21HL150373, R01HL114823 (Dr Body); BSF grants 2013269 and 2017245 (Drs. Sprinzak and Blacklow); a consolidator grant from the European Research Council (Genomia – ERC-COG-2017-771945; Dr Loeys); the European Reference Network on rare multisystemic vascular disorders (VASCERN - project ID: 769036 partly cofunded by the European Union Third Health Programme (Drs Loeys and Verstraeten); funding from the Outreach project (Dutch Heart Foundation; Dr Luyckx); funding from Heart and Stroke Foundation of Canada/Robert M Freedom Chair of Cardiovascular Science (Dr Mital); sample biobanking and sequencing from Canada were supported by grants from the Leducq Foundation Transatlantic Networks of Excellence grant, and the Ted Rogers Centre for Heart Research; ISF grant 1053/12 (Dr Durst); and grant R01HL150401 from National Heart, Lung, and Blood Institute (Dr Muehlschlegel).S

Candidate gene resequencing in a large bicuspid aortic valve-associated thoracic aortic aneurysm cohort: SMAD6 as an important contributor

Bicuspid aortic valve (BAV) is the most common congenital heart defect. Although many BAV patients remain asymptomatic, at least 20% develop thoracic aortic aneurysm (TAA). Historically, BAV-related TAA was considered as a hemodynamic consequence of the valve defect. Multiple lines of evidence currently suggest that genetic determinants contribute to the pathogenesis of both BAV and TAA in affected individuals. Despite high heritability, only very few genes have been linked to BAV or BAV/TAA, such as NOTCH1, SMAD6, and MAT2A. Moreover, they only explain a minority of patients. Other candidate genes have been suggested based on the presence of BAV in knockout mouse models (e.g., GATA5, NOS3) or in syndromic (e.g., TGFBR1/2, TGFB2/3) or non-syndromic (e.g., ACTA2) TAA forms. We hypothesized that rare genetic variants in these genes may be enriched in patients presenting with both BAV and TAA. We performed targeted resequencing of 22 candidate genes using Haloplex target enrichment in a strictly defined BAV/TAA cohort (n = 441; BAV in addition to an aortic root or ascendens diameter = 4.0 cm in adults, or a Z-score = 3 in children) and in a collection of healthy controls with normal echocardiographic evaluation (n = 183). After additional burden analysis against the Exome Aggregation Consortium database, the strongest candidate susceptibility gene was SMAD6 (p = 0.002), with 2.5% (n = 11) of BAV/TAA patients harboring causal variants, including two nonsense, one in-frame deletion and two frameshift mutations. All six missense mutations were located in the functionally important MH1 and MH2 domains. In conclusion, we report a significant contribution of SMAD6 mutations to the etiology of the BAV/TAA phenotype

Insuffisance mitrale ischémique (épidémiologie, physiopathologie, pronostic et traitements)

La transplantation de cellules musculaires autologues améliore la fonction cardiaque du cœur infarci. La préparation de ces cellules reste complexe. Cette étude compare les résultats fonctionnelles obtenus après injection de bupivacaine (48 heures avant le prélèvement musculaire périphérique) et après injection d un éminçât musculaire sans culture préalable. Après 7 jours de culture, le nombre de myoblastes disponible est plus important dans le groupe bupivacaine que dans le groupe culture seule (1 683 147 versus 85 300, P=0.0013). On compare ensuite l éminçât et la culture cellulaire sur 66 rats avec infarctus produit par ligature coronaire. Une semaine après l infarctus, les rats sont réopérés et on injecte en intra...PARIS5-BU-Necker : Fermée (751152101) / SudocSudocFranceF