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Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): CHU Rennes, Inserm, LTSI – UMR 1099, F-35000 Rennes, France Assistance Publique-Hôpitaux de Paris-Centre Université de Paris, University of Paris onbehalf REMY register Paroxysmal or chronic atrial fibrillation (AF) is frequent in hypertrophic cardiomyopathy (HCM),(20%-25% of patients), and is often considered as an important disease turning point. The aim of this study is to determine HCM-phenogroups with different risk of AF-occurrence at 5-year. We applied the Bayesian method to differentiate phenogroups of patients with different risks of AF across a French hospital registry of adult HCM(REMY). Data were prospectively recorded on 5 years follow-up. 1431 HCM patients were recruited, including 1275 analyzed. The population included 412 women. AF-occurred in 167 (11.6%) patients. 3 phenogroups were defined according to their common characteristics. Patients at the highest risk were more often female, with more frequent comorbidities, greatest anteroposterior LA diameter, diastolic dysfunction, outflow-tract obstruction or mitral valve abnormality, and presented higher sPAP or right ventricular dysfunction. These also had a higher risk of all-cause hospitalizations and death. Based on a clustering analysis, 3 phenogroups of HCM according to the risk of AF occurrence can be identified. It can indicate which patients should be more monitored. 3 different AF-risk groups Intermediate risk group n = 524 High-risk group n= 207 Low-risk group n = 544 P Gender = Males (%) 338 (64.5) 103 (49.8) 422 (77.6)

Background The EORP Cardiomyopathy Registry is a prospective, observational, multinational registry of consecutive patients with cardiomyopathies. The objective of this report is to describe the outcomes at one year of follow-up of adult patients (> 18 years old) enrolled in the registry. Methods A total of 3208 patients [median age: 55.0 (43.0;64.0) years, males: 65.1%] were recruited at baseline. Follow-up data at 1 year were obtained in 2,713 patients (84.6%), including 1420 with hypertrophic (HCM), 1,105 dilated (DCM), 128 arrhythmogenic right ventricular (ARVC) and 60 restrictive cardiomyopathy (RCM) ( Fig. 1 ). Results Improvement of symptoms (NYHA, chest pain, syncope) was globally observed over time (P Conclusions Despite symptomatic improvement in most cases, there is still a significant burden of arrhythmic and heart failure events in patients with cardiomyopathies. Outcomes were different not only according to cardiomyopathy subtypes but also in relatives versus index patients.

Background Appropriate advice for the practice of sport in patients with a cardiomyopathy is a challenging issue. Recent evolution towards more comprehensive and tailored recommendations may facilitate the clinical practice. However, neither their application in real life has been evaluated nor the concordance within clinicians. Methods We submitted six cases from real life to an expert panel of eighteen clinicians (7 cardiomyopathy experts, 7 arrhythmia experts, 4 sport physicians). The six athletes had Hypertrophic (HCM, n = 3), Dilated (DCM, n = 2), Right ventricular arythmogenic (ARVC, n = 1) cardiomyopathy. Advice for the practice of sport (competitive or recreational, globally or regarding the main usual activity of the athlete or according to detailed sports classification) was collected through a structured questionnaire. Results Experts authorize the practice of the usual sport in 28% of total cases. Global concordance within experts is significant but low (Kendall W = 0.34, P Conclusions Divergent advices were observed between experts regarding sports activity that can be authorized in athletes with a cardiomyopathy. Advices were also frequently discordant with recent European recommendations. These results underline difficulties for athletes’ personalized recommendation and the need for large prospective studies to progress towards optimal management.

Background and objectives 18F-FDG PET/CT has been added as a major criterion in the ESC 2015 infective endocarditis (IE) guidelines, but the value of this new diagnostic algorithm has never been prospectively assessed. Purposes primary objective To assess the value of the new ESC criteria including PET/CT in prosthetic valve infective endocarditis (PVIE). Secondary objectives: to determine the reproducibility of PET/CT and to assess its ability to predict embolic events. Methods Between 2014 and 2017, 175 patients with suspected PVIE were prospectively included in 3 French centers. After exclusion of patients with uninterpretable or not feasible PET/CT, 115 patients were finally included, including 91 definite IE and 24 rejected IE, as defined by a Consensus of Endocarditis Team after 3-month follow-up as Gold Standard. Nuclear data were blindly analyzed by two independent nuclear medicine physicians. Results Significant cardiac uptake by PET/CT was observed in 67 among 91 patients with definite PVIE and 6 patients with rejected IE (sensitivity 73.6%, specificity 75%, positive predictive value 91%, negative predictive value 42%). Considering cardiac uptake as a major criterion, the ESC 2015 classification increased the sensitivity of Duke criteria from 57 to 84% (P Conclusion The value of PET CT and ESC criteria is confirmed and may allow earlier diagnosis of PVIE. Reproducibility of nuclear measurements seems unsatisfactory, justifying efforts to standardize PET studies interpretation. Our study describes for the first time a positive correlation between a positive PET/Ct and occurrence of embolic events, warranting additional studies.

Introduction Mutations in FLNC encoding filamin C have been firstly reported to cause dominant myofibrillar and distal myopathy. More recently, dominant pathogenic variants in FLNC have also been linked to the development of isolated cardiac phenotypes. Objective Only few publications on cohorts with FLNC pathogenic variants are published and the pathophysiology of FLNC-related cardiomyopathy is poorly understood. The aim of this retrospective study is to establish the prevalence of mutation in the FLNC gene in the different subtypes of cardiomyopathies and search for genotype-phenotype associations. Methods DNAs from a cohort of 1150 unrelated index-patients with an isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non-compactions) have been sequenced on a custom panel of 52 cardiomyopathy disease-causing genes. Results A FLNC pathogenic mutation was identified in 28 patients corresponding to a prevalence ranging from 1 to 8% depending on the cardiomyopathy subtypes. Truncating mutations were always identified in patients with dilated cardiomyopathy, while mis-sense or in-frame mutations were found in other phenotypes. In the cohort, nine patients (32%) were implanted with an automatic defibrillator. In 7 families (25%), history of sudden cardiac death (SCD) before 50 years was reported. A personal or family history of SCD was significantly higher in patients with truncating variants than in patients carrying missense variants (P = 0.01). Acute heart failure was observed in 7 patients (25%). Four patients died of cardiac cause including 3 from SCD and 1 from heart failure. Conclusion This work highlights the role of FLNCin studied cardiomyopathy subtypes. A correlation between the type of the mutation and the cardiomyopathy subtype was observed as well as with SCD risk. These new data should be taken into consideration for patient's management and primary prevention of sudden cardiac death.

Aim Acute heart failure is a major health care problem and data on patient journey before/during/after hospitalization are limited. The aim of this study was to analyze patient journey from pre-hospital to discharge in acute heart failure in a multicentre observational study. Methods and results This observational study enrolled, one day per week, 257 patients with acute heart failure during five months (September 2014 – February 2015) in 14 departments of Paris (cardiology: 10; geriatrics: 4). Mean age was 77±15 years, 56% were male. First medical contact was an emergency department in 45% of cases, a general practitioner (GP) in 16%, and a cardiologist or a medical ambulance (13% each). There was a single medical actor intervention before hospitalization in 78% of cases. 64% of patients were finally admitted through emergency departments. Previous history of heart failure was common (71%) and most frequent precipitating factors were arrhythmia (29%), infection (26%) and non-compliance to medical therapy (16%). Diabetes (28%), chronic pulmonary disease (19%) and cognitive disabilities (18%) were the most frequent co-morbidities. LVEF was preserved (>50%) in 32%. In-hospital stay was 13±12 days and 61% of patients stayed in an intensive cardiologic care unit (ICCU) for an average duration of 5.5±3.9 days. 64% of patients were directly discharged home and 21% were transferred to rehabilitation care units. In-hospital mortality was 2.4%. Conclusion Although heterogeneous patient admission for acute heart failure is made through emergency departments and GPs in the majority of cases, a stay in intensive care unit is observed in 61% of cases. Discharge from hospital is made at home in 2/3 of cases. Therefore, actions to improve cooperation between professionals in the management of acute heart failure should target emergency departments and GPs. Download : Download high-res image (101KB) Download : Download full-size image Abstract 0440 – Figure

Mitral valve prolapse (MVP) affects 2-4% of the general population and remains one of the most frequent indications for valvular surgery. So far, the only gene described in MVP, with an X-linked form of inheritance, is FLNA but only represents a small part of MVP.To this respect, we investigated a french MVP pedigree to uncover new molecular insights associated to the disease. We focus on a family of 5 affected patients characterized by a dysmorphic myxomatous phenotype with 2 operated patients.From 4 MVP patients, we performed a Whole Exome Sequencing screening. From bioinformatics analysis, we focused on rare (MAFA; p. R1549Q) co-segregates in all affected members in the family. DOCK1 is highly expressed in the mitral valve as evidenced by RNA sequencing experiments using human mitral valve tissue.DOCK1, encodes an atypical Rac exchange factor, Dock180, which acts as a guanine exchange factors (GEF) for small Rho family G proteins. Interestingly, Sanematsu et al. (2010) described a major role of Dock180 during cardiovascular development. Mitral valves of Dock1 depleted mice are thickened and lead to blood retention in left atrium. We currently investigate repercussions of p. R1549Q (located in GEF activity domain of Dock180) on Dock180 activity in the cellular adhesion phenotype (XCELLigence; IF assays) and GEF activity (Pull-Down assays) using a heterologous transfection system. Finally, a cohort of 285 MVP affected patients is screened to evaluate the prevalence of DOCK1 in the disease. This study reports a familial approach, coupled to an exome sequencing strategy which identifies a novel DOCK1 missense mutation associated with MVP phenotype. In vivo previous studies and cellular mechanisms learning will allow us to better understand mechanisms involved in the MVP pathogenesis.

While the links between high blood pressure and heart failure (HF) are well known, the clinical profiles of hypertensive patients (pts) according to measure of left ventricular (LV) ejection fraction (EF) remain poorly investigated. O-PREDICT 2 was a multicentre observational study conducted among 1537 general practitioners who classified 4427 hypertensive outpatients (pts) (mean age 72±9 years; 66% males) according to the presence (Group 1, 2969 Pts) or absence (Group 2, age > 65 years) of a history of clinical HF. The study cohort included 2052 (46.4%) pts with an available measure of LVEF, 1713 (58%) from group 1 and 350 from group 2.ResultsIn group 1, 677 (39.5%) pts had a reduced EF ≤ 40% (1A) and 1036 (60.5%) had a preserved EF > 40% (1B), while, in group 2, 330 (94.3%) had a preserved EF. When comparing groups 1A, 1B and 2, a significant difference (p 50%)

Nonsyndromic mitral valve prolapse (MVP) is a common degenerative valvulopathy of unknown aetiology that predisposes to heart failure and sudden death. Here we investigate functional evidence for candidate genes near genome-wide association study (GWAS) loci to understand the mechanisms underlying the genetic susceptibility to MVP. To prioritize genes, we used literature and databases (e. g ENCODE, eQTLs). We analysed the expression pattern of 3 candidate genes during valve development in mouse embryos by immunohistochemistry (IHC) i) completion of endothelial-to-mesenchymal transformation (E13.5), ii) valve sculpting and elongation (E17.5) and iii) adult form (9 months). Morpholino knockdown (KD) was performed for 8 genes in zebrafish and assayed the function of developing atrioventrocular (AV) canal by scoring the embryos according to the presence of erythrocyte regurgitation. On chr3, the association is in an intron of LMCD1, a repressor of GATA6 previously implicated in cardiac hypertrophy. KD of Lmcd1 in zebrafish resulted in a significant atrioventricular valve defect with regurgitation. On Chr2, the associated variants were upstream to TNS1 encoding a focal adhesion and actin-interacting protein. Tensin1 is expressed during valve morphogenesis in mice and maintained in the adult endothelial and valvular interstitial cells. Hematoxylin and eosin histological staining in 9-month Tns1-/- mice show enlarged posterior mitral leaflets with myxomatous aspects. In addition, zebrafish KD of Tns1 induced AV regurgitation. The functional validation of genes located in or near MVP susceptibility loci identifies new MVP mechanisms and stresses the role of cytoskeleton integrity in valve development. This study reveals LMCD1 and TNS1 at play as early as during valve development and can potentially be targeted during adulthood to improve the natural history of MVP.

Background Changes in mitral valve (MV) elasticity or distensibility occur in disease and directly affect MV function, contributing to MV prolapse (MVP) or flail vs restricted coaptation of stiffer leaflets in functional mitral regurgitation (FMR) and MV stenosis (MS). Recent studies suggest MV distensibility may be modified to reduce MR, but distensibility has only been measured in excised MVs. Our aim was to test the feasibility of obtaining a noninvasive measure of MV distensibility in patients by measuring systolic change in anterior leaflet length (ALL) or anterior leaflet strain; and to test the hypothesis that these measures vary in diseases with known altered MV elasticity. Methods ALL was quantified in a long-axis view standardized by 3D echo in 80 patients: 20 each with normal hearts, MVP, FMR and MS. Distensibility was measured as end-systolic (ES) – end-diastolic (ED) total ALL normalized to an ED reference; and alternatively as mid-leaflet strain measured by tracking echo features. Results ALL was greater in all disease groups vs normal (p 2-fold higher (17.6 ± 11.2%) in MVP; it was 63-76% lower (2.9 ± 3.0%, 1.9 ± 3.1%) in FMR and MS, with comparable results for segmental AL strain (Table). Conclusion Noninvasive echocardiographic measures of MV distensibility based on systolic changes in total length or segmental strain are feasible. Results are consistent with excised valve biomechanics, showing increased distensibility in MVP and decreased values in FMR and MS. Ultimately, these techniques have the potential to monitor response to new therapies that aim to improve MV biology and mechanics to reduce MR. Parameter unit Norm MVP FMR MS ALL systole mm. 26.6 ± 2.7 39.7 ± 5.6 * 32.7 ± 4.1 * 33.4 ± 5.0 * ALL diastole mm. 24.5 ± 3.1 33.5 ± 3.2 * 32.0 ± 4.2 * 32.8 ± 4.9 * ALL (sys-dia)/dia % 7.9 ± 7.4 17.6 ± 11.2 * 2.9 ± 3.0 * 1.9 ± 3.1 * SegL (ES-ED)/ED % 9.1 ± 4.8 19.6 ± 10.9 * 3.2 ± 2.6 * 2.7 ± 3.7 * * P

AimTo assess the value of velocity and flow rate-related parameters obtained by cardiac magnetic resonance (CMR) for evaluation of left ventricular (LV) diastolic function (DF) in patients (pts) with hypertrophic cardiomyopathy (HCM).MethodsCMR was performed in 26 HCM pts and 24 healthy volunteers (HV) matched for age, gender, body surface area (BSA) and blood pressure. DF parameters were obtained using a semi-automated software enabling extraction of transmitral flow, including transmitral Ef and Af flow rate peaks, isovolumetric relaxation time (IVRT) and early peak diastolic longitudinal myocardial velocity E’ obtained using 2D phase contrast-CMR. LV mass and volumes and left atrial (LA) volumes were measured from cine CMR images.ResultsMean age was 47.0±20.2 years in HCM pts and 47.5±16.1 in HV (p=NS). LV mass, mass/end-diastolic volume and LA volumes were increased in HCM pts (table). Late gadolinium enhancement was found in 20 HCM pts. While there was no significant difference in Ef/Af, myocardial longitudinal velocity E’ and LA emptying fraction were markedly lower in HCM pts. Furthermore, E/E’ ratio and E wave deceleration time (DT) were higher in HCM pts. There was a linear relationship between increased LV mass and increased LA volumes (p

BackgroundIn ischemic mitral regurgitation (IMR), leaflet tethering is caused by post-MI LV and annular remodeling. Severing second-order mitral chordae significantly decreases tethering and MR. We tested whether undersized ring annuloplasty can improve chordal cutting efficacy by reducing annulus-related tethering.MethodsPosterolateral MI created chronic remodeling and MR in 28 sheep. At 3 months, sheep were randomized to sham surgery vs isolated annuloplasty undersized by 2 sizes vs isolated bileaflet chordal cutting vs at the combined therapy (n=7 each). At baseline, chronic MI (3 months) and sacrifice (6.6 months) we measured LV volumes and ejection fraction (EF), wall motion score index (WMSi), MR Regurgitation fraction (MRRF) and vena contracta (VC), Mitral annulus area (MAA) and posterior leaflet (PL) restriction angle (PL to MAA) by 2D and 3D echo.ResultsAll groups were comparable at baseline and chronic MI, with mild- moderate MR (MRVC 4.6±1.0mm, MRRF 24±2.6%) and MA dilatation (p

While the major role played by hypertension (HT) in the genesis of chronic heart failure (HF) is well known, the main risk factors leading to HF in hypertensive patients remain poorly investigated. O-PREDICT 2 was a multicentre, observational study conducted with 1537 general practitioners who recruited 4427 consecutive hypertensive outpatients (pts) (mean age 72±9 years; 66% males). We compared pts with a clinical history of HF (group 1, n=2969) and without HF (group 2, n=1458, age > 65 yrs).ResultsSex ratio and age were similar between groups. Duration of HT was higher (P 3 risk factors for HF. This study highlights the need for an early management of HF risk factors in hypertensive pts.

Objective Chordal 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. Methods Experiments 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. Results In 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. Conclusions Noninvasive 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.

International audience; Background Hereditary transthyretin cardiac amyloidosis (mTTR-CA) is a hypertrophic cardiomyopathy with challenging diagnosis and poor prognosis. The prevalence of m-TTR in patients with increased left ventricular wall thickness (LVWT) is unknown. Methods Prospective and consecutive multicenter study with systematic genetic screening for mTTR in adult patients with LVWT ≥15mm included in cardiology primary clinics. Results 298 patients were genotyped of whom 23% were African descendant. The median (IQR) age was 62(50,74), 74% were men and 36% were in NYHA class III-IV. The median of maximal LV thickness was 18 (16, 21)mm.17 patients had TTR mutation (5.7%) of whom 15 (5.0) had confirmed mTTR-CA. All the mTTR-CA were ≥55years meaning that the prevalence of mTTR-CA was 8.3% above this age. Of the 15 with mTTR-CA, 8 were Africans and 6 Caucasians. In Africans ≥55 years, the prevalence was 22% and reached 35% in those over 65 years. The most frequent mutations were V142I (8), V50M (2) and I127V (2). When adjusted to age, neuropathy (OR=20.1; 95%-CI, 5.86-69.4; P