Subjects -> JOURNALISM AND PUBLICATION (Total: 234 journals)
    - JOURNALISM (31 journals)
    - NEW AGE PUBLICATIONS (8 journals)
    - PUBLISHING AND BOOK TRADE (32 journals)

JOURNALISM AND PUBLICATION (163 journals)                     

Showing 1 - 17 of 17 Journals sorted alphabetically
#PerDebate     Open Access   (Followers: 1)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3)
Advances in Journalism and Communication     Open Access   (Followers: 33)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 21)
African Journalism Studies     Hybrid Journal   (Followers: 2)
American Journalism     Hybrid Journal   (Followers: 2)
Âncora : Revista Latino-Americana de Jornalismo     Open Access  
Annales françaises d'Oto-rhino-laryngologie et de Pathologie Cervico-faciale     Full-text available via subscription   (Followers: 3)
Anuario de investigaciones     Open Access  
Apparence(s)     Open Access   (Followers: 1)
Apunts. Medicina de l'Esport     Full-text available via subscription   (Followers: 1)
Archives of Cardiovascular Diseases Supplements     Full-text available via subscription   (Followers: 4)
Archivos de Medicina Veterinaria     Open Access   (Followers: 1)
Arethusa     Full-text available via subscription   (Followers: 4)
Arizona Journal of Hispanic Cultural Studies     Full-text available via subscription   (Followers: 6)
Arizona Quarterly: A Journal of American Literature, Culture, and Theory     Full-text available via subscription   (Followers: 17)
Asian Journal of Animal Sciences     Open Access   (Followers: 4)
Asian Journal of Information Management     Open Access   (Followers: 9)
Asian Journal of Marketing     Open Access   (Followers: 6)
Astérion     Open Access   (Followers: 1)
Atención Primaria     Open Access   (Followers: 2)
Australasian Marketing Journal (AMJ)     Hybrid Journal   (Followers: 5)     Open Access   (Followers: 2)
BMS: Bulletin of Sociological Methodology/Bulletin de Méthodologie Sociologique     Hybrid Journal   (Followers: 4)
Brazilian Journalism Research     Open Access   (Followers: 2)
British Journal of General Practice     Full-text available via subscription   (Followers: 41)
Brookings Papers on Economic Activity     Open Access   (Followers: 73)
Brookings-Wharton Papers on Financial Services     Full-text available via subscription   (Followers: 3)
Brookings-Wharton Papers on Urban Affairs     Full-text available via subscription   (Followers: 8)
Bulletin of the Comediantes     Full-text available via subscription   (Followers: 2)
Cahiers d'histoire. Revue d'histoire critique     Open Access   (Followers: 14)
Cahiers de la Méditerranée     Open Access   (Followers: 1)
CIC. Cuadernos de Informacion y Comunicacion     Open Access   (Followers: 7)
Comics Grid : Journal of Comics Scholarship     Open Access   (Followers: 9)
Communication & Society     Open Access   (Followers: 5)
Communication and Media in Asia Pacific (CMAP)     Open Access   (Followers: 2)
Communication Cultures in Africa     Open Access   (Followers: 6)
Communication Papers : Media Literacy & Gender Studies     Open Access   (Followers: 20)
Comunicação Pública     Open Access   (Followers: 2)
Comunicación y Ciudadanía     Open Access  
Comunicacion y Hombre     Open Access   (Followers: 3)     Open Access  
Cybergeo : European Journal of Geography     Open Access   (Followers: 6)
De Arte     Hybrid Journal   (Followers: 4)
Deutsche Zeitschrift für Akupunktur     Full-text available via subscription   (Followers: 2)
Développement durable et territoires     Open Access   (Followers: 2)
Die Kerkblad     Full-text available via subscription  
Digital Journalism     Hybrid Journal   (Followers: 6)
Documentación de las Ciencias de la Información     Open Access  
E-rea     Open Access   (Followers: 2)
El Argonauta español     Open Access   (Followers: 1)
English in Africa     Full-text available via subscription   (Followers: 4)
Espaço e Tempo Midiáticos     Open Access  
Estudios sobre el Mensaje Periodístico     Open Access   (Followers: 1)
Études caribéennes     Open Access   (Followers: 2)
European Science Editing     Open Access   (Followers: 5)
Filo de Palabra     Open Access  
French Studies in Southern Africa     Full-text available via subscription   (Followers: 1)
Frontiers in Research Metrics and Analytics     Open Access   (Followers: 6)
General Relativity and Gravitation     Hybrid Journal   (Followers: 2)
Géocarrefour     Open Access  
Grey Room     Hybrid Journal   (Followers: 18) : Anuario Académico sobre Documentación Digital y Comunicación Interactiva     Open Access  
IFE Psychologia : An International Journal     Full-text available via subscription   (Followers: 1)
Image & Text : a Journal for Design     Full-text available via subscription   (Followers: 17)
Improntas     Open Access  
In die Skriflig / In Luce Verbi     Open Access   (Followers: 3)
Index on Censorship     Hybrid Journal   (Followers: 4)
Information Today     Full-text available via subscription   (Followers: 41)
InMedia     Open Access  
International Journal of Bibliometrics in Business and Management     Hybrid Journal   (Followers: 3)
International Journal of Entertainment Technology and Management     Hybrid Journal   (Followers: 5)
Investment Analysts Journal     Hybrid Journal   (Followers: 3)
IRIS - Revista de Informação, Memória e Tecnologia     Open Access  
Journal of European Periodical Studies     Open Access   (Followers: 1)
Journal of Health Care for the Poor and Underserved     Full-text available via subscription   (Followers: 8)
Journal of Healthcare Risk Management     Hybrid Journal   (Followers: 8)
Journal of Illustration     Hybrid Journal   (Followers: 3)
Journal of Information Privacy and Security     Hybrid Journal   (Followers: 3)
Journal of Integrative Environmental Sciences     Hybrid Journal   (Followers: 4)
Journal of Interactive Marketing     Hybrid Journal   (Followers: 10)
Journal of International and Intercultural Communication     Hybrid Journal   (Followers: 23)
Journal of Investigative and Clinical Dentistry     Hybrid Journal   (Followers: 2)
Journal of Islamic Law and Culture     Hybrid Journal   (Followers: 4)
Journal of Jewish Identities     Full-text available via subscription   (Followers: 13)
Journal of Late Antiquity     Full-text available via subscription   (Followers: 6)
Journal of Latin American Geography     Full-text available via subscription   (Followers: 6)
Journal of LGBT Youth     Hybrid Journal   (Followers: 13)
Journal of Literacy Research     Hybrid Journal   (Followers: 10)
Journal of Literary & Cultural Disability Studies     Hybrid Journal   (Followers: 14)
Journal of Media Ethics : Exploring Questions of Media Morality     Hybrid Journal   (Followers: 14)
Journal of Medieval Iberian Studies     Hybrid Journal   (Followers: 9)
Journal of the Brazilian Society of Mechanical Sciences     Open Access   (Followers: 2)
Journal of the Early Republic     Full-text available via subscription   (Followers: 13)
Journal of the Short Story in English     Open Access   (Followers: 7)
Journal of Thyroid Research     Open Access   (Followers: 1)
Journal of Transatlantic Studies     Hybrid Journal   (Followers: 7)
Journal of World History     Full-text available via subscription   (Followers: 32)
Journalism & Mass Communication Educator     Hybrid Journal   (Followers: 23)
Journalism & Communication Monographs     Hybrid Journal   (Followers: 17)
Journalism & Mass Communication Quarterly     Hybrid Journal   (Followers: 31)
Journalism Research     Open Access   (Followers: 4)
Journalistica - Tidsskrift for forskning i journalistik     Open Access   (Followers: 2)
Komunika     Open Access   (Followers: 3)
L'Espace Politique     Open Access  
L'Homme     Open Access   (Followers: 10)
La corónica : A Journal of Medieval Hispanic Languages, Literatures, and Cultures     Full-text available via subscription   (Followers: 4)
La Presse Médicale     Full-text available via subscription   (Followers: 3)
Language     Full-text available via subscription   (Followers: 31)
Latin American Perspectives     Hybrid Journal   (Followers: 15)
Latin American Research Review     Full-text available via subscription   (Followers: 14)
Law, State and Telecommunications Review     Open Access   (Followers: 1)
Les Cahiers d'Outre-Mer     Open Access   (Followers: 1)
Media & Jornalismo     Open Access  
Memory     Hybrid Journal   (Followers: 21)
Merrill-Palmer Quarterly     Full-text available via subscription   (Followers: 1)
Missionalia : Southern African Journal of Mission Studies     Open Access   (Followers: 4)
Museum International Edition Francaise     Hybrid Journal   (Followers: 4)
Natural Language Semantics     Hybrid Journal   (Followers: 7)
Newspaper Research Journal     Full-text available via subscription  
Nordic Journal of Media Management     Open Access   (Followers: 4)
Norsk medietidsskrift     Open Access  
OJS på dansk     Open Access   (Followers: 3)
Papers of The Bibliographical Society of Canada     Open Access  
Periodica Mathematica Hungarica     Full-text available via subscription   (Followers: 1)
Physics of the Solid State     Hybrid Journal   (Followers: 5)
Pollack Periodica     Full-text available via subscription   (Followers: 1)
Pozo de Letras     Open Access  
Prometheus : Critical Studies in Innovation     Hybrid Journal   (Followers: 3)
Publishers Weekly     Free   (Followers: 3)
Qatar Foundation Annual Research Forum Proceedings     Open Access   (Followers: 4)
Religion, State and Society     Hybrid Journal   (Followers: 6)
Revista Observatório     Open Access  
Revue archéologique de l'Est     Open Access   (Followers: 4)
Revue archéologique du Centre de la France     Open Access   (Followers: 1)
Revue d’économie industrielle     Open Access  
Revue européenne des migrations internationales     Open Access   (Followers: 5)
RUDN Journal of Studies in Literature and Journalism     Open Access   (Followers: 3)
Scientometrics     Hybrid Journal   (Followers: 42)
Sensorium Journal     Open Access   (Followers: 1)
Signo y Pensamiento     Open Access  
South African Radiographer     Full-text available via subscription  
Southern African Forestry Journal     Full-text available via subscription   (Followers: 1)
Southern African Journal of Anaesthesia and Analgesia     Open Access   (Followers: 8)
Stellenbosch Theological Journal     Open Access   (Followers: 2)
Stilet : Tydskrif van die Afrikaanse Letterkundevereniging     Full-text available via subscription   (Followers: 1)
Studia Socialia Cracoviensia     Open Access   (Followers: 1)
Studies in Multidisciplinarity     Full-text available via subscription   (Followers: 2)
Syntax     Hybrid Journal   (Followers: 3)
Sztuka Edycji     Open Access   (Followers: 4)
TD : The Journal for Transdisciplinary Research in Southern Africa     Open Access  
Time     Full-text available via subscription   (Followers: 4)
Tracés     Open Access  
Transport Policy     Hybrid Journal   (Followers: 20)
Trípodos     Open Access  
Tydskrif vir Geesteswetenskappe     Open Access  
Tydskrif vir Letterkunde     Open Access  
Ufahamu : A Journal of African Studies     Open Access   (Followers: 2)
Variants : Journal of the European Society for Textual Scholarship     Open Access   (Followers: 1)
Veld & Flora     Full-text available via subscription   (Followers: 1)
Verbum et Ecclesia     Open Access   (Followers: 3)
Word and Action = Woord en Daad     Full-text available via subscription  
World Futures: Journal of General Evolution     Hybrid Journal   (Followers: 2)


Similar Journals
Journal Cover
Archives of Cardiovascular Diseases Supplements
Journal Prestige (SJR): 0.101
Number of Followers: 4  
  Full-text available via subscription Subscription journal
ISSN (Print) 1878-6480
Published by Elsevier Homepage  [3203 journals]
  • Mitral annular calcification still a risk factor in kidney transplant
           recipient' A 14 years follow-up cohort study
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): C. Henrard, M. Lucion, R. Thirionet, A. Robert, M. Jadoul, A. PasquetIntroductionMitral annular calcification (MAC) is a chronic degenerative process increasing with age and is considered as a risk factor for cardiovascular events and deaths. Prevalence of MAC is higher in patients with end stage disease.ObjectiveThe aim of this study was to assess if presence of MAC remains a risk factors in a population of kidney transplant recipient (KTR).MethodBetween February 2004 and January 2005, all the RTR followed in our institution a complete 2D echocardiography and a vascular scanner. All the echos were reanalysed for MAC. MAC extent and distribution were graded semiquantitatively (0 = no calcification, 4 severe calcification) using 2D echocardiography. Demographic and clinical characteristics (biological data, data related to renal failure and transplant) were extracted from the medical file. Follow-up data was obtained.ResultsFrom the 300 RTR, echodata could be analysed for 279 RTR, mean age 52 ± 13years (168 (80% males), dialysis time before renal transplant (RT): 2,3 ± 2,3 y, time after RT 7,6 ± 8,3y). Mean creat: 1,6 ± 0,8 mg/dl. During a mean follow-up of 11 ± 3 years, 114(48%) patients died. Because survival was related to time after RT, we divided our population in 3 groups:  10 years after RT. In Cox multivariate analysis adjusted for time after RT, survival was significantly related to: age (P = 0.027), ejection fraction (P 
  • 4D flow magnetic resonance post-operative pulmonary stenosis assessment in
           patients with transposition of the great arteries repaired by arterial
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): Z. Belhadjer, G. Soulat, E. Mousseaux, L. Iserin, D. BonnetPurposePatients operated for transposition of the great arteries by arterial switch defines a new population coming to adulthood with unknown long-term prognosis. The principle complication in adulthood is the pulmonary stenosis, occurring in 17% of patients and leading to re-intervention in 15% of cases. Repair of this right ventricle outflow is recommended in symptomatic patients when systolic pressure of the right ventricle is greater than 60 mmHg (velocity of tricuspid regurgitation (IT) > 3.5 m/sec). However pulmonary flow measurement cannot be always measured with transthoracic echocardiography Doppler (TTE) due to the peculiarity of the vessels anatomy.4D flow in magnetic resonance is a new imaging method, allowing analysis of blood velocity and flow in an entire volume, permitting detection, quantification and location of vascular stenosis.The objective of this study was to compare this 4D flow imaging to TTE for the diagnosis of pulmonary stenosis in adult with transposition of the great arteries corrected by arterial switch.Methods and resultsThirty-three patients (19 men, 14 women, mean age 25.5 years old) were prospectively included with a TTE and a MRI 4D flow examination the same day. In 16 of them (48.5%), right ventricle out flow was not correctly evaluated by TTE against 0(0%) in 4D flow. TTE detected 11 (33.3%) patients with an upper speed over 2 m/s and 2 (6%) patients with a higher speed over 3.5 m/s against 14 (42%) and 4 (12.1%) respectively with 4D flow. The peak flow velocities measurements in Doppler and 4D flow were highly correlated (r = 0.79; P 
  • Multi-parametric evaluation of right ventricular function in
           peri-operative surgery for aortic valve replacement
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): A. Coppin, H. Ridon, C. Seunes, S. Mouton, E. Woitrain, M. Koussa, B. Jegou, F. Pontana, T. Modine, A. Coisne, D. MontaigneIntroductionQuantitative assessment of right ventricular (RV) function is difficult with 2D-echocardiography (2D-TTE) and changes in RV longitudinal parameters are surprisingly not predictive of cardiovascular events after surgical Aortic Valve Replacement (SAVR).ObjectiveWe aimed at investigating peri-operative evolution of both RV longitudinal parameters and RV global function (assessed by 3D echocardiography (3D-TTE)) and their correlations with cardiac MRI (cMRI) RV function parameters in patients undergoing SAVR.MethodIn total, 52 patients with severe aortic stenosis referred to our Heart Valve Clinic for SAVR were explored with a pre-operative (Day-1) and post-operative (Day7) comprehensive 2D- and 3D-TTE assessing RV longitudinal (TAPSE, SDTI, 2D-RV free wall Longitudinal Strain) and global (FAC, 3DE-RVEF and RV-pulmonary arterial coupling) function. Eighteen patients underwent cMRI.ResultsIn peri-operative period, RV 3D-TTE was feasible in 94% of patients. Correlation between measurements of RV telediastolic volume by 3D-TTE and cMRI was good but not perfect (R2 = 0.65, P 
  • 2D-Strain analysis of left ventricular (LV) dyssynchrony and post-systolic
           contractions in young bodybuilders
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): A. Grandperrin, I. Schuster, P. Moronval, O. Izem, S. NottinIntroductionIt is well-known that bodybuilders (BB) using anabolic androgenic steroids (AAS) showed a majored concentric hypertrophy with an increase of cardiac fibrosis. Some studies demonstrated that cardiac fibrosis may altered electrical conduction and so promote intraventricular dyssynchrony. However, any study evaluated this dyssynchrony in BB using AAS.ObjectiveThis study aimed to evaluate the LV dyssynchrony (LVD) in strength-trained athletes and in bodybuilders using AAS. We hypothesized that BB using AAS showed an increase in LVD.Methods44 participants (aged 20–40 years) were divided into three age-matched groups: healthy sedentary men (Ctrl, N = 15), strength-trained athletes with no reported history of AAS use (Non-users, N = 15) and BB with at least two years of AAS use (Users, N = 14). After a survey, each participant underwent 2D-Strain echocardiography to assess LVD. Both longitudinal and radial strains were assessed to evaluate peak strains, time to peak (TTP) strains and delta between the peak strains of each segment. We also calculated the longitudinal strain delay index (LSDI) to assess the loss of contractility or the loss of energy during post-systolic contractions (PSC).ResultsRegarding radial strains TTP, no differences were found in both apical and basal view between our 3 groups. Despite a decrease of global longitudinal strain that characterized a decrease of LV contractility in Users, no differences were found in TTP between the 3 groups. However, the LSDI was higher in AAS group, underlying an increase of PSC. Regional analysis showed that this LSDI increases is specifically link to an alteration of longitudinal strain on the basal septal wall. Interestingly, our results also demonstrated a decrease of ejection fraction that could be linked to the increase of these PSC.ConclusionOur results didn’t showed an increase of LVD in BB using AAS. However, we observed an increase of PSC that could have a negative impact on systolic function.
  • Optimising micro computed tomography for large mammalian heart imaging at
           high resolution
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): N. Pallares Lupon, L. Yessad, M. Hocini, M. Haïssaguerre, O. Bernus, R. WaltonIntroductionMicroCT has emerged as a powerful imaging tool to study biological tissues with high resolution. Imaging soft tissues, such as cardiac samples, requires high molecular weight contrast agents. However, the combination of contrast agents and large sample sizes attenuates x-ray transmission almost completely, compromising the bandwidth of x-ray detection, signal/noise ratio and micro-structural definition.ObjectiveTo define tissue pre-treatment for optimal microCT image quality of large mammalian hearts.MethodHearts from male pigs (40-50 kg, N = 5) were excised and blood rinsed using cardioplegic solution (4 °C). The coronaries were cannulated and hearts treated either by:– hydrated samples with conventional contrast agent (iodine, 0.5%);– dehydrated in ethanol followed by acetone and air-dried under hexamethyldisilazane (HMDS).Hearts were imaged at 21.7 μm isotropic resolution by microCT (SkyScan 1276, Bruker).ResultsConventional tissue treatments required imaging samples immersed in water to prevent deformation during long acquisitions (18 hours). Yet air-dried samples remained morphologically stable in air. X-ray transmission of hydrated samples was attenuated 93% (Fig 1A), compared to 65% for dry samples: conforming better to the optimum bandwidth of the detector (Fig 1B). Histograms of 3D reconstructions show three populations corresponding to air, immersion solution and tissue with considerable overlap in frequency distribution of pixel intensity (Fig 1 C). But for dry samples, two distinct populations were found (Fig 1D). Using histogram minima to define segmentation thresholds, tissue boundaries and intramural structures were not discernible from the background in hydrated samples (Fig 1E), whereas for dry samples, tissue, including myocardial fiber bundles, vessels and fat were segmented (Fig 1F).ConclusionAir drying with HMDS vastly improved microCT imaging of large mammalian hearts while preserving micro-structure.
  • Reproducibility and reliability of echocardiography in a preclinical model
           of myocardial infarction in rodent
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): M. Isabelle, N. Harouki, C. Ragonnet, I. Laurent, S. Taupe, M. Lecomte, S. Butin, N. VilleneuveIntroductionEchocardiography is a useful non-invasive imaging modality to assess left ventricular remodeling and function post myocardial infarction (MI) in clinical and preclinical studies. Nevertheless, echocardiography is known to be highly observer-dependent and poorly reproducible. Coverage probability (CP) was recently defined as the best index to evaluate the echocardiography reproducibility in clinical settings [1], [2].ObjectiveWe aimed to use the CP in a preclinical model of MI in rats (R) and mice (M) to assess the reproducibility of our echocardiographic measurements.MethodsMI was induced by coronary ligation in Wistar rats or C57/BL6 mice. Echocardiography was performed, with a Vevo2100 machine, 2 and 3 months post-MI in mice and rats respectively. The echocardiography exams were analyzed by two trained and independent observers with VevoLab® LV trace tool to calculate the observed absolute difference (OAD). This OAD was determined for a CP = 80% for the left ventricular diastolic volume (LVEDV; μl), left ventricular systolic volume (LVESV; μl) and ejection fraction (EF; %). Good reproducibility was confirmed if OAD 
  • Prognosis of long QT syndrome patients: The experience of the French
           referral center of Nantes hospital
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): M. Minier, V. Probst, P. Mabo, G. Clerici, D. Babuty, J. Mansourati, F. Kyndt, A. Thollet, F. Sacher, J.B. GourraudIntroductionCongenital long QT syndrome (LQTS) is a hereditary disease characterized by prolonged QTc and a risk of sudden cardiac death (SCD) in young people. The aim of this study is to report the experience of the referral center of Nantes hospital.MethodsPatients were recruited from 15 tertiary centers in France between 1997 and 2018. Clinical data and 12-lead ECG were collected. Genetic screening was performed using dHPLC-DNA sequencing, HRM or targeted sequencing (Haloplex technology®) for at least KCNQ1, KCNH2 and SCN5A.ResultsThe population consisted in 741 patients affected by LQTS according to the Schwartz score (447 (60%) females, 404 (55%) index cases). Mean age at diagnosis was 33 ± 21 years. In this cohort, 343 patients (46%) were symptomatic: 66 patients experienced resuscitated SCD (9%), 211 (28%) syncope and 66 (9%) ventricular arrhythmias. One hundred and two patients (14%) had history of familial SCD. At baseline, heart rate was 69 ± 19 bpm, PR 149 ± 39 mm, QRS 86 ± 16 mm and QTc 479 ± 62 mm.Three hundred and eighty-six patients (52%) were treated with beta-blockers and 88 patients (12%) were implanted with an ICD.Genetic screening was performed in 668 (90%) patients. Genetic screening for the 3 major genes of LQTS was positive for 411 patients (62%): 165 variants (25%) in KCNQ1, 178 variants (27%) in KCNH2, 68 variants (10%) in SCN5A and 22 variants (3%) in minor genes of LQTS.During a mean follow-up of 6.2 ± 5.2 years, 64 patients (9%) underwent arrhythmic events, 7 SCD (1%), 8 appropriate ICD therapy (1%) and 49 ventricular arrhythmias (7%). The rate of arrhythmic event was 1.39%/y. Mean age at the first event was 41.7 ± 21.5 years. Sixteen patients (2%) died of non-arrhythmic causes.ConclusionCare in a specialized inherited arrhythmia center is associated with a low incidence of arrhythmic event (1.39%/y) in patients with LQTS.
  • Spatial QRS-T angle: A new risk marker for sudden cardiac arrest in
           Brugada syndrome'
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): A. Delinière, J. Fayn, F. Bessière, L. Restier-Miron, P. Rubel, P. ChevalierIntroductionVentricular arrhythmias in Brugada syndrome (BrS) may be due to a combination of myocardial depolarization and repolarization abnormalities. The spatial QRS-T angle, measured by 3D ECG, reflects both myocardial depolarization and repolarization and has been proposed as a marker for sudden cardiac death risk in several cardiomyopathies. This marker has never been evaluated in BrS patients.ObjectiveTo evaluate the prognostic significance of the spatial QRS-T angle in patients with a spontaneous Brugada type 1 pattern (SBT1).Method8 patients with a SBT1 were included (8 males, mean age 49.1 ± 10.9 years-old), 4 experienced sudden cardiac arrest or documented ventricular fibrillation (SCA/VF) at mean age of 38.8 ± 14.3 years-old. We analyzed conventional ECG and 3D ECG data using the CAVIAR method and compared data from VF/SCA group to other subjects.ResultsThe spatial angle between the onset of the QRS and the T-wave loop (ODIR angle) was significantly higher in the SCA/VF group (49.1 ± 26.0 vs. 19.8 ± 3.8, P = 0.029). There was no significant difference between patients for conventional ECG measurements (PR interval 187.0 ± 29.6 ms in the SCA/VF group vs. 186.0 ± 38.7 ms, P = 1, QRS duration 130.0 ± 38.7 ms vs. 106.5 ± 12.5 ms, P = 0.30, corrected QT interval 471.8 ± 8.4 ms vs. 404.3 ± 45.1 ms, P = 0.057, Tpeak–Tend interval 115.5 ± 3.8 ms vs. 107.5 ± 34.7 ms, P = 1) (Fig. 1).ConclusionThe spatial angle between the onset of QRS and the T-wave loop appears to be significantly correlated with the risk of VF/SCD in BrS patients. A prospective study is needed to confirm these findings.
  • Consistent histologic findings in Brugada syndrome: The stubborn
           structural substrate
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): A. Delinière, F. Bessière, N. Bencie, P. Maury, P. ChevalierIntroductionSince the first description of Brugada syndrome (BrS), there has been controversy about his association with structural abnormalities of the myocardium.ObjectiveTo identify an invariant histological substrate in patients with a definite BrS.MethodA BrT1 patient who had an autopsy after an episode of VF prompted us to perform a review of published case reports of autopsies and bi-ventricular histological samples to study patients with a spontaneous BrT1 who experienced VF and/or SCD and for whom there was no signs of an associated myocardial disease before the histological examinations.ResultsSixteen studies and cases reports were reviewed that included 127 patients; eight of these cases fulfilled the study criteria. In total, nine patients were evaluated in the present study (mean age 35.3 ± 10.4 years, eight males, four autopsies, five bi-ventricular myocardial biopsies). Eight patients had undergone cardiac imaging and no abnormality was found. None of the four patients in the autopsy series presented with a normal heart and all four had significant left ventricular hypertrophy. Pathological examination was abnormal in all patients. An occult myocarditis was diagnosed histologically in six of the nine patients and seven had criteria for myocardial inflammation. Local myocardial PCR were positive for parvovirus B19 in three patients. Only one patient had criteria consistent with an arrhythmogenic cardiomyopathy.ConclusionViral myocarditis and left ventricular hypertrophy appear to be recurrent findings in patients with Brugada syndrome who experience VF and/or SCD. In contrast to the classical definition of this disease, none of the BrS patients with detailed histologic investigations had a normal heart.
  • Prognostic significance of a low T/R ratio in Brugada Syndrome
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): A. Delinière, A. Baranchuk, F. Bessiere, P. Defaye, E. Marijon, O. Le Vavasseur, D. Dobreanu, A. Scridon, A. Da Costa, E. Delacrétaz, C. Kouakam, R. Eschalier, H. Burri, P.F. Winum, J. Taieb, J. Bouet, H. Rosianu, P. ChevalierIntroductionAbnormalities of myocardial repolarization may play a key role in the initiation of ventricular fibrillation (VF) in Brugada syndrome (BrS). Recent studies have shown that the height of the T-waves and the T/R ratio are inversely proportional to the sudden cardiac arrest (SCA) risk in early repolarization syndrome and hypertrophic cardiomyopathy.ObjectiveTo study the prognostic value of a low T/R ratio in patients (pts) with a spontaneous Brugada type 1 pattern (SBT1).MethodIn an international retrospective study, we reviewed 115 pts (mean age 45.1 ± 12.8 years, 91.3% males) with SBT1. Forty-five presented a documented VF and/or SCA at a mean age of 38.7 ± 11.5 years, 20 came from a review of published cases reports. Six ECG markers and the T/R ratio in leads V5 and II were studied. A low T/R ratio was defined by  
  • FLNC mutations in patients with cardiomyopathies: Prevalence and
           genotype-phenotype correlations
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): F. Ader, P. De Groote, P. Reant, C. Rooryck-Thambo, D. Dupin Deguine, C. Rambaud, D. Khraiche, C. Perret, J.F. Pruny, M. Mathieu Dramard, M. Gerard, Y. Troadec, L. Gouya, X. Jeunemaitre, L. Van Maldergem, A. Hagège, E. Villard, P. Charron, P. RichardIntroductionMutations 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.ObjectiveOnly 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.MethodsDNAs 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.ResultsA 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.ConclusionThis 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.
  • Modelling CPVT in a dish: Characterization of two novel ryanodine receptor
           mutations using human induced pluripotent stem cell-derived cardiomyocytes
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): S. De Waard, J. Montnach, C. Cortinovis, V. Forest, A. Girardeau, M. Ronjat, M. De Waard, P. Lemarchand, N. GaboritBackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac disease exposing afflicted patients to sudden cardiac death. Most CPVT cases have been linked to mutations of the gene encoding ryanodine receptor type 2 (RYR2). RyR2 is a calcium channel located in the membrane of the sarcoplasmic reticulum (SR). It mediates release of calcium stocks from the SR to the cytosol, playing a major role in excitation-contraction coupling. Although several studies have investigated mechanisms underlying CPVT in mice or in vitro models, little has been done concerning functional assessment of CPVT physiopathology in human cardiomyocytes.ObjectiveWe aimed at characterizing, at cellular level, CPVT phenotype of patients carrying two new RyR2 mutations.MethodHuman induced pluripotent stem cells (hiPSCs) were derived from three CPVT patients. Two patients belonging to the same family carry the R4959Q RyR2 pore mutation. The third patient harbors the Y2476D mutation located in the cytosolic domain of the protein. hiPSCs were differentiated into cardiomyocytes for functional studies. Action potentials were recorded using patch-clamp technique. Calcium handling and contractility were investigated using Ionoptix and CardioExcyte technologies.ResultshiPS-derived cardiomyocytes (hiPS-CMs) from CPVT patients displayed impaired beating properties. Calcium handling properties were also disrupted with changes in calcium transients, accompanied with increased diastolic calcium leak. At last, CPVT hiPS-CMs showed characteristics changes in action potential and arrhythmic events. Coherently with the patients’ phenotype, arrhythmic events were more frequent under beta-adrenergic stress.ConclusionThis work enabled us to characterize two novel CPVT mutations, providing more insight into functional mechanisms involved in this pathology, and further validating the use of human pluripotent stem cells for investigating complex cardiac rhythm disorders.
  • Mapping of the catecholaminergic automatic activity from its foci within
           the pulmonary veins to the left atria in rat
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): C. Pasqualin, C. Guilloteau, F. Gannier, N. Peineau, P. Bredeloux, V. MaupoilIntroductionParoxysmal atrial fibrillation (pAF) is triggered by ectopic foci of electrical activities located in pulmonary vein (PV) myocardial sleeves. Previously, we showed in rat that norepinephrine (NE) superfusion induced a catecholaminergic automatic activity (CAA) occurring in repetitive bursts of action potential (AP) in isolated PV strips but not in left atria (LA).ObjectiveThis study was realised to characterize the calcium activity induced during the CAA as well as its propagation through PV and LA.ResultsEctopic foci induced by NE were located in both proximal and distal parts of PV. Depending on the preparation, one isolated or several ectopic foci were identified, within the same or in two different PV of the preparation. This could explain the complex aspect of some bursts composed of electrical activities from these different foci. CAA triggered by these foci spread to the LA or remained confined to the PV where it originated. In this case, microelectrode recordings showed that CAA induced DAD-like electrotonic membrane potential oscillations in the LA, far from the PV foci. However, these electrical waves were not associated with calcium oscillations. Moreover, during bursting activity, re-entrant circuits sometimes occured in PV.ConclusionEctopic foci triggered by NE in rat PV present similarities with those observed during pAF in human. The conduction of CAA from PV to atria is variable, yet always causing electric oscillations of membrane potential which could be arrhythmogenic.
  • Mitochondria and L-Type Ca2+ channels interplay in the regulation of Ca2+
           dynamics in murine pacemaker cells
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): L. Fossier, A.G. Torrente, J. Louradour, I. Bidaud, M. Mangoni, P. Mesirca, J. FauconnierIntroductionSinoatrial cells generate cardiac automaticity through functional interactions between membrane ionic currents and intracellular Ca2+ dynamics. Mitochondrial Ca2+ plays a role in ATP synthesis regulation and intracellular Ca2+ levels. Interestingly, both could modify AMPc levels and possibly regulate cardiac automatism. We then hypothesized that mitochondrial Ca2+ homeostasis interact with β-adrenergic pathways and regulates cardiac automatism.ObjectiveTo determine whether pharmacological inhibition of the mitochondrial Ca2+ uniporter (MCU), which is responsible for Ca2+ influx in mitochondria, affects the sinoatrial node function and β-adrenergic responses.MethodBasal level and amplitude of Ca2+ transients were recorded using a ratiometric fluorescent probe (Fura-2/AM) in mice isolated sinoatrial cells. Optical voltage mapping was also used to study the spontaneous frequency of action potentials generated by intact sinoatrial tissue isolated from C57Bl6 mice.ResultsIn basal conditions, inhibition of mitochondrial Ca2+ influx with Ru360 in isolated sinoatrial cells did not affect automaticity. On the other hand, Ru360 prevents intracellular Ca2+ increase after stimulation of L-type Ca2+ channels. Similarly, MCU inhibition applied to intact sinoatrial tissues did not show significant effects under basal conditions, but induced a significant reduction of the spontaneous frequency (PA/min) under β-adrenergic stimulation.ConclusionWe here demonstrated that mitochondrial Ca2+ regulates intracellular Ca2+ dynamics, and that mitochondrial Ca2+ is needed to support cAMP production, by stimulating ATP synthesis during a β-adrenergic stimulation. We propose that this mechanism is required to maintain a high spontaneous frequency, especially under physiological stress conditions.
  • Ligand-grafted nanoparticles as tools to study L-type calcium channel and
           β-adrenergic receptor function on surface and T-tubule membranes
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): M. Barthe, F. Lefebvre, L. Moine, N. Tsapis, R. FischmeisterThe cell membrane of adult ventricular myocytes (AVMs) is characterized by many invaginations, constituting the transverse tubule (TT) system. TT membrane (TTM) is continuous with the outer surface membrane (OSM) to allow the rapid electrical coupling during the action potential and represents about 30% of the total cell membrane. Most membrane proteins, such as L-type Ca2+ channels (LTCC) and β-adrenergic receptors (β- AR) are located in both OSM and TTM, but at different densities. However, how the location of these proteins in OSM vs. TTM impacts on their function remains poorly understood, mainly because of the impossibility to selectively activate or inhibit a protein in one compartment without acting on its counterpart in the other compartment. For example, an important function of the TT system is to provide proximity between LTCCs in TTM and ryanodine receptor type 2 in the sarcoplasmic reticulum membrane. However, the role of their counterparts located in OSM is unknown. The goal of our study is to meet this challenge using an innovative nanotechnology approach. We designed nanoparticles (NPs) with immobilized ligands on their surface in order to prevent their access to TTM. The first step was to graft ligands on 5kDa PEG (polyethylene glycol) to favour ligand flexibility. PEG- and NPs-ligand affinity were determined by radioligand binding assays. PEG- and NPs-ligand potency were evaluated by FRET experiments. Confocal microscopy has been used to visualize the membrane distribution of the fluorescent PEGs and NPs after incubation of AVMs. PEG-ligand affinity and potency are lower than affinity and potency of free ligand. The confocal microscopy assay shows that neither NPs nor PEGs penetrate in the TT network. PEG-ligands seem to act on proteins located on the surface membrane. After this validation, functional experiments will be realized to discriminate the respective role of β-AR and LTCC subpopulations.
  • The cAMP-dependent protein kinase type I regulates cardiac
           excitation-contraction coupling
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): M. Gandon-Renard, I. Bedioune, S. Karam, A. Varin, P. Lechène, S. Bichali, J. Leroy, V. Algalarrondo, C. Stratakis, J.J. Mercadier, J.P. Benitah, A.M. Gomez, R. Fischmeister, G. VandecasteeleThe cAMP-dependent protein kinase (PKA) consists of two regulatory (R) and two catalytic (C) subunits and comprises two subtypes, PKAI and PKAII, defined by the nature of their regulatory subunits, RIα and RIIα respectively. Whereas PKAII is thought to play a key role in β-adrenergic (β-AR) regulation of cardiac contractility, the function of PKAI is unclear. To address this question, we generated mice with cardiomyocyte-specific and conditional invalidation of the RIα subunit of PKA. Tamoxifen injection in 8 weeks-old mice resulted in a> 70% decrease in RIα protein without modification of other PKA subunits, which was associated with ∼2-fold increased basal PKA activity in RIα-KO mice (P 
  • Influence of distinct cardiac-specific FKBP12.6 overexpression levels on
           cardiac function and [Ca2+]i cycling
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): M. Gandon-Renard, F. Lefebvre, D. Courilleau, S. Gomez, P. Gerbaud, A.M. Gomez, J.J. MercadierCardiac ryanodine receptors (RyR2) have a key role in excitation-contraction coupling by releasing Ca2+ from sarcoplasmic reticulum (SR). In cardiomyocytes, 2 FK506 binding protein (FKBP) isoforms have been shown to bind and to stabilize RyR2 opening: FKBP12 and FKBP12.6, the later having a stronger affinity for RyR2 despite its lower abundance. Cardiac-specific FKBP12.6 overexpressing mice have fewer arrhythmias induced by β-adrenergic stimulation than wild type (WT) mice, suggesting an implication of FKBP12.6 in an antiarrhythmic mechanism. Heart failure (HF) syndrome has a high incidence of arrhythmias, which may be explained by a decrease of FKBP isoform expression. The precise mechanism of the antiarrhythmic effect of FKBP12.6 overexpression remains unknown. To gain insight into this mechanism, we developed 2 transgenic mouse lines with cardiac-specific moderate- (TG1) and high- (TG2) FKBP12.6 overexpression levels. We characterized cardiac function, [Ca2+]i cycling and its response to β-adrenergic stimulation in both mouse lines. TG1 and TG2 mice developed mild and marked cardiac hypertrophy, respectively, associated with basal cardiac function increase in TG1 mice only. In stimulated cardiomyocytes, [Ca2+]i transient amplitude, measured by confocal microscopy, was higher in TG1 than in WT mice, without a significant difference in their SR Ca2+ content. The effect of β-adrenergic stimulation (50nM isoproterenol) was attenuated in TG1 mice compared to WT mice, in association with the prevention of pro-arrhythmogenic Ca2+ release events, such as Ca2+ waves. In contrast, TG2 mice showed [Ca2+]i handling characteristics similar to HF, with slower [Ca2+]i transient relaxation. Interestingly, and contrary to HF, pro-arrhythmogenic Ca2+ release events were also reduced in TG2. These results indicate that the level of FKBP12.6 overexpression has distinct effects on cardiac function and on Ca2+ cycling and its response to β-adrenergic stimulation.
  • Maurocalcine effects on calcium homeostasis in adult rat cardiomyocytes
           and human iPS cells derived cardiomyocytes
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): C. Cortinovis, S. De Waard, J. Montnach, O. Chkir, M. Erfanian, M. Ronjat, M. De WaardBackgroundRyanodine receptors type 2 (RyR2) the intracellular channels that control excitation-contraction (EC) coupling in cardiomyocytes represent an important target for treatment of arrhythmias accompanying cardiac pathologies. Maurocalcine (MCa), a peptide isolated from scorpion venom, has been described as a high affinity activator of RyR in skeletal muscle. Phosphorylation of MCa has been shown to induce a complete remodelling of its effect on RyR, making it a negative allosteric modulator of RyR.ObjectiveThe purpose of this study is to characterize the effects of MCa and different analogues on EC coupling in isolated adult ventricular cardiomyocytes and hiPS-derived cardiomyocytes (hiPS-CMs).MethodsAdult ventricular myocytes were isolated from 3–6 months-old Sprague Dawley rats with conventional collagenase type II and protease type XIV mix, and hiPS-CMs were obtained from urine cells of healthy volunteers. Changes of cytoplasmic calcium concentration were measured using Fura-2 and IonOptix software. hiPS-CMs contractions and extrafield potentials were recorded with CardioExcyte system (Nanion).ResultsWe first confirmed binding between MCa and RyR2. Next, we showed that MCa (500nM) induces asynchronous calcium release and contractions of isolated adult rat cardiomyocytes under electrical stimulation at 1Hz. Similar results were observed on hiPS-CMs in the presence of MCa. Effects of native MCa and analogues on isoprenaline-mediated stimulation of RyR2 are under investigation.ConclusionOur results demonstrate that MCa penetrates adult cardiomyocytes as well as human iPS derived cardiomyocytes and modulates RyR2 activity. MCa analogues exhibit different effects on RyR2, from positive to negative allosteric modulation. These results provide promising evidence that MCa could be used as an in cellulo modulator of RyR2 to control abnormal RyR activity in pathological situations.
  • Regional modulation of action potential duration and arrhythmias by ß1-
           and ß2-adrenergic receptor stimulation in the porcine right ventricle
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): V. Dubes, S. Charron Guitoger, C. Michel, M. Constantin, M. Haissaguerre, M. Hocini, O. Bernus, D. BenoistIntroductionThe right ventricular outflow tract (RVOT) is the main origin of idiopathic ventricular tachycardia (IVTs). Sympathetic stimulation is involved in IVTs but mechanisms underlying this preferential origin remain unknown.ObjectiveTo determine the role of ß1- and ß2-adrenergic receptors (ß1-AR, ß2-AR) in the regional modulation of right ventricular (RV) electrophysiological properties and arrhythmias.MethodsPorcine RVs were isolated and perfused via both right and left coronary arteries. Epicardial (EPI) electrical activity was optically mapped (di-4-ANEPPS 20 μM) and APD measured at 80% repolarization (APD80) in the RVOT and posterior RV free wall region (RVFW). Regional mRNA and protein expression for ß1-AR and ß2-AR was determined respectively by RT-PCR and Western-Blot.ResultsCombined ß1- and ß2-AR stimulation (50 nM isoprenaline, ISO) shortened APD80 EPI with a larger effect in the RVFW than the RVOT. Interestingly, isolated ß2-AR stimulation (10–25 μM salbutamol, SALBU with 4 μM metoprolol, METO) only decreased APD80 significantly in the RVOT EPI (P 
  • Development of new voltage-sensitive fluorescent dyes for cardiac optical
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): E. Renard, N.R. Faye, G. Dargazanli, P. Pasdois, O. BernusIntroductionCardiac arrhythmias are an important cause of morbidity and mortality. Optical mapping using voltage-sensitive dyes (VSDs) allows to study these disorders in isolated perfused tissues. Until recently, this technique remained limited to the myocardial surface due to the short excitation wavelengths of common VSDs. Using red excitation light allows to by-pass this problem, but availability of such dyes remains limited.ObjectiveTo develop new families of red-shifted VSDs and to characterize both their spectral and potentiometric properties.MethodThree families of VSDs were designed. The spectral properties of each VSD was assessed by spectrofluorometry in Langendorff perfused rat hearts. The potentiometric properties were assessed through optical mapping in Langendorff perfused rat hearts. For spectrofluorometry, hearts were freely beating and systolic and diastolic pressures were continuously monitored. In optical mapping experiments hearts were mechanically arrested by supplementation of blebbistatin (10 μM).ResultsOut of the three families, one showed a strong shift in excitation and emission wavelengths towards the near-infrared. Within this family, three VSDs, with variations in the hydrophilic tail and charged carrier, were tested. Results showed that these VSDs have peak excitation above 500 nm and peak emission around 730 nm. Although two of these dyes showed a low potentiometric sensitivity (5%) with a stable signal for over 2 hours after a bolus injection in the hearts. In mechanically arrested hearts, the VSDs had no impact on electrophysiological parameters. However, in beating hearts, the VSDs significantly increased diastolic pressure.ConclusionWe have developed new red-shifted VSDs and validate their use in cardiac applications, which might allow optimizing optical mapping of cardiac arrhythmia dynamics in deeper tissue layers and/or in blood-perfused tissues.
  • Impact of Beta adrenergic receptors polymorphism on the onset of
           ventricular fibrillation during the acute phase of myocardial infarction
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): E. Morel, A. Deliniere, G. Morgan, B. London, M. Bristow, W. Minobe, P. Roy, P. ChevalierIntroductionVentricular fibrillation complicating acute myocardial ischemia is the main cause of sudden cardiac death. We investigated whether two known ADBR2 and ADRB1 polymorphisms are associated with ventricular fibrillation (VF) in the context of myocardial infarction (MI).Materials and methodsA total of 831 patients were recruited during the MAP-IDM study: 392 patients who experienced VF during the acute phase of primary MI and 439 controls with MI without VF. Patients were genotyped for the ADRB2 Gln27Glu, the ADRB1 Arg389Gly polymorphisms by RT-PCR. Unconditional logistic regression models were fitted, after adjustment on center, age and sex. Age was included as a 5 age-group variable (27–44, 45–54, 55–64, 65–74, 75–88) using dummy variables, including interaction terms between sex and age-groups.ResultsCases and controls did not differ significantly in age, in sex-ratio, BMI, in smoker ratio and in troponin peak value. VF patients have a lower left ventricular ejection fraction (LVEF) (46.1% vs. 51.9%, P 
  • In vitro and in vivo characterization of a synthetic scorpion toxin
           AmmTx3, a potent inhibitor of cardiac voltage-gated potassium channel
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): S. Nicolas, C. Zoukimian, H. Meudal, S. De Waard, K. Ait Ouares, M. Canepari, R. Beroud, C. Landon, M. De Waard, D. BoturynBackgroundVoltage-gated potassium channel Kv4.2 (encoded by KCND2 gene) contributes to the cardiac transient outward potassium current (Ito1). This current is the main contributor to the repolarisation phase 1 of the cardiac action potential. The toxin AmmTx3, identified from the venom of the scorpion Androctonus mauretanicus, is a blocker of Kv4.x channels, and have interesting therapeutic potential for neurological disorders due to its effect in cerebellar granule neurons. Its effects on cardiac Kv4.2 channels remains unclear.ObjectiveThe aim of this study was to:– produce a synthetic AmmTx3 (AmmTx3-NCL);– evaluate in vitro and in vivo, effects of this toxin on Kv4.2 channels compared to native toxin.MethodWe did chemical synthesis of AmmTx3 using the native chemical ligation strategy (NCL). We characterized its biological activity compared to native AmmTx3 using an automated patch-clamp system (Syncropatch 384 PE, Nanion) on HEK cells co-expressing Kv4.2 α subunit and two auxiliaries subunits (KChIP and DPP6). Effects of AmmTx3 and AmmTx3-NCL on cardiac cellular electrophysiology were studied by patch clamp on adult rat cardiomyocytes and hiPSC-CMs. Integrated cardiac effects of AmmTx3 were studied on ECG of wild-type mice.ResultsIn this study, we report the total chemical synthesis of AmmTx3 and 3D structure was also determined. As expected, biological activity of folded AmmTx3-NCL is coherent to native toxin with a similar time course of Kv4.2 current inhibition without any change of activation kinetics. Characterisation of AmmTx3 effects on isolated cardiomyocytes, hiPSC-CMs and in vivo by ECG is ongoing.ConclusionAmmTx3 toxin can be chemically synthesized and used as a Kv4.2 channel inhibitor to contributed to the better understanding of the exact role of Ito1 in cardiac electrophysiology. Those first results seem to be a promising evidence that AmmTx3 could a potential inhibitor of Ito current in early repolarisation syndrome.
  • Transient Receptor Potential Vanilloid 4 channels participate in mouse
           ventricular action potentia
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): S. Chaigne, J. Louradour, S. Charron, F. Brette, T. Ducret, T. HofIntroductionTransient Receptor Potential Vanilloid 4 (TRPV4) channels, belonging to the TRP channels superfamily, are Ca2+-permeable channels activated by hypo-osmotic stress. In the heart, TRPV4 channels are expressed at the protein level in mouse and rat ventricular myocytes and fibroblasts. They are involved in valve development during embryogenesis, in ischemia-reperfusion injuries and in reactive fibrosis. Whether TRPV4 channel can participate in ventricular action potential (AP) is still unknown.ObjectiveThe aim of this study is to pharmacologically unmask the contribution of TRPV4 channels in left ventricular AP.MethodsLeft Ventricular myocytes were isolated from TRPV4 + / + and TRPV4 − / − mice and AP were recorded using the patch-clamp technique. Pharmacological activator (GSK1016790A) and inhibitors (HC-067047 and GSK2193874) were perfused during the recordings to evaluate the effect on AP parameters.ResultsTRPV4 activator GSK1016790A induces a transient and dose dependent increase in AP duration at 90% of repolarization (APD90) in TRPV4 + / + but not in TRPV4 − / − myocytes (+ 19.4 ± 3.8%; n = 11 vs − 0.6 ± 1.8%; n = 7 at 500 nM respectively). The activator mediated-APD increase is abolished by TRPV4 channels inhibitors and CamKII inhibitor KN93 at 1 μM. Conversely, TRPV4 channel inhibitor (GSK2193874) at 100 nM significantly decreases APD90 in TRPV4 + / + but not in TRPV4 − / −  myocytes (− 7.8 ± 2.6%; n = 11 vs 1.0 ± 1.3%; n = 7 respectively). Similarly, HC-067047 at 300 nM significantly decreases APD90 in TRPV4 + / + but not in TRPV4 − / − myocytes (− 10.9 ± 5.0%; n = 6 vs − 1.2 ± 2.4%;n = 4 respectively). At the concentrations mentioned above, activator and inhibitors have no effect on the other AP parameters.ConclusionThis study shows that TRPV4 channels exert a basal contribution in ventricular AP and could affect repolarization. It is thus a potential target for pharmacological approaches against ventricular arrhythmias.
  • High frame rate ultrasounds for electromechanical wave imaging to
           characterize and differentiate endocardial from epicardial activation of
           ventricular arrhythmia: A proof of concept study
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): F. Bessiere, A. Zorgani, L. Daunizeau, E. Cao, F. Vaillant, E. Abell, B. Quesson, S. Catheline, P. Chevalier, C. LafonBackground and objectiveDifferentiating an epicardial from an endocardial ventricular tachycardia (VT) can be really challenging despite the latest technologies available. We intended to develop a new tool method based on electromechanical wave imaging (EWI) to improve arrhythmogenic substrate activation analysis.MethodsExperiments were conducted on a left ventricle of a swine isolated working heart model. Our protocol aimed to demonstrate that, thanks to ultrasounds, a different pattern of mechanical activation could be obtained whether the ventricle was in sinus rhythm, paced from the epicardium or from the endocardium.ResultsEWI electrocardiogram-gated systematically differentiated with success endocardial from epicardial foci. When in paced ventricle, the origin of the wave front was focal and coming from the endocardium or the epicardium. In sinus rhythm, wave front was global and activating from the entire endocardium towards the epicardium at a speed of 1.47 ± 0.42 ms−1. Wave front speed through the thickness of the ventricle was similar when the endocardium was paced (1.42 ± 0.38 ms−1) and much slower when the epicardium was paced (0.59 ± 0.19 ms−1).ConclusionEWI activation mapping can locate ventricular activation inside the left ventricular wall thickness and calculate the propagation of the wave front through the muscle. In the future, this technology might help to differentiate endocardial from epicardial VT during complex ablation procedures.
  • Implantable Cardioverter Defibrillator in the elderly
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): P. Poupin, M.L. Bureau, B. Degand, F. Le Gal, L.P. Christiaens, B. Alos, P. Ingrand, M. Paccalin, R. GarciaBackgroundThe elderly are often underrepresented in ICD trials and evidence of ICD relevance in patients ≥ 75 years is not clear.ObjectiveWe aimed to evaluate the complications, and the rate of appropriate therapy in this population.MethodsThis monocentric case-control study included ICD recipients ≥ 75 years (cases) matched with ICD recipients 
  • Repolarization and arrhythmia modulation by K-ATP channel activation in
           the porcine right ventricle
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): C. Michel, S. Charron, V. Dubes, M. Martinez, M. Haïssaguerre, M. Hocini, O. Bernus, D. BenoistIntroductionThe RVOT is involved in arrhythmias in several diseases such as the Brugada syndrome (BrS). In a subpopulation of patients with BrS and early repolarization (ER) syndrome, a K-ATP gain-of-function (GOF) mutation has previously been described and was suggested to contribute to arrhythmogenicity in this context.ObjectiveTo determine the role of regional K-ATP channels expression on RV repolarization heterogeneity and in arrhythmia occurrence and modulation.MethodsPig right ventricles (RV) were perfused by both right and left coronary arteries, paced at 1 or 1.5 Hz and the electrical activity optically-mapped (di-4-ANEPPS, 20 μM). The preparation was perfused with pinacidil (PINA, 20 μM), and diazoxide (DIAZ, 100 μM), and subjected to 20 min no-flow (NF) ischemia episodes followed by 20 min reperfusion (RF). Arrhythmia susceptibility was assessed using a 20 Hz burst protocol while spontaneous arrhythmias were also recorded. Protein expression was assessed by western blot.ResultsPINA-induced action potential duration (APD) shortening was larger in RVOT than in the free wall (FW). DIAZ induced a slight but significant reduction in APD across the RV. SUR2A expression was greater in the RVOT epicardium vs. FW but Kir6.1/2 and SUR1 expression was similar in both regions. PINA induced spontaneous ventricular fibrillation (VF) in 80% of the preparations with higher dominant frequency (DF) and regularity index in the RVOT than the FW. DF of burst-induced VF were higher in PINA but not in DIAZ compared to CTRL VF. Similarly to PINA, NF-induced APD shortening was greater in the RVOT than in the FW. No spontaneous arrhythmia occurred during NF but slow ventricular tachycardias arose in 36% of the preparations during RF.ConclusionK-ATP activation leads to an increase in RV repolarization dispersion which is likely to contribute to arrhythmogenicity in BrS or ER patients with a K-ATP channel GOF mutation and may underlie BrS phenocopy induced by RV ischemia.
  • Modulation of a new pathway prevent valvular interstitial cells
           calcification, a potential innovative therapeutic target in aortic valve
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): S. Kabdani, Y. Sottejeau, R. Mickael, M. Tagzirt, D. Corseaux, F. Juthier, A. Vincentelli, E. Van Belle, R. Jashari, B. Staels, A. Dupont, S. SusenIntroductionAortic valve stenosis (AVS) is the narrowing of the aortic valve (AV) opening caused by fibrosis and calcification. Despite this paradigm, no targeted medical therapy has proven to prevent, slow down or treat AVS. Using transcriptomic approach on human valvular interstitial cells (VIC) isolated from fibrocalcific and normal valves, our team has identified an enzyme X downregulated in fibro-calcific VIC. This enzyme X and its product Y have documented anti-calcification effects in other cell types than VIC.ObjectiveOur goal is to decipher the implication of this pathway on an in vitro model of human primary cultures of VIC in ostegenic conditions.MethodNormal AV unsuitable for grafting and fibrocalcific AV from valve replacement (ATHERAO protocol) were collected. Levels of enzyme X in AV was assessing by histology and by Western Blot on tissue homogenate. VIC isolation was realized by enzymatic digestion of normal AV. Primary cultures were exposed to ostegenic media (OM) or control media with or without the product Y of the enzyme (1–1000 nM) during 7 days. Evaluation of calcification was realized by alizarin red staining, mRNA levels of calcification markers.ResultsWe confirmed a differential expression of enzyme X on tissue by histology and by western blot (− 5.2 fold, P 
  • Classical low-flow aortic stenosis with very low left ventricular ejection
           fraction or no flow reserve: Do they benefit from aortic valve
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): M.S. Annabi, A. Dahou, P.E. Bartko, I.G. Burwash, J. Bergler-Klein, J. Mascherbauer, S. Orwat, G. Mundigler, H. Baumgartner, H.B. Ribeiro, J. Rodes-Cabau, J. Cavalcante, M.A. Clavel, P. PibarotBackgroundIn patients with classical low-flow, low-gradient (CLF i.e. with left ventricular ejection fraction [LVEF]  25% (Fig. 1, Panel A);–in patients with vs. without FR (Fig. 1, Panel B).Furthermore, AVR was associated with improved survival in patients with LVEF ≤ 25% and in patients with no FR. Moreover, LVEF ≤ 25% or FR had no impact on mortality in the overall cohort in multivariate analysis (P = 0.19 and P = 0.31 respectively). AVR, particularly transfemoral transcatheter AVR associated with a markedly reduced adjusted risk of death, and no interaction was found with LVEF ≤ 25 (P = 0.44) or with FR (0.84).ConclusionIn this prospective series of CLF-AS, patients with very low LVEF or with no flow reserve benefit from AVR.
  • Risk Stratifying Low-Flow, Low-Gradient Aortic Stenosis using N-Terminal
           Pro B-Type Natriuretic Peptide: Results from TOPAS study
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): M.S. Annabi, J. Bergler-Klein, A. Dahou, I.G. Burwash, G. Ong, L. Tastet, E. Guzzetti, S. Orwat, H. Baumgartner, P.E. Bartko, J. Mascherbauer, G. Mundigler, J. Cavalcante, H.B. Ribeiro, J. Rodes-Cabau, P. Pibarot, M.A. ClavelBackgroundIn low-flow, low gradient aortic stenosis (LFLG-AS i.e. with low left ventricular [LV] ejection fraction), there is no data on the value of the clinical activation ratios of B-type natriuretic peptide (BNP-ratio) versus aminoterminal-proBNP (NT-proBNP-ratio) as surrogates of LV impairment to risk-stratify the patients.MethodsBNP and NT-proBNP-ratios were calculated by dividing the actual serum level by the upper normal reference value for age and sex in 238 prospectively recruited LFLG-AS patients.ResultsAfter adjustment for the severity of AS, initial treatment (aortic valve replacement [AVR] vs. conservative management), age, sex and the euroSCORE (Model#1), BNP-ratio > 7.4 had a trend to predict time to death (HR = 2.14[1.00–4.58], P = 0.05). NT-proBNP ratio significantly predicted one and three-year mortality (area under the curve [AUC] = 0.67 ± 0.04 and 0.66 ± 0.05, both P = 0.001), and independently predicted mortality (HR = 1.39 [1.11–1.74], per unit LogNT-proBNP-ratio, P = 0.004). In a head-to-head comparison, the AUCs for one and three-year mortality were higher with NT-proBNP-ratio versus BNP-ratio (P  11 (62% with severe AS), while those 
  • Hemocompatibility of Bioprosthetic valve in bovine pericardium is based on
           fibrin formation and its endothelization
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): U. Richez, C. Latremouille, I. Netuka, J.C. Roussel, B. Saubamea, E. Rossi, M. Kindo, Y. Pya, A. Capel, P. Jansen, A. Carpentier, D. SmadjaIntroductionBioprosthetic heart valves (BV) made of xenogenic pericardium fixed with glutaraldehyde have been developed more than 30 years ago. The concept of cross linking collagenous fibers to ensure in-vivo stability of the scaffold and reducing antigenic immune response by fixation resulted in successful clinical evaluations and a lower risk of thromboembolism thus eliminating the need for a lifelong anticoagulation. To explain these clinical results, an acquired hemocompatibility process has been proposed but never extensively studied because of the impossibility to access not degenerated material.ObjectiveTo study and understand mechanisms of acquired hemocompatibility, we explored non degenerated BV from 9 different patients implanted with a Carmat total artificial heart (C-TAH) and four BV duration from 45 to 270 days.MethodWe performed classic histopathology and immunophenotypic characterization of explanted BV. Biological deposit has been also explored by Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM).ResultIn short implantation duration time, we observed a fibrin deposit with inflammatory cells and pseudotubes formation. Histological sections showed superficial infiltration of cells, persisting in long duration but not damaging integrity of the pericardium. The fibrin deposit is then organized in a compacted smooth fibrin network in longer implantation durations. Endothelial cells (EC) monolayer covering has also been observed on this fibrin cap, the percentage of the BV surface with EC covering increasing along months. This endothelial cells covering is positive for VE-Cadherin, with flat nucleus and tight junctions.ConclusionHealthy BV implanted with C-TAH enabled us to study, for the first time, non-degenerated implanted valve in human. Biomaterial passivation by an organized fibrin deposit and formation of EC monolayer on top achieve an optimal hemocompatibility without any modification of pericardial tissue.
  • Functional characterization of PALMD risk locus in calcific aortic valve
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): R. Mickael, M.C. Boulanger, R. Devillers, A. Chignon, D. Argaud, G. Mkannez, Z. Li, G. Rhéaume, N. Gaudreault, S. Thériault, Y. Bossé, P. MathieuIntroductionCalcific aortic valve stenosis (CAVS) is the most common heart valve disorder. Genome and transcriptome-wide association studies identified risk variant rs6702619 at the PALMD locus as casually associated with CAVS and with lower PALMD expression.ObjectiveTo map and fine-grain molecular analyses to probe the regulation and function of PALMD.MethodsRegulation of the PALMD risk locus and its impact on valve interstitial cells (VICs) were evaluated. Reporter assays, DNA-binding assays and CRISPR-mediated gene activation were performed to study the role of rs6702619 on the expression of PALMD. PALMD interactome was assessed by LC/MS/MS and functions of PALMD were investigated.ResultsFunctional mapping prioritized rs6702619 as a causal noncoding variant. Analysis of chromatin interactions showed that the risk locus interacts with the promoter of PALMD. CRISPR activation at rs6702619 increased the expression of PALMD by 30%. The variant rs6702619 is located in a binding site for NFATC2, a transcription factor involved in valve embryology. The presence of the risk variant modifies DNA shape as shown by the analysis of atomic resolution structure. Reporter assays demonstrated a decrease in the response to NFATC2 by 5.8 fold with the risk allele. DNA-protein interaction ELISA revealed that the risk allele decreased the affinity for NFATC2. Actin was identified in PALMD interactome and in vitro data showed that PALMD is a novel regulator of actin polymerization. Downregulation of PALMD expression in VICs promoted a myofibroblastic program leading to actin polymerization in stress fibers and the expression of alpha-actin and collagen.ConclusionsThe risk variant rs6702619 is located in a binding site for NFATC2, modifies DNA shape and decreases enhancer-mediated expression of PALMD. PALMD downregulation in VICs results in actin polymerization, a myofibroblast-like phenotype and promotes fibrosis processes, a key feature in the pathogenesis of CAVS.
  • Implication of endothelin-1 in human aortic valve calcification
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): B. Colleville, N. Perzo, H. Eltchaninoff, V. Richard, E. DurandIntroductionAortic Stenosis (AS) is the most common acquired valvulopathy in the Western world. AS is characterized by the differenciation of valvular interstitial cells (VICs) into osteoblastic cells, leading to valvular calcification. The physiopathology of AS is not fully understood and there is, to date, no treatments to stop or slow the progression of AS.ObjectiveThe purpose of our study was to investigate the role of endothelin-1 (ET-1) on VICs calcification.MethodPrimary human valvular interstitial cells (hVICs) were first cultured in pro-osteogenic medium or incubated with ET-1. hVICs were also co-cultured with human valvular endothelial cells (hVECs) obtained from patients with (pathological) or without (healthy) AS in Transwell™ inserts. hVICs calcification was quantified using o-cresolphthalein assay. Real-time quantitative PCR (qRT-PCR) and Western blot analysis were performed to determine the expression of ET-1 (EDN1), inflammation (IL1B, IL6) and bone markers (RUNX2, OPG, OPN). Immunochemistry was performed using ACTA2 antibody to evaluate the phenotype of VICs.ResultshVICs showed an increase of calcification and a decrease of ACTA2 when cultured in pro-osteogenic medium or co-cultured with pathological hVECs. qRT-PCR revealed higher mRNA levels of EDN1, RUNX2, OPG, OPN, IL1B and IL6. At the same time, fibroblast marker ACTA2 was decreased. VIC fibroblastic phenotype was restored and calcification decreased when hVICs were co-cultured with healthy hVECs or incubated with ET-1 antagonist.ConclusionThe present study suggests that ET-1 play a role in the pathogenesis of AS, and therefore, pharmacological ET-1 antagonists could be used to attenuate or stop VIC calcification.
  • Characteristics, prognosis of moderate aortic stenosis
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): G. Delesalle, Y. Bohbot, C. TribouilloyIntroductionModerate aortic stenosis (MAS) has not been extensively studied and characterized, as no published study has been specifically devoted to this condition.ObjectiveWe aimed to describe the characteristics of patients with MAS and to evaluate their long-term survival compared to that of the general population.MethodThis study included 508 patients (mean age 75 ± 11 years) with MAS (aortic valve area [AVA] between 1 and 1.5 cm2, mean AVA 1.2 ± 0.15 cm2). Patients were mostly (86.4%) asymptomatic or minimally symptomatic, 78.3% had hypertension, 36.2% were diabetics and 48.3% had dyslipidemia. Survival of MAS patients was compared with the expected survival of age- and sex-matched individuals of the general population.ResultsDuring follow-up, 113 patients (22.2%) underwent aortic valve replacement (AVR) for severe aortic stenosis. The mean time between inclusion and surgery was 37 ± 22 months. During follow-up, 255 patients (50.2%) died. The 6-year survival of patients with MAS was lower than the expected survival (53 ± 2% vs 65%). In multivariate analysis, age (HR = 1.04 [1.02–1.05]; P 
  • Pluripotent stem cells derived cardiac progenitors cells graft improve
           right ventricular function in a porcine model of repaired Tetralogy of
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): A. Ernault, V. Fouilloux, E. Aries, S. Al-Dybiat, P. Brige, D. Arnaud, G. Gorincour, M. Pucéat, V. LambertIntroductionAdult individuals with a cardiac congenital disease are emerging as a major patient population in hospitals. Right ventricular (RV) failure with limited pharmacological therapeutic approaches is often the cause of premature death and morbidity.ObjectiveCell therapy turns out to be an alternative approach in order to regenerate the RV and/or to improve mechanical function through other biological mechanisms.MethodWe used an immune-suppressed porcine model of repaired Tetralogy of Fallot that features within 5 months a RV pressure and volume overload leading to a defect in its mechanical function. Pluripotent stem cells derived cardiac progenitors were seeded in a collagen/alginate/gelatin hydrogel (stiffness as low as 1 kPa) printed and polymerized on a collagen membrane patch with the size of the pig's RV. The elastic patch was then grafted on the surface of the pig's epicardium without any suture. Myocardial function was assessed by echocardiography using standard (TAPSE, s’wave, FAC) and strain parameters before and after cell therapy. Pigs were euthanized 2 months post-graft, the heart explanted and the RV used for histology and immunostaining to track the fate of human cells.ResultsAfter cell therapy, RV dilatation decreased, overall RV function and RV myocardial contractility were improved on echocardiography. A significant number of human cardiac progenitors were found in the patch and within the myocardium in fibrotic interstitial space. Cells were still differentiating after 2 months post-graft while others were differentiated as assessed by the presence of sarcomeric actinin. Markers of cell proliferation and senescence were further used to better characterize the origin of the RV function improvement.ConclusionCell therapy of RV failure could thus be a therapeutic option for adults cardiac congenital patients.
  • NIPBL haploinsufficient mice recapitulate valve defects observed in
           Cornelia de Lange syndrome patients
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): F. Boulet, T. Moore-Morris, M. PuceatIntroductionCornelia de Lange (CdL) syndrome, a rare developmental disorder (1/30000 live births), results from mutations in genes encoding the cohesin complex and its partners. The most commonly mutated gene is the cohesin loader, NIPBL. 25–40% of patients display heart malformations, including valve stenosis.ObjectiveWe sought to determine whether NIPBL + /− mice recapitulate valve defects observed in patients.MethodTo achieve our objectives, we are using a mouse model in which NIPBL exon 2 has been deleted. In order to investigate the effect of NIPBL haploinsufficiency on EMT, embryos were collected at E10.5, outflow tracts (OFT) were dissected and cultured as explants on collagen gels. Explants were treated for 3 weeks with chondrogenic medium to evaluate calcification. Also, valve morphogenesis and function were assessed at 3 and 8 months of age by histology and Doppler echocardiography.ResultsNIPBL + / − OFT explants did not reveal any epithelial-to-mesenchymal transition defects. The number of cells expressing osteocalcin after chondrogenic treatment in NIPBL + / − and WT explants did not significantly differ. We found no evidence for differences in calcification of NIPBL + / − cells. At 3 months, an increase in aortic flux was observed in mutants (1/7). Histological analysis revealed a tendency for an enlarged aortic valve in mutants (area of the valve/tibia length: NIPBL + / − = 7692 μm2/mm ± 1560, n = 10; WT = 5264 μm2/mm ± 1715, n = 10; P-value 
  • Congenitally corrected transposition of the great arteries: Is it really a
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): N. Arribard, M. Mostefa-Kara, D. Bonnet, S. Hascoët, L. HouyelIntroductionCongenitally corrected transposition of the great arteries (ccTGA) is a rare congenital malformation which associates atrioventricular discordance and ventriculo-arterial discordance. Although a ventricular septal defect (VSD) is frequently associated, its anatomy remains controversial.ObjectiveTo compare the right ventricular septal anatomy between ccTGA, transposition of the great arteries (TGA) and normal heart (NH) and to determine the anatomy of the VSD in ccTGA.MethodWe analyzed 102 human heart specimens: 31 ccTGA, 36 TGA, 35 NH. VSD were classified as outlet if located above the septal insertions of the tricuspid valve, inlet if underneath. We measured the lengths of the anterior (AL) and posterior (PL) limbs of the septal band and the angle between the two limbs. In order to assess the orientation of the septal band, we measured the angle between AL and the arterial valve above (AL-AV).ResultsVSD was present in 26 ccTGA (83.9%) and was an outlet VSD in 17 cases (65.4%). Mean AL-PL angle was 76.4° for ccTGA compared to 90.6° for TGA (P = 0.011) and 76.1° for NH (P = ns). Mean AL-AV was 70.6° for ccTGA compared to 90.6° for TGA (P = 0.0004) and 69.1° for NH (P = ns). PL was significantly shorter in ccTGA (P 
  • Study of aortic index of tortuosity in type A aortic dissection
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): F. Scalbert, O. Milleron, P. Ou, G. JondeauIntroductionThe risk of type A aortic dissection (AAD) depends on the degree of aortic wall's alteration, which can result in dilatation and tortuosity. The estimate of this risk currently relies solely on measuring the diameter of the ascending aorta.ObjectiveThe purpose of this study is to ascertain that patients with AAD don’t have higher aortic tortuosity, and more liver or renal cysts.MethodWe analyzed aortic scans of 109 patients with AAD after surgery and 109 control patients matched on gender and age. After 3D reconstruction, the total and geometrical lengths (Ltot and Lgeo) of the different aortic segments were measured to calculate the aortic index of tortuosity (IT = Ltot/Lgeo).ResultsThe different aortic segments of the AAD group have higher Ltot, Lgeo and IT than the control group. For the whole aorta, the mean Ltot is 527.7 ± 46.1 mm for the AAD group versus 475.8 ± 39.7 mm for the control group, i.e. 9.4% longer (P 
  • Valvular interstitial cells down regulate matrix metalloproteinase 9
           activity and expression in human monocyte-derived macrophages: Potential
           impact on aortic valve stenosis pathophysiology
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): M. Tagzirt, Y. Sottejeau, S. Kabdani, R. Mickael, D. Corseaux, F. Juthier, A. Vincentelli, E. Van Belle, R. Jashari, B. Staels, S. Susen, A. DupontIntroductionAortic valve stenosis (AVS) involves inflammation, excess deposition of collagen-rich extracellular matrix (ECM) and calcification. Recent studies have shown that M1 macrophages observed in stenosed valve promote calcification of valvular interstitial cells (VIC), the most prevalent cell type in aortic valve.ObjectiveOur aim was to investigate whether, in turn, human VIC could modulate M1 macrophages phenotype.MethodPatients with severe AVS (n = 43) were included in this study. Patients without AVS (n = 129) were used as controls. Human VIC were isolated from patients with severe AVS or from normal healthy donor (control valves).ResultsMMP-9 expression and activity of human M1 macrophages cultivated with conditioned medium of VIC (CM-VIC) from stenosed valves are lower compared to macrophages with CM-VIC from control valves (253 ± 18 vs 182 ± 10.5; P 
  • A Comparative monocentric prospective study of patients treated with TAVI
           Valve-in-Valve or with an aortic native valve at Rouen University
           Hospital: Immediate and long-term results
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): S. Gafsi, C. Tron, F. Bauer, J.N. Dacher, P.Y. Litzler, A. Cribier, H. Eltchaninoff, E. DurandIntroductionTAVI (Transcatheter Aortic Valve Implantation) by valve-in-valve (ViV) procedure has developed as an alternative to surgical reintervention in the event of aortic bioprosthesis degeneration.ObjectiveThe objective of our study is to describe the immediate results and long-term follow-up of patients treated with ViV at Rouen University Hospital.MethodAll patients who underwent a TAVI procedure in aortic position between January 2011 and May 2018 were included prospectively and comprehensively. A comparative study between ViV and TAVI procedures on native valve was performed.ResultsA total of 1164 patients were included including 61 ViV procedures. ViV patients had a mean age of 83.6 ± 5.46 years. In total, 88.6% of the patients were treated by the femoral route. Final mean trans-aortic gradient was significantly higher in the “ViV group” in comparison to the “Native Valve” group (18.7 ± 8.4 vs. 10.8 ± 4.5 mmHg; 
  • Aortic Valve Replacement is Superior to Conservative Management in
           Low-Flow, Low-Gradient Aortic Stenosis independently of the presence of
           true severe stenosis
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): M.S. Annabi, A. Dahou, I.G. Burwash, P.E. Bartko, J. Bergler-Klein, J. Mascherbauer, G. Mundigler, S. Orwat, H. Baumgartner, J. Cavalcante, H.B. Ribeiro, J. Rodes-Cabau, M.A. Clavel, P. PibarotBackgroundThe survival benefit of surgical (SAVR) or transcatheter (TAVR) aortic valve replacement over conservative management (ConsRx) remains unclear in patients with low-flow, low-gradient (LFLG) aortic stenosis (AS).Method476 LFLG AS patients (mean age 75 ± 10 yo, 71% males, 71% classical and 29% paradoxical LFLG, aortic valve area = 0.79 ± 0.15 cm2 and mean gradient = 26 ± 7 mmHg) were prospectively recruited. Survival was studied using Kaplan-Meier curves. Inverse probability-of-treatment-weighting (IPW) was used to balance patients’ characteristics between AVR and ConsRx groups. Cox proportional hazards regression was used to corroborate the findings and study the benefit associated with of SAVR, TAVR (including transfemoral and transapical accesses).ResultsDuring a median follow up of 32 months, 220 patients died and less than 5% were lost to follow up. AVR markedly reduced the risk of death (Fig. 1, Panel A). Interestingly, the benefit extended also to patients with pseudosevere AS (Fig. 1, Panel B). These results were consistent with non-weighted univariate and multivariate analyses. TAVR patients had significantly more comorbidities compared to ConsRx or SAVR patients, including older age, previous myocardial infarction, diabetes, renal failure, and more depressed left ventricular function as assessed by NT-proBNP (all with P 
  • Infective endocarditis after transcatheter aortic valve implantation. A
           comparison with endocarditis occurring in surgical aortic prosthesis and
           native aortic valve patients
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): C. Flouriot, G. Avinee, M. Joulakian, C. Alarçon, C. Marchand, A. Savouré, E. Durand, C. Tron, N. Frebourg, P.Y. Litzler, C. Chapuzet, H. EltchaninoffIntroductionInfective endocarditis is rare but serious. Epidemiology is well known in standard population and surgical valve patients (Pts). The recent development of Transcatheter Aortic Valve Implantation (TAVI) raise new questions about endocarditis in this population.ObjectiveTo assess the epidemiology and mortality of endocarditis in TAVI Pts and to compare the results to surgical valve owners and native patients.MethodWe included all patients presenting with endocarditis after TAVI between 2010 and 2018 hospitalized in our institution. We compared these patients to those discussed within the “endocarditis team staff” and presenting with endocarditis located on surgical aortic prosthetic valve or on native aortic valve.ResultsA total of 34 TAVI Pts were included, and compared to a population of 45 surgical aortic prosthetic valve and 68 native Pts. TAVI Pts were older (83.1 ± 1.1 yrs, vs 73.3 ± 1.7 and 66.0 ± 1.7, respectively; P 
  • Comparative regenerative properties of mesenchymal stem cells isolated
           from MRL (Murphy Roths Large) versus C57Bl6 mice
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): C. Sarre, G. Tejedor, P. Gonzalez, S. Bahraoui, C. Barrere, A. Vincent, J. Nargeot, S. Barrere-Lemaire, F. DjouadIntroductionAdult Mammals are unable to regenerate their injuried myocardium by contrast to Zebrafish or MRL mice. While myocardial repair has been shown after cryoinjury in MRL mice, it failed after coronary ligation leading to ischemic injury. This underlies the impact of the inflammatory environment on the intrinsic regenerative potential of MRL stem cells. Mesenchymal stem cells (MSC) administered as cardiac therapy have emerged as breakthrough immunomodulative and cytoprotective treatments for myocardial infarction.Objectiveto compare the intrinsic regenerative properties of MSC derived from C57BL/6 (MSC-BL6) and MRL (MSC-MRL) mice in an ex vivo myocardial ischemia-reperfusion (IR) injury model and decipher the underlying mechanisms.MethodsFACS analysis allowed characteristic phenotyping of MSC isolated from C57BL/6 (MSC-B6) or MRL (MSC-MRL) murine bone marrow. Their differentiation potential into chondrocytes, osteoblasts and adipocytes upon inductive conditions was studied. Their migration capacities were evaluated using the in vitro scratch wound healing assay. Infarct size was measured in mouse hearts subjected to ex vivo 30 min-ischemia and 1 hour-reperfusion and treated by MSCs.ResultsIn vitro, MSC-MRL showed a significantly higher migration potential than MSC-B6 in accordance with reduced expression levels of E-cadherin and cadherin 11 adhesion molecules. Using MRL-MSC conditioned medium, we demonstrated an increased migration capacity of MSC-B6 suggesting that the MRL-MSC release a soluble factor responsible for their potent homing potential to the wound site. Injected during reperfusion, MSC-MRL were able to protect the injured myocardium more efficiently than MSC-B6 in the ex vivo IR model (MSC-MRL: 47.18 ± 0.66%, n = 3 vs MSC-B6: 56.36 ± 3.17%, n = 3).ConclusionMSC-MRL have superior cardioprotective effects for the treatment of IR injury compared to MSC-B6 probably due to higher migration capacities and specific regenerative secretome.
  • Is the cardioprotective effect of LCZ696 linked to increased cardiac
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): A. Carboni, C. Bielmann, S. Rignault-Clerc, N. Rosenblatt-VelinLCZ696 treatment reduces the mortality and the risk of hospitalization of patients with hypertension or heart failure with a preserved ejection fraction by 20%. The LCZ696 molecule associates both an angiotensin receptor blocker (valsartan) and an inhibitor of neprilysin (NEP, sacubitril). NEP is an endopeptidase able to degrade several factors such as the natriuretic peptides, angiotensin II, bradykinin, endothelin-1.Despite the cardioprotective effect of LCZ696, its exact mechanism in the heart is not elucidated yet.The aim of this project is to determine whether a part of the cardioprotective effect of this treatment is due to the stimulation of heart regeneration.For this purpose, myocardial infarction was induced in 8–10 weeks-old C57BL/6 mice by ligature of the left anterior descending coronary artery. Mice were treated or not with LCZ696 (at 6 or 60 mg/kg) given by oral gavage once per day and sacrificed 10 days after surgery. For all mice, BrdU (1 mg/ml) was added to drinking water 1 day after surgery and during all the treatment period. The effect of the treatment on heart function, cardiomyocyte proliferation and neovascularization was evaluated.High dose of LCZ696 increases the ejection fraction (+23%) and the fractional shortening (+14%) of infarcted hearts. Heart remodeling (the percentage of increase of the left ventricular diameter) was decreased in systole (−49%). At the cellular level, the number of BrdU+ cardiomyocytes was increased with both doses of LCZ696 (+110% in the infarcted and border zone and + 216% in the remote zone for 6 mg/kg LCZ696). The total number of cardiomyocytes was also increased in the infarcted and border zone (+105%) and in the remote zone (+156%).In contrast, neovascularization measured after CD31 staining didn’t differ between groups.Understanding the cellular mechanisms underlying the beneficial effects of LCZ696 in patients suffering from chronic heart failure is crucial for its further clinical use.
  • Cardiac myocyte-specific expression of beta3-adrenergic receptors sustains
           AMPK activation and glucose uptake while reducing hypertrophy following
           pressure overload
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): L. Michel, E. Dubois-Deruy, R. Gelinas, H. Esfahani, V. Roelants, L. Bertrand, C. Beauloye, J.L. BalligandIntroductionCardiac beta3-adrenergic receptors (B3AR) produce effects antipathetic to those of B1 and B2 receptors. Importantly, B3AR are resistant to desensitization and their expression is upregulated in the diseased myocardium. We previously showed that mice with moderate cardiac-specific expression of the human B3AR (B3-TG) are protected from hypertrophy and fibrosis upon hemodynamic or neurohormonal stress.ObjectiveHere we tested the hypothesis that myocardial protection may be mediated by metabolic effects of B3AR in cardiac myocytes, akin to well-known B3AR metabolic effects in adipose tissue.MethodWe used both B3-TG mice (and WT littermate) and isolated adult cardiac myocytes exposed to hemodynamic overload (TAC) (or sham control).ResultsWe found that 9 week-TAC induced hypertrophy and fibrosis in WT mice, as expected. Notably this was paralleled with decreased activation of AMPK assessed by AMPK phosphorylation at Thr-172 and phosphorylation of its downstream target ACC. However, in B3-TG mice AMPK activation was preserved post TAC. Moreover, siRNA downregulation of alpha1/2 AMPK attenuated the protection from hypertrophy by B3AR expression, confirming AMPK implication in the B3AR control of hypertrophy. As cardiac AMPK controls metabolic substrate use and uptake, we examined glucose uptake in adult cardiac myocytes isolated from B3-TG (and WT) mice after TAC, with/without insulin. Cardiac myocytes from stressed B3-TG mice exhibited a significant increase in 2-3H glucose uptake upon insulin treatment, whereas WT myocytes developed insulinoresistance. In vivo B3-TG also exhibited an increased myocardial uptake of the glucose analog 18FDG compared to WT littermates, e.g. at 9 weeks post-TAC.ConclusionWe conclude that cardiac myocyte-specific expression of B3AR concurrently prevents the development of insulin resistance and maintains AMPK activation contributing to the protection from hypertrophic remodeling under hemodynamic stress.
  • Metabolic regulation of heart failure caused by imbalanced mitochondrial
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): L.E. De la Rosa Vargas, E. Dale Abel, T. Langer, T. WaiBackgroundDilated Cardiomyopathy (DCM) is characterized by an expansion of the left ventricle having as a consequence inefficient oxygenated blood pumping to the body. DCM can result in heart failure and is the most common cause of heart transplantation. The healthy adult heart relies mainly on free fatty acids as its main fuel source and rather than glucose but in the failing heart, a metabolic switch away from fatty acid oxidation and towards glucose uptake has been observed and has been proposed to represent an adaptive bioenergetic mechanism. We developed a mouse model of DCM caused my mitochondrial fragmentation in cardiomyocytes due to the deletion of the mitochondrial protease YME1L. This mouse model recapitulates all the clinical features of DCM as well as the metabolic features, such as cardiac glucose overload, progressing into chronic heart failure and middle-aged death.AimUsing our DCM mouse model, we will test whether reducing cardiac glucose overload to the heart diminishes or exacerbates cardiac and metabolic dysfunction. To his end, we will ablate the primary glucose transporter GLUT 4 either partially or completely in DCM mice to diminish glucose uptake to the heart.ResultsWe generated cardiac specific deletions of YME1L and GLUT4 by crossing the cardiomyocyte specific Cre-recombinase drive Myh6-Cre to conditional YME1LLoxp/LoxP and SLC2A4Loxp/LoxP mice. Cardiac function will be assessed using echocardiography and mitochondrial activity using high resolution oxygraphy (Oroboros) in isolated cardiac mitochondria.Conclusion and perspectivesOur studies will allow us to determine the importance of glucose uptake and usage in the failing adult heart.
  • Role of mitochondrial fusion in cardiac energy metabolism
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): E. Silva Ramos, N.G. Larsson, A. MourierIntroductionMitochondrial dynamics is an essential physiological process controlling mitochondrial content mixing and mobility to ensure proper function and localization of mitochondria at intracellular sites of high-energy demand. Intriguingly, for yet unknown reasons, severe impairment of mitochondrial fusion drastically affects mtDNA copy number.ObjectiveThe goal of our work was to determine the importance of mitochondrial fusion on heart energy homeostasis.Method and resultsTo decipher the link between mitochondrial dynamics and mtDNA maintenance and heart energy metabolism, we studied heart conditional knockout mouse and mouse embryonic fibroblasts (MEFs) with disruption of mitochondrial fusion. Super-resolution microscopy analyses revealed that loss of outer mitochondrial membrane (OMM) fusion, but not inner mitochondrial membrane (IMM) fusion, leads to clustering and loss of nucleoids. Remarkably, fluorescence in situ hybridization (FISH) in MEFs, bromouridine labeling of MEFs and assessment of mitochondrial transcription in tissue homogenates revealed that abolished OMM fusion does not affect transcription.ConclusionThe profound mtDNA depletion in hearts lacking OMM fusion is not caused by defective integrity or increased mutagenesis of mtDNA, but, instead, we show that mitochondrial fusion is necessary to maintain the stoichiometry of the protein components of the mtDNA replisome. OMM fusion is necessary for proliferating MEFs to recover from mtDNA depletion and for the marked increase of mtDNA copy number during postnatal heart development. Our findings thus link OMM fusion to replication and distribution of mtDNA.
  • Cardiac manifestations of inherited metabolic disease linked to cellular
           vitamin B12 (cobalamin) uptake: Study in murine model of invalidation of
           Mtr gene in the heart
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): V.J. Kosgei, C. Arnold, F. Elkhafifi, P. Lacolley, S. Hergalant, L. Monassier, M. Fatiha, J.L. Guéant, R.M. Guéant-RodriguezIntroductionHeart failure is one of the most common cause of death in Western societies. Deficiency in folates and vitamin B12 during gestation and lactation causes foetal programming effect with metabolic cardiomyopathy related to decreased synthesis of methionine by methionine synthase encoded by MTR Gene. Methionine is the precursor for S-adenosyl methionine (SAM) the universal methyl donor. Mutations in MTR gene causes cardiac decompensation in new-borns by unknown mechanisms.PurposeTo investigate cardiac metabolic and functional consequences of inhibition of methionine synthesis in conditional knock out of Mtr gene in the heart of C57BL/6 mice.MethodsSystolic Blood Pressure in conscious mice was measured using tail-cuff plethysmography. Left ventricular (LV) functions were assessed by Mini-PET and Echocardiography. Transcriptomics analysis was achieved by RNA deep sequencing and proteomic study by LC-MS/MS.ResultsSystolic hypertension, decreased LV ejection fraction, increased LV mass and heart/body weight ratio were observed in Mtr KO compared to control. RT-qPCR confirmed upregulated expression of natriuretic peptides (ANP and BNP) and decreased alpha MHC/beta MHC ratio in Mtr KO. Biochemical studies revealed decreased SAM/SAH ratio, elevated plasma acylcarnitine and cardiac fibrosis in Mtr KO. The whole heart transcriptome consisted of 16540 expressed genes which were clustered by K-means into three signatures, these signatures were correlated to proteomic results. Dysregulated genes and proteins in Mtr KO were implicated in cardiac contraction, cell growth and energy metabolism.ConclusionOur results suggest that silencing of Methionine synthase in the heart induces hypertension, hypertrophic cardiomyopathy with LV systolic dysfunction. The related mechanisms were dysregulation of energy metabolism and fibrosis. This data provides a novel insight on physiopathological mechanisms of cardiomyopathies of inherited disorders of cobalamin metabolism.
  • Cardio-metabolic complications of obstructive sleep apnea: Impact of
           chronic intermittent hypoxia on cardiac insulin signaling
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): C. Calissi, M. Pesse, M. Détrait, E. Belaidi-Corsat, C. ArnaudBackgroundChronic intermittent hypoxia (IH) is the major feature of obstructive sleep apnea syndrome (OSA), well known to induce cardiac remodeling and contractile dysfunction as well as systemic insulin resistance. Currently, no studies have investigated the impact of IH on cardiac insulin signaling. Thus, we aimed to highlight the effects of chronic IH in both lean and obese mice on:– cardiac insulin signaling;– cardiac function and remodeling.MethodsC57BL/6 J male mice were fed either low-fat (LF) or high-fat (HF) diet for 20 weeks, and exposed to IH (21–5% FiO2, 60 s cycle, 8 h/day) or normoxia (N) for the last 6 weeks. Systemic insulin sensitivity was evaluated by an insulin tolerance test (ITT). Cardiac remodeling and contractile function were assessed by echocardiography. Ultimately, hearts were withdrawn for biochemical analysis of the main effectors of the insulin signaling.ResultsIn LF mice, IH induced systemic insulin resistance and altered cardiac insulin signaling (insulin-induced PAkt: 1,05 vs. 3,01 fold increase vs. NaCl in IH and N respectively, P 
  • Myocardial glycogen depletion leads to improved left ventricular
           remodeling in a mouse MI model
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): E.P. Daskalopoulos, C. Dufeys, K. Sakamoto, C. Koentges, H. Bugger, L. Bertrand, C. Beauloye, S. HormanIntroductionHigh glycogen (GLN) content is generally considered deleterious in prolonged ischemia, however, the exact role of GLN during permanent myocardial infarction (MI) and left ventricular (LV) remodeling post-MI, remains poorly understood.PurposeThis study aimed to investigate whether myocardial GLN depletion can attenuate adverse LV remodeling post-MI.MethodsWe used a transgenic knock-in (KI) mouse, in which the allosteric pathway of GLN synthesis is inhibited in muscle, leading to dramatically suppressed myocardial GLN levels. WT and KI male mice (10–12 weeks old) were subjected to MI by left anterior descending (LAD) coronary artery permanent ligation. Heart function was measured by 2D-echo (Vevo 2100, Visualsonics). Mice were sacrificed 56 days post-MI and hearts were collected to measure myocardial GLN content and perform IHC and mRNA studies.ResultsBasal GLN content was dramatically depressed in KI hearts. We demonstrated a robustly reduced LV dilatation in KI mice 56 days post-MI, as evidenced by lower end-diastolic volume (WT: 167.69 ± 13.42 vs KI: 138.00 ± 4.62 μl; P 
  • Apolipoprotein screening by LC-MRM-MS for the prediction of cardiovascular
           death in patients with chronic systolic heart failure
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): G. Lemesle, V. Chouraki, P. De Groote, O. Beseme, A. Turkieh, H. Drobecq, P. Amouyel, N. Lamblin, C. Bauters, F. PinetBackgroundRisk stratification in systolic chronic heart failure (HF) is critical to identify the patients who may benefit the most from advanced HF therapies. We aimed identifying new biomarkers to improve prognosis evaluation and help to better understand HF physiopathology.MethodsProteomic analysis of plasma from a case/control population of 198 patients with chronic systolic HF (ejection fraction 
  • Inflammatory biomarkers kinetic in STEMI patients and their relationship
           with infarct size and LVEF
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): T. Bochaton, A. Paccalet, C. Crola Da Silva, D. Baetz, N. Genot, C. Prieur, D. Tomasevic, C. Jossan, C. Amaz, N. Dufay, E. Bonnefoy-Cudraz, N. Mewton, M. OvizeIntroductionMyocardial infarction (MI) is followed by an intense inflammatory response which is necessary for the healing of the infarcted area, but which can also have deleterious effect by increasing infarct size (IS). A good knowledge of this inflammatory response is necessary to develop new treatments targeting this phase.ObjectiveOur study aims at describing the temporal kinetic of inflammatory biomarkers in ST-elevation MI (STEMI) patients and to evaluate their correlation with IS and left ventricular ejection fraction (LVEF).MethodWe included 100 patients of our HIBISCUS cohort (STEMI patients cohort) with blood samples collected at admission (H0), then 4 (H4), 24 (H24), 48 hours (H48) and 1 month (M1) after reperfusion. C-reactive protein (CRP), interleukin(IL)-1β, IL-1α, IL-6, IL-8, IL-10, tumor necrosis factor (TNFα), Growth Differentiation Factor 15 (GDF15) and interleukin 1 receptor-like 1 (ST2) were assessed in the serum by ELISA. All patients underwent a cardiac magnetic resonance imaging (CMR) at 1 month.ResultsPatient were aged of 57 ± 10 years. Contrary to other biomarkers, IL-1β, IL-1α and TNFα were weakly detectable in the serum. CRP reached a peak at H48 with a median of 11.7 mg/L interquartile range (IQR) [2.3–29.1]. IL-6 peaked at H24 with 4.8 pg/mL IQR [1.9–14.3], IL-8 at H24 with 2.6 pg/mL IQR [1.3–4.7], IL-10 at H0 with 5.7 pg/mL IQR [2.9–11.3], GDF15 at H0 with 203.7 pg/mL IQR [106.0–301.6] and ST2 at H24 with 25.6 pg/mL IQR [16.8–37.7]. Only CRP, IL-6, IL-10 and ST2 were significantly corelated with IS (respectively r = 0.51, P 
  • Association of myocardial edema, hemorrhage and persistent microvascular
           obstruction with circulating inflammatory biomarkers in acute myocardial
           infarction patient
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): A. Paccalet, T. Bochaton, J. Lassus, F. Derimay, G. Rioufol, C. Prieur, E. Bonnefoy-Cudraz, C. Crola Da Silva, C. Amaz, C. Jossan, G. Monneret, M. Ovize, N. MewtonIntroduction and objectiveAlthough early reperfusion, ST-elevation myocardial infarction (STEMI) remain a major cause of mortality and heart failure. Reperfusion is commonly associated with persistent micro-vascular obstruction (MVO), edema and intramyocardial hemorrhage (IMH) which are detected using cardiovascular magnetic resonance (CMR) imaging. Furthermore, STEMI is associated with an important inflammatory reaction. So far, the correlation between CMR parameters and inflammation remain unclear.Methods and resultsThis study aims at deciphering the correlation between adverse events and inflammatory biomarkers. This is a prospective study including 21 STEMI patients referred for a primary percutaneous coronary intervention. Seven blood samples were collected at admission, 4, 12, 24, 48 hours, 7 and 30 days after reperfusion. The presence of inflammatory markers including fibrinogen, inteleukin-10, interleukine-6, C reactive protein (CRP), interleukine-8, and neutrophils count was assessed by enzyme-linked immunosorbent assay (ELISA) technique. At day 7 after reperfusion, CMR was performed to determine infarct size, MVO, IMH and edema. The study compares the expression level of each biomarker with CMR measures. MVO was present in 55% of patients and IMH in 33.3%. We observed a correlation between IL-6, CRP, fibrinogen, neutrophil levels and IMH (P = 0.033; P = 0.05; P = 0.0085; P = 0.0046 respectively). Patients with persistent MVO present a significantly higher rate of CRP (P = 0.0125). No significant difference was found for other markers and edema was not significantly correlated with inflammation.ConclusionFollowing acute myocardial infarction in human patient, IMH appears to be strongly correlated with inflammatory biomarkers. Targeting the couple IMH/inflammation could be a novel strategy in future adjunctive STEMI treatment.
  • SMIT1 is a novel cardiac sodium glucose co-transporter with potential
           implication in cardiac fibrosis
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): S. Battault, J. Cumps, C. Dufeys, A. Ginion, A. Van Steenbergen, A. Furtos, C. Des Rosiers, L.M. Jacquet, H. Esfahani, J.L. Balligand, C. Roy, A.C. Pouleur, L. Bertrand, S. Horman, C. BeauloyeIntroductionSodium glucose co-transporters (SGLT) are well known for their role in glucose transport in the intestin or in the kidney. In a systematic evaluation of SGLT transporters, our group recently confirmed the expression of SGLT1 but discovered that the heart also express a second isoform, SMIT1 (sodium myo-inositol co transporter 1). The absence of SMIT1 does not change heart function and structure under baseline condition. However, the role of SMIT1 or myo-inositol transport in diseased heart remains unexplored.ObjectiveIn this study, we aimed to determine the human and murine cardiac expression pattern of SMIT1 in health and diseases.MethodsMyocardial biopsies from 23 patients at end stage heart failure were obtained during Left Ventricle Assist Device (LVAD) implantation. Control biopsies corresponded to 11 patients with mitral regurgitation or stenosis without evidence of LV remodeling and were taken during valvular surgery. Mice model of heart failure were generated by a permanent ligation of left anterior descending artery (LAD).ResultsCompared to control hearts, human failing hearts exhibited higher SMIT1 expression. Increase in SMIT1 was more pronounced in ischemic versus non-ischemic cardiomyopathy. Interestingly, SMIT1 expression correlated with pro-fibroblastic markers in biopsies (αSmooth Muscle Actin and Collagen Ia), suggesting that SMIT1 was tightly associated with fibrosis. In mice model of myocardial infarction, SMIT1 expression was 2.5-fold higher in the scar compared to remote myocardium. As in human heart, SMIT1 expression correlated with pro-fibroblastic markers.ConclusionSMIT1 expression is increased in ischemic failing heart, reflecting increased cardiac fibrosis. The physiological and physiopathological role of SMIT1 in the heart remains to be determined.
  • Transcriptional remodeling of the interventricular septum in porcine
           models of right ventricular overload
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): S. Charron Guitoger, V. Dubes, F. Roubertie, M. Constantin, J. Naulin, C. Michel, B. Quesson, M. Haissaguerre, J.B. Thambo, O. Bernus, D. BenoistIntroductionSurgical repair of TOF is highly successful but may be complicated in adulthood by arrhythmias, sudden death, and right ventricular (RV) dysfunction. RV overload leads to interventricular septum (IVS) bulging and paradoxical movement but its contribution to RV dysfunction and arrhythmias remains unclear.ObjectiveWe aimed at characterizing IVS remodeling in a pig model of RV volume overload and a model of repaired TOF with combined pressure and volume overload.MethodsYoung piglets underwent surgery to induce RV volume overload (PINS, N = 5) or combined volume and pressure overload (rTOF, N = 5) and were compared to Sham animals (SHAM, N = 5). Animals came back for terminal experiments 4 months post-surgery. Cardiac function was assessed using MRI. Animals were euthanized, tissue samples were collected for molecular biology or fixed for histological analysis.ResultsRV end-systolic and diastolic volumes were increased and RV ejection fraction was decreased in rTOF and PINS pigs (P 
  • Protein acetylation, a new way of regulating glucose metabolism in
           diabetic heart
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): E. Renguet, L. Bultot, M. De Loof, A. Ginion, P. Morue, L. Hue, S. Horman, C. Beauloye, L. BertrandIntroductionAt rest, the heart favors fatty acids to produce its energy switching to glucose in response to insulin at postprandial state. Diabetic heart features metabolic adaptation defaults and is no longer able to switch, producing its energy exclusively through fatty acid oxidation. This metabolic inflexibility is a major factor of cardiac dysfunction. Observations made in high-fat diet mouse model lead to an increase in cardiac protein acetylation. We hypothesized that modulation of acetylation impacts the ability of the heart to uptake glucose with a special focus on tubulin.ObjectivesMicrotubules playing a key role in GLUT4 translocation to the plasma membrane, we evaluated the impact of tubulin acetylation on cardiac glucose uptake.MethodsThe model is primary cultured rat cardiomyocytes. Acetylation levels and signaling pathways are evaluated by western blotting. The impact of long term incubation (20 h) with different pharmacological reducers of acetylation (garcinol 10 μM and anacardic acid 25 μM) on basal and insulin (3 nM, 30 min)-stimulated glucose uptake are measured following the detritiation rate of 2-3H-glucose. Tubacin, the inhibitor of tubulin deacetylase and an adenovirus overexpressing a non-acetylable form of tubulin are used to modulate tubulin acetylation.ResultsInsulin induces a 6-fold increase in glucose transport. Pharmacologically inhibiting global acetylation increases basal glucose transport similarly to insulin stimulation. By contrast, increasing specifically tubulin acetylation using tubacin inhibits 40% of basal and insulin-induced glucose transport. Accordingly, the overexpression of a dominant negative form and non-acetylable form of tubulin decreases endogenous tubulin acetylation while increasing basal glucose transport. Finally, targeting tubulin acetylation partially restores fatty acid-mediated inhibition of glucose transport.ConclusionThere is a clear correlation between tubulin acetylation and glucose uptake level.
  • Istaroxime improves diabetic diastolic dysfunction through SERCA
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): E. Torre, A.M. Lodrini, P. Barassi, M. Ferrandi, E. Boz, C. Bussadori, P. Ferrari, G. Bianchi, M. RocchettiIntroductionCalcium handling is generally impaired in heart failure (HF). Mechanisms that can restore cardiac relaxation improving cellular Ca2 +  cycling, represent a promising therapeutic approach for HF. Istaroxime is a Na-K ATPase (NKA) inhibitor with the property of accelerating Ca2 +  re-uptake into sarcoplasmic reticulum (SR) through the SR Ca2 +  pump (SERCA) stimulation by displacing the interaction between SERCA and its inhibitor, phospholamban (PLB).ObjectiveTo characterize Istaroxime effects in a model of mild diabetes (type 1) with diastolic dysfunction and preserved global systolic function. Istaroxime was tested at a concentration mostly unaffecting NKA to isolate its effects dependent on SERCA only.MethodStreptozotocin (STZ)-treated rats were evaluated at 9 weeks after STZ injection in comparison to control (CTR) ones. STZ-induced changes were evaluated in vivo (echocardiography), in isolated left ventricular myocytes and in SERCA2a-enriched microsomes. SERCA and PLB protein levels were measured by western blot and SERCA activity as 32P hydrolysis. Action potential rate-dependency and intracellular Ca2 +  handling were evaluated in patch clamped or field-stimulated (2 Hz) cells.ResultsSTZ-induced cardiomyopathy was characterized by impaired diastolic relaxation which was associated to reduced SERCA protein level and activity at the cellular level. Moreover, the monomeric PLB/SERCA ratio was increased. In STZ group, action potentials (AP) were significantly prolonged at each cycle length; Ca2 +  transients were characterized by slower decay, delayed onset and increased diastolic Ca2 + . Istaroxime at a concentration of 100 nM significantly stimulated SERCA activity and SR Ca re-uptake after caffeine depletion in STZ group only. Moreover, Istaroxime reduced STZ-induced diastolic Ca2 +  enhancement but not affected AP prolongation.ConclusionSERCA stimulation can be considered a promising therapeutic approach for diastolic dysfunction treatment.
  • Exercise echocardiography in uncomplicated type 2 diabetic patients: Which
           parameters are useful'
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): I. Schuster, C. Maufrais-Buisson, M. Krastevich, G. Doucende, A. Perez-Martin, N. Jourdan, C. Demattei, S. NottinIntroductionEarly detection of preclinical left ventricular (LV) dysfunction in type 2 diabetic (T2D) patients is crucial because of its associated increased cardiovascular morbidity and mortality.ObjectiveThe aim of this study was to:– identify the most sensitive and clinically relevant echocardiographic variables in order to detect early left ventricular (LV) dysfunction in uncomplicated type 2 diabetic patients (T2D) in comparison with sedentary (SC) and trained controls (TC), at rest and during exercise;– to understand the mechanisms of exercise intolerance in these patients.Method20 T2D without micro- or macrovascular complications and without any other uncontrolled risk factor, 20 SC, and 20 TC were studied at rest and during a cardiopulmonary exercise test using conventional, tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE) including twist-untwist mechanics analysis.ResultsLV dysfunction was already detectable in T2D by resting echocardiography. During exercise, T2D had the lowest increase of LV diastolic and systolic function and the most limited vasodilation compared to SC and to TC who showed the highest adaptability. Exercise STE twist-untwist analysis showed lower feasibility and higher variability in T2D compared to SC and TC. T2D patients had lower longitudinal strain and higher untwist/twist ratio compared to SC but not in comparison to TC (Fig. 1).ConclusionConventional and TDI data were the most robust echocardiographic parameters, showing early LV dysfunction and evidencing the contribution of diastolic and systolic dysfunction to exercise intolerance with the expected pathophysiological continuum between groups. Exercise STE data, which showed low feasibility and high variability in T2D, did not exhibit the expected distribution between groups, underlining the fact that strain adaptations in different pathophysiological situations need further explorations.
  • Molecular basis of high glucose-mediated cardiac calcium mishandling
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): M. Samia el Hayek, P. Gerbaud, C. Valdivia, S. Gomez, F. Lefebvre, J. Chen, H. Valdivia, J.P. Benitah, A.M. Gomez, L. PereiraIntroductionEpidemiological and preclinical studies have pointed out a correlation between hyperglycemia and increasing risk of heart failure and cardiac death. In cardiomyocytes, hyperglycemia has been shown to alter Ca2 +  signalling via CaMKII. Yet, the underlying mechanisms are still unclear.ObjectiveTo determine the molecular basis of high glucose-mediated Ca2 +  mishandling.MethodsVentricular cardiomyocytes were isolated from control and Epac2-KO mice. Parallel experiments were repeated in human cardiomyocytes differentiated from induced pluripotent stem cells (h-iPSC-CM). Ca2 +  signaling was studied in cells loaded with a fluorescent Ca2 +  dye and treated with high glucose (HG) ± ESI-05 (Epac2 inhibitor). We assessed ryanodine receptor (RyR2) phosphorylation state by western blot and measured single RyR2 channel activity incorporated into bilayers.ResultsHG-mediated SR Ca2 +  leak and pro-arrhythmic events were prevented with Epac2 blocker (ESI-05) in normal mice cells and with Epac2 deletion (Epac2-KO) (Ca2 +  sparks frequency N/100 μm/s: 0.23 ± 0.15 for HG + ESI-05, 0.09 ± 0.04 for Epac2-KO + HG vs. 0.16 ± 0.06 for normal glucose, P = N.S.). HG treatment increased RyR2 phosphorylation at the CaMKII site (S2814, ∼ 29% increase, P 
  • Altered reticulum-mitochondria interactions contribute to mitochondrial
           Ca2 +  signaling dysfunction in the diabetic mice heart
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): M. Dia, J. Rieusset, E. Tubbs, N. Bendridi, L. Gomez, M. Ovize, M. Kurdi, M. PaillardIntroductionDiabetic cardiomyopathy has been linked to Ca2 + signaling alterations, notably a decreased mitochondrial Ca2 + uptake. Uncovering the changes occurring at Ca2 + microdomains between reticulum and mitochondria in the heart has launched a new area of investigation for cardiometabolic diseases.ObjectiveWe here aimed to study if the impairment of mitochondrial Ca2 +  handling could be due to a dysregulation of the reticulum-mitochondria interactions or of the mitochondrial Ca2 +  uniporter in the diabetic mice heart.MethodsMice were either fed with a standard diet (SD: 16.9% proteins, 4.3% lipids) or a high-fat high sucrose diet (HFHSD: 20% proteins, 36% lipids) for 16 weeks. Cardiac mitochondria associated membranes (MAM) composition was analyzed by proteomics and immunoblotting. Proximity ligation assay, calcium imaging and hypoxia/reoxygenation were performed on isolated cardiomyocytes.ResultsOur HFHSD mice displayed a cardiac insulin resistance and hypertrophy. Decreased MAM/pure mitochondria content in the HFHSD vs SD heart was observed, with an elevated level of proteins involved in lipid metabolism and a decrease in tethering proteins. Decreased IP3R-VDAC proximity upon HFHSD was concomitant to a reduced IP3R-stimulated Ca2 +  transfer to mitochondria, with no changes in mitochondrial calcium uniporter protein expression and function. Additionally, decreased amplitude of cytosolic Ca2 +  transients was seen in the HFHSD cardiomyocytes, with no significant changes in the reticular Ca2 +  release level. Besides, increased cell death susceptibility was measured after both in vitro hypoxia/reoxygenation and in vivo ischemia/reperfusion under HFHSD.ConclusionOur data, therefore, indicate that decreased reticulum-mitochondria interactions trigger an impaired mitochondrial Ca2 +  handling in the diabetic mice heart, with no alteration of the mitochondrial Ca2 +  uniporter, while the enhanced susceptibility to cell death could be referred to lipid toxicity.
  • Metformin reverses cardiac SR/ER-mitochondria remodeling and mitochondrial
           complex I dysfunction in Dystrophin-deficient mice
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): C. Angebault-Prouteau, M. Lacote, A. Lacampagne, J. FauconnierIntroductionBesides skeletal and diaphragmatic muscle dysfunction, Duchenne muscular dystrophy (DMD) exhibit a progressive cardiomyopathy with an altered Ca2 + handling and a defect in mitochondrial respiration capacity.AimThe aim of the present study was to determine if the sarco-endoplasmic reticulum (SR/ER)-mitochondria interaction and mitochondrial Ca2 + homeostasis contribute to the progression of the cardiomyopathy.Methods and resultsVentricular myocytes were isolated from 3-month old Dystrophin-deficient mice (mdx mice). Using proximity ligation assay, we observed an increase interaction between the SR/ER Ca2 + release channels, IP3R1, and the porine of the mitochondria, VDAC1, associated with an increase expression levels of IP3R1 and SIGMA1R. Similarly, the mitochondrial Ca2 + uniporter (MCU) and its regulated subunit, MICU1, expressions levels were enhanced in mdx heart. Furthermore the mitochondrial Ca2 + uptake kinetics and the mitochondrial Ca2 + content were significantly increased. Using oxygraphy experiment, we observed a severe decrease in respiration driven by the complex I with a stimulation in anion superoxide production measured with Mitosox red fluorescent dye. Finally, mdx mice were treated with the complex I modulator metformin at 200 mg/kg/day during one month. Metformin normalize the SR/ER-mitochondria interaction, decreases MICU1 expression and mitochondrial Ca2 +  content and tends to restore complex I alteration in cardiomyocytes.ConclusionsIn summary, our data demonstrate for the first time that in the DMD heart the mitochondrial dysfunction is linked to an excessive SR/ER-mitochondria coupling with an increase in mitochondrial Ca2 + uptake and complex I dysfunction. Such remodeling could be reversed by metformin providing a novel therapeutic perspective in DMD.
  • Intracardiac extracellular vesicle release in post-infarction diabetic
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): S.M.I. Mazlan, V. Duval, C. Devue, M. Robillard, C.M. Boulanger, J.S. Silvestre, X. LoyerIntroductionCardiovascular disease (CVD) is the main cause of death in non-communicable diseases. In response to myocardial infarction (MI), extracellular vesicles (EVs) including large (lEVs) and small (sEVs), are released within and from the heart to facilitate intercellular communication and maintaining cardiac homeostasis.ObjectiveAs diabetes increases the risk of CVD, the purpose of the study was to investigate how diabetes influences the release of intracardiac EVs after MI.MethodC57BL/6 J male mice were fed normal chow diet or high-fat diet (HFD) for 3 months. HFD fed mice were glucose intolerant as attested by the measure of GTT above 200 mg/mL. Mice were subjected to MI by permanent ligation of the left anterior descending artery and sham animals underwent similar surgical procedure without ligation. Left ventricles from sham or MI mice were then harvested at either 15, 24, 48 or 72 hours after surgery (N = 5 per group at each time point) and processed for EV extraction by differential centrifugation. EVs were quantified and analyzed via Tunable Resistive Pulse Sensing Technology (TRPS), flow cytometry and Western blot.ResultsIn chow diet fed mice, release of both lEVs and sEVs was increased at 24 h post-MI when compared to shams. These findings were in agreement with previous data obtained in younger control animals. In diabetic mice, lEVs peaked at 24 h post-MI and this increase was slightly greater than that observed in chow diet fed mice. However, there were no differences in sEV release between sham and MI diabetic mice. TRPS analysis revealed that diabetes does not change EV size and population. Furthermore, both control and diabetic derived EVs harboured cardiomyocyte marker (Troponin T) as revealed by Western blot.ConclusionOur results show that diabetes modulates the release of both intracardiac sEVs and lEVs after MI. Further work will be needed to fully investigate the functional impact of cardiac EVs in the diabetic heart after MI.
  • Metabolic and non-metabolic effects of cardiac-specific and inducible
           deletion of the AMPKalpha2 in female and male mice
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): L. Grimbert, M.N. Sanz, C. Rucker-Martin, M. Novotova, M. Gressette, S. Gomez, A. Solgadi, F. Dumont, R. Ventura-Clapier, V. Veksler, J. Piquereau, A. GarnierIntroductionMitochondrial dysfunction plays a major role in the Heart Failure (HF) pathophysiology. The AMP activated protein kinase (AMPK) is activated by a high AMP-ADP/ATP ratio and regulates a number of metabolic pathways. Many studies have highlighted a protective role of AMPK in HF, but its relevance to cardiac tissue, its metabolic part and its sex-specificity are not well established.ObjectiveThe aim of this study is to determine the role of AMPK in the healthy and failing heart in male and female mice.MethodWe developed and validated a mouse strain with an adult-inducible cardiac-specific deletion of AMPKα2, the major cardiac isoform, using the Cre-Lox system (40 mg/kg tamoxifen injection on two consecutive days at adult age). At four months after the deletion, cardiac contractility, morphology and metabolism were studied in control and KO mice from both sexes.ResultsWe observed only in male KO mice a decrease of left ventricular ejection fraction (− 10%), an increase of the total fibrosis (+ 64%) and defects in mitochondrial structures. Male KO mice also showed a reduced (− 28%) mitochondrial respiration via complex I associated with a different cardiolipin species distribution.ConclusionOur results reveal in adult healthy hearts, a sex-specificity in the effects of AMPKα2 deletion, leading to impaired contractile function related to metabolic and non-metabolic alterations only in male mice.
  • Role of the transcription factor Bcl11b in cardiac homeostasis and
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): M.T. Daher, N. Mougenot, O. Rohr, P. Bausero, P. Liu, Z. Li, A. ParlakianIntroductionBcl11b is a zinc finger transcription protein that acts as both a transcriptional repressor and activator in a context dependent manner. A genetic study in humans revealed the association between common genetic variations in the Bcl11b locus and increased risk for cardiovascular disease. Furthermore, microarray data comparisons showed that Bcl11b could modulate the expression of genes during cardiac hypertrophy.ObjectiveTo study the role of Bcl11b in the heart under normal and pathological conditions.MethodWe conducted a time course analysis on cardiac-specific Bcl11b KO adult mice (Bcl11b-HKO) under normal and hypertrophic conditions (Angiotensin II treatment).ResultsBcl11b-HKO mice showed an acute response marked by the presence of apoptotic cardiomyocytes associated with inflammation, 1 week after Bcl11b inactivation. An increased expression of hypertrophy markers (βMHC, skeletal actin) and pro-apoptotic genes (p53, Bax) was observed in the Bcl11b-HKO mice. Fibrosis-related genes (TGFβ, collagen) were promptly up-regulated, correlating with the formation of fibrotic areas in the Bcl11b-HKO mice over the time. A compromised contractile function, evidenced by a 20% decrease in the ejection fraction, was observed in the Bcl11b-HKO mice at later time points (2 to 6 months after Bcl11b inactivation). Finally, after Angiotensin II treatment, control mice showed a decreased cardiac function. This alteration is mitigated in treated Bcl11b-HKO mice, suggesting a role of Bcl11b in the regulation of cardiac hypertrophy.ConclusionOn-going analysis using isolated adult cardiomyocytes will allow us to decipher the molecular mechanisms affected by Bcl11b inactivation, specifically mechanisms implicated in the apoptosis and hypertrophy. Understanding the role of this protein in cardiac pathology could be clinically relevant and lead to a better understanding of the remodeling process and identify potential targets for pharmacological agents.
  • Renal resistive index changes in a murin acute heart failure model
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): B. Deniau, P.R. Koundé, P. Bonnin, J.L. Samuel, A. Mebazaa, A. BletIntroductionHeart failure (HF) affects more than 10% of people over the age of 651. Regardless the etiology, kidney injury is common during HF1. Correlation between the evolution, severity and mortality of HF and increase of renal resistance index (RRI) has been shown. The objective of this study is to describe the evolution of RRI in a mice acute heart failure (AHF) model.MethodsThe local ethics committee approved the study (S84/CNREEA#9). AHF was induced by subcutaneous injections of isoproterenol 3 and defined by a 10% decrease in the shortening fraction (SF) compared to baseline in C57Bl6 wild type male mice. The RRI was assessed by echography, after induction of AHF or in sham mice, as follow: RRI = (peak systolic velocity–end diastolic peak)/peak systolic velocity. RRI were compared by a Wilcoxon test (R software v3.4.4). A P value 
  • Isoproterenol-induced heart failure in rat heart: Evaluation and
           cardioprotective strategy
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): G. Bourdier, S. RobeletIntroductionIt is well established that cardiac remodelling plays a pivotal role in the development of heart failure (HF), a leading cause of death worldwide. Meanwhile, a preclinical rat model of isoproterenol (Iso)-induced HF causes sympathetic hyperactivity, an important factor of cardiac remodelling, hemodynamic changes and cardiac fibrosis development. Several studies showed that metoprolol, a β1-adrenergic receptor (β1-AR) blocker prevents cardiac dysfunction following prolonged β-AR stimulation in different preclinical models.ObjectiveWe evaluated the cardioprotective effects of metoprolol on cardiac remodelling and diastolic function in a severe Iso-induced HF model using echocardiography and cardiac pressure measurement.MethodRats received Iso injections (Iso; 5 mg/kg/day, N = 5), metoprolol (Meto; 24 mg/kg/day) + Iso 5 (Iso + Meto, N = 6), or vehicle (N = 9) for 7 days. Left ventricular (LV) dimensions and function were followed-up by echocardiography before and after the treatment to assess LV hypertrophy. After echocardiography, LV end-diastolic pressure (LVEDP) was recorded to assess ventricular compliance and rat hearts were used for cardiac remodelling analysis.ResultsOne week of Iso injections significantly increased LVEDP (+ 48%) and was associated with a major LV hypertrophy, characterised by a significant increase in LV mass (+ 33%) and a thickening of the LV walls observed by echocardiography. Simultaneous treatment with metoprolol prevented diastolic dysfunction and LV remodelling. Hypertrophy and fibrosis will be analysed in each group by histology (on-going experiments).ConclusionMetoprolol afforded a cardioprotective effect on cardiac remodelling and diastolic dysfunction in Iso-induced HF model. Echocardiography and LVEDP measurements validate the reversibility of hypertrophic HF, and Iso-induced HF developed in rat could represent an effective and predictive preclinical model for evaluating antihypertrophic and antifibrotic agents.
  • Validation of a preclinical model of heart failure with reduced ejection
           fraction by a dual angiotensin receptor-neprilysin inhibitor and an
           angiotensin-converting enzyme inhibitor
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): M. Isabelle, N. Harouki, C. Ragonnet, S. Butin, I. Laurent, M. Lecomte, D. Gransagne, F. Bertin, P. Berson, N. VilleneuveIntroductionHeart failure (HF) patients often suffer from several co-existing diseases and co-morbidities. Among them, hypertension and myocardial infarction (MI) are two of the most frequent causes of HF1. Thus, as expected, experimental induction of MI in Spontaneously Hypertensive Rats (SHR) provokes severe left ventricular dysfunction and is associated with signs of HF2. Therapeutic effects of Angiotensin-converting enzyme inhibitor (ACEi) and Angiotensin receptor-neprilysin inhibitor (ARNi) have been demonstrated in HF patients with reduced ejection fraction (HFrEF).ObjectiveThe aim of the present study was to validate the translational value of the HF preclinical model SHR PMI using ARNi (Valsartan/Sacubitril, LCZ696) and ACEi (perindopril) treatments recommended by the ESC guidelines for HFrEF patients.MethodsPermanent MI (PMI) was induced by coronary ligation in SHR (8-week-old; N = 30) randomized in three groups:–placebo, LCZ696 (68 mg/kg/d);–Perindopril (1 mg/kg/d);–compared to a sham operated group (N = 10).Three months post-MI, LV function was assessed by echocardiography and hemodynamic study. HF signs were assessed by LV end-diastolic pressure (LVEDP, mmHg), lung and right ventricle (RV) weights (mg).ResultsTwo vehicle-treated SHR PMI died during the follow-up, no death was observed in LCZ696 or Perindopril treated groups. Post-MI, both ARNi or ACEi treatments had beneficial effects on the adverse LV remodeling and seemed to prevent the mortality and signs of HF (further studies required to confirm these results).ConclusionsIn summary, the SHR PMI model has a good predictive value and can be used as preclinical model for the evaluation of new therapeutic strategy in HFrEF [1], [2].
  • Relevant preclinical model of heart failure in rat: Impact of myocardial
           infarction and hypertension
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): M. Isabelle, N. Harouki, F. Bertin, M. Lecomte, C. Ragonnet, S. Butin, D. Gransagne, I. Laurent, N. VilleneuveIntroductionIn acute myocardial infarction (MI) setting, successful revascularization of the ischemic myocardium improves prognosis. However, MI remains a leading cause of heart failure (HF) associated with mortality [1] and the risk to develop HF is increased by co-morbidities especially hypertension [2], [3]. Relevant preclinical models of heart failure with comorbidities as in human are needed to improve the selection of new therapeutic strategies.Objectiveto determine the best HF model by comparing left ventricular (LV) dysfunction and signs of HF in 3 preclinical models of MI in normotensive and hypertensive rats.MethodsIn total, 60 minutes MI was induced by coronary ligation in male rats (8-week old) followed by reperfusion (I/R) or not (permanent, PMI) in normotensive Wistar rats (Wi) or in hypertensive rats (SHR PMI). Ejection fraction (EF, %) and LV end-diastolic volume (LVEDV, μl) were measured using echocardiography. Signs of heart failure were assessed by LV end-diastolic pressure (LVEDP, mmHg), right ventricle weight (RV, mg) and plasma NT-Pro-BNP (pg/ml). These different parameters were assessed post-MI at 3 months for the groups (Wi Sham, Wi I/R and SHR PMI) and at 6 months for the Wi PMI group.ResultsMI led to a clear LV dysfunction and adverse eccentric remodeling. As expected, these alterations were limited by reperfusion of the ischemic myocardium in normotensive rats. Hypertension exacerbated post ischemic cardiac dysfunction. Three months post-MI, signs of HF were observed only in SHR PMI while no sign were detected in Wi rats 6 months after MI.Conclusionsin line with human disease, our results show that hypertensive rats are more prone to develop signs of HF after MI than normotensive rats. SHR PMI should be considered as a relevant preclinical model for the efficacy assessment of new HFrEF therapeutic strategies.
  • O-GlcNAcase inhibition by Thiamet G opposes acute cardiac decompensation
           in rats with chronic heart failure
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): M. Soulié, O. Beseme, L. Nicol, J.P. Henry, F. Pinet, V. Richard, P. MulderBackgroundExacerbation of heart failure (HF), better known as acute decompensated HF, is characterized by dyspnea, edema and fatigue, which is associated with a high morbi-mortality. O-linked β-N-acetylglucosamine (O-GlcNAc) is a key regulator of the cellular stress response and increased O-GlcNAc levels exerts protective effects in models of acute vascular injury and ischemia-reperfusion injury. However, whether increasing O-GlcNAc exerts similar protective effects in acute decompensation of HF is unknown.ObjectiveWe evaluated the cardiac effects of increasing O-GlcNAc levels by inhibiting O-GlcNAcase with Thiamet G (TG) in a rat model of acute decompensated HF.MethodsThree months after coronary artery ligation resulting in established HF, rats received 2.5 ml water (control) or 1.8 g/kg NaCl (dissolved in 2.5 ml water) provoking acute decompensation. Left ventricular (LV) fractional shortening and cardiac output (echography) as well as LV tissue perfusion (MRI) were assessed 1 and 14 days after NaCl-loading, and TG was administered 12 hours after NaCl (25 mg/kg IP).ResultsNaCl provoked acute decompensation in rats with HF. Indeed, 1 day after NaCl, the HF-related impairments of LV fractional shortening, cardiac output and myocardial tissue perfusion were aggravated. Fourteen days after NaCl, cardiac output partially recovered, but fractional shortening and myocardial perfusion remained impaired. As soon as 12 hours after administration, TG improved fractional shortening, cardiac output and tended to increase myocardial perfusion. Moreover, 14 days after TG, cardiac output and myocardial perfusion were still improved.ConclusionsThese data show that in an experimental model salt-induced acute decompensation of HF, a curative treatment with TG improves both cardiac output as well as myocardial perfusion. The cellular mechanisms, i.e. post-translational protein O-GlcNAcylation, implicated in the effects of TG, are currently under investigation.
  • A novel murine model for endothelial dysfunction and heart failure with
           preserved ejection fraction
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): A. Abelanet, S. Guimbal, M.A. Renault, T. Couffinhal, C. DuplàaIntroductionThe prevalence of Heart Failure with Preserved Ejection Fraction (HFpEF) is dramatically increasing and associated with high mortality. HFpEF predominantly affects elderly (> 65 years) hypertensive women with cardiovascular and non-cardiovascular comorbidities such as obesity, diabetes, atrial fibrillation or renal dysfunction. Mechanisms underlying HFpEF are poorly understood today. A new, but still untested paradigm, focusing on the role of endothelial cells (EC), has recently emerged. The ubiquitine ligase PDZRN3 is a component of the non-canonical Wnt pathway and its endothelial expression has been linked to vascular bed stability. Here, we investigated long-term consequences of endothelial PDZRN3 signaling activation, on heart failure.ObjectiveInvestigate the etiology and functional consequence of EC dysfunction in HFpEF.MethodWe have generated mice which had post-natal restrictive and inducible endothelial expression of Pdzrn3 (iEC-Pdzrn3). EC specific Pdzrn3 overexpression was induced under tamoxifen administration to 5-week-old mice. To potentiate EC dysfunction, mice were fed with high fat diet for 3 months and studied at 6 months by echocardiography, histology and hemodynamic parameters.ResultsAt 6 months, both iEC-Pdzrn3 female and male cohorts displayed hemodynamic parameters of HFpEF with a significant strong elevation of the end-diastolic pressure compared to their respective littermates (2.7-fold increase for females, P = 0.02, N = 10; and 1.5-fold increase for males, P = 0.04, N = 10) but did not show any other sign of echocardiography dysfunction. In both female and male cohorts, mutants presented low-grade of inflammation characterized by macrophages infiltration. Precocious times and histological parameters are currently under investigation.ConclusioniEC-Pdzrn3 mice fed with high fat diet develop markers of HFpEF within 6 months of life.
  • Empagliflozin, a sodium-glucose cotransporter inhibitor, improved heart
           remodeling and mesenteric artery endothelial function in the metabolic
           syndrome with HFpEF ZSF1 rat: Role of cyclooxygenases
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): S.H. Park, M.A. Farooq, S. Gaertner, C. Bruckert, A. Qureshi, H. Lee, D. Benrahla, B. Pollet, D. Stephan, P. Ohlmann, E. Mayoux, C. Auger, O. Morel, V.B. Schini-KerthIntroductionEmpagliflozin (EMPA), a selective SGLT2 inhibitor, significantly reduced cardiovascular mortality and hospitalization for heart failure in patients with type 2 diabetes at high cardiovascular risk, but the protective mechanisms remain unclear.ObjectiveThis study evaluates the effect of EMPA on the endothelial function, and the heart structure and function in an experimental model of metabolic syndrome with HFpEF, the ZSF1 rat, and its lean control (Ctrl).MethodRats received either the control diet or the diet containing EMPA (30mg/kg/day) for 6 weeks. Vascular reactivity was assessed in the mesenteric artery using organ chambers, and the heart function and structural changes by echocardiography.ResultsIn the mesenteric artery, acetylcholine (ACh)-induced endothelium-dependent relaxations were slightly but significantly reduced and endothelium-dependent contractile responses (EDCFs) increased in ZSF1 compared to Ctrl rats. The cyclooxygenase inhibitor indomethacin improved relaxations and abolished EDCFs to ACh in ZSF1 rats. The 6-week EMPA treatment improved the relaxation and blunted EDCFs to ACh in the ZSF1. The weight of the heart and of each part, and the left ventricle area were increased in the ZSF1, and significantly reduced by the EMPA treatment, except for left auricle plus septum weight, which did not reach significance. Left ventricle ejection fraction and cardiac output were similar in all groups. The EMPA treatment reduced the increased body weight and that of lungs, spleen, liver and perirenal fat, and hyperglycemia, and increased blood ketone levels and urinary glucose excretion in ZSF1 rats.ConclusionThe EMPA treatment improved body weight, hyperglycemia, and both endothelial function and cardiac remodeling in the metabolic syndrome with HFpEF ZSF1 rat. The protective vascular effect involves improved endothelium-dependent relaxations and blunted EDCFs most likely by targeting the cyclooxygenase pathway.
  • Leptin receptor deficient female mice as a mouse model of heart failure
           with preserve ejection fraction
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): S. Guimbal, T. Couffinhal, P.L. Hollier, C. Chapouly, C. Caradu, A.P. Gadeau, M.A. RenaultIntroductionHeart failure with preserved ejection fraction (HFpEF) is a growing epidemiologic problem and a major source of morbidity and mortality. However, to date, there are no therapies available to treat HFpEF mainly because of its poorly understood pathophysiology.ObjectiveThe purpose of this study is to investigate whether Leptin receptor deficient (Leprdb/db) female mice can be used as an appropriate mouse model of HFpEF to investigate its pathophysiology. Notably, Leprdb/db female mice exhibit 3 risk factors for HFpEF i.e. diabetes, obesity and female gender.MethodsWe assessed cardiac function, heart structure and heart microvessel phenotype in both leprdb/db female mice and their control Leprdb/+ littermates at 3, 6 and 12 months of age.ResultsFrom 3 months of age, Leprdb/db female mice present an elevated end-diastolic pressure (EDP) compared to their age-matched controls while their ejection fraction (EF) remain above 50% which indicate diastolic dysfunction with preserved EF. In addition, Leprdb/db mice have a significant cardiac hypertrophy characterized by an increased heart weight/tibia length ratio, increased left ventricular wall thickness and increased cardiomyocyte size. While both quantification of fibrosis after Picrosirius red staining and qPCR analysis and Col1a1 and Col3a1 mRNA expression did not reveal any significant changes is collagen amount, Lysyl oxidase mRNA was significantly increased in Leprdb/db female mice after 6 months of age indicating a probable increased collagen cross linking. The cardiac microvessel phenotype of these mice is characterized by an increased endothelium permeability (albumin extravasation) and activation (increased ICAM-1 and E-Selectin) while capillary density is not changed. This is associated with an increased macrophage infiltration.ConclusionLeprdb/db mice recapitulate most features of HFpEF including increased EDP, unchanged EF, cardiac hypertrophy, EC activation and cardiac inflammation.
  • Phytoestrogen: Protective effect in HFpEF through ageing'
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): J. Dhot, V. Prat, D. Stevant, M. Ferron, A. Persello, V. Aillerie, A. Erraud, M. Erfanian, M. De Waard, B. Rozec, J.N. Trochu, C. Gauthier, B. LauzierIntroductionHeart failure with preserved ejection fraction (HFpEF) is a public health burden associated to diastolic dysfunction with no effective treatment mostly affecting elderly women. We use the Tgβ3 rats to explore the potential impact of phytoestrogen in the development of this pathology as Tgβ3 females does not develop HFpEF with ageing while Tgβ3 male with a phytoestrogen-free diet does.ObjectiveThe aim of our study was to evaluate phytoestrogen impact on HFpEF development.MethodHFpEF development has been evaluated in males and females, ovariectomized or not, with or without a phytoestrogen-free diet. HFpEF was validated by echography study (E/A ratio), invasive hemodynamic study (LVEDP) and fibrosis. Then the heart was harvested to evaluated HFpEF impact on protein expression involved on cardiac metabolism and endothelial function.ResultsHFpEF was not established in rats with phytoestrogen diet (males and females, ovariectomized or not) and also in female's groups feed with phytoestrogen-free diet. In males with phytoestrogen-free diet, phenotype evaluation revealed diastolic dysfunction with significant modification of E/A ratio and LVEDP in Tgβ3 rats with ageing (E/A: + 15% vs WT and LVEDP: + 109% vs WT; P 
  • Optimization of preferential heart drug delivery targeting cardiovascular
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): C. Deflers, A.C. Le Fèvre, F. Puech, G. Pidoux, R. FischmeisterIntroductionCardiovascular diseases are the foremost causes of death morbidity in western industrialized countries, which remains a major health issue. Particularly, heart failure (HF) is defined by a defect of the heart pump function and ß-blockers are usual treatment. However, no cure exists and 5-years mortality remains high (50%). For this reason, new therapeutic strategies need to be considered. Our strategy relies on targeting cardiomyocytes to deliver therapeutic molecule to restore or improve contractile function. Thus, two peptides, CTP (Cardiac Targeting Peptide) and PCM (Primary CardioMyocyte) previously identified by phage display, exhibited a strong cardiac tropism.ObjectiveThis work aims to generate and optimize new cardiac targeting peptides derived from CTP and PCM, to deliver specific drugs in case of HF.MethodNeonatal rat ventricular cardiomyocytes (NRVC) were isolated and cultured with modified versions of carboxyfluorescein (6CF)-coupled CTP or PCM. Additionally two 6CF-coupled peptides targeting skeletal muscle cells in Duchenne disease were also studied (Duch1 and Duch2).Flow cytometry analyses were performed to quantify peptide cytotoxicity and cellular uptake as percentage of positive 6CF-loaded cells. In parallel, confocal microscopy was performed to underpin peptide subcellular distribution.ResultsModified-peptides CTP1, PCM1, PCM2 and PCM3 exhibited in NRVC culture a significant increase in cellular uptake with a low cytotoxicity effect compared to original peptide versions (approximately 50% increase in uptake and below 30% of dead cells). Although Duch2 displayed a high level of cellular uptake (above 99%) it showed a high cytotoxic effect in NRVC (97% of dead cells).ConclusionThis study established that optimization of original CTP or PCM peptide sequences increased cellular uptake efficiency and could putatively raise the potential of heart targeting agents for therapeutic delivery.
  • Cardiac gene therapy of heart failure with phosphodiesterase PDE4B in mice
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): A. Bourcier, C. Coquard, J. Margaria, S. Gomez, A. Varin, A. Ghigo, V. Algalarrondo, G. Vandecasteele, E. Hirsch, R. Fischmeister, J. LeroyChronic beta-AR activation is detrimental because it promotes cardiac remodeling and ultimately leads to heart failure (HF). Multiple cyclic nucleotide phosphodiesterases (PDEs) finely tune beta-AR responses by degrading and compartmentalizing cAMP. Since chronic treatment with PDE inhibitors increases mortality in HF, we postulated that decreasing cAMP levels by overexpressing PDE4B in the heart may have therapeutic effects. To test this hypothesis, we explored whether AAV9-mediated cardiac overexpression of PDE4B (1012 viral particles) could prevent maladaptive hypertrophy in mice subjected either to transverse aortic constriction (TAC) for 6 weeks or 2 weeks isoproterenol (Iso) and phenylephrine (Phe) infusion (30μg/g/day each). Cardiac function was assessed by echocardiography. In control mice injected with a Luciferase-AAV9 (LUC), TAC decreased ejection fraction (EF, - 34.2 ± 6%, N = 6, P 
  • Anticancer therapy induced cardiotoxicity: Involvement of EPAC1 in
           cardioprotection and anticancer therapy
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): A. Belhadef, E. MorelIntroductionDoxorubicin (Dox) is an anthracycline commonly used to treat many types of cancer; unfortunately this chemotherapeutic agent induces many side effects such as cardiotoxicity leading to dilated cardiomyopathy (DCM). The cardiotoxicity of Dox has been related to reactive oxygen species generation, DNA intercalation and topoisomerase II inhibition, bioenergetics alterations leading to cardiomyocyte death.ObjectiveNowadays the challenge is to find new treatment options aiming at reducing Dox cardiotoxicity. Epac (exchange protein directly activated by cAMP) signaling could be worth investigating as Epac activates small G proteins which are known to be involved in Dox-induced cardiotoxicity.MethodsWe investigated the time/dose-dependent Dox effect on Epac signaling in both in vivo mice model (C57Bl63/Knock-out Epac1 mice, iv injections, 12mg/kg cumulative dose) and in vitro (primary culture of neonatal rat cardiomyocytes (NRVM, 24h, Dox 1μM).ResultsIn vivo, Dox-treated mice developed a DCM associated with Ca2 + homeostasis dysfunction (increase of Ca2 + waves and Ca2 + leaks). In vitro, as measured by flow cytometry and western blot, Dox (1μM) induced DNA damage and cell death in NRVM. This cell death is associated with apoptotic features including mitochondrial membrane permeabilization, caspase activation and cell size reduction. The inhibition of Epac1 (ESI09, CE3F4) decreased Dox-induced DNA damage, loss of mitochondrial membrane potential, apoptosis and finally cardiomyocyte death. Moreover, in vivo, Epac1 KO mice were protected against Dox-induced cardiotoxicity by unaltered cardiac function (no DCM) and calcium homeostasis at 15 weeks post-treatment.ConclusionInhibition of Epac1 could be a valuable therapeutic strategy to limit Dox-induced cardiomyopathy during cancer chemotherapy. Indeed, preliminary data show also that preventing Dox-induced cardiotoxicity, the inhibition of Epac1 can also potentiate cancerous cells death.
  • Place of Drug Adherence in Patients with chronic heart failure
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): M. El Mourid, Z. Qechchar, M. Haraka, S. Zenouaki, R. HabbalIntroductionThe treatment of heart failure is one of the main pillars of the management of patients with chronic heart failure and adherence to treatment is a real problem in managing these patients. Several personal, social and environmental factors can participate in this component, which is why it is worthwhile to look into the question.AimThe aim of our work was to study the adherence of patients to different treatments for heart failure and to study the main influencing factors.MethodsWe carried out a cross-sectional study related to a survey at the heart failure unit in the cardiology department of the IBN ROCHD CHU Casablanca, conducted on 180 patients regularly followed in the service over a period of 6 months from January to June 2018, the data were collected by a survey: CARDIA, and analyzed by SPSS software.ResultsThe mean age of our patients was 60.6 years, with male predominance (62 vs 38%), the main cause of heart failure was ischemic and the ejection fraction was between 35 and 40% in 40%. Adherence to treatment was optimal in 59% of patients. Patient's knowledge of the importance of each drug was only present in 40%. In non-adherent patients, the main etiology was low socio-economic status (22%) followed by age and non-support (15%).ConclusionPoor adherence to treatment is a real public health problem in Morocco hence the interest to create support units and explanation to patients with heart failure.
  • Pharmacological effects of cardiac glycosides on cell death and autophagy:
           Impact on the mitochondrial network structure and function
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): D. Liu, F. Peyre, V. Nicolas, J.C. Cintrat, J.L. Perfettini, C. BrennerIntroductionBy 2030, 43.9% of the US adult population is projected to have some form of cardiovascular disease (CVD) highlighting the need for new therapeutic strategy or an improvement of existing treatments. In many cardiac diseases (i.e. heart failure, myocardial infarction, ischemia/reperfusion), mitochondria can receive harmful signals, dysfunction and then, participate actively in the pathogenesis. They can undergo either a decrease of their bioenergetic capacity, a process called mitochondrial permeability transition which leads to cell death, alterations of mitochondrial protein expression patterns or perturbations in the fusion/fission balance.ObjectiveIn a cardioprotective perspective, it is important to evaluate the effect of drugs on mitochondrial structure and function, because this can impact on cardiac function and health at a more general level.MethodIn this context, we evaluated the mitochondrial effects of Digoxine and Digitoxigenine, two cardiac glycosides used in clinics for heart failure treatment.ResultsWe selected these two compounds in a high throughput screening of cell death inhibitors revealing their activity as potent inhibitors of apoptosis and necrosis of cardiomyoblasts. We confirmed their activity in rat neonatal ventricular cardiomyocytes and showed their capacity to induce autophagy. We also analysed their effects on mitochondrial network structure by fluorescent confocal microscopy and on bioenergetics by Seahorse technology.ConclusionOur study offers new insights into the pharmacological effects of cardiac glycosides that could help to better understand their mechanisms of cardioprotection.
  • Identification of novel cardioprotective molecules for anti-cancer
           combination therapy
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): F. Peyre, D. Liu, D. Courilleau, J.L. Perfettini, J.C. Cintrat, C. BrennerIntroductionDo an improvement in cancer treatments, cancer survivors can develop treatment-related cardiotoxicity.ObjectiveThe aim of this project is to identify new compounds able to protect the cardiomyocytes from cell death to avoid cardiotoxicity.MethodA screening of 1.600 compounds (Prestwick and CEA Saclay libraries) was performed to identify potential cardioprotective compounds by methylene-blue cell survival assay. For this, a necrosis model induced by H2O2 and an apoptosis model induced by camptothecin were developped.ResultsThe screening allowed us to identify 21 molecules able to increase cell survival (> average + 3 standard deviation (SD)). Then, these molecules were validated as cardioprotective using permeability membrane tests: lactate deshydrogenasse (LDH) colorimetric assay and Propidium Iodid fluorescence assay. Mechanisms involved in the cardioprotective effect of the identified molecules are being investigated. Western-blots were performed in order to verify our hypothesis for autophagy activation. We showed that some of the 21 compounds tested increased LC3-II, a protein marker of autophagy. Rapamycin, known as autophagy activator trough inhibition of mTOR was used as positive control. Indeed, it has been shown that under stress condition, autophagy is activated, promoting cell survival by releasing energy substrates via degradation of the cellular components and by eliminating defective or damaged organelles. In addition, we verified that the molecules do not induce cancer cells proliferation during 48h using 3 cancer cell lines, e.g. A549, HepG2 and HeLa, which is crucial in the perspective of drug development.ConclusionAmong the 21 molecules identified, we chose to focus only on 5 more potent molecules to pursue the project. In order to complete the study on autophagy pathway, we plan to perform transcriptomic studies by RNA-seq method.
  • Efficacy and tolerance evaluation of an ambulatory use of
           sacubitril/valsartan among patients with heart failure due to reduced
           ejection fraction
    • Abstract: Publication date: April 2019Source: Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 2Author(s): C. Chong-Nguyen, M. Jullien, M. Lescroart, C. Morgat, T. Rolland, Y. Temmar, N. GhanemIntroductionHeart failure due to reduced ejection fraction (HFrEF) has a real functional impact in daily life for patients. Improving the quality of life is one of the main goals when treating HF. The study PARADIGM-HF showed a 20% reduction of mortality and hospitalization for patients treated with sacubitril/valsartan (LCZ696).ObjectiveThe aim of our study was to evaluate patients with HFrEF after an ambulatory introducing of LCZ696.MethodThirty patients were included and evaluated at baseline, 2 weeks, 1, 3 and 6 months of follow-up. The efficacy and the tolerance of the treatment were judged on clinical, biological, echocardiographic and functional tests.ResultsAt baseline, the mean age was 67 (39–89), with a majority of men (25; 83%) and ischemic cardiopathy (20; 67%). All patients had prior been hospitalized for HF at least once. Twenty-two (73%) patients were NYHA 2 and 8 (27%) were NYHA 3. NYHA class significantly improved during the follow up (Fig. 1). Left ventricular ejection fraction (LVEF) significantly improved: 28% at baseline, 33% at M1, 36% at M3 and 38% at M6 (P 
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