Elastomeric cardiopatch scaffold for myocardial repair and ventricular support

[EN] OBJECTIVES: Prevention of postischaemic ventricular dilatation progressing towards pathological remodelling is necessary to decrease ventricular wall deterioration. Myocardial tissue engineering may play a therapeutic role due to its capacity to replace the extracellular matrix, thereby creating niches for cell homing. In this experimental animal study, a biomimetic cardiopatch was created with elastomeric scaffolds and nanotechnologies. METHODS: In an experimental animal study in 18 sheep, a cardiopatch was created with adipose tissue-derived progenitor cells seeded into an engineered bioimplant consisting of 3-dimensional bioabsorbable polycaprolactone scaffolds filled with a peptide hydrogel (PuraMatrix (TM)). This patch was then transplanted to cover infarcted myocardium. Non-absorbable poly(ethyl) acrylate polymer scaffolds were used as controls. RESULTS: Fifteen sheep were followed with ultrasound scans at 6 months, including echocardiography scans, tissue Doppler and spectral flow analysis and speckle-tracking imaging, which showed a reduction in longitudinal left ventricular deformation in the cardiopatch-treated group. Magnetic resonance imaging (late gadolinium enhancement) showed reduction of infarct size relative to left ventricular mass in the cardiopatch group versus the controls. Histopathological analysis at 6 months showed that the cardiopatch was fully anchored and integrated to the infarct area with minimal fibrosis interface, thereby promoting angiogenesis and migration of adipose tissue-derived progenitor cells to surrounding tissues. CONCLUSIONS: This study shows the feasibility and effectiveness of a cardiopatch grafted onto myocardial infarction scars in an experimental animal model. This treatment decreased fibrosis, limited infarct scar expansion and reduced postischaemic ventricular deformity. A capillary network developed between our scaffold and the heart. The elastomeric cardiopatch seems to have a positive impact on ventricular remodelling and performance in patients with heart failure.The RECATABI Project (Regeneration of Cardiac Tissue Assisted by Bioactive Implants) was financially supported by the 7th Framework Programme (FP7) of the European Commission. Project ID: 229239. Funded under FP7-NMP and the European Regional Development Fund (FEDER Spain).Chachques, JC.; Lila, N.; Soler Botija, C.; Martínez-Ramos, C.; Vallés Lluch, A.; Autret, G.; Perier, M.... (2020). Elastomeric cardiopatch scaffold for myocardial repair and ventricular support. European Journal of Cardio-Thoracic Surgery. 57(3):545-555. https://doi.org/10.1093/ejcts/ezz252S545555573Madonna, R., Van Laake, L. W., Botker, H. E., Davidson, S. M., De Caterina, R., Engel, F. B., … Sluijter, J. P. G. (2019). ESC Working Group on Cellular Biology of the Heart: position paper for Cardiovascular Research: tissue engineering strategies combined with cell therapies for cardiac repair in ischaemic heart disease and heart failure. Cardiovascular Research, 115(3), 488-500. doi:10.1093/cvr/cvz010Nielsen, S. H., Mouton, A. J., DeLeon-Pennell, K. Y., Genovese, F., Karsdal, M., & Lindsey, M. L. (2019). Understanding cardiac extracellular matrix remodeling to develop biomarkers of myocardial infarction outcomes. Matrix Biology, 75-76, 43-57. doi:10.1016/j.matbio.2017.12.001Spinale, F. G., Frangogiannis, N. G., Hinz, B., Holmes, J. W., Kassiri, Z., & Lindsey, M. L. (2016). Crossing Into the Next Frontier of Cardiac Extracellular Matrix Research. Circulation Research, 119(10), 1040-1045. doi:10.1161/circresaha.116.309916Chachques, J. C., Pradas, M. M., Bayes-Genis, A., & Semino, C. (2013). Creating the bioartificial myocardium for cardiac repair: challenges and clinical targets. Expert Review of Cardiovascular Therapy, 11(12), 1701-1711. doi:10.1586/14779072.2013.854165Bayés-Genís, A., Gálvez-Montón, C., & Roura, S. (2016). Cardiac Tissue Engineering. Journal of the American College of Cardiology, 68(7), 724-726. doi:10.1016/j.jacc.2016.05.055Shafy, A., Fink, T., Zachar, V., Lila, N., Carpentier, A., & Chachques, J. C. (2012). Development of cardiac support bioprostheses for ventricular restoration and myocardial regeneration. European Journal of Cardio-Thoracic Surgery, 43(6), 1211-1219. doi:10.1093/ejcts/ezs480Castells-Sala, C., Recha-Sancho, L., Llucià-Valldeperas, A., Soler-Botija, C., Bayes-Genis, A., & Semino, C. E. (2016). Three-Dimensional Cultures of Human Subcutaneous Adipose Tissue-Derived Progenitor Cells Based on RAD16-I Self-Assembling Peptide. Tissue Engineering Part C: Methods, 22(2), 113-124. doi:10.1089/ten.tec.2015.0270Martínez-Ramos, C., Rodríguez-Pérez, E., Garnes, M. P., Chachques, J. C., Moratal, D., Vallés-Lluch, A., & Monleón Pradas, M. (2014). Design and Assembly Procedures for Large-Sized Biohybrid Scaffolds as Patches for Myocardial Infarct. Tissue Engineering Part C: Methods, 20(10), 817-827. doi:10.1089/ten.tec.2013.0489Biswas, M., Sudhakar, S., Nanda, N. C., Buckberg, G., Pradhan, M., Roomi, A. U., … Houle, H. (2013). Two- and Three-Dimensional Speckle Tracking Echocardiography: Clinical Applications and Future Directions. Echocardiography, 30(1), 88-105. doi:10.1111/echo.12079Dorsey, S. M., McGarvey, J. R., Wang, H., Nikou, A., Arama, L., Koomalsingh, K. J., … Burdick, J. A. (2015). MRI evaluation of injectable hyaluronic acid-based hydrogel therapy to limit ventricular remodeling after myocardial infarction. Biomaterials, 69, 65-75. doi:10.1016/j.biomaterials.2015.08.011Chachques, J. C. (2009). Cellular cardiac regenerative therapy in which patients? Expert Review of Cardiovascular Therapy, 7(8), 911-919. doi:10.1586/erc.09.84Chachques, J. (1997). Dynamic cardiomyoplasty: clinical follow-up at 12 years. European Journal of Cardio-Thoracic Surgery, 12(4), 560-568. doi:10.1016/s1010-7940(97)00214-5Varela, C. E., Fan, Y., & Roche, E. T. (2019). Optimizing Epicardial Restraint and Reinforcement Following Myocardial Infarction: Moving Towards Localized, Biomimetic, and Multitherapeutic Options. Biomimetics, 4(1), 7. doi:10.3390/biomimetics4010007Van den Borne, S. W. M., Cleutjens, J. P. M., Hanemaaijer, R., Creemers, E. E., Smits, J. F. M., Daemen, M. J. A. P., & Blankesteijn, W. M. (2009). Increased matrix metalloproteinase-8 and -9 activity in patients with infarct rupture after myocardial infarction. Cardiovascular Pathology, 18(1), 37-43. doi:10.1016/j.carpath.2007.12.012Ducharme, A., Frantz, S., Aikawa, M., Rabkin, E., Lindsey, M., Rohde, L. E., … Lee, R. T. (2000). Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. Journal of Clinical Investigation, 106(1), 55-62. doi:10.1172/jci8768Sieminski, A. L., Semino, C. E., Gong, H., & Kamm, R. D. (2008). Primary sequence of ionic self-assembling peptide gels affects endothelial cell adhesion and capillary morphogenesis. Journal of Biomedical Materials Research Part A, 87A(2), 494-504. doi:10.1002/jbm.a.31785Bagó, J. R., Soler-Botija, C., Casaní, L., Aguilar, E., Alieva, M., Rubio, N., … Blanco, J. (2013). Bioluminescence imaging of cardiomyogenic and vascular differentiation of cardiac and subcutaneous adipose tissue-derived progenitor cells in fibrin patches in a myocardium infarct model. International Journal of Cardiology, 169(4), 288-295. doi:10.1016/j.ijcard.2013.09.013Chachques, J. C., Trainini, J. C., Lago, N., Cortes-Morichetti, M., Schussler, O., & Carpentier, A. (2008). Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium (MAGNUM Trial): Clinical Feasibility Study. The Annals of Thoracic Surgery, 85(3), 901-908. doi:10.1016/j.athoracsur.2007.10.052Lee, H., Ahn, S., Bonassar, L. J., & Kim, G. (2012). Cell(MC3T3-E1)-Printed Poly(ϵ-caprolactone)/Alginate Hybrid Scaffolds for Tissue Regeneration. Macromolecular Rapid Communications, 34(2), 142-149. doi:10.1002/marc.201200524Strub, M., Van Bellinghen, X., Fioretti, F., Bornert, F., Benkirane-Jessel, N., Idoux-Gillet, Y., … Clauss, F. (2018). Maxillary Bone Regeneration Based on Nanoreservoirs Functionalizedε-Polycaprolactone Biomembranes in a Mouse Model of Jaw Bone Lesion. BioMed Research International, 2018, 1-12. doi:10.1155/2018/7380389Rohman, G., Huot, S., Vilas-Boas, M., Radu-Bostan, G., Castner, D. G., & Migonney, V. (2015). The grafting of a thin layer of poly(sodium styrene sulfonate) onto poly(ε-caprolactone) surface can enhance fibroblast behavior. Journal of Materials Science: Materials in Medicine, 26(7). doi:10.1007/s10856-015-5539-7Spadaccio, C., Nappi, F., De Marco, F., Sedati, P., Taffon, C., Nenna, A., … Rainer, A. (2017). Implantation of a Poly-l-Lactide GCSF-Functionalized Scaffold in a Model of Chronic Myocardial Infarction. Journal of Cardiovascular Translational Research, 10(1), 47-65. doi:10.1007/s12265-016-9718-9Monnet, E., & Chachques, J. C. (2005). Animal Models of Heart Failure: What Is New? The Annals of Thoracic Surgery, 79(4), 1445-1453. doi:10.1016/j.athoracsur.2004.04.002Bellin, G., Gardin, C., Ferroni, L., Chachques, J., Rogante, M., Mitrečić, D., … Zavan, B. (2019). Exosome in Cardiovascular Diseases: A Complex World Full of Hope. Cells, 8(2), 166. doi:10.3390/cells802016

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

Change in Cardiovascular Health and Incident Type 2 Diabetes and Impaired Fasting Glucose:The Whitehall II Study

Objective: Most previous studies on cardiovascular health (CVH) and incident type 2 diabetes (T2D) have used a single measure of CVH, and none have investigated the association with impaired fasting glucose (IFG). We examined the association between changes in CVH and incident T2D and IFG.Research Design and Methods: Within the Whitehall II study, CVH was examined every 5 years from 1991/93 until 2015/16. Subjects with 0-2, 3-4, and 5-6 ideal metrics of CVH from the American Heart Association were categorized as having low, moderate, or high CVH, respectively.Results: There were 6,234 participants (mean age 49.8 ± 6.0 years, 70% male) without prior cardiovascular disease and T2D, including 5,015 who were additionally free from IFG at baseline. Over a median follow-up of 24.8 (interquartile range 24.0-25.2) years, 895 and 1,703 incident cases of T2D and IFG occurred, respectively. Change in CVH between 1991/93 and 2002/04 was calculated among 4,464 participants free from CVD and T2D and among 2,795 participants additionally free from IFG. In multivariate analysis, compared with those with stable low CVH, risk of T2D was lower in those with initially high CVH (hazard ratio [HR] 0.21; 95% CI 0.09, 0.51), those who had persistently moderate CVH or changed from moderate to high CVH (moderate-moderate/high; HR 0.53; 95% CI 0.41, 0.69), low-moderate/high (HR 0.62; 95% CI 0.45, 0.86), and moderate-low (HR 0.74; 95% CI 0.56, 0.98). Results were similar for IFG, but the effect sizes were smaller.Conclusions: Compared with stable low CVH, other patterns of change in CVH were associated with lower risk of T2D and IFG

Recalled body silhouette trajectories over the lifespan and oral conditions in adulthood: A cross‐sectional analysis of the Paris Prospective Study 3

International audienceObjectives: To examine the association between life-course body silhouette changes and oral conditions in adulthood.Methods: At study recruitment (2008-2012), 5430 adults underwent a full-mouth clinical examination and recalled their body silhouettes at ages 8, 15, 25, 35 and 45. Life-course trajectories of body silhouettes were computed using group-based trajectory modelling. Gingival inflammation, dental plaque, masticatory units, numbers of healthy, missing, decayed and filled teeth at study recruitment were clustered. The associations between body silhouette trajectories and clusters of oral conditions were assessed by multinomial logistic regression.Results: The final analysis included 4472 participants. Five body silhouette trajectories were established: lean-stable (30.0%), lean-increased (19.3%), moderate stable (18.1%), lean-marked increased (25.8%) and heavy stable (6.7%). Three clusters of oral conditions were identified: optimal oral health and preserved masticatory capacity (70.0%, cluster 1), moderate oral health and moderately impaired masticatory capacity (25.4%, cluster 2) and poor oral health and severely impaired masticatory capacity (4.7%, cluster 3). Participants with a lean-increased trajectory were 58% more likely than those with a lean-stable trajectory to be in cluster 3 (aOR 1.58 [95% CI 1.07; 2.35]) relative to cluster 1, independently of covariates measured at study recruitment and including age, sex, smoking, socioeconomic status, BMI, hypertension, type 2 diabetes, cholesterol and triglycerides.Conclusions: A life-course lean-increased body silhouette trajectory is associated with higher likelihood of poor oral health and severely impaired masticatory capacity in adulthood

Outcome of Primary Prevention Implantable Cardioverter Defibrillator Therapy According to New York Heart Association Functional Classification

International audienceWe aimed to assess if the outcome of primary prevention implantable cardioverter defibrillators (ICDs) without cardiac resynchronization therapy is dependent on New York Heart Association (NYHA) class. Among the participants of Defibrillateur Automatique Implantable-Prevention Primaire (DAI-PP; NCT01992458) multicenter cohort study, 155 patients in NYHA class I, 504 in NYHA class II, and 188 in NYHA class III had a QRS width <120 ms and were implanted with an ICD without cardiac resynchronization therapy and, thus, were eligible for the purpose of this analysis. Total and specific mortalities and the incidence of appropriate therapies were assessed for every NYHA. During 2,606 patient-years (3.1 +/- 2.1 years), 104 (12.3%) subjects died and 188 (22.2%) experienced appropriate therapies. After adjustment, overall mortality increased with NYHA class (adjusted hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.11 to 2.41, p = 0.014), driven by an increase in cardiovascular death. Conversely, incidence of appropriate ICD intervention was comparable among the 3 NYHA groups (NYHA class I 7.43, NYHA class II 7.91, and NYHA class III 12.10 per 100 patient-years; HR 1.19, 95% CI 0.89 to 1.59, p = 0.231). Incidence of ICD-unresponsive sudden death was very low and also comparable (NYHA class I 0.22, NYHA class II 0.36, and NYHA class III 0.83 per 100 patient years (HR 6.34, 95% CI 0.32 to 124.49, p = 0.224). No significant differences were observed in the other specific modes of death. In conclusion, although patients in NYHA class III have higher overall mortality, they experience a comparable incidence of appropriate ICD therapies. The low incidence of ICD-unresponsive sudden death in all assessed NYHA classes also supports the efficacy of ICDs, irrespective of NYHA class. (C) 2016 Elsevier Inc. All rights reserved

Primary Prevention Implantable Cardioverter Defibrillator (ICD) Therapy in Women-Data From a Multicenter French Registry

International audienceBACKGROUND: There are limited data describing sex specificities regarding implantable cardioverter defibrillators (ICDs) in the real-world European setting. METHODS AND RESULTS: Using a large multicenter cohort of consecutive patients referred for ICD implantation for primary prevention (2002-2012), in ischemic and nonischemic cardiomyopathy, we examined the sex differences in subjects' characteristics and outcomes. Of 5539 patients, only 837 (15.1%) were women and 53.8% received cardiac resynchronization therapy. Compared to men, women presented a significantly higher proportion of nonischemic cardiomyopathy (60.2% versus 36.2%, P\textless0.001), wider QRS complex width (QRS \textgreater120 ms: 74.6% versus 68.5%, P=0.003), higher New York Heart Association functional class (≥III in 54.2%♀ versus 47.8%♂, P=0.014), and lower prevalence of atrial fibrillation (18.7% versus 24.9%, P\textless0.001). During a 16 786 patient-years follow-up, overall, fewer appropriate therapies were observed in women (hazard ratio=0.59, 95% CI 0.45-0.76; P\textless0.001). By contrast, no sex-specific interaction was observed for inappropriate shocks (odds ratio ♀=0.84, 95% CI 0.50-1.39, P=0.492), early complications (odds ratio=1.00, 95% CI 0.75-1.32, P=0.992), and all-cause mortality (hazard ratio=0.87 95% CI 0.66-1.15, P=0.324). Analysis of sex-by- cardiac resynchronization therapy interaction shows than female cardiac resynchronization therapy recipients experienced fewer appropriate therapies than men (hazard ratio=0.62, 95% CI 0.50-0.77; P\textless0.001) and lower mortality (hazard ratio=0.68, 95% CI 0.47-0.97; P=0.034). CONCLUSIONS: In our real-life registry, women account for the minority of ICD recipients and presented with a different clinical profile. Whereas female cardiac resynchronization therapy recipients had a lower incidence of appropriate ICD therapies and all-cause death than their male counterparts, the observed rates of inappropriate shocks and early complications in all ICD recipients were comparable. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT0199245

Efficacy of Epicardially Delivered Adipose Stromal Cell Sheets in Dilated Cardiomyopathy

International audienceno abstrac

Efficacy of epicardially delivered adipose stroma cell sheets in dilated cardiomyopathy

International audienceFew studies have assessed the effects of cell therapy in non-ischaemic cardiomyopathies which, however, contribute to a large number of cardiac failures. Assuming that such conditions are best suited for a global delivery of cells, we assessed the effects of epicardially delivered adipose tissue-derived stroma cell (ADSC) sheets in a mouse model of dilated cardiomyopathy based on cardiac-specific and tamoxifen-inducible invalidation of serum response factor. Three weeks after tamoxifen administration, the function of the left ventricle (LV) was assessed by echocardiography. Twenty-nine mice were then allocated to control (n 9, non-transgenic), sham (n 10, transgenic non-treated), and treated (n 10, transgenic) groups. In the treated group, 3 10(6) allogeneic ADSCs were cultured for 2 days onto temperature-responsive polymers and the generated sheets were then transplanted over the surface of the heart. In 10 additional mice, the sheet was made of green fluorescent protein (GFP)-labelled ADSCs to track cell fate. Function, engraftment, and fibrosis were blindly assessed after 3 weeks. In the non-treated group, fractional shortening declined compared with baseline, whereas the sheet application resulted in its stabilization. This correlated with a lesser degree of LV remodelling, as LV end-diastolic and end-systolic diameters did not differ from baseline values. Many GFP cells were identified in the epicardial graft and in the myocardium. Treated animals also displayed a reduced expression of the stress-induced atrial natriuretic factor and beta-myosin heavy chain genes. These protective effects were also accompanied by a reduction of myocardial fibrosis. These results strongly suggest the functional relevance of epicardially delivered cell-seeded biomaterials to non-ischaemic heart failure

Association Between Occupational, Sport, and Leisure Related Physical Activity and Baroreflex Sensitivity The Paris Prospective Study III

Physical activity (PA) is a preventative behavior for noncommunicable disease. However, little consideration is given as to whether different domains of PA have differing associations with health outcomes. We sought to determine the association between occupational, sport, leisure, and total PA with baroreflex sensitivity (BRS), distinguishing between neural (nBRS) and mechanical (mBRS) BRS. In a cross-sectional analysis of 8649 adults aged 50 to 75 years, resting nBRS (estimated by low-frequency gain, from carotid distension rate and heart rate) and mBRS (carotid stiffness) were measured by high-precision carotid echo-tracking. PA was self-reported using the validated Baecke questionnaire. The associations between PA and nBRS and mBRS were quantified using multivariate linear regression analysis, separately in the working and nonworking population. In working adults (n=5039), occupational PA was associated with worse nBRS (unstandardized β=-0.02; [95% CI, -0.04 to -0.003]; P=0.022) whereas sport PA was associated with better nBRS (β=0.04; [95% CI, 0.02-0.07]; P=0.003) and mBRS (β=-0.05; [95% CI, -0.09 to -0.00001]; P=0.049). Neither leisure PA nor total PA was associated with nBRS or mBRS. In nonworking adults (n=3610), sport PA and total PA were associated with better mBRS (β=-0.08; [95% CI, -0.15 to 0.02]; P=0.012 and β=-0.05; [95% CI, -0.10 to 0.009]; P=0.018) but not nBRS. These findings suggest differential associations between domains of PA and BRS and may provide insights into the mechanisms underlying the association between occupational PA and cardiovascular disease