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Cardiac valve disease

Romain Capoulade, Solena Le Scouarnec, Jean Mérot, Jean-Jacques Schott and Thierry Le Tourneau

Cardiac valve diseases are the one of most frequent cardiovascular diseases and are associated with important mobi-mortality. There is currently no medical therapy available to at least slow down the progression of these pathologies, the only option remaining is to replace or repair the diseased valve, via surgical or transcatheter approaches.

In our group, we develop a translational research program, from the genetics and basic researches to the clinical setting, designed to improve our understanding on native valve diseases, such as calcific aortic valve stenosis (CAVS) and mitral valve prolapse (MVP), as well as structural bioprosthetic valve degeneration.

This program is declined around 3 main axes:
  • One of the largest worldwide cohort of patients with valve diseases, with the recruitment of sporadic cases and large familial pedigrees.
  • Genetic investigations on familial and isolated cases presenting different degrees of valve diseases.
  • Study of the pathophysiological mechanisms leading to the initiation and progression of these cardiac valve diseases    
We are relying on in-house expertise on multi-omics and high-throughput genetic approaches, on established relevant cellular and animal models, and on clinical & pre-clinical multimodal imaging.  

 
  • AAP "Recherche fondamentale et clinique sur les maladies cardiovasculaires" (Fondation de France; 2022-2025) - Impacts of Lipid  in the Structural biological prosthetic Valve Degeneration (Romain Capoulade)
The aim of this project is to elucidate the role of lipids in the processes leading to structural bioprosthetic valve degeneration. This grant will allow him to implement a new large animal model to study this phenomenon.

 
  • Bourse A. Castaigne  (SFC; 2021-2022) – Study of the Molecular Mechanisms Involved in the Development and Progression of Mitral Valve Prolapse (Romain Capoulade)
This award is to support innovative clinical, fundamental or translational research, in the cardiovascular, cardio-renal and cardio-metabolic fields, and concerning both the understanding of pathophysiological mechanisms as well as diagnostic and therapeutic approaches.

Romain Capoulade hold this award in 2021 for his on-going work on the molecular mechanisms involved in the development and progression of mitral valve prolapse (MVP).

This support will allow him to pursue the study on the role of inflammation and immune response in the process leading to MVP, with a specific attention to the additive impact of stress-related mechanisms.

 
  • PICASSO project (ERA-CVD - Horizon 2020; 2019-2022) - Unravelling PCSK9 mechanisms in calcific aortic valve disease: from aortic valve sclerosis to stenosis (Romain Capoulade)
PICASSO's main goal is to validate PCSK9 as a therapeutic target for the prevention and treatment of patients with calcific aortic valve stenosis (CAVS).
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  • MechanoMVP project (MSCA - Horizon 2020; 2019-2021) – Mechanosensing and Mitral Valve Prolapse: from the Molecular Mechanisms to the Progression of the Disease (Romain Capoulade)
The aim of this project is to study stress-related mechanisms and regulation of signaling pathways involved in the development and progression of mitral valve prolapse based on the comprehensive analysis of the unique knock-in rat model for the FLNA-P637Q mutation, as well as the related-cellular models.
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  • Connect Talent - Advanced Multimodality Imaging Program and Translational Research in Chronic Cardiovascular Diseases (Romain Capoulade)

The cornerstone of genetic investigations is the precise phenotypic characterization. Emergence of a new research axis focused on the development of bio-imaging core facility and expertise in image analysis provide support to the research programs of the team, as well as offer the opportunity to develop new translational and innovative projects.
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  • I-CARE project (ANR; 2017-2021) – Mitral valve disease: from genetics to mechanisms and improved care (Jean-Jacques Schott)
The aim of this project is to investigate the genetic basis of mitral valve degeneration through an integrated research program combining high-throughput genetic screening and functional investigations
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Selected Publications

Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse. Roselli C, Yu M, Nauffal V, Georges A, Yang Q, Love K, Weng LC, Delling FN, Maurya SR, Schrölkamp M, Tfelt-Hansen J, Hagège A, Jeunemaitre X, Debette S, Amouyel P, Guan W, Muehlschlegel JD, Body SC, Shah S, Samad Z, Kyryachenko S, Haynes C, Rienstra M, Le Tourneau T, Probst V, Roussel R, Wijdh-Den Hamer IJ, Siland JE, Knowlton KU, Jacques Schott J, Levine RA, Benjamin EJ, Vasan RS, Horne BD, Muhlestein JB, Benfari G, Enriquez-Sarano M, Natale A, Mohanty S, Trivedi C, Shoemaker MB, Yoneda ZT, Wells QS, Baker MT, Farber-Eger E, Michelena HI, Lundby A, Norris RA, Slaugenhaupt SA, Dina C, Lubitz SA, Bouatia-Naji N, Ellinor PT, Milan DJ. Eur Heart J. 2022 May 1;43(17):1668-1680. doi: 10.1093/eurheartj/ehac049.
 

Multimodality imaging and transcriptomics to phenotype mitral valve dystrophy in a unique knock-in Filamin-A rat model. Delwarde C, Toquet C, Aumond P, Kayvanjoo AH, Foucal A, Le Vely B, Baudic M, Lauzier B, Blandin S, Véziers J, Paul-Gilloteaux P, Lecointe S, Baron E, Massaiu I, Poggio P, Rémy S, Anegon I, Le Marec H, Monassier L, Schott JJ, Mass E, Barc J, Le Tourneau T, Merot J, Capoulade R. Cardiovasc Res. 2022:cvac136.

The role of antibody responses against glycans in bioprosthetic heart valve calcification and deterioration.Senage T*, Paul A*, Le Tourneau T*, Fellah-Hebia I, Vadori M, Bashir S, Galiñanes M, Bottio T, Gerosa G, Evangelista A, Badano LP, Nassi A, Costa C, Cesare G, Manji RA, Cueff de Monchy C, Piriou N, Capoulade R, Serfaty JM, Guimbretière G, Dantan E, Ruiz-Majoral A, Coste du Fou G, Leviatan Ben-Arye S, Govani L, Yehuda S, Bachar Abramovitch S, Amon R, Reuven EM, Atiya-Nasagi Y, Yu H, Iop L, Casós K, Kuguel SG, Blasco-Lucas A, Permanyer E, Sbraga F, Llatjós R, Moreno-Gonzalez G, Sánchez-Martínez M, Breimer ME, Holgersson J, Teneberg S, Pascual-Gilabert M, Nonell-Canals A, Takeuchi Y, Chen X, Mañez R, Roussel JC#, Soulillou JP#, Cozzi E#, Padler-Karavani V#. Nat Med. 2022 Feb;28(2):283-294.

Replacement Myocardial Fibrosis in Patients With Mitral Valve Prolapse: Relation to Mitral Regurgitation, Ventricular Remodeling, and Arrhythmia. Constant Dit Beaufils AL, Huttin O, Jobbe-Duval A, Senage T, Filippetti L, Piriou N, Cueff C, Venner C, Mandry D, Sellal JM, Le Scouarnec S, Capoulade R, Marrec M, Thollet A, Beaumont M, Hossu G, Toquet C, Gourraud JB, Trochu JN, Warin-Fresse K, Marie PY, Schott JJ, Roussel JC, Serfaty JM, Selton-Suty C, Le Tourneau T. Circulation. 2021 May 4;143(18):1763-1774.

Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis. Perrot N, Valerio V, Moschetta D, Boekholdt SM, Dina C, Chen HY, Abner E, Martinsson A, Manikpurage HD, Rigade S, Capoulade R, Mass E, Clavel M-A, Le Tourneau T, Messika-Zeitoun D, Wareham NJ, Engert JC, Polvani G, Pibarot P, Esko T, Smith JG, Mathieu P, Thanassoulis G, Schott J-J, Bossé Y, Camera M, Thériault S, Poggio P, Arsenault BJ. J Am Coll Cardiol Basic Trans Science 2020;5:649–661.

Non-syndromic Mitral Valve Dysplasia Mutation Changes the Force Resilience and Interaction of Human Filamin A.Haataja TJK, Bernardi RC, Lecointe S, Capoulade R, Merot J, Pentikäinen U. Structure 2019;27:102-112.e4.

Genetic Association Analyses Highlight IL6, ALPL, and NAV1 As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis.​​​​​​​ Thériault S, Dina C, Messika-Zeitoun D, Le Scouarnec S, Capoulade R, Gaudreault N, Rigade S, Li Z, Simonet F, Lamontagne M, Clavel M-A, Arsenault BJ, Boureau A-S, Lecointe S, Baron E, Bonnaud S, Karakachoff M, Charpentier E, Fellah I, Roussel J-C, Philippe Verhoye J, Baufreton C, Probst V, Roussel R, D.E.S.I.R. Study Group, Redon R, Dagenais F, Pibarot P, Mathieu P, Bossé Y, Schott JJ. Circ Genom Precis Med 2019;12:e002617.

Primary cilia defects causing mitral valve prolapse. Toomer KA, Yu M, Fulmer D, Guo L, Moore KS, Moore R, Drayton KD, Glover J, Peterson N, Ramos-Ortiz S, Drohan A, Catching BJ, Stairley R, Wessels A, Lipschutz JH, Delling FN, Jeunemaitre X, Dina C, Collins RL, Brand H, Talkowski ME, Del Monte F, Mukherjee R, Awgulewitsch A, Body S, Hardiman G, Hazard ES, da Silveira WA, Wang B, Leyne M, Durst R, Markwald RR, Le Scouarnec S, Hagege A, Le Tourneau T, Kohl P, Rog-Zielinska EA, Ellinor PT, Levine RA, Milan DJ, Schott J-J*, Bouatia-Naji N*, Slaugenhaupt SA*, Norris RA*. Sci Transl Med 2019;11:.

 

New insights into mitral valve dystrophy: a Filamin-A genotype-phenotype and outcome study. Le Tourneau T, Le Scouarnec S, Cueff C, Bernstein D, Aalberts JJJ, Lecointe S, Mérot J, Bernstein JA, Oomen T, Dina C, Karakachoff M, Desal H, Al Habash O, Delling FN, Capoulade R, Suurmeijer AJH, Milan D, Norris RA, Markwald R, Aikawa E, Slaugenhaupt SA, Jeunemaitre X, Hagège A, Roussel J-C, Trochu J-N, Levine RA, Kyndt F, Probst V, Le Marec H, Schott JJ. Eur Heart J 2018;39:1269–1277.

PCSK9 Involvement in Aortic Valve Calcification. Poggio P, Songia P, Cavallotti L, Barbieri SS, Zanotti I, Arsenault BJ, Valerio V, Ferri N, Capoulade R, Camera M.J Am Coll Cardiol 2018;72:3225–3227.
 
Genetic association analyses highlight biological pathways underlying mitral valve prolapse. Dina* C, Bouatia-Naji* N, Tucker* N, Delling FN, Toomer K, Durst R, Perrocheau M, Fernandez-Friera L, Solis J, PROMESA investigators, Le Tourneau T, Chen M-H, Probst V, Bosse Y, Pibarot P, Zelenika D, Lathrop M, Hercberg S, Roussel R, Benjamin EJ, Bonnet F, Lo SH, Dolmatova E, Simonet F, Lecointe S, Kyndt F, Redon R, Le Marec H, Froguel P, Ellinor PT, Vasan RS, Bruneval P, Markwald RR, Norris* RA, Milan* DJ, Slaugenhaupt* SA, Levine* RA, Schott* J-J, Hagege* AA, MVP-France, Jeunemaitre* X, Leducq Transatlantic MITRAL Network. Nat Genet 2015;47:1206–1211.


Funding

This programme has been financed by :

  • ANR
  • CHU Nantes
  • ERA-CVD
  • Région Pays de la Loire
  • Inserm



 
  • Fondation de France
  • Fondation pour la Recherche Médicale
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Mis à jour le 26 June 2023 - Stéphanie CHATEL.
https://umr1087.univ-nantes.fr/research/research-teams/genetics-and-pathophysiology-of-cardiac-valve-dystrophy