Sudden deaths and deaths « undeserved » from heart diseases are responsible for over one million deaths per year in Europe. The majority of these deaths are due to the occurrence of malignant ventricular arrhythmias that fires after a myocardial infarction, heart failure may progress.
Team 1 seeks to understand the sequence of intracellular events leading to impaired calcium homeostasis and its effects on cellular and in vivo arrhythmogenesis. Considering that studying the heart in isolation from the rest of the body allows only partial approach of arrhythmogenic mechanisms, we study parallel functional alterations of membrane ion channels, the role of the autonomic nervous system and circulating factors the functional and structural remodeling of the heart but also the autonomic nervous system.
To develop fatal ventricular arrhythmias require 1) a trigger, such as a « disorder » electrophysiological giving birth to a premature ventricular contraction, 2) a substrate allowing the trigger to be released and servicing this lethal event, and 3) a modulator such as the autonomic nervous system that can play on the 2 previous elements in a longer or shorter time scale (acute or chronic).
Our team researchs to understand the role of the autonomic nervous system in the genesis of arrhythmias and what are the elements that may affect circulating. Among the circulating factors studied, we have demonstrated that the B-type natriuretic peptide (BNP) released by the heart itself is involved in the mechanisms of cardiac structural and functional remodeling but also of the autonomic nervous system. This leads to long-term alterations in the expression and function of proteins involved in the calcium SERCA cycle such that proteins, NCX, S100A1 and ryanodine receptors. The BNP in chronic and induces abnormal activity of ryanodine receptors, causing a leak calcium from the sarcoplasmic reticulum in diastole generating a pro-arrhythmogenic cell status disorders initiator ventricular rhythm in vivo.
We are currently investigating the mechanisms by which the BNP is able to induce remodeling of the autonomic nervous system, particularly the sympathetic nervous system. We are also interested in the roles of neurotrophins secreted by the left ventricle using in vivo telemetry techniques (ECG, Heart rate variability), echocardiography, and also by cell techniques (calcium imaging, cellular electrophysiology, biochemistry, immune-fluorescence) . Our team is also working with other groups on the involvement of defects activity in the autonomic nervous system according to different conditions or terms such as restless legs syndrome (Willis-Ekbom disease).
- Dr Frédéric Marmigère (Institut des neurosciences de Montpellier),
- Pr Dominique Babuty (Service de cardiologie, Hôpital Trousseau, Tours),
- Pr Yves Dauvilliers (Unité des troubles du sommeil et de l’éveil, CHRU Gui de Chauliac, INSERM U1061 Montpellier),
- Drs Jérémy Fauconnier & Alain Lacampagne (Equipe 2 du laboratoire),
- Pascal Champeroux (C.E.R.B., Centre Recherches Biologiques, Baugy).
Financial support :
- Fondation de France (Projets PepNarythm et SynaptoCard)
- Association France Ekbom.
Major Publications :
- Andre L., Boissière J., Reboul C., Perrier R., Meyer G., Zalvidea S., Thireau J., Tanguy S., Bideaux P., Hayot M., Boucher F., Obert P., Cazorla O., Richard S. Carbon monoxide pollution promotes cardiac remodeling and ventricular arrhythmia in healthy rats.. J. of Resp. & Critical Care Medicine, 2010.
- Fauconnier J*, Thireau J*, Reiken S, Cassan C, Richard S, Matecki S, Marks AR, Lacampagne A. Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy.. Proc Natl Acad Sci U S A. 2010.
- Thireau J, Pasquie JL, Martel E, Le Guennec JY, Richard S. New drugs vs. old concepts: a fresh look at antiarrhythmics. Pharmacol Ther. 2011
- Thireau J, Karam S, Fauconnier J, Roberge S, Cassan C, Cazorla O, Aimond F, Lacampagne A, Babuty D, Richard S. Functional evidence for an active role of B-type natriuretic peptide in cardiac remodelling and pro-arrhythmogenicity. Cardiovasc Res., 2012
- Zalvidea S., Andre L., Loyer X., Cassan C., Sainte-Marie Y., Thireau J., Sjaastad I., Heymes C., Pasquie JL., Cazorla O., Aimond F. and Richard S. ACE inhibition prevents diastolic Ca2+ overload and loss of myofilament Ca2+ sensitivity after myocardial infarction.. Current Molecular Medicine, 2012.
- Thireau J, Karam S, Roberge S, Roussel J, Aimond F, Cassan C, Gac A, Babuty D, Le Guennec JY, Lacampagne A, Fauconnier J, Richard S. Β-adrenergic blockade combined with subcutaneous B-type natriuretic peptide: a promising approach to reduce ventricular arrhythmia in heart failure? Heart. 2014
- Champeroux P, Thireau J, Judé S, Laigot-Barbé C, Maurin A, Sola M, Fowler J, Richard S, Le Guennec JL. “Short-term variability in QT interval and ventricular arrhythmias induced by dofetilide are dependent on high-frequency autonomic oscillations.“ Br J Pharmacol. 2015.
- Roussel J, Labarthe F, Thireau J, Ferro F, Farah C, Roy J, Horiuchi M, Tardieu M, Lefort B, Benoist JF, Lacampagne A, Richard S, Fauconnier J, Babuty D, Le Guennec JY. “Carnitine Deficiency Induces A Short Qt Syndrome. “ Heart Rhythm. 2015.
- Thireau J, Zalvidea S, Meschin P, Pasquié JL, Aimond F, Richard S. “ACE inhibitor delapril prevents Ca2+-dependent blunting of IK1 and ventricular arrhythmia in ischemic heart disease. “ Curr Mol Med. 2015.