SCN5A-related Progressive Cardiac Conduction Disease: pathophysiological mechanisms, biomarkers and prevention – PREVENTPCCD

More than 1,000,000 pacemakers have been implanted worldwide in 2009. Progressive Cardiac Conduction Disease (PCCD), also called Lenègre or Lev disease, represents the major cause of pacemaker implantation in developed countries. It is a slowly evolving lifespan disease that progressively affects cardiac conduction, leading ultimately to pacemaker implantation to prevent the risk of complete atrioventricular block and Stokes-Adams syncope. There is no available pharmacological treatment to prevent the progression of the disease. There is thus a need to understand perfectly the pathophysiological mechanisms of the disease and to identify molecular targets involved in its early phases. There is also a need to identify prognostic biomarkers because patients at risk of developing high degree atrioventricular block are uneasy to identify.
We previously identified SCN5A as the first gene associated to PCCD and shown that mutations lead to a loss of function of SCN5A gene product, the cardiac sodium channel Nav1.5. To understand the pathophysiology of PCCD, we studied a Scn5a heterozygous knockout (Scn5a+/-) mouse model and showed that this model exhibits an age-related deterioration in conduction due to progressive occurrence of fibrosis. Scn5a+/- mice represent a unique model to elucidate PCCD pathophysiological mechanisms and identify molecular targets for developing selective preventive treatments, identify biomarkers for diagnosis and prognosis, and test preventive pharmacological treatments.
In this context, the objectives of the PreventPCCD project are to:
1. identify the molecular and cellular mechanisms of fibrotic remodelling in Scn5a+/- mice in order to propose putative specific targets for developing a selective preventive therapy of PCCD;
2. evaluate the potential of Magnetic Resonance Imaging (MRI) to detect development of fibrosis in Scn5a+/- mice in order to propose it as a tool for early detection of fibrosis in PCCD patients;
3. discover early circulating biomarkers of the severity of fibrotic remodelling in Scn5a+/- mice that can be easily evaluated in a clinical context;
4. evaluate the potential of Renin-Angiotensin-Aldosterone System (RAAS) inhibitors to prevent fibrosis development.
This project, which combines basic research in cell and mouse models, molecular, biochemical and functional analyses in vitro and in vivo, as well as complementary competences in electrophysiology, investigation of contractile activity, and imaging, should lead to rapid clinical applications. We expect to identify at least one putative target for developing a preventive therapy and one circulating biomarker. We also expect to validate MRI as a PCCD diagnostic tool.