Neuregulin-1 as a therapy for atrial fibrillation and the role of the NRG-1/ErbB4 system in atrial remodelling.

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and one of the most common causes of stroke and heart failure. AF is induced by electrical, contractile, and structural remodeling of the atria. Moreover, AF itself induces these changes, leading to a vicious circle ("AF begets AF"). Tissue inflammation and fibrosis play an important role in the structural changes, and form the basis of subsequent electrical and contractile atrial dysfunction. Current therapy is limited to rhythm control using antiarrhythmic drugs, but these drugs do not target the structural problem. That may explain why they are only marginally effective. Ablation by electrical isolation of the pulmonary veins (PVI) has broadened the medical opportunities, but it is also unsatisfactory since it addresses only part of the atria. This explains the high relapse rate in patients with more widespread atrial disease (and more persistent forms of AF). More extensive ablations have not shown better results, as can be anticipated by the fact that more destruction will not solve a primarily structural problem. There is a clear medical need for a treatment targeting the underlying pathophysiology leading to structural atrial remodeling. In this project, we will test the hypothesis that the neuregulin-1 (NRG-1)/ErbB pathway is an inhibitory pathway in development of atrial fibrillation. NRG-1 is a member of the epidermal growth factor family that binds to tyrosine kinase receptors and has cell protective and regenerative properties in the heart during heart failure. We recently discovered that NRG-1 has anti-inflammatory and anti-fibrotic properties in different organs, including the heart. As mentioned, fibrosis and inflammation are the main features of structural atrial remodeling present in AF. We hypothesize that (1) the endothelium-derived NRG-1 – ErbB4 system is activated in atrial tissue of patients with atrial fibrillation. We will harvest atrial tissue samples during cardiac surgery procedures from patients with and without AF and determine expression of NRG-1 and its receptors by histology. We will determine (2) whether NRG-1 attenuates atrial fibrosis and atrial fibrillation in two mouse models of atrial fibrillation. For this aim we will use transgenic mouse models that spontaneously develop atrial fibrosis and AF. We will treat these mice with different doses of NRG-1, continuously monitor cardiac rhythm and function, and evaluate histological changes in atria after 4 weeks of treatment. We will (3) develop a sterile pericarditis large animal model of AF in pigs. We will fully characterize reprogramming of different atrial cell types by RNA sequencing. Finally, we will determine (4) whether NRG-1 attenuates atrial fibrosis and atrial fibrillation in these pigs. If successful, this project could open new avenues for treatment of atrial fibrillation by addressing atrial tissue remodeling.

Keywords:ATRIAL FIBRILLATION, NEUREGULIN-1, ENDOTHELIUM

Disciplines:Cardiology, Vascular diseases