Decoupling mitral valve-left ventricular fibrotic remodeling in degenerative mitral regurgitation via serotonin 2B receptor

PROJECT SUMMARY/ABSTRACT Mitral regurgitation (MR) is one of the most prevalent heart valve diseases. If left untreated, patients will experience left ventricle (LV) structural and functional alterations. These include chronic increases in wall stress and changes in cellular and extracellular matrix response that leads to progressive LV hypertrophy and fibrosis, leading to atrial fibrillation (AFib), heart failure, and death. The only effective, long-term treatment for MR remains valve repair or replacement. Minimally invasive mitral valve (MV) repair and percutaneous MV replacement are becoming stronger alternatives to open-chest, MV replacement surgery; however, they are not indicated for all patients, may result in MR recurrence, or have limited durability. Thus, there is a pressing need to develop a therapeutic pharmacological alternative to surgery. Furthermore, there is a need for MV-specific therapies that also address MR-mediated LV dysfunction. Serotonin 2B receptor (5-HT2B) signaling impacts both MV and LV remodeling; however, the interdependence between the mitral valve interstitial cell (MVIC) and cardiac fibroblast (CF) populations remains unknown. Given our ability to selectively remove 5-HT2B from MVICs and/or CFs, we possess the tools to decouple, for the first time, 5-HT2B-mediated MV dysfunction from LV remodeling both in murine models, as well as in human-derived MVICs and CFs. Additionally, our recent development of novel 5- HT2B antagonists that are unable to cross the blood-brain-barrier provides the first treatment option for targeting this pathway for human disease. These studies will result in clarification on the causal role of 5-HT2B in MV disease, while also examining the down-stream role of the receptor in MV-mediated LV dysfunction. We believe that due to the dual citizenship of the 5-HT2B receptor on the MVICs and CFs, which is unique to these cell types vs other valve and heart cells, this strategy can provide a ‘two-hit’ therapy for MV-LV disease, which encompasses nearly all patients with MR.