Abstract 2894: Cardiac Mast Cells Cause Atrial Fibrillation Through PDGF-A-mediated Atrial Fibrosis in Pressure-overloaded Hearts
Background: Atrial fibrillation (AF), the most common arrhythmia encountered in clinical practice, is associated with increased morbidity and mortality worldwide. Several cardiovascular disorders predispose to AF, and hypertension with left ventricular hypertrophy is one of the most important risk factors for AF. Recently, AF is considered as an inflammatory disorder, however the underlying mechanism how inflammatory cells contribute to AF pathogenesis remains unclear.
Methods and Results: We established an experimental model to evaluate the AF inducibility. Pressure overload induced by transverse aortic constriction (TAC) operation promoted atrial fibrosis and infiltration of mast cells to the atrium. We applied electrical stimulation to TAC-operated hearts under Langendorff perfusion to evoke AF, and we recorded the frequency and duration of the induced AF. AF could be easily evoked in TAC-operated heart. Interestingly, the atrial remodeling and AF inducibility were prominently suppressed in mice administered with mast cell stabilizer cromolyn and in mice reconstituted with bone marrow cells from mast cell-deficient WBB6F1-KitW/W-v mice after TAC. Notably, the expression of platelet-derived growth factor A (PDGF-A) was remarkably increased in TAC-operated WT atirum, while it was unchanged in the atrium of mice reconstituted with bone marrow cells from WBB6F1-KitW/W-v mice. In vitro, bone marrow-derived mast cells (BMMC) co-cultured with cardiac fibroblasts augmented the synthesis and the release of PDGF-A. Concurrently, the proliferation and collagen gene expression of cardiac fibroblasts were also promoted after co-culture, while the administration of cromolyn and PDGFα-receptor neutralization antibody abolished these processes. Furthermore, intra-peritoneal administration of PDGFα-receptor neutralization antibody suppressed the atrial remodeling and AF events in TAC-operated mice.
Conclusion: This study demonstrates that mast cells, key participants of allergic and immune response, contribute to the pathogenesis of AF in murine pressure-overload hearts. It also highlights a potential application of controlling the mast cell-PDGF-A axis to achieve upstream prevention of AF in stressed hearts.