Inhibition of platelet-derived growth factor-AB signaling prevents electromechanical remodeling of adult atrial myocytes that contact myofibroblasts

BackgroundPersistent atrial fibrillation (PAF) results in electromechanical and structural remodeling by mechanisms that are poorly understood. Myofibroblast proliferation and fibrosis are major sources of structural remodeling in PAF. Myofibroblasts also interact with atrial myocytes via direct physical contact and release of signaling molecules, which may contribute to remodeling.ObjectiveTo determine whether myofibroblasts contribute to atrial myocyte electromechanical remodeling via direct physical contact and platelet-derived growth factor (PDGF) signaling.MethodsMyofibroblasts and myocytes from adult sheep atria were co-cultured for 24 hours. Alternatively adult sheep atrial myocytes were exposed to 1ng/mL recombitant PDGF AB peptide for 24 hours.ResultsMyocytes making contact with myofibroblasts demonstrated significant reduction (P ≤ .05) in peak L-type calcium current density, shortening of action potential duration (APD), and reduction in calcium transients. These effects were blocked by pretreatment with a PDGF-AB neutralizing anti-body. Heterocellular contact also severely disturbed the localization of the L-type calcium channel. Myocytes exposed to recombinant PDGF-AB peptide for 24 hours demonstrated reduced APD50, APD80 and Peak L-type calcium current. Pretreatment with a PDGF-AB neutralizing antibody prevented these effects. Finally, while control atrial myocytes did not respond in a 1:1 manner to pacing frequencies of 3Hz or higher, atrial myocytes from hearts that were tachypaced for 2 months and normal myocytes treated with PDGF-AB for 24 hours could be paced up to 10Hz.ConclusionsIn addition to leading to fibrosis, atrial myofibroblasts contribute to electromechanical remodeling of myocytes via direct physical contact and release of PDGF-AB, which may be a factor in PAF-induced remodeling.