High rate triggers increased atrial release of BMP10, a biomarker for atrial fibrillation and stroke, and BMP10 affects ventricular cardiomyocytes

Background Bone morphogenetic protein 10 (BMP10) is a ligand of the TGFß superfamily secreted mainly by atrial cardiomyocytes. Elevated BMP10 blood concentrations predict atrial fibrillation (AF), AF recurrence after ablation and AF-related cardiovascular complications like stroke. The conditions increasing BMP10 secretion and downstream effects of BMP10 in cardiomyocytes are poorly understood. We assessed BMP10 secretion dynamics and BMP10 effects in a human 3D model of atrial and ventricular engineered heart tissue (EHT). Methods Cardiomyocytes differentiated from human induced pluripotent stem cells (atrial and ventricular) were cast into a fibrin-matrix to generate EHT. Atrial EHTs were optogenetically paced (3-5 Hz) or maintained at intrinsic beating rate for 24 h up to 15 days. Release of BMP10 and other cardiac biomarkers from EHT were quantified. BMP10 plasma concentrations were compared between 1370 patients in different atrial rhythm at blood draw. Additionally, ventricular EHTs were exposed to BMP10 for 10 days. Results Atrial but not ventricular EHT released BMP10 within 48 h of culture. High rate optogenetic pacing increased atrial EHT BMP10 release by ~3-fold after a latency of at least 24 h post pacing initiation. BMP10 plasma concentrations were elevated in patients with documented AF compared to sinus rhythm and even higher in patients with current AF. BMP10 induced upregulation of TGFß pathway transcripts, increased expression of genes related to AF and heart failure, including PITX2 and NPPB, and increased relative contraction times in ventricular EHTs. Conclusions High atrial rates elevate BMP10 expression and release, and higher plasma concentrations of BMP10 are observed in patients with active AF. BMP10 exposure induces transcriptomic changes linked to AF and heart failure in ventricular EHT. These findings support BMP10 as a biomarker and potential mediator of AF-related remodeling and tachycardiomyopathy. Overall design: Effects of BMP10 on ventricular EHT (vEHT) were assessed by longer-term (10 days) exposure of vEHT to recombinant human BMP10 (rhBMP10, 2926-BP-025, R&D Systems, Minneapolis, USA) dissolved in water containing 0.1% bovine serum albumin and 4 mM HCl (vehicle). RNA was harvested and subjected to RNAseq.