High Rate Triggers Increased Atrial Release of BMP10, A Biomarker for Atrial Fibrillation and Stroke, and BMP10 Affects Ventricular Cardiomyocytes

BACKGROUND: BMP10 (bone morphogenetic protein 10) is a ligand of the TGF (transforming growth factor) β 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 the downstream effects of BMP10 in cardiomyocytes are poorly understood. We assessed BMP10 secretion dynamics and BMP10 effects in a human 3-dimensional model of atrial and ventricular engineered heart tissue (EHT). METHODS: Cardiomyocytes (atrial and ventricular) differentiated from human induced pluripotent stem cells 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 hours up to 15 days. Release of BMP10 and other cardiac biomarkers from EHT was quantified. BMP10 plasma concentrations were compared between 1370 patients with different atrial rhythms at blood draw. Additionally, ventricular EHTs were exposed to BMP10 for 10 days. RESULTS: Atrial but not ventricular EHT released BMP10 within 48 hours of culture. High-rate optogenetic pacing increased atrial EHT BMP10 release by ≈3-fold after a latency of at least 24 hours post initiation of pacing. BMP10 plasma concentrations were elevated in patients with documented AF compared with sinus rhythm and even higher in patients with current AF. BMP10 induced upregulation of TGFβ 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.