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

  1. LC Sommerfeld
  2. J Schrapers
  3. KF Müller
  4. L Bravo
  5. B Siebels
  6. AMS Vermeer-Stoter
  7. B Pan
  8. G Höppner
  9. C O’Shea
  10. J Ridder
  11. H Wieboldt
  12. P Sander
  13. T Zeller
  14. W Chua
  15. Y Purmah
  16. RS Gardner
  17. NR Tucker
  18. P Kirchhof
  19. MN Hirt
  20. T Eschenhagen
  21. J Stenzig
  22. L Fabritz
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Abstract

Background

Bone morphogenetic protein 10 (BMP10) is a ligand of the TGFβ 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 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 increase BMP10 expression and release, and BMP10 blood concentrations are higher in patients with current AF than in AF patients in sinus rhythm. High BMP10 concentrations induce expression of AF- and heart failure-related transcript networks in ventricular EHT. These findings support a role of BMP10 as a biomarker for AF and identify BMP10 as a potential player in AF-induced remodeling and tachycardiomyopathy.

Clinical perspective

What is known?

  • Bone morphogenetic protein 10 (BMP10) is a secreted member of the TGFβ-superfamily that is expressed in the heart.

  • Elevated blood cof BMP10 are associated with AF, recurrent AF, and with AF-related complications such as stroke.

What the study adds

  • High atrial rates lead to BMP10 release from engineered atrial cardiac tissue.

  • BMP10 activates cardiac expression of genes associated with AF and heart failure including PITX2 and NPPB .

  • BMP10 can play a role as a contributor to atrial cardiomyopathy and potentially to AF-induced ventricular dysfunction, specifically tachyarrhythmia-induced cardiomyopathy.

Abstract Figure

Graphical abstract:

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

BMP10: bone morphogenetic protein 10; EHT: engineered heart tissue. Created in https://BioRender.com .

Article activity feed

  1. Version published to 10.1101/2025.02.24.25322820v1 on medRxiv