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

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).

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.

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.

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. 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. Competing Interest Statement There is no direct competing interest, but we declare the following interests: LF received institutional research grants by EU 633196 [CATCH ME] and EU 965286 [MAESTRIA]. British Heart Foundation (AA/18/2/34218), German Center for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK), Medical Research Council (UK), NIHR and several biomedical companies active in the field of research. LF is listed as inventor on two issued patents held by the employing institution (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). PK received research support for basic, translational, and clinical research projects from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), Else-Kröner-Fresenius-Stiftung, Dutch Heart Foundation and German Center for Cardiovascular Research, from several drug and device companies active in atrial fibrillation and has received honoraria from several such companies in the past, but not in the last three years. PK is listed as inventor on two issued patents held by the employing institution (Atrial Fibrillation Therapy WO 2015140571 Clinical Trial Birmingham-Black Country-Atrial Fibrillation registry, IRAS ID: 97753 Funding Statement Cofunded by UKE starter grant to LF and PK, by EU [CATCH-ME] to LF and PK, EU 965286 [MAESTRIA] to LF, British Heart Foundation Accelarator Award (AA/18/2/34218) to University of Birmingham, Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK, German Center for Cardiovascular Research) supported by the German Ministry of Education and Research, including a postdoc start-up grant to LCS; German Research Foundation (Ki 509167694, STE2596/2-1, STE2596/4-1, STE2596/5-1, INST 337/15-1, INST 337/16-1, INST 152/837-1 and INST 152/947-1 FUGG). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Health Research Authority (HRA), United Kingdom I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Data will be shared upon reasonable request to the corresponding author. Non-standard abbreviations and acronyms - BMP10 - bone morphogenetic protein 10 - EHT - engineered heart tissue