@article{51bf0f9dcdc141779bb8df83861f2190,
title = "Reduced left atrial cardiomyocyte PITX2 and elevated circulating BMP10 predict atrial fibrillation after ablation",
abstract = "BACKGROUND. Genomic and experimental studies suggest a role for PITX2 in atrial fibrillation (AF). To assess if this association is relevant for recurrent AF in patients, we tested whether left atrial PITX2 affects recurrent AF after AF ablation.METHODS. mRNA concentrations of PITX2 and its cardiac isoform, PITX2c, were quantified in left atrial appendages (LAAs) from patients undergoing thoracoscopic AF ablation, either in whole LAA tissue (n = 83) or in LAA cardiomyocytes (n = 52), and combined with clinical parameters to predict AF recurrence. Literature suggests that BMP10 is a PITX2-repressed, atrial-specific, secreted protein. BMP10 plasma concentrations were combined with 11 cardiovascular biomarkers and clinical parameters to predict recurrent AF after catheter ablation in 359 patients.RESULTS. Reduced concentrations of cardiomyocyte PITX2, but not whole LAA tissue PITX2, were associated with AF recurrence after thoracoscopic AF ablation (16% decreased recurrence per 2(-(Delta Delta Ct)) increase in PITX2). RNA sequencing, quantitative PCR, and Western blotting confirmed that BMP10 is one of the most PITX2-repressed atrial genes. Left atrial size (HR per mm increase [95% CI], 1.055 [1.028, 1.082]); nonparoxysmal AF (HR 1.672 [1.206, 2.318]), and elevated BMP10 (HR 1.339 [CI 1.159, 1.546] per quartile increase) were predictive of recurrent AF. BMP10 outperformed 11 other cardiovascular biomarkers in predicting recurrent AF.CONCLUSIONS. Reduced left atrial cardiomyocyte PITX2 and elevated plasma concentrations of the PITX2-repressed, secreted atrial protein BMP10 identify patients at risk of recurrent AF after ablation.",
keywords = "LEFT-RIGHT ASYMMETRY, RADIOFREQUENCY ABLATION, NATRIURETIC PEPTIDE, SHORT-TERM, RECURRENCE, RISK, VARIANTS, 4Q25, AMIODARONE, EXPRESSION",
author = "Reyat, {Jasmeet S.} and Winnie Chua and Cardoso, {Victor R.} and Anika Witten and Kastner, {Peter M.} and Kabir, {S. Nashitha} and Sinner, {Moritz F.} and Robin Wesselink and Holmes, {Andrew P.} and Davor Pavlovic and Monika Stoll and Stefan Kaeaeb and Georgios Gkoutos and {de Groot}, {Joris R.} and Paulus Kirchhof and Larissa Fabritz",
note = "Funding Information: We would like to acknowledge Matthew C. Hill (Baylor College of Medicine, Houston, Texas, USA) for input on cardiomyocyte isolation protocols, Samantha P. Tull and Marcel Kemper (University of Birmingham) for help with preparation of samples, and Nigel Brown for providing Pitx2c+/–mice. We would like to thank Andr{\'e} Ziegler (Roche Diagnostics International) for his contribution to biomarker quantification. In addition, we would like to thank the Translational Research on Heart Failure and Arrhythmias Cluster for useful insights and thoughtful discussions on the manuscript. This work was partially supported by the European Union (grant agreement 633196 [CATCH ME] to PK and LF), European Union BigDa-ta@Heart (grant agreement EU IMI 116074), British Heart Foundation (FS/13/43/30324 to PK and LF; PG/17/30/32961 to PK and APH; AA/18/2/34218 to PK and LF; PG/17/55/33087, RG/17/15/33106, FS/19/12/34204, and FS/19/16/34169 to DP and PK), German Centre for Cardiovascular Research supported by the DZHK (via a grant to AFNET to PK), and a Foundation Leducq Transatlantic Networks of Excellence in Cardiovascular Research grant (14CVD01 to PK). Funding Information: We would like to acknowledge Matthew C. Hill (Baylor College of Medicine, Houston, Texas, USA) for input on cardiomyocyte isolation protocols, Samantha P. Tull and Marcel Kemper (University of Birmingham) for help with preparation of samples, and Nigel Brown for providing Pitx2c+/? mice. We would like to thank Andr? Ziegler (Roche Diagnostics International) for his contribution to biomarker quantification. In addition, we would like to thank the Translational Research on Heart Failure and Arrhythmias Cluster for useful insights and thoughtful discussions on the manuscript. This work was partially supported by the European Union (grant agreement 633196 [CATCH ME] to PK and LF), European Union BigData@Heart (grant agreement EU IMI 116074), British Heart Foundation (FS/13/43/30324 to PK and LF; PG/17/30/32961 to PK and APH; AA/18/2/34218 to PK and LF; PG/17/55/33087, RG/17/15/33106, FS/19/12/34204, and FS/19/16/34169 to DP and PK), German Centre for Cardiovascular Research supported by the DZHK (via a grant to AFNET to PK), and a Foundation Leducq Transatlantic Networks of Excellence in Cardiovascular Research grant (14CVD01 to PK). Funding Information: Conflict of interest: MS, MFS, SK, LF, and PK received support from the European Union CATCH ME. JRDG reports grants from Atricure Inc., Boston Scientific, Abbott, and Medtronic; personal fees from Atricure Inc., Bayer, Daiichi Sankyo, Servier, Johnson & Johnson, Medtronic, and Novartis. PK and LF receive research support for basic, translational, and clinical research projects from the British Heart Foundation, Leducq Foundation, Medical Research Council (United Kingdom), and German Centre for Cardiovascular Research; and from several drug and device companies active in atrial fibrillation. PK has previously received honoraria from several such companies. PK and LF are listed as inventors on 2 patents held by the University of Birmingham (“Atrial fibrillation therapy,” WO 2015140571; “Markers for atrial fibrillation,” WO 2016012783). Publisher Copyright: Copyright: {\textcopyright} 2020, Reyat et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",
year = "2020",
month = aug,
day = "20",
doi = "10.1172/jci.insight.139179",
language = "English",
volume = "5",
journal = "JCI INSIGHT",
issn = "2379-3708",
publisher = "American Society for Clinical Investigation",
number = "16",
}