Reduced left atrial cardiomyocyte PITX2 and elevated circulating BMP10 predict atrial fibrillation after ablation
Jasmeet S. Reyat, Winnie Chua, Victor R. Cardoso, Anika Witten, Peter M. Kastner, S. Nashitha Kabir, Moritz F. Sinner, Robin Wesselink, Andrew P. Holmes, Davor Pavlovic, Monika Stoll, Stefan Kääb, Georgios V. Gkoutos, Joris R. de Groot, Paulus Kirchhof, Larissa Fabritz
Jasmeet S. Reyat, Winnie Chua, Victor R. Cardoso, Anika Witten, Peter M. Kastner, S. Nashitha Kabir, Moritz F. Sinner, Robin Wesselink, Andrew P. Holmes, Davor Pavlovic, Monika Stoll, Stefan Kääb, Georgios V. Gkoutos, Joris R. de Groot, Paulus Kirchhof, Larissa Fabritz
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Clinical Research and Public Health Cardiology

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–(ΔΔCt) 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.TRIAL REGISTRATION ClinicalTrials.gov NCT01091389, NL50069.018.14, Dutch National Registry of Clinical Research Projects EK494-16.FUNDING British Heart Foundation, European Union (H2020), Leducq Foundation.

Authors

Jasmeet S. Reyat, Winnie Chua, Victor R. Cardoso, Anika Witten, Peter M. Kastner, S. Nashitha Kabir, Moritz F. Sinner, Robin Wesselink, Andrew P. Holmes, Davor Pavlovic, Monika Stoll, Stefan Kääb, Georgios V. Gkoutos, Joris R. de Groot, Paulus Kirchhof, Larissa Fabritz

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Figure 6

Increased BMP10 predicts recurrent atrial fibrillation in 359 patients after catheter ablation.

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Increased BMP10 predicts recurrent atrial fibrillation in 359 patients a...
(A) By univariate analysis, BMP10 confers the highest relative risk for recurrent AF among 11 other common cardiovascular biomarkers after adjustment for age, sex, type of AF, and left atrial diameter. (B) BMP10 levels are significantly elevated in patients with recurrent AF. (C) In multivariate analysis, increased left atrial (LA) size, nonparoxysmal type of AF, and elevated BMP10 predict recurrent AF. (D) When patients were stratified into quartiles based on BMP10 concentration, the largest proportion of patients with recurrent AF were in the highest BMP10 quartile. The numbers of patients that experienced recurrent AF in the respective quartiles are shown. (E) Stratification of patients by BMP10 quartiles corresponds with their rhythm outcome up to 2 years follow-up, with the worst outcomes in patients in the highest quartile (Q4). ANG2, angiopoietin 2; CRP, high-sensitivity C-reactive protein; CA125, cancer antigen 125; ESM1, endothelial cell–specific molecule 1; FABP3, fatty acid binding protein 3; GDF15, growth differentiation factor 15; IGFBP7, insulin like growth factor binding protein 7; TnT, high-sensitivity cardiac troponin T.