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 2

Expression of PITX2 or PITX2c in whole left atrial tissue does not predict recurrent atrial fibrillation.

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Expression of PITX2 or PITX2c in whole left atrial tissue does not predi...
Left atrial appendage samples were digested and assessed for levels of PITX2 (A; PITX2 median [Q1, Q3] 8.67 [3.90, 16.78]) and PITX2c (B; 0.47 [0.16, 1.20]) using qPCR. Results are expressed as an average normalized to 2 housekeeping genes (GAPDH and POLR2A) (n = 94). Expression levels of PITX2 (C; PITX2 No AF Rec 7.81 [3.96, 16.72]), Rec AF 11.28 [3.70, 16.96]; P = 0.704) and PITX2c (D; PITX2c No AF Rec 0.44 [0.18, 1.19], Rec AF 0.53 [0.16, 1.50]; P = 0.543) were stratified by clinical outcomes of having recurrent AF within 1 year after ablation surgery. AF Rec, patients with recurrent AF, n = 23; No AF Rec, patients without recurrent AF, n = 71. (E) Example biopsies of left atrial appendage tissue, highlighting tissue heterogeneity. Scale bar: 10 mm.