Reduced left atrial cardiomyocyte PITX2 and elevated circulating BMP10 predict atrial fibrillation after ablation

Background: Genomic and experimental studies suggest a role for PITX2 in atrial fibrillation (AF). To assess whether 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 (LAA) 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 bone morphogenetic protein 10 (BMP10) as a PITX2-repressed, atrial-specific, secreted protein. BMP10 plasma concentrations were combined with eleven cardiovascular biomarkers and clinical parameters to predict recurrent AF after catheter ablation in 359 patients. Results: Reduced cardiomyocyte PITX2 concentrations, but not whole LAA tissue PITX2, were associated with AF recurrence after thoracoscopic AF ablation (16% decreased recurrence per 2-(deltadeltaCt) increase in PITX2). RNA sequencing, qPCR and Western blotting confirmed BMP10 as one of most PITX2-repressed atrial genes. Left atrial size (hazard ratio per mm increase, HR [95%CI] 1.055 [1.028, 1.082], non-paroxysmal 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 eleven 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. Left atrial tissue samples from WT and Pitx2+/- mice背景：基因组学与实验研究表明，配对样同源盒转录因子2（PITX2）在心房颤动（AF）中发挥调控作用。为评估该关联是否与患者的复发性心房颤动相关，我们探究了左心房PITX2是否会影响心房颤动消融术后的复发性AF。 方法：我们对接受胸腔镜AF消融术患者的左心耳（LAA）样本中的PITX2及其心脏亚型PITX2c的mRNA浓度进行了定量分析，分别检测了完整左心耳组织（n=83）与左心耳心肌细胞（n=52）的样本，并结合临床参数构建预测模型以评估AF复发风险。已有文献证实，骨形态发生蛋白10（BMP10）是受PITX2抑制的心房特异性分泌蛋白。我们将BMP10血浆浓度与11种心血管生物标志物及临床参数相结合，在359例患者中预测导管消融术后的复发性AF。 结果：仅左心耳心肌细胞中PITX2浓度降低（而非完整左心耳组织的PITX2水平）与胸腔镜AF消融术后的AF复发显著相关（PITX2的2-ΔΔCt值每升高1，复发风险降低16%）。RNA测序、实时定量聚合酶链反应（qPCR）与蛋白质印迹法（Western blotting）实验证实，BMP10是受PITX2抑制程度最高的心房基因之一。左心房内径（每毫米增加对应的风险比[95%置信区间]：HR 1.055 [1.028, 1.082]）、非阵发性AF（HR 1.672 [1.206, 2.318]）以及血浆BMP10浓度升高（每四分位数升高对应的HR 1.339 [1.159, 1.546]）均可有效预测复发性AF。且在11种心血管生物标志物中，BMP10的预测性能最优。 结论：左心房心肌细胞中PITX2表达降低，以及受PITX2抑制的分泌型心房蛋白BMP10的血浆浓度升高，可有效识别消融术后存在复发性AF风险的患者。野生型（WT）与Pitx2+/-小鼠的左心房组织样本