What is the clinical evidence from this study?

Study design: Cohort. Population: Atrial fibrillation (n=359). Intervention: Elevated circulating BMP10 vs. Lower circulating BMP10. Primary outcome: Recurrent atrial fibrillation after ablation (HR 1.339, 95% CI 1.159-1.546, p=<0.001).

August 19, 2020Open Access

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

Q: What are the key findings of this study?

Elevated plasma concentrations of BMP10 predicted recurrent atrial fibrillation after catheter ablation, with a 34% increased risk per quartile increase (HR 1.339).

Key Result

Elevated plasma concentrations of BMP10 predicted recurrent atrial fibrillation after catheter ablation, with a 34% increased risk per quartile increase (HR 1.339).

Study Design

Type

Cohort (n=359)

Multicenter

Yes

Structured PICO

Do left atrial cardiomyocyte PITX2 and plasma BMP10 concentrations predict recurrent atrial fibrillation in patients undergoing AF ablation?

Population

359 patients with atrial fibrillation undergoing catheter ablation, followed for a median of approximately 1 year to assess arrhythmia recurrence.

Exposure

Measurement of left atrial cardiomyocyte PITX2 mRNA concentrations and plasma BMP10 concentrations

Outcome

Recurrent atrial fibrillation after ablation

Reduced left atrial cardiomyocyte PITX2 and elevated plasma BMP10 are novel biomarkers that predict the risk of recurrent atrial fibrillation after ablation.

Main Result

Hazard Ratio: 1.339 (95% CI 1.159–1.546)

p-value: p=<0.001

Limitations

Relatively small cohorts for multivariate analysis
Further experiments (e.g., ChIP-Seq or ATAC-Seq) are warranted to demonstrate directly that BMP10 is controlled by PITX2
Further studies in independent patient datasets are warranted to confirm findings
Did not address whether common gene variants on chromosome 4q25 regulate PITX2

Abstract

BACKGROUNDGenomic 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.METHODSmRNA 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.RESULTSReduced 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.CONCLUSIONSReduced 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 REGISTRATIONClinicalTrials.gov NCT01091389, NL50069.018.14, Dutch National Registry of Clinical Research Projects EK494-16.FUNDINGBritish Heart Foundation, European Union (H2020), Leducq Foundation.

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