Bone Morphogenetic Protein 10-A Novel Biomarker to Predict Adverse Outcomes in Patients With Atrial Fibrillation

Abstract

Background Patients with atrial fibrillation (AF) face an increased risk of death and major adverse cardiovascular events (MACE). We aimed to assess the predictive value of the novel atrial-specific biomarker BMP10 (bone morphogenetic protein 10) for death and MACE in patients with AF in comparison with NT-proBNP (N-terminal prohormone of B-type natriuretic peptide). Methods and Results BMP10 and NT-proBNP were measured in patients with AF enrolled in Swiss-AF (Swiss Atrial Fibrillation Study), a prospective multicenter cohort study. A total of 2219 patients were included (median follow-up 4.3 years [interquartile range 3.9, 5.1], mean age 73±9 years, 73% male). In multivariable Cox proportional hazard models, the adjusted hazard ratio (aHR) associated with 1 ng/mL increase of BMP10 was 1.60 (95% CI, 1.37-1.87) for all-cause death, and 1.54 (95% CI, 1.35-1.76) for MACE. For all-cause death, the concordance index was 0.783 (95% CI, 0.763-0.809) for BMP10, 0.784 (95% CI, 0.765-0.810) for NT-proBNP, and 0.789 (95% CI, 0.771-0.815) for both biomarkers combined. For MACE, the concordance index was 0.732 (95% CI, 0.715-0.754) for BMP10, 0.747 (95% CI, 0.731-0.768) for NT-proBNP, and 0.750 (95% CI, 0.734-0.771) for both biomarkers combined. When grouping patients according to NT-proBNP categories (<300, 300-900, >900 ng/L), higher aHRs were observed in patients with high BMP10 in the categories of low NT-proBNP (all-cause death aHR, 2.28 [95% CI, 1.15-4.52], MACE aHR, 1.88 [95% CI, 1.07-3.28]) and high NT-proBNP (all-cause death aHR, 1.61 [95% CI, 1.14-2.26], MACE aHR, 1.38 [95% CI, 1.07-1.80]). Conclusions BMP10 strongly predicted all-cause death and MACE in patients with AF. BMP10 provided additional prognostic information in low- and high-risk patients according to NT-proBNP stratification. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02105844.

Keywords: BMP10; MACE; atrial fibrillation; bone morphogenetic protein 10; death.

Figure 1. Kaplan–Meier curves for the primary outcomes stratified by bone morphogenetic protein 10 (BMP10) quartiles.

Cumulative incidence per follow‐up years for all‐cause death (A) and major adverse cardiovascular events (MACE; B) stratified by BMP10 quartiles. MACE is a composite of heart failure hospitalization, cardiovascular death, stroke, systemic embolism, and myocardial infarction. P values were calculated by log‐rank test. BMP10 indicates bone morphogenetic protein 10.

Figure 2. Subgroup analysis for the primary outcomes.

Association of BMP10 (bone morphogenetic protein 10) with all‐cause death (A) and major adverse cardiovascular events (MACE; B) across various subgroups. Hazard ratio (HR) and 95% CIs for BMP10 were calculated using multivariable adjusted Cox proportional hazard models. AF indicates atrial fibrillation; and TIA, transient ischemic attack.

Figure 3. Receiver operating characteristic curves for the primary outcomes.

Area under the curve (AUC) and 95% CI for all‐cause death (A) and major adverse cardiovascular events (MACE; B) according to multivariable adjusted logistic regression models of BMP10 (bone morphogenetic protein 10), NT‐proBNP (N‐terminal prohormone of B‐type natriuretic peptide), and both biomarkers combined. MACE is a composite of heart failure hospitalization, cardiovascular death, stroke, systemic embolism, and myocardial infarction. *Multivariable models were adjusted for age, sex, body mass index, heart rate, systolic blood pressure, rhythm at baseline, current smoking, history of diabetes, coronary artery disease, hypertension, heart failure, stroke/transient ischemic attack, oral anticoagulation, antiplatelet therapy, and estimated glomerular filtration rate.

Figure 4. Kaplan–Meier curves for primary outcomes stratified by biomarker categories.

Cumulative incidence per follow‐up years for all‐cause death (A) and major adverse cardiovascular events (MACE; B) stratified by NT‐proBNP (N‐terminal prohormone of B‐type natriuretic peptide) and BMP10 (bone morphogenetic protein 10) categories. MACE is a composite of heart failure hospitalization, cardiovascular death, stroke, systemic embolism, and myocardial infarction. NT‐proBNP categories: low (<300 ng/L), intermediate (300–900 ng/L), high (>900 ng/L). BMP10 categories according to median: low (<2.247 ng/mL), high (≥2.247 ng/mL). P values were calculated by log‐rank test.