Bone Morphogenetic Protein 10 Research Articles

Abstract 4136316: BMP10 as novel marker for right atrial dilatation and pressure in precapillary pulmonary hypertension

Introduction: Precapillary pulmonary hypertension (precPH) leads to increased right atrial (RA) stretch and pressure. The right atrium is the major source of bone morphogenetic protein 10 (BMP10) in adults. Aim: This study aims to investigate BMP10 in relation to RA dilatation and pressure overload. Methods: We studied BMP10 mRNA in fresh RA tissue of N=5 Chronic Thromboembolic Pulmonary Hypertension (CTEPH) patients and N=9 controls and protein expression in paraffin-embedded RA tissue of N=4 Pulmonary Arterial Hypertension (PAH) patients and N=6 controls. We prospectively included 48 precPH patients (N=22 idiopathic PAH, N=14 hereditary PAH and N=12 CTEPH, and N=16 controls. To study BMP10-induced transcriptional activity, we assayed serum samples in human microvascular endothelial cells (HMEC) with a BMP-responsive transcriptional luciferase assay. BMP10 activity was calculated by subtracting BMP activity after incubation with antibodies for Alk1Fc and bone morphogenetic protein 9 (BMP9). We assessed correlations between BMP10 activity and RA dilatation (RA max volume>79 ml/m 2 for male or >69 ml/m 2 for female) and right ventricular (RV) dilatation (RV end-diastolic volume>108 ml/m 2 for male and >96 ml/m 2 for female). In a cohort of CTEPH patients that underwent pulmonary endarterectomy (PEA) we assessed the effect of pressure unloading on BMP10 activity. Normality of data was checked and statistical differences between groups were tested using an independent sample t-test or Wilcoxon rank-sum test. Results: BMP10 mRNA, protein and downstream activity were higher in the precPH RA tissue (Figure 1A-F). High systemic BMP10 activity was associated with RA dilatation and high RA pressure, but not RV dilatation in precPH (Figure 2A-C). Finally, pressure unloading after PEA in CTEPH patients results in a reduction in BMP10 activity (figure 2D). Conclusions: Local RA BMP10 expression and activity is increased in precPH. Increased systemic BMP10 activity was related to RA dilatation and pressure. Pressure unloading of the right heart leads to a reduction of systemic BMP10 activity. Future studies are needed to determine whether increased BMP10 release is an adaptative mechanism or can be used as therapeutic target.

Assessment of experimental circulating biomarkers in volume and pressure overload: insights from a cohort study

Abstract Introduction Experimental biomarkers including Angiopoietin-2 (ANG2), bone morphogenetic protein 10 (BMP10), fibroblast growth factor 23 (FGF23), and insulin-like growth factor-binding protein 7 (IGFBP7) are hypothesized to reflect cardiac pathophysiological processes that are potentially present in adverse cardiac remodeling in volume or pressure overload. This study aims to elucidate the relationship between these circulating biomarkers and the presence of hemodynamically significant pressure or volume overload and adverse outcomes and compare it to N-terminal pro B-type natriuretic peptide (NT-proBNP). Methods We studied the association between the four experimental circulating biomarkers in patients with pressure or volume overload with reference to none/mild valvular disease in N=1302 of an observational outpatient cardiology cohort. The median age was 63.0 (25th/75th quartile 51.5, 71.4) years, 445 (34.2%) were women. Circulating biomarkers were quantified using a novel antibody-based method. Logistic regression models with cox regression plots were employed to assess the association of each biomarker with the severity of valve disease concerning volume or pressure overload, adjusted for age and sex. Results In the overall population, elevated levels of ANG2, BMP10, FGF23 and IGFB7 were positively associated with the presence of significant volume overload (ANG2: Odds ratio (OR) 1.26 (95% confidence interval (CI) 1.17-1.35), p<0.001; BMP10: OR 2.57 (CI 1.89-3.48), p<0.001; FGF23: OR 1.51 (CI 1.14-1.20), p=0.004; IGFBP7: OR 1.39 (CI 1.14-1.69), p=0.001, NT-proBNP: OR 1.69 (CI 1.47-1.95), p<0.001). No statistically significant association between circulating biomarkers and pressure overload was observed. Over a median follow-up of 4 years, 31 (20.1%) participants died in the group of volume overload and 9 (40.9%) individuals in the group of pressure overload. After multivariable-adjustment, elevated levels of BMP 10 showed a borderline association with an increased risk of all-cause mortality in individuals with volume overload compared to none/mild valvular disease: hazard ratio (HR) 1.51 (CI 0.96- 2.38), p=0.075. Higher concentrations of all biomarkers were predictive of all-cause mortality for both individuals with volume overload and those with none/mild valvular disease (ANG2: HR 3.72 (CI 1.67-8.33), p=0.001; BMP10: HR 1.65 (CI 1.20-2.26), p=0.002; FGF23: HR 2.08 (CI 1.65-2.62), p<0.001; IGFBP7: HR 1.55 (CI 1.25-1.91), p<0.001; NT-proBNP: HR 1.72 (CI 1.47-2.00), p<0.001). Conclusions This study demonstrates that circulating biomarkers involved in distinct pathophysiological pathways of inflammation, fibrosis and calcification are elevated in patients with hemodynamically significant volume overload. Since they are also related to mortality, their clinical role needs to be explored further, also in context with the routine biomarker NT-proBNP.

Biomarker-based prediction of sinus rhythm in atrial fibrillation patients: the EAST-AFNET 4 biomolecule study.

In patients with atrial fibrillation (AF), recurrent AF and sinus rhythm during follow-up are determined by interactions between cardiovascular disease processes and rhythm-control therapy. Predictors of attaining sinus rhythm at follow-up are not well known. To quantify the interaction between cardiovascular disease processes and rhythm outcomes, 14 biomarkers reflecting AF-related cardiovascular disease processes in 1586 patients in the EAST-AFNET 4 biomolecule study (71 years old, 46% women) were quantified at baseline. Mixed logistic regression models including clinical features were constructed for each biomarker. Biomarkers were interrogated for interaction with early rhythm control. Outcome was sinus rhythm at 12 months. Results were validated at 24 months and in external datasets. Higher baseline concentrations of three biomarkers were independently associated with a lower chance of sinus rhythm at 12 months: angiopoietin 2 (ANGPT2) (odds ratio [OR] 0.76 [95% confidence interval 0.65-0.89], p=0.001), bone morphogenetic protein 10 (BMP10) (OR 0.83 [0.71-0.97], p=0.017) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (OR 0.73 [0.60-0.88], p=0.001). Analysis of rhythm at 24 months confirmed the results. Early rhythm control interacted with the predictive potential of NT-proBNP (pinteraction=0.033). The predictive effect of NT-proBNP was reduced in patients randomized to early rhythm control (usual care: OR 0.64 [0.51-0.80], p<0.001; early rhythm control: OR 0.90 [0.69-1.18], p=0.453). External validation confirmed that low concentrations of ANGPT2, BMP10 and NT-proBNP predict sinus rhythm during follow-up. Low concentrations of ANGPT2, BMP10 and NT-proBNP identify patients with AF who are likely to attain sinus rhythm during follow-up. The predictive ability of NT-proBNP is attenuated in patients receiving rhythm control.

Increased bone morphogenetic protein 10 in precapillary pulmonary hypertension patients

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Netherlands Organization for Scientific Research: NWO-VICI num. 918.16.610 and NWO-VIDI num. 917.18.338. Dutch Heart Foundation Dekker senior post-doc grant num. 2018T059 and the Netherlands CardioVascular Research Initiative: CVON-2017-10 DOLPHIN-GENESIS and CVON-2018-29 PHAEDRA-IMPACT. Fundació La Marató de TV3 num.202038. The Spanish Ministry of Science through the Ramón y Cajal grant num.RYC2021-030866-I. Introduction Precapillary pulmonary hypertension (PH) results in increased right atrial (RA) stretch and pressure. The right atrium is the major source of bone morphogenetic protein (BMP) 10 (BMP10) in adults, mostly produced by RA cardiomyocytes. The major predisposing risk factor for PH involves loss-of-function mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, through which BMP10 and BMP9 transduce signals. Purpose The aim of this study was to investigate if BMP10 expression is altered in PH, and whether BMP10 signaling activity associates with right ventricular (RV) adaptation, RA function and disease progression. Methods We investigated BMP10 gene and protein expressions in RA tissue. We determined BMP10 and BMP9 plasma levels by ELISA. We studied BMP10 signaling activity in PH and CTEPH patients before and after pulmonary endarterectomy (PEA). Results BMP10 mRNA, protein and activity were significantly increased in the PH right atrium. While circulating levels of BMP10 and BMP9 proteins were increased, no significant changes were observed in BMP10 signaling activity between PH and controls. In a cohort of CTEPH patients, BMP10 signaling activity was reduced after PEA which coincided with improved hemodynamics and RV function. Interestingly, high BMP10 activity was associated with reduced RV function and adaptation, increased RA dilation and decreased RA function. No associations were observed with hemodynamics or general disease markers. Conclusions RA BMP10 expression and plasma levels are increased in precapillary PH. High BMP10 transcriptional activity was associated with worse RV function, RV adaptation, RA dilation and RA function. Future studies are needed to further understand the mechanism underlying BMP10 secretion and function in PH.

Increased circulating BMP10 levels are associated with late postoperative atrial fibrillation after cardiac surgery and left atrial endomysial fibrosis

Abstract Background Serum bone morphogenetic protein 10 (BMP10) levels are a marker for history of atrial fibrillation (AF) and for major adverse cardiovascular events in AF-patients, including stroke, recurrence after catheter ablation, and mortality. The predictive value of BMP10 in patients undergoing cardiac surgery and association with morphological properties of atrial tissue are unknown. Objective To study the correlation between BMP10 levels and pre-operative clinical traits, occurrence of early and late postoperative atrial fibrillation (POAF), and atrial fibrosis in patients undergoing cardiac surgery. Methods Patients with and without preoperative AF history undergoing first cardiac surgery were included (RACE V, n=147). Pre-operative blood biomarkers were analyzed, left (n=114) and right (n=125) atrial appendage biopsies were histologically assessed following WGA-staining, and post-operative rhythm was monitored continuously with implantable loop recorders (n=134, 2.5yrs). Results Multiple logistic regression indicated that BMP10 accurately predicts a history of persistent AF (OR=1.24, 95%CI: 1.10-1.40, p=4.32e-4), similar to NT-pro-BNP. BMP10 levels were associated with increased late-POAF90 occurrence after adjusting for age, sex, AF history, and early-POAF occurrence (HR=1.07 [per 0.1ng/ml increase], 95%CI: 1.00-1.14, p=0.04). Left atrial endomysial fibrosis (St.β=0.22, p=0.04), but not overall fibrosis (St. β= , p=), was associated with circulating BMP10, after adjusting for age, sex, AF history, reduced LVF, and valvular surgery indication. Conclusion Increased BMP10 levels were associated with persistent AF-history, increased late-POAF incidence, and LAA endomysial fibrosis in a diverse population of patients undergoing cardiac surgery.

Clinical determinants of blood biomarkers of atrial cardiomyopathy: results from the ISOLATION AF ablation cohort study

Abstract Background In patients with atrial fibrillation (AF), significant advances have been made in identifying biomarkers representing diverse pathophysiological pathways, such as inflammation, myocyte injury, collagen deposition, and fatty-fibrotic infiltration. Data on clinical determinants of biomarkers in patients with AF, however, are lacking. Objective Our primary aim was to explore the relationships between clinical determinants and biomarker levels in AF patients scheduled for catheter ablation. Methods A cross-sectional analysis was conducted in AF patients undergoing catheter ablation included in the prospective multicenter ISOLATION study between July 2020 and May 2022. Clinical characteristics, routine tests and blood samples were collected before ablation. Blood samples were analyzed for known and novel cardiovascular biomarkers, including Bone morphogenetic protein 10 (BMP10), Angiopoietin-2 (Ang-2), Fibroblast growth factor 23 (FGF-23), Dickkopf-related protein 3 (DKK-3), Endocan (ESM-1), Insulin-like growth factor-binding protein 7 (IGFBP-7), B-type natriuretic peptides (proBNP, NTproBNP), High sensitive Troponin-T (hsTnT)&amp;lt; Growth differentiation factor 15 (GDF-15), interleukin 6 (IL-6), Fatty acid binding protein 3 (FABP3), Cancer antigen-125 (Ca-125) (Table 1). For each biomarker we trained a lasso regression model to identify the most important clinical determinants out of all the 60 available determinants (including anthropometry, ECG, comorbidities). The strongest associations are summarized in figure 1. Results Blood samples of 508 patients were analyzed. The mean age was 63 ±9 years, and 31.1% were female. 354 patients (69.7%) had paroxysmal AF and 154 patients (30.3%) had persistent AF. Heart failure was reported in 77 patients (15.2%). 355 (72.3%) patients were in sinus rhythm during sample collection. The following clinical determinants of biomarker levels were frequently identified as important: rhythm during blood phlebotomy, age, heart failure, decreased kidney function and female sex (Figure 1). Most notably, rhythm at the time of sampling was strongly associated with various biomarker levels. Female sex was positively associated with BMP10 and FGF23 (atrial fibrosis), but negatively associated with hsTNT (cardiac injury). Conclusion In patients with AF scheduled for catheter ablation, we identified several clinical determinants of biomarker levels with potential implications for disease mechanisms. In women, pro-fibrotic biomarkers were frequently higher, while male patients more often showed signs of myocardial injury. Importantly, rhythm during blood draw is a very strong determinant of many biomarkers and should be taken into account in future biomarker studies.Figure 1.Table 1.

Bone morphogenetic protein 10, a rising star in the field of diabetes and cardiovascular disease.

Early research suggested that bone morphogenetic protein 10 (BMP10) is primarily involved in cardiac development and congenital heart disease processes. BMP10 is a newly identified cardiac-specific protein. In recent years, reports have emphasized the effects of BMP10 on myocardial apoptosis, fibrosis and immune response, as well as its synergistic effects with BMP9 in vascular endothelium and role in endothelial dysfunction. We believe that concentrating on this aspect of the study will enhance our knowledge of the pathogenesis of diabetes and the cardiovascular field. However, there have been no reports of any reviews discussing the role of BMP10 in diabetes and cardiovascular disease. In addition, the exact pathogenesis of diabetic cardiomyopathy is not fully understood, including myocardial energy metabolism disorders, microvascular changes, abnormal apoptosis of cardiomyocytes, collagen structural changes and myocardial fibrosis, all of which cause cardiac function impairment directly or indirectly and interact with one another. This review summarizes the research results of BMP10 in cardiac development, endothelial function and cardiovascular disease in an effort to generate new ideas for future research into diabetic cardiomyopathy.

Recurrence After Atrial Fibrillation Ablation and Investigational Biomarkers of Cardiac Remodeling.

Recurrence after atrial fibrillation (AF) ablation remains common. We evaluated the association between recurrence and levels of biomarkers of cardiac remodeling, and their ability to improve recurrence prediction when added to a clinical prediction model. Blood samples collected before de novo catheter ablation were analyzed. Levels of bone morphogenetic protein-10, angiopoietin-2, fibroblast growth factor-23, insulin-like growth factor-binding protein-7, myosin-binding protein C3, growth differentiation factor-15, interleukin-6, N-terminal pro-brain natriuretic peptide, and high-sensitivity troponin T were measured. Recurrence was defined as ≥30 seconds of an atrial arrhythmia 3 to 12 months postablation. Multivariable logistic regression was performed using biomarker levels along with clinical covariates: APPLE score (Age >65 years, Persistent AF, imPaired eGFR [<60 ml/min/1.73m2], LA diameter ≥43 mm, EF <50%; which includes age, left atrial diameter, left ventricular ejection fraction, persistent atrial fibrillation, and estimated glomerular filtration rate), preablation rhythm, sex, height, body mass index, presence of an implanted continuous monitor, year of ablation, and additional linear ablation. A total of 1873 participants were included. A multivariable logistic regression showed an association between recurrence and levels of angiopoietin-2 (odds ratio, 1.08 [95% CI, 1.02-1.15], P=0.007) and interleukin-6 (odds ratio, 1.02 [95% CI, 1.003-1.03]; P=0.02). The area under the receiver operating characteristic curve of a model that only contained clinical predictors was 0.711. The addition of any of the 9 studied biomarkers to the predictive model did not result in a statistically significant improvement in the area under the receiver operating characteristic curve. Higher angiopoietin-2 and interleukin-6 levels were associated with recurrence after atrial fibrillation ablation in multivariable modeling. However, the addition of biomarkers to a clinical prediction model did not significantly improve recurrence prediction.

From cells to circulating biomarker: BMP10 is a myocyte-secreted peptide with potential to detect atrial fibrillation

Abstract Background Early onset detection and recurrence prediction of atrial fibrillation (AF) may improve therapeutic decision-making, prognosis and long-term outcome. Plasma proteome analyses and mechanistic studies identified bone morphogenetic protein 10 (BMP10) as an atrial-specific secreted biomolecule for AF associated with reduced paired-like homeodomain transcription factor 2 (PITX2) expression. Purpose Our aim is 1) to confirm BMP10 synthesis and secretion by human atrial isolated myocytes, 2) to compare BMP10 secreted levels between right atrial, left atrial and left ventricular myocytes, and 3) to assess if BMP10 secretion is indeed associated with AF in human myocytes. Methods Right atrial (RA), left atrial (LA) and left ventricular (LV) myocytes were isolated from 16 tissues samples of patients undergoing open heart surgery which were currently in sinus rhythm (SR) or AF. Freshly isolated myocytes were resuspended in minimal essential medium (MEM, M1) containing fetal bovine serum (FBS) and plated in laminin coated dishes. M1 was collected after 3 hours of culture and substituted by FBS-free medium (M2), which was collected after 48 hours of culture. Cardiomyocyte-released BMP10 levels were measured in M1 and M2 by ELISA. Results Cardiomyocytes from twelve patients (68±2.7 years, 52±2.1 % ejection fraction, 17 % women, 50 % with AF, 50 % valvular surgery and 75 % bypass) were cultured and BMP10 secreted levels analyzed. BMP10 concentrations were high in medium from atrial cardiomyocytes (2.76±1.8 ng/µl) and negligible in medium from ventricular cardiomyocytes (0.01±0.005 ng/µl). Left atrial cardiomyocytes released less BMP10 than right atrial cardiomyocytes (LA 0.02±0.007 ng/µl; RA 3.50±2.3 ng/µl). In addition, BMP10 concentrations were higher in right atrial cardiomyocytes from patients with AF (3.76±3.6 ng/µl) than in the right atrial cardiomyocytes from patients in SR (0.97±0.9 ng/µl). Conclusion Our results provide a direct proof that BMP10 is secreted by human atrial myocytes, mainly right atrial myocytes. Furthermore, atrial myocytes from patients with AF secreted significantly more BMP10 than myocytes from patients in sinus rhythm. These observations validate the atrial cardiomyocyte origin of circulating BMP10, making BMP10 a potentially attractive atrial-specific cardiac biomarker.

Abstract 14576: Circulating Bone Morphogenetic Protein 10 as a Prognostic Biomarker in Heart Failure: A BIOSTAT-CHF Study

Introduction: Bone morphogenetic protein 10 (BMP10) plays a central role in cardiac embryogenesis and is known to facilitate cardiac repair after myocardial injury in adults. The prognostic value of BMP10 in heart failure (HF) remains largely unknown. Objectives: To identify biological processes related to elevated BMP10 concentrations and to investigate the prognostic utility of circulating BMP10 in HF patients. Methods: Serum BMP10 concentrations were measured in 2085 chronic HF patients from the European BIOSTAT cohort using a prototype electrochemiluminescence immunoassay developed by Roche Diagnostics. First, we performed gene set enrichment analysis to identify biological pathways related to elevated BMP10. Next, we examined the predictive value of BMP10 for all-cause mortality, HF hospitalization and a combined endpoint of mortality and/or HF hospitalization on top of an established risk score, atrial fibrillation (AF) and stroke using Cox-regression analysis after log-transformation and standardization. Results were validated in an independent cohort of HF patients (n=1487). Results: High BMP10 was related to pathways of growth and growth factor activity, regulation of bone, extracellular region, and response to hormones/glucocorticoids. After adjusting for the BIOSTAT risk scores, AF and stroke, log-BMP10 remained a strong predictor of 2-year all-cause mortality (Hazard Ratio [HR] =1.17, Confidence Interval [CI]= 1.06-1.28), HF hospitalization (HR [CI]=1.13 [1.03-1.25]) and the combined endpoint (HR [CI]=1.10 [1.02-1.19]). Similar trends were seen in the validation cohort (Figure 1). Conclusions: BMP10 is an independent predictor of HF-rehospitalization and all-cause mortality in patients with HF.

Abstract 17725: Prognostic Implications and the Impact of Empagliflozin on Bone Morphogenetic Protein-10 in Heart Failure: Results from the EMPEROR Program

Background: Bone morphogenetic protein (BMP)-10 is upregulated in response to cardiac injury and exerts a protective role via activating transforming growth factor β/Smad and STAT3-pathways preserving normal cardiac function by inhibiting cell death and fibrosis. Aim: To assess association of baseline characteristics and prognostic significance of BMP-10 in patients with heart failure (HF) with reduced or preserved ejection fraction, and the effect of empagliflozin on BMP-10 level. Methods: Serum BMP-10 (Elecsys®, Roche Diagnostics) was assessed in 1127 patients from the EMPEROR-Reduced and Preserved trials, categorized by tertiles of baseline BMP-10 (&lt;2.35; ≥2.35-&lt;3.11; ≥3.11 ng/mL). Results: Median baseline BMP-10 was 2.71 ng/mL. Patients in higher tertiles tended to be older, women, NYHA class III-IV, with obesity, atrial fibrillation, and worse renal function (all P&lt;0.05). Baseline BMP-10 level correlated with N-terminal pro B-type natriuretic peptides and high-sensitivity troponin T levels (Spearman rho=0.41, 0.26 respectively). Higher baseline BMP-10 was associated with increased risk for adverse outcomes ( Table 1 ). For each 2-fold increase in BMP-10, the adjusted hazard ratio (HR) for cardiovascular death (CV) or HF hospitalization was 2.85 (95% CI 1.99, 4.09, P&lt;0.0001). Empagliflozin treatment was associated with reduction in BMP-10 at week 12 (adjusted gMean ratio 0.94 [0.91-0.97], P&lt;0.001) but not week 52 (1.00 [0.96-1.04], P=0.86). Empagliflozin reduced the risk of CV death or HF hospitalization, particularly for patients at highest baseline BMP-10 level (&lt;1 st tertile HR 1.03 [0.56-1.88]; ≥1 st and &lt;2 nd tertile HR 0.74 [0.40-1.35]; ≥2 nd tertile HR 0.61 [0.40-0.92], P-trend=0.15). Conclusion: BMP-10 levels were associated with worse disease severity and outcomes in patients with HF. Empagliflozin was associated with reduction of BMP-10 at week 12. The benefit of empagliflozin on outcomes was more pronounced with higher BMP-10 levels.

Abstract 12519: Biomarker Characterisation of Heart Failure Subtypes: A Population-Based Bioresource Linked Study

Background: Deep learning (DL)-based interpretation of echocardiographic images can help create pragmatic cohort studies to validate novel biomarkers. In this study, we have characterised biomarkers implicated in heart failure (HF) pathophysiology across the ejection fraction (EF) range in a DL-supported pragmatic cohort study. Methods: We used electronic health record data from Tayside, representing 20% of the Scottish population, between 1993 and 2021. Utilising record linkage to DL automated reading of echocardiographic DICOM images, we identified patients with HFrEF or HFpEF and patients without HF. We then linked identified patients to available plasma samples from the Go-SHARE BioBank. We analysed multi-panel biomarkers, such as NT-proBNP, high-sensitivity cardiac troponin-T (hs-cTnT), growth differentiation factor-15 (GDF-15), insulin-like growth factor-binding protein-7 (IGFBP-7), bone morphogenetic protein-10 (BMP-10), Dickkopf WNT Signaling Pathway Inhibitor-3 (DKK-3), fibroblast growth factor-23 (FGF-23), angiopoietin-2 (Ang2), and fatty acid-binding protein-3 (FABP-3), all with electrochemiluminescence immunoassays (Roche Diagnostics, Germany). Results: We identified 236 patients with HFpEF, 156 with HFrEF, and 185 patients without HF with available plasma samples from 3680 patient records linked to echocardiographic DICOMs and blood samples. Patients with HFrEF and HFpEF had significantly higher median values of hs-cTnT, GDF-15, NT-proBNP, IGFBP-7, DKK-3, and FGF-23 than controls. The diagnostic accuracy (AUC) of NT-proBNP, hs-cTnT, GDF-15, IGFBP-7, and FABP-3 was &gt;0.8 for identifying patients with HFrEF or HFpEF from controls. DL-algorithm-based interpretation of DICOM images provided further coverage of echocardiographic parameters relevant for diagnosis of HF subtypes. All biomarkers were associated with all-cause mortality and HF-related hospitalisation during a median follow-up of 1089 days. Conclusions: In this population-based study, we demonstrated a novel approach utilising a bioresource linked to a DL-supported pragmatic study to explore biomarkers in HF and demonstrated that multiple biomarkers to have diagnostic and prognostic significance for patients with HFrEF and HFpEF.

Association of bone morphogenetic protein 10 and recurrent atrial fibrillation after catheter ablation.

Atrial remodelling, defined as a change in atrial structure, promotes atrial fibrillation (AF). Bone morphogenetic protein 10 (BMP10) is an atrial-specific biomarker released to blood during atrial development and structural changes. We aimed to validate whether BMP10 is associated with AF recurrence after catheter ablation (CA) in a large cohort of patients. We measured baseline BMP10 plasma concentrations in AF patients who underwent a first elective CA in the prospective Swiss-AF-PVI cohort study. The primary outcome was AF recurrence lasting longer than 30 s during a follow-up of 12 months. We constructed multivariable Cox proportional hazard models to determine the association of BMP10 and AF recurrence. A total of 1112 patients with AF (age 61 ± 10 years, 74% male, 60% paroxysmal AF) was included in our analysis. During 12 months of follow-up, 374 patients (34%) experienced AF recurrence. The probability for AF recurrence increased with increasing BMP10 concentration. In an unadjusted Cox proportional hazard model, a per-unit increase in log-transformed BMP10 was associated with a hazard ratio (HR) of 2.28 (95% CI 1.43; 3.62, P < 0.001) for AF recurrence. After multivariable adjustment, the HR of BMP10 for AF recurrence was 1.98 (95% CI 1.14; 3.42, P = 0.01), and there was a linear trend across BMP10 quartiles (P = 0.02 for linear trend). The novel atrial-specific biomarker BMP10 was strongly associated with AF recurrence in patients undergoing CA for AF. NCT03718364; https://clinicaltrials.gov/ct2/show/NCT03718364.

Bone morphogenetic protein 10 as a predictor for recurrent atrial fibrillation after catheter ablation

Abstract Funding Acknowledgements Type of funding sources: None. Background Atrial fibrillation (AF) recurrence after catheter ablation (CA) poses a major challenge. The novel atrial-specific biomarker, bone morphogenetic protein 10 (BMP10), might aid in the selection of appropriate patients for CA. Purpose We aimed to assess the predictive value BMP10 for AF recurrence after CA in a large cohort of AF patients. Methods We measured baseline BMP10 concentrations in AF patients who underwent elective CA for the first time. Patients were enrolled in a single-center prospective cohort study. The primary outcome variable was AF recurrence during 12 months’ follow-up using 2 x 24h and 1 x at least 4-day Holter. We constructed Cox proportional hazard models to determine the association of BMP10 and AF recurrence. The multivariable model was adjusted for age, sex, body mass index, and cardiovascular risk factors. Results A total of 1,112 AF patients (74% male) with a mean age of 61 ± 10 years were included in our analysis (60% paroxysmal AF, 40% persistent AF). The 12-month follow-up examination revealed that AF recurred in 374 (33.6%) patients. Kaplan-Meier curves for recurrent AF according to BMP10 quartiles are shown in the Figure (BMP10 quartile I: 0.76-1.50 ng/mL, quartile II: 1.50-1.72 ng/mL, quartile III: 1.72-1.99 ng/mL, quartile IV: 1.99-3.75 ng/mL). In the unadjusted Cox proportional hazard model, a per-unit increase in log transformed BMP10 was associated with a hazard ratio (HR) of 2.28 (95% CI 1.43, 3.62; p &amp;lt; 0.001) for AF recurrence. After multivariable adjustment, the HR of BMP10 was 1.98 (95% CI 1.14; 3.42, p = 0.01) for AF recurrence. Conclusion The novel atrial-specific biomarker BMP10 was associated with AF recurrence after CA in our large cohort of AF patients.

Association of clinical characteristics and biomarkers with recurrent atrial fibrillation after hybrid ablation

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Atrial fibrillation ablation research at our institution was supported by an unrestricted grant from AtriCure. Background Hybrid ablation is an alternative treatment for both persisting and therapy-resistant, symptomatic atrial fibrillation (AF), combining the strengths of endocardial catheter and epicardial surgical ablation. Although results exhibit lower rates of recurrence and higher reduction of AF burden, there is a considerable risk of procedure-related complications. Therefore, the identification of patient groups who benefit most of this procedure can help in pre-procedural selection and tailoring of optimal therapy post-ablation. Purpose This study aimed to identify clinical factors and blood biomarkers associated with recurrence of AF within 1 year post-ablation. Methods A total of 96 consecutive patients undergoing hybrid ablation between January 2015 and December 2018 in a tertiary care center were enrolled. Blood samples were collected pre-ablation. Seven biomarkers [Bone Morphogenetic Protein 10 (BMP10), angiopoietin-2 (ANG2), Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3), Endothelial Cell Specific Molecule 1 (ESM1), Fibroblast Growth Factor 23 (FGF23), Insulin Like Growth Factor Binding Protein 7 (IGFBP7) and total N-terminal pro b-type natriuretic peptide (NT-proBNP)] were assayed at Roche Diagnostics based on their possible association with recurrence of AF. Clinical follow-up visits combined with 12-lead ECG and 24-hour Holter monitoring were scheduled at 3, 6 and 12 months post-procedure. Cox proportional hazards regression models were used to study the association with recurrence of AF. Results Out of the 96 patients (mean age 58±8 years; 18% women), 17 (17.7%) developed recurrence of AF within 1 year post-ablation. Median time to diagnosis was 191 days (range: 92-344). Comparisons between patients with and without recurrence of AF are depicted in Table 1. Multivariable Cox proportional hazard regression, adjusted for sex, showed that older age (HR 1.104, 95% CI 1.003-1.215, p=0.043), type of AF (HR 0.322, 95% CI 0.117-0.886, p=0.028), a history of peripheral vascular disease (HR 13.84, 95% CI 3.13-61.14, p&amp;lt;0.001) and recurrence in the blanking period (HR 14.25, 95% CI 3.99-50.85, p&amp;lt;0.001) were associated with recurrence of AF within 1 year post-ablation, but no blood biomarkers (Figure 1). Conclusion In AF patients undergoing extensive ablation, older age, type of AF, a history of peripheral vascular disease and recurrence in the blanking period were determinants of AF recurrence within 1 year post-ablation.

Astragalus polysaccharides alleviates cardiac hypertrophy in diabetic cardiomyopathy via inhibiting the BMP10-mediated signaling pathway

BackgroundCardiac hypertrophy can lead to cardiac dysfunction and is closely associated with mortality in diabetic cardiomyopathy (DCM). Astragalus polysaccharides (APS) is the main component extracted from Astragalus membranaceus (Fisch.) Bunge (AM), which exhibits anti-hypertrophic effects on cardiomyocytes in various diseases. However, whether APS exerts anti-hypertrophic effects in DCM remains unclear. PurposeTo investigate whether APS can attenuate cardiac hypertrophy in DCM and exert anti-hypertrophic effects by inhibiting the bone morphogenetic protein 10 (BMP10) pathway. MethodsThe anti-hypertrophic effects of APS were studied in high-glucose (HG)-stimulated H9c2 cardiomyocytes and streptozotocin (STZ)-induced DCM rats. BMP10 siRNA was used to inhibit BMP10 expression in H9c2 cardiomyocytes. Cardiac function was assessed by echocardiography. Cardiac hypertrophy was evaluated using heart weight/body weight (HW/BW), RT-PCR, hematoxylin-eosin (HE), and rhodamine phalloidin staining. Changes in hypertrophic components, including BMP10 and downstream factors, were measured using western blotting. ResultsIn vitro, HG treatment increased the relative cell surface area of H9c2 cardiomyocytes, whereas BMP10 siRNA transfection or APS treatment alleviated the increase induced by HG. APS treatment improved the general condition, increased cardiac function, and decreased the HW/BW ratio, ANP mRNA level, and cardiomyocyte cross-sectional area of DCM rats in vivo. Molecular experiments demonstrated that APS downregulated the levels of the pro-hypertrophic protein BMP10 and its downstream proteins ALK3, BMPRII, and p-Smad1/5/8 without affecting the level of total Smad1/5/8. ConclusionsOur study demonstrates that APS can alleviate cardiac hypertrophy and protect against DCM by inhibiting activation of the BMP10 pathway. APS is a promising candidate for DCM treatment.

Bone morphogenetic protein 10: a novel risk marker of ischaemic stroke in patients with atrial fibrillation.

Biomarkers specifically related to atrial tissue may increase the understanding of the pathophysiology of atrial fibrillation (AF) and further improve risk prediction in this setting. Bone morphogenetic protein 10 (BMP10) is a protein expressed in the atrial myocardium. We evaluated the association between BMP10 and the risk of ischaemic stroke and other cardiovascular events in large cohorts of patients with AF, treated with and without oral anticoagulation (OAC). BMP10 was measured in plasma samples collected at randomisation in patients with AF without OAC in the ACTIVE A and AVERROES trials (n = 2974), and with OAC in the ARISTOTLE trial (n = 13 079). BMP10 was analysed with a prototype Elecsys immunoassay. Associations with outcomes were evaluated by Cox-regression models adjusted for clinical characteristics, kidney function, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Median concentrations of BMP10 were 2.47 and 2.44 ng/mL, in the non-OAC and OAC cohort, respectively. Increasing BMP10 was associated with lower body mass index, older age, female sex, kidney dysfunction, and AF rhythm. BMP10 was consistently associated with ischaemic stroke. In the non-OAC cohort, BMP10 increased the concordance index of the multivariable model from 0.713 to 0.733 (P = 0.004) and in the OAC cohort from 0.673 to 0.694 (P < 0.001). Additionally, BMP10 maintained a significant prognostic value after additionally adjusting for NT-proBNP. BMP10 was not independently associated with bleeding or with death. The novel atrial biomarker BMP10 was independently associated with ischaemic stroke in patients with AF irrespective of OAC treatment. BMP10 seems to be more specifically related to the risk of ischaemic stroke in AF. In this study, BMP10 may be a novel specific biomarker of ischaemic stroke in patients with atrial fibrillation, irrespective of oral anticoagulation.

Bone morphogenetic protein 10 as predictor for 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). Bone morphogenetic protein 10 (BMP10) is a novel atrial-specific biomarker, but data about its prognostic value in AF patients are lacking. Purpose We aimed to assess the predictive value of BMP10 for death and MACE in AF patients in comparison to N-terminal prohormone of B-type natriuretic peptide (NT-proBNP). Methods Baseline concentrations of BMP10 and NT-proBNP were measured in stable patients with AF enrolled in Swiss-AF, a prospective multicenter observational cohort study. Primary outcomes were all-cause death and MACE (composite of heart failure hospitalization, cardiovascular death, stroke, systemic embolism, myocardial infarction). Measures of discriminative power were used to compare multivariable Cox proportional hazard models using the different biomarkers. Results A total of 2219 AF patients were included with a median follow-up of 4.3 years (IQR 3.9, 5.1). Mean age was 73±9 years and 27% were women. Incidence rate per 100 patient-years of all-cause death and MACE increased across BMP10 quartiles (Figure 1). In the multivariable adjusted Cox proportional hazard model, the hazard ratio (HR) and 95% confidence interval (CI) of BMP10 was 1.60 (1.37; 1.87) to predict all-cause death, and 1.54 (1.35; 1.76) to predict MACE. For all-cause death, the C-index (95% CI) was 0.783 (0.763; 0.809) for BMP10, 0.784 (0.765; 0.810) for NT-proBNP, and 0.789 (0.771; 0.815) for both biomarkers combined. For MACE, the C-index (95% CI) was 0.732 (0.715; 0.754) for BMP10, 0.747 (0.731; 0.768) for NT-proBNP, and 0.750 (0.734; 0.771) for both biomarkers combined. When grouping patients according to clinical used NT-proBNP categories (&amp;lt;300, 300–900, &amp;gt;900 ng/l), higher incidence rates and adjusted HRs were observed for the primary outcomes in patients with high BMP10 in the categories of low NT-proBNP (all-cause death aHR 2.28 [1.15; 4.52], MACE aHR 1.88 [1.07; 3.28]) and high NT-proBNP (all-cause death aHR 1.61 [1.14; 2.26], MACE aHR 1.38 [1.07; 1.80]) (Figure 2). Conclusion The novel atrial-specific biomarker BMP10 strongly predicts all-cause death and MACE in patients with AF. BMP10 provides additional prognostic information in low- and high-risk patients according to NT-proBNP stratification. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Swiss National Science Foundation, Swiss Heart Foundation

Effects of constitutively active IKKβ on cardiac development

NF-κB is a major transcription factor regulating cell survival, organ development and inflammation, but its role in cardiac development has been inadequately explored. To examine this function, we generated mice in which IKKβ, an essential kinase for NF-κB activation, was constitutively activated in embryonic cardiomyocytes. For this purpose, we used smooth muscle-22α (SM22α)-Cre mice, which are frequently used for gene recombination in embryonic cardiomyocytes. Embryonic hearts of SM22αCre-CA (constitutively active) IKKβflox/flox mice revealed remarkably thin, spongy and hypoplastic myocardium. In exploring the mechanism, we found that the expression of bone morphogenetic protein 10 (BMP10) and T-box transcription factor 20 (Tbx20), major regulators of cardiac development, was significantly downregulated and upregulated, respectively, in the SM22αCre-CAIKKβflox/flox mice. We also generated NK2 homeobox 5 (Nkx2.5) Cre-CAIKKβflox/wt mice since Nkx2.5 is also expressed in embryonic cardiomyocytes and confirmed that the changes in these genes were also observed. These results implicated that the activation of NF-κB affects cardiac development.

Bone morphogenetic protein 10 alleviates doxorubicin-induced cardiac injury via signal transducer and activator of transcription 3 signaling pathway

ABSTRACT Doxorubicin (DOX) has limited antitumor applications owing to its association with life-threatening cardiac injury. Oxidative damage and cardiac apoptosis are crucial in DOX-induced cardiac injury. Bone morphogenetic protein 10 (BMP10) is predominantly distributed in the heart and acts as a cardioprotective factor that preserves cardiac function. However, the role of BMP10 in DOX-induced cardiac injury has not yet been explored. The current study aimed to examine the function and mechanism of action of BMP10 in DOX-induced cardiac injury. An adeno-associated viral system was used for the overexpression or silencing of cardiac-specific BMP10, and subsequently, a single dose of DOX was intraperitoneally injected to induce cardiac injury. Results showed that DOX exposure decreased BMP10 expression in the heart. Cardiac-specific overexpression of BMP10 alleviated the oxidative stress and apoptosis and improved cardiac function. Conversely, cardiac-specific silencing of BMP10 aggravated the redox disorder and apoptosis and worsened the cardiac dysfunction caused by DOX. Exogenous BMP10 supplementation amelioratesd the DOX-induced cardiac contractile dysfunction. Mechanistically, we found that phosphorylation of signal transducer and activator of transcription 3 (STAT3) is reduced in DOX-induced cardiotoxicity, and, BMP10 activated impaired STAT3 via a non-canonical pathway. BMP10 lost its cardioprotective function in cardiomyocyte-specific STAT3 knockout (STAT3-cKO) mice. Based on our findings, we suggested that BMP10 is a potential therapeutic agent against DOX-induced cardiac injury and that the cardioprotective effects of BMP10 are dependent on the activation of STAT3.