Bone Morphogenetic Protein 10 Research Articles

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.

BMP10 expression in the adult rat central nervous system

Bone morphogenetic protein 10 (BMP10), is a member of the transforming growth factor β (TGFβ) superfamily. Although BMP10 plays pivotal roles during development, including vascular development and cardiogenesis, little information is available for BMP10 expression in the central nervous system (CNS). We, thus, investigated BMP10 expression in the adult rat CNS using immunohistochemistry. BMP10 was intensely expressed in most neurons and their axons. Furthermore, we found that astrocytes and ependymal cells also express BMP10 protein. These data indicate that BMP10 is widely expressed throughout the adult CNS, and this abundant expression strongly supports the idea that BMP10 also plays important roles in the adult CNS.

Biomarkers associated with rhythm status after cardioversion in patients with atrial fibrillation

Biomarkers may help to improve our knowledge about the complex pathophysiology of atrial fibrillation (AF). In this study we sought to identify significant changes in biomarkers and clinical measures in patients with and without AF recurrence after electrical cardioversion. We measured 21 conventional and new biomarkers before and 30 days after electrical cardioversion and assessed the associations of changes in biomarker levels with rhythm status at follow-up. Significant between-group changes were observed for bone morphogenetic protein 10 (BMP10), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and total bilirubin. Their respective changes were − 10.4%, − 62.0% and − 25.6% in patients with sinus rhythm, and 3.1%, 1.1% and − 9.4% in patients with recurrent AF, for a between-group difference of − 13.5% (95% confidence interval [CI] − 19.3% to − 7.6%; P < 0.001), − 63.1% (95% CI − 76.6% to − 49.6%; P < 0.001) and − 16.3% (95% CI − 27.9% to − 4.7%; P = 0.007). In multivariable models, the reductions of BMP10 and NT-proBNP were significantly associated with follow-up rhythm status (β coefficient per 1 − SD decrease, − 3.85; 95% CI − 6.34 to − 1.35; P = 0.003 for BMP10 and − 5.84; 95% CI − 10.22 to − 1.47; P = 0.009 for NT-proBNP. In conclusion, changes in BMP10 und NT-proBNP levels were independently associated with rhythm status after cardioversion, suggesting that these markers may be dependent on the actual heart rhythm.

Abstract 13230: Bone Morphogenetic Protein 10 - A Novel Biomarker of Ischemic Stroke in Patients With Atrial Fibrillation

Background: Biomarkers specifically related to the atrial tissue might increase the understanding of the pathophysiology and improve risk prediction in atrial fibrillation (AF). Bone morphogenetic protein 10 (BMP10) is a novel biomarker expressed in atrial myocardium. We evaluated the association between BMP10 and the risk of stroke, bleeding, and death in patients with AF not treated with oral anticoagulation. Methods: BMP10 was measured in 2,974 plasma samples collected at randomisation in patients with AF randomized to aspirin in two cohorts, the ACTIVE-A (n=951) and AVERROES (n=2023) trials, median follow-up of 3.8 and 1.2 years, respectively. BMP10 was analysed with a prototype Elecsys electrochemiluminescence immunoassay. Associations between BMP10 and outcomes were evaluated by Cox-regression analyses adjusted for clinical characteristics, kidney function, and NT-proBNP. Results: Median age was 71 years, 58.1% were men. The median concentration of BMP10 was 2.46 (25 th -75 th percentiles, 2.09 - 2.94) ng/L. The variables most strongly associated with higher BMP10 levels were: heart rhythm (AF vs sinus), older age, female sex, lower BMI, and kidney dysfunction. BMP10 was the baseline variable most strongly associated with ischemic stroke during follow-up (Figure). After adjustments, the hazard ratio for ischemic stroke (BMP10 3rd vs 1st quartile) was 1.57 [95%CI 1.08-2.28], p=0.025), and the discriminatory value (c-index) was 0.643 (vs 0.634 of CHA 2 DS 2 -VASc score) and improved the full model from 0.737 to 0.746. BMP10 was not associated with bleeding or death. The results were consistent across both cohorts and irrespective of cardiac rhythm at blood sampling. Conclusions: In patients with AF, circulating plasma levels of BMP10 are independently associated with the risk of ischemic stroke but not with bleeding or death. BMP10 has an incremental discriminatory value for the risk of ischemic stroke, and may be a novel specific biomarker in patients with AF.

Exploring a Functional Role for BMP10 in Heart Failure

<h3>Purpose</h3> Cardiac fibrosis leads to adverse clinical outcomes in heart failure. Published studies have identified that bone morphogenetic protein-10 (BMP-10), a member of the transforming growth factor-b (TGB-b) superfamily, may form a heterodimer with BMP-9, which binds to the TGF-b co-receptor endoglin with high affinity and has been shown to limit cardiac fibrosis in heart failure. We hypothesized that a model of pressure overload-induced heart failure increases BMP-10 expression in the left ventricle, which limits cardiac fibrosis by increasing signaling via Smad1. <h3>Methods</h3> Adult, male 10-week-old mice were subjected to transverse aortic constriction (TAC) using a 27G needle for all studies. C57 Bl/6 wild-type mice were subjected to TAC for 2 (acute) or 8 (chronic) weeks to quantify BMP-9 and BMP-10 expression. LV pressure-volume loop and echocardiographic data were obtained. <h3>Results</h3> A total of 6 mice underwent sham operations, 8 underwent 2-week TAC, and 8 underwent 8-week TAC. All mice survived until harvest. Compared to sham, there was a reduced ejection fraction and a dilated LV internal diastolic dimension in the chronic TAC cohort (Sham: 71±4 % v 8-week: 30±14%, p=0.001; Sham: 2.2±0.3 mm v 8-week: 3.8±0.6 mm, p=0.02). Additionally, compared to sham, both LV end-diastolic and end-systolic volumes were increased in the chronic TAC group (Sham: 57±11 uL v 8-week: 91±419 uL, p=0.02; Sham: 17±5 uL v 8-week: 64±23 uL, p=0.007). Compared to sham, minimum LV pressure was elevated in the chronic TAC cohort (Sham: -4.5±1.3 mmHg v 8-week: 8.8±10.3 mmHg, p=0.04). BMP-10 mRNA expression was elevated in the right atrium, but reduced in the ventricles, at 8 weeks of TAC, while BMP-10 protein expression was increased at 8 weeks of TAC (Figure 1A-B). BMP-9 expression was reduced in the chronic TAC cohort in the left ventricle while endoglin levels were unchanged (Figure 1C). <h3>Conclusion</h3> BMP-10 mRNA levels are downregulated, while protein levels are upregulated, in the LV at 8 weeks of TAC. Further studies are needed to fully explore the functional role of BMP-10 in the heart.

Expression of bone morphogenetic protein 10 in cases with endometrial carcinoma and its clinical significance.

To investigate the expression of bone morphogenetic protein 10 (BMP-10) in patients with endometrial carcinoma (EC) and its clinical significance. Totally 143 cancer tissue specimens were sampled from patients with EC and retrospectively analyzed. The immunohistochemical method was adopted for quantifying BMP-10 in EC tissues. Then the patients were assigned to high and low BMP-10 expression groups. The Kaplan-Meier method and log-rank test were adopted to compare the difference of tumor-free survival (TFS) rate and overall survival (OS) rate between the two groups. The COX proportional hazard model was used to analyze independent risk factors affecting the TFS rate and OS rate of patients with EC. There were 80 patients (55.94%) with low BMP-10 expression and 63 patients with high BMP-10 expression (54.06%). BMP-10 expression was significantly correlated with International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.001), myometrial invasion depth (P < 0.001), histological grade (P < 0.001), and lymph node metastasis (P = 0.009). Additionally, TFS rate (P = 0.004) and OS rate (P = 0.003) in the low BMP-10 expression group were notably lower than those in the high BMP-10 expression group. Multivariate analysis showed that BMP-10 expression (HR: 13.712, 95% CI 1.823-103.158, P = 0.011) was an independent risk factor for the TFS of patients with EC. FIGO stage (P = 0.001) and BMP-10 expression (HR: 8.655, 95% CI 1.098-68.215, P = 0.020) were independent risk factors for the OS of such patients. BMP-10 can be adopted as a molecular marker for predicting the poor prognosis of patients with EC.

Abstract 16626: Endothelial Zinc Transporter Zip8 Regulates Ventricular Trabeculation and Compaction

Trabeculation and subsequent compaction of the ventricular wall are essential for normal heart morphogenesis. In human, excessive trabeculation and impaired myocardial compaction during earlyheart development lead to left ventricular non compaction (LVNC), a third most common cardiomyopathies after dilated and hypertrophic cardiomyopathies. LVNC is also associated with cardiac arrhythmia and sudden cardiac death. The etiology of LVNC is poorly understood. Recently our group identified that Zip8, a Zinc transporter, implicated in ventricular trabeculation and compaction (JCI, 2018,PMID: 29337306). However, it remains elusive how Zip8 regulates these processes through cellular and molecular mechanisms. We conditionally ablated Zip8 in the endothelial cells, epicardial cells and cardiomyocytes in the developing heart respectively. Strikingly, deletion of Zip8 in the endothelial cellsgave rise to LVNC phenotypes, identical to cardiac phenotypes from the global Zip8 knockouts. Incontrast, hearts with deletions of Zip8 in either epicardium or myocardium developed normally. Further,we found only conditional deletion of Zip8 in the endothelium in the early developing hearts (at E8.5)generated LVNC but not in the late gestation stage (E13.5), suggesting that Zip8 plays critical roles during the initial trabeculation stage. Interestingly, we found that endocardial Zip8 deficiency resulted inthe upregulation of Notch signaling, as evidenced by the increase of intracellular domain of notch protein(NICD) and its downstream target gene, bone morphogenetic protein 10 (BMP10). When the notch signaling is inhibited in the endothelial Zip8 knockout hearts either by DAPI, a γ secretase inhibitor, or by genetic deletion of Rbpj, the LVNC cardiac phenotypes are partially rescued. These results suggest thatZip8 orchestrates myocardial trabeculation and compaction by regulating notch signaling.Collectively, our study provides novel insights into the mechanisms of LVNC, suggesting that genetic mutations in Zip8 or zinc deficiency may contribute to LNVC in humans.

BMP10 preserves cardiac function through its dual activation of SMAD-mediated and STAT3-mediated pathways

Bone morphogenetic protein 10 (BMP10) is a cardiac peptide growth factor belonging to the transforming growth factor β superfamily that critically controls cardiovascular development, growth, and maturation. It has been shown that BMP10 elicits its intracellular signaling through a receptor complex of activin receptor-like kinase 1 with morphogenetic protein receptor type II or activin receptor type 2A. Previously, we generated and characterized a transgenic mouse line expressing BMP10 from the α-myosin heavy chain gene promoter and found that these mice have normal cardiac hypertrophic responses to both physiological and pathological stimuli. In this study, we report that these transgenic mice exhibit significantly reduced levels of cardiomyocyte apoptosis and cardiac fibrosis in response to a prolonged administration of the β-adrenoreceptor agonist isoproterenol. We further confirmed this cardioprotective function with a newly generated conditional Bmp10 transgenic mouse line, in which Bmp10 was activated in adult hearts by tamoxifen. Moreover, the intraperitoneal administration of recombinant human BMP10 was found to effectively protect hearts from injury, suggesting potential therapeutic utility of using BMP10 to prevent heart failure. Gene profiling and biochemical analyses indicated that BMP10 activates the SMAD-mediated canonical pathway and, unexpectedly, also the signal transducer and activator of transcription 3 (STAT3)-mediated signaling pathway both in vivo and in vitro Additional findings further supported the notion that BMP10's cardioprotective function likely is due to its dual activation of SMAD- and STAT3-regulated signaling pathways, promoting cardiomyocyte survival and suppressing cardiac fibrosis.