Packer Milton, Butler Javed, Ferreira João Pedro, Siddiqi Tariq Jamal, Januzzi James L, Sattar Naveed, Maldonado Sandra González, Panova-Noeva Marina, Prochaska Jürgen H, Sumin Mikhail, Masson Serge, Pocock Stuart J, Filippatos Gerasimos, Anker Stefan D, Zannad Faiez
Baylor University Medical Center, Dallas, TX, USA.
Imperial College, London, UK.
Eur J Heart Fail. 2025 Jul 14. doi: 10.1002/ejhf.3764.
Bone morphogenetic protein 10 (BMP10), activin receptor-like kinase 1 (ALK1) and endoglin form a single transforming growth factor-β family signalling complex that is the principal driver of cardiac and vascular morphogenesis and maturation during hypoxic embryonic development. These proteins are down-regulated with the onset of normoxia at birth, but are up-regulated following experimental cardiac injury. Yet, little is known about the expression of this protein complex in patients with heart failure.
In the EMPEROR Program, we measured serum levels of BMP10 by electrochemiluminescence immunoassay in 1127 patients in Cohort 1 (n = 1127) and plasma levels of BMP10, ALK1 and endoglin by proximity extension assay in a distinct Cohort 2 (n = 1120). In both cohorts, patients were characterized at baseline and were followed for the occurrence of major adverse heart failure events. Levels of BMP10, ALK1 and endoglin at baseline and changes in these levels during follow-up were closely correlated with each other. Higher levels of BMP10, ALK1 and endoglin were associated with worse functional class, higher likelihood of atrial fibrillation and higher levels of natriuretic peptides and troponin T (p for trend <0.001 for all). Increasing levels of BMP10, ALK1 and endoglin were associated with progressively higher risks of major adverse outcomes (p for trend <0.001 for all three proteins and for all heart failure endpoints). The hazard ratios for the risks associated with tertiles of the three proteins in Cohort 2 were remarkably similar to those seen with BMP10 in Cohort 1. Treatment with empagliflozin had a modest effect to reduce BMP10 in both cohorts.
The coordinated circulating expression of proteins critical to foetal cardiac and vascular development tracks closely with the severity of heart failure, as reflected by symptoms, cardiac injury and stress, prevalence of atrial fibrillation and other comorbidities, and prognosis, suggesting a role of BMP10/ALK1/endoglin signalling in the progression of heart failure.
骨形态发生蛋白10（BMP10）、激活素受体样激酶1（ALK1）和内皮糖蛋白形成一个单一的转化生长因子-β家族信号复合物，是缺氧胚胎发育过程中心脏和血管形态发生及成熟的主要驱动因素。这些蛋白质在出生时随着常氧状态的开始而下调，但在实验性心脏损伤后会上调。然而，关于该蛋白复合物在心力衰竭患者中的表达情况知之甚少。
在EMPEROR项目中，我们通过电化学发光免疫分析法测量了队列1中1127例患者（n = 1127）的血清BMP10水平，并通过邻位延伸分析法测量了另一队列2中1120例患者的血浆BMP10、ALK1和内皮糖蛋白水平。在两个队列中，患者均在基线时进行特征描述，并随访主要不良心力衰竭事件的发生情况。基线时BMP10、ALK1和内皮糖蛋白水平以及随访期间这些水平的变化彼此密切相关。较高的BMP10、ALK1和内皮糖蛋白水平与较差的功能分级、房颤发生的较高可能性以及较高的利钠肽和肌钙蛋白T水平相关（所有趋势p < 0.001）。BMP10、ALK1和内皮糖蛋白水平的升高与主要不良结局的风险逐渐增加相关（三种蛋白质以及所有心力衰竭终点的趋势p < 0.001）。队列2中三种蛋白质三分位数相关风险的风险比与队列1中BMP10的风险比非常相似。恩格列净治疗在两个队列中对降低BMP10有适度作用。
对胎儿心脏和血管发育至关重要的蛋白质的循环表达协同变化，与心力衰竭的严重程度密切相关，这通过症状、心脏损伤和应激、房颤及其他合并症的患病率以及预后得以体现，提示BMP10/ALK1/内皮糖蛋白信号通路在心力衰竭进展中起作用。
