Zhang Qianru, Ye Jiawen, Yang Gan, Yang Ling, Chen Zhongli, Yang Ke, Sun Jia Teng, Liu Yan
Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Cardiology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
Front Cardiovasc Med. 2023 Jan 6;9:1050310. doi: 10.3389/fcvm.2022.1050310. eCollection 2022.
Calcific aortic valve disease (CAVD) is a progressive disease resulting in severe calcific aortic stenosis (AS), and there is increasing interest in the discovery of novel biomarkers to identify patients with potential future calcific AS at an early stage. This study aimed to determine whether follistatin-like 1 (FSTL1) is associated with calcific AS events and its exact role in aortic valve calcification.
A prospective observational cohort study involving 656 patients was performed to investigate the relationship between serum FSTL1 and calcific AS incidence during a follow-up of 5 years. Furthermore, we detected FSTL1 levels in valvular interstitial cells (VICs) from calcified valves and explored the effects of FSTL1 on VIC osteogenic differentiation as well as the signaling pathways involved.
During a median follow-up of 5 years, lower FSTL1 levels were associated with a significantly higher risk of calcific AS events (log rank test, = 0.007). In addition, Cox multivariable regression analyses verified the predictive value of FSTL1 after adjusting for both demographic features and laboratory confounders. Consistent with our results for serum, a lower concentration of FSTL1 was observed in calcified human valves ( = 11) and mainly colocalized with VICs. Recombinant human FSTL1 (rhFSTL1) stimulation inhibited calcium deposition, alkaline phosphatase (ALP) activity, and osteogenic gene expression partly through the downregulation of the ERK1/2 pathway.
Taken together, this study provides a strong rationale to consider FSTL1 as a potential therapeutic target for calcific AS.
钙化性主动脉瓣疾病（CAVD）是一种进展性疾病，可导致严重的钙化性主动脉瓣狭窄（AS），人们对发现新的生物标志物以早期识别未来可能发生钙化性AS的患者的兴趣与日俱增。本研究旨在确定卵泡抑素样蛋白1（FSTL1）是否与钙化性AS事件相关及其在主动脉瓣钙化中的具体作用。
进行了一项前瞻性观察队列研究，纳入656例患者，以调查血清FSTL1与5年随访期间钙化性AS发病率之间的关系。此外，我们检测了钙化瓣膜中瓣膜间质细胞（VICs）的FSTL1水平，并探讨了FSTL1对VIC成骨分化的影响以及相关信号通路。
在中位5年的随访期间，较低的FSTL1水平与钙化性AS事件的显著更高风险相关（对数秩检验，P = 0.007）。此外，Cox多变量回归分析在调整人口统计学特征和实验室混杂因素后证实了FSTL1的预测价值。与我们的血清结果一致，在钙化的人体瓣膜中观察到较低浓度的FSTL1（n = 11），且主要与VICs共定位。重组人FSTL1（rhFSTL1）刺激部分通过下调ERK1/2途径抑制钙沉积、碱性磷酸酶（ALP）活性和成骨基因表达。
综上所述，本研究为将FSTL1视为钙化性AS的潜在治疗靶点提供了有力依据。
