Shelbaya Khaled, Arthur Victoria, Yang Yimin, Dorbala Pranav, Buckley Leo, Claggett Brian, Skali Hicham, Dufresne Line, Yang Ta-Yu, Engert James C, Thanassoulis George, Floyd James, Austin Thomas R, Bortnick Anna, Kizer Jorge, Freitas Renata C C, Singh Sasha A, Aikawa Elena, Hoogeveen Ron C, Ballantyne Christie, Yu Bing, Coresh Josef, Blaha Michael J, Matsushita Kunihiro, Shah Amil M
Brigham and Women's Hospital, Boston, Massachusetts, USA.
McGill University Health Centre, Montreal, Quebec, Canada.
J Am Coll Cardiol. 2024 Feb 6;83(5):577-591. doi: 10.1016/j.jacc.2023.11.021.
Limited data exist regarding risk factors for aortic stenosis (AS). The plasma proteome is a promising phenotype for discovery of novel biomarkers and potentially causative mechanisms.
The aim of this study was to discover novel biomarkers with potentially causal associations with AS.
We measured 4,877 plasma proteins (SomaScan aptamer-affinity assay) among ARIC (Atherosclerosis Risk In Communities) study participants in mid-life (visit 3 [V3]; n = 11,430; age 60 ± 6 years) and in late-life (V5; n = 4,899; age 76 ± 5 years). We identified proteins cross-sectionally associated with aortic valve (AV) peak velocity (AVmax) and dimensionless index by echocardiography at V5 and with incident AV-related hospitalization after V3 with the use of multivariable linear and Cox proportional hazard regression. We assessed associations of candidate proteins with changes in AVmax over 6 years and with AV calcification with the use of cardiac computed tomography, replicated analysis in an independent sample, performed Mendelian randomization, and evaluated gene expression in explanted human AV tissue.
Fifty-two proteins cross-sectionally were associated with AVmax and dimensionless index at V5 and with risk of incident AV-related hospitalization after V3. Among 3,413 participants in the Cardiovascular Health Study, 6 of those proteins were significantly associated with adjudicated moderate or severe AS, including matrix metalloproteinase 12 (MMP12), complement C1q tumor necrosis factor-related protein 1 (C1QTNF1), and growth differentiation factor-15. MMP12 was also associated with greater increase in AVmax over 6 years, greater degree of AV calcification, and greater expression in calcific compared with normal or fibrotic AV tissue. C1QTNF1 had consistent potential causal effects on both AS and AVmax according to Mendelian randomization analysis.
These findings identify MMP12 as a potential novel circulating biomarker of AS risk and C1QTNF1 as a new putative target to prevent AS progression.
关于主动脉瓣狭窄（AS）危险因素的数据有限。血浆蛋白质组是发现新型生物标志物及潜在致病机制的一个有前景的表型。
本研究旨在发现与AS有潜在因果关联的新型生物标志物。
我们在社区动脉粥样硬化风险（ARIC）研究的中年参与者（访视3 [V3]；n = 11430；年龄60±6岁）和老年参与者（V5；n = 4899；年龄76±5岁）中测量了4877种血浆蛋白（SomaScan适配体亲和测定法）。我们通过多变量线性回归和Cox比例风险回归，确定了在V5时经超声心动图与主动脉瓣（AV）峰值速度（AVmax）和无量纲指数横断面相关的蛋白，以及在V3后与AV相关住院事件相关的蛋白。我们使用心脏计算机断层扫描评估了候选蛋白与6年内AVmax变化以及AV钙化的关联，在独立样本中进行重复分析，进行孟德尔随机化，并评估了移植的人AV组织中的基因表达。
52种蛋白在横断面与V5时的AVmax和无量纲指数以及V3后AV相关住院风险相关。在心血管健康研究的3413名参与者中，其中6种蛋白与经判定的中度或重度AS显著相关，包括基质金属蛋白酶12（MMP12）、补体C1q肿瘤坏死因子相关蛋白1（C1QTNF1）和生长分化因子15。MMP12还与6年内AVmax的更大增加、AV钙化程度更高以及钙化AV组织与正常或纤维化AV组织相比更高的表达相关。根据孟德尔随机化分析，C1QTNF1对AS和AVmax均具有一致的潜在因果效应。
这些发现确定MMP12为AS风险的一种潜在新型循环生物标志物，C1QTNF1为预防AS进展的一个新的假定靶点。
