Vilades David, Martínez-Camblor Pablo, Ferrero-Gregori Andreu, Bär Christian, Lu Dongchao, Xiao Ke, Vea Àngela, Nasarre Laura, Sanchez Vega Jesus, Leta Rubén, Carreras Francesc, Thum Thomas, Llorente-Cortés Vicenta, de Gonzalo-Calvo David
Cardiac Imaging Unit, Cardiology Service, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
Geisel School of Medicine, Dartmouth College, Hanover, NH, USA.
FASEB J. 2020 Mar;34(3):4403-4414. doi: 10.1096/fj.201902507R. Epub 2020 Jan 30.
The role of circular RNAs (circRNAs) as biomarkers remains poorly characterized. Here, we investigated the performance of the circRNA hsa_circ_0001445 as a biomarker of coronary artery disease (CAD) in a real-world clinical practice setting. Plasma hsa_circ_0001445 was measured in a study population of 200 consecutive patients with suspected stable CAD who had undergone coronary computed tomographic angiography (CTA). Multivariable logistic models were constructed combining conventional risk factors with established biomarkers and hsa_circ_0001445. Model robustness was internally validated by the bootstrap technique. Biomarker accuracy was evaluated using the C-index. The integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were also calculated. Risk groups were developed via classification tree models. The stability of plasma hsa_circ_0001445 was evaluated under different clinical conditions. hsa_circ_0001445 levels were associated with higher coronary atherosclerosis extent and severity with a 2-fold increase across tertiles (28.4%-50.0%). Levels of hsa_circ_0001445 were proportional to coronary atherosclerotic burden, even after comprehensive adjustment for cardiovascular risk factors, medications, and established biomarkers (fully adjusted OR = 0.432 for hsa_circ_0001445 as a continuous variable and fully adjusted OR = 0.277 for hsa_circ_0001445 as a binary variable). The classification of patients was improved with the incorporation of hsa_circ_0001445 into a base clinical model (CM) composed of conventional cardiovascular risk factors, showing an IDI of 0.047 and NRI of 0.482 for hsa_circ_0001445 as a continuous variable and an IDI of 0.056 and NRI of 0.373 for hsa_circ_0001445 as a binary variable. A trend toward higher discrimination capacity was also observed (C-index = 0.833, C-index = 0.856 and C-index = 0.855). Detailed analysis of stability showed that hsa_circ_0001445 was present in plasma in a remarkably stable form. In vitro, hsa_circ_0001445 was downregulated in extracellular vesicles secreted by human coronary smooth muscle cells upon exposure to atherogenic conditions. In patients with suspected stable CAD referred for coronary CTA, plasma hsa_circ_0001445 improves the identification of coronary artery atherosclerosis.
环状RNA（circRNAs）作为生物标志物的作用仍未得到充分表征。在此，我们在真实世界的临床实践环境中研究了环状RNA hsa_circ_0001445作为冠状动脉疾病（CAD）生物标志物的性能。在连续200例疑似稳定CAD且已接受冠状动脉计算机断层扫描血管造影（CTA）的患者研究队列中测量了血浆hsa_circ_0001445。构建了多变量逻辑模型，将传统危险因素与已确立的生物标志物及hsa_circ_0001445相结合。模型稳健性通过自举技术进行内部验证。使用C指数评估生物标志物准确性。还计算了综合判别改善（IDI）和净重新分类改善（NRI）。通过分类树模型建立风险组。在不同临床条件下评估血浆hsa_circ_0001445的稳定性。hsa_circ_0001445水平与较高的冠状动脉粥样硬化程度和严重程度相关，三分位数间增加了2倍（28.4% - 50.0%）。即使在对心血管危险因素、药物和已确立的生物标志物进行全面调整后，hsa_circ_0001445水平仍与冠状动脉粥样硬化负担成正比（hsa_circ_0001445作为连续变量时，完全调整后的OR = 0.432；hsa_circ_0001445作为二元变量时，完全调整后的OR = 0.277）。将hsa_circ_0001445纳入由传统心血管危险因素组成的基础临床模型（CM）后，患者分类得到改善，hsa_circ_0001445作为连续变量时，IDI为0.047，NRI为0.482；hsa_circ_0001445作为二元变量时，IDI为0.056，NRI为0.373。还观察到判别能力有提高的趋势（C指数 = 0.833、C指数 = 0.856和C指数 = 0.855）。稳定性的详细分析表明，hsa_circ_0001445以非常稳定的形式存在于血浆中。在体外，人冠状动脉平滑肌细胞暴露于致动脉粥样硬化条件下分泌的细胞外囊泡中，hsa_circ_0001445表达下调。在因冠状动脉CTA就诊的疑似稳定CAD患者中，血浆hsa_circ_0001445可改善冠状动脉粥样硬化的识别。
