Zuo Yu, NaveenKumar Somanathapura K, Navaz Sherwin, Liang Wenying, Sugur Kavya, Kmetova Katarina, Ayers Colby R, Kluge Lyndsay, Chong Emily, Shah Amil M, Rohatgi Anand, Berry Jarett D, Knight Jason S, de Lemos James A
Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor.
Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.
JAMA Cardiol. 2025 May 7. doi: 10.1001/jamacardio.2025.0945.
Innate immunity, particularly neutrophil activation, plays a crucial role in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). The potential of calprotectin, a biomarker of neutrophil activation, as a mechanistically informed biomarker for ASCVD in an ethnically diverse population requires further investigation.
To examine the prospective association between circulating calprotectin and ASCVD in a diverse, population-based cohort while also exploring calprotectin's mechanistic contributions to ASCVD in vitro.
DESIGN, SETTING, AND PARTICIPANTS: Circulating calprotectin was measured in plasma collected from 2412 participants during phase 2 of the Dallas Heart Study, a multiethnic, population-based cohort study. The median follow-up after plasma collection was 8 years.
Associations with future ASCVD events (defined as first nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or death from a cardiovascular cause) were assessed using Cox proportional hazards models, adjusted for known cardiovascular disease risk factors as well as high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and high-sensitivity cardiac troponin T (hs-cTnT).
Higher calprotectin levels were associated with older age, male sex, Black race, hypertension, diabetes, and smoking history. Individuals with higher calprotectin had higher hemoglobin A1c, very low-density lipoprotein cholesterol, and triglycerides, and lower high-density lipoprotein cholesterol and cholesterol efflux capacity. Log-transformed calprotectin levels were associated with an increased risk of ASCVD events over 8 years (hazard ratio [HR], 1.98 per log increase [95% CI, 1.54-2.53]). This association remained statistically significant after adjusting for prior ASCVD and traditional risk factors (HR, 1.61 [95% CI, 1.22-2.13]) and hs-CRP, NT-proBNP, and hs-cTnT (HR, 1.43 [95% CI, 1.04-1.96]). Higher calprotectin also correlated with higher coronary artery calcium scores (P < .001). In vitro studies revealed that calprotectin impaired coronary endothelial integrity, diminished nitric oxide production, and fostered endothelial to mesenchymal transition, providing potential mechanisms for ASCVD progression.
The findings suggest that calprotectin may serve as a mechanistically informed biomarker for ASCVD, independent of traditional and contemporary cardiovascular risk factors and biomarkers. However, its clinical utility warrants further evaluation.
固有免疫，尤其是中性粒细胞活化，在动脉粥样硬化性心血管疾病（ASCVD）的发病机制中起关键作用。钙卫蛋白作为中性粒细胞活化的生物标志物，在不同种族人群中作为ASCVD的一种有机制依据的生物标志物的潜力需要进一步研究。
在一个多样化的、基于人群的队列中研究循环钙卫蛋白与ASCVD之间的前瞻性关联，同时在体外探索钙卫蛋白对ASCVD的机制性作用。
设计、设置和参与者：在达拉斯心脏研究的第2阶段，对从2412名参与者收集的血浆中的循环钙卫蛋白进行了测量，该研究是一项多民族、基于人群的队列研究。血浆采集后的中位随访时间为8年。
使用Cox比例风险模型评估与未来ASCVD事件（定义为首次非致命性心肌梗死、非致命性中风、冠状动脉血运重建或心血管原因死亡）的关联，并对已知的心血管疾病风险因素以及高敏C反应蛋白（hs-CRP）、N末端脑钠肽前体（NT-proBNP）和高敏心肌肌钙蛋白T（hs-cTnT）进行调整。
较高的钙卫蛋白水平与年龄较大、男性、黑人种族、高血压、糖尿病和吸烟史相关。钙卫蛋白水平较高的个体血红蛋白A1c、极低密度脂蛋白胆固醇和甘油三酯水平较高，而高密度脂蛋白胆固醇和胆固醇流出能力较低。对数转换后的钙卫蛋白水平与8年内ASCVD事件风险增加相关（风险比[HR]，每对数增加1.98[95%CI，1.54 - 2.53]）。在调整先前的ASCVD和传统风险因素（HR，1.61[95%CI，1.22 - 2.13]）以及hs-CRP、NT-proBNP和hs-cTnT后，这种关联仍具有统计学意义（HR，1.43[95%CI，1.04 - 1.96]）。较高的钙卫蛋白水平也与较高的冠状动脉钙化评分相关（P <.001）。体外研究表明，钙卫蛋白损害冠状动脉内皮完整性，减少一氧化氮生成，并促进内皮向间充质转化，为ASCVD进展提供了潜在机制。
研究结果表明，钙卫蛋白可能作为ASCVD的一种有机制依据的生物标志物，独立于传统和当代心血管风险因素及生物标志物。然而，其临床实用性值得进一步评估。
