Shitole Sanyog G, Heckbert Susan R, Marcus Gregory M, Shah Sanjiv J, Sotoodehnia Nona, Walston Jeremy D, Reiner Alexander P, Tracy Russell P, Psaty Bruce M, Kizer Jorge R
Cardiology Section San Francisco Veterans Affairs Health Care System San Francisco CA USA.
Department of Medicine University of California San Francisco San Francisco CA USA.
J Am Heart Assoc. 2024 Dec 17;13(24):e035710. doi: 10.1161/JAHA.124.035710. Epub 2024 Dec 6.
Available evidence supports the importance of inflammation in atrial fibrillation (AF) pathogenesis, yet general anti-inflammatory therapies have failed to show benefit for prevention of the arrhythmia. Better understanding of the specific inflammatory pathways involved is necessary to advance therapeutics.
We evaluated 9 circulating markers of inflammation measured by immunoassays and incidence of AF in a population-based older cohort. Biomarkers included measures of general inflammation and the NLR (nucleotide-binding oligomerization domain-like receptor) family pyrin domain containing 3 inflammasome, TNF-α (tumor necrosis factor α), monocyte activation markers, and sIL-2 (soluble interleukin-2). Among 5726 participants (median age 72 years), 1836 developed AF over median follow-up of 11.5 years. After adjustment for conventional risk factors, 5 biomarkers were positively associated with incident AF: IL-6 (interleukin-6), hazard ratio (HR), 1.14 (95% CI, 1.07-1.21); hs-CRP (high-sensitivity C-reactive protein), HR, 1.05 (95% CI, 1.01-1.09); white blood cell count, HR, 1.18 (95% CI, 1.04-1.35); sTNFR1 (soluble TNF receptor 1), HR, 1.21 (95% CI, 1.05-1.39); and sIL-2Rα (sIL-2 receptor α), HR, 1.16 (95% CI, 1.05-1.29) (all per doubling of biomarker). sCD14, sCD163, IL-18, and IL-1 receptor antagonist showed no association with AF. Upon concurrent adjustment for all biomarkers, only IL-6 remained significantly associated with the arrhythmia, HR, 1.17 (95% CI, 1.07-1.26).
Among older adults, IL-6, hs-CRP, white blood cell count, sTNFR1, and sIL-2Rα were positively associated with incident AF, but only IL-6 retained significance on concurrent adjustment. These findings newly document associations for sTNFR1 and sIL-2Rα and lend support to a preeminent role for IL-6 in development of this arrhythmia. The efficacy of IL-6 blockade for AF prevention awaits completion of appropriate clinical trials.
现有证据支持炎症在心房颤动（AF）发病机制中的重要性，但一般抗炎治疗未能显示出预防心律失常的益处。更好地了解所涉及的特定炎症途径对于推进治疗方法是必要的。
我们评估了通过免疫测定法测量的9种循环炎症标志物以及基于人群的老年队列中的AF发病率。生物标志物包括一般炎症指标、含3个吡啉结构域的NLR（核苷酸结合寡聚化结构域样受体）家族炎性小体、肿瘤坏死因子α（TNF-α）、单核细胞活化标志物和可溶性白细胞介素-2（sIL-2）。在5726名参与者（中位年龄72岁）中，1836人在中位随访11.5年期间发生了AF。在对传统危险因素进行调整后，5种生物标志物与新发AF呈正相关：白细胞介素-6（IL-6），风险比（HR）为1.14（95%CI，1.07 - 1.21）；高敏C反应蛋白（hs-CRP）为1.05（95%CI，1.01 - 1.09）；白细胞计数为1.18（95%CI，1.04 - 1.35）；可溶性肿瘤坏死因子受体1（sTNFR1）为1.21（95%CI，1.05 - 1.39）；可溶性白细胞介素-2受体α（sIL-2Rα）为1.16（95%CI，1.05 - 1.29）（所有均为生物标志物加倍时）。可溶性CD14、可溶性CD163、白细胞介素-18和白细胞介素-1受体拮抗剂与AF无关联。在对所有生物标志物进行同时调整后，只有IL-6仍与心律失常显著相关，HR为1.17（95%CI，1.07 - 1.26）。
在老年人中，IL-6、hs-CRP、白细胞计数、sTNFR1和sIL-2Rα与新发AF呈正相关，但只有IL-6在同时调整时仍具有显著性。这些发现首次记录了sTNFR1和sIL-2Rα的关联，并支持IL-6在这种心律失常发生中起主要作用。IL-6阻断预防AF的疗效有待适当临床试验完成。
