Aims Atrial fibrillation (AF) and heart failure (HF) are two growing epidemics that frequently co-exist. We aimed to gain insights into the underlying pathophysiological pathways in HF patients with AF by comparing circulating biomarkers using pathway overrepresentation analyses. Methods and results From a panel of 92 biomarkers from different pathophysiological domains available in 1620 patients with HF, we first tested which biomarkers were dysregulated in patients with HF and AF (n = 648) compared with patients in sinus rhythm (n = 972). Secondly, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in patients who had HF and AF. Findings were validated in an independent HF cohort (n = 1219, 38% with AF). Patient with AF and HF were older, less often women, and less often had a history of coronary artery disease compared with those in sinus rhythm. In the index cohort, 24 biomarkers were up-regulated in patients with AF and HF. In the validation cohort, eight biomarkers were up-regulated, which all overlapped with the 24 biomarkers found in the index cohort. The strongest up-regulated biomarkers in patients with AF were spondin-1 (fold change 1.18, P = 1.33 × 10−12), insulin-like growth factor-binding protein-1 (fold change 1.32, P = 1.08 × 10−8), and insulin-like growth factor-binding protein-7 (fold change 1.33, P = 1.35 × 10−18). Pathway overrepresentation analyses revealed that the presence of AF was associated with activation amyloid-beta metabolic processes, amyloid-beta formation, and amyloid precursor protein catabolic processes with a remarkable consistency observed in the validation cohort. Conclusion In two independent cohorts of patients with HF, the presence of AF was associated with activation of three pathways related to amyloid-beta. These hypothesis-generating results warrant confirmation in future studies.

中文翻译：

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心力衰竭和心房颤动患者的病理生理通路

目的 心房颤动 (AF) 和心力衰竭 (HF) 是两种日益严重且经常并存的流行病。我们旨在通过使用通路过度代表性分析比较循环生物标志物来深入了解 AF 患者的潜在病理生理通路。方法和结果 从 1620 名 HF 患者的一组来自不同病理生理学领域的 92 种生物标志物，我们首先测试了与窦性心律患者（n = 972）相比，哪些生物标志物在 HF 和 AF 患者（n = 648）中失调。其次，进行了通路过度代表性分析，以确定与 HF 和 AF 患者血浆生物标志物浓度较高相关的生物学通路。结果在一个独立的 HF 队列中得到验证（n = 1219，38% 患有 AF）。AF 和 HF 患者年龄较大，女性较少，与窦性心律患者相比，较少有冠状动脉疾病史。在指数队列中，24 种生物标志物在 AF 和 HF 患者中上调。在验证队列中，8 个生物标志物被上调，它们都与指数队列中发现的 24 个生物标志物重叠。AF 患者最强的上调生物标志物是 spondin-1（倍数变化 1.18，P = 1.33 × 10-12）、胰岛素样生长因子结合蛋白-1（倍数变化 1.32，P = 1.08 × 10-8 ）和胰岛素样生长因子结合蛋白7（倍数变化1.33，P = 1.35 × 10−18）。通路过度代表性分析表明，AF 的存在与激活淀粉样蛋白-β 代谢过程、淀粉样蛋白-β 形成和淀粉样蛋白前体蛋白分解代谢过程相关，在验证队列中观察到了显着的一致性。结论 在两个独立的 HF 患者队列中，房颤的存在与淀粉样蛋白-β 相关的三个通路的激活有关。这些产生假设的结果需要在未来的研究中得到证实。