Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands; National Heart Centre Singapore, Singapore; Duke-NUS Medical School, Singapore.
Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
JACC Heart Fail. 2020 Mar;8(3):234-242. doi: 10.1016/j.jchf.2019.11.005. Epub 2020 Feb 5.
The aims of this study were to compare the characteristics of patients with and without diabetes and to use network analyses to compare biomarker profiles and associated pathways in patients with diabetes compared with those without diabetes, which might offer new avenues for potential therapeutic targets.
Diabetes adversely affects clinical outcomes and complicates treatment in patients with heart failure (HF). A clear understanding of the pathophysiological processes associated with type 2 diabetes in HF is lacking.
Network and pathway over-representation analyses were performed to identify unique pathological pathways in patients with and without diabetes using 92 biomarkers from different pathophysiological domains measured in plasma samples from 1,572 patients with HF (31% with diabetes) with reduced ejection fraction (left ventricular ejection fraction <40%). The results were validated in an independent cohort of 729 patients (30% with diabetes).
Biomarker profiles were first compared between patients with HF with and without diabetes. Patients with diabetes showed higher levels of galectin-4, growth differentiation factor 15, and fatty acid binding protein 4 and lower levels of paraoxonase 3. Network analyses were then performed, revealing that epidermal growth factor receptor and galectin-3 were the most prominent connecting proteins. Translation of these networks to biologic pathways revealed that diabetes was associated with inflammatory response and neutrophil degranulation. Diabetes conferred worse outcomes after correction for an established risk model (hazard ratio: 1.20; 95% confidence interval: 1.01 to 1.42).
Concomitant diabetes in patients with HF with reduced ejection fraction is associated with distinct pathophysiological pathways related to inflammation, protein phosphorylation, and neutrophil degranulation. These data support the evaluation of anti-inflammatory therapeutic approaches, epidermal growth factor receptor in particular, for patients with HF and diabetes.
本研究旨在比较伴有和不伴糖尿病患者的特征，并利用网络分析比较糖尿病患者与无糖尿病患者的生物标志物谱及相关通路，这可能为潜在的治疗靶点提供新的途径。
糖尿病会对心力衰竭（HF）患者的临床结局产生不利影响，并使治疗复杂化。对于 2 型糖尿病与 HF 相关的病理生理过程，目前尚缺乏清晰的认识。
利用来自不同病理生理领域的 92 种生物标志物，对来自 1572 例射血分数降低（左心室射血分数 <40%）HF 患者（31%患有糖尿病）的血浆样本进行网络和通路过度表达分析，以识别伴有和不伴有糖尿病患者的独特病理通路。研究结果在 729 例独立患者（30%患有糖尿病）中得到了验证。
首先比较了伴有和不伴有糖尿病的 HF 患者的生物标志物谱。患有糖尿病的患者表现出更高水平的半乳糖凝集素-4、生长分化因子 15 和脂肪酸结合蛋白 4，以及更低水平的对氧磷酶 3。然后进行了网络分析，结果显示表皮生长因子受体和半乳糖凝集素-3 是最突出的连接蛋白。将这些网络转化为生物学通路显示，糖尿病与炎症反应和中性粒细胞脱颗粒有关。在校正了既定风险模型后，糖尿病使患者预后恶化（危险比：1.20；95%置信区间：1.01 至 1.42）。
射血分数降低的 HF 患者合并糖尿病与炎症、蛋白磷酸化和中性粒细胞脱颗粒等相关的独特病理生理通路有关。这些数据支持针对 HF 合并糖尿病患者评估抗炎治疗方法，特别是表皮生长因子受体。
