Aims Wild-type transthyretin cardiac amyloidosis (ATTRwt-CM) is an under-recognized aetiology of heart failure (HF), necessitating early detection for timely treatment. Our study aimed to differentiate patients with ATTRwt-CM from ATTRwt-negative HFpEF/HFmrEF patients by identifying and validating circulating protein biomarkers. In addition, we measured the same biomarkers in patients with cardiomyopathy due to light chain amyloidosis (AL)-CM to gain disease-specific insights. Methods and results In this observational study, serum concentrations of 363 protein biomarkers were measured in a discovery cohort consisting of 73 ATTRwt-CM, 55 AL-CM, and 59 ATTRwt-negative HFpEF/HFmrEF patients, using multiplex proximity extension assays. Sparse partial least squares analyses showed overlapping ATTRwt-CM and AL-CM biomarker profiles with clear visual differentiation from ATTRwt-negative patients. Pathway analyses with g:Profiler revealed significantly up-regulated proteoglycans (PG) and cell adhesion pathways in both ATTRwt-CM and AL-CM. Penalized regression analysis revealed that the proteoglycan decorin (DCN), lysosomal hydrolase alpha-L-iduronidase (IDUA) and glycosyl hydrolase galactosidase β-1 (GLB-1) most effectively distinguished ATTRwt-CM from ATTRwt-negative patients (R2 = 0.71). In a prospective validation cohort of 35 ATTRwt-CM patients and 25 ATTRwt-negative patients, DCN and IDUA significantly predicted ATTRwt-CM in the initial analysis (DCN: OR 3.3, IDUA: OR 0.4). While DCN remained significant after correcting for echocardiographic parameters, IDUA did not. DCN showed moderate discriminative ability (AUC, 0.74; 95% CI, 0.61–0.87; sensitivity, 0.91; specificity, 0.52) as did IDUA (AUC, 0.78; 95% CI, 0.65–0.91; sensitivity, 0.91; specificity, 0.61). A model combining clinical factors (AUC 0.92) outperformed DCN but not IDUA, a combination of the biomarkers was not significantly better. Neither DCN nor IDUA correlated with established disease markers. Conclusion ATTRwt-CM has a distinctly different biomarker profile compared with HFpEF/HFmrEF, while ATTRwt-CM patients share a similar biomarker profile with AL-CM patients characterized by up-regulation of proteoglycans and cell-adhesion pathways. The biomarkers DCN and IDUA show the potential to serve as an initial screening tool for ATTTRwt-CM. Further research is needed to determine the clinical usefulness of these and other extracellular matrix components in identifying ATTRwt-CM.

中文翻译：

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循环 ECM 蛋白核心蛋白聚糖和 α-L-艾杜糖醛酸酶区分 ATTRwt-CM 和 ATTRwt 阴性 HFpEF/HFmrEF


野生型转甲状腺素蛋白心脏淀粉样变性 (ATTRwt-CM) 是一种未被充分认识的心力衰竭 (HF) 病因，需要早期发现并及时治疗。我们的研究旨在通过识别和验证循环蛋白生物标志物来区分 ATTRwt-CM 患者与 ATTRwt 阴性 HFpEF/HFmrEF 患者。此外，我们还测量了轻链淀粉样变性 (AL)-CM 引起的心肌病患者的相同生物标志物，以获得针对特定疾病的见解。方法和结果 在这项观察性研究中，使用多重邻近延伸测定法测量了由 73 名 ATTRwt-CM、55 名 AL-CM 和 59 名 ATTRwt 阴性 HFpEF/HFmrEF 患者组成的发现队列中 363 种蛋白质生物标志物的血清浓度。稀疏偏最小二乘分析显示 ATTRwt-CM 和 AL-CM 生物标志物谱重叠，与 ATTRwt 阴性患者有明显的视觉差异。使用 g:Profiler 进行的通路分析显示 ATTRwt-CM 和 AL-CM 中的蛋白聚糖 (PG) 和细胞粘附通路显着上调。惩罚回归分析显示，蛋白聚糖核心蛋白聚糖 (DCN)、溶酶体水解酶 α-L-艾杜糖醛酸酶 (IDUA) 和糖基水解酶半乳糖苷酶 β-1 (GLB-1) 最有效区分 ATTRwt-CM 和 ATTRwt 阴性患者 (R2 = 0.71) 。在由 35 名 ATTRwt-CM 患者和 25 名 ATTRwt 阴性患者组成的前瞻性验证队列中，DCN 和 IDUA 在初始分析中显着预测了 ATTRwt-CM（DCN：OR 3.3，IDUA：OR 0.4）。虽然 DCN 在校正超声心动图参数后仍然显着，但 IDUA 却没有。 DCN 与 IDUA 一样表现出中等辨别能力（AUC，0.74；95% CI，0.61-0.87；敏感性，0.91；特异性，0.52）（AUC，0.78；95% CI，0.65-0.91；敏感性，0.91；特异性，0.61） 。 结合临床因素的模型（AUC 0.92）优于 DCN，但不优于 IDUA，生物标志物的组合并没有明显更好。 DCN 和 IDUA 均与已确定的疾病标志物相关。结论 与 HFpEF/HFmrEF 相比，ATTRwt-CM 具有明显不同的生物标志物特征，而 ATTRwt-CM 患者与 AL-CM 患者具有相似的生物标志物特征，其特征是蛋白多糖和细胞粘附途径上调。生物标志物 DCN 和 IDUA 显示出作为 ATTTRwt-CM 初始筛选工具的潜力。需要进一步的研究来确定这些和其他细胞外基质成分在识别 ATTRwt-CM 中的临床用途。