循环中的 ECM 蛋白质装饰素和α-L-iduronidase 可区分 ATTRwt-CM 和 ATTRwt 阴性 HFpEF/HFmrEF

IF 10.2 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Cardiovascular Research Pub Date : 2024-09-17 DOI:10.1093/cvr/cvae189
Alwin Tubben, George Markousis-Mavrogenis, Laura M G Meems, Bart J van Essen, Lukas Baumhove, Milou Berends, Hendrea S A Tingen, Johan Bijzet, Bouke P C Hazenberg, Adriaan A Voors, Dirk J van Veldhuisen, Riemer H J A Slart, Hans L A Nienhuis, Peter van der Meer
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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. 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引用次数: 0

摘要

目的 野生型转甲状腺素心脏淀粉样变性(ATTRwt-CM)是一种未被充分认识的心力衰竭(HF)病因,需要早期发现以便及时治疗。我们的研究旨在通过识别和验证循环蛋白生物标记物,将 ATTRwt-CM 患者与 ATTRwt 阴性的高频心衰患者区分开来。此外,我们还测量了轻链淀粉样变性(AL)-CM 心肌病患者的相同生物标志物,以获得疾病特异性的见解。方法和结果 在这项观察性研究中,我们使用多重近距离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。稀疏偏最小二乘法分析显示,ATTRwt-CM 和 AL-CM 的生物标记物特征相互重叠,与 ATTRwt 阴性患者有明显的直观区分。使用g:Profiler进行的通路分析表明,ATTRwt-CM和AL-CM中的蛋白多糖(PG)和细胞粘附通路都明显上调。惩罚性回归分析显示,蛋白多糖decorin(DCN)、溶酶体水解酶α-L-iduronidase(IDUA)和糖基水解酶半乳糖苷酶β-1(GLB-1)能最有效地区分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 在初步分析中可显著预测 ATTRwt-CM(DCN:OR 3.3,IDUA:OR 0.4)。在校正超声心动图参数后,DCN 仍具有显著性,而 IDUA 则没有。DCN 和 IDUA(AUC,0.78;95% CI,0.65-0.91;灵敏度,0.91;特异性,0.61)显示出中等程度的鉴别能力(AUC,0.74;95% CI,0.61-0.87;灵敏度,0.91;特异性,0.52)。结合临床因素的模型(AUC 0.92)优于 DCN,但不如 IDUA,结合生物标记物的模型也没有明显优势。DCN和IDUA均与已确定的疾病标志物无关。结论 ATTRwt-CM 与 HFpEF/HFmrEF 相比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,其特点是蛋白聚糖和细胞粘附途径的上调。生物标志物 DCN 和 IDUA 显示出作为 ATTTRwt-CM 初步筛查工具的潜力。还需要进一步研究,以确定这些和其他细胞外基质成分在识别 ATTRwt-CM 方面的临床实用性。
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Circulating ECM proteins decorin and alpha-L-iduronidase differentiate ATTRwt-CM from ATTRwt-negative HFpEF/HFmrEF
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.
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来源期刊
Cardiovascular Research
Cardiovascular Research 医学-心血管系统
CiteScore
21.50
自引率
3.70%
发文量
547
审稿时长
1 months
期刊介绍: Cardiovascular Research Journal Overview: International journal of the European Society of Cardiology Focuses on basic and translational research in cardiology and cardiovascular biology Aims to enhance insight into cardiovascular disease mechanisms and innovation prospects Submission Criteria: Welcomes papers covering molecular, sub-cellular, cellular, organ, and organism levels Accepts clinical proof-of-concept and translational studies Manuscripts expected to provide significant contribution to cardiovascular biology and diseases
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