AbstractThe pathophysiology of variant transthyretin (TTR) amyloidosis (ATTRv) is associated with destabilizing mutations in the TTR tetramer. However, why TTR with a wild-type genetic sequence misfolds and aggregates in wild-type transthyretin amyloidosis (ATTRwt) is unknown. Here, we evaluate kinetic TTR stability with a newly developed ELISA system in combination with urea-induced protein denaturation.

摘要变体运甲状腺素蛋白（TTR）淀粉样变性（ATTRv）的病理生理学与TTR四聚体中的不稳定突变有关。然而，为什么具有野生型遗传序列的TTR在野生型运甲状腺素蛋白淀粉样变性（ATTRwt）中错误折叠和聚集尚不清楚。在这里，我们使用新开发的ELISA系统结合尿素诱导的蛋白质变性来评估动力学TTR稳定性。

Compared with that in control patients, endogenous TTR in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) exhibited thermodynamic instability, indicating that circulating TTR instability may be associated with the pathogenesis of ATTRwt as well as ATTRv. Our findings provide new insight into the underlying mechanisms of ATTRwt..

与对照组患者相比，野生型运甲状腺素蛋白淀粉样心肌病（ATTRwt-CM）患者的内源性TTR表现出热力学不稳定性，表明循环TTR不稳定性可能与ATTRwt和ATTRv的发病机制有关。我们的发现为ATTRwt的潜在机制提供了新的见解。。

IntroductionTransthyretin (TTR) amyloidosis (ATTR) is a systemic disease caused by deposition of TTR-derived amyloid in various organs represented by the peripheral nervous system and heart1. TTR is a 127-amino acid, 55-kDa homotetrameric protein that is synthesized mainly in the liver and functions as a transporter of thyroxine and retinol-binding protein in the bloodstream2.

引言运甲状腺素蛋白（TTR）淀粉样变性（ATTR）是一种全身性疾病，由TTR衍生的淀粉样蛋白沉积在以周围神经系统和心脏为代表的各种器官中引起1。TTR是一种127个氨基酸，55 kDa的同型四聚体蛋白，主要在肝脏中合成，并在血流中充当甲状腺素和视黄醇结合蛋白的转运蛋白2。

The TTR tetramer is known to dissociate into an aggregation-prone monomer that forms amorphous aggregates and subsequent amyloid fibrils, leading to tissue dysfunction and clinical phenotypes of ATTR3,4,5. ATTR is classified as wild-type transthyretin amyloidosis (ATTRwt, nonhereditary form) or variant transthyretin amyloidosis (ATTRv, hereditary form) according to the presence or absence of TTR genetic mutations.

已知TTR四聚体解离成易于聚集的单体，形成无定形聚集体和随后的淀粉样原纤维，导致ATTR3,4,5的组织功能障碍和临床表型。根据TTR基因突变的存在与否，ATTR被分类为野生型甲状腺素转运蛋白淀粉样变性（ATTRwt，非遗传形式）或变异型甲状腺素转运蛋白淀粉样变性（ATTRv，遗传形式）。

Previous studies have reported that ATTRv pathophysiology is associated with destabilizing mutations in the TTR tetramer, but the mechanisms involved in the development of ATTRwt remain unknown6,7.Over the past decade, transthyretin amyloid cardiomyopathy (ATTR-CM) has been recognized as a significant cause of HF and has been increasingly diagnosed due to advances in noninvasive imaging modalities, including cardiac bone scintigraphy with diphosphonate or pyrophosphate tracers.

先前的研究报道，ATTRv病理生理学与TTR四聚体的不稳定突变有关，但ATTRwt发生的机制尚不清楚6,7。在过去的十年中，运甲状腺素蛋白淀粉样心肌病（ATTR-CM）已被认为是HF的重要原因，并且由于非侵入性成像方式的进步而被越来越多地诊断出来，包括使用双磷酸盐或焦磷酸盐示踪剂的心骨闪烁扫描。

Although ATTR-CM is thought to be a rare disorder, an improved imaging modality and newly emerging therapies, such as TTR stabilizers8 or small interfering RNA drugs9,10, have facilitated recognition of the disease, as did epidemiological studies, which indicate that there are likely more undiagnosed ATTR-CM patients11.

虽然ATTR-CM被认为是一种罕见的疾病，但改进的成像方式和新出现的疗法，如TTR稳定剂8或小干扰RNA药物9,10，促进了对该疾病的认识，流行病学研究也表明，可能有更多未确诊的ATTR-CM患者11。

Indeed, 16% of patients with severe aortic stenosis who underwent transcatheter aortic valve replacement were positive by technetium-99 m pyrophosphate (99mTc-PYP) scintigraphy, an established diag.

事实上，16%接受经导管主动脉瓣置换术的严重主动脉瓣狭窄患者的锝-99 m焦磷酸盐（99mTc-PYP）闪烁扫描呈阳性，这是一种既定的诊断方法。

Data availability

数据可用性

Any data not included in this manuscript will be made available upon reasonable request to the corresponding author.

本手稿中未包含的任何数据将在相应作者的合理要求下提供。

AbbreviationsTTR:

缩写TTR：

Transthyretin

转甲状腺素蛋白

ATTR:

ATTR：

Transthyretin amyloidosis

转甲状腺素蛋白淀粉样变性

ATTRv:

ATTRv:

Variant transthyretin amyloidosis

变异性运甲状腺素蛋白淀粉样变性

ATTRwt:

ATTRwt:

Wild-type transthyretin amyloidosis

野生型运甲状腺素蛋白淀粉样变性

ATTR-CM:

ATTR-CM：

Transthyretin amyloid cardiomyopathy

运甲状腺素蛋白淀粉样心肌病

ATTRv-CM:

属性CM：

Variant transthyretin amyloid cardiomyopathy

变异型运甲状腺素蛋白淀粉样心肌病

ATTRwt-CM:

属性CM：

Wild-type transthyretin amyloid cardiomyopathy

野生型运甲状腺素蛋白淀粉样心肌病

ELISA:

ELISA：

Enzyme -linked immunosorbent assay

酶联免疫吸附试验

HF:

高频：

Heart failure

心力衰竭

HFpEF:

HFpEF：

Heart failure with preserved ejection fraction

射血分数保留的心力衰竭

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Download referencesFundingThis work was supported by a Grant-in-Aid for Young Scientists (23K15102) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and a Japan Heart Foundation Research Grant.Author informationAuthors and AffiliationsDivision of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, JapanTakuya Iino, Hidekazu Tanaka, Sachiko Yoshikawa, Junko Asakura, Tatsuro Ishida & Ken-ichi HirataCentral Research Laboratories, Sysmex Corporation, Kobe, JapanTakuya Iino & Amane HaradaDivision of Evidence-Based Laboratory Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, JapanManabu Nagao, Ken-ichi Hirata & Ryuji TohDivision of Molecular Epidemiology, Kobe University Graduate School of Medicine, Kobe, JapanMakoto Nishimori & Masakazu ShinoharaThe Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Kobe, JapanMasakazu ShinoharaBio-Diagnostic Reagent Technology Center, Sysmex Corporation, Kobe, JapanShunsuke WatanabeDivision of Nursing Practice, Kobe University Graduate School of Health Sciences, Kobe, JapanTatsuro IshidaAuthorsTakuya IinoView author publicationsYou can also search for this author in.

下载参考文献资助这项工作得到了日本教育、文化、体育、科学和技术部对年轻科学家的资助（23K15102）和日本心脏基金会研究资助的支持。作者信息作者和附属机构神户大学医学研究生院心血管医学系，神户，日本九谷三野，田中秀树，吉川昭子，浅仓纯子，石田达夫和平田健一中央研究实验室，Sysmex Corporation，神户，日本九谷三野和阿曼尼·哈拉达神户大学医学研究生院循证实验室医学系，7-5-1 Kusunoki Cho，中央区，神户，650-0017，日本长尾，平田健一和东良二分子流行病学系，神户大学研究生院医学，神户，日本Makoto Nishimori＆Masakazu Shinohara神户大学医学研究生院质谱综合中心，神户，日本Masakazu ShinoharaBio诊断试剂技术中心，Sysmex Corporation，神户，日本渡边淳介神户大学健康科学研究生院护理实践部，JapanTatsuro IshidaAuthorsTakuya IinoView作者出版物您也可以在中搜索此作者。

PubMed Google ScholarManabu NagaoView author publicationsYou can also search for this author in

PubMed Google ScholarManabu NagaoView作者出版物您也可以在

PubMed Google ScholarHidekazu TanakaView author publicationsYou can also search for this author in

PubMed Google ScholarHidekazu TanakaView作者出版物您也可以在

PubMed Google ScholarSachiko YoshikawaView author publicationsYou can also search for this author in

PubMed Google ScholarSachiko YoshikawaView作者出版物您也可以在

PubMed Google ScholarJunko AsakuraView author publicationsYou can also search for this author in

PubMed Google ScholarJunko AsakuraView作者出版物您也可以在

PubMed Google ScholarMakoto NishimoriView author publicationsYou can also search for this author in

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PubMed Google ScholarMasakazu ShinoharaView author publicationsYou can also search for this author in

PubMed Google ScholarMasakazu ShinoharaView作者出版物您也可以在

PubMed Google ScholarAmane HaradaView author publicationsYou can also search for this author in

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PubMed Google ScholarShunsuke WatanabeView author publicationsYou can also search for this author in

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PubMed Google ScholarTatsuro IshidaView author publicationsYou can also search for this author in

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PubMed Google ScholarKen-ichi HirataView author publicationsYou can also search for this author in

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PubMed Google ScholarRyuji TohView author publicationsYou can also search for this author in

PubMed Google ScholarRyuji TohView作者出版物您也可以在

PubMed Google ScholarContributionsKI.H., T.I., and R.T. designed and supervised the study. T.I. and M.N. wrote the manuscript. H.T., M.N., S.Y., and J.A. collected the serum of the patients. T.I., S.W., and A.H. performed the experiments. M.N. and M.S. analyzed the data. All authors reviewed the manuscript.Corresponding authorCorrespondence to.

PubMed谷歌学术贡献（ScholarContributionsKI）。H、 ，T.I.和R.T.设计并监督了这项研究。T、 I.和M.N.写了手稿。H、 T.，M.N.，S.Y。和J.A.收集了患者的血清。T、 I.，S.W。和A.H.进行了实验。M、 N.和M.S.分析了数据。所有作者都审阅了手稿。对应作者对应。

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Manabu Nagao。道德宣言

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Reprints and permissionsAbout this articleCite this articleIino, T., Nagao, M., Tanaka, H. et al. Assessment of transthyretin instability in patients with wild-type transthyretin amyloid cardiomyopathy.

转载和许可本文引用本文Iino，T.，Nagao，M.，Tanaka，H。等人对野生型运甲状腺素蛋白淀粉样心肌病患者运甲状腺素蛋白不稳定性的评估。

Sci Rep 14, 20508 (2024). https://doi.org/10.1038/s41598-024-71446-8Download citationReceived: 29 May 2024Accepted: 28 August 2024Published: 03 September 2024DOI: https://doi.org/10.1038/s41598-024-71446-8Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Sci Rep 142058（2024）。https://doi.org/10.1038/s41598-024-71446-8Download引文接收日期：2024年5月29日接受日期：2024年8月28日发布日期：2024年9月3日OI：https://doi.org/10.1038/s41598-024-71446-8Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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KeywordsTransthyretinWild-type transthyretin amyloid cardiomyopathyHeart failureHeart failure with preserved ejection fractionAging

关键词SThyretinwild型运甲状腺素蛋白淀粉样心肌病心力衰竭伴射血分数保留

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