SCAN-MP (Screening for Cardiac Amyloidosiswith Nuclear imaging in Minority Populations)

SCAN-MP（在少数人群中用核成像筛查心脏淀粉样变性）

• 批准号: 10579994
• 负责人: MATHEW S MAURER
• 金额: $ 146.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579994
• 关键词: Address; African; African American population; African ancestry; Age; All-Trans-Retinol; Alleles; Amyloid; Amyloidosis; Autopsy; Binding; Biological Assay; Biological Markers; Biopsy; Black American; Black Populations; Black race; Blood; Blood Tests; Calibration; Cardiac; Caribbean Hispanic; Carrier Proteins; Caucasians; Cessation of life; Classification; Clinic; Clinical; Clinical Trials; Communities; Data; Deposition; Diagnosis; Diagnostic tests; Diphosphates; Disease; Disease Progression; Dissociation; EFRAC; Early Diagnosis; Early treatment; Echocardiography; Elderly; Gene Frequency; Genes; Genetic; Genetic Carriers; Genotype; Heart failure; Hispanic; Hispanic Americans; Hispanic Populations; Hospitalization; Human; Image; Individual; Institution; Isoleucine; Kinetics; Knowledge; Label; Measurement; Measures; Medical; Methodology; Minority Groups; Multicenter Studies; Mutate; Mutation; Myocardial; Pathogenesis; Patients; Persons; Phenotype; Plasma; Point Mutation; Population; Positioning Attribute; Prealbumin; Prevalence; Prospective, cohort study; Proteins; RBP4 gene; Renal clearance function; Reporting; Reproducibility; Research; Risk; Serum; Sex Distribution; Techniques; Testing; Thyroid Hormones; United States; Urine; Valine; Variant; age related; autosome; black patient; cardiac amyloidosis; carrier status; clinical phenotype; clinical practice; cohort; diagnostic accuracy; diagnostic tool; effective therapy; genotyped patients; heart imaging; improved outcome; insight; male; monomer; mutant; mutation carrier; novel marker; nuclear imaging; older patient; patient population; point-of-care diagnostics; preservation; prevent; prospective; recruit; screening; sex; uptake

Heart failure with preserved ejection fraction (HFpEF) disproportionately afflicts older Black and Hispanic Americans. ATTR cardiac amyloidosis (ATTR CA) is caused by myocardial deposition of misfolded transthyretin protein (TTR or prealbumin) and is classified by the genetics of TTR into wild-type (ATTRwt) or mutant (ATTRm). ATTR CA, irrespective of genotype, is an age-dependent, often unrecognized, mechanism underlying HFpEF. While ATTRm CA results from point mutations that promote TTR misfolding and amyloid aggregation, factors that contribute to ATTRwt CA are not well defined. While previously thought to be untreatable, promising therapies in late-stage clinical trials will likely be most effective if administered early in disease course. Only a small proportion of individuals with wild-type TTR will develop ATTRwt CA, overwhelmingly reported in Caucasian males beyond age 60 years. However, as an autosomal protein, allele distribution is not sex specific. For ATTRm, a substitution of isoleucine for valine (V122I) is the most frequent TTR mutation in the US, observed exclusively in Black Americans with an allele frequency of 3.4%. But there are no data regarding the prevalence of ATTRwt CA in African Americans and no data for ATTR CA prevalence, irrespective of genotype, in the Hispanic population. One of the reasons for the knowledge deficit is the challenge of diagnosis. Endomyocardial biopsy, while nearly 100% sensitive and specific, is impractical as a screening test and genotyping alone of patients is insufficient to identify ATTR CA because wild-type patients develop disease. We have developed a highly accurate technique for ATTR CA identification using Tc99m-pyrophosphate (PYP) imaging that avoids the need for biopsy. Tc99m-PYP myocardial uptake can occur before echocardiographic or clinical changes, suggesting enhanced sensitivity. While studies using the technique have suggested that 10-15% of elderly hospitalized patients with HF may have ATTR CA, Tc99m- PYP has not been applied broadly in HF patients as a means to facilitate early diagnosis. In addition, we have also reported both a point-of-care diagnostic tool that utilizes a novel biomarker, retinol binding protein 4 (RBP4), and an assay to measure TTR stability. We hypothesize that a significant proportion of HF in elderly Blacks and Hispanics is caused ATTR CA. We propose to leverage our methodologies to establish the prevalence of ATTR CA and explore the relationship between RBP4 concentration and TTR stability in a prospective cohort study of elderly Black and Hispanic Americans with HF. Aim 1 will determine the prevalence and clinical progression of ATTR CA relative to genotype, clarify sex distribution, and calibrate the aforementioned point-of-care diagnostic tool. Aim 2 will explore the relationships between RBP4 concentration in serum and urine, TTR stability, and genotype in ATTR CA. Successful completion of these Aims will inform understanding of ATTR CA pathogenesis and may modify clinical practice, alter PYP indication labeling, and improve outcomes for older adult Black Americans and Hispanics with HF.

射血分数保留的心力衰竭（HFpEF）尤其困扰老年黑人和西班牙裔 美国人。 ATTR 心脏淀粉样变性 (ATTR CA) 是由错误折叠的心肌沉积引起的 运甲状腺素蛋白（TTR 或前白蛋白），根据 TTR 遗传学分为野生型 (ATTRwt) 或 突变体（ATTRm）。 ATTR CA，无论基因型如何，都是一种年龄依赖性的、常常未被识别的机制 潜在的 HFpEF。 ATTRm CA 是由促进 TTR 错误折叠和淀粉样蛋白的点突变引起的 聚合，导致 ATTRwt CA 的因素尚未明确定义。虽然之前认为是 晚期临床试验中无法治疗的、有希望的疗法如果在早期进行治疗可能会最有效 病程。只有一小部分具有野生型 TTR 的个体会出现 ATTRwt CA， 绝大多数报告在 60 岁以上的白人男性中。然而，作为常染色体蛋白质，等位基因 分布不分性别。对于 ATTRm，最常见的是用异亮氨酸替代缬氨酸 (V122I) 美国的 TTR 突变仅在美国黑人中观察到，等位基因频率为 3.4%。但有 没有关于非裔美国人中 ATTRwt CA 患病率的数据，也没有 ATTR CA 的数据 西班牙裔人群中的患病率，无论基因型如何。知识匮乏的原因之一 是诊断的挑战。心内膜心肌活检虽然具有近 100% 的敏感性和特异性，但并不实用 作为筛查测试，仅对患者进行基因分型不足以识别 ATTR CA，因为野生型 患者患病。我们开发了一种高精度的 ATTR CA 识别技术，使用 Tc99m-焦磷酸 (PYP) 成像，无需活检。 Tc99m-PYP 心肌摄取可发生 在超声心动图或临床变化之前，表明敏感性增强。在研究中使用 技术表明，10-15% 的老年住院心衰患者可能患有 ATTR CA、Tc99m- PYP 作为促进早期诊断的手段尚未广泛应用于心力衰竭患者。此外，我们还有 还报道了一种利用新型生物标志物视黄醇结合蛋白 4 的即时诊断工具 (RBP4)，以及测量 TTR 稳定性的测定。我们假设老年人中很大比例的心力衰竭 黑人和西班牙裔是 ATTR CA 造成的。我们建议利用我们的方法来建立 ATTR CA 的患病率并探讨 RBP4 浓度与 TTR 稳定性之间的关系 针对患有心力衰竭的老年黑人和西班牙裔美国人的前瞻性队列研究。目标 1 将确定 相对于基因型的 ATTR CA 患病率和临床进展，阐明性别分布，并校准 上述的即时诊断工具。目标 2 将探讨 RBP4 之间的关系 血清和尿液中的浓度、TTR 稳定性以及 ATTR CA 中的基因型。顺利完成这些 目标将有助于理解 ATTR CA 发病机制，并可能修改临床实践、改变 PYP 适应症标签，并改善老年美国黑人和西班牙裔心力衰竭的治疗结果。

项目成果

Impact of Genetic Testing in Transthyretin (ATTR) Cardiac Amyloidosis.

基因检测对甲状腺素运载蛋白 (ATTR) 心脏淀粉样变性的影响。

• 发表时间: 2019
• 作者: Gopal, Deepa M;Ruberg, Frederick L;Siddiqi, Omar K
• 通讯作者: Siddiqi, Omar K

Phenotype Mapping in Cardiac Amyloidosis.

心脏淀粉样变性的表型作图。

• 发表时间: 2021
• 影响因子: 24
• 作者: Ruberg; Frederick L
• 通讯作者: Frederick L

Temporal Outcomes of Patients Diagnosed With Transthyretin Cardiac Amyloidosis.

诊断为运甲状腺素蛋白心脏淀粉样变性患者的时间结果。

• 发表时间: 2024-03-06
• 影响因子: 6
• 作者: Chan, Nicholas;Teruya, Sergio;Mirabal, Alfonsina;Weinsaft, Ariel Y;Santos, Jeffeny DE Los;Guadalupe, Samantha;Jimenez, Massiel;Rodriguez, Carlos;Helmke, Stephen;Cuomo, Margaret;Smiley, Dia;Maurer, Mathew S
• 通讯作者: Maurer, Mathew S

Avoiding misdiagnosis: expert consensus recommendations for the suspicion and diagnosis of transthyretin amyloidosis for the general practitioner.

避免误诊：针对全科医生疑似转甲状腺素蛋白淀粉样变性的专家共识建议。

• 发表时间: 2020-09-23
• 影响因子: 2.9
• 作者: Gertz, Morie;Adams, David;Ando, Yukio;Beirão, João Melo;Bokhari, Sabahat;Coelho, Teresa;Comenzo, Raymond L;Damy, Thibaud;Dorbala, Sharmila;Drachman, Brian M;Fontana, Marianna;Gillmore, Julian D;Grogan, Martha;Hawkins, Philip N;Lousada, Isabe
• 通讯作者: Lousada, Isabe

Clinical approach to genetic testing in amyloid cardiomyopathy: from mechanism to effective therapies.

淀粉样心肌病基因检测的临床方法：从机制到有效疗法。

• 发表时间: 2021-05-01
• 影响因子: 2.3
• 作者: Alreshq, Rabah;Ruberg, Frederick L
• 通讯作者: Ruberg, Frederick L