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.

射血分数保留性心力衰竭（HFpEF）不成比例地折磨老年黑人和西班牙裔 美国人ATTR心脏淀粉样变性（ATTR CA）是由心肌沉积的错误折叠的 甲状腺素运载蛋白（TTR或前白蛋白），并根据TTR的遗传学分为野生型（ATTRwt）或 突变体（ATTRm）。无论基因型如何，ATTR CA都是一种年龄依赖性的，通常未被识别的机制 基础HFpEF。而ATTRm CA是由促进TTR错误折叠和淀粉样蛋白的点突变引起的， 聚集，导致ATTRwt CA的因素没有很好地定义。虽然之前被认为是 在晚期临床试验中无法治愈的有希望的疗法如果在早期给药可能是最有效的。 病程。只有一小部分具有野生型TTR的个体将发展ATTRwt CA， 绝大多数在60岁以上的白人男性中报告。然而，作为常染色体蛋白，等位基因 分布没有性别特异性。对于ATTRm，异亮氨酸取代缬氨酸（V122 I）是最常见的 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 没有关于非裔美国人中ATTRwt CA患病率的数据，也没有关于ATTR CA的数据。 在西班牙裔人群中，无论基因型如何，知识匮乏的原因之一 是诊断的挑战。肌内膜活检，虽然接近100%的敏感性和特异性， 作为筛选试验和单独的患者基因分型不足以鉴定ATTR CA，因为野生型 病人会发病。我们已经开发出一种高度准确的技术，用于ATTR CA鉴定， Tc 99 m-焦磷酸（PYP）成像，避免了活检的需要。Tc 99 m-PYP心肌摄取可发生 在超声心动图或临床变化之前，提示敏感性增强。虽然研究使用 技术表明，10-15%的老年HF住院患者可能患有ATTR CA，Tc 99 m- PYP尚未广泛应用于HF患者作为促进早期诊断的手段。另外我们有 还报道了一种利用新生物标志物视黄醇结合蛋白4的即时诊断工具 （RBP 4），和测量TTR稳定性的测定。我们假设老年人中很大比例的HF 黑人和西班牙裔是由ATTR CA引起的。我们建议利用我们的方法来建立 ATTR CA的患病率，并探讨RBP 4浓度和TTR稳定性之间的关系， 对患有HF的老年黑人和西班牙裔美国人的前瞻性队列研究。目标1将决定 与基因型相关的ATTR CA的患病率和临床进展，澄清性别分布，并校准 上述即时诊断工具。目标2将探讨RBP 4与 血清和尿中的浓度、TTR稳定性和ATTR CA中的基因型。成功完成这些 目的将有助于理解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HF患者的结局。

项目成果

Association of Tafamidis With Health Status in Patients With ATTR Cardiac Amyloidosis: A Post Hoc Analysis of the ATTR-ACT Randomized Clinical Trial.

Tafamidis 与 ATTR 心脏淀粉样变性患者健康状况的关联：ATTR-ACT 随机临床试验的事后分析。

• DOI: 10.1001/jamacardio.2022.5251
• 发表时间: 2023
• 期刊: JAMA cardiology
• 影响因子: 24
• 作者: Sperry,BrettW;Hanna,Mazen;Maurer,MathewS;Nativi-Nicolau,Jose;Floden,Lysbeth;Stewart,Michelle;Wyrwich,KathleenW;Barsdorf,AlexandraI;Kapadia,Heli;Spertus,JohnA
• 通讯作者: Spertus,JohnA

Stabilization of Cardiac Function With Diflunisal in Transthyretin (ATTR) Cardiac Amyloidosis.

• DOI: 10.1016/j.cardfail.2019.11.024
• 发表时间: 2020-09
• 期刊: Journal of cardiac failure
• 影响因子: 6
• 作者: Lohrmann G;Pipilas A;Mussinelli R;Gopal DM;Berk JL;Connors LH;Vellanki N;Hellawell J;Siddiqi OK;Fox J;Maurer MS;Ruberg FL
• 通讯作者: Ruberg FL

Clinical Penetrance of the Transthyretin V122I Variant in Older Black Patients With Heart Failure: The SCAN-MP (Screening for Cardiac Amyloidosis With Nuclear Imaging in Minority Populations) Study.

• DOI: 10.1161/jaha.122.028973
• 发表时间: 2023-08
• 期刊: JOURNAL OF THE AMERICAN HEART ASSOCIATION
• 影响因子: 5.4
• 作者: Madhani, Avni;Sabogal, Natalia;Massillon, Daniel;Paul, Ludwine D.;Rodriguez, Carlos;Fine, Denise;Helmke, Stephen;Winburn, Morgan;Kurian, Damian;Raiszadeh, Farbod;Teruya, Sergio;Cohn, Elizabeth;Einstein, Andrew J.;Miller, Edward J.;Connors, Lawreen H.;Maurer, Mathew S.;Ruberg, Frederick L.
• 通讯作者: Ruberg, Frederick L.

Tafamidis and Incidence of Atrial Fibrillation in Transthyretin Amyloid Cardiomyopathy.

Tafamidis 与运甲状腺素蛋白淀粉样心肌病中心房颤动的发生率。

• DOI: 10.1016/j.jacep.2022.11.005
• 发表时间: 2023
• 期刊: JACC. Clinical electrophysiology
• 作者: Girvin,ZacharyP;Sweat,AustinO;Kochav,StephanieM;Maurer,MathewS;Dizon,Jose;Wan,ElaineY;Biviano,Angelo;Garan,Hasan;Yarmohammadi,Hirad
• 通讯作者: Yarmohammadi,Hirad

Cardiac Amyloidosis Due to Transthyretin Protein: A Review.

运甲状腺素蛋白引起的心脏淀粉样变性：综述。

• DOI: 10.1001/jama.2024.0442
• 发表时间: 2024
• 期刊: JAMA
• 作者: Ruberg,FrederickL;Maurer,MathewS
• 通讯作者: Maurer,MathewS