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

SCAN-MP（在少数群体中用核成像筛查心脏淀粉样变性）

• 批准号: 9922373
• 负责人: MATHEW S MAURER
• 金额: $ 142.47万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922373
• 关键词: Address; African; African American; African Caribbean; Age; All-Trans-Retinol; Alleles; Amyloid; Amyloidosis; Autopsy; Binding; Biological Assay; Biological Markers; Biopsy; Blood; Blood Tests; Cardiac; Caribbean Hispanic; Carrier Proteins; Caucasians; Cessation of life; Clinic; Clinical; Clinical Trials; Communities; Data; Deposition; Diagnosis; Diagnostic tests; Diphosphates; Disease; Disease Progression; Dissociation; EFRAC; Early Diagnosis; Early treatment; Elderly; Failure; Gene Frequency; Genes; Genetic; Genotype; Heart failure; Hispanic Americans; Hispanics; Human; Image; Individual; Institution; Isoleucine; Kinetics; Knowledge; Label; Measurement; Measures; Medical; Methodology; Minority; Multicenter Studies; Mutate; Mutation; Myocardial; Pathogenesis; Patients; Phenotype; 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; aggregation factor; base; carrier status; clinical phenotype; clinical practice; cohort; diagnostic accuracy; effective therapy; genotyped patients; genotypic sex; 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; tool; 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)对老年黑人和西班牙裔的影响不成比例 美国人。心脏淀粉样变性(ATTRCA)是由错误折叠的心肌沉积引起的 转甲状腺激素蛋白(TtR或前白蛋白)，根据TtR的遗传学分类为野生型(ATTRUT)或 突变体(ATTRm)。无论基因型如何，ATTRCA是一种年龄相关的机制，通常未被认识到 潜在的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ATTRUT CA的因素没有被很好地定义。虽然之前人们认为 晚期临床试验中无法治愈、前景看好的疗法如果及早使用可能是最有效的 病程。只有一小部分携带野生型TTR的个体会患上ATTRUT CA， 在60岁以上的高加索男性中占压倒性多数。然而，作为一种常染色体蛋白，等位基因 分布并不是针对性别的。对于ATTRm，用异亮氨酸取代缬氨酸(V122I)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%。但是在那里 没有关于非裔美国人中ATTRUT CA患病率的数据，也没有ATTRCA的数据 西班牙裔人群中的流行率，无论是哪种基因型。造成知识赤字的原因之一 是诊断的挑战。心内膜心肌活检虽然几乎100%敏感和特异，但不切实际。 仅作为筛查试验和患者的基因分型不足以识别ATTRCA，因为野生型 病人会发展成疾病。我们已经开发了一种高精度的ATTRCA识别技术，使用 ~(99m)Tc99m-焦磷酸(PYP)显像，无需活组织检查。Tc99m-PYP可发生心肌摄取 在超声心动图或临床改变之前，提示敏感性增强。虽然研究使用 技术提示，10-15%的老年心力衰竭住院患者可能患有ATTRCA，Tc99m- 作为一种促进早期诊断的手段，PYP尚未被广泛应用于心衰患者。此外，我们还有 还报道了一种使用新的生物标记物视黄醇结合蛋白4的护理点诊断工具 (RBP4)，以及一种测量TTR稳定性的方法。我们假设，在老年人中有相当大比例的心衰 黑人和西班牙裔是由ATTRCA引起的。我们建议利用我们的方法来建立 老年人ATTRCA的患病率及RBP4浓度与TTR稳定性的关系 老年黑人和西班牙裔美国人心力衰竭的前瞻性队列研究。目标1将决定 与基因相关的ATTRCA的患病率和临床进展，明确性别分布，并校正 上述护理点诊断工具。目标2将探索RBP4与 血、尿浓度、TTR稳定性、ATTRCA基因分型。成功完成这些任务 AIMS将有助于理解ATTRCA的发病机制，并可能改变临床实践，改变PYP 适应症标签，并改善老年美国黑人和西班牙裔心衰患者的预后。