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: 10370416
• 负责人: MATHEW S MAURER
• 金额: $ 143.45万
• 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/10370416
• 关键词: Address; African; African American population; African Caribbean; 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; 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; Hispanic Americans; Hispanic Populations; Human; Image; Individual; Institution; Isoleucine; Kinetics; Knowledge; Label; Measurement; Measures; Medical; Methodology; Minority Groups; Multicenter Studies; Mutate; Mutation; Myocardial; Pathogenesis; Patients; Persons; 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; cardiac amyloidosis; carrier status; clinical phenotype; clinical practice; cohort; diagnostic accuracy; diagnostic tool; 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; 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.

心力衰竭，保留的射血分数（HFPEF）不成比例地折磨着较老的黑色和西班牙裔 美国人。 attriac淀粉样变性（ATTA CA）是由心肌沉积错误折叠引起的 经硫代蛋白蛋白（TTR或prealbumin），由TTR的遗传学分类为野生型（ATTRWT）或 突变体（attrm）。 Attr Ca，无论基因型如何 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，促成Attrwt CA的因素没有很好地定义。以前被认为是 如果在早期进行给药，在晚期临床试验中不可治疗，有希望的疗法可能最有效 疾病课程。只有一小部分具有野生型TTR的个体会发展出attrwt CA， 在60岁以上的高加索男性中，绝大多数报告了。但是，作为常染色体蛋白，等位基因 分布不是特定的。对于Attrm，异亮氨酸替代valine（V122i）是最常见的 在美国的TTR突变，仅在3.4％的等位基因频率的黑人美国人中观察到。但是那里 没有关于非裔美国人attrwt CA的患病率的数据，也没有attr ca的数据 在西班牙裔人群中，患病率，无论基因型如何。知识不足的原因之一 是诊断的挑战。心内膜活检虽然敏感近100％，但不切实际 作为筛查测试和仅患者的基因分型，由于野生型 患者发展疾病。我们已经开发了一种高度精确的技术，用于使用Attr CA识别 TC99M-磷酸（PYP）成像，避免了活检的需求。 TC99M型心肌摄取可能发生 在超声心动图或临床变化之前，表明灵敏度增强。而研究使用 技术表明，有10-15％的HF老年住院患者可能具有ATTA CA，TC99M- PYP并未广泛应用于HF患者，以促进早期诊断。此外，我们还有 还报道了使用新型生物标志物视黄醇结合蛋白4的护理点诊断工具4 （RBP4）和测量TTR稳定性的测定法。我们假设老年人的HF很大一部分 黑人和西班牙裔是造成的。我们建议利用我们的方法来建立 att ca的患病率并探讨了RBP4浓度与TTR稳定性之间的关系 对HF的黑人和西班牙裔美国人的前瞻性队列研究。 AIM 1将确定 ATT CA相对于基因型的患病率和临床进展，澄清性别分布并校准 前面提到的护理点诊断工具。 AIM 2将探索RBP4之间的关系 在Attr Ca中的血清和尿液，TTR稳定性和基因型的浓度。这些成功完成 目标将告知对Att CA发病机理的理解，并可能改变临床实践，改变PYP 指示标签，并通过HF改善成年黑人美国人和西班牙裔的结果。