IDENTIFYING SUBCLINICAL TRANSTHYRETIN CARDIAC AMYLOIDOSIS IN ASYMPTOMATIC CARRIERS OF THE V122I TTR ALLELE

鉴定 V122I TTR 等位基因无症状携带者中的亚临床甲状腺素运载蛋白心脏淀粉样变性

• 批准号: 10645211
• 负责人: Justin Lee Grodin
• 金额: $ 70.94万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645211
• 关键词: Age; Amyloid; Amyloidosis; Biological Markers; Biophysics; Biopsy; Black Populations; Blood Tests; Cardiac; Cardiology; Carrier State; Cessation of life; Clinic; Data; Diagnosis; Diagnostic Specificity; Disease; Disease Progression; Early Diagnosis; Early treatment; Enrollment; Epidemiology; Exercise; Family member; Functional disorder; Gadolinium; Genetic Screening; Heart; Heart Diseases; Heart failure; Image; Imaging Techniques; Individual; Infiltration; Inherited; Isoleucine; Kinetics; Left ventricular structure; Maps; Measures; Medical Genetics; Methods; Mission; Modeling; Monitor; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Onset of illness; Patients; Phenotype; Population; Positioning Attribute; Prealbumin; Prevention; Preventive treatment; Process; Proteins; Public Health; RBP4 gene; Race; Research; Risk; Role; Sampling; Serum; Severities; Testing; Thick; Tissues; Treatment Failure; United States; Universities; Valine; Variant; Work; amyloid imaging; amyloidogenesis; biobank; biomarker identification; cardiac amyloidosis; cardiac magnetic resonance imaging; carrier status; carrier testing; circulating biomarkers; clinical care; clinical research site; cohort; contrast enhanced; diagnostic tool; diagnostic value; disease diagnosis; extracellular; genetic testing; imaging detection; improved; innovation; mortality; multidisciplinary; novel; novel marker; novel therapeutics; phenotypic biomarker; phenotypic data; premature; prevent; recruit; screening; sex; specific biomarkers; treatment strategy; virtual

PROJECT SUMMARY Approximately 1.5 million of the 44 million Blacks in the United States are carriers of the valine-to-isoleucine substitution at position 122 (V122I) in the transthyretin (TTR) protein. Virtually exclusive to Blacks, this is the most common cause of hereditary cardiac amyloidosis (hATTR-CA) worldwide. hATTR-CA leads to worsening heart failure (HF) and premature death. Fortunately, new therapies that stabilize TTR improve morbidity and mortality in hATTR-CA, especially when prescribed early in the disease.(5) However, hATTR-CA is often diagnosed at an advanced stage and conventional diagnostic tools lack diagnostic specificity to detect early disease. Recent work from the author demonstrated that young V122I TTR carriers had indirect imaging and biomarker evidence of cardiac amyloid infiltration. Thus, the overall objectives of this proposal are to determine the presence of subclinical hATTR-CA and to identify biomarkers that indicate amyloid progression in V122I TTR carriers. The central hypothesis of this proposal is that hATTR-CA has a long latency period that will be detected through subclinical amyloidosis imaging and biomarker phenotyping. The central hypothesis will be tested by pursuing 2 specific aims: Aim 1) determine the association of V122I TTR carrier status with CMRI evidence of amyloid infiltration; Sub-aim 1) determine the association of V122I TTR carrier status with cardiac reserve; Aim 2) determine the association between amyloid-specific biomarkers and V122I TTR carrier status; and Sub-aim 2) determine the association of amyloid-specific biomarkers with imaging-based parameters and evaluate their diagnostic utility for identifying subclinical hATTR-CA. In Aim 1, CMRI will be used to compare metrics associated with cardiac amyloid infiltration between a cohort of V122I TTR carriers without HF formed by cascade genetic testing and age-, sex-, and race-matched non-carrier controls. For Sub-Aim 1, a sub-sample of carriers and non- carrier controls enrolled in Aim 1 will undergo novel exercise CMRI to measure and compare cardiac systolic and diastolic reserve. Aim 2 involves measuring and comparing amyloid-specific biomarkers in V122I TTR carriers without HF with samples matched non-carriers (both from Aim 1) and individuals with symptomatic V122I hATTR-CA from our clinical sites. These biomarkers detect and quantify different processes of TTR amyloidogenesis and include circulating TTR, retinol binding protein 4, TTR kinetic stability, and misfolded TTR oligomers. Sub-aim 2 will establish the role of these biomarkers to detect imaging evidence of subclinical hATTR- CA disease. The research proposed in this application is innovative, in the applicant's opinion, because it will enroll a large population of V122I TTR carriers without HF through cascade genetic testing that will model clinical care. Then, it will employ detailed, advanced imaging techniques with tissue characterization and novel biomarkers that directly quantify processes of hATTR-CA disease progression to identify subclinical hATTR-CA. Identifying evidence of cardiac amyloid progression prior to hATTR-CA disease onset will change how we think about this disease and justify future research in screening and treatment strategies to prevent hATTR-CA.

项目摘要 美国4400万黑人中约有150万人是缬氨酸-异亮氨酸的携带者。 在甲状腺素运载蛋白（TTR）蛋白中的位置122（V122 I）处的取代。实际上是黑人独有的，这是 遗传性心脏淀粉样变性（hATTR-CA）是世界范围内最常见的原因。hATTR-CA导致恶化 心力衰竭（HF）和过早死亡。幸运的是，稳定TTR的新疗法改善了发病率， hATTR-CA的死亡率，特别是在疾病早期开药时。(5)然而，hATTR-CA通常 在晚期诊断，常规诊断工具缺乏诊断特异性， 疾病作者最近的工作表明，年轻的V122 I TTR携带者有间接成像， 心脏淀粉样蛋白浸润的生物标志物证据。因此，本提案的总体目标是确定 亚临床hATTR-CA的存在以及鉴定指示V122 I TTR中淀粉样蛋白进展的生物标志物 载波该提议的中心假设是hATTR-CA具有将被检测到的长潜伏期 通过亚临床淀粉样变性成像和生物标志物表型。中心假设将通过以下方式进行检验： 追求2个具体目标：目标1）确定V122 I TTR携带者状态与CMRI证据的关联， 淀粉样蛋白浸润;子目的1）确定V122 I TTR携带状态与心脏储备的相关性;目的 2)确定淀粉样蛋白特异性生物标志物与V122 I TTR携带者状态之间的关联;以及 2)确定淀粉样蛋白特异性生物标志物与基于成像的参数的关联，并评估其 用于鉴定亚临床hATTR-CA的诊断效用。在目标1中，CMRI将用于比较相关指标， 在一组V122 I TTR携带者之间，心脏淀粉样蛋白浸润，而没有HF，这是由级联遗传学形成的。 测试和年龄、性别和种族匹配的非携带者对照。对于子目标1，携带者和非携带者的子样本 纳入Aim 1的携带者对照将接受新的运动CMRI，以测量和比较心脏收缩压 和舒张期储备。目的2涉及测量和比较V122 I TTR中淀粉样蛋白特异性生物标志物 无HF的携带者与样本匹配的非携带者（均来自Aim 1）和有症状的V122 I个体 hATTR-CA从我们的临床研究中心。这些生物标志物检测和量化TTR的不同过程 淀粉样蛋白生成和包括循环TTR、视黄醇结合蛋白4、TTR动力学稳定性和错误折叠TTR 低聚物子目标2将确定这些生物标志物在检测亚临床hATTR的成像证据中的作用。 CA疾病。申请人认为，本申请中提出的研究具有创新性，因为它将 通过级联基因检测招募大量无HF的V122 I TTR携带者， 在乎然后，它将采用详细的，先进的成像技术与组织表征和新颖的 这些生物标志物直接量化hATTR-CA疾病进展的过程以鉴定亚临床hATTR-CA。 在hATTR-CA疾病发作之前确定心脏淀粉样蛋白进展的证据将改变我们的想法 关于这种疾病，并证明未来的研究在筛选和治疗策略，以防止hATTR-CA。