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

项目总结 在美国4400万黑人中，大约有150万是缬氨酸到异亮氨酸的携带者 转甲状腺素(TTR)蛋白第122位(V122I)的替换。这几乎是黑人的专属，这是 遗传性心脏淀粉样变性(hATTR-CA)是全球最常见的病因。HAttr-CA导致病情恶化 心力衰竭(HF)和过早死亡。幸运的是，稳定TTR的新疗法可以改善发病率和 HATTR-CA的死亡率，特别是在疾病早期服用的时候。(5)然而，hATTR-CA通常 诊断处于晚期，常规诊断工具缺乏早期发现的诊断特异性 疾病。作者最近的工作表明，年轻的V122I TTR携带者具有间接成像和 心脏淀粉样蛋白浸润的生物标志物证据。因此，这项提案的总体目标是确定 亚临床hATTR-CA的存在和识别指示V122I TTR中淀粉样蛋白进展的生物标记物 承运人。这一提议的中心假设是hAttr-CA具有长的潜伏期，将被检测到 通过亚临床淀粉样变性成像和生物标记物表型。核心假设将通过以下方式进行检验 追求两个特定目标：目标1)确定V122I TTR携带者状态与CMRI证据的相关性 淀粉样蛋白渗透；次级目标1)确定V122I TTR携带者状态与心脏储备的关系 2)确定淀粉样特异性生物标志物与V122I TTR携带者状态之间的关联；以及子目标 2)确定淀粉样蛋白特异性生物标记物与基于成像的参数的关联，并评估其 用于识别亚临床hATTR-CA的诊断效用。在AIM 1中，将使用CMRI来比较相关指标 在一组无心衰的V122I TTR型携带者之间由级联基因形成的心脏淀粉样蛋白浸润 检测和年龄、性别和种族匹配的非携带者对照。对于子目标1，载波和非载波的子样本 参加AIM 1的携带者对照组将接受新的运动CMRI来测量和比较心脏收缩压 和舒张期储备。目标2涉及测量和比较V122I TTR中的淀粉样特异性生物标记物 样本与非携带者匹配的无心衰携带者(均来自AIM 1)和有症状的V122I患者 HAttr-CA来自我们的临床站点。这些生物标志物可以检测和量化TTR的不同过程。 淀粉样变性的发生，包括循环中的TTR、视黄醇结合蛋白4、TTR的动力学稳定性和错误折叠的TTR 齐聚物。次级目标2将确定这些生物标记物在检测亚临床hATTR成像证据方面的作用。 CA疾病。申请者认为，这项申请中提出的研究是创新的，因为它将 通过级联基因测试招募大量无心衰的V122I TTR携带者，这将模拟临床 关心。然后，它将使用详细的、先进的成像技术，具有组织特征和新颖的 直接量化hATTR-CA疾病进展过程的生物标记物，以识别亚临床hATTR-CA。 在hATTR-CA疾病发病前确定心脏淀粉样蛋白进展的证据将改变我们的思维方式 并证明未来在筛查和治疗策略方面预防hATTR-CA的研究是合理的。

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.