Early Detection of Transthyretin Cardiac Amyloidosis: Defining a Novel Target for HFpEF Treatment and Prevention in Late Life

甲状腺素运载蛋白心脏淀粉样变性的早期检测：确定晚年 HFpEF 治疗和预防的新目标

• 批准号: 10115113
• 负责人: Sharmila Dorbala
• 金额: $ 111万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115113
• 关键词: Affect; Age; Amyloidosis; Atherosclerosis Risk in Communities; Biological Markers; Biopsy; Blood; Cardiac; Cardiovascular system; Cessation of life; Clinical; Cohort Studies; Data; Databases; Deltastab; Deposition; Diagnosis; Diagnostic; Diphosphates; EFRAC; Early Diagnosis; Elderly; Extracellular Matrix; Functional disorder; Goals; Heart; Heart Atrium; Heart failure; Hospitalization; Image; Individual; Knowledge; Left; Measures; Myocardial; Myocardium; Participant; Pathway interactions; Persons; Prealbumin; Prevalence; Prevention; Proteins; Proteomics; Public Health; Pump; Resources; Risk; Scanning; Structure; Therapeutic; Thick; Treatment Failure; Troponin; Ubiquitin; Ventricular; age related; aptamer; base; biracial; circulating biomarkers; clinical biomarkers; early detection biomarkers; early screening; effective therapy; heart imaging; high risk; imaging biomarker; improved; middle age; multicatalytic endopeptidase complex; new therapeutic target; noninvasive diagnosis; novel; novel strategies; preservation; prevent; pro-brain natriuretic peptide (1-76); prognostic; prognostic significance; reduce symptoms; single photon emission computed tomography

Project Abstract Heart failure (HF) with preserved ejection fraction (HFpEF) is a major public health concern that disproportionately affects the elderly and currently has no effective therapy. Accumulating evidence suggests that myocardial deposition of misfolded transthyretin proteins (ATTR) increases with age and is responsible for 13-18% of HFpEF in late life. ATTR cardiac amyloidosis (CA) is one of the most-deadly forms of HF with a median survival of 25-41 months. The diagnosis of ATTR-CA has commonly been delayed, often by several years, because of the need for invasive endocardial biopsy for diagnosis and lack of urgency due to limited therapeutic options. This has changed recently. ATTR CA can now be diagnosed non-invasively using 99mtechnetium pyrophosphate (99mTc-PYP) imaging, and recent therapeutic breakthroughs (e.g., tafamidis, inotersen, patisiran) have improved survival, alleviated symptoms, and reduced HF hospitalizations. However, lack of knowledge regarding the early changes in cardiac structure, function, and circulating biomarkers that reflect myocardial ATTR deposition, and their prognostic relevance in elderly persons free of HF are key barriers to effectively harnessing recent diagnostic and therapeutic breakthroughs to treat and prevent this important cause of HFpEF. Over the past 8 years, we have been building a unique database detailing longitudinal changes in cardiac structure and function over 5 years in >4,000 elderly participants (age 70-95 years) in the largely biracial Atherosclerosis Risk in Communities (ARIC) cohort study. We now aim to leverage this rich resource, in addition to serial clinical and circulating biomarker data over 25 years, to define the prevalence, predictors, and prognostic importance of incidentally detected late-life cardiac ATTR deposits. We will perform 99mTc-PYP SPECT imaging in 900 ARIC participants with either prevalent HFpEF (n=300) or asymptomatic cardiac remodeling/dysfunction (n=600). Our specific aims are to: 1) Define antecedent alterations in cardiac structure, function, and circulating biomarkers that discriminate late-life HFpEF with compared to without ATTR-CA. ; 2) Determine the predictors and prognostic relevance of ATTR-CA in elderly persons without HF but with cardiac remodeling/dysfunction; and 3) Define the extent to which novel candidate proteins and protein networks in mid- and late-life predict ATTR-CA in late-life. At the completion of this project, we will have defined the cardiac changes that antecede and predict HF from ATTR-CA, established the prognostic importance of asymptomatic ATTR-CA in late life, and identified novel circulating biomarkers of ATTR-CA. These findings will facilitate identification of persons at high risk to screen for ATTR-CA to facilitate HF treatment and, possibly, prevention. The results of these studies are likely to identify novel therapeutic targets to transform the management of ATTR-CA.

项目摘要 具有保留的射血分数（HFPEF）的心力衰竭（HF）是一个主要的公共卫生问题 不成比例地影响老年人，目前没有有效的治疗。积累的证据表明 错误折叠的经甲状腺素蛋白蛋白（attr）的心肌沉积随着年龄的增长而增加，并负责 晚期HFPEF的13-18％。 Attr cariac淀粉样变性（CA）是中位数最令人垂涎​​的HF形式之一 25-41个月的生存。通常，Attr-CA的诊断通常被推迟了几年，因为 由于治疗选择有限，需要进行侵袭性心内膜活检和缺乏紧迫性。 最近发生了变化。现在可以使用99mtechnetium pyrophophate诊断出ATTA CA。 （99MTC-PYP）成像和最近的治疗突破（例如Tafamidis，Inotersen，patisiran）已改善 生存，减轻症状和HF住院减少。但是，缺乏关于早期的知识 反映心肌沉积的心脏结构，功能和循环生物标志物的变化， 他们在没有HF的老年人中的预后相关性是有效利用最近的关键障碍 诊断和治疗突破，以治疗和防止HFPEF的这一重要原因。在过去的8个 多年来，我们一直在建立一个独特的数据库，详细说明心脏结构和功能的纵向变化 超过5年的4,000名老年参与者（年龄70-95岁），主要是混蛋动脉粥样硬化风险 社区（ARIC）队列研究。现在，除了连续临床和 在25年内循环生物标志物数据，以定义 偶然检测到后期的心脏归纳沉积物。我们将在900 ARIC中执行99MTC-PYP SPECT成像 患有普遍的HFPEF（n = 300）或无症状心脏重塑/功能障碍（n = 600）的参与者。 我们的具体目的是：1）定义心脏结构，功能和循环的先例改变 与没有attr-CA相比，将晚期HFPEF区分的生物标志物与后期的HFPEF相比。 ; 2）确定预测因子 Attr-Ca在没有HF的老年人中的预后相关性，但心脏重塑/功能障碍； 3）定义新型候选蛋白质和蛋白质网络在中期和晚期预测的程度 attr-ca在晚年中。该项目完成时，我们将定义前编程的心脏变化 并预测Attr-CA的HF，确定了无症状Attr-CA在后期的预后重要性， 并确定了新颖的Attr-CA循环生物标志物。这些发现将有助于确定人 筛选Attr-CA的高风险，以促进HF治疗以及可能的预防。这些结果 研究可能会确定新的治疗靶标，以改变ATTR-CA的管理。