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 射血分数保留的心力衰竭（HFpEF）是一个主要的公共卫生问题， 对老年人的影响尤为严重，目前尚无有效的治疗方法。越来越多的证据表明 错误折叠的运甲状腺素蛋白 (ATTR) 的心肌沉积随着年龄的增长而增加，并导致 晚年 HFpEF 的 13-18%。 ATTR 心脏淀粉样变性 (CA) 是最致命的心力衰竭形式之一，中位数为 生存期25-41个月。 ATTR-CA 的诊断通常会延迟数年，因为 需要进行侵入性心内膜活检进行诊断，并且由于治疗选择有限而缺乏紧迫性。 这种情况最近发生了变化。现在可以使用 99m 焦磷酸锝非侵入性诊断 ATTR CA (99mTc-PYP) 成像和最近的治疗突破（例如，tafamidis、inotersen、patisiran）有所改善 生存率、症状减轻和心衰住院率减少。但由于对早期的认识不足 反映心肌 ATTR 沉积的心脏结构、功能和循环生物标志物的变化，以及 它们与无心力衰竭老年人的预后相关性是有效利用近期研究的主要障碍 治疗和预防 HFpEF 这一重要原因的诊断和治疗突破。过去8 多年来，我们一直在建立一个独特的数据库，详细描述心脏结构和功能的纵向变化 超过 4,000 名老年参与者（年龄 70-95 岁）超过 5 年，主要是混血儿的动脉粥样硬化风险 社区（ARIC）队列研究。除了系列临床和临床试验之外，我们现在的目标是利用这一丰富的资源。 超过 25 年的循环生物标志物数据，以确定患病率、预测因子和预后重要性 偶然发现晚年心脏 ATTR 沉积物。我们将在 900 ARIC 中进行 99mTc-PYP SPECT 成像 患有普遍 HFpEF (n=300) 或无症状心脏重塑/功能障碍 (n=600) 的参与者。 我们的具体目标是： 1) 定义心脏结构、功能和循环的先前变化 与没有 ATTR-CA 的情况相比，区分晚年 HFpEF 的生物标志物。 ; 2) 确定预测变量 ATTR-CA 对无心力衰竭但有心脏重塑/功能障碍的老年人的预后相关性； 3) 定义新的候选蛋白质和蛋白质网络在中年和晚年预测的程度 晚年的 ATTR-CA。在这个项目完成时，我们将定义之前的心脏变化 并根据 ATTR-CA 预测心力衰竭，确立了无症状 ATTR-CA 对晚年预后的重要性， 并鉴定出 ATTR-CA 的新型循环生物标志物。这些调查结果将有助于识别人员身份 筛查 ATTR-CA 以促进心力衰竭治疗和可能的预防的高风险人群。这些结果 研究可能会确定新的治疗靶点来改变 ATTR-CA 的治疗。