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

项目摘要 射血分数正常的心力衰竭（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方法。越来越多的证据表明 错误折叠的甲状腺素运载蛋白（ATTR）的心肌沉积随着年龄的增长而增加， 晚期HFpEF为13-18%。ATTR心脏淀粉样变性（CA）是HF最致命的形式之一， 存活25-41个月。ATTR-CA的诊断通常会延迟，通常会延迟几年，因为 需要侵入性内镜活检诊断和缺乏紧迫性，由于有限的治疗选择。 这种情况最近有所改变。ATTR CA现在可以使用99 m焦磷酸锝进行非侵入性诊断 （99 mTc-PYP）成像和最近的治疗突破（例如，tafamaltine、inotersen、patisiran）的情况有所改善 存活率、缓解症状和减少HF住院治疗。然而，由于缺乏对早期 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 它们在无HF的老年人中的预后相关性是有效利用最近 诊断和治疗突破，以治疗和预防HFpEF的这一重要原因。在过去的8年里， 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 在> 4，000名老年参与者（年龄70-95岁）中， 社区（ARIC）队列研究。我们现在的目标是利用这一丰富的资源，除了系列临床和 超过25年的循环生物标志物数据，以确定以下疾病的患病率、预测因子和预后重要性： 偶然检测到晚期心脏ATTR沉积物。我们将在900个ARIC中进行99 mTc-PYP SPECT成像 患有流行性HFpEF（n=300）或无症状心脏重塑/功能障碍（n=600）的受试者。 我们的具体目标是：1）确定心脏结构，功能和循环的先行改变 与没有ATTR-CA相比，区分晚期HFpEF的生物标志物。（2）确定预测因子 ATTR-CA在无HF但有心脏重塑/功能障碍的老年人中的预后相关性; 以及3）定义新的候选蛋白质和蛋白质网络在生命中期和晚期预测的程度 ATTR-CA在晚年。在这个项目完成后，我们将确定心脏的变化， 并通过ATTR-CA预测HF，确立了无症状ATTR-CA在晚年的预后重要性， 并鉴定了ATTR-CA的新循环生物标志物。这些调查结果将有助于查明 筛查ATTR-CA以促进HF治疗和可能的预防。的结果予以 这些研究有可能确定新的治疗靶点以改变ATTR-CA的管理。

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.