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

项目摘要 心力衰竭(HF)伴保留射血分数(HFpEF)是一个主要的公共卫生问题， 对老年人的影响不成比例，目前还没有有效的治疗方法。越来越多的证据表明 错误折叠的转甲状腺素蛋白(Attr)在心肌中的沉积随年龄增加而增加，这与 老年高血压性肺功能的13-18%。心脏淀粉样变性(CA)是最致命的心衰类型之一。 存活25-41个月。ATTR-CA的诊断通常会被推迟，往往会推迟几年，因为 有必要进行有创心内膜活检进行诊断，但由于治疗选择有限，缺乏紧迫性。 这种情况最近发生了变化。现在可以使用99mTc焦磷酸盐无创地诊断ATTRCA (99mTc-PYP)显像和最近的治疗突破(如他法米迪、诺特生、帕西兰)都有所改善 存活，缓解症状，减少心衰住院。然而，对早期的知识缺乏了解 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 在没有心力衰竭的老年人中，它们与预后的相关性是有效利用最近的 诊断和治疗方面的突破，以治疗和预防HFpEF的这一重要原因。在过去8年中 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，年龄超过5年的人中，动脉粥样硬化的风险主要来自两个民族 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 25年来循环使用的生物标记物数据，以确定该病的患病率、预测因素和预后重要性 偶然发现了晚年心脏ATTR沉积。我们将在900例ARIC中进行99mTc-PYP SPECT显像 有HFpEF盛行(n=300)或无症状心脏重构/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、功能和循环的先期改变 区分晚年HFpEF与不使用ATTR-CA的生物标记物。2)确定预测因子 在无心衰但有心脏重构/功能障碍的老年人中，ATTR-CA与预后相关； 以及3)确定新的候选蛋白质和蛋白质网络在中老年预测的程度 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。 并从ATTR-CA预测心力衰竭，确立无症状的ATTR-CA在老年预后中的重要性， 并鉴定出新的循环生物标记物。这些发现将有助于辨认身份 有很高的风险筛查ATTR-CA以促进心衰的治疗和可能的预防。这些研究的结果 研究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.