Mapping the Progression to HFpEF in the Elderly through Longitudinal Changes in Cardiac Function

心力衰竭(HF)对老年人的影响不成比例，老年人主要发生心力衰竭并保留左心衰 左心室射血分数(HFpEF)，目前尚无有效的治疗方法。我们将聘请严谨的 流行病学方法和一系列最先进的心脏成像，以解决关键的知识差距 由ACC/AHA和ESC HF指南列举的关于高龄老年人心力衰竭的病理生理学 HFpEF，以及预防心力衰竭的策略。我们将利用动脉粥样硬化的全面回声数据 社区风险(ARIC)研究访问5次(2011-2013，年龄76±5岁)，并对资助对象进行辅助 参观7(2018-2019年)，届时参与者将是≥75岁。关于……纵向变化的数据很少 心力衰竭发病率最高的这一生命阶段的心功能。在中执行新的后续回声 访问7(年龄约82±5岁)的约3,900名参与者是评估以下纵向变化的独特机会 6年来对左心功能的新的敏感测量(应变、组织多普勒、压力-容量分析)注意 在以前的研究中连续可用。将其与新的和计划中的途径生物标记物和临床 评估(包括2分钟步行距离和心力衰竭症状)和现有结果监测 独一无二地使我们能够探索HFpEF下的一种新的、有希望的和可修改的生物途径 这涉及炎症、一氧化氮(NO)耗竭和cGMP活性改变。虽然最近的翻译是 数据表明在心肌细胞僵硬、肥大和纤维化中起着重要作用，但很少有人类数据 更广泛的样本将这一途径与进行性左心功能障碍和HFpEF联系起来。我们的中心假设是 心血管疾病(高血压、冠心病、房颤)、非心脏疾病(糖尿病、肥胖症、肾脏 功能障碍)和非传统的(肺功能障碍、贫血、缺乏体力活动)心衰危险因素被激活 炎症途径，通过抑制cGMP促进进行性舒缩功能障碍， 最终导致心力衰竭。我们的具体目标是：(1)前瞻性地确定临床预测因素 老年人左心功能纵向恶化；(2)炎症途径与利钠肽 已知影响cGMP活性对左心功能纵向变化的影响；(3)确定 与这些途径生物标志物相关的左心功能恶化可预测高龄患者发生心力衰竭。我们的 创新的方法是通过询问非传统的心力衰竭危险因素，在纵向变化中进行高级回声 左心功能的测量和新的生物学途径来了解高血压性心衰的进展 未被研究的人群：非常年长的人。这项提议意义重大，因为它将使我们能够确定 进展性左心功能不全的高危老年人和发生HFpEF，并确定其重要性 一种有希望的生物途径，被几种现有的药物靶向，可以迅速转化为 预防性干预。因此，这是向干预措施迈出的关键一步，以防止非常 老年人，以及相关的发病率、死亡率和成本。

Heart failure (HF) disproportionately affects the elderly who predominantly develop HF with preserved left ventricular (LV) ejection fraction (HFpEF), for which no efficacious therapies exist. We will employ rigorous epidemiologic approaches and serial state-of-the-art cardiac imaging to tackle the critical knowledge gaps enumerated by ACC/AHA & ESC HF guidelines regarding HF in the very elderly, the pathophysiology of HFpEF, and strategies to prevent HF. We will leverage the comprehensive echo data from the Atherosclerosis Risk in Communities (ARIC) study Visit 5 (2011-2013, age 76±5 years) and conduct an ancillary to the funded Visit 7 (2018-2019), when participants will be ≥75 years old. Few data exist regarding longitudinal changes in cardiac function during this period of life when HF incidence is greatest. Performing new follow-up echos in ~3,900 participants at Visit 7 (age ~82±5 years) is a unique opportunity to evaluate longitudinal changes over 6 years in novel sensitive measures of LV function (strain, tissue Doppler, pressure-volume analysis) not available serially in previous studies. Integrating this with new and planned pathway biomarkers and clinical assessments (including 2 minute walk distance and HF symptoms) and existing outcomes surveillance uniquely positions us to interrogate a novel, promising, and modifiable biologic pathway underlying HFpEF that involves inflammation, nitric oxide (NO) depletion, and altered cGMP activity. While recent translational data suggest an important role in myocyte stiffness, hypertrophy, and fibrosis, little human data exist from broader samples linking this pathway to progressive LV dysfunction and HFpEF. Our central hypothesis is that cardiovascular (hypertension, coronary disease, atrial fibrillation), non-cardiac (diabetes, obesity, renal dysfunction), and non-traditional (pulmonary dysfunction, anemia, physical inactivity) HF risk factors activate inflammatory pathways, promoting progressive diastolic and systolic dysfunction via depressed cGMP, ultimately resulting in HF. We specifically aim to: (1) prospectively determine the clinical predictors of longitudinal worsening of LV function in the elderly; (2) relate inflammatory pathways and natriuretic peptides known to influence cGMP activity to longitudinal changes in LV function; (3) determine the extent to which worsening LV function, related to these pathway biomarkers, predicts incident HF in the very elderly. Our approach is innovative by interrogating non-traditional HF risk factors, longitudinal changes in advanced echo measures of LV function, and novel biologic pathways to understand the progression to HFpEF in an understudied population: the very elderly. This proposal is significant because it will allow us to identify very elderly persons at high risk of progressive LV dysfunction and incident HFpEF, and determine the importance of a promising biologic pathway targeted by several existing agents that could translate rapidly into preventative interventions. This is therefore a critical step towards intervening to prevent HF in the very elderly, and the associated morbidity, mortality, and cost.