Left Atrial Abnormality and Atrial Fibrillation-Related Cerebral Infarcts and Cognitive Decline

心房颤动(房颤)是一个严重的公共卫生问题，因为它在老年人中的患病率越来越高。 人群及其与缺血性中风、痴呆症、心力衰竭和死亡风险增加的相关性。近期 有证据表明，左房(LA)扩大的患者中风风险也会增加， 即使在没有房颤的情况下，绝大多数缺血性卒中在时间上也与房颤无关 剧集。这些观察提出了一个令人着迷的问题，无论是房颤还是下层LA底物 导致由房颤引起的心血管(CV)结果。这一提议将检验我们的假设：它是 功能受损和/或增大的异常左房底物，而不是房颤本身，这是主要的 目前被归因于房颤的不良后果的驱动因素，如脑梗塞和认知能力下降。 为了验证这一假设，我们不仅将评估左房扩大，而且还将评估左房功能受损，与 新的MRI定义的脑梗塞和认知改变的发展，说明了房颤。我们将利用 访问时对社区动脉粥样硬化风险(ARIC)研究参与者进行的广泛测试 5(V5,2011-13)作为基线数据：认知测试、二维超声心动图(2DE)和脑MRI扫描。我们会 在V5中执行的3,600个2DE上测量LA函数，并利用其他2个 V6和V7的辅助研究(2016-19年)：(1)使用ZIOXT贴片对4,000名参与者进行心率监测 (2)对1000名受试者进行重复脑MRI扫描(R01AG05449)。认知测试将会是 反复和轻微的认知障碍(MCI)和痴呆症将作为V6和V7考试的一部分进行判定。 通过测量来自V5 2DE的LA函数并有效地利用在V5以及从V6和V7收集的数据 辅助性研究，我们将实现以下具体目标：(1)评估LA的预期关联性 伴有和不伴有新的MRI脑梗塞、认知改变和发生MCI或痴呆的异常 调整房颤；(2)评估房颤与新的MRI脑梗塞、认知功能障碍的前瞻性关联 变化，事件MCI或痴呆，有和没有调整LA异常；(3)定义机制 通过评估(A)左房异常或房颤与纵向的关联来治疗房颤相关的认知能力下降 特定脑部MRI表现的改变；(B)左房异常或房颤伴认知改变，根据临床调整 缺血性中风、MRI脑梗塞或其他脑MRI异常。如果我们的假设得到证实，这就是 该项目将对公共卫生和临床产生重要影响。我们的发现可能(1)将我们的注意力转移到 心房基质作为不良结果的主要驱动因素，重新引导了未来发现新的 预防左房异常的策略，而不是目前侧重于已建立的房颤的节律控制，以及 (2)推动未来的临床试验，测试LA异常患者的抗凝状态，以预防中风。 最终，这个项目将强调潜在的异常心房底的重要性。 了解房颤的相关发病情况，从而促进房颤的科学和临床实践。

Atrial fibrillation (AF) is a serious public health problem because of its increasing prevalence in the aging population and its association with elevated risks of ischemic stroke, dementia, heart failure, and death. Recent evidence suggests that an increased stroke risk is also observed in patients with left atrial (LA) enlargement, even in the absence of AF, and that the vast majority of ischemic strokes are not temporally related to AF episodes. These observations raise the tantalizing question whether it is AF or the underlying LA substrate that causes the cardiovascular (CV) outcomes attributed to AF. This proposal will test our hypothesis: It is the abnormal LA substrate of impaired function and/or enlargement, and not AF per se, that is the principal driver of adverse outcomes currently attributed to AF, such as cerebral infarct and cognitive decline. To test this hypothesis, we will not only assess LA enlargement, but also impaired LA function, in relation to development of new MRI-defined brain infarcts and cognitive change, accounting for AF. We will leverage the extensive tests that were performed on Atherosclerosis Risk in Communities (ARIC) Study participants at visit 5 (V5, 2011-13) as baseline data: cognitive tests, 2D-echocardiograms (2DE), and brain MRI scans. We will measure LA function on 3,600 2DEs that were performed at V5 and leverage the data collected by 2 other ancillary studies at V6 and 7 (2016-19): (1) heart rhythm monitoring on 4,000 participants by ZioXT Patch (R01HL126637), and (2) repeat brain MRI scans on 1,000 participants (R01AG05449). Cognitive tests will be repeated and mild cognitive impairment (MCI) and dementia will be adjudicated as part of the V6 and 7 exams. By measuring LA function from V5 2DEs and efficiently leveraging the data collected at V5 and from V6 and 7 ancillary studies, we will accomplish these specific aims: (1) Evaluate the prospective association of LA abnormality with new MRI cerebral infarcts, cognitive change, and incident MCI or dementia, with and without adjusting for AF; (2) Evaluate the prospective association of AF with new MRI cerebral infarcts, cognitive change, and incident MCI or dementia, with and without adjusting for LA abnormality; (3) Define mechanisms for AF-related cognitive decline by evaluating the associations of (a) LA abnormality or AF with longitudinal changes in specific brain MRI findings; (b) LA abnormality or AF with cognitive change, adjusting for clinical ischemic stroke, MRI cerebral infarcts, or other brain MRI abnormalities. If our hypothesis is confirmed, this project will have important public health and clinical impact. Our findings may (1) shift our attention to the atrial substrate as the principal driver of adverse outcomes, re-directing future efforts to discover novel strategies to prevent LA abnormality, in contrast to the current focus on rhythm control of established AF, and (2) motivate future clinical trials to test anticoagulation for patients with LA abnormality to prevent stroke. Ultimately, this project will underscore the importance of the underlying abnormal atrial substrate in understanding AF-related morbidities, and consequently advance the science and clinical practice of AF.