Chronic Renal Insufficiency and Silent Progression of Aortic Stenosis (CRISP-AS)

项目总结 主动脉瓣狭窄(AS)很常见，如果不治疗，进展为有症状、严重的AS通常是致命的。 接受主动脉瓣置换术(AVR)，尽管只有三分之一的人接受AVR，部分原因是担心 围手术期风险高，瓣膜快速钙化/变性。尽管半个多世纪以来 关于这一课题的研究，目前对血流动力学进展的危险因素知之甚少。 目前还没有已被证实有益于延缓或预防AS进展的药物疗法。在……里面 在这种背景下，慢性肾脏疾病(CKD)代表了一个有吸引力的模型，用于研究由于快速的进展 和过早的瓣膜钙化，产生了可以应用于非CKD人群的机制见解。 这一建议充分利用了慢性肾功能不全参与者的独特和颗粒性表型。 队列研究(CRIC)和社区动脉粥样硬化风险(ARIC)研究。审评委是一个大型、多中心、 前瞻性、表型良好的观察性研究，始于2003年，由NIDDK资助，招募成年人(老年人 21-74)，具有不同的CKD严重程度，目的是检查CKD中心血管疾病的进展 病人。共有3,552名CRIC参与者在几年内接受了全面的经胸超声心动图(TTE) 注册后1、4和7以及开始透析时，使其成为唯一基于预期人群的 队列招募了大量患有连续TTE的CKD成人，从而独特地允许我们测试 AIMS 1-3中的几个重要生物学假设(将在没有CKD的个体中进行额外测试 世卫组织在社区动脉粥样硬化风险的5[2011-2013]和7[2018-2019年]访问中接受了TTES [ARIC]学习目标4)。CRIC的初步数据表明，主动脉峰值速度的进展更快 高于一般人群，但低于透析人群的先前估计。因为这项措施只是一项 在几个AS严重程度指标中，我们建议审查现有的CRIC TTE图像(7,317 tte)以计算所有AS严重性参数，然后分析现有的和新的 测量数据以解决几个问题。在目标1中，我们将评估CKD的进展情况是否有所不同 根据肾功能的两项指标(估计的肾小球滤过率和蛋白尿)并量化 AS进展率的个体间差异。在目标2中，我们将确定临床和生物标记物风险因素 与AS的进展有关，以及这些联系是否因肾功能而异。在《目标3》中，我们将 确定慢性肾脏病的快速AS进展与不良心血管结局之间的关系 这是否会因肾功能不同而不同。在目标4中，在ARIC队列中，我们将检查类似的临床和 在没有慢性肾脏病的队列中，生物标记物风险因素确定AS进展的相似风险。这样做，我们将 利用CKD的独特生理学来提高对AS进展的理解，提供生物 对这一严重而重要的瓣膜疾病进展机制的洞察。

PROJECT SUMMARY Aortic stenosis (AS), is common and progression to symptomatic, severe AS is universally fatal without treatment with aortic valve replacement (AVR), though only 1/3 of individuals receive AVR, due in part to concerns about high perioperative risk and rapid valvular calcification/degeneration. Despite more than half a century of research on this topic, comparatively little is known about risk factors for hemodynamic progression of AS and there are no medical therapies of proven benefit for slowing or preventing AS progression. In this setting, chronic kidney disease (CKD) represents an attractive model to study AS progression due to rapid and premature valvular calcification, yielding mechanistic insights that could be applied to non-CKD population. This proposal leverages the unique and granular phenotyping of participants in the Chronic Renal Insufficiency Cohort (CRIC) and Atherosclerosis Risk in Communities (ARIC) Studies. CRIC is a large, multicenter, prospective, well-phenotyped observational study, begun in 2003 and funded by NIDDK, enrolling adults (aged 21-74) with varying severity of CKD, with a goal to examine progression of cardiovascular disease amongst CKD patients. A total of 3,552 CRIC participants had comprehensive transthoracic echocardiograms (TTEs) at years 1, 4, and 7 post-enrollment and upon initiation of dialysis, making it the only prospective population-based cohort enrolling a large number of adults with CKD with serial TTEs, and thus uniquely allows us to test several important biologic hypotheses in Aims 1-3 (to be additionally tested in individuals without CKD who received TTEs in visits 5 [2011-2013] and 7 [2018-2019] of the Atherosclerosis Risk in Communities [ARIC] Study in Aim 4). Preliminary data from CRIC indicate that progression of aortic peak velocity was greater than the general population but lower than prior estimates in the dialysis population. As this measure is only one of several AS severity measures and is influenced by transvalvular flow, we propose to review existing CRIC TTE images (7,317 TTEs) to calculate all AS severity parameters, and then analyze existing and newly measured data to address several questions. In Aim 1, we will evaluate if AS progression in CKD varies according to two measures of kidney function (estimated glomerular filtration and albuminuria) and quantify the inter-individual variability in AS progression rate. In Aim 2, we will identify clinical and biomarker risk factors that associate with progression of AS, and whether these associations vary by kidney function. In Aim 3, we will determine the relationship between rapid AS progression in CKD and adverse cardiovascular outcomes, and whether this varies by kidney function. In Aim 4, in the ARIC cohort, we will examine if similar clinical and biomarker risk factors identify an analogous risk of AS progression in a cohort without CKD. Doing so, we will leverage the unique physiology of CKD to improve understanding of AS progression, providing biologic insights into the mechanisms of progression of this serious and important valvular disease.