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

慢性肾功能不全和无症状进展的主动脉瓣狭窄 (CRISP-AS)

基本信息

批准号：
10718275
负责人：
Jordan Blair Strom
金额：
$ 87.14万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10718275
关键词：
Address Adult Age Albuminuria Aorta Aortic Valve Stenosis Atherosclerosis Atherosclerosis Risk in Communities Atrial Fibrillation Biological Biological Markers Biological Models Blood Pressure Blood Vessels Calcium Cardiovascular Diseases Cardiovascular system Cessation of life Chest Chronic Kidney Failure Chronic Kidney Insufficiency Clinical Clinical Data Cohort Studies Communities Data Development Diabetes Mellitus Dialysis patients Dialysis procedure Disease Echocardiography Effectiveness Enrollment Etiology Fibrinogen Funding General Population Goals Heart Heart Valve Diseases Heart failure Image Individual Interleukin-6 Kidney Diseases Knowledge Link Lipoprotein (a)Measures Medical Modeling Myocardial Infarction National Heart, Lung, and Blood Institute National Institute of Diabetes and Digestive and Kidney Diseases Observational Study Obstruction Operative Surgical Procedures Outcome Participant Patients Perioperative Peripheral arterial disease Phenotype Physiologic pulse Physiology Population Prosthesis Race Renal function Reporting Research Risk Risk Factors Serum Severities Severity of illness Stroke TNF gene Testing Tobacco smoking behavior Transforming Growth Factor beta Visit adjudication aged alpha-Fetoproteins aortic valve aortic valve replacement calcification cardiovascular risk factor clinical risk cohort comparative coronary calcium scoring glomerular filtration hemodynamics human old age (65+)improved inorganic phosphate insight inter-individual variation mortality risk novel population based pre-clinical premature prevent prospective risk prediction sex

项目摘要

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.

项目概要主动脉瓣狭窄 (AS) 很常见，如果不治疗，进展为有症状的严重主动脉瓣狭窄通常是致命的主动脉瓣置换术 (AVR)，尽管只有 1/3 的人接受 AVR，部分原因是担心围手术期风险高和瓣膜快速钙化/变性。尽管半个多世纪以来关于这一主题的研究，对于血流动力学进展的危险因素知之甚少目前尚无任何药物疗法已被证明可有效减缓或预防 AS 进展。在在这种情况下，慢性肾脏病（CKD）代表了一个有吸引力的模型来研究 AS 进展，因为快速和过早瓣膜钙化，产生可应用于非 CKD 人群的机制见解。该提案利用了慢性肾功能不全参与者的独特且精细的表型队列 (CRIC) 和社区动脉粥样硬化风险 (ARIC) 研究。 CRIC 是一个大型、多中心、前瞻性、表型良好的观察性研究，于 2003 年开始，由 NIDDK 资助，招募成年人（年龄 21-74）具有不同严重程度的 CKD，目的是检查 CKD 中心血管疾病的进展患者。多年来，共有 3,552 名 CRIC 参与者接受了全面的经胸超声心动图 (TTE) 入组后 1、4 和 7 以及开始透析后，使其成为唯一基于人群的前瞻性研究该队列招募了大量患有 CKD 的成年人并进行了系列 TTE，因此我们能够独特地进行测试目标 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）在社区动脉粥样硬化风险的第 5 次 [2011-2013 年] 和第 7 次 [2018-2019 年] 访视中接受 TTE 的人 [ARIC] 目标 4) 的研究。 CRIC 的初步数据表明主动脉峰值速度的进展更大高于一般人群，但低于透析人群之前的估计。由于这项措施只是其中一项由于多种 AS 严重程度测量的影响，并且受到跨瓣血流的影响，我们建议审查现有的 CRIC TTE 图像（7,317 个 TTE）用于计算所有 AS 严重性参数，然后分析现有的和新的测量数据来解决几个问题。在目标 1 中，我们将评估 CKD 中的 AS 进展是否有所不同根据肾功能的两项测量（估计肾小球滤过和白蛋白尿）并量化 AS 进展率的个体差异。在目标 2 中，我们将确定临床和生物标志物风险因素与 AS 进展相关，以及这些相关性是否因肾功能而异。在目标 3 中，我们将确定 CKD 快速 AS 进展与不良心血管结局之间的关系，以及这是否因肾功能而异。在目标 4 中，在 ARIC 队列中，我们将检查是否有类似的临床和生物标志物风险因素可识别无 CKD 的队列中类似的 AS 进展风险。这样做，我们将利用 CKD 独特的生理学来提高对 AS 进展的理解，提供生物制剂深入了解这种严重且重要的瓣膜疾病的进展机制。