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

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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.