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Circulating Proteomics to Phenotype the Development and Reversal of Myocardial Remodeling in Aortic Stenosis

Award Number: R01HL164526
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Circulating Proteomics to Phenotype the Development and Reversal of Myocardial Remodeling in Aortic Stenosis - ABSTRACT: Approximately 5-10% of older adults have aortic stenosis (AS) with anticipated doubling by 2050; with no available medical therapy to slow progression, treatment is limited to aortic valve replacement (AVR). While AVR has historically been reserved for symptomatic severe AS, cardiac remodeling and irreversible injury occur before the onset of symptoms and before AS is severe and contribute to death and persistent heart failure (HF) symptoms/rehospitalization in up to 40% of patients 1 year after AVR, suggesting that AVR before onset of irreversible changes to the heart is likely to improve post-AVR outcomes. Fortunately, randomized strategy trials are underway to test the benefit of earlier less invasive transcatheter AVR (TAVR) before symptoms and severe AS. However, earlier TAVR isn't a panacea; beyond inherent procedural risks, this will also lead to more repeat procedures (with risks/costs) when prosthetic valves degenerate. Echocardiography and standard biomarkers (e.g., left ventricular hypertrophy [LVH], BNP) have limited sensitivity/specificity for detecting maladaptive remodeling and lack relevant biological insight. In preparation for this application, we identified circulating proteomic signatures of tissue/global cardiac phenotypes in the heart (e.g. LVH, fibrosis, systolic/diastolic function with cardiac magnetic resonance [CMR]/echo) in a group of 115 individuals across a spectrum of AS (mild to severe), defining subsets of biologically plausible and novel proteins associated with an increased risk of HF/mortality, with validation in a broader at-risk population without AS. Our central hypothesis is that myocardial remodeling/dysfunction early in the course of AS (mild-moderate; asymptomatic severe) will be accompanied by alterations in the circulating proteome pointing to known/novel pathways contributing to HF and providing an early molecular barometer for clinical surveillance and pharmacologic targeting. We will utilize state-of-the-art cardiac imaging alongside high-throughput proteomics on longitudinal samples from four cohorts of AS, including mild to severe asymptomatic AS, controls, pre- and post-TAVR sampling, and two randomized trials to: (1) develop/validate circulating proteomic signatures that reflect adverse myocardial remodeling/dysfunction relevant to AS surveillance and personalized timing of AVR; and (2) identify known/novel pathways underlying cardiac remodeling (before AVR) and cardiac recovery (after AVR) for downstream pharmacological targeting to reduce residual risk from HF. Our specific aims are: (1) identify whether proteomic signatures of myocardial remodeling/dysfunction are present early in AS before traditional clinical thresholds for intervention; (2) identify proteomic signatures of LVH regression after AVR in severe AS; and (3) determine whether proteomic signatures of cardiac health are associated with post-AVR outcomes and able to identify asymptomatic patients who benefit from prompt AVR. If successful, the current application will identify a set of circulating proteins (known/novel) linked to early cardiac remodeling phenotypes in AS for clinical surveillance, precision therapy, mechanistic study, and pharmacologic targeting.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $706,491 )
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	3	1/9/2025	NON-COMPETING CONTINUATION	$706,491
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	001	3	4/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $706,491

Issue Date FY: 2024 ( Subtotal = $771,295 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	001	2	6/24/2024	NON-COMPETING CONTINUATION	$62,961
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	2	1/22/2024	NON-COMPETING CONTINUATION	$708,334
														Subtotal = $771,295

Issue Date FY: 2023 ( Subtotal = $1,330,290 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	1	4/1/2023	NEW	$797,168
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	001	1	8/22/2023	SUPPLEMENT FOR EXPANSION	$533,122
														Subtotal = $1,330,290

Grand Total All Awards = $2,808,076

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Circulating Proteomics to Phenotype the Development and Reversal of Myocardial Remodeling in Aortic Stenosis

Award Number: R01HL164526

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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