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Mediators of Systemic Inflammation and Heart Failure Risk in the Community

Award Number: R01HL143227
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Mediators of Systemic Inflammation and Heart Failure Risk in the Community - PROJECT SUMMARY/ABSTRACT Chronic inflammation, defined by a persistent elevation of local and systemic pro-inflammatory factors, has been implicated in the development and progression of heart failure in the community. Nonetheless, evidence in humans is scant and conflicting regarding the potential for specific inflammatory pathways to serve as key mechanistic drivers of disease and, in turn, as potentially high-yield therapeutic targets. This problem has arisen, in part, from a predominant prior focus on downstream rather than upstream mediators of inflammation. Accumulating evidence suggests that upstream mediators of inflammation are more likely to play a causal role in disease pathogenesis and, thus, serve as effective therapeutic targets. The upstream initiation of inflammation in humans is governed primarily by small lipid molecule effectors of polyunsaturated fatty acid metabolism, termed eicosanoids. These bioactive lipid species exhibit both pro- and anti-inflammatory activity and include prostaglandins, lipoxins, and leukotrienes. To date, the interactions between eicosanoid pathways and heart failure traits and outcomes remain poorly understood. Therefore, we proposed to provide a more detailed understanding of how upstream eicosanoid pathways can be variably active, imbalanced, and perturbed in relation to an individual’s propensity for developing heart failure. Advanced mass spectrometry methods now allow for the rapid and accurate quantification of up to hundreds of upstream eicosanoid mediators representing multiple enzymatic origins. We will use these methods to comprehensively assay distinct pro- and anti-inflammatory eicosanoids and examine their relation to heart failure risk factors and outcomes in a longitudinal study of men and women living in the community. In parallel, we will profile eicosanoids in a longitudinal study of an animal model of impending heart failure. Our specific aims are: (1) to assess whether circulating eicosanoid mediators of inflammation are associated with heart failure risk factors and incidence in the community; (2) to relate circulating eicosanoids with adverse outcomes in the setting of established heart failure; and, (3) to investigate the temporal and tissue-specific correlates of eicosanoid variation in an experimental model of heart failure. Our systematic approach to comprehensively investigating the components of upstream inflammatory activity in relation to heart failure outcomes across the spectrum of risk promises to yield important insights into the determinants of clinically important cardiac dysfunction. Given its focus on upstream inflammatory activity, this work will pave the way for follow-up studies investigating the efficacy of anti-inflammatory therapies (both existing and novel agents) for modulating variation in distinct eicosanoids as well as outcomes.


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: 2024 ( Subtotal = $0 )
2024	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	4	8/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $808,739 )
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	4	4/12/2022	NON-COMPETING CONTINUATION	$727,863
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	001	4	6/8/2022	NON-COMPETING CONTINUATION	$80,876
														Subtotal = $808,739

Issue Date FY: 2021 ( Subtotal = $816,288 )
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	3	7/2/2021	NON-COMPETING CONTINUATION	$816,288
														Subtotal = $816,288

Issue Date FY: 2020 ( Subtotal = $816,522 )
2020	2020	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	2	4/1/2020	NON-COMPETING CONTINUATION	$816,522
														Subtotal = $816,522

Issue Date FY: 2019 ( Subtotal = $868,069 )
2019	2019	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	1	3/15/2019	NEW	$868,069
														Subtotal = $868,069

Grand Total All Awards = $3,309,618

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Mediators of Systemic Inflammation and Heart Failure Risk in the Community

Award Number: R01HL143227

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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