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Mechanisms of Lipotoxic Arrhythmias

Award Number: R01HL147044
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/11/2021
PERIOD OF PERFORMANCE END DATE: 02/29/2024

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Mechanisms of Lipotoxic Arrhythmias - Project Summary/Abstract: High-fat diet induced lipotoxicity is an epidemic that poses a significant public health problem with over one-third of the world population being either overweight or obese, and is associated with arrhythmias. While lipotoxicity has been linked to atrial fibrillation (AF) in patients and in animal disease models, little is known about the underlying molecular pathways for dysregulation. We propose that a critical contributor to lipotoxic atrial disease involves pathological dysregulation of the delayed rectifier K current IK composed of the rapidly (IKr) and slowly activating (IKs) components, both of which are critical for cardiac repolarization. In ventricles, pathological decreases in pore-forming subunits of IKr (hERG) and IKs (KCNQ1) have been linked by our group and others to arrythmogenic IKr and IKs currents. We recently discovered for the first time that IK currents are upregulated in obese guinea pigs atria contribute prominently to enhanced action potential repolarization. We also found that palmitic acid abbreviated action potential duration and increased IKr and IKs densities; while oleic acid prolonged action potential duration, and severely reduced IKr but had no effect on IKs. Our new preliminary data indicate that these guinea pigs exhibit lipotoxicity with no signs of hyperglycemia or inflammation. Furthermore, intracardiac injection of palmitic acid increased IK density and vulnerability to spontaneous atrial arrhythmias in guinea pigs as early as 5 weeks of age. We now propose to use this unique model to more comprehensively define the molecular mechanisms of arrhythmogenesis, to explore whether altered functional expression of IKr and IKs contributes to the pathogenesis and maintenance of AF, and whether targeting altered IK channel function could be an effective treatment for AF. Three specific aims are proposed: Aim 1: To examine the downstream pathways by which lipotoxicity increases IK channel function. We will test, using genetic and pharmacological approaches, whether increased IKr and IKs functional expression is involved in the remodeling of the myocardium in response to lipotoxicity and whether activators of AMPK and inhibitors of PI3K downstream pathways can normalize IK channel functional expression. Aim 2: To test the causal link between increased IK and susceptibility to AF in lipotoxic heart. We will utilize genetic and pharmacological interventions to see whether IK plays a role in AF and whether it may be a novel therapeutic target. Aim 3: To test therapeutically the causal link between PP2A activation, selective downregulation of IKr and prevention of AF in lipotoxicity. The proposed studies may identify important links between dysfunctional IKr and IKs channels, defective lipid-dependent signaling pathways in AF, and protein kinase-phosphatase dysfunction. Our proposed comprehensive studies are designed to provide rigorous and robust hypothesis driven testing to reveal new understandings of the molecular basis of AF. By establishing AMPK/PI3K/PP2A or downstream targets as predictive markers of AF, our data may inform the development of novel, mechanism-based effective treatment options.


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 = -$7,200 )
2024	2022	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	000	5	6/25/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2022	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	001	5	7/11/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$7,200
														Subtotal = -$7,200

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	004	5	5/4/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$506,592
2023	2021	MASONIC MEDICAL RESEARCH LAB	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	003	3	5/4/2023	NON-COMPETING CONTINUATION	-$437,500
2023	2020	MASONIC MEDICAL RESEARCH LAB	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	002	2	5/4/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$69,092
2023	2020	MASONIC MEDICAL RESEARCH LAB	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	005	2	5/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$69,092
2023	2020	MASONIC MEDICAL RESEARCH LAB	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	006	2	6/7/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$69,092
2023	2020	MASONIC MEDICAL RESEARCH LAB	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	001	2	12/13/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$161,986
2023	2019	NARROWS INSTITUTE FOR BIOMEDICAL RESEARCH, INC., THE	800 POLY PL 151	BROOKLYN	NY	11209	KINGS	USA	Cardiovascular Diseases Research	000	1	12/13/2022	NEW	-$161,986
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $383,750 )
2022	2022	MASONIC MEDICAL RESEARCH LABORATORY	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	000	4	2/18/2022	NON-COMPETING CONTINUATION	$393,750
2022	2022	MASONIC MEDICAL RESEARCH LAB	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	001	4	7/19/2022	NON-COMPETING CONTINUATION	-$393,750
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	002	5	7/20/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$383,750
														Subtotal = $383,750

Issue Date FY: 2021 ( Subtotal = $437,500 )
2021	2021	MASONIC MEDICAL RESEARCH LABORATORY	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	000	3	3/25/2021	NON-COMPETING CONTINUATION	$437,500
														Subtotal = $437,500

Issue Date FY: 2020 ( Subtotal = $437,500 )
2020	2020	MASONIC MEDICAL RESEARCH LABORATORY	2150 BLEECKER ST	UTICA	NY	13501	ONEIDA	USA	Cardiovascular Diseases Research	001	2	3/9/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$437,500
2020	2019	NARROWS INSTITUTE FOR BIOMEDICAL RESEARCH, INC., THE	800 POLY PL 151	BROOKLYN	NY	11209	KINGS	USA	Cardiovascular Diseases Research	000	1	3/8/2020	NEW	$0
														Subtotal = $437,500

Issue Date FY: 2019 ( Subtotal = $273,750 )
2019	2019	NARROWS INSTITUTE FOR BIOMEDICAL RESEARCH, INC., THE	800 POLY PL 151	BROOKLYN	NY	11209	KINGS	USA	Cardiovascular Diseases Research	000	1	4/16/2019	NEW	$273,750
														Subtotal = $273,750

Grand Total All Awards = $1,525,300

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Mechanisms of Lipotoxic Arrhythmias

Award Number: R01HL147044

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/11/2021

PERIOD OF PERFORMANCE END DATE: 02/29/2024

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