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STUDIES ON ENDOTHELIAL DYSFUNCTION IN HEART FAILURE

Award Number: R01HL051433
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/1995
PERIOD OF PERFORMANCE END DATE: 02/28/2005

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STUDIES ON ENDOTHELIAL DYSFUNCTION IN HEART FAILURE - DESCRIPTION (Adapted from the application): The applicant has previously demonstrated that impaired endothelium-dependent vasodilation in response to hormonal agonists and shear stress in patients with heart failure is attributable to reduced synthetic activity of the L-arginine-nitric oxide metabolic pathway and that endothelial dysfunction in heart failure is reversible with physical training. These findings indicate that endothelial dysfunction is a modifiable determinant of reduced aerobic capacity in heart failure and thereby is a target for therapy. We now propose: 1) to perform controlled clinical trials to determine whether specific therapies which decrease oxidative stress (Vitamin C, Vitamin E), increase L-arginine availability (supplemental oral L-arginine), or increase cGMP-mediated vasodilation (sildenafil) chronically enhance endothelial function in patients with heart failure; 2) to determine the role of endothelial dysfunction in disease progression with serial assessment of endothelial function in a large population of ambulatory patients with heart failure; and 3) to identify specific cellular mechanisms which contribute to impaired nitric oxide synthesis in heart failure with studies in cell culture. In clinical studies, endothelial function will be assessed non-invasively with a battery of tests for physiological testing of flow-mediated nitric oxide-induced vasodilation (Doppler ultrasonography and venous occlusion plethysmography) and determination of nitric oxide metabolism (isotope tracer techniques with '5N-L-arginine and measurement of nitric oxide production in expired gases). In laboratory studies, PKC and PKBIAkt activation, eNOS-calveolin-1 interactions, and regulation of substrate availability for eNOS (L-arginine transport and ADMA metabolism) will be investigated with molecular biology techniques in cultured human endothelial cells incubated with autocrine/paracrine factors and serum from normal subjects and patients with heart failure. The hypotheses to be tested are: 1) endothelial dysfunction is reversible with chronic interventions to decrease oxidative stress, increase availability of L-arginine, and enhance cGMP-dependent vasodilator effector mechanisms in vascular smooth muscle; 2) endothelial dysfunction is linked to disease progression in heart failure; and 3) reduced synthetic activity of the L-arginine-nitric oxide metabolic pathway in heart failure is attributable serum-induced decreases in PKC isoform or PKB/Akt activation, increased inhibitory eNOS-caveolin-1 interactions, or reduced substrate availability for eNOS (due to decreased L-arginine transport or decreased ADMA metabolism). Proposed studies will provide new data to develop novel therapeutic strategies to improve outcome in patients with heart failure.


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: 2004 ( Subtotal = $327,000 )
2004	2004	YALE UNIVERSITY, SCHOOL OF MEDICINE	451 COLLEGE STREET, POB 1931	NEW HAVEN	CT	06409		USA	Cardiovascular Diseases Research	000	9	2/28/2004	NON-COMPETING CONTINUATION	$327,000
														Subtotal = $327,000

Issue Date FY: 2003 ( Subtotal = $327,000 )
2003	2003	YALE UNIVERSITY, SCHOOL OF MEDICINE	451 COLLEGE STREET, POB 1931	NEW HAVEN	CT	06409		USA	Cardiovascular Diseases Research	000	8		NON-COMPETING CONTINUATION	$327,000
														Subtotal = $327,000

Issue Date FY: 2002 ( Subtotal = $327,000 )
2002	2002	YALE UNIVERSITY, SCHOOL OF MEDICINE	451 COLLEGE STREET, POB 1931	NEW HAVEN	CT	06409		USA	Cardiovascular Diseases Research	000	7	9/24/2002	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$327,000
														Subtotal = $327,000

Issue Date FY: 2001 ( Subtotal = $341,000 )
2001	2001	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Cardiovascular Diseases Research	000	6	3/18/2001	COMPETING CONTINUATION	$341,000
														Subtotal = $341,000

Issue Date FY: 1999 ( Subtotal = $122,879 )
1999	1999	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Cardiovascular Diseases Research	000	5	9/13/1999	NON-COMPETING CONTINUATION	$122,879
														Subtotal = $122,879

Issue Date FY: 1998 ( Subtotal = $140,663 )
1998	1998	COLUMBIA UNIVERSITY, SCHOOL OF ARTS & SCIENCES	106 LOW LIBRARY	NEW YORK-NEW YORK	NY	10027		USA	Cardiovascular Diseases Research	000	4	8/13/1998	NON-COMPETING CONTINUATION	$140,663
														Subtotal = $140,663

Grand Total All Awards = $1,585,542

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STUDIES ON ENDOTHELIAL DYSFUNCTION IN HEART FAILURE

Award Number: R01HL051433

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/1995

PERIOD OF PERFORMANCE END DATE: 02/28/2005

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