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Disruption of the Cardiac-Coronary Axis as a Mechanism of HFpEF

Award Number: R01HL167196
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Disruption of the Cardiac-Coronary Axis as a Mechanism of HFpEF - Heart failure is the leading cause of mortality, and about 6.2 million adults in the United States have heart failure. Heart failure with preserved ejection fraction (HFpEF) has typical heart failure symptoms with mostly diastolic LV dysfunction but preserved ejection fraction. HFpEF is characterized by pronounced coronary microvascular dysfunction (CMD), the causal contribution of which is unclear. CMD is associated with coronary artery diseases (CAD), diabetic cardiomyopathy (DCM), ischemia with the non- obstructive coronary artery (INOCA), and HFpEF. Patients with CMD exhibit impaired acetylcholine-induced endothelial-dependent relaxation. Impaired endothelium- dependent vasodilation (EDD) decreases coronary blood flow and myocardium perfusion and might lead to myocardial ischemia even without an obstructive coronary artery. We hypothesize that the myocardial deficiency perfusion caused by CMD will lead to myocardial ischemia, diastolic cardiac dysfunction, and fibrosis in HFpEF. So CMD plays a critical role in HFpEF. Moreover, our ex vivo study shows a deficiency of miR-21 that restores the NO- dependent coronary vasodilation. This application will address the underlying mechanism of how miR-21 regulates the coronary microvascular function, cardiac function and remodeling in HFpEF in a mouse model of HFpEF induced by a long-term high fat and high sugar diet. Such a preclinical modelof HFpEF has been validated in our preliminary data. We hypothesize that restoring “normal” coronary microvascular function (restoring endothelial-dependent dilation) by modulating miR-21can ameliorate HFpEF. We will test our hypothesis by an interdisciplinary approach encompassing a range of approaches and disciplines from molecular and cell analyses, vascular biology to physiology and pathophysiology, engendering the study of a novel mechanism of coronary microvascular dysfunction, such as tissue-specific knockouts and lineage tracing with 3D fluorescent imaging, measurement of vasodilation and myocardial blood flow in vivo by contrast echocardiography and cardiac function by echocardiography along with RNA-seq, sc RNA-seq, etc. Completing this project may lead to a new strategy to treat microvascular dysfunction and HFpEF and improve the cardiovascular prognosis of HFpEF.


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 = $639,380 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	002	3	7/7/2025	NON-COMPETING CONTINUATION	$657,378
2025	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	001	2	4/23/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$645,671
2025	2024	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 STATE ROUTE 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Cardiovascular Diseases Research	000	1	4/22/2025	NEW	-$663,669
														Subtotal = $639,380

Issue Date FY: 2024 ( Subtotal = $663,669 )
2024	2024	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 STATE ROUTE 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Cardiovascular Diseases Research	000	1	6/24/2024	NEW	$663,669
														Subtotal = $663,669

Grand Total All Awards = $1,303,049

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Disruption of the Cardiac-Coronary Axis as a Mechanism of HFpEF

Award Number: R01HL167196

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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