Wednesday, July 16, 2025 7/16/2025

Noninvasive Testing of Coronary Microvascular Reactivity Using High-resolution Free-breathing MRI

Award Number: R01HL153430
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Noninvasive Testing of Coronary Microvascular Reactivity Using High-resolution Free-breathing MRI - PROJECT SUMMARY It was long taken for granted that obstructive coronary artery disease (CAD) is the primary driver of angina and major adverse cardiac events. However, recent landmark studies have shown that up to 50% of the patients referred for diagnostic testing have ischemia with no obstructive CAD (INOCA). A large proportion of INOCA patients have coronary microvascular dysfunction (CMD), which even in the absence of flow-limiting stenoses can lead to myocardial ischemia and carries a high risk of adverse events. The reference standard for assessment of CMD is the functional coronary reactivity (CR) test, which is invasive. Despite key studies showing value of stratifying therapy based on CR testing, the practical utility of CR testing in the INOCA population is limited by its invasive nature, which carries serious risks even at experienced centers. Hence, a noninvasive approach that can detect and stage the severity of CMD would be invaluable for managing INOCA patients. Driven by this unmet need, prior studies have employed imaging approaches to index myocardial perfusion reserve (MPR) against CR; however, the association shown to date between MPR and CR impairment has been weak, likely due to the suboptimal sensitivity of MPR to subendocardial myocardial blood flow (MBF) deficits which is a hallmark of CMD. Studies using invasive microsphere-based methods have established a stress subendocardial-to-subepicardial (endo-epi) MBF gradient of larger than 1.0 in healthy animals, and shown that it decreases well below 1 under abnormally elevated microvascular resistance. However, noninvasive detection of endo-epi MBF gradients using existing imaging strategies is challenging because of the need to resolve MBF transmurally. We have developed new MRI strategies aimed at overcoming key barriers for accurate evaluation of endo-epi MBF gradients and applied them in preliminary animal and patient studies. Based on our preliminary data, we hypothesize that in the setting of CMD, impaired microvascular CR manifests as a stress-induced endo- epi MBF gradient, and the magnitude of this gradient significantly correlates with CMD severity. To test this hypothesis, we propose 3 specific aims. In Aim 1, we will develop a free-breathing artifact-free MRI technique optimized for high-resolution imaging of endo-epi MBF gradients, combined with a machine learning approach for fully-automated objective quantification of MBF gradients. In Aim 2, we will test the hypothesis that CMD severity can be staged on the basis of MRI-derived stress MBF gradient in a pig model of CMD. In Aim 3, we will test the hypothesis that CMD severity in INOCA patients is highly correlated with MRI-derived stress MBF gradient. This project brings together multiple interdisciplinary investigators with a strong collective track record in developing cardiac imaging strategies to advance a noninvasive approach for determining CMD severity based on the MRI-derived stress MBF gradient. Hence the proposal is a major step towards improving the management of INOCA patients and towards imaging-guided evaluation of novel therapies aimed at CMD.


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 = -$1,802,174 )
2025	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	003	5	5/29/2025	NON-COMPETING CONTINUATION	-$409,458
2025	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	002	5	3/6/2025	NON-COMPETING CONTINUATION	-$603,027
2025	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cardiovascular Diseases Research	004	6	5/30/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$409,458
2025	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	001	4	3/6/2025	NON-COMPETING CONTINUATION	-$626,586
2025	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	000	3	3/6/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$572,561
														Subtotal = -$1,802,174

Issue Date FY: 2024 ( Subtotal = $603,027 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	001	5	6/20/2024	NON-COMPETING CONTINUATION	$49,226
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	000	5	4/11/2024	NON-COMPETING CONTINUATION	$553,801
														Subtotal = $603,027

Issue Date FY: 2023 ( Subtotal = $626,586 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	004	4	3/30/2023	NON-COMPETING CONTINUATION	$626,586
2023	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	003	3	12/22/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$918,368
2023	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	000	3	11/1/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	002	2	12/22/2022	NON-COMPETING CONTINUATION	-$760,832
2023	2020	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	001	1	12/22/2022	NEW	-$157,536
														Subtotal = $626,586

Issue Date FY: 2022 ( Subtotal = $669,107 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	001	3	8/6/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$669,107
2022	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	2	8/5/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $669,107

Issue Date FY: 2021 ( Subtotal = $760,832 )
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	2	4/1/2021	NON-COMPETING CONTINUATION	$760,832
														Subtotal = $760,832

Issue Date FY: 2020 ( Subtotal = $699,398 )
2020	2020	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cardiovascular Diseases Research	000	1	7/15/2020	NEW	$699,398
														Subtotal = $699,398

Grand Total All Awards = $1,556,776

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Noninvasive Testing of Coronary Microvascular Reactivity Using High-resolution Free-breathing MRI

Award Number: R01HL153430

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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