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The identification and pathophysiology of non-infarcted but injured myocardium in the post-ischemic heart

Award Number: R01HL152712
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The identification and pathophysiology of non-infarcted but injured myocardium in the post-ischemic heart - ABSTRACT - In the post-ischemic heart, relatively little is known about the injured-but-not-infarcted myocardium, which we call the intermediate zone as it is neither normal nor infarcted. We recently identified compelling evidence that the intermediate zone is not merely a "lesser infarct", but has a set of unique pathological characteristics and contributes significantly to cardiac impairment. These novel discoveries were made possible by overcoming a technological challenge. We developed a high-sensitivity phosphatidylethanolamine (PE)- based imaging technique, enabling the mapping of the intermediate zone which is otherwise missed by conventional methods. Using imaging-guided pathological analyses, we discovered that, in contrast to the infarct zone where there is necrosis across all cell types, in the intermediate zone different cell types survive differently. This disparity between surviving cardiomyocytes (residual contractility) and loss of sympathetic neurons (dysinnervation) creates chaos in electrophysiology. Chronically, the intermediate zone exhibits functional deficiency with signaling activation associated with hypertrophy. The data strongly support that the intermediate zone has significant contractile dysfunction as well as being a substrate for arrhythmias. As such, there are significant prognostic values both for assessing the full scope of myocardial impairment and for predicting the risk for arrhythmias. Based on these findings, we propose a central hypothesis that the intermediate zone constitutes a distinct pathological entity which contributes to cardiac dysfunction in the post-ischemic heart. The hypothesis will be tested in three integrated and synergistic Specific Aims: 1) to refine the in vivo imaging methodology for mapping the intermediate zone, and characterize the pathology of this tissue in an imaging- guided approach; 2) to determine the signaling changes in the intermediate zone; and 3) to investigate the roles of the intermediate zone in arrhythmogenesis. Collectively, the ability to positively identify the intermediate zone in vivo provides a critical technological breakthrough. By understanding the signaling, pathological and functional changes in this tissue, our findings will ultimately have a transformative impact on enriching the knowledge base and shaping clinical practices in ACS.


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 = $729,842 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	001	4	6/12/2024	NON-COMPETING CONTINUATION	$59,580
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	4	12/20/2023	NON-COMPETING CONTINUATION	$670,262
														Subtotal = $729,842

Issue Date FY: 2023 ( Subtotal = $755,936 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	001	3	3/15/2023	NON-COMPETING CONTINUATION	$75,594
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	3	12/27/2022	NON-COMPETING CONTINUATION	$680,342
														Subtotal = $755,936

Issue Date FY: 2022 ( Subtotal = $763,064 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	001	2	6/9/2022	NON-COMPETING CONTINUATION	$76,307
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	2	1/16/2022	NON-COMPETING CONTINUATION	$686,757
														Subtotal = $763,064

Issue Date FY: 2021 ( Subtotal = $766,173 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	000	1	12/29/2020	NEW	$689,554
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cardiovascular Diseases Research	001	1	7/28/2021	NEW	$76,619
														Subtotal = $766,173

Grand Total All Awards = $3,015,015

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The identification and pathophysiology of non-infarcted but injured myocardium in the post-ischemic heart

Award Number: R01HL152712

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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