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Increasing Ischemic Myocardial Tissue Perfusion by Mechanical LV Support

Award Number: R01HL139963
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Increasing Ischemic Myocardial Tissue Perfusion by Mechanical LV Support - PROJECT ABSTRACT/SUMMARY Emerging evidence suggests a possible limitation of myocardial infarction (MI) size by acute mechanical left ventricular (LV) support. A phase II clinical trial of mechanical LV unloading for acute MI has begun enrolling after the recent completion of the Door-to-Unloading (DTU) STEMI Trial, which demonstrated both safety and feasibility of this approach. This is an exciting area of medicine, where no new therapy has become clinically routine for salvaging ischemic myocardium in MI after establishing coronary reperfusion. Despite the strong enthusiasm and repeatedly shown efficacy in animal experiments, limited knowledge exists on how it limits infarct size. This proposal focuses on understanding the physiological effects of mechanical LV support in acute MI and its mechanisms of infarct size reduction. Our preliminary data suggests that mechanical LV support increases ischemic myocardial tissue flow and perfusion by lowering LV diastolic wall stress. Based on our data, we expect that “reduced diastolic wall stress” and “improved tissue perfusion” play the key roles in infarct size reduction during mechanical LV support, rather than generally accepted mechanism that “reduced cardiac work” limits infarct size. To examine our hypothesis, we will use large animal models of myocardial ischemia/reperfusion and study the impact of acute LV support on coronary flow. In Aim 1, we will study the relationship between diastolic LV wall stress and ischemic tissue perfusion under different LV loading conditions. Comprehensive assessment of LV pressure/volume, coronary flow, and myocardial tissue perfusion during different LV loading conditions will offer improved mechanistic understanding. In Aim 2, we will determine the factors that regulate ischemic tissue perfusion during LV support. This Aim will define patient characteristics that benefit most from mechanical LV support in acute MI. In Aim 3, molecular mechanisms of coronary flow regulation is examined by focusing on microRNA-146. We expect that decreased diastolic LV wall stress increases exosomal microRNA-146 secretion from the heart, which inhibits coronary vascular oxidative stress and improves tissue perfusion. Understanding the mechanisms of infarct size reduction is essential to improve patient selection for this novel and promising, but invasive therapy for acute MI. Results of proposed studies will help define optimal support settings, establish effective clinical protocols, and identify appropriate patient population.


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: 2027 ( Subtotal = $0 )
2027	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	000	9	10/21/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2026 ( Subtotal = $672,494 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	000	9	2/16/2026	NON-COMPETING CONTINUATION	$651,907
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	001	9	4/23/2026	NON-COMPETING CONTINUATION	$20,587
														Subtotal = $672,494

Issue Date FY: 2025 ( Subtotal = $696,576 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	000	8	11/26/2024	NON-COMPETING CONTINUATION	$626,919
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	002	8	1/27/2025	SUPPLEMENT FOR EXPANSION	-$105,395
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	001	8	12/6/2024	SUPPLEMENT FOR EXPANSION	$105,395
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	004	8	8/5/2025	NON-COMPETING CONTINUATION	$69,657
2025	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	003	5	1/30/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $696,576

Issue Date FY: 2024 ( Subtotal = $682,644 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	000	7	11/17/2023	NON-COMPETING CONTINUATION	$626,919
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	001	7	6/8/2024	NON-COMPETING CONTINUATION	$55,725
														Subtotal = $682,644

Issue Date FY: 2023 ( Subtotal = $706,363 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	000	6	12/19/2022	COMPETING CONTINUATION	$706,363
														Subtotal = $706,363

Issue Date FY: 2022 ( Subtotal = $423,750 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	001	5	6/9/2022	NON-COMPETING CONTINUATION	$42,375
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	000	5	12/3/2021	NON-COMPETING CONTINUATION	$381,375
														Subtotal = $423,750

Issue Date FY: 2021 ( Subtotal = $423,750 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	000	4	12/17/2020	NON-COMPETING CONTINUATION	$381,375
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	001	4	5/15/2021	NON-COMPETING CONTINUATION	$42,375
														Subtotal = $423,750

Issue Date FY: 2020 ( Subtotal = $423,750 )
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	001	3	3/7/2020	NON-COMPETING CONTINUATION	$21,188
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	000	3	12/6/2019	NON-COMPETING CONTINUATION	$402,562
														Subtotal = $423,750

Issue Date FY: 2019 ( Subtotal = $423,750 )
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	000	2	12/13/2018	NON-COMPETING CONTINUATION	$423,750
														Subtotal = $423,750

Issue Date FY: 2018 ( Subtotal = $419,580 )
2018	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cardiovascular Diseases Research	000	1	12/15/2017	NEW	$419,580
														Subtotal = $419,580

Grand Total All Awards = $4,872,657

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Increasing Ischemic Myocardial Tissue Perfusion by Mechanical LV Support

Award Number: R01HL139963

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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