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Resuscitating the Brain and Heart Following Cardiac Arrest: Targeting Oxygen Toxicity

Award Number: R01HL169679
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/02/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Resuscitating the Brain and Heart Following Cardiac Arrest: Targeting Oxygen Toxicity - ABSTRACT Oxygen is administered to unconscious, mechanically ventilated patients following successful cardiopulmonary resuscitation (CPR) from sudden cardiac arrest to ensure adequate oxygenation and to avoid potential worsening tissue hypoxia. The liberal use of oxygen is near universal because it is regarded as benign and to be of potential benefit. This dogma is being challenged by growing evidence that oxygen contributes to multi-organ injury and decreased neurologically intact survival. Understanding the role of oxygen toxicity on post-CA outcomes represents a major knowledge gap and barrier to improving outcomes. Antioxidants have not been found to be beneficial and the patterns of injury and mechanism underlying its effects are poorly understood. This project attempts to address these barriers by testing the effects of restricting oxygen availability through the administration of hypoxia with a fractional inspired oxygen (FiO2) of 10% between the first- and 7-hours following CA. We term this therapy oxygen restriction therapy (O2RT). Paradoxically, O2RT increased oxygen consumption, lowered biomarkers of glycolysis, decreased cellular injury and improved physiological recovery of the heart and brain resulting in improved survival. In contrast, hyperoxia (FiO2 30%) or room air (FiO2 21%) had the opposite effects. Both hyperoxia and normoxia following CA stabilized the hypoxia inducible factor 1a (HIF1a) while O2RT lowered HIF1a. This finding is relevant because HIF1a regulates changes glycolysis and inflammation. Our findings of HIF1a stabilization suggest potential worsening of tissue hypoxia by hyperoxia or alternatively aberrant HIF1a stabilization resulting in aerobic glycolysis and inflammation that occurs in pathologies like cancer. Aim1 further investigates the effects of O2RT vs. hyperoxia on post-CA injury during a critical 6-hour window of injury. Aim 2 tests the influence of O2RT and hyperoxia on changing patterns of breathing, blood flow, and metabolism in the heart and brain and Aim 3 interrogates the role of HIF1a in the brain and heart using cell specific knock out mice. Success of this research will establish the role of oxygen in mediating post-CA secondary injury while identifying a critical window of injury that can be targeted for therapeutic benefit and identifying HIF1a as a new therapeutic target for limiting oxygen toxicity.


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 = $809,442 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cardiovascular Diseases Research	001	2	8/4/2025	NON-COMPETING CONTINUATION	$80,944
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cardiovascular Diseases Research	000	2	1/3/2025	NON-COMPETING CONTINUATION	$728,498
														Subtotal = $809,442

Issue Date FY: 2024 ( Subtotal = $796,322 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cardiovascular Diseases Research	001	1	7/4/2024	NEW	$79,632
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cardiovascular Diseases Research	000	1	4/2/2024	NEW	$716,690
														Subtotal = $796,322

Grand Total All Awards = $1,605,764

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Resuscitating the Brain and Heart Following Cardiac Arrest: Targeting Oxygen Toxicity

Award Number: R01HL169679

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/02/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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