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Atrial and blood JNK in Postoperative AF

Award Number: R01HL168728
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/14/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Atrial and blood JNK in Postoperative AF - Atrial fibrillation (AF) is the most common arrhythmia and has a high risk of mortality and morbidities. Among the general AF population, new-onset postoperative atrial fibrillation (POAF) is the most common complication after open- heart surgery, which significantly increased mortality and amplifies hospital and patient costs. The mechanisms underlying POAF are unclear, thus effective prediction and/or prevention remain unavailable. This proposal aims to fill this knowledge gap by identifying stress-response kinase JNK as a novel POAF biomarker for surgery patients and exploring the translational potential of local JNK inhibition in atria as a novel anti-POAF therapeutic approach. Predisposing factors for POAF include advanced age, binge alcohol, as well as intraoperative and postoperative atrial injury and/or ischemia. One common element among these factors is tremendously increased cellular stress, which is known to activate the c-Jun N-terminal kinases (JNKs), an important stress-response kinase. We recently discovered and reported a previously unrecognized causal link between cardiac JNK activation and abnormal cell-cell communication (via gap junction channels) as well as abnormal Ca triggered activities which enhance AF propensity. Our intriguing preliminary findings suggest that atrial JNK activation is well correlated to POAF incidence in patients within 10 days of coronary artery bypass graft (CABG) surgery, indicating POAF likely involves JNK activation and possible JNK-driven atrial arrhythmogenesis. Intriguingly, our preliminary results show for the first time that JNK is present in blood. And JNK activation in the heart increases blood JNK. Accordingly, the concordant atrial JNK activation and rise in plasma JNK levels correlates nicely to the increased incidence of AF. Next, we found that most of the plasma JNKs are carried by microparticles (MPs) circulating in the blood. Our pilot data further suggest that heart cells shed JNK-microparticles (JNK-MPs). All these intriguing preliminary results combined with our previous findings point to a unique heart-blood JNK relationship that links to AF pathogenesis. Here, we will use a series of cutting-edge biochemical assays and electrophysiological techniques on surgically removed intact atrial tissue, isolated atrial myocytes and blood samples from CABG patients and human donor hearts as well as animal models recapitulating AF risk factors (aging & binge alcohol). Our Specific Aims are: 1) Establish the electrophysiology & biochemistry profiles of JNK, pro-inflammatory cytokins, and arrhythmic substrates in atrial tissue/blood of CABG patients and their correlation to POAF incidence; 2) Prove activated JNK in the blood is a biomarker of POAF risk and test a potential AF therapeutic atrial painting gene transfer intervention in aged rabbits. Establishing the atrial/blood JNK as a possible biomarker of POAF risk is entirely novel here. Clinical accessibility for both atrial tissue and blood samples and POAF events make CABG patients an ideal population for studying the JNK-AF link in humans. Developing an atrial painting gene transfer intervention that could be applied to high POAF risk patients during surgery is innovative. The unique combination of cardiac research expertise and novel electrophysiology/biochemistry techniques makes this proposal technically & experimentally innovative.


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 = $616,206 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	9	1/27/2025	NON-COMPETING CONTINUATION	$616,206
														Subtotal = $616,206

Issue Date FY: 2024 ( Subtotal = $670,980 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	001	8	6/24/2024	NON-COMPETING CONTINUATION	$54,774
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	8	3/1/2024	NON-COMPETING CONTINUATION	$616,206
														Subtotal = $670,980

Issue Date FY: 2023 ( Subtotal = $699,047 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cardiovascular Diseases Research	000	7	4/14/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$699,047
														Subtotal = $699,047

Grand Total All Awards = $1,986,233

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Atrial and blood JNK in Postoperative AF

Award Number: R01HL168728

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/14/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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