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Novel Mechanisms that Restore Cardiac Parasympathetic Activity Limits Arrhythmias and Cardiac Dysfunction After Myocardial Infarction

Award Number: R01HL147279
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Sudden Cardiac Death (SCD) is responsible for between 15 and 20% of all deaths, and ~50% of all cardiovascular deaths in the United States. The most common cascade of events leading to SCD is acute coronary syndrome (ACS) progressing to acute myocardial ischemia and/or inflammation that triggers electrical instability and lethal arrhythmias. Preventing SCD is particularly difficult as approximately one-half of men and two-thirds of women who succumb to SCD had no known history of prior heart disease. Autonomic imbalance is a major risk factor for SCD. Augmented sympathetic activity induces changes in ECG repolarization and reduction of fibrillation threshold facilitating the initiation of ventricular fibrillation (VF). In contrast, the generation of fatal ventricular arrhythmias and risk of SCD is markedly reduced by increasing parasympathetic activity. However a rapid, safe and feasible approach to increase parasympathetic activity to the heart in patients at risk for fatal arrhythmias is severely lacking and is a major medical need. Our preliminary results provide critical new information for the field that identifies a novel target that could restore parasympathetic cardiac tone and reduce the incidence of arrhythmias and cardiac dysfunction following a MI. Our prior work in subjects with sleep apnea has shown intranasal (IN) application of oxytocin increases parasympathetic cardiac activity. In an animal model of ACS with ligation of the left anterior descending coronary artery (LAD) animals develop ischemia, arrhythmias and mortality similar to clinical studies. We show that LAD-ligated animals have reduced endogenous excitatory oxytocin-mediated neurotransmission to parasympathetic cardiac vagal neurons (CVNs) in the brainstem. We further show that selective and chronic activation of hypothalamic paraventricular nucleus (PVN) oxytocin neurons restores oxytocin release, increases parasympathetic activity to the heart and substantially reduces the incidence and initiation of arrhythmias, inflammation, fibrosis and other adverse cardiac outcomes. Based upon our novel results, our overall hypothesis is that chronic selective activation of PVN oxytocin neurons, as well as nasal oxytocin administration, markedly reduces arrhythmias and cardiac dysfunction in an animal model of ACS. In Aim 1 we will test the hypothesis that the critical excitatory pathway from PVN oxytocin neurons to CVNs that helps maintain protective parasympathetic activity to the heart is blunted in animals following LAD ligation, and that this key neurotransmission can be restored with nasal oxytocin treatment and chronic and selective activation of PVN oxytocin neurons. In Aim 2 we will test whether treatment by nasal oxytocin and chronic and selective activation of PVN oxytocin neurons increases parasympathetic activity to the heart in-vivo, reduce the incidence of arrhythmias, improves autonomic balance and effort capacity in exercise stress tests and cardiac function. In Aim 3 we will quantify the electrical and mechanical function of ex-vivo perfused hearts to identify the mechanisms responsible for the cardiac benefits of nasal oxytocin and selective activation of PVN oxytocin neurons in LAD-ligated animals.


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: 2023 ( Subtotal = $579,162 )
2023	2023	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	4	3/21/2023	NON-COMPETING CONTINUATION	$579,162
														Subtotal = $579,162

Issue Date FY: 2022 ( Subtotal = $579,162 )
2022	2022	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	001	3	5/31/2022	NON-COMPETING CONTINUATION	$57,917
2022	2022	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	3	4/6/2022	NON-COMPETING CONTINUATION	$521,245
														Subtotal = $579,162

Issue Date FY: 2021 ( Subtotal = $582,089 )
2021	2021	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	2	3/5/2021	NON-COMPETING CONTINUATION	$582,089
														Subtotal = $582,089

Issue Date FY: 2020 ( Subtotal = $591,110 )
2020	2020	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Cardiovascular Diseases Research	000	1	4/10/2020	NEW	$591,110
														Subtotal = $591,110

Grand Total All Awards = $2,331,523

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Novel Mechanisms that Restore Cardiac Parasympathetic Activity Limits Arrhythmias and Cardiac Dysfunction After Myocardial Infarction

Award Number: R01HL147279

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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