# Hypothalamic neuron activation to blunt myocardial remodeling during chronic sleep apnea

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2020 · $548,683

## Abstract

PROJECT SUMMARY
Obstructive sleep apnea (OSA) is involved in the progression of multiple cardiovascular diseases including
sudden death, hypertension, arrhythmias, myocardial ischemia, and heart failure. Even though these
comorbidities are generally known, very little is known about how OSA directly increases the risk for
myocardial damage and dysfunction. Our goal is to identify the independent impact of chronic intermittent
hypoxia (CIH), a model of OSA, on in-vivo cardiovascular and LV electromechanical dysfunction in rats.
Unfortunately, there are also very few effective treatment options for OSA. We have recently identified a novel
mechanism for restoring cardio-protective parasympathetic tone to the heart to reduce myocardial damage
during CIH. Brainstem parasympathetic cardiac vagal neurons (CVNs) receive powerful excitation from a
population of oxytocin (OXT) neurons that originate in the paraventricular nucleus of the hypothalamus (PVN).
These unique neurons co-release OXT and enhance excitatory glutamatergic neurotransmission to CVNs.
Although we have shown that PVN OXT neuron activation at the onset of CIH exposures can be beneficial in
preventing the development of hypertension, an essential and clinically relevant question remains: Can
activation of PVN OXT neurons reverse and/or mitigate the hypertension, incidence of arrhythmias, cardiac
inflammation, and ventricular dysfunction when initiated after the onset of CIH? This overarching hypothesis
will be tested in two Specific Aims. Aim 1 is to determine how chronic exposure to CIH alters cardiac
tissue function and autonomic tone. In-vivo studies using telemetry-instrumented animals will test the
hypothesis that animals chronically exposed to CIH will have reduced exercise tolerance, increased incidence
of in-vivo cardiac ischemia during peak effort capacity tests, and reduced heart rate recovery after peak effort
capacity. Ex-vivo perfused heart studies will test whether hearts of animals exposed to CIH have reduced
contractile function, increased incidence of demand ischemia, increased incidence of arrhythmia, and reduced
responses to cardiac muscarinic stimulation. Additional assessments of inflammation and fibrosis will probe
potential mechanisms of loss-of-function and arrhythmogenesis. Aim 2 is to determine the effective
treatment window(s) by which appropriately timed activation of PVN OXT neurons could slow or
reverse adverse changes in cardiac physiology and autonomic tone that are caused by CIH. Effective
treatment window(s) will be identified by increasing the time interval between the onset of CIH and the
initiation of chronic activation of PVN OXT neurons. These studies will also quantify the delay between onset
of PVN oxytocin neuron activation and the amount of endogenous synaptic release of oxytocin from PVN
neurons that facilitates CVNs - thereby increasing cardiac parasympathetic tone. We will further assess the
delay/reward relationship of PVN OXT neuron activatio...

## Key facts

- **NIH application ID:** 9841463
- **Project number:** 5R01HL146169-02
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Matthew W. Kay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $548,683
- **Award type:** 5
- **Project period:** 2018-12-21 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841463

## Citation

> US National Institutes of Health, RePORTER application 9841463, Hypothalamic neuron activation to blunt myocardial remodeling during chronic sleep apnea (5R01HL146169-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9841463. Licensed CC0.

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