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 activation in blunting or reversing alterations in cardiac physiology (ex-vivo) and autonomic tone, blood pressure and heart rate (in-vivo) caused by CIH.

Public Health Relevance

Patients suffering from obstructive sleep apnea (OSA) have a 3-fold increase in cardiovascular mortality, yet very little is known regarding how OSA directly increases the risk for myocardial injury and disease. A goal of this project is to identify the specific impact of OSA on the cardiac function of rats exposed to chronic intermittent hypoxia (CIH), a model of OSA. Our studies will also test the innovative hypothesis that appropriately timed activation of a small population of hypothalamic paraventricular neurons will slow the development of, or reverse, the deleterious autonomic and cardiac function alterations that occur during OSA.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Tjurmina, Olga A
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George Washington University
Engineering (All Types)
Biomed Engr/Col Engr/Engr Sta
United States
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