Hypothalamic neuron activation to blunt myocardial remodeling during chronic sleep apnea

下丘脑神经元激活可减弱慢性睡眠呼吸暂停期间的心肌重塑

• 批准号: 10321896
• 负责人: Matthew W. Kay
• 金额: $ 52.52万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-21 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321896
• 关键词: Adult; Animal Model; Animals; Apnea; Arrhythmia; Autonomic Dysfunction; Blood Pressure; Brain Stem; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Chronic; Clinical Research; Conscious; Continuous Positive Airway Pressure; Development; Diagnosis; Disease; Dose; Equilibrium; Event; Exercise Tolerance; Exposure to; Fibrosis; Foundations; Functional disorder; Future; Glutamates; Goals; Heart; Heart Hypertrophy; Heart Rate; Heart failure; Hour; Hypertension; Hypothalamic structure; Hypoxia; Incidence; Inflammation; Ischemia; Modeling; Muscarinic Acetylcholine Receptor; Muscarinics; Myocardial; Myocardial Ischemia; Myocardial dysfunction; Myocarditis; Neurons; Obstructive Sleep Apnea; Oxytocin; Patient Self-Report; Patients; Physiology; Population; Rattus; Recovery; Recurrence; Rewards; Risk; Sleep; Sleep Apnea Syndromes; Sudden Death; Synapses; Telemetry; Testing; Time; Tissues; Ventricular; Ventricular Dysfunction; Ventricular Remodeling; Withdrawal; Woman; Work; blood pressure reduction; cardioprotection; clinically relevant; comorbidity; effective therapy; experience; heart function; improved; in vivo; innovation; instrument; loss of function; men; mortality; myocardial damage; myocardial injury; neurotransmission; novel; novel therapeutics; paraventricular nucleus; prevent; response; satisfaction; time interval; translational potential

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

项目总结

项目成果

TRPV1 expressed throughout the arterial circulation regulates vasoconstriction and blood pressure.

TRPV1在整个动脉循环中表达，调节血管收缩和血压。

• DOI: 10.1113/jp279909
• 发表时间: 2020-12
• 期刊: The Journal of physiology
• 作者: Phan TX;Ton HT;Gulyás H;Pórszász R;Tóth A;Russo R;Kay MW;Sahibzada N;Ahern GP
• 通讯作者: Ahern GP

Ischemic damage to every segment of the oxidative phosphorylation cascade elevates ETC driving force and ROS production in cardiac mitochondria.

• DOI: 10.1152/ajpheart.00129.2022
• 发表时间: 2022-09-01
• 期刊: American journal of physiology. Heart and circulatory physiology

Ephaptic Coupling Is a Mechanism of Conduction Reserve During Reduced Gap Junction Coupling.

• DOI: 10.3389/fphys.2022.848019
• 发表时间: 2022
• 期刊: Frontiers in physiology
• 影响因子: 4

TRPV1 in arteries enables a rapid myogenic tone.

• DOI: 10.1113/jp281873
• 发表时间: 2022-04
• 期刊: The Journal of physiology
• 作者: Phan TX;Ton HT;Gulyás H;Pórszász R;Tóth A;Russo R;Kay MW;Sahibzada N;Ahern GP
• 通讯作者: Ahern GP

Cholinergic stimulation improves electrophysiological rate adaptation during pressure overload-induced heart failure in rats.

• DOI: 10.1152/ajpheart.00293.2020
• 发表时间: 2020-10-02
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Zasadny FM;Dyavanapalli J;Dowling NM;Mendelowitz D;Kay MW
• 通讯作者: Kay MW