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
基本信息
- 批准号:10321896
- 负责人:
- 金额:$ 52.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AdultAnimal ModelAnimalsApneaArrhythmiaAutonomic DysfunctionBlood PressureBrain StemCardiacCardiomyopathiesCardiovascular DiseasesCardiovascular systemChronicClinical ResearchConsciousContinuous Positive Airway PressureDevelopmentDiagnosisDiseaseDoseEquilibriumEventExercise ToleranceExposure toFibrosisFoundationsFunctional disorderFutureGlutamatesGoalsHeartHeart HypertrophyHeart RateHeart failureHourHypertensionHypothalamic structureHypoxiaIncidenceInflammationIschemiaModelingMuscarinic Acetylcholine ReceptorMuscarinicsMyocardialMyocardial IschemiaMyocardial dysfunctionMyocarditisNeuronsObstructive Sleep ApneaOxytocinPatient Self-ReportPatientsPhysiologyPopulationRattusRecoveryRecurrenceRewardsRiskSleepSleep Apnea SyndromesSudden DeathSynapsesTelemetryTestingTimeTissuesVentricularVentricular DysfunctionVentricular RemodelingWithdrawalWomanWorkblood pressure reductioncardioprotectionclinically relevantcomorbidityeffective therapyexperienceheart functionimprovedin vivoinnovationinstrumentloss of functionmenmortalitymyocardial damagemyocardial injuryneurotransmissionnovelnovel therapeuticsparaventricular nucleuspreventresponsesatisfactiontime intervaltranslational potential
项目摘要
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
期刊论文数量(14)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 影响因子:0
- 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:
- 影响因子:0
- 作者:
- 通讯作者:
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:
- 影响因子:4
- 作者:
- 通讯作者:
TRPV1 in arteries enables a rapid myogenic tone.
- DOI:10.1113/jp281873
- 发表时间:2022-04
- 期刊:
- 影响因子:0
- 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:
- 影响因子:0
- 作者:Zasadny FM;Dyavanapalli J;Dowling NM;Mendelowitz D;Kay MW
- 通讯作者:Kay MW
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Matthew W. Kay其他文献
Feasibility of Long-Distance Transfer for High Resolution Optical Mapping of Cardiac Tissue Constructs
- DOI:
10.1016/j.bpj.2011.11.3677 - 发表时间:
2012-01-31 - 期刊:
- 影响因子:
- 作者:
Nina Tandon;Luther M. Swift;Matthew W. Kay;Gordana Vunjak-Novakovic;Narine Sarvazyan - 通讯作者:
Narine Sarvazyan
PO-05-140 NADH CATHETER MAPPING IDENTIFIES GAP FORMATION BETWEEN PULSED FIELD ABLATION LESIONS
PO-05-140 NADH 导管测绘识别脉冲场消融病变之间的间隙形成
- DOI:
10.1016/j.hrthm.2025.03.1538 - 发表时间:
2025-04-01 - 期刊:
- 影响因子:5.700
- 作者:
Rebekah Russo;Terry Ransbury;Catherine Ruffino;Bridget Alber;Omar Amirana;Narine Sarvazyan;Matthew W. Kay - 通讯作者:
Matthew W. Kay
The Inter-Dependency of Local Myocardial Metabolism and Epicardial Electrical Activity during Acute Ischemia and Reperfusion
- DOI:
10.1016/j.bpj.2009.12.2879 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
- 作者:
Huda Asfour;Luther M. Swift;Alta Berger;Ara Arutunyan;Narine Sarvazyan;Matthew W. Kay - 通讯作者:
Matthew W. Kay
Exploring the Effects of Conduction Reserve and Ephaptic Coupling in Cardiac Cells
- DOI:
10.1016/j.bpj.2019.11.2733 - 发表时间:
2020-02-07 - 期刊:
- 影响因子:
- 作者:
Joyce Lin;Steven Poelzing;Sharon A. George;Amara Greer-Short;Matthew W. Kay - 通讯作者:
Matthew W. Kay
MP-470543-008 PANORAMIC HYPERSPECTRAL OPTICAL MAPPING OF CARDIAC MEMBRANE POTENTIAL AND TISSUE TYPE IN INFARCTED HEARTS
MP-470543-008 梗死心脏中心肌膜电位和组织类型的全景高光谱光学映射
- DOI:
10.1016/j.hrthm.2024.03.371 - 发表时间:
2024-05-01 - 期刊:
- 影响因子:5.700
- 作者:
Grant Kowalik;Murray Loew;Emilia Entcheva;Matthew W. Kay - 通讯作者:
Matthew W. Kay
Matthew W. Kay的其他文献
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{{ truncateString('Matthew W. Kay', 18)}}的其他基金
Novel Mechanisms that Restore Cardiac Parasympathetic Activity Limits Arrhythmias and Cardiac Dysfunction After Myocardial Infarction
恢复心脏副交感神经活动的新机制可限制心肌梗死后的心律失常和心脏功能障碍
- 批准号:
10366054 - 财政年份:2020
- 资助金额:
$ 52.52万 - 项目类别:
Novel Mechanisms that Restore Cardiac Parasympathetic Activity Limits Arrhythmias and Cardiac Dysfunction After Myocardial Infarction
恢复心脏副交感神经活动的新机制可限制心肌梗死后的心律失常和心脏功能障碍
- 批准号:
10604331 - 财政年份:2020
- 资助金额:
$ 52.52万 - 项目类别:
Novel Mechanisms that Restore Cardiac Parasympathetic Activity Limits Arrhythmias and Cardiac Dysfunction After Myocardial Infarction
恢复心脏副交感神经活动的新机制可限制心肌梗死后的心律失常和心脏功能障碍
- 批准号:
9981104 - 财政年份:2020
- 资助金额:
$ 52.52万 - 项目类别:
Oxygen-rich perfusate that is compatible with optical assessments of myocardial physiology
与心肌生理学光学评估兼容的富氧灌注液
- 批准号:
9252529 - 财政年份:2016
- 资助金额:
$ 52.52万 - 项目类别:
Oxygen-rich perfusate that is compatible with optical assessments of myocardial physiology
与心肌生理学光学评估兼容的富氧灌注液
- 批准号:
9112060 - 财政年份:2016
- 资助金额:
$ 52.52万 - 项目类别:
Low flow reperfusion after acute myocardial ischemia: when too little is too much
急性心肌缺血后的低流量再灌注:太少就是太多
- 批准号:
8454499 - 财政年份:2010
- 资助金额:
$ 52.52万 - 项目类别:
Low flow reperfusion after acute myocardial ischemia: when too little is too much
急性心肌缺血后的低流量再灌注:太少就是太多
- 批准号:
7889518 - 财政年份:2010
- 资助金额:
$ 52.52万 - 项目类别:
Low flow reperfusion after acute myocardial ischemia: when too little is too much
急性心肌缺血后的低流量再灌注:太少就是太多
- 批准号:
8645695 - 财政年份:2010
- 资助金额:
$ 52.52万 - 项目类别:
Low flow reperfusion after acute myocardial ischemia: when too little is too much
急性心肌缺血后的低流量再灌注:太少就是太多
- 批准号:
8063598 - 财政年份:2010
- 资助金额:
$ 52.52万 - 项目类别:
Low flow reperfusion after acute myocardial ischemia: when too little is too much
急性心肌缺血后的低流量再灌注:太少就是太多
- 批准号:
8238372 - 财政年份:2010
- 资助金额:
$ 52.52万 - 项目类别:
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