ECG-derived cardiopulmonary coupling biomarkers of sleep, sleep-breathing, and ca

ECG 衍生的睡眠、睡眠呼吸和 ca 的心肺耦合生物标志物

• 批准号: 7938776
• 负责人: Robert Joseph Thomas
• 金额: $ 50万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938776
• 关键词: Address; Adult; Age; Altitude; Apnea; Applications Grants; Archives; Area; Arousal; Auditory; Autonomic Pathways; Award; Biological Markers; Biology; Blood; Blood Pressure; Blood Vessels; Brain; Breathing; Carbon Dioxide; Cardiac; Cardiopulmonary; Cardiovascular Physiology; Cardiovascular system; Central Sleep Apnea; Characteristics; Child; Clinical; Clinical Research; Complex; Computer Assisted; Congestive Heart Failure; Continuous Positive Airway Pressure; Coupled; Coupling; Data Set; Detection; Development; Diagnostic; Disease; Electrocardiogram; Electroencephalogram; Epilepsy; Event; Feedback; Frequencies; Functional disorder; Health; Heart; Heart Rate; Heart failure; High Prevalence; Hospitalization; Hypercapnic respiratory failure; Link; Lower Extremity; Lung; Manuals; Maps; Measures; Mediating; Methods; Modeling; Modification; Morphology; Motor; Muscle; Muscle Tonus; Music; Nerve; Neurologic; Obesity; Obstructive Sleep Apnea; Outcome; Oxygen; Patients; Pattern; Phenotype; Physiological; Physiology; Polysomnography; Process; REM Sleep; Receiver Operating Characteristics; Respiration; Respiratory System; Respiratory tract structure; Restless Legs Syndrome; Sensitivity and Specificity; Sentinel; Severities; Severity of illness; Signal Transduction; Simulate; Sleep; Sleep Apnea Syndromes; Sleep Fragmentations; Sleep Stages; Slow-Wave Sleep; Speed; Staging; Stimulus; Stream; Syndrome; System; Techniques; Therapeutic; Tidal Volume; Time; Titrations; Treatment Effectiveness; Validation; auditory stimulus; base; clinically relevant; heart function; heart rate variability; hemodynamics; improved; non rapid eye movement; novel; pressure; public health relevance; research study; respiratory; response; sex

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03) Biomarker Discovery and Validation, and specific Challenge Topic, 03-HL-101* Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction. The traditional approach to quantifying sleep and sleep-respiration relies on manual or computer assisted scoring of 30 second epochs, tagging of discrete fast phasic electroencephalographic events as arousals, and thresholds to identify pathological breathing. The scoring rules are usually reliant on a single physiological stream to make a determination, such as arousals from the electroencephalogram. However, arousing stimuli reliably induce simultaneous transient changes in numerous physiological systems - electrocortical, respiratory, autonomic, hemodynamic, and motor. These multiple linked physiological systems seem to show important patterns of coupled activity that current staging / scoring systems do not recognize. The respiratory chemoreflexes track oxygen (O2) and carbon dioxide (CO2) levels in the blood. Disease states can alter the set-point or response slope of the respiratory chemoreflexes, such that they are less (e.g., obesity hypoventilation syndrome) or more (e.g., central sleep apnea) sensitive to O2 and CO2 fluctuations. An ability to quantify and track the respiratory chemoreflexes during sleep could have clinical use, as 1) In certain conditions like congestive heart failure, chemoreflex sensitivity is reliably increased, correlates with disease severity and outcomes, and contributes to the high prevalence of sleep-disordered breathing. 2) Heightened respiratory chemoreflexes may contribute to obstructive sleep apnea severity, be associated with induction of central apneas when continuous positive airway pressure (CPAP) is used for treatment, and possibly impair long term efficacy and tolerance. Patients with obstructive sleep apnea who fail CPAP therapy due to induction of central apneas and periodic breathing (called "complex sleep apnea") are not otherwise distinguishable from CPAP-responsive patients. A biomarker that can track chemoreflex modulation of sleep respiration will provide a new view of short and long-term dynamic sleep physiology with important clinical implications. The approach proposed here is to analyze coupled sleep oscillations to mathematically extract state characteristics and modulatory influences. The fundamental idea is that mapping common themes encoded within multiple (2 or more) physiologically distinct but biologically linked signal streams (such as electrocortical, autonomic, respiratory and motor) yields evidence of deeper regulatory processes not evident by the current approach of scoring / staging sleep with electroencephalogram or airflow patterns alone. We have developed a method that needs only a single channel electrocardiogram (ECG), is automated, can have parametrically varied detection thresholds, and is readily repeatable. From the ECG, we extract heart rate variability (HRV) and ECG R-wave amplitude fluctuations associated with respiratory tidal volume changes (the ECG-derived respiration, EDR). The next step is to mathematically combine the HRV and EDR to generate the cross-product coherence of cardiopulmonary coupling, which yields the sleep spectrogram. The sleep spectrogram shows high (0.1-1 Hz, low (0.1-0.01) and very low (0.01-0 Hz) coupling spectra that show spontaneous shifts between states in health and disease. High frequency coupling (HFC) is the biomarker of stable and physiologically restful sleep, low frequency coupling (LFC) is unstable or physiologically aroused sleep, and very low frequency coupling (VLFC) is wake or REM sleep. Health is dominated by HFC, diseases such as sleep apnea by LFC. A subset of LFC that correlate with apneas and hypopneas is elevated LFC (e-LFC). The stronger the chemoreflex modulatory influence on e-LFC, the more likely the coupling spectral dispersion narrows, yielding narrow band e-LFC (i.e., metronomic oscillations with a relatively fixed frequency). Narrow band e-LFC is induced by high altitude, heart failure, and predicts central apnea induction during positive pressure titration. The development and progression of heart failure is associated with fragmented sleep and heightened chemoreflex sensitivity. We predict that HFC will decrease and narrow band e-LFC will emerge and increase with worsening heart failure. These spectral biomarkers should change dynamically with heart failure progression or regression - viewing cardiac function through the window of sleep. Our experiments will take the following approach. We will establish the hemodynamic correlates of spectrographic stable and unstable sleep and night-to-night stability / variability of the ECG-derived biomarkers in adults and children in health, and in those with sleep apnea. Next, we will use a model of altitude-induced periodic breathing, which is relatively pure chemoreflex-mediated sleep apnea, to adjust the spectrogram's parameters that allow the best sensitivity and specificity for detecting chemoreflex influences on sleep respiration. We will in parallel track the progress of heart failure patients from a hospitalization episode for 6 months, attempting to show that reductions of HFC and emergence or increases in narrow band e-LFC are sentinel biomarker events that predict worsening of heart failure (an early warning system). Finally, we will assess clinical outcomes based on spectral phenotyping of an archived data set, the Apnea Positive Pressure Long-term Efficacy Study. In the 2-year duration of the award, we will validate a unique biomarker of sleep, sleep-breathing, and cardiovascular biology that can be applied immediately to improve health outcomes. PUBLIC HEALTH RELEVANCE: Simple measures of sleep, sleep-breathing and heart function that are cheap, readily repeatable, and which can track disease fluctuations would be useful, for clinical and research purposes. A new method based on a single channel of electrocardiogram (ECG) has been developed; it uses changes in the speed of the heart beat and breathing-related size modifications of the ECG, to create a "picture of the "music of sleep". We propose to show its usefulness as a monitor of sleep in health, in those with simple and complicated forms of sleep apnea, and in patients with heart failure.

描述（由申请人提供）：此申请解决了广泛的挑战领域（03）生物标志物发现和验证以及特定的挑战主题，03-HL-101*识别并验证并验证诊断和治疗性反应的临床相关，可量化的生物标志物，以诊断和治疗性反应，血管，心脏和呼吸道功能障碍。量化睡眠和睡眠的传统方法依赖于30秒时代的手动或计算机辅助评分，将离散的快速阶段性脑电图事件标记为唤醒，以及识别病理呼吸的阈值。评分规则通常依赖于单个生理流来确定，例如脑电图中的唤醒。然而，引起刺激可靠地诱导许多生理系统的同时瞬时变化 - 皮质，呼吸，自主神经，血液动力学和运动。这些多个链接的生理系统似乎显示了当前分期 /评分系统无法识别的耦合活动的重要模式。血液中的呼吸道化学反射跟踪氧（O2）和二氧化碳（CO2）水平。疾病状态可以改变呼吸道化学反射剂的设定点或反应斜率，从而使它们较小（例如肥胖综合症综合征）或更多（例如，中央睡眠呼吸暂停）对O2和CO2的波动敏感。在睡眠期间量化和跟踪呼吸道化学反射剂的能力可能具有临床用途，因为1）在某些情况下，例如充血性心力衰竭，化学反射敏感性可靠地提高，与疾病的严重程度和结果相关，并有助于呼吸呼吸呼吸的高流行。 2）呼吸道化学反射剂的增强可能导致阻塞性睡眠呼吸暂停严重程度，当使用连续的正气道压力（CPAP）进行治疗时，与中央呼吸暂停有关，并可能降低长期效力和耐受性。由于诱导中央呼吸暂停和周期性呼吸（称为“复杂的睡眠呼吸呼吸暂停”），患有阻塞性睡眠呼吸暂停的患者无法与CPAP反应性患者区分开来。可以跟踪睡眠呼吸的化学反射调制的生物标志物将提供具有重要临床意义的短期和长期动态睡眠生理学的新视图。这里提出的方法是分析耦合的睡眠振荡，以数学提取状态特征和调节影响。基本思想是，在多个（2个或多个）生理上不同但生物学上连接的信号流中编码的共同主题（例如电气，自主，呼吸和运动）产生了更深入的调节过程的证据，这些过程无法通过单独使用电源频率或空气流量模式的当前评分 /分期睡眠的方法来证明。我们已经开发了一种仅需要单个通道心电图（ECG）的方法，自动化，可以具有参数变化的检测阈值，并且很容易重复。从心电图中，我们提取与呼吸道潮汐体积变化相关的心率变异性（HRV）和ECG R波振幅波动（EDR EDR）。下一步是数学上结合HRV和EDR，以产生心肺耦合的交叉产物相干性，从而产生睡眠光谱。睡眠频谱图显示高（0.1-1 Hz，低（0.1-0.01）和非常低的（0.01-0 Hz）耦合光谱，显示健康和疾病状态之间的自发性移动。高频耦合（HFC）是稳定的稳定和生理上的频率低频率，低频率，低频率，LFC的频率很高（LFC）耦合（VLFC）是醒来的，或者由HFC占主导地位，例如，LFC的睡眠呼吸暂停。 （即，具有相对固定的频率的计量振荡是由高海拔，心力衰竭诱导的，并且在正压滴定期间预测中央呼吸暂停。我们预测，HFC将减少，狭窄的E-LFC会随着心力衰竭的恶化而出现并增加。这些光谱生物标志物应随着心力衰竭进展或回归的方式动态变化 - 通过睡眠窗口查看心脏功能。我们的实验将采用以下方法。我们将建立光谱学稳定和不稳定的睡眠以及成人和健康儿童以及睡眠呼吸暂停患者的ECG衍生生物标志物的夜晚稳定性 /变异性的血液动力学相关性。接下来，我们将使用高度引起的周期性呼吸模型，该模型是相对纯净的化学反射介导的睡眠呼吸呼吸器，以调整频谱图的参数，从而允许检测化学反射对睡眠呼吸影响的最佳灵敏度和特异性。我们将同时跟踪6个月内的心力衰竭患者从住院发作中的进展，试图表明HFC和出现的减少或狭窄带E-LFC中的出现或增加是前哨生物标志物事件，这些事件预测了心力衰竭恶化（预警系统）。最后，我们将基于存档数据集的光谱表型（呼吸暂停呼吸峰值长期疗效研究）评估临床结果。在奖项的两年期间，我们将验证可以立即应用的睡眠，睡眠呼吸和心血管生物学的独特生物标志物，以改善健康状况。 公共卫生相关性：简单的睡眠，睡眠呼吸和心脏功能便宜，易于重复，并且可以跟踪疾病波动对于临床和研究目的是有用的。已经开发了一种基于心电图（ECG）单个通道的新方法。它利用心脏跳动的速度变化和心电图的呼吸相关尺寸修饰，创建“睡眠音乐”的图片。我们建议在患有简单且复杂形式的睡眠呼吸暂停的人和心脏衰竭的患者中显示其作为健康中的睡眠监控性的有用性。