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: 7818786
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7818786
• 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）：本申请涉及广泛的挑战领域 (03) 生物标志物发现和验证，以及具体的挑战主题 03-HL-101* 识别和验证血液、血管、心脏和呼吸道功能障碍的诊断和治疗反应的临床相关、可量化的生物标志物。量化睡眠和睡眠呼吸的传统方法依赖于 30 秒周期的手动或计算机辅助评分、将离散快速阶段性脑电图事件标记为唤醒以及识别病理性呼吸的阈值。评分规则通常依赖于单个生理流来做出决定，例如脑电图的唤醒。然而，唤醒刺激可靠地引起许多生理系统（电皮质、呼吸、自主、血流动力学和运动）的同时短暂变化。这些多重关联的生理系统似乎显示出当前分期/评分系统无法识别的重要的耦合活动模式。呼吸化学反射追踪血液中的氧气 (O2) 和二氧化碳 (CO2) 水平。疾病状态可以改变呼吸化学反射的设定点或反应斜率，从而使它们对 O2 和 CO2 波动的敏感性降低（例如，肥胖通气不足综合征）或升高（例如，中枢性睡眠呼吸暂停）。量化和跟踪睡眠期间呼吸化学反射的能力可能具有临床用途，因为 1) 在充血性心力衰竭等某些情况下，化学反射敏感性确实会增加，与疾病的严重程度和结果相关，并导致睡眠呼吸障碍的高患病率。 2) 呼吸化学反射增强可能导致阻塞性睡眠呼吸暂停的严重程度，与使用持续气道正压通气 (CPAP) 治疗时诱发中枢性呼吸暂停有关，并可能损害长期疗效和耐受性。由于诱发中枢性呼吸暂停和周期性呼吸（称为“复杂性睡眠呼吸暂停”）而导致 CPAP 治疗失败的阻塞性睡眠呼吸暂停患者与 CPAP 反应性患者没有其他区别。可以跟踪睡眠呼吸的化学反射调节的生物标志物将为短期和长期动态睡眠生理学提供新的观点，具有重要的临床意义。这里提出的方法是分析耦合睡眠振荡，以数学方式提取状态特征和调制影响。其基本思想是，映射多个（2个或更多）生理上不同但生物上相关的信号流（例如皮层电信号、自主信号、呼吸信号和运动信号）中编码的共同主题，可以产生更深层次调节过程的证据，而当前单独使用脑电图或气流模式对睡眠进行评分/分期的方法并不明显。我们开发了一种仅需要单通道心电图 (ECG) 的方法，该方法是自动化的，可以具有参数变化的检测阈值，并且易于重复。从心电图中，我们提取与呼吸潮气量变化相关的心率变异性 (HRV) 和心电图 R 波振幅波动（心电图衍生呼吸，EDR）。下一步是以数学方式结合 HRV 和 EDR，生成心肺耦合的叉积相干性，从而生成睡眠频谱图。睡眠频谱图显示高 (0.1-1 Hz)、低 (0.1-0.01) 和极低 (0.01-0 Hz) 耦合频谱，显示健康和疾病状态之间的自发变化。高频耦合 (HFC) 是稳定和生理宁静睡眠的生物标志物，低频耦合 (LFC) 是不稳定或生理唤醒的睡眠，极低频耦合 (LFC) 是不稳定或生理唤醒睡眠的生物标志物。 耦合 (VLFC) 是唤醒或 REM 睡眠。健康以HFC为主，睡眠呼吸暂停等疾病则以LFC为主。与呼吸暂停和呼吸不足相关的 LFC 的一个子集是升高的 LFC (e-LFC)。 chemoreflex 调制对 e-LFC 的影响越强，耦合光谱色散就越有可能变窄，从而产生窄带 e-LFC （即具有相对固定频率的节拍振荡）。窄带 e-LFC 由高海拔、心力衰竭引起，并预测正压滴定过程中中枢性呼吸暂停的诱发。心力衰竭的发生和进展与睡眠碎片化和化学反射敏感性升高有关。我们预测，随着心力衰竭的恶化，HFC 将减少，窄带 e-LFC 将出现并增加。这些光谱生物标志物应该改变 随心力衰竭进展或消退动态变化——通过睡眠窗口观察心脏功能。我们的实验将采用以下方法。我们将建立健康成人和儿童以及睡眠呼吸暂停患者中心电图衍生生物标志物的光谱稳定和不稳定睡眠以及夜间稳定性/变异性的血流动力学相关性。接下来，我们将使用海拔引起的周期性呼吸模型，该模型相对纯净 化学反射介导的睡眠呼吸暂停，调整频谱图的参数，从而为检测化学反射对睡眠呼吸的影响提供最佳的灵敏度和特异性。我们将同时跟踪心力衰竭患者住院后 6 个月的进展，试图证明 HFC 的减少和窄带 e-LFC 的出现或增加是预测心力衰竭恶化的哨兵生物标志物事件（早期预警） 系统）。最后，我们将根据存档数据集的光谱表型评估临床结果，即呼吸暂停正压长期疗效研究。在该奖项的两年期限内，我们将验证一种独特的睡眠、睡眠呼吸和心血管生物学生物标志物，该标志物可以立即应用于改善健康结果。 公共卫生相关性：对于临床和研究目的而言，廉价、易于重复且可以跟踪疾病波动的睡眠、睡眠呼吸和心脏功能的简单测量方法将是有用的。开发了一种基于单通道心电图（ECG）的新方法；它利用心跳速度的变化和心电图与呼吸相关的大小变化来创建“睡眠音乐”的图片。我们建议展示其作为健康睡眠监测器、简单和复杂形式的睡眠呼吸暂停患者以及心力衰竭患者的有用性。