Mechanisms of Sympathetic Overactivity in Post-traumatic Stress Disorder

创伤后应激障碍中交感神经过度活跃的机制

• 批准号: 10409640
• 负责人: Jeanie Park
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10409640
• 关键词: Acute; Address; Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Afghanistan; Anti-Cholinergics; Anti-Inflammatory Agents; Baroreflex; Biological Markers; Blood Flow Velocity; Blood Pressure; Blood Vessels; Brain Stem; Cardiovascular Diseases; Cervical; Chronic Disease; Data; Development; Devices; Disease; Doppler Ultrasound; Dose; Efferent Neurons; Electrocardiogram; Future; General Population; Goals; Gold; Health; Human; Hypertension; Impairment; Inflammation; Inflammatory; Intervention; Iraq; Kidney; Measures; Mediating; Mental disorders; Muscle; Nerve; Nerve Fibers; Nervous System Physiology; Nucleus solitarius; Organ; Output; Parasympathetic Nervous System; Pathogenesis; Patients; Peripheral Resistance; Pharmacology; Phenylephrine; Physiology; Plasma; Post-Traumatic Stress Disorders; Psyche structure; Regulation; Renal Blood Flow; Renin; Renin-Angiotensin System; Research; Rest; Risk; Risk Factors; Role; Sodium; Stress; Sympathetic Nervous System; Techniques; Testing; Therapeutic; Time; Vagus nerve structure; Vascular resistance; Veterans; Work; afferent nerve; alpha-1 adrenergic receptors; blood pressure elevation; blood pressure regulation; cardiovascular disorder risk; cardiovascular risk factor; disorder control; experimental study; hemodynamics; high risk population; improved; insight; kidney vascular structure; military veteran; neurovascular; novel; patient population; peripheral blood; post 9/11; prevent; programs; receptor sensitivity; response; therapeutic target; time use; vagus nerve stimulation; vascular abnormality; vasoconstriction; young man; young woman

Post-traumatic stress disorder (PTSD) is a highly prevalent and debilitating mental health disorder that is independently associated with an increased risk of cardiovascular (CV) disease and hypertension. Given the large numbers of post-9/11 Veterans afflicted with PTSD, addressing this under-recognized but highly significant consequence of PTSD is of paramount importance to protect the future health of these young Veterans. We have shown that post-9/11 Veterans with PTSD have overactivation of the sympathetic nervous system (SNS) during mental stress and impaired arterial baroreflex sensitivity (BRS) that could contribute to the pathogenesis of hypertension and CV disease in these patients. While we have now established that central sympathetic output is augmented in PTSD, the downstream effects of SNS output on blood pressure (BP) regulation in PTSD remain unknown and is a major goal of this proposal. We hypothesize that augmented sympathetic nerve activity in PTSD leads to augmented SNS-mediated vasoconstriction within the kidney, an organ with a critical role in BP regulation. Exaggerated increases in sympathetically mediated renal vasoconstriction could perpetuate sustained increases in BP over time via renal sodium reabsorption and activation of the renin-angiotensin system (RAS). To test this hypothesis, we will measure renal blood flow velocity using Doppler ultrasound, continuous hemodynamics, muscle sympathetic nerve activity (MSNA) using microneurography, plasma renin activity and inflammatory biomarkers at rest and during mental stress in post 9/11 Veterans and matched controls. We further hypothesize that SNS activation leads to an exaggerated vasoconstrictive response (i.e. heightened neurovascular transduction of SNS activity) mediated by abnormal vascular adrenergic receptor sensitivity in PTSD. To test this hypothesis, we will determine vascular alpha-1 adrenergic receptor (α1AR) sensitivity by measuring vasoconstriction in response to exponentially increasing doses of the selective α1AR agonist phenylephrine using a linear variable differential transformer in PTSD and controls. Finally, prior studies have shown that transcutaneous vagus nerve stimulation (tVNS) reduces SNS activity, improves BRS, and lowers inflammation in healthy humans and a number of chronic diseases; however, the potential benefits of tVNS on SNS function and regulation in PTSD have never previously been investigated. We hypothesize that tVNS acutely lowers SNS activity and improves sympathetic and cardiovagal BRS in PTSD. To test this hypothesis, we will measure MSNA, EKG, hemodynamics, inflammation, and BRS using pharmacologic manipulation of BP at rest and during tVNS (versus sham stimulation) in PTSD patients. tVNS could be a novel nonpharmacologic approach to reducing SNS activity and restoring BRS in these patients. Improving SNS overactivity and BRS may have long term benefits on reducing CV risk in PTSD patients.

创伤后应激障碍（PTSD）是一种高度流行和衰弱的心理健康 与心血管（CV）疾病风险增加独立相关的疾病 和高血压。考虑到大量9/11事件后的退伍军人患有创伤后应激障碍， 解决创伤后应激障碍的这种未被充分认识但非常重要的后果是至关重要的， 保护这些年轻退伍军人的未来健康。我们已经证明 9/11后患PTSD的退伍军人交感神经系统（SNS）过度激活 在精神压力和受损的动脉压力反射敏感性（BRS），可能有助于 这些患者中高血压和CV疾病的发病机制。虽然我们现在 建立了中枢交感神经输出在创伤后应激障碍中增强， SNS输出对PTSD患者血压（BP）调节的作用尚不清楚，这是研究的一个主要目标。 这个提议。我们假设PTSD中交感神经活动增强导致 增强肾脏内SNS介导的血管收缩，肾脏是一个在BP中起关键作用的器官 调控交感神经介导的肾血管收缩的过度增加可能 随着时间的推移，通过肾钠重吸收和激活 肾素-血管紧张素系统（RAS）。为了验证这一假设，我们将测量肾血流量 多普勒血流速度，连续血流动力学，肌交感神经 活动（MSNA）使用显微神经造影术，血浆肾素活性和炎症生物标志物， 在9/11事件后的退伍军人和匹配的对照组中休息和精神压力期间。我们进一步 假设SNS激活导致过度的血管收缩反应（即， SNS活性的神经血管转导增强）由异常血管 肾上腺素能受体敏感性为了验证这一假设，我们将确定血管 α 1肾上腺素能受体（α 1 AR）敏感性，通过测量血管收缩反应， 使用线性方法，指数增加选择性α 1 AR激动剂苯肾上腺素的剂量， PTSD和控制中的可变差动Transformer。最后，先前的研究表明， 经皮迷走神经刺激（tVNS）减少SNS活动，改善BRS， 降低健康人的炎症和许多慢性疾病;然而， tVNS对PTSD患者SNS功能和调节的潜在益处以前从未被 研究了我们假设，tVNS急性降低SNS活动和改善交感神经系统， 和心迷走神经BRS的关系为了验证这一假设，我们将测量MSNA，EKG， 血流动力学、炎症和BRS，使用静息时BP的药理学操作， 在PTSD患者中进行tVNS（与假刺激相比）。TVNS可能是一部小说 非药物方法减少SNS活动和恢复这些患者的BRS。 改善SNS过度活跃和BRS可能对降低PTSD患者的CV风险具有长期益处 患者