Cardiovagal baroreflex deficits impair neurovascular coupling and cognition in Postural Tachycardia Syndrome

项目总结/摘要 体位性心动过速综合征（POTS）是一种慢性直立性不耐受，与过度 直立心动过速，主要发生在年轻女性（>85%）。它最令人不安的症状之一 头晕、疲劳和记忆力下降，通常被患者称为“脑雾”。任务相关 神经血管偶联（NVC）将神经活动与CBF的增加联系起来，称为“功能性充血”。 尽管POTS的记忆任务表现和NVC随着倾斜角度而恶化，但健康对照组则没有， 脑血流量（CBF）保持与对照相似。相反，我们观察到广泛的窄带低 频率（0.07-0.13 Hz）的BP（OBP）振荡，其夹带并放大了CBF（OCBF）振荡。 OBP和OCBF随倾斜角度增加而增加，并导致工作记忆受损和功能减退 充血。心迷走神经压力感受性反射将BP耦合到HR以缓冲BP变化。我们假设 在POTS中，心迷走神经压力感受性反射随着直立性而逐渐受损，但在健康志愿者中没有， 并解释了OBP、OCBF和NVC的损失;此外，改善压力反射降低了OBP、OCBF和 脑雾在锅。 我们将招募15-30岁的女性POTS受试者（N=60），这些受试者未接受药物治疗，且无其他全身性疾病。 疾病和健康受试者（N=20）。我们的方法是三重的：1）我们将使用参考标准 改良Oxford技术测量心迷走神经压力感受性反射，并评估工作记忆和功能 而POTS和健康受试者经历从仰卧到60 °的分级直立倾斜，增量为15 °。 我们预期POTS患者低频时OBP和OCBF逐步升高，而低频时OBP和OCBF逐步降低。 功能性充血和N-Back记忆任务的表现2）我们将在外部强制OBP和OCBF 使用振荡下体负压来证明OCBF和 减少功能性充血和N-Back记忆任务的表现3）我们将比较急性 使用上述方法1）的实验方法，地高辛和吡啶斯的明相对于安慰剂的作用。 文献表明，这些药物增加心脏迷走神经压力感受器反射，并改善副交感神经张力， 无论是疾病还是健康;它们可以减少POTS中的心动过速和症状。这项工作不仅将提供一个 在POTS中，心迷走神经压力感受性反射受损与认知丧失之间存在联系，但可能适用于各种 出现压力反射缺陷的循环系统疾病。

Project Summary/Abstract Postural tachycardia syndrome (POTS), is the chronic form of orthostatic intolerance associated with excessive upright tachycardia, and occurs predominantly in young females (>85%). Among its most troubling symptoms are lightheadedness, fatigue, and decreased memory often called “brain fog” by patients. Task-related neurovascular coupling (NVC) links neural activity to an increase in CBF known as “functional hyperemia”. Although memory task performance and NVC deteriorated with angle of tilt in POTS but not healthy controls, cerebral blood flow (CBF) remained similar to control. Instead, we observed extensive narrow band low frequency (0.07-0.13 Hz) oscillations in BP (OBP) that entrained and amplified oscillations in CBF (OCBF). OBP and OCBF increased with tilt angle and caused impaired working memory and reduced functional hyperemia. The cardiovagal baroreflex couples BP to HR to buffer BP changes. We hypothesize that the cardiovagal baroreflex becomes progressively impaired with orthostasis in POTS, but not in healthy volunteers, and accounts for OBP, OCBF, and loss of NVC; further, improving the baroreflex reduces OBP, OCBF and Brain Fog in POTS. We will recruit female POTS subjects aged 15-30 years (N=60) off medication and free of other systemic disease, and healthy subjects (N=20). Our approach is three-fold: 1) we will use the reference standard modified Oxford technique to measure the cardiovagal baroreflex, and assess working memory and functional hyperemia while POTS and healthy subjects undergo a graded upright tilt from supine to 60o in15o increments. We anticipate step-wise increased OBP and OCBF at low frequency in POTS, with step-wise decreased functional hyperemia and performance on an N-Back memory task 2) We will externally force OBP and OCBF using oscillatory lower body negative pressure to demonstrate the causal connection between OCBF and decreased functional hyperemia and performance on an N-Back memory task 3) We will compare the acute effects of digoxin and pyridostigmine, against placebo using the experimental methods of approach 1) above. Literature suggest that these drugs increase cardiovagal baroreflex and improve parasympathetic tone in sickness and in health; they may reduce tachycardia and symptoms in POTS. This work will not only furnish a link between impaired cardiovagal baroreflex and cognitive loss in POTS, but may find applicability in diverse circulatory illnesses in which baroreflex deficits appear.