Fear conditioning as a pathogenic mechanism in the postural tachycardia syndrome

Abstract

Despite its increasing recognition and extensive research, there is no unifying hypothesis on the pathophysiology of the postural tachycardia syndrome. In this cross-sectional study, we examined the role of fear conditioning and its association with tachycardia and cerebral hypoperfusion on standing in 28 patients with postural tachycardia syndrome (31 ± 12 years old, 25 females) and 21 matched controls. We found that patients had higher somatic vigilance (P = 0.0167) and more anxiety (P < 0.0001). They also had a more pronounced anticipatory tachycardia right before assuming the upright position in a tilt-table test (P = 0.015), a physiological indicator of fear conditioning to orthostasis. While standing, patients had faster heart rate (P < 0.001), higher plasma catecholamine levels (P = 0.020), lower end-tidal CO2 (P = 0.005) and reduced middle cerebral artery blood flow velocity (P = 0.002). Multi-linear logistic regression modelling showed that both epinephrine secretion and excessive somatic vigilance predicted the magnitude of the tachycardia and the hyperventilation. These findings suggest that the postural tachycardia syndrome is a functional disorder in which standing may acquire a frightful quality, so that even when experienced alone it may elicit a fearful conditioned response. Heightened somatic anxiety is associated with and may predispose to a fear-conditioned hyperadrenergic state when standing. Our results have therapeutic implications.

Keywords: autonomic nervous system; hyperventilation; orthostatic intolerance; postural tachycardia syndrome; somatic anxiety.

Figure 1

Anticipatory conditioned tachycardia in patients with postural tachycardia syndrome. (A) Continuous averaged heart rate in the supine and tilted positions in the group of patients with postural tachycardia syndrome (POTS, red) and group of healthy controls (black). Dotted line marks timing of a false auditory stimulus warning the patient of imminent tilt, which triggered a significant conditioned anticipatory tachycardia shaded (highlighted in yellow, two-way ANOVA), which occurred before head-up tilt, while still in the supine position. Second dotted line marks actual movement of the tilt table and continuing tachycardia. (B) Box and whisker plots (depicting the median with minimum to the maximum values) show 2-fold larger anticipatory conditioned tachycardia (change in heart rate induced by tilt warning while still supine) in patients with POTS compared to controls (t-test).

Figure 2

Neuroendocrine and hyperventilation profiles. (A) Plasma epinephrine concentrations in the supine and head-up tilt positions in patients with POTS and age-matched healthy controls. (B) Plasma norepinephrine levels. Note the marked increase in epinephrine levels while upright, which are not under baroreflex control. (C) Greater hypocapnic-hyperventilation in patients with POTS while upright. (D) More pronounced drop in blood flow velocity in the upright position. (E) An xy plot showing the significant relationship between the fall in end-tidal CO₂ and decline in cerebral blood flow velocity. Data are available for 19 participants who had a stable, technically adequate middle cerebral artery recording to measure flow velocity. Box and whisker plots show median with minimum and maximum values. EPI = epinephrine; MCA = middle cerebral artery insonated with transcranial Doppler; NE = norepinephrine; POTS = postural tachycardia syndrome. Red plots/dots = POTS patients; white plots/dots = control participants.

Figure 3

Pathophysiological model of postural tachycardia syndrome. (A) Pathophysiological pathways involved in auditory fear conditioning. The auditory warning of tilt is relayed to the cortex. This, in turn, stimulates a conditioned fear response involving neurons in the insula and amygdala, involved in the acquisition, storage and expression of fear memories. Outputs from these cortical areas (green), activate sympathetic outflow at the level of the rostroventrolateral medulla (RVLM) to the peripheral vasculature, heart and adrenal gland. Projections from the amygdala to the ventral respiratory group (VRG), elicit an increase in phrenic nerve activity and hyperventilation. (B) Pathophysiological model of postural tachycardia syndrome from multivariant analysis. Conditioned tachycardia occurs through activation of the limbic system (green) on anticipation of standing. This triggers tachycardia and hyperventilation. Hypocapnia, in turn, causes cerebral vasoconstriction and peripheral vasodilatation. Peripheral vasodilation requires a compensatory baroreflex response, with tachycardia and further norepinephrine release. This information is relayed back to the CNS, specifically to the anterior cingulate cortex, which provides emotional valence to somatic signals. Heightened somatic vigilance and anxiety have a feed-forward effect to further stimulate epinephrine release and hyperventilation while upright. Ach = acetylcholine; epi = epinephrine; ne = norepinephrine; NTS = nucleus of the solitary tract; SAN = sinoatrial node.