Fear Response Fueling Postural Tachycardia Syndrome?

Some patients with symptoms of postural tachycardia syndrome (POTS) may be experiencing a fear response caused by previous fainting episodes, new research suggests.

Investigators compared adult patients with POTS symptoms with healthy controls and found that patients with POTS had higher somatic vigilance and more anxiety.

They also had more pronounced anticipatory tachycardia immediately before assuming the upright position in a tilt-table test, suggesting orthostasis-related fear. In addition, patients with POTS had a more rapid heart rate, hypocapnia, cerebral hypoperfusion, and release of epinephrine into the blood stream.

“Overall, the findings strongly suggest that many patients with POTS, due to previous orthostatic episodes, develop a fear response that anticipates standing and triggers a hyperadrenergic state that can contribute to and perpetuate the condition,” senior investigator Horacio Kaufmann, MD, director, Division of Autonomic Disorders, Dysautonomia Center, NYU Grossman School of Medicine, New York City, told Medscape Medical News.

“Patients’ symptoms are very distressing, and an anticipatory fear response is present — which, although may be appropriate because of the patient’s previous experiences, should nevertheless be managed,” said Kaufmann, who is also a professor of neurology and a professor in the Departments of Medicine and Pediatrics.

“We emphasize that this is not an imaginary illness; the brain is triggering the pathophysiological manifestations,” he added.

The findings were published online July 8.

Pavlovian Fear Conditioning?

Patients with POTS develop “marked tachycardia with symptoms of cerebral hypoperfusion upon standing, despite not experiencing orthostatic hypotension,” the investigators write.

There is currently no “unifying hypothesis” that fully explains the pathophysiology of POTS. Proposed mechanisms include an array of cardiovascular abnormalities, but whether they are a “cause or a consequence of the syndrome is unknown,” the researchers note.

Based on clinical observations and a detailed analysis of data from a large number of patients documented in their database, the investigators hypothesize that “classic Pavlovian fear conditioning could mediate the pathogenesis” of POTS.

“POTS has been assumed to be a multifactorial syndrome and we have seen countless patients that remain symptomatic, despite being treated with a variety of drugs,” Kaufmann said.

“We postulated that the neuronal connections between the cortex and autonomic control centers in the brainstem could play a role in POTS,” he added.

The researchers examined “hemodynamic and neuroendocrine responses, as well as the degree of ‘somatic vigilance’ of affected patients and whether this hypervigilance could contribute to the patients’ symptoms,” said Kaufmann.

They compared 28 consecutive patients with POTS (mean age, 31 years; 25 women) with 21 matched peers without POTS.

Participants completed the Spielberger State-Trait Anxiety Inventory, the Zung depression scale, and the somatic vigilance scale and underwent a tilt-table test, before which physiologic symptoms were acquired during a 30-minute supine rest period.

The same physiologic symptoms were measured after participants, while still in the supine resting state, received an auditory warning 30 seconds prior to the tilt that the table “would immediately move upright and that they might feel unwell.”

The tilt consisted of moving the table into a 60-degree upright position for 10 minutes, after which participants returned to the horizontal position, and the test was concluded.

Plasma catecholamine concentrations were sampled at supine rest and after 10 minutes in the upright position.

More Anxiety, Depression, Somatic Vigilance

Compared with the healthy participants, patients with POTS had higher scores in anxiety, depression, and somatic vigilance. There was especially greater attentiveness to surveying bodily sensations of chest discomfort and symptoms of hyperventilation, which are used to “determine susceptibility to fear conditioning,” the investigators note.

Test score (total) Patients Control Group P Value
Somatic vigilance 24 ± 19 17 ± 10 = .0167
State anxiety 57 ± 13 37 ± 12 < .0001
Zung depression 59 ± 12 30 ± 6 < .0001

During the 30-second window between the auditory warning and the tilt, the POTS group had a twofold greater heart rate increase compared with the healthy controls group.

The POTS group also had a greater increase in heart rate during the head-up tilt (24 [±12] beats/min vs 51 [± 13] beats/min, respectively; P < .0001).

All participants with POTS developed some “characteristic symptoms” upon head-up tilt, including palpitations, dizziness/light-headedness, diaphoresis, shakeness/anxiety, flushing, hyperventilation, shortness of breath, numbness, and tingling. No member of the healthy-controls group experienced these symptoms.

Plasma epinephrine levels in the supine position were similar and within the normal range in both groups, although slightly (but significantly) higher in the POTS group. During head-up tilt, patients with POTS had significantly higher plasma catecholamine levels compared with their healthy peers (P = .02).

They also had a greater increase in cerebral vascular resistance, (+ 63% [±4%] vs + 23% [±10%]respectively; P = .005), and a fall in cerebral blood flow velocity — all associated with orthostatic hypocapnia.

“The magnitude of the fall in cerebral blood flow velocity was directly related to end-tidal CO2levels (R2 = .4984, P < .0011)," the researchers report.

A multivariate regression model showed that anticipatory tachycardia correlated positively with state anxiety and somatic vigilance scores. In fact, the magnitude of anticipatory tachycardia predicted the extent of hyperventilation, as well as the maximum heart rate during tilt, which is correlated with epinephrine release (P = .003).

The best four predictors of maximum heart rate were hypocapnia and somatic vigilance (P = .002), accounting for 67% of the variance, whereas end-tidal CO2 was “directly related” to increased somatic body vigilance scores, the investigators write.

“Fainting or near fainting on standing, which patients with POTS experience frequently, is very frightening,” Kaufmann noted.

After a few fainting episodes provoked by orthostasis, even the mere thought of standing activates the amygdala and results in tachycardia and hyperventilation, Kaufmann noted.

“Somatic hypervigilance appears to be a contributor to hyperventilation and epinephrine secretion, which worsens the symptoms,” he said.

“The final cause of POTS remains to be ascertained. The disorder is heterogeneous and may have different mechanisms. Considering the neural pathways involved is crucial to understanding the syndrome and finding an effective treatment,” he added.

Heterogeneous Disorder

Commenting for Medscape Medical NewsBrian Olshansky, MD, emeritus professor of internal medicine-cardiovascular medicine, Carver College of Medicine, University of Iowa, Iowa City, noted the study’s “very small number of patients.”

Olshanksy, who was not involved with the research, also questioned whether the patients in the study actually had POTS.

“If your definition [of POTS] is simply a heart rate increase of 20 bpm when standing up, with orthostatic intolerance, you might say the patient has POTS. But here, it occurred before they were placed upright, so that doesn’t meet the definition of POTS,” he said.

Olshansky acknowledged that patients with POTS may experience somatic vigilance and that POTS may “potentially be confused with a functional psychogenic disorder, but it is not necessarily the same thing.”

Moreover, “it’s unclear why these patients were fear conditioned. The cause is not necessarily orthostatic intolerance,” he said.

The study was funded in part by the National Institutes of Health and the Familial Dysautonomia Foundation, Inc. The investigators report no relevant financial relationships. Olshansky reports sometimes serving as an expert witness in court cases with patients who present with symptoms that are consistent with POTS.

Brain. Published online July 8, 2022. Abstract

Batya Swift Yasgur MA, LSW is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMDand is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her story).

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