Hyperadrenergic Postural Tachycardia Syndrome: Clinical Biomarkers and Response to Guanfacine, 2024, Okamoto et al.

Abstract
BACKGROUND:
A subset of patients with postural tachycardia syndrome (POTS) are thought to have a primary hyperadrenergic cause. We assessed clinical biomarkers to identify those that would benefit from sympatholytic therapy.
METHODS:
We measured sympathetic function (supine muscle sympathetic nerve activity, upright plasma norepinephrine, and blood pressure responses to the Valsalva maneuver) in 28 patients with POTS (phenotyping cohort) to identify clinical biomarkers that are associated with responsiveness to the central sympatholytic guanfacine in a separate uncontrolled treatment cohort of 38 patients that had received guanfacine clinically for suspected hyperadrenergic POTS (HyperPOTS).
RESULTS:
In the phenotyping cohort, an increase in diastolic blood pressure (DBP) >17 mm Hg during late phase 2 of the Valsalva maneuver identified patients with the highest quartile of resting muscle sympathetic nerve activity (HyperPOTS) with 71% sensitivity and 85% specificity. In the treatment cohort, patients with HyperPOTS, identified by this clinical biomarker, more often reported clinical improvement (85% versus 44% in nonhyperadrenergic; P=0.016), had better orthostatic tolerance (∆Orthostatic Hypotension Daily Activities Scale: −1.9±0.9 versus 0.1±0.5; P=0.032), and reported less chronic fatigue (∆PROMIS Fatigue Short Form 7a: −12.9±2.7 versus −2.2±2.2; P=0.005) in response to guanfacine.
CONCLUSIONS:
These results are consistent with the concept that POTS is caused by a central sympathetic activation in a subset of patients, which can be identified clinically by an exaggerated DBP increase during phase 2 of the Valsalva maneuver and improved by central sympatholytic therapy. These results support further clinical trials to determine the safety and efficacy of guanfacine in patients with POTS enriched for the presence of this clinical biomarker.

https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.124.23035 Paywalled

 

Related editorial (also paywalled): https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.124.23716#

 

From a very brief skim: No blinding, no control group. Patients pre-selected for having a "presumed hyperadrenergic phenotype" who were already undergoing treatment at a specialist centre. Small numbers of patients: n=28 in the phenotyping & n=38 in the treatment cohort. The "HyperPOTS" vs "non-HyperPOTS" groups were differentiated by ∆DBP threshold; in previous work "hyperadrenergic POTS" has been defined in a number of different ways but I do not remember it being defined precisely like this before but more often by plasma noradrenaline levels exceeding a certain threshold upon standing. The authors have submitted a patent application for the use of guanfacine. Haven't looked at the statistics.

The accompanying editorial is a sympathetic one, albeit a little too credulous about the mechanisms & the definition of POTS. I smiled at the quote it begins with:

I also had no idea that there were ongoing trials for pyridostigmine, efgartgimod and naltrexone in POTS patient cohorts; it seems that rather more work is being done with these patients than in the ME/CFS field.