Hyperadrenergic Postural Tachycardia Syndrome: Clinical Biomarkers and Response to Guanfacine

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.