Hyperadrenergic Postural Tachycardia Syndrome: Clinical Biomarkers and Response to Guanfacine
VIEW EDITORIAL:Tackling POTS Needs More Than Just a Sympathetic Approach
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.
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REFERENCES
1.
Benrud-Larson LM, Dewar MS, Sandroni P, Rummans TA, Haythornthwaite JA, Low PA. Quality of life in patients with postural tachycardia syndrome. Mayo Clin Proc. 2002;77:531–537. doi: 10.4065/77.6.531
2.
Raj SR, Black BK, Biaggioni I, Paranjape SY, Ramirez M, Dupont WD, Robertson D. Propranolol decreases tachycardia and improves symptoms in the postural tachycardia syndrome: less is more. Circulation. 2009;120:725–734. doi: 10.1161/CIRCULATIONAHA.108.846501
3.
Bryarly M, Phillips LT, Fu Q, Vernino S, Levine BD. Postural orthostatic tachycardia syndrome. J Am Coll Cardiol. 2019;73:1207–1228. doi: 10.1016/j.jacc.2018.11.059
4.
Jordan J, Shannon JR, Diedrich A, Black BK, Robertson D. Increased sympathetic activation in idiopathic orthostatic intolerance: role of systemic adrenoreceptor sensitivity. Hypertension. 2002;39:173–178. doi: 10.1161/hy1201.097202
5.
Zhang Q, Chen X, Li J, Du J. Clinical features of hyperadrenergic postural tachycardia syndrome in children. Pediatr Int. 2014;56:813–816. doi: 10.1111/ped.12392
6.
Kanjwal K, Saeed B, Karabin B, Kanjwal Y, Grubb BP. Clinical presentation and management of patients with hyperadrenergic postural orthostatic tachycardia syndrome. A single center experience. Cardiol J. 2011;19:527–531. doi: 10.5603/cj.2011.0008
7.
Raj SR, Guzman JC, Harvey P, Richer L, Schondorf R, Seifer C, Thibodeau-Jarry N, Sheldon RS. Canadian cardiovascular society position statement on Postural Orthostatic Tachycardia Syndrome (POTS) and related disorders of chronic orthostatic intolerance. Can J Cardiol. 2020;36:357–372. doi: 10.1016/j.cjca.2019.12.024
8.
Sheldon RS, Grubb BP, Olshansky B, Shen WK, Calkins H, Brignole M, Raj SR, Krahn AD, Morillo CA, Stewart JM, et al. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm. 2015;12:e41–e63. doi: 10.1016/j.hrthm.2015.03.029
9.
Jacob G, Robertson D, Mosqueda-Garcia R, Ertl AC, Robertson RM, Biaggioni I. Hypovolemia in syncope and orthostatic intolerance role of the renin-angiotensin system. Am J Med. 1997;103:128–133. doi: 10.1016/s0002-9343(97)00133-2
10.
Fu Q, VanGundy TB, Galbreath MM, Shibata S, Jain M, Hastings JL, Bhella PS, Levine BD. Cardiac origins of the postural orthostatic tachycardia syndrome. J Am Coll Cardiol. 2010;55:2858–2868. doi: 10.1016/j.jacc.2010.02.043
11.
Thieben MJ, Sandroni P, Sletten DM, Benrud-Larson LM, Fealey RD, Vernino S, Lennon VA, Shen WK, Low PA. Postural orthostatic tachycardia syndrome: the Mayo clinic experience. Mayo Clin Proc. 2007;82:308–313. doi: 10.4065/82.3.308
12.
Shibao C, Arzubiaga C, Roberts LJ, Raj S, Black B, Harris P, Biaggioni I. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension. 2005;45:385–390. doi: 10.1161/01.HYP.0000158259.68614.40
13.
Garland EM, Gamboa A, Nwazue VC, Celedonio JE, Paranjape SY, Black BK, Okamoto LE, Shibao CA, Biaggioni I, Robertson D, et al. Effect of high dietary sodium intake in patients with postural tachycardia syndrome. J Am Coll Cardiol. 2021;77:2174–2184. doi: 10.1016/j.jacc.2021.03.005
14.
Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, Cheshire WP, Chelimsky T, Cortelli P, Gibbons CH, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Autono Neurosci. 2011;161:46–48. doi: 10.1016/j.autneu.2011.02.004
15.
Rampakakis E, Ste-Marie PA, Sampalis JS, Karellis A, Shir Y, Fitzcharles MA. Real-life assessment of the validity of patient global impression of change in fibromyalgia. RMD Open. 2015;1:e000146. doi: 10.1136/rmdopen-2015-000146
16.
Kaufmann H, Malamut R, Norcliffe-Kaufmann L, Rosa K, Freeman R. The Orthostatic Hypotension Questionnaire (OHQ): validation of a novel symptom assessment scale. Clin Auton Res. 2012;22:79–90. doi: 10.1007/s10286-011-0146-2
17.
Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS 31: a refined and abbreviated composite autonomic symptom score. Mayo Clin Proc. 2012;87:1196–1201. doi: 10.1016/j.mayocp.2012.10.013
18.
Yang M, Keller S, Lin JMS. Psychometric properties of the PROMIS® Fatigue Short Form 7a among adults with myalgic encephalomyelitis/chronic fatigue syndrome. Qual Life Res. 2019;28:3375–3384. doi: 10.1007/s11136-019-02289-4
19.
Jacob G, Costa F, Shannon JR, Robertson RM, Wathen M, Stein M, Biaggioni I, Ertl A, Black B, Robertson D. The neuropathic postural tachycardia syndrome. N Engl J Med. 2000;343:1008–1014. doi: 10.1056/NEJM200010053431404
20.
Raj SR, Biaggioni I, Yamhure PC, Black BK, Paranjape SY, Byrne DW, Robertson D. Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome. Circulation. 2005;111:1574–1582. doi: 10.1161/01.CIR.0000160356.97313.5D
21.
Pena C, Moustafa A, Mohamed AR, Grubb B. Autoimmunity in syndromes of orthostatic intolerance: an updated review. J Pers Med. 2024;14:435. doi: 10.3390/jpm14040435
22.
Benarroch EE. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin Proc. 2012;87:1214–1225. doi: 10.1016/j.mayocp.2012.08.013
23.
Stickford ASL, VanGundy TB, Levine BD, Fu Q. Menstrual cycle phase does not affect sympathetic neural activity in women with postural orthostatic tachycardia syndrome. J Physiol. 2015;593:2131–2143. doi: 10.1113/JP270088
24.
Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology. 1993;43:132–137. doi: 10.1212/wnl.43.1_part_1.132
25.
Jacob G, Costa F, Biaggioni I. Spectrum of autonomic cardiovascular neuropathy in diabetes. Diabetes Care. 2003;26:2174–2180. doi: 10.2337/diacare.26.7.2174
26.
Mar PL, Shibao CA, Garland EM, Black BK, Biaggioni I, Diedrich A, Paranjape SY, Robertson D, Raj SR. Neurogenic hyperadrenergic orthostatic hypotension: a newly recognized variant of orthostatic hypotension in older adults with elevated norepinephrine (noradrenaline). Clin Sci (Lond). 2015;129:107–116. doi: 10.1042/CS20140766
27.
Liao Y, Chen S, Liu X, Zhang Q, Ai Y, Wang Y, Jin H, Tang C, Du J. Flow-mediated vasodilation and endothelium function in children with postural orthostatic tachycardia syndrome. Am J Cardiol. 2010;106:378–382. doi: 10.1016/j.amjcard.2010.03.034
28.
Medow MS, Stewart JM. The postural tachycardia syndrome. Cardiol Rev. 2007;15:67–75. doi: 10.1097/01.crd.0000233768.68421.40
29.
Ross AJ, Ocon AJ, Medow MS, Stewart JM. A double-blind placebo-controlled cross-over study of the vascular effects of midodrine in neuropathic compared with hyperadrenergic postural tachycardia syndrome. Clin Sci (Lond). 2014;126:289–296. doi: 10.1042/CS20130222
30.
Furlan R, Jacob G, Snell M, Robertson D, Porta A, Harris P, Mosqueda-Garcia R. Chronic orthostatic intolerance: a disorder with discordant cardiac and vascular sympathetic control. Circulation. 1998;98:2154–2159. doi: 10.1161/01.cir.98.20.2154
31.
Bonyhay I, Freeman R. Sympathetic nerve activity in response to hypotensive stress in the postural tachycardia syndrome. Circulation. 2004;110:3193–3198. doi: 10.1161/01.CIR.0000147280.90339.E9
32.
Muenter Swift N, Charkoudian N, Dotson RM, Suarez GA, Low PA. Baroreflex control of muscle sympathetic nerve activity in postural orthostatic tachycardia syndrome. Am J Physiol Heart Circ Physiol. 2005;289:H1226–H1233. doi: 10.1152/ajpheart.01243.2004
33.
Lambert E, Eikelis N, Esler M, Dawood T, Schlaich M, Bayles R, Socratous F, Agrotis A, Jennings G, Lambert G, et al. Altered sympathetic nervous reactivity and norepinephrine transporter expression in patients with postural tachycardia syndrome. Circ Arrhythm Electrophysiol. 2008;1:103–109. doi: 10.1161/CIRCEP.107.750471
34.
Kuchel O. Pseudopheochromocytoma. Hypertension. 1985;7:151–158. doi: 10.1016/j.ecl.2019.08.004
35.
Mann SJ, Solanki KV. Clarifying the cause and treatment of paroxysmal hypertension (pseudopheochromocytoma). Curr Hypertens Rep. 2022;24:353–359. doi: 10.1007/s11906-022-01198-1
36.
Strawn JR, Compton SN, Robertson B, Albano AM, Hamdani M, Rynn MA. Extended release guanfacine in pediatric anxiety disorders: a pilot, randomized, placebo-controlled trial. J Child Adolesc Psychopharmacol. 2017;27:29–37. doi: 10.1089/cap.2016.0132
37.
Srour H, Pandya K, Flannery A, Hatton K. Enteral guanfacine to treat severe anxiety and agitation complicating critical care after cardiac surgery. Semin Cardiothorac Vasc Anesth. 2018;22:403–406. doi: 10.1177/1089253218768537
38.
Raj V, Haman KL, Raj SR, Byrne D, Blakely RD, Biaggioni I, Robertson D, Shelton RC. Psychiatric profile and attention deficits in postural tachycardia syndrome. J Neurol Neurosurg Psychiatry. 2009;80:339–344. doi: 10.1136/jnnp.2008.144360
39.
Wilkinson DJ, Thompson JM, Lambert GW, Jennings GL, Schwarz RG, Jefferys D, Turner AG, Esler MD. Sympathetic activity in patients with panic disorder at rest, under laboratory mental stress, and during panic attacks. Arch Gen Psychiatry. 1998;55:511–520. doi: 10.1001/archpsyc.55.6.511
40.
Gaffney FA, Lane LB, Pettinger W, Blomqvist CG. Effects of long-term clonidine administration on the hemodynamic and neuroendocrine postural responses of patients with dysautonomia. Chest. 1983;83:436–438. doi: 10.1378/chest.83.2_supplement.436
41.
Biaggioni I, Shibao CA, Diedrich A, Muldowney JAS, Laffer CL, Jordan J. Blood pressure management in afferent baroreflex failure: JACC review topic of the week. J Am Coll Cardiol. 2019;74:2939–2947. doi: 10.1016/j.jacc.2019.10.027
42.
Sorkin EM, Heel RC. Guanfacine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of hypertension. Drugs. 1986;31:301–336. doi: 10.2165/00003495-198631040-00003
43.
Newcorn JH, Schulz K, Harrison M, DeBellis MD, Udarbe JK, Halperin JM. Alpha 2 adrenergic agonists. Neurochemistry, efficacy, and clinical guidelines for use in children. Pediatr Clin North Am. 1998;45:1099–1022, viii. doi: 10.1016/s0031-3955(05)70064-x
44.
Cornish LA. Guanfacine hydrochloride: a centrally acting antihypertensive agent. Clin Pharm. 1988;7:187–197.
45.
Wilson MF, Haring O, Lewin A, Bedsole G, Stepansky W, Fillingim J, Hall D, Roginsky M, McMahon FG, Jagger P. Comparison of guanfacine versus clonidine for efficacy, safety and occurrence of withdrawal syndrome in step-2 treatment of mild to moderate essential hypertension. Am J Cardiol. 1986;57:43E–49E. doi: 10.1016/0002-9149(86)90723-x
46.
Van Zwieten PA, Thoolen MJ, Timmermans PB. The hypotensive activity and side effects of methyldopa, clonidine, and guanfacine. Hypertension. 1984;6:II28. doi: 10.1161/01.HYP.6.5_Pt_2.II28
47.
Costa F, Biaggioni I. Role of adenosine in the sympathetic activation produced by isometric exercise in humans. J Clin Invest. 1994;93:1654–1660. doi: 10.1172/JCI117147
48.
Delius W, Hagbarth KE, Hongell A, Wallin BG. General characteristics of sympathetic activity in human muscle nerves. Acta Physiol Scand. 1972;84:65–81. doi: 10.1111/j.1748-1716.1972.tb05158.x
49.
Diedrich A, Charoensuk W, Brychta RJ, Ertl AC, Shiavi R. Analysis of raw microneurographic recordings based on wavelet de-noising technique and classification algorithm: wavelet analysis in microneurography. IEEE Trans Biomed Eng. 2003;50:41–50. doi: 10.1109/TBME.2002.807323
50.
Goldstein DS, Eisenhofer G, Stull R, Folio CJ, Keiser HR, Kopin IJ. Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans. J Clin Invest. 1988;81:213–220. doi: 10.1172/JCI113298
51.
Liu H, Cella D, Gershon R, Shen J, Morales LS, Riley W, Hays RD. Representativeness of the patient-reported outcomes measurement information system internet panel. J Clin Epidemiol. 2010;63:1169–1178. doi: 10.1016/j.jclinepi.2009.11.021
52.
Vernino S, Hopkins S, Bryarly M, Hernandez RS, Salter A. Randomized controlled trial of intravenous immunoglobulin for autoimmune postural orthostatic tachycardia syndrome (iSTAND). Clin Auton Res. 2024;34:153–163. doi: 10.1007/s10286-024-01020-9
53.
Bartlett SJ, Gutierrez AK, Andersen KM, Bykerk VP, Curtis JR, Haque UJ, Orbai AM, Jones MR, Bingham CO. Identifying minimal and meaningful change in PROMIS® for rheumatoid arthritis: use of multiple methods and perspectives. Arthritis Care Res (Hoboken). 2022;74:588–597. doi: 10.1002/acr.24501
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© 2024 American Heart Association, Inc.
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History
Received: 16 March 2024
Accepted: 22 July 2024
Published online: 7 August 2024
Published in print: November 2024
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Disclosures
I. Biaggioni has received consultant fees and research support from Lundbeck and Theravance Biopharma Inc for the development of therapies for orthostatic hypotension. I. Biaggioni, L.E. Okamoto, J.K. Shirey-Rice, and J.M. Pulley have submitted a patent application for the use of guanfacine for the treatment of CFS. The other authors report no conflicts.
Sources of Funding
This study was supported by the National Institutes of Health (NIH) grants HL142583, HL159203, HL149386, and UL1 TR002243. Additional support was provided by the Overton and Jeannette Smith Fund and the Lori Ann Fishel Fund. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences or the NIH.
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