5.1. Hyperadrenergic POTS

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Hypovolemic POTS]] → -------- ##### Summary >[!Summary] >**Biomarker** >- systolic BP increment ≥10 mmHg during 10 minutes of HUT[[#^2]] >- orthostatic plasma norepinephrine ≥600 pg/mL[[#^2]] > >**Details** >- comprises about 10% of all POTS patients[[#^12]] >- tends to have a gradual and progressive onset of symptoms as opposed to an abrupt onset[[#^14]] >- 20% of hyperadrenergic POTS patients in one study demonstrated a BP rise of more than 20 mmHg[[#^15]] >- these patients appear to have an increased centrally mediated drive of norepinephrine or a defect in norepinephrine reuptake, resulting in increased availability of norepinephrine at the synaptic junctions[[#^16]] >- should be identified and differentiated from those with neuropathic POTS[[#^17]] >- usually difficult to treat[[#^17]] >- these patients have similar HR increment to nonhyperadrenergic POTS, but tend to have prominent symptoms of sympathetic activation (e.g. palpitations, anxiety, tachycardia, and tremulousness)[[#^2]] >- these patients complain of extremity tremor, anxiety, migraine and angina-like chest pain[[#^7]][[#^10]] >- 30-60% POTS patients have evidence of increased central sympathetic drive, as reflected by standing plasma NE levels of 600 pg/mL or more[[#^1]] ; 29.0%[[#^3]][[#^6]] >- an exaggerated sympathetic vasoconstrictor response during the recovery and overshoot phases of the Valsalva maneuver may also reflect a hyperadrenergic state in patients with POTS[[#^8]] >- in these patients, the episodes can be triggered not only by orthostatic stress, but also by emotional stimuli and physical activity[[#^1]] >- this subgroup may correspond to the so-called low-volume POTS characterized by supine vasoconstriction, supine tachycardia, pale and cold skin and increased supine muscle sympathetic nerve activity[[#^1]] >- approximately 5 to 10% of cases are categorized into a primary or central hyperadrenergic subgroup with plasma NE levels often between 1000 and 2000 pg/mL[[#^1]][[#^4]] >- loss-of-function sequence variation of the norepinephrine transporter (NET) and reduced clearance of synaptic NE were found in a case of hyperadrenergic POTS[[#^1]] ; some POTS patients may have decreased expression of NET protein, leading to a functional NET deficiency [[#^9]] >- the large increase in BP found in this subgroup of patients indicates that baroreflex buffering is somehow impaired[[#^5]] >- an excessive sympathetic nervous system tone (“hyperadrenergic state”) may be treatable with central sympatholytic medications[[#^11]] >- most of these patients receive a combination of various first and second line medications[[#^13]] -------- >_“Between 30% and 60% of patients with POTS have evidence of increased central sympathetic drive, as reflected by standing plasma NE levels of 600 pg/mL or more (to convert to pmol/L, multiply by 5.911); fluctuating blood pressure or hypertensive response during HUT; and episodes of tachycardia, hypertension, and hyperhidrosis. In these patients, the episodes can be triggered not only by orthostatic stress but also by emotional stimuli and physical activity._ ([p. 3](zotero://open-pdf/library/items/WEZLT9QC?page=3&annotation=5IARRZT2)) This subgroup of patients may correspond to the so-called low-volume POTS characterized by supine vasoconstriction, supine tachycardia, pale and cold skin, and increased supine muscle sympathetic nerve activity. ( [p. 3](zotero://open-pdf/library/items/WEZLT9QC?page=3&annotation=WG2S4VX5)) These patients have been categorized into a primary or central hyperadrenergic subgroup with plasma NE levels often between 1000 and 2000 pg/mL that compromises approximately 5% to 10% of cases and a heterogeneous group of secondary hyperadrenergic POTS_ ([p. 3](zotero://open-pdf/library/items/WEZLT9QC?page=3&annotation=WMR5NHTC)) Loss-of-function sequence variation of the norepinephrine transporter (NET) and reduced clearance of synaptic NE were found in a case of hyperadrenergic POTS.”_ ([[Benarroch-2012]], [p. 3](zotero://open-pdf/library/items/WEZLT9QC?page=3&annotation=72DT3P3X))^1 >*“One subset of POTS is characterized by an excessive increase of plasma norepinephrine and a rise of BP on standing. [14,24] Hyperadrenergic POTS is defined as POTS associated with a systolic BP increment ≥10 mmHg during 10 minutes of HUT, and an orthostatic plasma norepinephrine ≥600 pg/mL (Fig. 1). These patients have similar HR increment to nonhyperadrenergic POTS, but tend to have prominent symptoms of sympathetic activation, [24] such as palpitations, anxiety, tachycardia, and tremulousness. These patients have a larger fall in BP following ganglionic blockade with trimethaphan, and higher upright plasma norepinephrine levels than did nonhyperadrenergic POTS patients, [24] presumably indicating a major role of orthostatic sympathetic activation.” *([[Low-2009]], [p. 4](zotero://open-pdf/library/items/I4WAD8AG?page=4&annotation=64S7CXR9))^2 >*“Elevation of plasma *([p. 4](zotero://open-pdf/library/items/I4WAD8AG?page=4&annotation=CUN678XR))* norepinephrine (≥600 pg/mL) was documented in 29.0% of patients tested in a recent study.” *([[Low-2009]], [p. 5](zotero://open-pdf/library/items/I4WAD8AG?page=5&annotation=AL53SE4J))^3 >*“Many patients with POTS have elevated levels of plasma NE, suggestive of a hyperadrenergic state. This is most commonly secondary to a partial dysautonomia or hypovolemia. There is a small subgroup of patients in whom the primary underlying problem seems to be excessive sympathetic discharge. These patients often have extremely high levels of upright plasma norepinephrine (>1000 pg/ml and occasionally >2000 pg/ml, with an upper limit of normal of 475 pg/ml in our clinical laboratory).” *([[Raj-2013]], [p. 3](zotero://open-pdf/library/items/CCJLQKRB?page=3&annotation=CLFVWHL8))^4 >*“This subgroup of patients sometimes has large increases in blood pressure on standing, indicating that baroreflex buffering is somehow impaired.” *([[Raj-2013]], [p. 3](zotero://open-pdf/library/items/CCJLQKRB?page=3&annotation=QID4CSZQ))^5 >*“Hyperadrenergic status was documented in 29.0% of patients (standing plasma norepinephrine level ≥600 pg/mL)” *([[Thieben-2007]], [p. 1](zotero://open-pdf/library/items/5WXWEQWX?page=1&annotation=FHNZZY6L))^6 >*“In this form, which is characterized by high level of circulating norepinephrine during orthostasis, patients demonstrate tendency to orthostatic hypertension and often complain of extremity tremor, anxiety, migraine and angina-like chest pain [55]. In a subgroup of these patients, a rare mutation of norepinephrine-transporter gene was found, resulting in reduced synaptic norepinephrine reuptake and excessive sympathetic activation” *([[Fedorowski-2019]], [p. 6](zotero://open-pdf/library/items/BZ35QDLR?page=6&annotation=3AESRSX2))^7 >*“When measured during upright posture, norepinephrine is elevated in many patients with POTS [>3.55 nmol/L (600 pg/mL) and sometimes >5.91 nmol/L (1000 pg/mL)], consistent with the sympathetic neuronal activation elicited by standing in these patients [19]. This is sometimes used as a criterion for the “hyperadrenergic subtype” of POTS. An exaggerated sympathetic vasoconstrictor response during the recovery and overshoot phases of the Valsalva maneuver may also reflect a hyperadrenergic state in patients with POTS [2;19]. These patients may have orthostatic hypertension (increase in systolic blood pressure >10 mmHg on standing) and complain of tremor, anxiety and cold, sweaty extremities [7;25].” *([[Garland-2015]], [p. 7](zotero://open-pdf/library/items/CAWTWYLR?page=7&annotation=D4UPDVFY))^8 >*“A very rare form of hyperadrenergic POTS is caused by a loss-of-function mutation in the gene for the norepinephrine transporter (NET) [54]. NET is a clearance transporter for norepinephrine, and this genetic form of NET deficiency leads to increased synaptic norepinephrine. The mutation has been identified in one kindred thus far. Lambert et al. have reported that some POTS patients may have decreased expression of NET protein, leading to a functional NET deficiency” *([[Garland-2015]], [p. 7](zotero://open-pdf/library/items/CAWTWYLR?page=7&annotation=LBIF2MX7))^9 >*“Hyperadrenergic features can include tremulousness, anxiety, migraine and angina-like chest pain.22 Some perturbations of the autonomic nervous system, particularly the sympathetic nervous system, may be primary (i.e., central hyperadrenergic POTS) or secondary to another physiologic abnormality (e.g, hypovolemia).”* ([[Raj-2022]], [p. 3](zotero://open-pdf/library/items/YN8BG2FZ?page=3&annotation=FZFHNKU2))^10 >*“Excessive increases in plasma norepinephrine on standing may point to an excessive sympathetic nervous system tone (“hyperadrenergic state”) that may be treatable with central sympatholytic medications.”* ([[Raj-2022]], [p. 5](zotero://open-pdf/library/items/YN8BG2FZ?page=5&annotation=ZAXKTEFX))^11 >*“This form of postural tachycardia syndrome is called hyperadrenergic POTS, and comprises about 10% of all POTS patients.”* ([[Kanjwal-2011]], [p. 2](zotero://open-pdf/library/items/R4GMHSS7?page=2&annotation=FPMHMWVF))^12 >*“Most of these patients were receiving a combination of various first and second line medications.”* ([[Kanjwal-2011]], [p. 3](zotero://open-pdf/library/items/R4GMHSS7?page=3&annotation=GH9JG3YL))^13 >*“The less common form of primary POTS, the hyperadrenergic form, tends to have a gradual and progressive onset of symptoms as opposed to an abrupt onset”* ([[Kanjwal-2011]], [p. 4](zotero://open-pdf/library/items/R4GMHSS7?page=4&annotation=5AMRRAE6))^14 >*“Almost 20% of our patients demonstrated orthostatic rise in their blood pressure of more than 20 mm Hg.”* ([[Kanjwal-2011]], [p. 4](zotero://open-pdf/library/items/R4GMHSS7?page=4&annotation=HCNU9NE7))^15 >*“The patients suffering from hyperadrenergic variant of POTS appear to have an increased centrally mediated drive of norepinephrine or a defect in norepinephrine reuptake, resulting in increased availability of norepinephrine at the synaptic junctions.”* ([[Kanjwal-2011]], [p. 4](zotero://open-pdf/library/items/R4GMHSS7?page=4&annotation=L349F57C))^16 >*“Patients of hyperadrenergic POTS should be identified and differentiated from those with neu- ([p. 4](zotero://open-pdf/library/items/R4GMHSS7?page=4&annotation=5E656HYP)) ropathic POTS. These patients are usually difficult to treat and there are no standardized treatment protocols known at this time for patients with hyperadrenergic POTS.”* ([[Kanjwal-2011]], [p. 5](zotero://open-pdf/library/items/R4GMHSS7?page=5&annotation=NS9BVGIC))^17