<span class="center-menu">← <small>PREVIOUS: [[3.1. Genetic factors and familial patterns]]</small> | <small>NEXT: [[3.3. Environmental factors and triggers]]</small> →</span> -------- ##### Summary >[!Summary] >- frequent onset after viral illness[[#^10]] and presence of ganglionic acetylcholine receptor (g-AChR) antibody in 14.6% suggests autoimmune cause[[#^1]][[#^2]][[#^8]][[#^9]][[#^15]] >- some patients report "viral like" illness 2 - 6 months prior to onset of symptoms (supporting hypothesis that an autoimmune-mediated molecular mimicry might be present)[[#^4]] >- ≤ 50% have antecedent viral illness[[#^01]][[#^02]][[#^03]] >- patients with antecedent viral illness appeared, in a qualitative analysis, to do better than those with spontaneous POTS[[#^04]] >- 27.6% report history of preceding illness (11.9% viral gastrointestinal ; 14.4% viral upper respiratory tract ; 64.3% viral unspecified)[[#^05]] >- antecedent history of suspected viral infection reported by 20% - 50%[[#^06]]; 11.1%[[#^07]] >- recently, numerous cases of POTS and other forms of sinus tachycardia (e.g., inappropriate sinus tachycardia) after a SARS-CoV-2 infection have been reported[[#^08]] >------- > >- |Multiple facts supporting possibility of immune involvement in POTS[[#^10]] | >|:--| >|predominance of women & temporal association with antecedent viral infection, vaccination or trauma are similar to typical features of autoimmune disease | >|indicators of immune system dysfunction and positive autoimmune tests frequently seen among POTS patients (1/4 patients have positive tests for antinuclear antibodies & 20% report history of autoimmune disorder (gastrointestinal dysmotility, antiphospholipid antibodies found in 76%, novel Sjögren antibodies in 42%), which is more than in general population) | > >------- >- | Autoantibodies detected in POTS exceeding expected prevalence in general population[[#^12]] | >|:----------------------------------------------------------------------------------- | >| G-protein coupled receptors | >| Ganglionic Acetylcholine-receptor (g-AChR) | >| Sjögren autoantibodies [[#^16]]| >| Antinuclear antibodies (ANAs) | >| Antiphospholipid antibodies | >| Anti-NMDA (N-methyl-D-aspartate)-type glutamate receptor | >| Thyroid gland | >| Cardiac lipid raft-associated proteins and other cardiac proteins | > >------- > - cardiovascular G-protein-coupled membrane complexes (such as adrenergic, muscarinic, angiotensin II type-1 receptors) may have causative role in POTS = symptoms could be evoked by direct action on sinus rate controlling system (via adrenergic and muscarinic receptors) or through compensatory mechanism responding to peripheral vasodilation (via adrenergic, angiotensin & other possible vasoactive receptors)[[#^11]] > - nicotinic acetylcholine-receptor in autonomic ganglia & Sjögren autoantibodies also have a proposed aetiological role in POTS[[#^13]] > - antibodies to the alpha-1, beta1, and beta-2 adrenergic receptors have been detected in POTS which may explain insufficient vasoconstriction and tachycardia[[#^17]] > - antibodies to M1 and M2 muscarinic acetylcholine receptors are also present in a significant proportion of POTS patients tested and may contribute to tachycardia among other symptoms[[#^17]] >----------- >- **Healthy**:  Upright → Pooling of blood in veins  → Normal a1AR mediated vasoconstriction → Slightly increased HR, contractility & cardiac output[[#^7]] >- **POTS**: Upright → Pooling of blood in veins → a1AR-AAb Impaired vasoconstriction → Impaired a1AR mediated vasoconstriction → Increased drop of BP → Exaggerated baroreceptor activation → Exaggerated sympatho-neural response → Increased neuronal and circulating NE → Hemodynamic manifestations in POTS >→ 1. Partially blocked vascular a1AR → Compensated BP in POTS >→ 2. Unblocked cardiac β1AR → Marked tachycardia in POTS[[#^7]] >- POTS patients have elevated a1AR autoantibodies, which cause a partial peripheral antagonist effect - which - results in a compensatory sympathoneural activation of a1AR for vasoconstriction and concurrent bAR-mediated tachycardia (coexisting b1AR and b2AR agonistic autoantibodies facilitate this tachycardia)[[#^3]][[#^5]] >- ideally a pharmacological approach to management would block autoantibody activity and leave the receptors unblocked[[#^6]] -------- >_“The frequent onset after a viral illness and the presence of a ganglionic acetylcholine receptor antibody in 14% of patients suggest an autoimmune <small>([p. 2](zotero://open-pdf/library/items/WEZLT9QC?page=2&annotation=VGQJD2EB))</small> cause of neuropathic POTS in some cases”_ <small>([[Benarroch-2012]], [p. 3](zotero://open-pdf/library/items/WEZLT9QC?page=3&annotation=IP6F6TBW))</small>^1 >*“Support for the notion of neuropathic POTS comes also from the 1 in 7 patients who have low titer of A3 acetylcholine receptor antibodies, a finding that suggests an autoimmune attach of autonomic nerves.” *<small>([[Low-2009]], [p. 4](zotero://open-pdf/library/items/I4WAD8AG?page=4&annotation=ARLTXVQV))</small>^2 >*“POTS patients have elevated a1AR autoantibodies exerting a partial peripheral antagonist effect resulting in a compensatory sympathoneural activation of a1AR for vasoconstriction and concurrent bAR-mediated tachycardia. Coexisting b1AR and b2AR agonistic autoantibodies facilitate this tachycardia.” *<small>([[Li-2014]], [p. 1](zotero://open-pdf/library/items/4RG2IND3?page=1&annotation=974SJJI9))</small>^3 >*“Some subjects report a “viral-like” illness 2 to 6 months prior to the onset of symptoms, thus supporting the hypothesis that an autoimmune-mediated molecular mimicry might be present.” *<small>([[Li-2014]], [p. 1](zotero://open-pdf/library/items/4RG2IND3?page=1&annotation=FZHC82KZ))</small>^4 >*“subjects with POTS manifest autoantibodies to the pressor a1-adrenergic receptor (a1AR) and could partially block the effectiveness of the normal a1AR endogenous ligand norepinephrine central to the homeostatic response to upright posture. This impaired vasoconstrictor response would increase baroreceptor activation, increase central sympathetic nervous activity, and normalize vasoconstriction and blood pressure. The relatively unprotected b1AR cardiac chronotropic receptors would respond to this increased sympathoneural output and circulating norepinephrine with an exaggerated tachycardia. The presence of b1/2AR-activating autoantibodies potentially would enhance this tachycardia.” *<small>([[Li-2014]], [p. 2](zotero://open-pdf/library/items/4RG2IND3?page=2&annotation=UZQ2QLRU))</small>^5 >*“data support the addition of POTS to a growing number of cardiovascular entities with an autoimmune pathophysiology. A pharmacological approach to management would ideally block autoantibody activity and leave the receptors unblocked.” *<small>([[Li-2014]], [p. 9](zotero://open-pdf/library/items/4RG2IND3?page=9&annotation=KCRS6MI4))</small>^6 >![[Li-2014-9-x39-y352.png#invert_B| 500]] ><small>([[Li-2014]], [p. 9](zotero://open-pdf/library/items/4RG2IND3?page=9&annotation=R7VL5KDF))</small>^7 >*“Vernino et al'" found in 1 of 7 patients with POTS the antibody against ganglionic acetylcholine receptor” *<small>([[Sandroni-1999]], [p. 5](zotero://open-pdf/library/items/X25GXI7E?page=5&annotation=RJR8A9QN))</small>^8 >*“ganglionic acetylcholine receptor antibody was detected in 14.6%, suggesting an autoimmune origin in at least 1 in 7 patients” *<small>([[Thieben-2007]], [p. 1](zotero://open-pdf/library/items/5WXWEQWX?page=1&annotation=DWCBVIII))</small>^9 >*“Early clinical observations pointed to the fact that illness often started with an acute infection, typically viral, and that the onset was similar to Guillain–Barr e syndrome [7, 17]. This has directed attention to the possibility of immune involvement in POTS, although not unanimously accepted and rarely proven. There are, however, multiple facts supporting this idea. First, the predominance of women and temporal association with an antecedent viral infection, vaccination or trauma are similar to the typical features of autoimmune disease [39]. Secondly, indicators of immune system dysfunction and positive autoimmune tests are frequently seen among POTS patients. For instance, positive tests for antinuclear antibodies can be found in one of four POTS patients, whereas 20% report history of autoimmune disorders such as Hashimoto’s thyroiditis, rheumatoid arthritis or Sjögren syndrome [40], more than expected in a general population [39]. In a series of 38 patients with POTS and gastrointestinal dysmotility, antiphospholipid antibodies were found in 76%, whereas novel Sjögren antibodies in 42% of all subjects [41]. However, the presence of these autoantibodies cannot satisfactorily explain the characteristic plethora of POTS symptoms, which rather suggests the overall immune system dysfunction and susceptibility to autoimmune disorders.” *<small>([[Fedorowski-2019]], [p. 5](zotero://open-pdf/library/items/BZ35QDLR?page=5&annotation=HEFMHPAR))</small>^10 >*“In recent years, search for the presence of a hypothetical immunological fingerprint in POTS has resulted in a discovery of diverse autoantibodies with a proposed causative role in the syndrome [25, 26, 40–48]. A specific focus was given cardiovascular G-protein-coupled membrane complexes, such as adrenergic, muscarinic and angiotensin II type-1 receptors The symptoms of POTS, especially *<small>([p. 5](zotero://open-pdf/library/items/BZ35QDLR?page=5&annotation=V7QHWPGS))</small> tachycardia, could be evoked by the direct action on sinus rate controlling system (via adrenergic and muscarinic receptors) or through a compensatory mechanism responding to peripheral vasodilation (via adrenergic, angiotensin and other possible vasoactive receptors)” *<small>([[Fedorowski-2019]], [p. 6](zotero://open-pdf/library/items/BZ35QDLR?page=6&annotation=ZKH26235))</small>^11 >![[Fedorowski-2019-5-x67-y146.png#invert_B| 400]] ><small>([[Fedorowski-2019]], [p. 5](zotero://open-pdf/library/items/BZ35QDLR?page=5&annotation=TSN9IUJ2))</small>^12 >*“Other autoantibodies with a proposed aetiological role in POTS include antibodies against nicotinic acetylcholine-receptor in autonomic ganglia [26] and Sjögren autoantibodies [41, 49], detected in POTS through antibody screening programmes” *<small>([[Fedorowski-2019]], [p. 6](zotero://open-pdf/library/items/BZ35QDLR?page=6&annotation=3C2QC8RP))</small>^13 >*“A significant minority of POTS patients are diagnosed following a virus-like syndrome. This suggests an autoimmune cause for POTS in some patients.” *<small>([[Garland-2015]], [p. 8](zotero://open-pdf/library/items/CAWTWYLR?page=8&annotation=ZB6Y3WMQ))</small>^14 >*“A low titer of an antibody to the ganglionic acetylcholine receptor (nAChR) was reported in 15% of adult POTS patients evaluated at the Mayo Clinic between 1993 and 2003” *<small>([[Garland-2015]], [p. 8](zotero://open-pdf/library/items/CAWTWYLR?page=8&annotation=2LQWKTZU))</small>^15 >*“Some patients develop POTS secondary to an autoimmune disorder such as Guillian Barré syndrome, Sjögren's syndrome, celiac disease, or systemic lupus erythematosus.”* <small>([[Miller-2018]], [p. 7](zotero://open-pdf/library/items/A3CIPE3G?page=7&annotation=BIC6DGDE))</small>^16 >*“Growing evidence is emerging to suggest that in some patients, their POTS may have an autoimmune basis. Antibodies to the alpha-1, beta1, and beta-2 adrenergic receptors have been detected in POTS which may explain insufficient vasoconstriction and tachycardia (Li et al., 2014). Antibodies to M1 and M2 muscarinic acetylcholine receptors are also present in a significant proportion of POTS patients tested and may contribute to tachycardia among other symptoms (Vernino et al., 2000). Similar antibodies have also been identified in patients with chronic fatigue syndrome which overlaps with the POTS patient population (Loebel et al., 2016). The origin of these antibodies still remains elusive.”* <small>([[Miller-2018]], [p. 7](zotero://open-pdf/library/items/A3CIPE3G?page=7&annotation=AI2XFPNU))</small>^17 ##### Viral Infections >_“Up to 50% of cases have antecedent viral illness”_ <small>([[Benarroch-2012]], [p. 1](zotero://open-pdf/library/items/WEZLT9QC?page=1&annotation=GCH7SDK8))</small>^01 >*“Early studies suggested that approximately one-half of patients have an antecedent presumed viral illness, although recent experience suggests that this is less common” *<small>([[Low-2009]], [p. 2](zotero://open-pdf/library/items/I4WAD8AG?page=2&annotation=ZVEU87WM))</small>^02 >*“approximately half of POTS patients appear to have a postinfectious autonomic neuropathy” *<small>([[Sandroni-1999]], [p. 1](zotero://open-pdf/library/items/X25GXI7E?page=1&annotation=3CTX266Z))</small>^03 >![[Sandroni-1999-5-x38-y533.png#invert_B| 450]] ><small>([[Sandroni-1999]], [p. 5](zotero://open-pdf/library/items/X25GXI7E?page=5&annotation=4ASYHE8G))</small>^04 >![[Thieben-2007-3-x308-y75.png#invert_B| 500]] ><small>([[Thieben-2007]], [p. 3](zotero://open-pdf/library/items/5WXWEQWX?page=3&annotation=GTHC9YR2))</small>^05 >*“The onset of POTS may be precipitated by typical immunological stressors such as viral infection, frequently of the upper respiratory or gastrointestinal tract, vaccination, trauma, pregnancy, surgery or even a period of intensive psychosocial stress [17, 21, 23–29]. The antecedent history of suspected viral infection is reported by between 20% and 50% of all patients [23, 26]. However, a substantial number of POTS patients do not report any triggering event and experience rather slowly progressing or even stationary symptoms over a long period of time [21].” *<small>([[Fedorowski-2019]], [p. 3](zotero://open-pdf/library/items/BZ35QDLR?page=3&annotation=VM36S36S))</small>^06 >![[Zotero/Zotero Images/Kanjwal-2011-3-x61-y377.png]] ><small>([[Kanjwal-2011]], [p. 3](zotero://open-pdf/library/items/R4GMHSS7?page=3&annotation=BT6QUA97))</small>^07 >*“Recently, numerous cases of POTS33 and other forms of sinus tachycardia (e.g., inappropriate sinus tachycardia)34 after a SARS-CoV-2 infection have been reported. Good data on the frequency of POTS among patients with long-term complications from COVID-19 (“long COVID syndrome”) are lacking.”* <small>([[Raj-2022]], [p. 3](zotero://open-pdf/library/items/YN8BG2FZ?page=3&annotation=4ZDPHZN9))</small>^08