4. Pathophysiological Mechanisms

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Dysautonomia - Dysfunction of the autonomic nervous system]] → -------- ##### Summary >[!Summary] >- pathophysiology underlying POTS remains incompletely understood, is likely to be multifactorial and varies in different subgroups of POTS patients[[#^15]] >- persistence of orthostatic symptoms despite adequate control of the heart rate and the coexistence of many nonorthostatic symptoms commonly reported by patients with POTS suggest that impaired processing of viscerosensory (including cardiovascular) information, conditioning, and behavioral amplification also play a contributory role in this disorder[[#^4]] >- pathophysiologic mechanisms are multifactoral[[#^1]] and heterogenous[[#^2]][[#^10]][[#^14]] > >**Mechanisms (not mutually exclusive)** >- impaired sympathetically mediated vasoconstriction in the lower limbs[[#^2]] ; peripheral denervation[[#^9]] >- inadequate venous return (due to impaired vasocontriction) or excessive blood venous pooling[[#^15]] >- volume dysregulation[[#^2]] >- excessive cardiac sympathoexcitatory responses[[#^2]] ; β-receptor supersensitivity[[#^9]] >- presumed impairment of brain stem regulation[[#^9]] >- physical deconditioning[[#^2]][[#^15]] >- moderate autonomic dysfunction[[#^15]] > > **Processes that may lead to reduced circulating blood volume** >- absolute hypovolemia related to abnormal RAAS system[[#^13]] >- cardiovascular deconsitioning - low stroke volume[[#^13]] >- small fibre neuropathy impaired innervation (lower limbs[[#^13]] >- connective tissue laxitiy (hypermobile EDS)[[#^13]] >- autoantibody-inhibiting vascular receptors[[#^13]] > >**Primary processes affecting sinus node response to orthostatic challenge and abnormal chronotropic response on standing** >- Inflammatory mediators (MCAS, etc.)[[#^13]] >- Excessive central sympathetic activation[[#^13]][[#^12]] >- Autoantibody-activating cardiac receptors[[#^13]][[#^12]] > >**Course** > 1. inability of the peripheral vasculature to maintain adequate resistance in the face of orthostatic stress[[#^14]] > 2. excessive pooling of blood in the more dependent areas of the body[[#^14]] > 3. resultant functional decline in circulatory volume elicits a compensatory increase in HR and myocardial contractility[[#^14]] > 4. this mechanism is unable to fully compensate in more severe cases, resulting in a reduction in effective circulation and varying degrees of cerebral hypoperfusion[[#^14]] -------- >_“The pathophysiologic mechanisms of orthostatic intolerance in POTS are multifactorial and include hypovolemia, venous pooling, hyperadrenergic states, and restricted adrenergic neuropathies in the lower limb.”_ ([[Benarroch-2012]], [p. 2](zotero://open-pdf/library/items/WEZLT9QC?page=2&annotation=AFCK2XUY))^1 >_“The experience from extensive series indicates that POTS is pathophysiologically heterogeneous”_ ([[Benarroch-2012]], [p. 1](zotero://open-pdf/library/items/WEZLT9QC?page=1&annotation=5NQYSP2I))^2 >![[Benarroch-2012-3-x41-y448.png#invert_B| 900]] >([[Benarroch-2012]], [p. 3](zotero://open-pdf/library/items/WEZLT9QC?page=3&annotation=953Y7LPN))^3 >_“The persistence of orthostatic symptoms despite adequate control of the heart rate and the coexistence of many nonorthostatic symptoms commonly reported by patients with POTS suggest that impaired processing of viscerosensory (including cardiovascular) information, conditioning, and behavioral amplification also play a contributory role in this disorder.”_ ([[Benarroch-2012]], [p. 5](zotero://open-pdf/library/items/WEZLT9QC?page=5&annotation=BG69GYMG))^4 >_“For example, many triggers, such as viral illness (particularly if associated with gastrointestinal fluid loss), prolonged bed rest, or both, may result in relatively rapid development of symptoms of orthostatic intolerance and sympathoexcitation.”_ ([[Benarroch-2012]], [p. 5](zotero://open-pdf/library/items/WEZLT9QC?page=5&annotation=P9M93TTH))^5 >_“Abnormal processing of sensory information, including somatic hypervigilance and behavioral amplification, may also contribute to persistence of symptoms, including those not triggered by orthostatic stress, such as visceral pain, fibromyalgia, and chronic dizziness.”_ ([[Benarroch-2012]], [p. 5](zotero://open-pdf/library/items/WEZLT9QC?page=5&annotation=P7WC5NTB))^6 >_“Furthermore, deconditioning, poor sleep, and psychological factors such as anxiety or depression may all lead to relative predominance of sympathetic over vagal control the heart rate.”_ ([[Benarroch-2012]], [p. 5](zotero://open-pdf/library/items/WEZLT9QC?page=5&annotation=2N3RSQDF))^7 >![[Benarroch-2012-6-x67-y225.png#invert_B| 900]] >([[Benarroch-2012]], [p. 6](zotero://open-pdf/library/items/WEZLT9QC?page=6&annotation=7645BPZG))^8 >*“Pathophysiologic mechanisms (not mutually exclusive) include peripheral denervation, hypovolemia, venous pooling, β-receptor supersensitivity, psychologic mechanisms, and presumed impairment of brain stem regulation.” *([[Low-2009]], [p. 1](zotero://open-pdf/library/items/I4WAD8AG?page=1&annotation=LA2CH3MQ))^9 >*“POTS is heterogeneous in presentation and mechanisms.” *([[Low-2009]], [p. 1](zotero://open-pdf/library/items/I4WAD8AG?page=1&annotation=SG2RIS4Z))^10 >*“Investigators and clinicians have been impressed with different aspects of the conditions and have approached orthostatic intolerance from different perspectives. Terms such as effort syndrome, neurasthenia, idiopathic hypovolemia, [3] sympathotonic orthostatic hypotension, emphasizing sympathetic overactivity, [4] and mitral valve prolapse syndrome [5] exemplify the concentration on particular components of the patient’s disease.” *([[Low-2009]], [p. 2](zotero://open-pdf/library/items/I4WAD8AG?page=2&annotation=54HM2WPP))^11 >![[Fedorowski-2019-4-x42-y242.png#invert_B| 750]] >([[Fedorowski-2019]], [p. 4](zotero://open-pdf/library/items/BZ35QDLR?page=4&annotation=28G6Z9T4))^12 >![[Zotero/Zotero Images/Raj-2022-4-x25-y378.png#invert_B| 800]] >([[Raj-2022]], [p. 4](zotero://open-pdf/library/items/YN8BG2FZ?page=4&annotation=CJNY3NLH))^13 >*“POTS is better understood as a physiological state most commonly due to an inability of the peripheral vasculature to maintain adequate resistance in the face of orthostatic stress, allowing for excessive pooling of blood in the more dependent areas of the body [1, 13, 14]. The resultant functional decline in circulatory volume elicits a compensatory increase in HR and myocardial contractility. While compensatory in mild cases, this mechanism is unable to fully compensate in more severe cases, resulting in a reduction in effective circulation and varying degrees of cerebral hypoperfusion. Later investigations revealed that POTS is not a single condition, but rather a heterogeneous group of disorders resulting in a similar physiological state”* ([[Kanjwal-2011]], [p. 4](zotero://open-pdf/library/items/R4GMHSS7?page=4&annotation=SGZUTWKI))^14 >*“The pathophysiology underlying POTS remains incompletely understood, is likely to be multifactorial and varies in different subgroups of POTS patients. Factors such as moderate autonomic dysfunction, increased sympathetic tone, severe deconditioning, inadequate venous return or excessive blood venous pooling may contribute to POTS symptoms.2 Poor venous return may be a result of impaired vasoconstriction secondary to a number of factors and concurrent clinical syndromes.”* ([[Wells-2017]], [p. 1](zotero://open-pdf/library/items/HLELIN7I?page=1&annotation=TBGPEUAP))^15