graph LR
T_Cell_Immunometabolic_Dysfunction["T-Cell Immunometabolic Dysfunction"]
Possible_Neuroimmune_Activation["Possible Neuroimmune Activation"]
Cognitive_Impairment["Cognitive Impairment"]
Proposed_Muscle_Sodium_Calcium_Loading["Proposed Muscle Sodium-Calcium Loading"]
Low_Dose_Naltrexone["Low-Dose Naltrexone"]
Patient_Derived_Skeletal_Myotubes["Patient-Derived Skeletal Myotubes"]
Patient_NK_Cell_TRPM3_Assays["Patient NK-Cell TRPM3 Assays"]
Patient_Serum_Vesicle_Microglia_Assay["Patient Serum Vesicle-Microglia Assay"]
TRPM3_Associated_NK_Cell_Calcium_Dysregulation["TRPM3-Associated NK-Cell Calcium Dysregulation"]
Small_Fiber_Neuropathy["Small-Fiber Neuropathy"]
Erythrocyte_Microfluidic_Deformability_Assay["Erythrocyte Microfluidic Deformability Assay"]
Pyridostigmine["Pyridostigmine"]
Central_Motor_Activation_Abnormality["Central Motor Activation Abnormality"]
Individualized_Energy_Management["Individualized Energy Management"]
Proposed_Peripheral_Vesicle_Microglial_Signaling["Proposed Peripheral Vesicle-Microglial Signaling"]
Post_Exertional_Malaise["Post-Exertional Malaise"]
Orthostatic_Cerebral_Hypoperfusion["Orthostatic Cerebral Hypoperfusion"]
Atg13_Depleted_Mouse["Atg13-Depleted Mouse"]
Reduced_Erythrocyte_Deformability["Reduced Erythrocyte Deformability"]
Orthostatic_Intolerance["Orthostatic Intolerance"]
Fatigue["Fatigue"]
Elevated_Skeletal_Muscle_Tissue_Sodium["Elevated Skeletal Muscle Tissue Sodium"]
Autophagy_Associated_Macrophage_Dysfunction["Autophagy-Associated Macrophage Dysfunction"]
Endothelial_Vasodilator_Dysfunction["Endothelial Vasodilator Dysfunction"]
Impaired_Peripheral_Oxygen_Extraction["Impaired Peripheral Oxygen Extraction"]
Patient_T_Cell_Metabolic_Assays["Patient T-Cell Metabolic Assays"]
Exercise_Intolerance["Exercise Intolerance"]
Natural_Killer_Cell_Dysfunction["Natural Killer Cell Dysfunction"]
Skeletal_Muscle_Bioenergetic_Disturbance["Skeletal Muscle Bioenergetic Disturbance"]
Impaired_Venous_Return["Impaired Venous Return"]
Reduced_Exercise_Cardiac_Output["Reduced Exercise Cardiac Output"]
Myalgia["Myalgia"]
Proposed_Delayed_Immunometabolic_Amplification["Proposed Delayed Immunometabolic Amplification"]
Exertion_Beyond_Individual_Tolerance["Exertion Beyond Individual Tolerance"]
Small_Fiber_Neuropathy --> Impaired_Venous_Return
Small_Fiber_Neuropathy --> Impaired_Peripheral_Oxygen_Extraction
Impaired_Venous_Return --> Reduced_Exercise_Cardiac_Output
Reduced_Exercise_Cardiac_Output --> Exercise_Intolerance
Impaired_Peripheral_Oxygen_Extraction --> Exercise_Intolerance
Impaired_Peripheral_Oxygen_Extraction --> Skeletal_Muscle_Bioenergetic_Disturbance
Endothelial_Vasodilator_Dysfunction --> Skeletal_Muscle_Bioenergetic_Disturbance
Reduced_Erythrocyte_Deformability --> Myalgia
Reduced_Erythrocyte_Deformability --> Fatigue
Skeletal_Muscle_Bioenergetic_Disturbance --> Proposed_Delayed_Immunometabolic_Amplification
Elevated_Skeletal_Muscle_Tissue_Sodium --> Proposed_Muscle_Sodium_Calcium_Loading
Proposed_Muscle_Sodium_Calcium_Loading --> Skeletal_Muscle_Bioenergetic_Disturbance
TRPM3_Associated_NK_Cell_Calcium_Dysregulation --> Natural_Killer_Cell_Dysfunction
Proposed_Delayed_Immunometabolic_Amplification --> Post_Exertional_Malaise
Orthostatic_Cerebral_Hypoperfusion --> Orthostatic_Intolerance
Orthostatic_Cerebral_Hypoperfusion --> Cognitive_Impairment
Central_Motor_Activation_Abnormality --> Exercise_Intolerance
Proposed_Peripheral_Vesicle_Microglial_Signaling --> Possible_Neuroimmune_Activation
Exertion_Beyond_Individual_Tolerance --> Post_Exertional_Malaise
Individualized_Energy_Management --> Post_Exertional_Malaise
Pyridostigmine --> Reduced_Exercise_Cardiac_Output
Pyridostigmine --> Impaired_Venous_Return
Low_Dose_Naltrexone --> TRPM3_Associated_NK_Cell_Calcium_Dysregulation
Patient_Derived_Skeletal_Myotubes --> Skeletal_Muscle_Bioenergetic_Disturbance
Patient_NK_Cell_TRPM3_Assays --> TRPM3_Associated_NK_Cell_Calcium_Dysregulation
Patient_T_Cell_Metabolic_Assays --> T_Cell_Immunometabolic_Dysfunction
Erythrocyte_Microfluidic_Deformability_Assay --> Reduced_Erythrocyte_Deformability
Patient_Serum_Vesicle_Microglia_Assay --> Proposed_Peripheral_Vesicle_Microglial_Signaling
Atg13_Depleted_Mouse --> Autophagy_Associated_Macrophage_Dysfunction
style T_Cell_Immunometabolic_Dysfunction fill:#dbeafe
style Possible_Neuroimmune_Activation fill:#dbeafe
style Cognitive_Impairment fill:#fef3c7
style Proposed_Muscle_Sodium_Calcium_Loading fill:#dbeafe
style Low_Dose_Naltrexone fill:#fce7f3
style Patient_Derived_Skeletal_Myotubes fill:#ccfbf1
style Patient_NK_Cell_TRPM3_Assays fill:#ccfbf1
style Patient_Serum_Vesicle_Microglia_Assay fill:#ccfbf1
style TRPM3_Associated_NK_Cell_Calcium_Dysregulation fill:#dbeafe
style Small_Fiber_Neuropathy fill:#dbeafe
style Erythrocyte_Microfluidic_Deformability_Assay fill:#ccfbf1
style Pyridostigmine fill:#fce7f3
style Central_Motor_Activation_Abnormality fill:#dbeafe
style Individualized_Energy_Management fill:#fce7f3
style Proposed_Peripheral_Vesicle_Microglial_Signaling fill:#dbeafe
style Post_Exertional_Malaise fill:#fef3c7
style Orthostatic_Cerebral_Hypoperfusion fill:#dbeafe
style Atg13_Depleted_Mouse fill:#ede9fe
style Reduced_Erythrocyte_Deformability fill:#dbeafe
style Orthostatic_Intolerance fill:#fef3c7
style Fatigue fill:#fef3c7
style Elevated_Skeletal_Muscle_Tissue_Sodium fill:#dbeafe
style Autophagy_Associated_Macrophage_Dysfunction fill:#dbeafe
style Endothelial_Vasodilator_Dysfunction fill:#dbeafe
style Impaired_Peripheral_Oxygen_Extraction fill:#dbeafe
style Patient_T_Cell_Metabolic_Assays fill:#ccfbf1
style Exercise_Intolerance fill:#fef3c7
style Natural_Killer_Cell_Dysfunction fill:#dbeafe
style Skeletal_Muscle_Bioenergetic_Disturbance fill:#dbeafe
style Impaired_Venous_Return fill:#dbeafe
style Reduced_Exercise_Cardiac_Output fill:#dbeafe
style Myalgia fill:#fef3c7
style Proposed_Delayed_Immunometabolic_Amplification fill:#dbeafe
style Exertion_Beyond_Individual_Tolerance fill:#dcfce7
graph LR
Exercise_Training["Exercise Training"]
Pharmacotherapy___Midodrine["Pharmacotherapy - Midodrine"]
Tremor["Tremor"]
Headache["Headache"]
Syncope["Syncope"]
Orthostatic_Tachycardia["Orthostatic Tachycardia"]
Compression_Garments["Compression Garments"]
Dyspnea["Dyspnea"]
Abnormal_Autonomic_Nervous_System_Physiology["Abnormal Autonomic Nervous System Physiology"]
Transcutaneous_Auricular_Vagus_Nerve_Stimulation["Transcutaneous Auricular Vagus Nerve Stimulation"]
Pharmacotherapy___Pyridostigmine["Pharmacotherapy - Pyridostigmine"]
Pharmacotherapy___Ivabradine["Pharmacotherapy - Ivabradine"]
Pharmacotherapy___Beta_Blockers["Pharmacotherapy - Beta-Blockers"]
Venous_Pooling_and_Reduced_Preload["Venous Pooling and Reduced Preload"]
Acrocyanosis["Acrocyanosis"]
Pharmacotherapy___Fludrocortisone["Pharmacotherapy - Fludrocortisone"]
Nausea["Nausea"]
Chest_Pain["Chest Pain"]
Fatigue["Fatigue"]
Post_Infectious_Trigger["Post-Infectious Trigger"]
Volume_Expansion_and_Salt_Supplementation["Volume Expansion and Salt Supplementation"]
Autoimmune_Autonomic_Dysfunction["Autoimmune Autonomic Dysfunction"]
Sympathetic_Denervation["Sympathetic Denervation"]
Exercise_Intolerance["Exercise Intolerance"]
Palpitations["Palpitations"]
Cardiovascular_Deconditioning["Cardiovascular Deconditioning"]
Excessive_Sympathetic_Activation["Excessive Sympathetic Activation"]
Compensatory_Reflex_Tachycardia["Compensatory Reflex Tachycardia"]
Dizziness["Dizziness"]
Brain_Fog["Brain Fog"]
Sympathetic_Denervation --> Venous_Pooling_and_Reduced_Preload
Venous_Pooling_and_Reduced_Preload --> Compensatory_Reflex_Tachycardia
Venous_Pooling_and_Reduced_Preload --> Dizziness
Venous_Pooling_and_Reduced_Preload --> Syncope
Venous_Pooling_and_Reduced_Preload --> Brain_Fog
Venous_Pooling_and_Reduced_Preload --> Headache
Venous_Pooling_and_Reduced_Preload --> Acrocyanosis
Compensatory_Reflex_Tachycardia --> Palpitations
Compensatory_Reflex_Tachycardia --> Chest_Pain
Compensatory_Reflex_Tachycardia --> Dyspnea
Compensatory_Reflex_Tachycardia --> Exercise_Intolerance
Compensatory_Reflex_Tachycardia --> Fatigue
Excessive_Sympathetic_Activation --> Compensatory_Reflex_Tachycardia
Excessive_Sympathetic_Activation --> Tremor
Autoimmune_Autonomic_Dysfunction --> Sympathetic_Denervation
Autoimmune_Autonomic_Dysfunction --> Venous_Pooling_and_Reduced_Preload
Autoimmune_Autonomic_Dysfunction --> Nausea
Post_Infectious_Trigger --> Autoimmune_Autonomic_Dysfunction
Cardiovascular_Deconditioning --> Venous_Pooling_and_Reduced_Preload
Exercise_Training --> Cardiovascular_Deconditioning
Exercise_Training --> Venous_Pooling_and_Reduced_Preload
Volume_Expansion_and_Salt_Supplementation --> Venous_Pooling_and_Reduced_Preload
Pharmacotherapy___Beta_Blockers --> Compensatory_Reflex_Tachycardia
Pharmacotherapy___Midodrine --> Venous_Pooling_and_Reduced_Preload
Pharmacotherapy___Fludrocortisone --> Venous_Pooling_and_Reduced_Preload
Compression_Garments --> Venous_Pooling_and_Reduced_Preload
Pharmacotherapy___Ivabradine --> Compensatory_Reflex_Tachycardia
Pharmacotherapy___Pyridostigmine --> Compensatory_Reflex_Tachycardia
Transcutaneous_Auricular_Vagus_Nerve_Stimulation --> Compensatory_Reflex_Tachycardia
Compensatory_Reflex_Tachycardia -.-> Orthostatic_Tachycardia
Sympathetic_Denervation -.-> Abnormal_Autonomic_Nervous_System_Physiology
Excessive_Sympathetic_Activation -.-> Abnormal_Autonomic_Nervous_System_Physiology
style Exercise_Training fill:#fce7f3
style Pharmacotherapy___Midodrine fill:#fce7f3
style Tremor fill:#fef3c7
style Headache fill:#fef3c7
style Syncope fill:#fef3c7
style Orthostatic_Tachycardia fill:#fef3c7
style Compression_Garments fill:#fce7f3
style Dyspnea fill:#fef3c7
style Abnormal_Autonomic_Nervous_System_Physiology fill:#fef3c7
style Transcutaneous_Auricular_Vagus_Nerve_Stimulation fill:#fce7f3
style Pharmacotherapy___Pyridostigmine fill:#fce7f3
style Pharmacotherapy___Ivabradine fill:#fce7f3
style Pharmacotherapy___Beta_Blockers fill:#fce7f3
style Venous_Pooling_and_Reduced_Preload fill:#dbeafe
style Acrocyanosis fill:#fef3c7
style Pharmacotherapy___Fludrocortisone fill:#fce7f3
style Nausea fill:#fef3c7
style Chest_Pain fill:#fef3c7
style Fatigue fill:#fef3c7
style Post_Infectious_Trigger fill:#dbeafe
style Volume_Expansion_and_Salt_Supplementation fill:#fce7f3
style Autoimmune_Autonomic_Dysfunction fill:#dbeafe
style Sympathetic_Denervation fill:#dbeafe
style Exercise_Intolerance fill:#fef3c7
style Palpitations fill:#fef3c7
style Cardiovascular_Deconditioning fill:#dbeafe
style Excessive_Sympathetic_Activation fill:#dbeafe
style Compensatory_Reflex_Tachycardia fill:#dbeafe
style Dizziness fill:#fef3c7
style Brain_Fog fill:#fef3c7
name: com_Myalgic_Encephalomyelitis_Chronic_Fatigue_Syndrome__Postural_Orthostatic_Tachycardia_Syndrome
creation_date: '2026-11-02T13:25:53Z'
curation_status: CANDIDATE
notes: >-
Postural orthostatic tachycardia syndrome (POTS) is frequently found in
people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and
orthostatic intolerance is a core feature in several ME/CFS case
definitions. Reported POTS prevalence in ME/CFS cohorts varies widely with
the setting and the test used: 27% with a 2-minute active stand against 9%
in matched controls (UK), 11% with a 20-minute standing test (Australia),
25% (155/627) with a 10-minute head-up tilt (Netherlands), and 19% in an
autonomic-laboratory cohort (US). Short tests miss cases, because a
2-minute tilt misses about half of those who meet heart-rate criteria within
10 minutes. Against this, a large Dutch cohort found POTS in only 5.7% of
adults with CFS and in a similar 6.9% of fatigued patients who did not meet
CFS criteria, so POTS does not appear specific to ME/CFS once the
comparison group is other fatigued patients rather than healthy controls.
Both conditions often follow an infection, and both show reduced cerebral
blood flow on tilt, preload failure and small-fiber neuropathy in autonomic
laboratory series, so a shared orthostatic-circulatory mechanism is
plausible but unproven. Directionality is UNKNOWN. No ICEES KG signal is
possible for this pair, because POTS (MONDO:0011479) is not a node in the
ICEES KG 8-20-2024 snapshot (recorded when the hEDS-POTS comorbidity entry
was curated).
disease_a:
slug: Myalgic_Encephalomyelitis_Chronic_Fatigue_Syndrome
preferred_term: myalgic encephalomyelitis/chronic fatigue syndrome
term:
id: MONDO:0005404
label: myalgic encephalomeyelitis/chronic fatigue syndrome
disease_b:
slug: Postural_Orthostatic_Tachycardia_Syndrome
preferred_term: postural orthostatic tachycardia syndrome
term:
id: MONDO:0011479
label: postural orthostatic tachycardia syndrome
directionality: UNKNOWN
hypotheses:
- description: >-
Hypothesis: ME/CFS and POTS share an orthostatic-circulatory mechanism.
On standing, inadequate venous return (preload failure), often alongside
small-fiber autonomic neuropathy, lowers cardiac output and cerebral blood
flow, and the heart rate rises to compensate. In some patients the
tachycardia reaches POTS criteria, and in others the cerebral
hypoperfusion occurs without it. This would explain why POTS is common but
not universal in ME/CFS. Autonomic-laboratory series show these
abnormalities in both conditions, but they do not show that one condition
causes the other, or that the shared findings have a single cause.
evidence:
- reference: PMID:41576003
reference_title: Shared autonomic phenotype of long COVID and myalgic encephalomyelitis/chronic fatigue syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "reduced orthostatic CBFv (92%/88% in Long COVID/ME/CFS), mild-to-moderate widespread autonomic failure (95%/89%), presence of SFN (67%/53%), postural tachycardia syndrome (POTS) (22%/19%), neurogenic orthostatic hypotension (15%/15%) and preload failure (96%/92%, assessed in 25/66 Long COVID/ME/CFS)"
explanation: >-
In 170 ME/CFS patients tested in an autonomic laboratory, reduced
orthostatic cerebral blood flow, preload failure and small-fiber
neuropathy were far more common than POTS itself (19%). This fits a
shared circulatory mechanism in which POTS is one possible expression.
- reference: PMID:24601948
reference_title: "Malfunctioning of the autonomic nervous system in patients with chronic fatigue syndrome: a systematic literature review."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "The heart rate dynamic response during the head-up tilt test differs between patients with CFS and healthy controls, supporting the increased prevalence of postural orthostatic tachycardia syndrome."
explanation: >-
A systematic review of 27 case-control studies concludes that heart-rate
responses to tilt differ in CFS, which is consistent with a higher POTS
prevalence in this population.
pathophysiology:
- name: Orthostatic preload failure and cerebral hypoperfusion
description: >-
Proposed shared mechanism: reduced venous return on standing lowers
cardiac preload and cerebral blood flow, and a compensatory rise in heart
rate reaches POTS criteria in a subset of patients.
association_signals:
- source: LITERATURE
method: LITERATURE_ASSOCIATION
signal_disorder_a_id: MONDO:0005404
signal_disorder_b_id: MONDO:0011479
population: >-
59 patients with CFS/ME (Fukuda criteria) and 52 age- and sex-matched
controls with formal autonomic assessment, including a 2-minute active
stand, at a UK cardiovascular laboratory.
directionality: UNKNOWN
statistics:
metrics:
- metric_type: PREVALENCE
metric_value: 27.0
p_value: 0.006
notes: POTS in 16/59 CFS/ME patients, against 9% (5/52) in controls.
evidence:
- reference: PMID:18805903
reference_title: Postural orthostatic tachycardia syndrome is an under-recognized condition in chronic fatigue syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Of the CFS/ME group, 27% (16/59) had POTS compared with 9% (5) in the control population (P = 0.006)."
explanation: >-
Case-control comparison showing POTS three times as common in CFS/ME
as in matched healthy controls.
- source: LITERATURE
method: LITERATURE_ASSOCIATION
signal_disorder_a_id: MONDO:0005404
signal_disorder_b_id: MONDO:0011479
population: >-
306 consecutive patients at an Australian CFS clinic (2009-2012), each
completing a 20-minute standing test at initial assessment.
directionality: UNKNOWN
statistics:
metrics:
- metric_type: PREVALENCE
metric_value: 11.0
notes: POTS in 33/306 CFS patients; no control group.
evidence:
- reference: PMID:24206536
reference_title: Comorbidity of postural orthostatic tachycardia syndrome and chronic fatigue syndrome in an Australian cohort.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Comorbidity of CFS and POTS (CFS-POTS) was observed in 11% (33/306) of patients."
explanation: >-
Clinic cohort prevalence of POTS among CFS patients. The CFS-POTS
patients were younger and had a shorter illness than CFS-only patients.
- source: LITERATURE
method: LITERATURE_ASSOCIATION
signal_disorder_a_id: MONDO:0005404
signal_disorder_b_id: MONDO:0011479
population: >-
627 consecutive adults meeting ME/CFS study criteria evaluated with a
10-minute 70-degree head-up tilt at a Dutch cardiology clinic
(2012-2018), excluding those on medication for orthostatic intolerance.
directionality: UNKNOWN
statistics:
metrics:
- metric_type: PREVALENCE
metric_value: 24.7
notes: >-
155/627 met POTS heart-rate criteria within 10 minutes upright; the
percentage is computed from the counts the source reports.
evidence:
- reference: PMID:30505831
reference_title: Low Sensitivity of Abbreviated Tilt Table Testing for Diagnosing Postural Tachycardia Syndrome in Adults With ME/CFS.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Of 627 individuals with ME/CFS evaluated during the study period, 155 met criteria for POTS."
explanation: >-
The largest tilt-tested ME/CFS series, which also shows that a
2-minute test would miss 55% of these cases.
- source: LITERATURE
method: LITERATURE_ASSOCIATION
signal_disorder_a_id: MONDO:0005404
signal_disorder_b_id: MONDO:0011479
population: >-
863 consecutive patients with persistent fatigue screened at a Dutch
university centre (2013-2014) with an active standing test: 419 meeting
CFS criteria and 341 fatigued patients who did not.
mapping_notes: >-
Recorded as REFUTE because the comparison group is other fatigued
patients, not healthy controls, and POTS was no more common in CFS. This
argues against POTS being specific to ME/CFS. It does not argue against
POTS being more common in ME/CFS than in the general population, which
this study did not test.
directionality: UNKNOWN
statistics:
metrics:
- metric_type: PREVALENCE
metric_value: 5.7
p_value: 0.54
notes: >-
POTS in adults with CFS, against 6.9% in non-CFS fatigued adults
(adolescents 18.2% against 17.4%, P = 0.93).
evidence:
- reference: PMID:27696568
reference_title: Postural orthostatic tachycardia is not a useful diagnostic marker for chronic fatigue syndrome.
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "POTS prevalence in adult patients with CFS was 5.7% vs. 6.9% in non-CFS adults (P = 0.54)."
explanation: >-
In this large cohort, POTS was uncommon in adults with CFS and no more
frequent than in other fatigued patients.
- source: ICEES
method: EHR_COHORT_ASSOCIATION
signal_disorder_a_id: MONDO:0005404
signal_disorder_b_id: MONDO:0011479
population: ICEES KG snapshot 8-20-2024 (RENCI/UNC).
mapping_notes: >-
No ICEES signal exists for this pair. POTS (MONDO:0011479) is not a node
in the 8-20-2024 snapshot, which holds about 226 cohort-specific concepts;
this was confirmed by inspecting the node list when the hEDS-POTS
comorbidity entry was curated.
directionality: UNKNOWN