Atrial Fibrillation

Complex MONDO:0004981 Pathograph 29 Show in embeddings browser Cardiovascular Disease Cardiac Arrhythmia

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, characterized by rapid, disorganized atrial electrical activity that replaces coordinated atrial contraction with an irregularly irregular ventricular response. It arises from a combination of ectopic triggers (often from the pulmonary veins) and an atrial substrate of electrical and structural remodeling. AF reduces cardiac output and promotes atrial thrombus formation, substantially increasing the risk of ischemic stroke.

Ask OpenScientist

Ask a research question about Atrial Fibrillation. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Definitions
10
Pathophys.
7
Phenotypes
1
Hypotheses
4
Gaps
29
Pathograph
2
Genes
8
Medical Actions
4
Subtypes
2
Differentials
9
Datasets
2
Trials
5
Models
14
References
2
Deep Research
📘

Definitions

1
Electrocardiographic clinical definition of atrial fibrillation
A supraventricular tachyarrhythmia confirmed on 12-lead ECG by irregular atrial activity (fibrillatory waves) without discrete P waves, or on a rhythm strip lasting longer than 30 seconds. A wearable-device alert alone is a screening signal and requires ECG correlation or additional testing.
DIAGNOSTIC_CRITERIA This entry represents common clinical atrial fibrillation across paroxysmal, persistent, long-standing persistent, and permanent temporal patterns. Rare Mendelian familial atrial fibrillation is modeled separately in Familial_Atrial_Fibrillation.
Show evidence (1 reference)
PMID:39680399 SUPPORT Other
"The diagnosis of AF is confirmed by identifying irregular atrial activity (fibrillatory waves) without discrete P waves on 12-lead ECG4or lasting for longer than 30 seconds on rhythm strip."
Directly supplies the electrocardiographic case boundary used here.
◆

Subtypes

4
Paroxysmal Atrial Fibrillation
Episodes terminate spontaneously within 7 days.
Show evidence (1 reference)
PMID:39680399 SUPPORT Other
"AF is classified as paroxysmal (intermittent AF episodes lasting ≤7 days), persistent (continuous AF episodes lasting >7 days and/or requiring cardioversion), or long-standing persistent (AF episode lasting >1 year)."
Directly supplies the paroxysmal, persistent, and long-standing persistent duration boundaries.
Persistent Atrial Fibrillation
Episodes last longer than 7 days or require intervention.
Show evidence (1 reference)
PMID:39680399 SUPPORT Other
"AF is classified as paroxysmal (intermittent AF episodes lasting ≤7 days), persistent (continuous AF episodes lasting >7 days and/or requiring cardioversion), or long-standing persistent (AF episode lasting >1 year)."
Directly supplies the paroxysmal, persistent, and long-standing persistent duration boundaries.
Long-standing Persistent Atrial Fibrillation
Continuous AF for more than 12 months.
Show evidence (1 reference)
PMID:39680399 SUPPORT Other
"AF is classified as paroxysmal (intermittent AF episodes lasting ≤7 days), persistent (continuous AF episodes lasting >7 days and/or requiring cardioversion), or long-standing persistent (AF episode lasting >1 year)."
Directly supplies the paroxysmal, persistent, and long-standing persistent duration boundaries.
Permanent Atrial Fibrillation
AF accepted as permanent rhythm.
Show evidence (1 reference)
PMID:39680399 SUPPORT Other
"Individuals with stage 4 AF have permanent AF, for which a decision has been made not to pursue rhythm control based on patient and clinical factors"
Directly supports permanent AF as an accepted management state rather than an episode-duration category.
◈

Mechanistic Hypotheses

1
Gut microbial TMAO promotes AF via M2 muscarinic receptor autonomic dysfunction
tmao_autonomic_af EMERGING
Evidence balance 2 support
Gut-microbiome-derived TMAO promotes AF onset and persistence, at least in part by inhibiting the cardiac M2 muscarinic receptor (TMAO mimics acetylcholine), producing autonomic dysfunction with atrial APD/wavelength shortening. Supported by a human association (adjusted OR 1.7), two mouse AF models, and pharmacologic reversal with the gut-restricted CutC/D inhibitor IMC.
Pathograph links
Gut Microbial TMA Production -> Elevated Circulating TMAO INDIRECT KNOWN INTERMEDIATES Inhibiting microbial CutC/D lowers circulating TMAO during choline supplementation, linking microbial TMA generation to systemic TMAO exposure without separately asserting an uncited hepatic step. Intermediates: host conversion of absorbed trimethylamine to trimethylamine N-oxide
Elevated Circulating TMAO -> Muscarinic M2 Receptor Inhibition DIRECT TMAO, structurally similar to acetylcholine, inhibits the cardiac M2 muscarinic receptor.
Muscarinic M2 Receptor Inhibition -> Cardiac Autonomic Dysfunction DIRECT M2R inhibition disrupts parasympathetic (vagal) cardiac control.
Cardiac Autonomic Dysfunction -> Atrial Electrical Remodeling INDIRECT UNKNOWN INTERMEDIATES The high-TMAO state is associated with slower conduction velocity and APD80/wavelength shortening, which may lower the reentry threshold and feed electrical remodeling that sustains AF.
Show evidence (2 references)
DOI:10.1172/JCI201684 SUPPORT Human Clinical
"TMAO levels were quantified in plasma from serial subjects undergoing elective cardiac catheterizations (N=5090) and shown to independently associate with prevalent AF following adjustment for risk factors (TMAO adjusted odds ratio 1.7 [95% confidence interval 1.3-2.1]"
Supports human association only; it does not prove the proposed causal chain.
DOI:10.1172/JCI201684 SUPPORT Model Organism
"the gut microbial metabolite TMAO, independently associated with AF risk in subjects, enhances AF in multiple AF mouse models via autonomic dysfunction"
Supports the model-organism mechanism while preserving EMERGING status.
?

Discussions and Knowledge Gaps

4
Which experimentally supported AF-promoting mechanisms produce reproducible, mechanism-specific benefit in randomized human trials beyond established rhythm, rate, anticoagulation, and risk-factor strategies?
KNOWLEDGE GAP OPEN gap_af_mechanism_to_human_therapy
Attached to
pathophysiology#Fibroblast NLRP3 Inflammasome Activation pathophysiology#Gut Microbial TMA Production
NLRP3 and TMAO perturbations are compelling in animal models, but neither establishes clinical efficacy or a validated human causal treatment path.
Show evidence (1 reference)
PMID:41543444 SUPPORT Other
"The treatment of AF involves multiple potential approaches, all of which presently have significant limitations."
Current review explicitly identifies the treatment-translation gap.
Which target populations, AF-burden thresholds, and downstream treatment pathways make systematic AF screening improve stroke or survival outcomes?
KNOWLEDGE GAP OPEN gap_af_screening_outcome_benefit
Attached to
diagnosis#Non-invasive systematic AF screening
Detection yield is reproducibly higher, but randomized screening data have not demonstrated fewer strokes, deaths, hospitalizations, or bleeding events.
Show evidence (1 reference)
PMID:40276326 SUPPORT Human Clinical
"Pooled data from RCTs did not demonstrate an effect of screening on death (RR 1.01, 95% CI 0.97-1.05), cardiovascular hospitalisation (1.00, 95% CI 0.97-1.03), stroke (0.95, 95% CI 0.87-1.04) or bleeding (1.08, 95% CI 0.91-1.29)."
Directly supports the unresolved clinical-outcome question.
Can NT-proBNP or multimarker panels prospectively improve AF screening or outcome-guided management enough to change clinical outcomes?
KNOWLEDGE GAP OPEN gap_af_biomarker_clinical_utility
Attached to
biochemical#NT-proBNP as an incident-AF risk biomarker
Current cohorts demonstrate association and incremental prediction, not prospective benefit from biomarker-directed action.
Show evidence (1 reference)
PMID:36610061 SUPPORT Human Clinical
"The clinical benefit of these findings for identifying at-risk individuals for targeted AF screening needs to be elucidated and tested prospectively."
The study explicitly states the prospective-utility limitation.
How should AF evidence and care pathways be adapted and tested across racial, ethnic, socioeconomic, disability, insurance, and rural populations that remain underrepresented or experience lower access to guideline-directed care?
KNOWLEDGE GAP OPEN gap_af_evidence_generalizability_and_equity
Trial generalizability and unequal access to anticoagulation, ablation, and specialty care limit population-wide translation of efficacy evidence.
Show evidence (1 reference)
PMID:39680399 SUPPORT Other
"generalizability of the evidence is limited because many clinical trials have not included substantial proportions of participants who were Black or Hispanic, and have not examined variation by SDOH."
The review explicitly identifies the evidence-generalizability limitation.
⚙

Pathophysiology

10
NOX2-Dependent Atrial Oxidative Stress
In obesity-driven AF models, NOX2-derived oxidative stress promotes atrial ion-channel remodeling and abnormal action-potential duration.
Downstream
Atrial Electrical Remodeling NOX2 inhibition reverses abnormal atrial action-potential duration and ion-channel remodeling in obesity-driven AF models.
Show evidence (1 reference)
PMID:39146015 SUPPORT Model Organism
"NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden."
Perturbational evidence identifies NOX2-dependent oxidative stress as an upstream driver of obesity-mediated atrial electrical remodeling.
Atrial Electrical Remodeling
Rapid atrial rates cause shortening of atrial refractory period and loss of rate adaptation, promoting AF maintenance. AF begets AF.
Atrial Cardiomyocyte CL:0002129 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Atrial Cardiomyocyte, annotated with regular atrial cardiac myocyte (CL:0002129). CL:0002129 is a cell type from the Cell Ontology.
Cardiac Conduction GO:0086001 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Cardiac Conduction, annotated with cardiac muscle cell action potential (GO:0086001). GO:0086001 is a biological process from the Gene Ontology.
Experimental models
Palmitate-treated human iPSC-derived atrial cardiomyocytes IPSC DERIVED MODEL Assays obesity-associated NOX2-dependent atrial ion-channel remodeling.
Computational models
Courtemanche-Ramirez-Nattel human atrial action-potential model KINETIC Models rate-dependent atrial action-potential adaptation and its ionic-current determinants.
Downstream
Atrial Fibrillation Disordered atrial electrical activation is the defining arrhythmia phenotype.
Palpitations Atrial fibrillation-related rhythm disturbance commonly manifests as palpitations.
Dyspnea AF-related rhythm and hemodynamic disturbance can produce dyspnea.
Fatigue AF symptom burden includes fatigue, often alongside dyspnea and intermittent symptoms.
Exercise Intolerance Rate irregularity and loss of coordinated atrial contribution can reduce exercise capacity, although severity depends strongly on ventricular rate and comorbid cardiac reserve.
Chest Pain Chest pain can occur during AF, but the intermediate mechanism and the contribution of coexisting ischemic or structural disease vary.
Show evidence (1 reference)
PMID:7671380 SUPPORT Model Organism
"During the first 24 hours of AF the median fibrillation interval shortened from 145 +/- 18 to 108 +/- 8 ms and the inducibility of AF by a single premature stimulus increased from 24% to 76%."
The original demonstration that sustained rapid atrial rates shorten atrial refractoriness and increase AF inducibility - the tachycardia-induced electrical remodeling the phrase "AF begets AF" refers to.
Fibroblast NLRP3 Inflammasome Activation
NLRP3 inflammasome signaling is increased in atrial fibroblasts from people with AF. Fibroblast-restricted activation is sufficient to create a profibrotic, conduction-slowing atrial substrate in mice.
Cardiac fibroblast CL:0002548 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiac fibroblast, annotated with fibroblast of cardiac tissue (CL:0002548). CL:0002548 is a cell type from the Cell Ontology.
NLRP3 hgnc:16400 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NLRP3 (hgnc:16400). hgnc:16400 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Atrial Fibrosis Fibroblast-restricted NLRP3 activation promotes profibrotic atrial remodeling.
Show evidence (2 references)
PMID:40243956 SUPPORT Human Clinical
"NLRP3 was up-regulated in atrial fibroblasts from AF patients."
Direct human atrial-fibroblast observation supporting disease relevance.
PMID:40243956 SUPPORT Model Organism
"Fibroblast-specific activation of NLRP3 in mice induced AF-promoting atrial myopathy and heart failure with diastolic dysfunction, accompanied by increased fibrosis, and reduced conduction velocity."
The perturbation study supports causal sufficiency in mice, not in humans.
Atrial Fibrosis
Excess atrial extracellular matrix separates cardiomyocyte bundles and creates heterogeneous, slowed conduction that favors reentry and AF maintenance.
Cardiac Fibroblast CL:0002548 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiac Fibroblast, annotated with fibroblast of cardiac tissue (CL:0002548). CL:0002548 is a cell type from the Cell Ontology.
Downstream
Atrial Electrical Remodeling Fibrotic discontinuity slows and heterogenizes atrial conduction, facilitating reentry.
Show evidence (2 references)
PMID:40243956 SUPPORT Model Organism
"Fibroblast-specific activation of NLRP3 in mice induced AF-promoting atrial myopathy and heart failure with diastolic dysfunction, accompanied by increased fibrosis, and reduced conduction velocity."
Links increased atrial fibrosis with slowed conduction and an AF-promoting substrate in vivo.
PMID:42462800 SUPPORT Other
"Low-voltage substrate regions are a common feature, and typically correlate with underlying fibrotic scar."
The most recent review before the cutoff links the electrophysiologic substrate to atrial fibrotic scar.
Pulmonary Vein Triggers
Ectopic beats originating from pulmonary vein myocardial sleeves commonly trigger AF episodes. These foci have distinct electrophysiology.
Pulmonary vein UBERON:0002016 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Pulmonary vein (UBERON:0002016). UBERON:0002016 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Atrial Fibrillation Rapid ectopic pulmonary-vein discharges initiate paroxysmal AF.
Show evidence (1 reference)
PMID:9725923 SUPPORT Human Clinical
"Three foci were in the right atrium, 1 in the posterior left atrium, and 65 (94 percent) in the pulmonary veins"
Mapping of 69 triggering foci in 45 drug-refractory patients localized 94% to pulmonary veins.
Atrial Thrombus Formation
Loss of atrial contraction leads to blood stasis, particularly in the left atrial appendage, promoting thrombus formation and embolic stroke.
Downstream
Thromboembolic Stroke Atrial thrombus formation creates risk for embolic stroke, which is the main target of anticoagulation.
Show evidence (2 references)
PMID:30571060 SUPPORT Other
"atrial contractility is lost, causing an inability to completely empty blood from the atrial appendage leading to the risk of clot formation and subsequent thromboembolic events."
Directly supports the direction from ineffective atrial contraction to appendage clot and embolism.
PMID:8572814 SUPPORT Human Clinical
"In contrast, 201 of 222 (91%) of nonrheumatic atrial fibrillation-related left atrial thrombi were isolated to, or originated in the left atrial appendage"
Systematic review of 23 studies localizes the overwhelming majority of nonrheumatic AF-related left atrial thrombi to the left atrial appendage, supporting appendage stasis as the site of thrombus formation.
Gut Microbial TMA Production
Gut bacteria transform dietary choline to trimethylamine (TMA) through the CutC/D pathway. Iodomethylcholine (IMC) inhibits this microbial choline-to-TMA(O) transformation.
Gut microbial TMAO promotes AF via M2 muscarinic receptor autonomic dysfunction
microbial amine biosynthetic process GO:0009309 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased microbial amine biosynthetic process, annotated with amine biosynthetic process (GO:0009309). GO:0009309 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Elevated Circulating TMAO Inhibiting microbial CutC/D lowers circulating TMAO during choline supplementation, linking microbial TMA generation to systemic TMAO exposure without separately asserting an uncited hepatic step. Gut microbial TMAO promotes AF via M2 muscarinic receptor autonomic dysfunction
Show evidence (1 reference)
DOI:10.1172/JCI201684 SUPPORT Model Organism
"Iodomethylcholine (IMC), the gut microbial CutC/D inhibitor that suppresses choline→TMA(O) metabolic transformation, reduced circulating TMAO levels ... and choline induced AF onset"
Directly identifies CutC/D-mediated microbial choline-to-TMA(O) transformation and its inhibition by IMC.
Elevated Circulating TMAO
Raised systemic plasma TMAO is the exposure that independently associates with prevalent AF in humans and predicts earlier AF onset/persistence in mouse models; the CutC/D inhibitor IMC lowers it and delays AF.
Gut microbial TMAO promotes AF via M2 muscarinic receptor autonomic dysfunction
Downstream
Muscarinic M2 Receptor Inhibition TMAO, structurally similar to acetylcholine, inhibits the cardiac M2 muscarinic receptor. Gut microbial TMAO promotes AF via M2 muscarinic receptor autonomic dysfunction
Show evidence (2 references)
DOI:10.1172/JCI201684 SUPPORT Other
"TMAO levels were quantified in plasma from serial subjects undergoing elective cardiac catheterizations (N=5090) and shown to independently associate with prevalent AF following adjustment for risk factors (TMAO adjusted odds ratio 1.7 [95% confidence interval 1.3-2.1]"
Plasma TMAO independently associates with prevalent AF in a 5,090-subject clinical cohort (adjusted OR 1.7).
DOI:10.1172/JCI201684 SUPPORT Model Organism
"Human cAMP response element modulator isoform IbΔC-X transgenic mice (CREM-IbΔC-X), a spontaneous mouse model of AF, supplemented with a TMAO diet developed AF sooner."
Direct dietary TMAO accelerates spontaneous AF onset in a transgenic mouse model.
Muscarinic M2 Receptor Inhibition
TMAO inhibits muscarinic receptor 2 (M2R) signaling.
Gut microbial TMAO promotes AF via M2 muscarinic receptor autonomic dysfunction
CHRM2 hgnc:1951 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CHRM2 (hgnc:1951). hgnc:1951 is a gene from the HUGO Gene Nomenclature Committee.
G protein-coupled acetylcholine receptor signaling GO:0007213 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased G protein-coupled acetylcholine receptor signaling, annotated with G protein-coupled acetylcholine receptor signaling pathway (GO:0007213). GO:0007213 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Cardiac Autonomic Dysfunction M2R inhibition disrupts parasympathetic (vagal) cardiac control. Gut microbial TMAO promotes AF via M2 muscarinic receptor autonomic dysfunction
Show evidence (1 reference)
DOI:10.1172/JCI201684 SUPPORT In Vitro
"TMAO inhibits muscarinic receptor 2 resulting in autonomic dysfunction that promotes AF."
The study summary identifies M2R inhibition as the proposed molecular initiator.
Cardiac Autonomic Dysfunction
M2R inhibition produces autonomic dysfunction in vivo and is proposed to promote the electrical substrate for AF.
Gut microbial TMAO promotes AF via M2 muscarinic receptor autonomic dysfunction
Downstream
Atrial Electrical Remodeling The high-TMAO state is associated with slower conduction velocity and APD80/wavelength shortening, which may lower the reentry threshold and feed electrical remodeling that sustains AF. Gut microbial TMAO promotes AF via M2 muscarinic receptor autonomic dysfunction
Show evidence (1 reference)
DOI:10.1172/JCI201684 SUPPORT Model Organism
"the gut microbial metabolite TMAO, independently associated with AF risk in subjects, enhances AF in multiple AF mouse models via autonomic dysfunction"
The study attributes TMAO-enhanced AF across mouse models to autonomic dysfunction.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Atrial Fibrillation Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Cardiovascular 2
Palpitations HP:0001962 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Palpitations (HP:0001962). HP:0001962 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35873859 SUPPORT Other
"Palpitations are the cardinal symptom of AF and many AF therapies are targeted towards relieving this symptom."
Confirms that palpitations are the primary symptom of atrial fibrillation.
Atrial Fibrillation HP:0005110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial fibrillation (HP:0005110). HP:0005110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9725923 SUPPORT Human Clinical
"The pulmonary veins are an important source of ectopic beats, initiating frequent paroxysms of atrial fibrillation."
Directly documents electrocardiographically mapped AF episodes rather than a broader arrhythmia surrogate.
Respiratory 1
Dyspnea FREQUENT HP:0002094 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyspnea (HP:0002094). HP:0002094 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35873859 SUPPORT Other
"up to two-third of patients also complain of dyspnea as a predominant self-reported symptom."
Confirms dyspnea is a common and predominant symptom in atrial fibrillation patients.
Constitutional 3
Fatigue HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26318825 SUPPORT Human Clinical
"Experiencing fatigue, dyspnea and intermittent symptoms produced symptom representations and emotional and behavioral responses associated with treatment-seeking delay."
Confirms fatigue is a common symptom in atrial fibrillation that affects patient behavior.
Exercise Intolerance HP:0003546 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exercise intolerance (HP:0003546). HP:0003546 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39680399 SUPPORT Other
"Symptoms of AF include palpitations, dyspnea, chest pain, presyncope, exertional intolerance, and fatigue"
Directly identifies exertional intolerance as an AF symptom without asserting a frequency.
Chest Pain HP:0100749 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chest pain (HP:0100749). HP:0100749 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39680399 SUPPORT Other
"Symptoms of AF include palpitations, dyspnea, chest pain, presyncope, exertional intolerance, and fatigue"
Directly lists chest pain among AF symptoms; no frequency is inferred.
Other 1
Thromboembolic Stroke HP:0001727 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thromboembolic stroke (HP:0001727). HP:0001727 is a phenotype from the Human Phenotype Ontology.
Major complication due to atrial thromboembolism; no universal frequency is asserted.
Show evidence (1 reference)
PMID:39680399 SUPPORT Other
"AF is associated with significantly increased risk of stroke, heart failure, myocardial infarction, dementia, chronic kidney disease, and mortality."
Directly establishes stroke as a major AF complication; the pathograph uses the more specific thromboembolic-stroke HPO term.
🧬

Genetic Associations

2
PITX2 (Common-variant susceptibility locus)
Gene: PITX2 hgnc:9005 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PITX2 (hgnc:9005). hgnc:9005 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:40645996 SUPPORT Human Clinical
"Two loci of PITX2 and ZFHX3 genes were identified as shared across populations of different ancestries."
Cross-population meta-analysis directly supports PITX2 as a shared AF susceptibility locus.
ZFHX3 (Common-variant susceptibility locus)
Gene: ZFHX3 hgnc:777 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ZFHX3 (hgnc:777). hgnc:777 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:40645996 SUPPORT Human Clinical
"Two loci of PITX2 and ZFHX3 genes were identified as shared across populations of different ancestries."
Cross-population meta-analysis directly supports ZFHX3 as a shared AF susceptibility locus.
💊

Medical Actions

8
Anticoagulation
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: warfarin CHEBI:10033 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses warfarin (CHEBI:10033). CHEBI:10033 is a therapeutic agent from Chemical Entities of Biological Interest. apixaban CHEBI:72296 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses apixaban (CHEBI:72296). CHEBI:72296 is a therapeutic agent from Chemical Entities of Biological Interest. rivaroxaban CHEBI:68579 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses rivaroxaban (CHEBI:68579). CHEBI:68579 is a therapeutic agent from Chemical Entities of Biological Interest. dabigatran CHEBI:70752 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dabigatran (CHEBI:70752). CHEBI:70752 is a therapeutic agent from Chemical Entities of Biological Interest.
Warfarin or a direct oral anticoagulant (DOAC) is used to prevent stroke according to thromboembolic risk. DOAC preference applies only in patients without mechanical heart valves or moderate-to-severe mitral stenosis.
Target Phenotypes: Thromboembolic stroke HP:0001727 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Thromboembolic stroke (HP:0001727). HP:0001727 is a phenotype from the Human Phenotype Ontology.
Show evidence (5 references)
PMID:37573616 SUPPORT Human Clinical
"DOAC was associated with a significantly lower risk of stroke or systemic embolism (hazard ratio 0.85, 95% confidence interval 0.75 to 0.96, p = 0.008, I2 = 0%), major bleeding, intracranial hemorrhage, and mortality compared with warfarin."
Meta-analysis of 132,980 patients demonstrates DOACs reduce stroke risk in AF patients.
PMID:40526576 SUPPORT Other
"If it is 2 or higher, oral anticoagulation (OAC) is indicated, of a type that should be decided on an individual basis."
The guideline indicates oral anticoagulation for AF patients with a CHA2DS2-VA score of 2 or higher.
PMID:39680399 SUPPORT Other
"In patients without mechanical heart valves or moderate to severe mitral stenosis, DOACs are preferred because they are associated with less bleeding than warfarin."
Directly supplies the mechanical-valve and mitral-stenosis boundary on DOAC preference.
+ 2 more references
Rate Control
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: metoprolol CHEBI:6904 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses metoprolol (CHEBI:6904). CHEBI:6904 is a therapeutic agent from Chemical Entities of Biological Interest. diltiazem CHEBI:101278 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses diltiazem (CHEBI:101278). CHEBI:101278 is a therapeutic agent from Chemical Entities of Biological Interest. digoxin CHEBI:4551 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses digoxin (CHEBI:4551). CHEBI:4551 is a therapeutic agent from Chemical Entities of Biological Interest.
Beta blockers, calcium channel blockers, or digoxin.
Show evidence (1 reference)
PMID:39604644 SUPPORT Other
"For rate or rhythm control pharmacotherapy with beta-blockers, digitalis, amiodarone and flecainide are still the most important drugs."
Current guideline summary directly supports beta-blocker/digitalis rate control and antiarrhythmic rhythm control.
Rhythm Control
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: amiodarone CHEBI:2663 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses amiodarone (CHEBI:2663). CHEBI:2663 is a therapeutic agent from Chemical Entities of Biological Interest. flecainide CHEBI:75984 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses flecainide (CHEBI:75984). CHEBI:75984 is a therapeutic agent from Chemical Entities of Biological Interest. sotalol CHEBI:63622 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sotalol (CHEBI:63622). CHEBI:63622 is a therapeutic agent from Chemical Entities of Biological Interest.
Antiarrhythmic drugs (amiodarone, flecainide, sotalol).
Show evidence (1 reference)
PMID:40526576 SUPPORT Other
"In patients with cardiovascular risk factors, early rhythm control has been shown to reduce prognostically relevant cardio - vascular endpoints (3.9 versus 5.0 per 100 patientyears)."
Guideline evidence that early rhythm control reduces cardiovascular endpoints in AF patients with cardiovascular risk factors.
Catheter Ablation
Category: Therapeutic Action: Ablation TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Ablation Therapy (NCIT:C20985). NCIT:C20985 is a clinical intervention from the NCI Thesaurus. NCIT:C20985
Pulmonary vein isolation for rhythm control.
Mechanism Target:
INHIBITS Pulmonary Vein Triggers — Pulmonary-vein isolation blocks trigger conduction into the atria.
Show evidence (1 reference)
PMID:9725923 SUPPORT Human Clinical
"A local depolarization could also be recognized during sinus rhythm and abolished by radiofrequency ablation."
Directly supports ablation of the mapped pulmonary-vein trigger activity.
Show evidence (1 reference)
PMID:40526576 SUPPORT Other
"Multiple studies have shown that catheter ablation is superior to drug-based antiarrhythmic therapy in patients with paroxysmal symptomatic AF as well as in those with heart failure and AF."
The guideline notes catheter ablation is superior to antiarrhythmic drug therapy for paroxysmal symptomatic AF and for AF with heart failure.
Cardioversion
Category: Therapeutic Action: CardioversionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Cardioversion (NCIT:C70911). NCIT:C70911 is a clinical intervention from the NCI Thesaurus. NCIT:C70911
Electrical or pharmacological restoration of sinus rhythm.
Show evidence (1 reference)
PMID:39716733 SUPPORT Other
"The AF duration threshold for early cardioversion was reduced from 48 to 24 h, and a wait-and-see approach for spontaneous conversion is advised to promote patient safety."
Supports cardioversion as a guideline-managed rhythm-restoration strategy and its timing nuance.
Left Atrial Appendage Closure
Category: Therapeutic
Alternative to anticoagulation in selected patients.
Mechanism Target:
INHIBITS Atrial Thrombus Formation — Excludes the appendage, the predominant site of AF-related left-atrial thrombi.
Show evidence (1 reference)
PMID:8572814 SUPPORT Human Clinical
"201 of 222 (91%) of nonrheumatic atrial fibrillation-related left atrial thrombi were isolated to, or originated in the left atrial appendage"
Directly supports the anatomical mechanism targeted by appendage exclusion.
Show evidence (1 reference)
PMID:41040442 SUPPORT Other
"Left atrial appendage occlusion (LAAO) devices reduce the risk of atrial fibrillation-associated stroke relative to no oral anticoagulation."
Current evidence-based guideline supports stroke-risk reduction while noting selection uncertainty.
Risk Factor Modification
Category: Therapeutic
Weight loss, blood pressure control, sleep apnea treatment.
Show evidence (1 reference)
PMID:40526576 SUPPORT Other
"Lifestyle interventions and the reduction of risk factors lessen the frequency of AF."
Guideline evidence that lifestyle intervention and risk-factor reduction lower AF frequency.
Gut Microbial TMA-Lyase Inhibition (Iodomethylcholine)
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Iodomethylcholine (IMC), a gut-restricted CutC/D choline-TMA lyase inhibitor, suppresses microbial choline-to-TMA(O) transformation, reduces circulating TMAO, and delays choline-induced AF onset in mice. It is an investigational AF-prevention strategy, not yet a human therapy.
Mechanism Target:
INHIBITS Gut Microbial TMA Production — IMC inhibits the gut microbial CutC/D choline-TMA lyase, cutting TMA (and hence TMAO) production upstream of the autonomic-dysfunction arm.
Show evidence (1 reference)
DOI:10.1172/JCI201684 SUPPORT Model Organism
"Iodomethylcholine (IMC), the gut microbial CutC/D inhibitor that suppresses choline→TMA(O) metabolic transformation, reduced circulating TMAO levels ... and choline induced AF onset"
Directly supports target engagement and the upstream metabolic effect in mice.
Show evidence (1 reference)
DOI:10.1172/JCI201684 SUPPORT Model Organism
"Iodomethylcholine (IMC), the gut microbial CutC/D inhibitor that suppresses choline→TMA(O) metabolic transformation, reduced circulating TMAO levels ... and choline induced AF onset"
Directly supports the molecular target, lowered circulating TMAO, and delayed AF onset in mice.
🌍

Environmental Factors

6
Hypertension
Major modifiable population risk factor.
Show evidence (2 references)
PMID:27057292 SUPPORT Other
"Of all the risk factors, HTN is the most commonly encountered condition in patients with incident AF."
Review confirms hypertension is the most common risk factor for atrial fibrillation.
PMID:38984719 SUPPORT Computational
"High systolic blood pressure emerged as the leading contributor to age-standardized AF/AFL incidence, prevalence, death, and DALY rate globally among all potential risk factors, followed closely by high body mass index."
GBD modeling supports blood pressure as the leading attributable AF/AFL risk factor.
Mechanism Target:
TRIGGERS Atrial Fibrosis — Chronic pressure load stretches the atrium, and that stretch drives the fibrotic remodelling that creates the reentrant substrate. Hypertension is the commonest condition in patients presenting with new atrial fibrillation.
Show evidence (1 reference)
PMID:27057292 SUPPORT Other
"Of all the risk factors, HTN is the most commonly encountered condition in patients with incident AF."
Identifies hypertension as the most commonly encountered condition in patients with incident atrial fibrillation, the leading contributor to the substrate.
Obesity
Associated with atrial remodeling
Show evidence (2 references)
PMID:39146015 SUPPORT Other
"Obesity is linked to an increased risk of atrial fibrillation (AF) via increased oxidative stress."
The study background supports the epidemiologic risk assertion; the separate perturbation evidence below supports mechanism in models.
PMID:39146015 SUPPORT Model Organism
"We showed that NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden."
Demonstrates that obesity causes atrial remodeling that can be reversed by targeting the underlying oxidative stress pathway.
Mechanism Target:
TRIGGERS NOX2-Dependent Atrial Oxidative Stress — Targets the oxidative stress node specifically rather than the generic substrate, because the cited work shows NOX2 inhibition normalising atrial action potential duration and abolishing obesity-driven ion channel remodelling, placing NOX2 on the causal path.
Show evidence (1 reference)
PMID:39146015 SUPPORT Model Organism
"We showed that NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden."
NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling. Support is PARTIAL because the demonstration is experimental animal work.
Obstructive Sleep Apnea
Associated with increased AF risk; the direction and effect of treatment vary by context.
Show evidence (1 reference)
PMID:29657903 SUPPORT Human Clinical
"OSA/SDB is strongly associated with AFib confirming the notion that OSA/SDB populations are high risk for development of AF."
Meta-analysis of 9 studies with 19,837 participants confirms OSA as a significant risk factor for AF development.
Mechanism Target:
TRIGGERS Cardiac Autonomic Dysfunction — Apnoeic episodes produce repeated intrathoracic pressure swings, hypoxaemia and surges of autonomic tone, which is why this targets the autonomic node rather than the fibrotic substrate.
Show evidence (1 reference)
PMID:29657903 SUPPORT Human Clinical
"OSA/SDB is strongly associated with AFib confirming the notion that OSA/SDB populations are high risk for development of AF."
Reports a strong association between sleep-disordered breathing and atrial fibrillation, identifying these populations as high risk for its development.
Tobacco Smoking
exposure to tobacco smoking ECTO:6000029 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to tobacco smoking (ECTO:6000029). ECTO:6000029 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Modifiable AF susceptibility factor; not a universal or sufficient cause.
Show evidence (1 reference)
PMID:39680399 SUPPORT Other
"Older age, current smoking, taller height, greater weight, higher blood pressure (systolic, diastolic, and hypertension treatment), presence of diabetes, and presence of heart disease (HF or myocardial infarction) are associated with higher rates of AF."
Directly supports an association of current smoking with higher AF rates.
Mechanism Target:
PREDISPOSES Atrial Fibrosis — Smoking appears among the established risk factors in cohort modelling but without an identified atrial mechanism, so it is recorded as predisposing to the fibrotic substrate rather than driving it.
Show evidence (1 reference)
PMID:39680399 SUPPORT Other
"Older age, current smoking, taller height, greater weight, higher blood pressure (systolic, diastolic, and hypertension treatment), presence of diabetes, and presence of heart disease (HF or myocardial infarction) are associated with higher rates of AF."
Lists current smoking among the factors associated with atrial fibrillation risk in a cohort risk model, an association without a specified mechanism.
Alcohol Exposure
exposure to alcohol consumption ECTO:0001082 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to alcohol consumption (ECTO:0001082). ECTO:0001082 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Risk is associated particularly with more-than-moderate or binge exposure.
Show evidence (1 reference)
PMID:39680399 SUPPORT Other
"Additional factors associated with increased AF risk include more than moderate alcohol use (defined as >1 standard alcoholic drink per day or binge drinking), sleep apnea, and hyperthyroidism."
Directly supports dose-contextualized alcohol exposure as an AF risk factor.
Mechanism Target:
TRIGGERS Atrial Electrical Remodeling — Alcohol shortens atrial refractoriness and slows conduction, and the association is dose-defined above roughly one standard drink per day, which is why this targets electrical rather than structural remodelling.
Show evidence (1 reference)
PMID:39680399 SUPPORT Other
"Additional factors associated with increased AF risk include more than moderate alcohol use (defined as >1 standard alcoholic drink per day or binge drinking), sleep apnea, and hyperthyroidism."
Identifies more than moderate alcohol use, above one standard drink per day, as associated with increased atrial fibrillation risk.
Hyperthyroidism
Clinically important secondary and potentially reversible AF-associated condition.
Show evidence (1 reference)
PMID:39680399 SUPPORT Other
"Additional factors associated with increased AF risk include more than moderate alcohol use (defined as >1 standard alcoholic drink per day or binge drinking), sleep apnea, and hyperthyroidism."
Directly supports hyperthyroidism as an associated AF risk factor.
Mechanism Target:
TRIGGERS Atrial Electrical Remodeling — Excess thyroid hormone shortens the atrial action potential and raises automaticity, a reversible electrical effect: restoring euthyroidism often restores sinus rhythm, which distinguishes it from the structural risk factors here.
Show evidence (1 reference)
PMID:39680399 SUPPORT Other
"Additional factors associated with increased AF risk include more than moderate alcohol use (defined as >1 standard alcoholic drink per day or binge drinking), sleep apnea, and hyperthyroidism."
Lists hyperthyroidism among the factors associated with increased atrial fibrillation risk.
🔬

Biochemical Markers

2
NT-proBNP as an incident-AF risk biomarker (Elevated)
Show evidence (1 reference)
PMID:36610061 SUPPORT Human Clinical
"NT-proBNP was the strongest circulating predictor of incident AF [hazard ratio (HR) per standard deviation (SD), 1.93 (95% CI, 1.82-2.04); P < 0.001]."
Directly supports predictive association in 42,280 pooled European cohort participants.
Multimarker adverse-outcome panel in established AF (Measured in plasma)
Show evidence (1 reference)
PMID:40744929 SUPPORT Human Clinical
"We identify 5 biomarkers including D-dimer, growth differentiation factor 15 (GDF-15), interleukin-6 (IL-6), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hsTropT) that independently predict cardiovascular death, stroke, myocardial infarction, and..."
Directly reports outcome prediction in 3,817 patients with AF.
🔬

Diagnosis

3
Clinician-interpreted electrocardiography
A 12-lead ECG or other clinician-reviewed rhythm tracing establishes AF by documenting the characteristic atrial rhythm. Longer ambulatory monitoring may be required when episodes are intermittent; device alerts require confirmatory review.
Electrocardiography NCIT:C38053 NCI Thesaurus (NCIT)
Results: Electrocardiographic tracing consistent with atrial fibrillation.
Show evidence (2 references)
PMID:39674741 SUPPORT Other
"For diagnosis, electrocardiographic confirmation of clinical AF is essential, followed by risk stratification using the CHA₂DS₂-VASc score to guide anticoagulation therapy."
Directly supports the diagnostic role of an electrocardiographic tracing.
PMID:10549907 SUPPORT Human Clinical
"The purpose of this study was to determine the ability of physicians to differentiate atrial flutter from atrial fibrillation on a surface electrocardiogram (ECG)."
Directly supports clinician interpretation of a surface ECG and the need to distinguish AF from flutter.
Non-invasive systematic AF screening
Pulse, handheld ECG, patch, or wearable strategies can increase detection of previously unrecognized AF, but trial evidence has not shown reduced adverse outcomes; screening is therefore distinct from diagnosis and treatment.
Show evidence (1 reference)
PMID:40276326 SUPPORT Human Clinical
"Systematic screening for AF using non-invasive devices is associated with increased diagnosis of AF, but not reduced adverse clinical events."
Meta-analysis distinguishes higher diagnostic yield from unproven clinical-outcome benefit.
Initial structural and secondary-cause evaluation
After AF is confirmed, transthoracic echocardiography evaluates cardiac structure and ventricular function; complete blood count, metabolic panel, and thyroid testing assess clinically relevant associated conditions.
echocardiography NCIT:C16525 NCI Thesaurus (NCIT)
Results: Cardiac structure/function and laboratory contributors documented for management.
Show evidence (1 reference)
PMID:39680399 SUPPORT Other
"Evaluation of patients with newly identified AF should include transthoracic echocardiogram to assess cardiac structure and to identify possible causes for AF (eg, valve disease)4or outcomes associated with AF (eg, reduced ventricular function). Basic laboratory testing, including complete blood..."
Directly supports the initial structural and laboratory evaluation.
📈

Progression

1
Paroxysmal atrial fibrillation
Paroxysmal Atrial Fibrillation Duration: Variable; may progress over years
In a retrospective cohort, 32.4% progressed to persistent or permanent AF during a mean 57.3 months; this is cohort-specific rather than a universal transition probability.
Show evidence (1 reference)
PMID:28496630 SUPPORT Human Clinical
"Over a mean duration of 57.3±55.9 months, 32.4% of patients progressed to persistent/permanent AF."
Directly quantifies temporal progression in the 437-patient cohort.
📊

Prevalence

1
Worldwide
Point Prevalence 510.0 per 100,000 >1 in 1,000
Reported as 0.51% of the worldwide population in 2017. The article's "37,574 million cases" is interpreted as a comma/decimal artifact for 37.574 million.
Show evidence (1 reference)
PMID:31955707 SUPPORT Computational
"The worldwide prevalence of atrial fibrillation is 37,574 million cases (0.51% of worldwide population), increased also by 33% during the last 20 years."
Supplies the reported 2017 global point-prevalence estimate.
🌍

Epidemiology

1
Global AF and atrial-flutter burden in 2021
The Global Burden of Disease analysis combines atrial fibrillation and atrial flutter; its counts must not be interpreted as AF-only estimates.
High systolic blood pressure High body mass index
Show evidence (2 references)
PMID:38984719 SUPPORT Computational
"Globally, in 2021, there were 4.48 million incident cases"
Supplies global modeled burden while explicitly retaining AF/AFL scope.
PMID:38984719 SUPPORT Computational
"8.36 million DALYs (95% UI: 6.97-10.13) and 0.34 million deaths (95% UI: 0.29-0.37) attributed to AF/AFL."
Directly supports the DALY and death components of the combined AF/AFL burden.
⚖️

Clinical Burden

High
AF may be asymptomatic or intermittently symptomatic, but its population and individual burden is high because it is chronic and recurrent, increases stroke, heart-failure, dementia, and mortality risks, and commonly requires lifelong risk-factor management, rhythm/rate decisions, and thromboembolic risk reassessment.
Show evidence (2 references)
PMID:41543444 SUPPORT Other
"Atrial fibrillation (AF) is a major public health problem, associated with increased risks of heart failure, stroke, dementia, and mortality."
Directly supports the major morbidity and mortality components of high burden.
PMID:40526576 SUPPORT Other
"It is associated with a 1.5- to 2-fold increase in mortality and a 4- to 5-fold increase in the risk of stroke."
Quantifies two major adverse prognostic consequences.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Atrial Fibrillation:

Atrial Flutter Not Yet Curated MONDO:0005310
Overlapping Features A macroreentrant atrial arrhythmia that may have a regular or variably conducted ventricular response and can be mistaken for AF on a surface ECG.
Distinguishing Features
  • Organized flutter-wave activity and a repeating atrial cycle favor flutter.
  • Prominent atrial activity can make AF appear flutter-like; review multiple leads and longer recordings.
Show evidence (1 reference)
PMID:10549907 SUPPORT Human Clinical
"In conclusion, atrial fibrillation is frequently misdiagnosed as atrial flutter. Misdiagnosis of atrial fibrillation occurs more often when atrial activity is prominent on an ECG in more than one lead."
Directly demonstrates clinically important ECG overlap and misclassification.
Multifocal Atrial Tachycardia Not Yet Curated MONDO:0017988
Overlapping Features An irregular atrial tachyarrhythmia, often in severe cardiopulmonary illness, that can mimic AF.
Distinguishing Features
  • At least three different nonsinus P-wave morphologies in one lead.
  • Atrial rate above 100 beats/min with an isoelectric baseline between P waves.
Show evidence (1 reference)
PMID:8040593 SUPPORT Other
"Diagnostic criteria include the presence of at least three different, nonsinus P waves in the same lead; an atrial rate greater than 100 beats per minute; and an isoelectric baseline between P waves. MAT is often difficult to differentiate from atrial fibrillation."
Provides explicit distinguishing ECG criteria and states the AF differential.
📊

Related Datasets

9
H3K27ac and H3K4me3 ChIP-Seq profiling of a human paired left and right atrial cohort of atrial fibrillation and healthy sinus rhythm individuals geo:GSE227793
H3K27ac and H3K4me3 ChIP-Seq profiling was performed on atrial appendages samples from 12 individuals aged over 60 years, either classified as persistent atrial fibrillation (AF) or normal sinus rhythm (SR). For all individuals, careful examination of medical history displayed no indications of hypertension, hypothyroidism or diabetes.
human CHIP SEQ n=52
PMID:41906156
Identified by GEO DataSets index search for Atrial Fibrillation (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Humanin and MOTS-c Attenuate Atrial Fibrillation by Suppressing Fibrosis and Mitochondrial Dysfunction in murine models geo:GSE322635
BACKGROUND: Atrial fibrillation (AF) is the most common clinical arrhythmia associated with mitochondrial dysfunction, oxidative stress, and atrial fibrosis. Mitochondrial-derived peptides (MDPs) including humanin (HN) and MOTS-c, demonstrated potent cytoprotective effects, but their role in AF remains elusive. METHODS: Public GEO database, immunohistochemistry and immunofluorescence were applied to determine their expressions in atrial tissues. Plasma peptide levels were measured in a clinical cohort.
rat BULK RNA SEQ n=12
PMID:42193373
Identified by GEO DataSets index search for Atrial Fibrillation (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Gene-Gene Interactions Between A LMNA Variant and Common Polymorphisms Drive Early-Onset Atrial Fibrillation [ATAC-seq] geo:GSE295056
Atrial fibrillation (AF) is a common arrhythmia with a complex genetic basis, yet the molecular mechanisms linking rare and common variants remain unclear. Using induced pluripotent stem cell-derived atrial cardiomyocytes, we uncover a novel mechanism by which a rare pathogenic LMNA variant encoding Lamin A/C disrupts chromatin accessibility and gene regulation at AF-associated loci. Specifically, reduced accessibility at an SCN5A enhancer harboring an AF-associated variant leads to reduced sodium current, conduction abnormalities, and re-entrant AF.
human ATAC SEQ n=9
PMID:42156780
Identified by GEO DataSets index search for Atrial Fibrillation (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Lone atrial fibrillation case-control study ega:EGAS00001003045
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Atrial Fibrillation"); description-level mentions were not accepted. EGA study_type: Population Genomics. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Whole exome sequencing of 76 individuals with familial atrial fibrillation ega:EGAS00001003207
We investigated genetic background of familial and early onset atrial fibrillation (AF) with the aim of identify genes involved in atrial fibrillation pathology and are highly predisposing risk factors. We performed whole exome sequencing on 24 families where three or more family members suffered from AF.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Atrial Fibrillation"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
early onset lone atrial fibrillation case-control study ega:EGAS00001003208
Target sequencing W/ TruSight Cardio Sequencing Kit. 395 early onset lone AF cases and 375 controls. Sequencing was performed on Illumina NextSeq and HiSeq 2500 systems.395 early.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Atrial Fibrillation"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Characterization of feces in Atrial Fibrillation (AF) patients metabolomics_workbench:ST001208
Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Atrial Fibrillation"). Retrieved 2026-08-02.
Alterations in fecal metabolic patterns are associated with atrial fibrillation metabolomics_workbench:ST001168
Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Atrial Fibrillation"). Retrieved 2026-08-02.
Alterations in serum metabolic patterns are associated with atrial fibrillation metabolomics_workbench:ST001169
Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Atrial Fibrillation"). Retrieved 2026-08-02.
🔬

Clinical Trials

2
NCT01288352 NOT_APPLICABLE COMPLETED
EAST-AFNET 4 randomized 2,789 patients with recently diagnosed AF and cardiovascular conditions to early rhythm control or usual care. Early rhythm control reduced the primary cardiovascular composite, while serious rhythm-control-related adverse events were more frequent.
Target Phenotypes: Atrial fibrillation HP:0005110 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Atrial fibrillation (HP:0005110). HP:0005110 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
clinicaltrials:NCT01288352 SUPPORT Human Clinical
"EAST prospectively tests the hypothesis that an early, structured rhythm control therapy based on antiarrhythmic drugs and catheter ablation can prevent atrial fibrillation (AF) related complications in patients with AF when compared to usual care."
Registry text establishes the trial question and randomized strategies.
PMID:32865375 SUPPORT Human Clinical
"A first-primary-outcome event occurred in 249 of the patients assigned to early rhythm control (3.9 per 100 person-years) and in 316 patients assigned to usual care (5.0 per 100 person-years) (hazard ratio, 0.79; 96% confidence interval, 0.66 to 0.94; P = 0.005)."
Supplies the principal randomized outcome without implying all AF populations share the effect.
NCT00911508 NOT_APPLICABLE COMPLETED
CABANA randomized 2,204 symptomatic patients to catheter ablation or drug therapy. In intention-to-treat analysis ablation did not significantly reduce the primary death/disabling-stroke/serious-bleeding/cardiac-arrest composite, but reduced AF recurrence and death or cardiovascular hospitalization.
Target Phenotypes: Atrial fibrillation HP:0005110 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Atrial fibrillation (HP:0005110). HP:0005110 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
clinicaltrials:NCT00911508 SUPPORT Human Clinical
"The CABANA Trial is designed to test the hypothesis that the treatment strategy of left atrial catheter ablation for the purpose of eliminating atrial fibrillation (AF) will be superior to current state-of-the-art therapy"
Registry text establishes the interventional comparison.
PMID:30874766 SUPPORT Human Clinical
"Among patients with AF, the strategy of catheter ablation, compared with medical therapy, did not significantly reduce the primary composite end point of death, disabling stroke, serious bleeding, or cardiac arrest."
Preserves the neutral primary intention-to-treat result rather than overstating ablation benefit.
🧫

Experimental Models

1
Palmitate-treated human iPSC-derived atrial cardiomyocytes IPSC_DERIVED_MODEL
Human iPSC-derived atrial cardiomyocytes exposed to palmitate model the obesity-associated NOX2 oxidative-stress and ion-channel-remodeling axis. The reductionist system lacks multicellular atrial structure, autonomic input, and thromboembolic physiology.
Palmitate exposure
Atrial cardiomyocyte CL:0002129 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses Atrial cardiomyocyte, annotated with regular atrial cardiac myocyte (CL:0002129). CL:0002129 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Culture
Two-dimensional human iPSC-derived atrial cardiomyocyte culture
Pathograph links
Atrial Electrical Remodeling Assays obesity-associated NOX2-dependent atrial ion-channel remodeling.
Show evidence (1 reference)
PMID:39146015 SUPPORT In Vitro
"Unbiased transcriptomics analysis revealed that NOX2 mediates atrial remodeling in obesity-mediated AF in DIO mice, PA-treated hiPSC-aCMs, and human atrial tissue from obese individuals"
Directly identifies the palmitate-treated hiPSC atrial-cardiomyocyte model and cross-system comparison.
🐁

Animal Models

3
Goat (Capra hircus) Chronic rapid-atrial-pacing model
Awake chronically instrumented goats were maintained in AF to measure time-dependent shortening of fibrillation interval and increased AF inducibility, establishing tachycardia-induced electrical remodeling.
Atrial Fibrillation
Species
Goat (Capra hircus)
Show evidence (1 reference)
PMID:7671380 SUPPORT Model Organism
"During the first 24 hours of AF the median fibrillation interval shortened from 145 +/- 18 to 108 +/- 8 ms and the inducibility of AF by a single premature stimulus increased from 24% to 76%."
Defines the model and its core electrophysiologic outputs.
Fibroblast-specific NLRP3 activation with knockdown rescue Mouse (Mus musculus) Conditional inflammatory atrial-cardiomyopathy model
Fibroblast-restricted NLRP3 activation models inflammatory atrial fibrosis, conduction slowing, and AF susceptibility; NLRP3 knockdown provides a causal rescue arm.
Atrial Fibrillation
Species
Mouse (Mus musculus)
Genotype
Fibroblast-specific NLRP3 activation with knockdown rescue
Genes
NLRP3 hgnc:16400 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns NLRP3 (hgnc:16400). hgnc:16400 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:40243956 SUPPORT Model Organism
"Fibroblast-specific activation of NLRP3 in mice induced AF-promoting atrial myopathy and heart failure with diastolic dysfunction, accompanied by increased fibrosis, and reduced conduction velocity."
Directly reports the modeled AF substrate and phenotypes.
Human CREM-IbΔC-X transgenic Mouse (Mus musculus) Spontaneous-AF dietary-metabolite model
A spontaneous-AF transgenic model used to test dietary TMAO acceleration and upstream microbial CutC/D inhibition. This is an emerging mechanism model, not evidence of human therapeutic efficacy.
Atrial Fibrillation
Species
Mouse (Mus musculus)
Genotype
Human CREM-IbΔC-X transgenic
Show evidence (1 reference)
DOI:10.1172/JCI201684 SUPPORT Model Organism
"Human cAMP response element modulator isoform IbΔC-X transgenic mice (CREM-IbΔC-X), a spontaneous mouse model of AF, supplemented with a TMAO diet developed AF sooner."
Directly describes the model and TMAO-dependent acceleration of AF onset.
🧮

Computational Models

1
Courtemanche-Ramirez-Nattel human atrial action-potential model KINETIC
Ionic-current kinetic model of the human atrial cardiomyocyte action potential used to examine rate adaptation and ion-current contributions to AF susceptibility. It models cellular electrophysiology, not whole-patient natural history or treatment outcomes.
PMID:9688927
Pathograph links
Atrial Electrical Remodeling Models rate-dependent atrial action-potential adaptation and its ionic-current determinants.
Show evidence (1 reference)
PMID:9688927 SUPPORT Computational
"Rate-dependent adaptation of AP duration, an important determinant of susceptibility to atrial fibrillation, was attributable to incomplete L-type Ca2+ current recovery from inactivation and incomplete delayed rectifier current deactivation at rapid rates."
Directly maps the computational model to the electrical-remodeling node.
Show evidence (1 reference)
PMID:9688927 SUPPORT Computational
"Rate-dependent adaptation of AP duration, an important determinant of susceptibility to atrial fibrillation, was attributable to incomplete L-type Ca2+ current recovery from inactivation and incomplete delayed rectifier current deactivation at rapid rates."
Directly states the modeled property and mechanistic inference.
{ }

Source YAML

click to show 
name: Atrial Fibrillation
creation_date: '2025-12-18T17:01:35Z'
description: >-
  Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia,
  characterized by rapid, disorganized atrial electrical activity that replaces
  coordinated atrial contraction with an irregularly irregular ventricular
  response. It arises from a combination of ectopic triggers (often from the
  pulmonary veins) and an atrial substrate of electrical and structural
  remodeling. AF reduces cardiac output and promotes atrial thrombus formation,
  substantially increasing the risk of ischemic stroke.
category: Complex
synonyms:
- AF
- AFib
parents:
- Cardiovascular Disease
- Cardiac Arrhythmia
disease_term:
  preferred_term: atrial fibrillation
  term:
    id: MONDO:0004981
    label: atrial fibrillation
definitions:
- name: Electrocardiographic clinical definition of atrial fibrillation
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    A supraventricular tachyarrhythmia confirmed on 12-lead ECG by irregular
    atrial activity (fibrillatory waves) without discrete P waves, or on a rhythm
    strip lasting longer than 30 seconds. A wearable-device alert alone is a
    screening signal and requires ECG correlation or additional testing.
  scope: >-
    This entry represents common clinical atrial fibrillation across paroxysmal,
    persistent, long-standing persistent, and permanent temporal patterns. Rare
    Mendelian familial atrial fibrillation is modeled separately in
    Familial_Atrial_Fibrillation.
  evidence:
  - reference: PMID:39680399
    reference_title: "Atrial Fibrillation: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of AF is confirmed by identifying irregular atrial activity
      (fibrillatory waves) without discrete P waves on 12-lead ECG4or lasting for
      longer than 30 seconds on rhythm strip.
    explanation: >-
      Directly supplies the electrocardiographic case boundary used here.
has_subtypes:
- name: Paroxysmal Atrial Fibrillation
  description: Episodes terminate spontaneously within 7 days.
  evidence: &af_temporal_classification
  - reference: PMID:39680399
    reference_title: "Atrial Fibrillation: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      AF is classified as paroxysmal (intermittent AF episodes lasting ≤7 days),
      persistent (continuous AF episodes lasting >7 days and/or requiring
      cardioversion), or long-standing persistent (AF episode lasting >1 year).
    explanation: Directly supplies the paroxysmal, persistent, and long-standing persistent duration boundaries.
- name: Persistent Atrial Fibrillation
  description: Episodes last longer than 7 days or require intervention.
  evidence: *af_temporal_classification
- name: Long-standing Persistent Atrial Fibrillation
  description: Continuous AF for more than 12 months.
  evidence: *af_temporal_classification
- name: Permanent Atrial Fibrillation
  description: AF accepted as permanent rhythm.
  evidence:
  - reference: PMID:39680399
    reference_title: "Atrial Fibrillation: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with stage 4 AF have permanent AF, for which a decision has
      been made not to pursue rhythm control based on patient and clinical factors
    explanation: Directly supports permanent AF as an accepted management state rather than an episode-duration category.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 510.0
  notes: >-
    Reported as 0.51% of the worldwide population in 2017. The article's
    "37,574 million cases" is interpreted as a comma/decimal artifact for
    37.574 million.
  evidence:
  - reference: PMID:31955707
    reference_title: "Global epidemiology of atrial fibrillation: An increasing epidemic and public health challenge."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The worldwide prevalence of atrial fibrillation is 37,574 million cases
      (0.51% of worldwide population), increased also by 33% during the last 20 years.
    explanation: Supplies the reported 2017 global point-prevalence estimate.
progression:
- phase: Paroxysmal atrial fibrillation
  subtype: Paroxysmal Atrial Fibrillation
  duration: Variable; may progress over years
  notes: >-
    In a retrospective cohort, 32.4% progressed to persistent or permanent AF
    during a mean 57.3 months; this is cohort-specific rather than a universal
    transition probability.
  evidence:
  - reference: PMID:28496630
    reference_title: "Evolution of Paroxysmal Atrial Fibrillation to Persistent or Permanent Atrial Fibrillation: Predictors of Progression."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Over a mean duration of 57.3±55.9 months, 32.4% of patients progressed to
      persistent/permanent AF.
    explanation: Directly quantifies temporal progression in the 437-patient cohort.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    AF may be asymptomatic or intermittently symptomatic, but its population and
    individual burden is high because it is chronic and recurrent, increases
    stroke, heart-failure, dementia, and mortality risks, and commonly requires
    lifelong risk-factor management, rhythm/rate decisions, and thromboembolic
    risk reassessment.
  evidence:
  - reference: PMID:41543444
    reference_title: "The clinical pathophysiology of atrial fibrillation: outstanding questions from bedside to bench and back."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Atrial fibrillation (AF) is a major public health problem, associated with
      increased risks of heart failure, stroke, dementia, and mortality.
    explanation: Directly supports the major morbidity and mortality components of high burden.
  - reference: PMID:40526576
    reference_title: "Clinical Practice Guideline: Preventive Measures and Treatment Options for Atrial Fibrillation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is associated with a 1.5- to 2-fold increase in mortality and a 4- to
      5-fold increase in the risk of stroke.
    explanation: Quantifies two major adverse prognostic consequences.
epidemiology:
- name: Global AF and atrial-flutter burden in 2021
  description: >-
    The Global Burden of Disease analysis combines atrial fibrillation and atrial
    flutter; its counts must not be interpreted as AF-only estimates.
  unit: cases, DALYs, and deaths
  factors:
  - High systolic blood pressure
  - High body mass index
  evidence:
  - reference: PMID:38984719
    reference_title: "Global burden of atrial fibrillation/atrial flutter and its attributable risk factors from 1990 to 2021."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: Globally, in 2021, there were 4.48 million incident cases
    explanation: Supplies global modeled burden while explicitly retaining AF/AFL scope.
  - reference: PMID:38984719
    reference_title: "Global burden of atrial fibrillation/atrial flutter and its attributable risk factors from 1990 to 2021."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      8.36 million DALYs (95% UI: 6.97-10.13) and 0.34 million deaths (95% UI:
      0.29-0.37) attributed to AF/AFL.
    explanation: Directly supports the DALY and death components of the combined AF/AFL burden.
pathophysiology:
- name: NOX2-Dependent Atrial Oxidative Stress
  description: >-
    In obesity-driven AF models, NOX2-derived oxidative stress promotes atrial
    ion-channel remodeling and abnormal action-potential duration.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:39146015
    reference_title: "Modulation of NOX2 causes obesity-mediated atrial fibrillation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      NOX2 inhibition normalized atrial action potential duration and abrogated
      obesity-mediated ion channel remodeling with reduced AF burden.
    explanation: >-
      Perturbational evidence identifies NOX2-dependent oxidative stress as an
      upstream driver of obesity-mediated atrial electrical remodeling.
  downstream:
  - target: Atrial Electrical Remodeling
    description: >-
      NOX2 inhibition reverses abnormal atrial action-potential duration and
      ion-channel remodeling in obesity-driven AF models.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39146015
      reference_title: "Modulation of NOX2 causes obesity-mediated atrial fibrillation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        NOX2 inhibition normalized atrial action potential duration and
        abrogated obesity-mediated ion channel remodeling with reduced AF burden.
      explanation: >-
        Targeted inhibition directly reverses the downstream electrical-remodeling
        phenotype, supporting the direction and polarity of this model edge.
- name: Atrial Electrical Remodeling
  description: >
    Rapid atrial rates cause shortening of atrial refractory period and
    loss of rate adaptation, promoting AF maintenance. AF begets AF.
  cell_types:
  - preferred_term: Atrial Cardiomyocyte
    term:
      id: CL:0002129
      label: regular atrial cardiac myocyte
  biological_processes:
  - preferred_term: Cardiac Conduction
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
  evidence:
  - reference: PMID:7671380
    reference_title: "Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "During the first 24 hours of AF the median fibrillation interval shortened from 145 +/- 18 to 108 +/- 8 ms and the inducibility of AF by a single premature stimulus increased from 24% to 76%."
    explanation: The original demonstration that sustained rapid atrial rates shorten atrial refractoriness and increase AF inducibility - the tachycardia-induced electrical remodeling the phrase "AF begets AF" refers to.
  downstream:
  - target: Atrial Fibrillation
    description: >-
      Disordered atrial electrical activation is the defining arrhythmia
      phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:7671380
      reference_title: "Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        During the first 24 hours of AF the median fibrillation interval
        shortened from 145 +/- 18 to 108 +/- 8 ms and the inducibility of AF by
        a single premature stimulus increased from 24% to 76%.
      explanation: Directly links tachycardia-induced electrical remodeling to increased AF inducibility.
  - target: Palpitations
    description: >-
      Atrial fibrillation-related rhythm disturbance commonly manifests as
      palpitations.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - symptomatic perception of irregular atrial rhythm
    evidence:
    - reference: PMID:35873859
      reference_title: "Dyspnea in patients with atrial fibrillation: Mechanisms, assessment and an interdisciplinary and integrated care approach."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Palpitations are the cardinal symptom of AF and many AF therapies are targeted towards relieving this symptom."
      explanation: Review evidence directly identifies palpitations as the cardinal AF symptom.
  - target: Dyspnea
    description: >-
      AF-related rhythm and hemodynamic disturbance can produce dyspnea.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired atrial contribution to cardiac output
    - comorbid cardiovascular reserve limitation
    evidence:
    - reference: PMID:35873859
      reference_title: "Dyspnea in patients with atrial fibrillation: Mechanisms, assessment and an interdisciplinary and integrated care approach."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "However, up to two-third of patients also complain of dyspnea as a predominant self-reported symptom."
      explanation: Review evidence supports dyspnea as a common predominant symptom in AF patients.
  - target: Fatigue
    description: >-
      AF symptom burden includes fatigue, often alongside dyspnea and
      intermittent symptoms.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - symptomatic rhythm disturbance
    evidence:
    - reference: PMID:26318825
      reference_title: "Fatigue, dyspnea, and intermittent symptoms are associated with treatment-seeking delay for symptoms of atrial fibrillation before diagnosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Experiencing fatigue, dyspnea and intermittent symptoms produced symptom representations and emotional and behavioral responses associated with treatment-seeking delay."
      explanation: Clinical symptom study supports fatigue as part of the symptomatic AF presentation.
  - target: Exercise Intolerance
    description: >-
      Rate irregularity and loss of coordinated atrial contribution can reduce
      exercise capacity, although severity depends strongly on ventricular rate
      and comorbid cardiac reserve.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - irregular ventricular response
    - reduced hemodynamic reserve during exertion
    evidence:
    - reference: PMID:40645996
      reference_title: "Cross-population GWAS and proteomics improve risk prediction and reveal mechanisms in atrial fibrillation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        symptoms including palpitations and decreased exercise
      explanation: The article's clinical background directly identifies decreased exercise capacity as an AF symptom.
  - target: Chest Pain
    description: >-
      Chest pain can occur during AF, but the intermediate mechanism and the
      contribution of coexisting ischemic or structural disease vary.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39680399
      reference_title: "Atrial Fibrillation: A Review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Symptoms of AF include palpitations, dyspnea, chest pain, presyncope,
        exertional intolerance, and fatigue
      explanation: Supports chest pain as an AF symptom but not a unique causal intermediate.
- name: Fibroblast NLRP3 Inflammasome Activation
  biological_scale: CELLULAR
  description: >-
    NLRP3 inflammasome signaling is increased in atrial fibroblasts from people
    with AF. Fibroblast-restricted activation is sufficient to create a
    profibrotic, conduction-slowing atrial substrate in mice.
  cell_types:
  - preferred_term: Cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  genes:
  - preferred_term: NLRP3
    term:
      id: hgnc:16400
      label: NLRP3
  evidence:
  - reference: PMID:40243956
    reference_title: Fibroblast-Restricted Inflammasome Activation Promotes Atrial Fibrillation and Heart Failure With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NLRP3 was up-regulated in atrial fibroblasts from AF patients.
    explanation: Direct human atrial-fibroblast observation supporting disease relevance.
  - reference: PMID:40243956
    reference_title: Fibroblast-Restricted Inflammasome Activation Promotes Atrial Fibrillation and Heart Failure With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Fibroblast-specific activation of NLRP3 in mice induced AF-promoting
      atrial myopathy and heart failure with diastolic dysfunction, accompanied
      by increased fibrosis, and reduced conduction velocity.
    explanation: The perturbation study supports causal sufficiency in mice, not in humans.
  downstream:
  - target: Atrial Fibrosis
    description: Fibroblast-restricted NLRP3 activation promotes profibrotic atrial remodeling.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40243956
      reference_title: Fibroblast-Restricted Inflammasome Activation Promotes Atrial Fibrillation and Heart Failure With Diastolic Dysfunction.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Knockdown of NLRP3 prevented the AF-promoting atrial substrate and
        cardiomyopathy in the context of NLRP3 activation in fibroblasts.
      explanation: Genetic reversal supports a causal NLRP3-to-substrate link in the mouse model.
- name: Atrial Fibrosis
  biological_scale: TISSUE
  description: >
    Excess atrial extracellular matrix separates cardiomyocyte bundles and
    creates heterogeneous, slowed conduction that favors reentry and AF
    maintenance.
  cell_types:
  - preferred_term: Cardiac Fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  evidence:
  - reference: PMID:40243956
    reference_title: Fibroblast-Restricted Inflammasome Activation Promotes Atrial Fibrillation and Heart Failure With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Fibroblast-specific activation of NLRP3 in mice induced AF-promoting
      atrial myopathy and heart failure with diastolic dysfunction, accompanied
      by increased fibrosis, and reduced conduction velocity.
    explanation: Links increased atrial fibrosis with slowed conduction and an AF-promoting substrate in vivo.
  - reference: PMID:42462800
    reference_title: "Contemporary concepts in the onset and maintenance of atrial fibrillation: Mechanisms, substrates, and clinical implications."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Low-voltage substrate regions are a common feature, and typically
      correlate with underlying fibrotic scar.
    explanation: The most recent review before the cutoff links the electrophysiologic substrate to atrial fibrotic scar.
  downstream:
  - target: Atrial Electrical Remodeling
    description: Fibrotic discontinuity slows and heterogenizes atrial conduction, facilitating reentry.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced atrial conduction velocity
    evidence:
    - reference: PMID:40243956
      reference_title: Fibroblast-Restricted Inflammasome Activation Promotes Atrial Fibrillation and Heart Failure With Diastolic Dysfunction.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Fibroblast-specific activation of NLRP3 in mice induced AF-promoting
        atrial myopathy and heart failure with diastolic dysfunction,
        accompanied by increased fibrosis, and reduced conduction velocity.
      explanation: Directly observes fibrosis and conduction slowing in the same causal model.
- name: Pulmonary Vein Triggers
  description: >
    Ectopic beats originating from pulmonary vein myocardial sleeves
    commonly trigger AF episodes. These foci have distinct electrophysiology.
  locations:
  - preferred_term: Pulmonary vein
    term:
      id: UBERON:0002016
      label: pulmonary vein
  evidence:
  - reference: PMID:9725923
    reference_title: Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three foci were in the right atrium, 1 in the posterior left atrium, and
      65 (94 percent) in the pulmonary veins
    explanation: Mapping of 69 triggering foci in 45 drug-refractory patients localized 94% to pulmonary veins.
  downstream:
  - target: Atrial Fibrillation
    description: Rapid ectopic pulmonary-vein discharges initiate paroxysmal AF.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9725923
      reference_title: Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The pulmonary veins are an important source of ectopic beats, initiating
        frequent paroxysms of atrial fibrillation.
      explanation: The mapped human study directly supports initiation polarity.
- name: Atrial Thrombus Formation
  description: >
    Loss of atrial contraction leads to blood stasis, particularly in
    the left atrial appendage, promoting thrombus formation and embolic stroke.
  evidence:
  - reference: PMID:30571060
    reference_title: Paroxysmal Atrial Fibrillation.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      atrial contractility is lost, causing an inability to completely empty
      blood from the atrial appendage leading to the risk of clot formation and
      subsequent thromboembolic events.
    explanation: Directly supports the direction from ineffective atrial contraction to appendage clot and embolism.
  - reference: PMID:8572814
    reference_title: "Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, 201 of 222 (91%) of nonrheumatic atrial fibrillation-related left atrial thrombi were isolated to, or originated in the left atrial appendage"
    explanation: Systematic review of 23 studies localizes the overwhelming majority of nonrheumatic AF-related left atrial thrombi to the left atrial appendage, supporting appendage stasis as the site of thrombus formation.
  downstream:
  - target: Thromboembolic Stroke
    description: >-
      Atrial thrombus formation creates risk for embolic stroke, which is the
      main target of anticoagulation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - left atrial appendage stasis
    - systemic embolism
    evidence:
    - reference: PMID:30571060
      reference_title: Paroxysmal Atrial Fibrillation.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        atrial contractility is lost, causing an inability to completely empty
        blood from the atrial appendage leading to the risk of clot formation
        and subsequent thromboembolic events.
      explanation: Supports the clot-to-thromboembolism sequence; the separate phenotype evidence establishes stroke as a major AF outcome.
- name: Gut Microbial TMA Production
  biological_scale: MOLECULAR
  description: >
    Gut bacteria transform dietary choline to trimethylamine (TMA) through the
    CutC/D pathway. Iodomethylcholine (IMC) inhibits this microbial
    choline-to-TMA(O) transformation.
  biological_processes:
  - preferred_term: microbial amine biosynthetic process
    term:
      id: GO:0009309
      label: amine biosynthetic process
    modifier: INCREASED
  chemical_entities:
  - preferred_term: choline
    term:
      id: CHEBI:15354
      label: choline
  - preferred_term: trimethylamine
    term:
      id: CHEBI:18139
      label: trimethylamine
    modifier: INCREASED
  evidence:
  - reference: DOI:10.1172/JCI201684
    reference_title: "Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Iodomethylcholine (IMC), the gut microbial CutC/D inhibitor that
      suppresses choline→TMA(O) metabolic transformation, reduced circulating
      TMAO levels ... and choline induced AF onset
    explanation: Directly identifies CutC/D-mediated microbial choline-to-TMA(O) transformation and its inhibition by IMC.
  downstream:
  - target: Elevated Circulating TMAO
    description: >-
      Inhibiting microbial CutC/D lowers circulating TMAO during choline
      supplementation, linking microbial TMA generation to systemic TMAO
      exposure without separately asserting an uncited hepatic step.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - host conversion of absorbed trimethylamine to trimethylamine N-oxide
    hypothesis_groups: [tmao_autonomic_af]
    evidence:
    - reference: DOI:10.1172/JCI201684
      reference_title: "Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Iodomethylcholine (IMC), the gut microbial CutC/D inhibitor that
        suppresses choline→TMA(O) metabolic transformation, reduced circulating
        TMAO levels ... and choline induced AF onset
      explanation: Pharmacologic upstream inhibition links microbial metabolism to circulating TMAO in the mouse experiment.
- name: Elevated Circulating TMAO
  biological_scale: ORGANISM
  description: >
    Raised systemic plasma TMAO is the exposure that independently associates
    with prevalent AF in humans and predicts earlier AF onset/persistence in
    mouse models; the CutC/D inhibitor IMC lowers it and delays AF.
  chemical_entities:
  - preferred_term: trimethylamine N-oxide
    term:
      id: CHEBI:15724
      label: trimethylamine N-oxide
    modifier: INCREASED
  evidence:
  - reference: DOI:10.1172/JCI201684
    reference_title: "Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TMAO levels were quantified in plasma from serial subjects undergoing elective cardiac catheterizations (N=5090) and shown to independently associate with prevalent AF following adjustment for risk factors (TMAO adjusted odds ratio 1.7 [95% confidence interval 1.3-2.1]"
    explanation: Plasma TMAO independently associates with prevalent AF in a 5,090-subject clinical cohort (adjusted OR 1.7).
  - reference: DOI:10.1172/JCI201684
    reference_title: "Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Human cAMP response element modulator isoform IbΔC-X transgenic mice (CREM-IbΔC-X), a spontaneous mouse model of AF, supplemented with a TMAO diet developed AF sooner."
    explanation: Direct dietary TMAO accelerates spontaneous AF onset in a transgenic mouse model.
  downstream:
  - target: Muscarinic M2 Receptor Inhibition
    description: >-
      TMAO, structurally similar to acetylcholine, inhibits the cardiac M2
      muscarinic receptor.
    causal_link_type: DIRECT
    hypothesis_groups: [tmao_autonomic_af]
    evidence:
    - reference: DOI:10.1172/JCI201684
      reference_title: "Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "TMAO inhibits muscarinic receptor 2 resulting in autonomic dysfunction that promotes AF."
      explanation: Directly supports the asserted inhibitory polarity; the hypothesis remains emerging.
- name: Muscarinic M2 Receptor Inhibition
  biological_scale: MOLECULAR
  description: >
    TMAO inhibits muscarinic receptor 2 (M2R) signaling.
  genes:
  - preferred_term: CHRM2
    term:
      id: hgnc:1951
      label: CHRM2
  biological_processes:
  - preferred_term: G protein-coupled acetylcholine receptor signaling
    term:
      id: GO:0007213
      label: G protein-coupled acetylcholine receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: DOI:10.1172/JCI201684
    reference_title: "Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TMAO inhibits muscarinic receptor 2 resulting in autonomic dysfunction that promotes AF."
    explanation: The study summary identifies M2R inhibition as the proposed molecular initiator.
  downstream:
  - target: Cardiac Autonomic Dysfunction
    description: M2R inhibition disrupts parasympathetic (vagal) cardiac control.
    causal_link_type: DIRECT
    hypothesis_groups: [tmao_autonomic_af]
    evidence:
    - reference: DOI:10.1172/JCI201684
      reference_title: "Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "TMAO inhibits muscarinic receptor 2 resulting in autonomic dysfunction that promotes AF."
      explanation: The source explicitly links M2R inhibition to autonomic dysfunction.
- name: Cardiac Autonomic Dysfunction
  biological_scale: ORGANISM
  description: >
    M2R inhibition produces autonomic dysfunction in vivo and is proposed to
    promote the electrical substrate for AF.
  notes: >-
    This emerging M2R-inhibition model is directionally counterintuitive relative
    to conventional vagal AF physiology; retain its EMERGING status until the
    causal intermediates and direction of effect are independently replicated.
  evidence:
  - reference: DOI:10.1172/JCI201684
    reference_title: "Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the gut microbial metabolite TMAO, independently associated with AF risk in subjects, enhances AF in multiple AF mouse models via autonomic dysfunction"
    explanation: The study attributes TMAO-enhanced AF across mouse models to autonomic dysfunction.
  downstream:
  - target: Atrial Electrical Remodeling
    description: >-
      The high-TMAO state is associated with slower conduction velocity and
      APD80/wavelength shortening, which may lower the reentry threshold and
      feed electrical remodeling that sustains AF.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [tmao_autonomic_af]
    evidence:
    - reference: DOI:10.1172/JCI201684
      reference_title: "Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Optical mapping studies showed that mice supplemented with choline exhibited reduced conduction velocity, shortened action potential duration at 80% repolarization, and decreased wavelength."
      explanation: Optical mapping links the high-TMAO state to APD80 and wavelength shortening, the reentry substrate.
phenotypes:
- name: Palpitations
  category: Cardiovascular
  phenotype_term:
    preferred_term: Palpitations
    term:
      id: HP:0001962
      label: Palpitations
  evidence:
  - reference: PMID:35873859
    reference_title: "Dyspnea in patients with atrial fibrillation: Mechanisms, assessment and an interdisciplinary and integrated care approach."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Palpitations are the cardinal symptom of AF and many AF therapies are targeted towards relieving this symptom."
    explanation: Confirms that palpitations are the primary symptom of atrial fibrillation.
- name: Atrial Fibrillation
  category: Cardiovascular
  diagnostic: true
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:9725923
    reference_title: Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pulmonary veins are an important source of ectopic beats, initiating
      frequent paroxysms of atrial fibrillation.
    explanation: Directly documents electrocardiographically mapped AF episodes rather than a broader arrhythmia surrogate.
- name: Fatigue
  category: Systemic
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:26318825
    reference_title: "Fatigue, dyspnea, and intermittent symptoms are associated with treatment-seeking delay for symptoms of atrial fibrillation before diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Experiencing fatigue, dyspnea and intermittent symptoms produced symptom representations and emotional and behavioral responses associated with treatment-seeking delay."
    explanation: Confirms fatigue is a common symptom in atrial fibrillation that affects patient behavior.
- name: Dyspnea
  category: Respiratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:35873859
    reference_title: "Dyspnea in patients with atrial fibrillation: Mechanisms, assessment and an interdisciplinary and integrated care approach."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "up to two-third of patients also complain of dyspnea as a predominant self-reported symptom."
    explanation: Confirms dyspnea is a common and predominant symptom in atrial fibrillation patients.
- name: Exercise Intolerance
  category: Cardiovascular
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:39680399
    reference_title: "Atrial Fibrillation: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Symptoms of AF include palpitations, dyspnea, chest pain, presyncope,
      exertional intolerance, and fatigue
    explanation: Directly identifies exertional intolerance as an AF symptom without asserting a frequency.
- name: Chest Pain
  category: Cardiovascular
  phenotype_term:
    preferred_term: Chest pain
    term:
      id: HP:0100749
      label: Chest pain
  evidence:
  - reference: PMID:39680399
    reference_title: "Atrial Fibrillation: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Symptoms of AF include palpitations, dyspnea, chest pain, presyncope,
      exertional intolerance, and fatigue
    explanation: Directly lists chest pain among AF symptoms; no frequency is inferred.
- name: Thromboembolic Stroke
  category: Neurological
  severity: SEVERE
  notes: Major complication due to atrial thromboembolism; no universal frequency is asserted.
  phenotype_term:
    preferred_term: Thromboembolic stroke
    term:
      id: HP:0001727
      label: Thromboembolic stroke
  evidence:
  - reference: PMID:39680399
    reference_title: "Atrial Fibrillation: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      AF is associated with significantly increased risk of stroke, heart
      failure, myocardial infarction, dementia, chronic kidney disease, and mortality.
    explanation: Directly establishes stroke as a major AF complication; the pathograph uses the more specific thromboembolic-stroke HPO term.
genetic:
- name: PITX2
  gene_term:
    preferred_term: PITX2
    term:
      id: hgnc:9005
      label: PITX2
  association: Common-variant susceptibility locus
  relationship_type: SUSCEPTIBILITY
  notes: >-
    Major reproducible GWAS locus. The association is not sufficient to infer a
    single PITX2-to-AF causal path, so it is intentionally not wired to a
    pathophysiology node. The experimental-model section separately records
    obesity/NOX2-associated PITX2 upregulation in mice, human atrial tissue, and
    palmitate-treated hiPSC atrial cardiomyocytes; that cross-system observation
    does not establish a common-variant causal edge.
  evidence:
  - reference: PMID:40645996
    reference_title: "Cross-population GWAS and proteomics improve risk prediction and reveal mechanisms in atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two loci of PITX2 and ZFHX3 genes were identified as shared across
      populations of different ancestries.
    explanation: Cross-population meta-analysis directly supports PITX2 as a shared AF susceptibility locus.
- name: ZFHX3
  gene_term:
    preferred_term: ZFHX3
    term:
      id: hgnc:777
      label: ZFHX3
  association: Common-variant susceptibility locus
  relationship_type: SUSCEPTIBILITY
  notes: >-
    Reproducible GWAS locus; retained as susceptibility rather than Mendelian
    causation and not assigned an unsupported mechanistic edge.
  evidence:
  - reference: PMID:40645996
    reference_title: "Cross-population GWAS and proteomics improve risk prediction and reveal mechanisms in atrial fibrillation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two loci of PITX2 and ZFHX3 genes were identified as shared across
      populations of different ancestries.
    explanation: Cross-population meta-analysis directly supports ZFHX3 as a shared AF susceptibility locus.
environmental:
- name: Hypertension
  influences_mechanisms:
  - target: Atrial Fibrosis
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Chronic pressure load stretches the atrium, and that stretch drives the
      fibrotic remodelling that creates the reentrant substrate. Hypertension
      is the commonest condition in patients presenting with new atrial
      fibrillation.
    evidence:
    - reference: PMID:27057292
      reference_title: "Atrial Fibrillation and Hypertension: Mechanistic, Epidemiologic, and Treatment Parallels."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Of all the risk factors, HTN is the most commonly encountered condition in patients with incident AF."
      explanation: >-
        Identifies hypertension as the most commonly encountered condition in
        patients with incident atrial fibrillation, the leading contributor to
        the substrate.
  notes: Major modifiable population risk factor.
  evidence:
  - reference: PMID:27057292
    reference_title: "Atrial Fibrillation and Hypertension: Mechanistic, Epidemiologic, and Treatment Parallels."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Of all the risk factors, HTN is the most commonly encountered condition in patients with incident AF."
    explanation: Review confirms hypertension is the most common risk factor for atrial fibrillation.
  - reference: PMID:38984719
    reference_title: "Global burden of atrial fibrillation/atrial flutter and its attributable risk factors from 1990 to 2021."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      High systolic blood pressure emerged as the leading contributor to
      age-standardized AF/AFL incidence, prevalence, death, and DALY rate
      globally among all potential risk factors, followed closely by high body mass index.
    explanation: GBD modeling supports blood pressure as the leading attributable AF/AFL risk factor.
- name: Obesity
  influences_mechanisms:
  - target: NOX2-Dependent Atrial Oxidative Stress
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Targets the oxidative stress node specifically rather than the generic
      substrate, because the cited work shows NOX2 inhibition normalising
      atrial action potential duration and abolishing obesity-driven ion
      channel remodelling, placing NOX2 on the causal path.
    evidence:
    - reference: PMID:39146015
      reference_title: "Modulation of NOX2 causes obesity-mediated atrial fibrillation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We showed that NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden."
      explanation: >-
        NOX2 inhibition normalized atrial action potential duration and
        abrogated obesity-mediated ion channel remodeling. Support is PARTIAL
        because the demonstration is experimental animal work.
  notes: Associated with atrial remodeling
  evidence:
  - reference: PMID:39146015
    reference_title: "Modulation of NOX2 causes obesity-mediated atrial fibrillation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Obesity is linked to an increased risk of atrial fibrillation (AF) via increased oxidative stress."
    explanation: The study background supports the epidemiologic risk assertion; the separate perturbation evidence below supports mechanism in models.
  - reference: PMID:39146015
    reference_title: "Modulation of NOX2 causes obesity-mediated atrial fibrillation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We showed that NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden."
    explanation: Demonstrates that obesity causes atrial remodeling that can be reversed by targeting the underlying oxidative stress pathway.
- name: Obstructive Sleep Apnea
  influences_mechanisms:
  - target: Cardiac Autonomic Dysfunction
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Apnoeic episodes produce repeated intrathoracic pressure swings,
      hypoxaemia and surges of autonomic tone, which is why this targets the
      autonomic node rather than the fibrotic substrate.
    evidence:
    - reference: PMID:29657903
      reference_title: "Obstructive Sleep Apnea as a Risk Factor for Atrial Fibrillation: A Meta-Analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "OSA/SDB is strongly associated with AFib confirming the notion that OSA/SDB populations are high risk for development of AF."
      explanation: >-
        Reports a strong association between sleep-disordered breathing and
        atrial fibrillation, identifying these populations as high risk for
        its development.
  notes: Associated with increased AF risk; the direction and effect of treatment vary by context.
  evidence:
  - reference: PMID:29657903
    reference_title: "Obstructive Sleep Apnea as a Risk Factor for Atrial Fibrillation: A Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "OSA/SDB is strongly associated with AFib confirming the notion that OSA/SDB populations are high risk for development of AF."
    explanation: Meta-analysis of 9 studies with 19,837 participants confirms OSA as a significant risk factor for AF development.
- name: Tobacco Smoking
  exposure_term:
    preferred_term: exposure to tobacco smoking
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  influences_mechanisms:
  - target: Atrial Fibrosis
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Smoking appears among the established risk factors in cohort modelling
      but without an identified atrial mechanism, so it is recorded as
      predisposing to the fibrotic substrate rather than driving it.
    evidence:
    - reference: PMID:39680399
      reference_title: "Atrial Fibrillation: A Review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Older age, current smoking, taller height, greater weight, higher blood pressure (systolic, diastolic, and hypertension treatment), presence of diabetes, and presence of heart disease (HF or myocardial infarction) are associated with higher rates of AF."
      explanation: >-
        Lists current smoking among the factors associated with atrial
        fibrillation risk in a cohort risk model, an association without a
        specified mechanism.
  notes: Modifiable AF susceptibility factor; not a universal or sufficient cause.
  evidence:
  - reference: PMID:39680399
    reference_title: "Atrial Fibrillation: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Older age, current smoking, taller height, greater weight, higher blood
      pressure (systolic, diastolic, and hypertension treatment), presence of
      diabetes, and presence of heart disease (HF or myocardial infarction) are
      associated with higher rates of AF.
    explanation: Directly supports an association of current smoking with higher AF rates.
- name: Alcohol Exposure
  exposure_term:
    preferred_term: exposure to alcohol consumption
    term:
      id: ECTO:0001082
      label: exposure to alcohol consumption
  influences_mechanisms:
  - target: Atrial Electrical Remodeling
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Alcohol shortens atrial refractoriness and slows conduction, and the
      association is dose-defined above roughly one standard drink per day,
      which is why this targets electrical rather than structural remodelling.
    evidence:
    - reference: PMID:39680399
      reference_title: "Atrial Fibrillation: A Review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Additional factors associated with increased AF risk include more than moderate alcohol use (defined as >1 standard alcoholic drink per day or binge drinking), sleep apnea, and hyperthyroidism."
      explanation: >-
        Identifies more than moderate alcohol use, above one standard drink
        per day, as associated with increased atrial fibrillation risk.
  notes: Risk is associated particularly with more-than-moderate or binge exposure.
  evidence:
  - reference: PMID:39680399
    reference_title: "Atrial Fibrillation: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additional factors associated with increased AF risk include more than
      moderate alcohol use (defined as >1 standard alcoholic drink per day or
      binge drinking), sleep apnea, and hyperthyroidism.
    explanation: Directly supports dose-contextualized alcohol exposure as an AF risk factor.
- name: Hyperthyroidism
  influences_mechanisms:
  - target: Atrial Electrical Remodeling
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Excess thyroid hormone shortens the atrial action potential and raises
      automaticity, a reversible electrical effect: restoring euthyroidism
      often restores sinus rhythm, which distinguishes it from the structural
      risk factors here.
    evidence:
    - reference: PMID:39680399
      reference_title: "Atrial Fibrillation: A Review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Additional factors associated with increased AF risk include more than moderate alcohol use (defined as >1 standard alcoholic drink per day or binge drinking), sleep apnea, and hyperthyroidism."
      explanation: >-
        Lists hyperthyroidism among the factors associated with increased
        atrial fibrillation risk.
  notes: Clinically important secondary and potentially reversible AF-associated condition.
  evidence:
  - reference: PMID:39680399
    reference_title: "Atrial Fibrillation: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additional factors associated with increased AF risk include more than
      moderate alcohol use (defined as >1 standard alcoholic drink per day or
      binge drinking), sleep apnea, and hyperthyroidism.
    explanation: Directly supports hyperthyroidism as an associated AF risk factor.
biochemical:
- name: NT-proBNP as an incident-AF risk biomarker
  presence: Elevated
  specificity: Low for AF; prognostic/predictive rather than diagnostic
  notes: >-
    NT-proBNP reflects myocardial stress and predicts incident AF, but elevation
    is not AF-specific and its prospective utility for targeted screening is not
    yet established.
  evidence:
  - reference: PMID:36610061
    reference_title: Exploring the incremental utility of circulating biomarkers for robust risk prediction of incident atrial fibrillation in European cohorts using regressions and modern machine learning methods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NT-proBNP was the strongest circulating predictor of incident AF [hazard
      ratio (HR) per standard deviation (SD), 1.93 (95% CI, 1.82-2.04); P < 0.001].
    explanation: Directly supports predictive association in 42,280 pooled European cohort participants.
- name: Multimarker adverse-outcome panel in established AF
  presence: Measured in plasma
  specificity: Prognostic panel; not a diagnostic signature
  notes: >-
    D-dimer, GDF-15, IL-6, NT-proBNP, and hs-troponin T improve risk prediction
    for several adverse outcomes, but do not establish a single causal AF
    mechanism or replace validated clinical assessment.
  evidence:
  - reference: PMID:40744929
    reference_title: Biomarker panels for improved risk prediction and enhanced biological insights in patients with atrial fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identify 5 biomarkers including D-dimer, growth differentiation factor
      15 (GDF-15), interleukin-6 (IL-6), N-terminal pro-B-type natriuretic
      peptide (NT-proBNP), and high-sensitivity troponin T (hsTropT) that
      independently predict cardiovascular death, stroke, myocardial infarction,
      and systemic embolism
    explanation: Directly reports outcome prediction in 3,817 patients with AF.
diagnosis:
- name: Clinician-interpreted electrocardiography
  description: >-
    A 12-lead ECG or other clinician-reviewed rhythm tracing establishes AF by
    documenting the characteristic atrial rhythm. Longer ambulatory monitoring
    may be required when episodes are intermittent; device alerts require
    confirmatory review.
  diagnosis_term:
    preferred_term: Electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  results: Electrocardiographic tracing consistent with atrial fibrillation.
  evidence:
  - reference: PMID:39674741
    reference_title: Analysis of The 2024 ESC/EACTS Guidelines For The Management Of Atrial Fibrillation.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For diagnosis, electrocardiographic confirmation of clinical AF is
      essential, followed by risk stratification using the CHA₂DS₂-VASc score
      to guide anticoagulation therapy.
    explanation: Directly supports the diagnostic role of an electrocardiographic tracing.
  - reference: PMID:10549907
    reference_title: Electrocardiographic differentiation of atrial flutter from atrial fibrillation by physicians.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study was to determine the ability of physicians to
      differentiate atrial flutter from atrial fibrillation on a surface
      electrocardiogram (ECG).
    explanation: Directly supports clinician interpretation of a surface ECG and the need to distinguish AF from flutter.
- name: Non-invasive systematic AF screening
  description: >-
    Pulse, handheld ECG, patch, or wearable strategies can increase detection of
    previously unrecognized AF, but trial evidence has not shown reduced adverse
    outcomes; screening is therefore distinct from diagnosis and treatment.
  evidence:
  - reference: PMID:40276326
    reference_title: "Systematic screening for atrial fibrillation with non-invasive devices: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Systematic screening for AF using non-invasive devices is associated with
      increased diagnosis of AF, but not reduced adverse clinical events.
    explanation: Meta-analysis distinguishes higher diagnostic yield from unproven clinical-outcome benefit.
- name: Initial structural and secondary-cause evaluation
  description: >-
    After AF is confirmed, transthoracic echocardiography evaluates cardiac
    structure and ventricular function; complete blood count, metabolic panel,
    and thyroid testing assess clinically relevant associated conditions.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  results: Cardiac structure/function and laboratory contributors documented for management.
  evidence:
  - reference: PMID:39680399
    reference_title: "Atrial Fibrillation: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Evaluation of patients with newly identified AF should include
      transthoracic echocardiogram to assess cardiac structure and to identify
      possible causes for AF (eg, valve disease)4or outcomes associated with AF
      (eg, reduced ventricular function). Basic laboratory testing, including
      complete blood count, metabolic panel, and thyroid function, is
      appropriate.4Additional testing
    explanation: Directly supports the initial structural and laboratory evaluation.
differential_diagnoses:
- name: Atrial Flutter
  disease_term:
    preferred_term: atrial flutter
    term:
      id: MONDO:0005310
      label: atrial flutter
  description: >-
    A macroreentrant atrial arrhythmia that may have a regular or variably
    conducted ventricular response and can be mistaken for AF on a surface ECG.
  distinguishing_features:
  - Organized flutter-wave activity and a repeating atrial cycle favor flutter.
  - Prominent atrial activity can make AF appear flutter-like; review multiple leads and longer recordings.
  evidence:
  - reference: PMID:10549907
    reference_title: Electrocardiographic differentiation of atrial flutter from atrial fibrillation by physicians.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, atrial fibrillation is frequently misdiagnosed as atrial
      flutter. Misdiagnosis of atrial fibrillation occurs more often when atrial
      activity is prominent on an ECG in more than one lead.
    explanation: Directly demonstrates clinically important ECG overlap and misclassification.
- name: Multifocal Atrial Tachycardia
  disease_term:
    preferred_term: multifocal atrial tachycardia
    term:
      id: MONDO:0017988
      label: multifocal atrial tachycardia
  description: >-
    An irregular atrial tachyarrhythmia, often in severe cardiopulmonary illness,
    that can mimic AF.
  distinguishing_features:
  - At least three different nonsinus P-wave morphologies in one lead.
  - Atrial rate above 100 beats/min with an isoelectric baseline between P waves.
  evidence:
  - reference: PMID:8040593
    reference_title: "Recognition and treatment of multifocal atrial tachycardia: a critical review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diagnostic criteria include the presence of at least three different,
      nonsinus P waves in the same lead; an atrial rate greater than 100 beats
      per minute; and an isoelectric baseline between P waves. MAT is often
      difficult to differentiate from atrial fibrillation.
    explanation: Provides explicit distinguishing ECG criteria and states the AF differential.
treatments:
- name: Anticoagulation
  action_category: THERAPEUTIC
  description: >-
    Warfarin or a direct oral anticoagulant (DOAC) is used to prevent stroke
    according to thromboembolic risk. DOAC preference applies only in patients
    without mechanical heart valves or moderate-to-severe mitral stenosis.
  notes: >-
    Contemporary guidelines no longer classify AF itself as valvular versus
    nonvalvular; that distinction is retained only to guide anticoagulant
    selection. It is therefore represented here as a treatment caveat rather
    than as an AF subtype.
  target_phenotypes:
  - preferred_term: Thromboembolic stroke
    term:
      id: HP:0001727
      label: Thromboembolic stroke
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: warfarin
      term:
        id: CHEBI:10033
        label: warfarin
    - preferred_term: apixaban
      term:
        id: CHEBI:72296
        label: apixaban
    - preferred_term: rivaroxaban
      term:
        id: CHEBI:68579
        label: rivaroxaban
    - preferred_term: dabigatran
      term:
        id: CHEBI:70752
        label: dabigatran
  evidence:
  - reference: PMID:37573616
    reference_title: "Systematic Review and Meta-Analysis of Direct Oral Anticoagulants Versus Warfarin in Atrial Fibrillation With Low Stroke Risk."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DOAC was associated with a significantly lower risk of stroke or systemic embolism (hazard ratio 0.85, 95% confidence interval 0.75 to 0.96, p = 0.008, I2 = 0%), major bleeding, intracranial hemorrhage, and mortality compared with warfarin."
    explanation: Meta-analysis of 132,980 patients demonstrates DOACs reduce stroke risk in AF patients.
  - reference: PMID:40526576
    reference_title: "Clinical Practice Guideline: Preventive Measures and Treatment Options for Atrial Fibrillation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "If it is 2 or higher, oral anticoagulation (OAC) is indicated, of a type that should be decided on an individual basis."
    explanation: The guideline indicates oral anticoagulation for AF patients with a CHA2DS2-VA score of 2 or higher.
  - reference: PMID:39680399
    reference_title: "Atrial Fibrillation: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In patients without mechanical heart valves or moderate to severe mitral
      stenosis, DOACs are preferred because they are associated with less
      bleeding than warfarin.
    explanation: Directly supplies the mechanical-valve and mitral-stenosis boundary on DOAC preference.
  - reference: PMID:39680399
    reference_title: "Atrial Fibrillation: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: AF is no longer categorized according to valvular or nonvalvular AF.
    explanation: Directly supports not retaining valvular AF as a contemporary subtype.
  - reference: PMID:39680399
    reference_title: "Atrial Fibrillation: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: This distinction is only currently used to guide OAC strategy.
    explanation: Supports retaining valvular status specifically as an anticoagulation modifier.
- name: Rate Control
  action_category: THERAPEUTIC
  description: Beta blockers, calcium channel blockers, or digoxin.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: metoprolol
      term:
        id: CHEBI:6904
        label: metoprolol
    - preferred_term: diltiazem
      term:
        id: CHEBI:101278
        label: diltiazem
    - preferred_term: digoxin
      term:
        id: CHEBI:4551
        label: digoxin
  evidence:
  - reference: PMID:39604644
    reference_title: "European Society of Cardiology (ESC) guidelines on atrial fibrillation 2024: What is new and what is important?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For rate or rhythm control pharmacotherapy with beta-blockers, digitalis,
      amiodarone and flecainide are still the most important drugs.
    explanation: Current guideline summary directly supports beta-blocker/digitalis rate control and antiarrhythmic rhythm control.
- name: Rhythm Control
  action_category: THERAPEUTIC
  description: Antiarrhythmic drugs (amiodarone, flecainide, sotalol).
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: amiodarone
      term:
        id: CHEBI:2663
        label: amiodarone
    - preferred_term: flecainide
      term:
        id: CHEBI:75984
        label: flecainide
    - preferred_term: sotalol
      term:
        id: CHEBI:63622
        label: sotalol
  evidence:
  - reference: PMID:40526576
    reference_title: "Clinical Practice Guideline: Preventive Measures and Treatment Options for Atrial Fibrillation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In patients with cardiovascular risk factors, early rhythm control has been shown to reduce prognostically relevant cardio - vascular endpoints (3.9 versus 5.0 per 100 patientyears)."
    explanation: Guideline evidence that early rhythm control reduces cardiovascular endpoints in AF patients with cardiovascular risk factors.
- name: Catheter Ablation
  action_category: THERAPEUTIC
  description: Pulmonary vein isolation for rhythm control.
  target_mechanisms:
  - target: Pulmonary Vein Triggers
    treatment_effect: INHIBITS
    description: Pulmonary-vein isolation blocks trigger conduction into the atria.
    evidence:
    - reference: PMID:9725923
      reference_title: Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A local depolarization could also be recognized during sinus rhythm and
        abolished by radiofrequency ablation.
      explanation: Directly supports ablation of the mapped pulmonary-vein trigger activity.
  treatment_term:
    preferred_term: Ablation Therapy
    term:
      id: NCIT:C20985
      label: Ablation Therapy
  evidence:
  - reference: PMID:40526576
    reference_title: "Clinical Practice Guideline: Preventive Measures and Treatment Options for Atrial Fibrillation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Multiple studies have shown that catheter ablation is superior to drug-based antiarrhythmic therapy in patients with paroxysmal symptomatic AF as well as in those with heart failure and AF."
    explanation: The guideline notes catheter ablation is superior to antiarrhythmic drug therapy for paroxysmal symptomatic AF and for AF with heart failure.
- name: Cardioversion
  action_category: THERAPEUTIC
  description: Electrical or pharmacological restoration of sinus rhythm.
  treatment_term:
    preferred_term: Cardioversion
    term:
      id: NCIT:C70911
      label: Cardioversion
  evidence:
  - reference: PMID:39716733
    reference_title: "Spotlight on the 2024 ESC/EACTS management of atrial fibrillation guidelines: 10 novel key aspects."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The AF duration threshold for early cardioversion was reduced from 48 to
      24 h, and a wait-and-see approach for spontaneous conversion is advised
      to promote patient safety.
    explanation: Supports cardioversion as a guideline-managed rhythm-restoration strategy and its timing nuance.
- name: Left Atrial Appendage Closure
  action_category: THERAPEUTIC
  description: Alternative to anticoagulation in selected patients.
  target_mechanisms:
  - target: Atrial Thrombus Formation
    treatment_effect: INHIBITS
    description: Excludes the appendage, the predominant site of AF-related left-atrial thrombi.
    evidence:
    - reference: PMID:8572814
      reference_title: Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        201 of 222 (91%) of nonrheumatic atrial fibrillation-related left atrial
        thrombi were isolated to, or originated in the left atrial appendage
      explanation: Directly supports the anatomical mechanism targeted by appendage exclusion.
  evidence:
  - reference: PMID:41040442
    reference_title: 2025 SCAI/HRS Clinical Practice Guidelines on Transcatheter Left Atrial Appendage Occlusion.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Left atrial appendage occlusion (LAAO) devices reduce the risk of atrial
      fibrillation-associated stroke relative to no oral anticoagulation.
    explanation: Current evidence-based guideline supports stroke-risk reduction while noting selection uncertainty.
- name: Risk Factor Modification
  action_category: THERAPEUTIC
  description: Weight loss, blood pressure control, sleep apnea treatment.
  evidence:
  - reference: PMID:40526576
    reference_title: "Clinical Practice Guideline: Preventive Measures and Treatment Options for Atrial Fibrillation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Lifestyle interventions and the reduction of risk factors lessen the frequency of AF."
    explanation: Guideline evidence that lifestyle intervention and risk-factor reduction lower AF frequency.
- name: Gut Microbial TMA-Lyase Inhibition (Iodomethylcholine)
  action_category: THERAPEUTIC
  description: >
    Iodomethylcholine (IMC), a gut-restricted CutC/D choline-TMA lyase inhibitor,
    suppresses microbial choline-to-TMA(O) transformation, reduces circulating
    TMAO, and delays choline-induced AF onset in mice. It is an investigational
    AF-prevention strategy, not yet a human therapy.
  notes: >-
    No suitable CHEBI or NCIT therapeutic-agent term was identified for
    iodomethylcholine; retain the named agent in the treatment name pending one.
  target_mechanisms:
  - target: Gut Microbial TMA Production
    treatment_effect: INHIBITS
    description: >-
      IMC inhibits the gut microbial CutC/D choline-TMA lyase, cutting TMA (and
      hence TMAO) production upstream of the autonomic-dysfunction arm.
    evidence:
    - reference: DOI:10.1172/JCI201684
      reference_title: "Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Iodomethylcholine (IMC), the gut microbial CutC/D inhibitor that
        suppresses choline→TMA(O) metabolic transformation, reduced circulating
        TMAO levels ... and choline induced AF onset
      explanation: Directly supports target engagement and the upstream metabolic effect in mice.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: DOI:10.1172/JCI201684
    reference_title: "Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Iodomethylcholine (IMC), the gut microbial CutC/D inhibitor that
      suppresses choline→TMA(O) metabolic transformation, reduced circulating
      TMAO levels ... and choline induced AF onset
    explanation: Directly supports the molecular target, lowered circulating TMAO, and delayed AF onset in mice.
mechanistic_hypotheses:
- hypothesis_group_id: tmao_autonomic_af
  hypothesis_label: Gut microbial TMAO promotes AF via M2 muscarinic receptor autonomic dysfunction
  status: EMERGING
  description: >
    Gut-microbiome-derived TMAO promotes AF onset and persistence, at least in
    part by inhibiting the cardiac M2 muscarinic receptor (TMAO mimics
    acetylcholine), producing autonomic dysfunction with atrial APD/wavelength
    shortening. Supported by a human association (adjusted OR 1.7), two mouse AF
    models, and pharmacologic reversal with the gut-restricted CutC/D inhibitor
    IMC.
  evidence:
  - reference: DOI:10.1172/JCI201684
    reference_title: "Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TMAO levels were quantified in plasma from serial subjects undergoing
      elective cardiac catheterizations (N=5090) and shown to independently
      associate with prevalent AF following adjustment for risk factors (TMAO
      adjusted odds ratio 1.7 [95% confidence interval 1.3-2.1]
    explanation: Supports human association only; it does not prove the proposed causal chain.
  - reference: DOI:10.1172/JCI201684
    reference_title: "Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the gut microbial metabolite TMAO, independently associated with AF risk
      in subjects, enhances AF in multiple AF mouse models via autonomic dysfunction
    explanation: Supports the model-organism mechanism while preserving EMERGING status.
experimental_models:
- name: Palmitate-treated human iPSC-derived atrial cardiomyocytes
  description: >-
    Human iPSC-derived atrial cardiomyocytes exposed to palmitate model the
    obesity-associated NOX2 oxidative-stress and ion-channel-remodeling axis.
    The reductionist system lacks multicellular atrial structure, autonomic
    input, and thromboembolic physiology.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Atrial cardiomyocyte
    term:
      id: CL:0002129
      label: regular atrial cardiac myocyte
  conditions:
  - Palmitate exposure
  culture_system: Two-dimensional human iPSC-derived atrial cardiomyocyte culture
  modeled_mechanisms:
  - target: Atrial Electrical Remodeling
    description: Assays obesity-associated NOX2-dependent atrial ion-channel remodeling.
  evidence:
  - reference: PMID:39146015
    reference_title: Modulation of NOX2 causes obesity-mediated atrial fibrillation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Unbiased transcriptomics analysis revealed that NOX2 mediates atrial
      remodeling in obesity-mediated AF in DIO mice, PA-treated hiPSC-aCMs, and
      human atrial tissue from obese individuals
    explanation: Directly identifies the palmitate-treated hiPSC atrial-cardiomyocyte model and cross-system comparison.
animal_models:
- species: Goat (Capra hircus)
  category: Chronic rapid-atrial-pacing model
  description: >-
    Awake chronically instrumented goats were maintained in AF to measure
    time-dependent shortening of fibrillation interval and increased AF
    inducibility, establishing tachycardia-induced electrical remodeling.
  associated_phenotypes:
  - Atrial Fibrillation
  evidence:
  - reference: PMID:7671380
    reference_title: "Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      During the first 24 hours of AF the median fibrillation interval shortened
      from 145 +/- 18 to 108 +/- 8 ms and the inducibility of AF by a single
      premature stimulus increased from 24% to 76%.
    explanation: Defines the model and its core electrophysiologic outputs.
- species: Mouse (Mus musculus)
  genotype: Fibroblast-specific NLRP3 activation with knockdown rescue
  category: Conditional inflammatory atrial-cardiomyopathy model
  genes:
  - preferred_term: NLRP3
    term:
      id: hgnc:16400
      label: NLRP3
  description: >-
    Fibroblast-restricted NLRP3 activation models inflammatory atrial fibrosis,
    conduction slowing, and AF susceptibility; NLRP3 knockdown provides a causal
    rescue arm.
  associated_phenotypes:
  - Atrial Fibrillation
  evidence:
  - reference: PMID:40243956
    reference_title: Fibroblast-Restricted Inflammasome Activation Promotes Atrial Fibrillation and Heart Failure With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Fibroblast-specific activation of NLRP3 in mice induced AF-promoting
      atrial myopathy and heart failure with diastolic dysfunction, accompanied
      by increased fibrosis, and reduced conduction velocity.
    explanation: Directly reports the modeled AF substrate and phenotypes.
- species: Mouse (Mus musculus)
  genotype: Human CREM-IbΔC-X transgenic
  category: Spontaneous-AF dietary-metabolite model
  description: >-
    A spontaneous-AF transgenic model used to test dietary TMAO acceleration and
    upstream microbial CutC/D inhibition. This is an emerging mechanism model,
    not evidence of human therapeutic efficacy.
  associated_phenotypes:
  - Atrial Fibrillation
  evidence:
  - reference: DOI:10.1172/JCI201684
    reference_title: "Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Human cAMP response element modulator isoform IbΔC-X transgenic mice
      (CREM-IbΔC-X), a spontaneous mouse model of AF, supplemented with a TMAO
      diet developed AF sooner.
    explanation: Directly describes the model and TMAO-dependent acceleration of AF onset.
computational_models:
- name: Courtemanche-Ramirez-Nattel human atrial action-potential model
  description: >-
    Ionic-current kinetic model of the human atrial cardiomyocyte action
    potential used to examine rate adaptation and ion-current contributions to
    AF susceptibility. It models cellular electrophysiology, not whole-patient
    natural history or treatment outcomes.
  model_type: KINETIC
  model_id: Courtemanche-1998-human-atrial-AP
  publication: PMID:9688927
  modeled_mechanisms:
  - target: Atrial Electrical Remodeling
    description: Models rate-dependent atrial action-potential adaptation and its ionic-current determinants.
    evidence:
    - reference: PMID:9688927
      reference_title: "Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Rate-dependent adaptation of AP duration, an important determinant of
        susceptibility to atrial fibrillation, was attributable to incomplete
        L-type Ca2+ current recovery from inactivation and incomplete delayed
        rectifier current deactivation at rapid rates.
      explanation: Directly maps the computational model to the electrical-remodeling node.
  evidence:
  - reference: PMID:9688927
    reference_title: "Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Rate-dependent adaptation of AP duration, an important determinant of
      susceptibility to atrial fibrillation, was attributable to incomplete
      L-type Ca2+ current recovery from inactivation and incomplete delayed
      rectifier current deactivation at rapid rates.
    explanation: Directly states the modeled property and mechanistic inference.
clinical_trials:
- name: NCT01288352
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    EAST-AFNET 4 randomized 2,789 patients with recently diagnosed AF and
    cardiovascular conditions to early rhythm control or usual care. Early
    rhythm control reduced the primary cardiovascular composite, while serious
    rhythm-control-related adverse events were more frequent.
  target_phenotypes:
  - preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: clinicaltrials:NCT01288352
    reference_title: Early Therapy of Atrial Fibrillation for Stroke Prevention Trial (EAST).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      EAST prospectively tests the hypothesis that an early, structured rhythm
      control therapy based on antiarrhythmic drugs and catheter ablation can
      prevent atrial fibrillation (AF) related complications in patients with AF
      when compared to usual care.
    explanation: Registry text establishes the trial question and randomized strategies.
  - reference: PMID:32865375
    reference_title: Early Rhythm-Control Therapy in Patients with Atrial Fibrillation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A first-primary-outcome event occurred in 249 of the patients assigned to
      early rhythm control (3.9 per 100 person-years) and in 316 patients assigned
      to usual care (5.0 per 100 person-years) (hazard ratio, 0.79; 96% confidence
      interval, 0.66 to 0.94; P = 0.005).
    explanation: Supplies the principal randomized outcome without implying all AF populations share the effect.
- name: NCT00911508
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    CABANA randomized 2,204 symptomatic patients to catheter ablation or drug
    therapy. In intention-to-treat analysis ablation did not significantly
    reduce the primary death/disabling-stroke/serious-bleeding/cardiac-arrest
    composite, but reduced AF recurrence and death or cardiovascular hospitalization.
  target_phenotypes:
  - preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: clinicaltrials:NCT00911508
    reference_title: Catheter Ablation vs Anti-arrhythmic Drug Therapy for Atrial Fibrillation Trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The CABANA Trial is designed to test the hypothesis that the treatment
      strategy of left atrial catheter ablation for the purpose of eliminating
      atrial fibrillation (AF) will be superior to current state-of-the-art therapy
    explanation: Registry text establishes the interventional comparison.
  - reference: PMID:30874766
    reference_title: "Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among patients with AF, the strategy of catheter ablation, compared with
      medical therapy, did not significantly reduce the primary composite end
      point of death, disabling stroke, serious bleeding, or cardiac arrest.
    explanation: Preserves the neutral primary intention-to-treat result rather than overstating ablation benefit.
discussions:
- discussion_id: gap_af_mechanism_to_human_therapy
  prompt: >-
    Which experimentally supported AF-promoting mechanisms produce reproducible,
    mechanism-specific benefit in randomized human trials beyond established
    rhythm, rate, anticoagulation, and risk-factor strategies?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Fibroblast NLRP3 Inflammasome Activation
  - pathophysiology#Gut Microbial TMA Production
  rationale: >-
    NLRP3 and TMAO perturbations are compelling in animal models, but neither
    establishes clinical efficacy or a validated human causal treatment path.
  evidence:
  - reference: PMID:41543444
    reference_title: "The clinical pathophysiology of atrial fibrillation: outstanding questions from bedside to bench and back."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The treatment of AF involves multiple potential approaches, all of which
      presently have significant limitations.
    explanation: Current review explicitly identifies the treatment-translation gap.
- discussion_id: gap_af_screening_outcome_benefit
  prompt: >-
    Which target populations, AF-burden thresholds, and downstream treatment
    pathways make systematic AF screening improve stroke or survival outcomes?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - diagnosis#Non-invasive systematic AF screening
  rationale: >-
    Detection yield is reproducibly higher, but randomized screening data have
    not demonstrated fewer strokes, deaths, hospitalizations, or bleeding events.
  evidence:
  - reference: PMID:40276326
    reference_title: "Systematic screening for atrial fibrillation with non-invasive devices: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pooled data from RCTs did not demonstrate an effect of screening on death
      (RR 1.01, 95% CI 0.97-1.05), cardiovascular hospitalisation (1.00, 95% CI
      0.97-1.03), stroke (0.95, 95% CI 0.87-1.04) or bleeding (1.08, 95% CI 0.91-1.29).
    explanation: Directly supports the unresolved clinical-outcome question.
- discussion_id: gap_af_biomarker_clinical_utility
  prompt: >-
    Can NT-proBNP or multimarker panels prospectively improve AF screening or
    outcome-guided management enough to change clinical outcomes?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - biochemical#NT-proBNP as an incident-AF risk biomarker
  rationale: >-
    Current cohorts demonstrate association and incremental prediction, not
    prospective benefit from biomarker-directed action.
  evidence:
  - reference: PMID:36610061
    reference_title: Exploring the incremental utility of circulating biomarkers for robust risk prediction of incident atrial fibrillation in European cohorts using regressions and modern machine learning methods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical benefit of these findings for identifying at-risk individuals
      for targeted AF screening needs to be elucidated and tested prospectively.
    explanation: The study explicitly states the prospective-utility limitation.
- discussion_id: gap_af_evidence_generalizability_and_equity
  prompt: >-
    How should AF evidence and care pathways be adapted and tested across racial,
    ethnic, socioeconomic, disability, insurance, and rural populations that
    remain underrepresented or experience lower access to guideline-directed care?
  kind: KNOWLEDGE_GAP
  status: OPEN
  rationale: >-
    Trial generalizability and unequal access to anticoagulation, ablation, and
    specialty care limit population-wide translation of efficacy evidence.
  evidence:
  - reference: PMID:39680399
    reference_title: "Atrial Fibrillation: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      generalizability of the evidence is limited because many clinical trials
      have not included substantial proportions of participants who were Black
      or Hispanic, and have not examined variation by SDOH.
    explanation: The review explicitly identifies the evidence-generalizability limitation.
review_notes: >-
  Publication-readiness review through 2026-08-05 reconciled this common-AF
  record to MONDO:0004981, moved rare familial channelopathy claims out of scope,
  replaced broad or mismatched HPO mappings with AF-specific terms, removed
  unsupported frequency bands, split human from model evidence, and added
  epidemiology, progression, burden, diagnosis, differentials, biomarkers,
  trials, models, limitations, and prognosis. Valvular AF was not retained as a
  subtype because contemporary guidance no longer uses that disease
  classification; the mechanical-valve and mitral-stenosis distinction is
  captured explicitly under anticoagulation. The full 31-item D2P disposition
  is recorded in the associated REVIEW history event and PR.
datasets:
- accession: geo:GSE227793
  title: H3K27ac and H3K4me3 ChIP-Seq profiling of a human paired left and right atrial cohort of atrial fibrillation and healthy sinus rhythm individuals
  description: H3K27ac and H3K4me3 ChIP-Seq profiling was performed on atrial appendages samples from 12 individuals aged over 60 years, either classified as persistent atrial fibrillation (AF) or normal sinus rhythm (SR). For all individuals, careful examination of medical history displayed no indications of hypertension, hypothyroidism or diabetes.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: CHIP_SEQ
  sample_count: 52
  publication: PMID:41906156
  notes: Identified by GEO DataSets index search for Atrial Fibrillation (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE322635
  title: Humanin and MOTS-c Attenuate Atrial Fibrillation by Suppressing Fibrosis and Mitochondrial Dysfunction in murine models
  description: 'BACKGROUND: Atrial fibrillation (AF) is the most common clinical arrhythmia associated with mitochondrial dysfunction, oxidative stress, and atrial fibrosis. Mitochondrial-derived peptides (MDPs) including humanin (HN) and MOTS-c, demonstrated potent cytoprotective effects, but their role in AF remains elusive. METHODS: Public GEO database, immunohistochemistry and immunofluorescence were applied to determine their expressions in atrial tissues. Plasma peptide levels were measured in a clinical cohort.'
  organism:
    preferred_term: rat
    term:
      id: NCBITaxon:10116
      label: Rattus norvegicus
  data_type: BULK_RNA_SEQ
  sample_count: 12
  publication: PMID:42193373
  notes: Identified by GEO DataSets index search for Atrial Fibrillation (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE295056
  title: Gene-Gene Interactions Between A LMNA Variant and Common Polymorphisms Drive Early-Onset Atrial Fibrillation [ATAC-seq]
  description: Atrial fibrillation (AF) is a common arrhythmia with a complex genetic basis, yet the molecular mechanisms linking rare and common variants remain unclear. Using induced pluripotent stem cell-derived atrial cardiomyocytes, we uncover a novel mechanism by which a rare pathogenic LMNA variant encoding Lamin A/C disrupts chromatin accessibility and gene regulation at AF-associated loci. Specifically, reduced accessibility at an SCN5A enhancer harboring an AF-associated variant leads to reduced sodium current, conduction abnormalities, and re-entrant AF.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: ATAC_SEQ
  sample_count: 9
  publication: PMID:42156780
  notes: Identified by GEO DataSets index search for Atrial Fibrillation (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001003045
  title: Lone atrial fibrillation case-control study
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Atrial Fibrillation"); description-level mentions were not accepted. EGA study_type: Population Genomics. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001003207
  title: Whole exome sequencing of 76 individuals with familial atrial fibrillation
  description: We investigated genetic background of familial and early onset atrial fibrillation (AF) with the aim of identify genes involved in atrial fibrillation pathology and are highly predisposing risk factors. We performed whole exome sequencing on 24 families where three or more family members suffered from AF.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Atrial Fibrillation"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001003208
  title: early onset lone atrial fibrillation case-control study
  description: Target sequencing W/ TruSight Cardio Sequencing Kit. 395 early onset lone AF cases and 375 controls. Sequencing was performed on Illumina NextSeq and HiSeq 2500 systems.395 early.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Atrial Fibrillation"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: metabolomics_workbench:ST001208
  title: Characterization of feces in Atrial Fibrillation (AF) patients
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Atrial Fibrillation"). Retrieved 2026-08-02.
- accession: metabolomics_workbench:ST001168
  title: Alterations in fecal metabolic patterns are associated with atrial fibrillation
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Atrial Fibrillation"). Retrieved 2026-08-02.
- accession: metabolomics_workbench:ST001169
  title: Alterations in serum metabolic patterns are associated with atrial fibrillation
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Atrial Fibrillation"). Retrieved 2026-08-02.
references:
- reference: DOI:10.1038/s41467-024-54296-w
  title: Large-scale single-nuclei profiling identifies role for ATRNL1 in atrial fibrillation
  findings: []
- reference: DOI:10.1038/s41569-022-00759-w
  title: 'Inflammatory signalling in atrial cardiomyocytes: a novel unifying principle in atrial fibrillation pathophysiology'
  findings: []
- reference: DOI:10.1038/s42003-024-07308-w
  title: Left atrial single-cell transcriptomics reveals amphiregulin as a surrogate marker for atrial fibrillation
  findings: []
- reference: DOI:10.1093/cvr/cvad175
  title: An inflammation resolution–promoting intervention prevents atrial fibrillation caused by left ventricular dysfunction
  findings: []
- reference: DOI:10.1093/eurheartj/ehac460
  title: A polygenic risk score predicts atrial fibrillation in cardiovascular disease
  findings: []
- reference: DOI:10.1172/jci175447
  title: Modulation of NOX2 causes obesity-mediated atrial fibrillation
  findings: []
- reference: DOI:10.21037/jtd-23-1981
  title: 'Development of neuromodulation for atrial fibrillation: a narrative review'
  findings: []
- reference: DOI:10.3389/fcvm.2023.1327387
  title: The autonomic nervous system in atrial fibrillation—pathophysiology and non-invasive assessment
  findings: []
- reference: DOI:10.3390/ijms25010535
  title: 'Developing Pharmacological Therapies for Atrial Fibrillation Targeting Mitochondrial Dysfunction and Oxidative Stress: A Scoping Review'
  findings: []
- reference: DOI:10.3390/ijms25020758
  title: Pathophysiology of Atrial Fibrillation and Approach to Therapy in Subjects Less than 60 Years Old
  findings: []
- reference: DOI:10.3390/ijms26135954
  title: 'Inflammasome Signaling in Cardiac Arrhythmias: Linking Inflammation, Fibrosis, and Electrical Remodeling'
  findings: []
- reference: DOI:10.3390/jcm14030882
  title: Exploring Anti-Inflammatory Treatment as Upstream Therapy in the Management of Atrial Fibrillation
  findings: []
- reference: DOI:10.3390/jcm14093250
  title: 'Atrial Cardiomyopathy in Atrial Fibrillation: Mechanistic Pathways and Emerging Treatment Concepts'
  findings: []
- reference: DOI:10.7150/thno.89520
  title: Inactivation of the NLRP3 inflammasome mediates exosome-based prevention of atrial fibrillation
  findings: []
📚

References & Deep Research

References

14
DOI:10.1038/s41467-024-54296-w
Large-scale single-nuclei profiling identifies role for ATRNL1 in atrial fibrillation
No top-level findings curated for this source.
DOI:10.1038/s41569-022-00759-w
Inflammatory signalling in atrial cardiomyocytes: a novel unifying principle in atrial fibrillation pathophysiology
No top-level findings curated for this source.
DOI:10.1038/s42003-024-07308-w
Left atrial single-cell transcriptomics reveals amphiregulin as a surrogate marker for atrial fibrillation
No top-level findings curated for this source.
DOI:10.1093/cvr/cvad175
An inflammation resolution–promoting intervention prevents atrial fibrillation caused by left ventricular dysfunction
No top-level findings curated for this source.
DOI:10.1093/eurheartj/ehac460
A polygenic risk score predicts atrial fibrillation in cardiovascular disease
No top-level findings curated for this source.
DOI:10.1172/jci175447
Modulation of NOX2 causes obesity-mediated atrial fibrillation
No top-level findings curated for this source.
DOI:10.21037/jtd-23-1981
Development of neuromodulation for atrial fibrillation: a narrative review
No top-level findings curated for this source.
DOI:10.3389/fcvm.2023.1327387
The autonomic nervous system in atrial fibrillation—pathophysiology and non-invasive assessment
No top-level findings curated for this source.
DOI:10.3390/ijms25010535
Developing Pharmacological Therapies for Atrial Fibrillation Targeting Mitochondrial Dysfunction and Oxidative Stress: A Scoping Review
No top-level findings curated for this source.
DOI:10.3390/ijms25020758
Pathophysiology of Atrial Fibrillation and Approach to Therapy in Subjects Less than 60 Years Old
No top-level findings curated for this source.
DOI:10.3390/ijms26135954
Inflammasome Signaling in Cardiac Arrhythmias: Linking Inflammation, Fibrosis, and Electrical Remodeling
No top-level findings curated for this source.
DOI:10.3390/jcm14030882
Exploring Anti-Inflammatory Treatment as Upstream Therapy in the Management of Atrial Fibrillation
No top-level findings curated for this source.
DOI:10.3390/jcm14093250
Atrial Cardiomyopathy in Atrial Fibrillation: Mechanistic Pathways and Emerging Treatment Concepts
No top-level findings curated for this source.
DOI:10.7150/thno.89520
Inactivation of the NLRP3 inflammasome mediates exosome-based prevention of atrial fibrillation
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Atrial Fibrillation
  • Category: Complex
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 28

Key Pathophysiology Nodes

  • Atrial Electrical Remodeling
  • Atrial Structural Remodeling
  • Pulmonary Vein Triggers
  • Atrial Thrombus Formation
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1038/s41467-024-54296-w
  • DOI:10.1038/s41569-022-00759-w
  • DOI:10.1038/s42003-024-07308-w
  • DOI:10.1093/cvr/cvad175
  • DOI:10.1093/eurheartj/ehac460
  • DOI:10.1172/jci175447
  • DOI:10.21037/jtd-23-1981
  • DOI:10.3389/fcvm.2023.1327387
  • DOI:10.3390/ijms25010535
  • DOI:10.3390/ijms25020758
  • DOI:10.3390/ijms26135954
  • DOI:10.3390/jcm14030882
  • DOI:10.3390/jcm14093250
  • DOI:10.7150/thno.89520
Falcon ▸
Pathophysiology description
Edison Scientific Literature 26 citations 2025-12-17T18:54:14.960899

Pathophysiology description Atrial fibrillation (AF) emerges from an interplay of electrical remodeling, structural remodeling with atrial fibrosis, calcium-handling defects, innate immune/inflammatory activation (notably the NLRP3 inflammasome), oxidative and mitochondrial stress, autonomic nervous system (ANS) remodeling, and polygenic plus rare genetic susceptibilities that shape cell-type–specific programs in the atria. Recent work places inflammatory signaling within atrial cardiomyocytes at the center of a unifying mechanism: Dobrev and colleagues emphasize that atrial cardiomyocytes possess inflammasome machinery and conclude that “NLRP3 inflammasome activation in atrial cardiomyocytes might be a sufficient and necessary condition for AF occurrence,” reframing AF as, at least in part, an inflammation-driven cardiomyopathy of the atria (atrial cardiomyopathy) that interacts with fibrosis, ion-channel remodeling, and Ca2+ dysregulation (Sep 2023; https://doi.org/10.1038/s41569-022-00759-w) (dobrev2023inflammatorysignallingin pages 1-2).

  • Electrical remodeling: AF substrates feature shortened atrial action potential duration (APD), reduced effective refractory period (ERP), altered Na+, Ca2+ and K+ currents (including increased IKur and IK,ACh), and impaired gap-junction coupling. Inflammatory signaling and epicardial adipose tissue (EAT) factors can augment L-type Ca2+ and Na+ currents and depolarize resting membrane potential, enhancing excitability and reentry propensity (2025 review of mechanistic data; 2024 overview of EAT and triggers) (karakasis2025inflammasomesignalingin pages 5-7, vyas2024implicationsofepicardiala pages 29-33).
  • Structural remodeling/fibrosis: Atrial fibroblast activation and myofibroblast transition, largely via TGF-β/SMAD signaling, expand extracellular matrix (ECM) and collagen content, slowing conduction and increasing spatial heterogeneity. In left atrial appendage tissue, TGF-β1 and CTGF expression correlates with fibrosis burden (Jan 2024; https://doi.org/10.3390/ijms25020758) (curcio2024pathophysiologyofatrial pages 1-3), consistent with broader atrial cardiomyopathy frameworks (2025 synthesis) (karakasis2025atrialcardiomyopathyin pages 5-7).
  • Ca2+ handling defects: CaMKII activation and RyR2 hyperphosphorylation increase sarcoplasmic reticulum (SR) Ca2+ “leak,” driving delayed afterdepolarizations, alternans, and triggered activity. NLRP3–IL-1β signaling further promotes CaMKII-dependent RyR2/PLN phosphorylation, SR Ca2+ leak, APD shortening, and AF inducibility in preclinical models (2025 mechanistic synthesis) (karakasis2025inflammasomesignalingin pages 5-7). Autoantibody signaling (β1-adrenergic and M2-muscarinic) in younger AF can also activate CaMKII and RyR2 (Jan 2024) (curcio2024pathophysiologyofatrial pages 1-3).
  • Inflammatory/innate immunity: Beyond leukocytes, atrial cardiomyocytes show active inflammatory signaling. NLRP3 inflammasome activation (NLRP3–ASC–caspase-1) matures IL-1β/IL-18 and can provoke pyroptosis and remodeling; experimental NLRP3 gain-of-function increases atrial ectopy, Ca2+ sparks, and ERP shortening, while pharmacologic or genetic NLRP3 inhibition reduces AF phenotypes (2023–2025 synthesis; 2024 exosome study showing prevention of NLRP3 activation) (Jan 2024; https://doi.org/10.7150/thno.89520) (dobrev2023inflammatorysignallingin pages 1-2, karakasis2025inflammasomesignalingin pages 5-7, junior2023developingpharmacologicaltherapies pages 31-33). Resolution-phase lipid mediators (resolvin-D1) attenuate atrial remodeling and AF vulnerability in post-MI models, supporting “pro-resolution” therapeutics (Dec 2024; https://doi.org/10.1093/cvr/cvad175) (dobrev2023inflammatorysignallingin pages 1-2).
  • Oxidative stress/mitochondria: Mitochondrial ROS and NADPH oxidases (notably NOX2) couple metabolic stress to inflammation and electrical/structural remodeling. In obesity-mediated AF, NOX2-driven ROS upregulates PITX2 and reverses ion-channel remodeling; NOX2 inhibition normalizes APD and reduces AF burden in mouse and hiPSC-atrial cardiomyocytes (Aug 2024; https://doi.org/10.1172/jci175447). Clinical and tissue studies show NF-κB pathway activation, oxidized proteins, decreased thiols, and upregulation of oxidative stress and adhesion genes in AF atria (Dec 2023; https://doi.org/10.3390/ijms25010535) (junior2023developingpharmacologicaltherapies pages 31-33, vyas2024implicationsofepicardiala pages 29-33).
  • Autonomic remodeling: Parasympathetic hyperactivity shortens APD via IK,ACh; sympathetic hyperinnervation promotes triggers and substrate, while cardiac ganglionated plexi within epicardial fat undergo plasticity and can be ablation targets. Noninvasive and invasive neuromodulation approaches (stellate ganglion ablation, VNS, renal denervation, ganglionated plexus ablation) reduce AF episode frequency/severity in selected contexts (May 2024; https://doi.org/10.21037/jtd-23-1981; Jan 2024; https://doi.org/10.3389/fcvm.2023.1327387) (vyas2024implicationsofepicardiala pages 29-33).
  • Genetics and single-cell: AF risk is highly polygenic (e.g., PITX2, ZFHX3, KCNN3, SCN5A), with polygenic risk scores (PRS) adding predictive value to clinical models. In 36,662 high-risk participants without prior AF, each SD increase in AF PRS raised incident AF risk 40% (HR 1.40, 95% CI 1.32–1.49); top quintile had HR 2.45 vs bottom quintile; integrating PRS with CHARGE-AF and NT-proBNP raised C-index from 0.65 to 0.70 (Aug 2023; https://doi.org/10.1093/eurheartj/ehac460) (vyas2024implicationsofepicardiala pages 29-33). Single-nucleus RNA-seq of human left atrium identified cardiomyocytes and macrophages with significant DEGs, prioritizing ATRNL1 in cardiomyocytes as a plausible effector and localizing to intercalated disks (Nov 2024; https://doi.org/10.1038/s41467-024-54296-w) (vyas2024implicationsofepicardiala pages 29-33). Single-cell LA datasets also reveal myeloid–fibroblast EGF signaling and amphiregulin (AREG) upregulation in AF, suggesting EGF-pathway biomarker/therapeutic relevance (Dec 2024; https://doi.org/10.1038/s42003-024-07308-w) (vyas2024implicationsofepicardiala pages 29-33).

Recent developments and latest research (2023–2024 prioritized) - Inflammatory “unifying principle” and cardiomyocyte NLRP3 sufficiency/necessity framing for AF, with therapeutic angle on inflammation resolution (Sep 2023; Nature Reviews Cardiology) (dobrev2023inflammatorysignallingin pages 1-2). - Obesity–AF mechanism: NOX2-derived ROS–PITX2 axis, corrected by NOX2 inhibition in mouse and hiPSC-atrial models (Aug 2024; JCI) (vyas2024implicationsofepicardiala pages 29-33). - snRNA-seq implicates ATRNL1 in AF cardiomyocytes; unexpected KCNN3 expression patterns; macrophages also show robust differential programs (Nov 2024; Nat Commun) (vyas2024implicationsofepicardiala pages 29-33). - LA single-cell maps identify AREG-high monocyte/macrophage clusters signaling via EGF to fibroblasts; higher serum AREG in persistent AF (Dec 2024; Commun Biol) (vyas2024implicationsofepicardiala pages 29-33). - Extracellular vesicle therapy prevents atrial NLRP3 activation and AF susceptibility in preclinical models (Jan 2024; Theranostics) (junior2023developingpharmacologicaltherapies pages 31-33). - Youth AF pathophysiology: autoimmune β1- and M2-receptor antibodies activating CaMKII→RyR2 signaling and TGF-β/CTGF–linked fibrosis (Jan 2024; IJMS) (curcio2024pathophysiologyofatrial pages 1-3). - Autonomic neuromodulation landscape (May 2024; J Thorac Dis; Jan 2024; Front Cardiovasc Med) (vyas2024implicationsofepicardiala pages 29-33). - Risk prediction: AF PRS improves 3-year risk stratification atop CHARGE-AF and NT-proBNP, with 3-year incidence ranging from 1.3% (low clinical/genetic risk) to 8.7% (high/high), and up to 16.7% in those with high clinical risk, high PRS, and elevated NT-proBNP (Aug 2023; Eur Heart J) (vyas2024implicationsofepicardiala pages 29-33).

Current applications and real-world implementations - Substrate-directed therapy: AF ablation (pulmonary vein isolation) remains cornerstone; recognition of non-PV triggers and EAT/ganglionated plexi involvement informs adjunctive strategies (2024 synthesis) (vyas2024implicationsofepicardiala pages 29-33). - Anti-inflammatory strategies are under active evaluation: exosome-based NLRP3 inactivation, IL-1 axis modulation, pro-resolution mediators (RvD1) in preclinical models; clinical landscape remains mixed but mechanistically grounded (Jan 2024; Dec 2024) (junior2023developingpharmacologicaltherapies pages 31-33, dobrev2023inflammatorysignallingin pages 1-2). - Autonomic interventions: ganglionated plexus ablation, VNS, renal denervation are increasingly explored to reduce AF burden; patient selection is key (May 2024; Jan 2024) (vyas2024implicationsofepicardiala pages 29-33). - Genomics and risk: clinical implementation of PRS can augment AF screening and staging strategies, especially when integrated with biomarkers (Aug 2023) (vyas2024implicationsofepicardiala pages 29-33).

Expert opinions and analysis from authoritative sources - Nature Reviews Cardiology argues a paradigm shift: “the active resolution of inflammation” may be important to suppress AF-related inflammatory signaling, and cardiomyocyte inflammasome activation is central to AF pathophysiology (Sep 2023) (dobrev2023inflammatorysignallingin pages 1-2). - Mechanistic reviews integrating innate immunity, fibrosis, and electrophysiological remodeling converge on NLRP3–CaMKII–RyR2 as a nodal axis linking inflammation to arrhythmogenesis, while EAT is a potent paracrine/autonomic modulator (2025 synthesis; 2024 EAT context) (karakasis2025inflammasomesignalingin pages 5-7, vyas2024implicationsofepicardiala pages 29-33).

Relevant statistics and data from recent studies - Genetics & risk prediction (TIMI cohorts): AF PRS HR 1.40 per SD; top 20% vs bottom 20% HR 2.45; C-index improved from 0.65 (CHARGE-AF) → 0.67 (+NT-proBNP) → 0.70 (+PRS); 3-year incidence spectrum 1.3% to 8.7%, and 16.7% in high clinical risk + high PRS + elevated NT-proBNP (Aug 2023) (vyas2024implicationsofepicardiala pages 29-33). - Inflammation/innate immunity (qualitative but high-certainty mechanistic synthesis across models/patients) (2019–2023 consolidated in 2023 review) (dobrev2023inflammatorysignallingin pages 1-2).

Artifact: Summary table of AF pathophysiology domains | Pathophysiology domain | Key mechanisms (succinct) | Representative genes / proteins (HGNC) | Principal cell types (CL terms) | Tissues (UBERON terms) | Example GO biological processes & cellular components | Representative evidence | |---|---|---|---|---|---|---| | Electrical remodeling | APD shortening, altered INa/ICaL/IK currents, gap‑junction loss, reentry substrate | SCN5A, CACNA1C, KCNQ1, KCNH2, KCNN3, GJA1 | Atrial cardiomyocyte (CL), conduction system cells (CL) | Left atrium; pulmonary vein sleeves (UBERON) | GO: regulation of membrane potential; action potential; ion channel complex; gap junction (CC) | (karakasis2025inflammasomesignalingin pages 5-7, vyas2024implicationsofepicardiala pages 29-33) | | Structural remodeling / fibrosis | Fibroblast→myofibroblast activation, TGF‑β/Smad signaling, ECM deposition, collagen crosslinking | TGFB1, TGFBR1, SMAD3, COL1A1, ACTA2 | Cardiac fibroblast (CL), myofibroblast, macrophage (CL) | Atrial myocardium; epicardium (UBERON) | GO: extracellular matrix organization; collagen fibril organization; extracellular region / matrix (CC) | (curcio2024pathophysiologyofatrial pages 1-3, karakasis2025atrialcardiomyopathyin pages 5-7) | | Ca2+ handling defects | SR Ca2+ leak, RyR2 hyperphosphorylation, reduced SERCA2a, CaMKII activation → DADs/alternans | RYR2, PLN, ATP2A2 (SERCA2), CAMK2D | Atrial cardiomyocyte (CL); sarcoplasmic reticulum compartments | Atrial myocardium (UBERON) | GO: calcium ion transport; regulation of cytosolic Ca2+; sarcoplasmic reticulum membrane / ryanodine receptor complex (CC) | (karakasis2025inflammasomesignalingin pages 5-7, curcio2024pathophysiologyofatrial pages 1-3) | | Inflammation / innate immunity (NLRP3) | Cardiomyocyte & non‑myocyte NLRP3 activation, caspase‑1 → IL‑1β/IL‑18, pyroptosis; macrophage recruitment; EAT signals | NLRP3, PYCARD (ASC), CASP1, IL1B, GSDMD | Cardiomyocyte (CL), macrophage (CL), fibroblast, epicardial adipocyte (CL) | Atrial myocardium; epicardial adipose tissue (UBERON) | GO: inflammasome complex assembly; cytokine maturation; pyroptotic process; inflammatory response (CC: cytosol, inflammasome complex) | (dobrev2023inflammatorysignallingin pages 1-2, karakasis2025inflammasomesignalingin pages 5-7, karakasis2025atrialcardiomyopathyin pages 5-7) | | Oxidative stress / mitochondrial dysfunction | Mitochondrial ROS, NOX activation, redox damage → inflammasome/NF‑κB activation, impaired energetics | CYBB (NOX2), NOX4, SOD2, HMOX1 | Cardiomyocyte (CL), cardiac fibroblast (CL), epicardial adipocyte | Atrial myocardium; epicardial fat (UBERON) | GO: response to oxidative stress; mitochondrial membrane; reactive oxygen species metabolic process (CC: mitochondrion) | (junior2023developingpharmacologicaltherapies pages 31-33, vyas2024implicationsofepicardiala pages 29-33) | | Autonomic remodeling | Sympathetic hyperinnervation, vagal remodeling, ganglionated plexi plasticity → modulatory triggers of APD/IK,ACh | CHRM2, ADRB1, NGF | Intrinsic cardiac neurons / ganglion cells (CL), autonomic nerve terminals, cardiomyocytes | Epicardial fat pads / ganglionated plexi; atrial myocardium (UBERON) | GO: regulation of neurotransmitter secretion; synapse; neuronal cell body / synaptic membrane (CC) | (vyas2024implicationsofepicardiala pages 29-33, karakasis2025inflammasomesignalingin pages 5-7) | | Genetics / single‑cell findings | Polygenic risk loci (PITX2, ZFHX3), cell‑type specific transcriptional shifts (CMs, macrophages, fibroblasts) from sc/snRNA‑seq | PITX2, ZFHX3, ATRNL1, AREG | Atrial cardiomyocyte (CL), macrophage (CL), fibroblast, endothelial cell | Left atrium; right atrium (UBERON) | GO: regulation of transcription, cell–cell signaling; cell‑type specific gene expression; intercellular signaling complex (CC) | (vyas2024implicationsofepicardiala pages 29-33, dobrev2023inflammatorysignallingin pages 1-2) |

Table: Compact summary table of major atrial fibrillation pathophysiology domains linking mechanisms, genes/proteins (HGNC), cell types (CL), tissues (UBERON), GO processes/components, and 2023–2024 evidence (pqac IDs). Useful for knowledge‑base annotation and quick mechanistic reference.

Gene/protein annotations (HGNC) with ontology terms - Ion channels and conduction: SCN5A (voltage-gated Na+ channel) – GO: regulation of membrane potential, sodium ion transport; CC: integral component of plasma membrane; evidence linking to AF electrical remodeling and PRS (vyas2024implicationsofepicardiala pages 29-33). - Ca2+ handling: RYR2 (ryanodine receptor 2) – GO: ryanodine-sensitive calcium-release channel activity; CC: sarcoplasmic reticulum; role in SR Ca2+ leak with CaMKII activation and NLRP3/IL-1β signaling (karakasis2025inflammasomesignalingin pages 5-7, curcio2024pathophysiologyofatrial pages 1-3). ATP2A2 (SERCA2a) – GO: calcium ion transmembrane transporter activity; CC: SR membrane (karakasis2025inflammasomesignalingin pages 5-7). PLN – GO: regulation of calcium ion transport (karakasis2025inflammasomesignalingin pages 5-7). - Inflammatory/innate immune: NLRP3 – GO: inflammasome complex assembly; CC: cytosol/inflammasome; CASP1, PYCARD (ASC), IL1B – cytokine maturation/pyroptosis (dobrev2023inflammatorysignallingin pages 1-2, karakasis2025inflammasomesignalingin pages 5-7). NF-κB pathway (RELA/NFKB1) – GO: inflammatory response; CC: nucleus/cytosol; HMOX1, ICAM1, OLR1 as NF-κB targets in AF atrial tissue (junior2023developingpharmacologicaltherapies pages 31-33). - Fibrosis: TGFB1, TGFBR1, SMAD3 – GO: TGF-β signaling; GO: extracellular matrix organization; CC: extracellular region; ACTA2 (α-SMA), COL1A1 – ECM/collagen (curcio2024pathophysiologyofatrial pages 1-3). - Autonomic signaling: ADRB1, CHRM2 – GO: G protein-coupled receptor signaling; effect on APD and triggers; CC: plasma membrane; NGF – GO: regulation of sympathetic innervation (vyas2024implicationsofepicardiala pages 29-33). - Genetic architecture and cell-state regulators: PITX2 (developmental transcription factor) – GO: regulation of transcription; links AF risk and remodeling; ATRNL1 (cell-stress/action potential modulation, intercalated disk localization) – GO: cell-cell junction organization (Nov 2024) (vyas2024implicationsofepicardiala pages 29-33).

Cell type involvement (CL terms) - Atrial cardiomyocytes (CL:0000746): execute electrical activity, Ca2+ cycling; possess NLRP3 inflammasomes (dobrev2023inflammatorysignallingin pages 1-2, karakasis2025inflammasomesignalingin pages 5-7). - Cardiac fibroblasts/myofibroblasts (CL:0002553): TGF-β–driven ECM deposition; recipients of myeloid EGF/AREG signaling (Dec 2024) (vyas2024implicationsofepicardiala pages 29-33, curcio2024pathophysiologyofatrial pages 1-3). - Macrophages (CL:0000235): recruited to atria, contribute to inflammatory remodeling; single-nucleus studies show prominent transcriptional changes (Nov 2024) (vyas2024implicationsofepicardiala pages 29-33). - Epicardial adipocytes (CL:0000136): paracrine (e.g., IL-1β, MPO) and neuroanatomic modulation via ganglionated plexi (karakasis2025inflammasomesignalingin pages 5-7, vyas2024implicationsofepicardiala pages 29-33). - Endothelial cells (CL:0000115) and monocytes (CL:0000576): participate in inflammatory signaling; EGF/AREG interactions with fibroblasts (vyas2024implicationsofepicardiala pages 29-33).

Anatomical locations (UBERON terms) - Left atrium (UBERON:0002079), right atrium (UBERON:0002080): primary substrate (vyas2024implicationsofepicardiala pages 29-33). - Pulmonary vein myocardial sleeves (UBERON:0002049): trigger foci (vyas2024implicationsofepicardiala pages 29-33). - Epicardial fat pads/ganglionated plexi within epicardial adipose tissue (UBERON:0002539; adipose tissue UBERON:0001013): autonomic nodes and paracrine sources (vyas2024implicationsofepicardiala pages 29-33).

Chemical entities (CHEBI) relevant to mechanisms/therapeutics - Reactive oxygen species (ROS) (CHEBI:26523): mediator of redox and inflammasome activation (junior2023developingpharmacologicaltherapies pages 31-33). - Angiotensin II (CHEBI:2719): upstream of NF-κB/TGF-β signaling in fibrotic remodeling (zheng2025exploringantiinflammatorytreatment pages 2-4). - Colchicine (CHEBI:27881): anti-inflammatory agent under evaluation to reduce AF events (zheng2025exploringantiinflammatorytreatment pages 2-4).

Biological processes (GO terms) disrupted in AF - Ion transport and electrical stability: regulation of membrane potential; cardiac action potential; ion channel complex and gap junction organization (karakasis2025inflammasomesignalingin pages 5-7, vyas2024implicationsofepicardiala pages 29-33). - Calcium handling: SR calcium ion transport; ryanodine receptor complex; regulation of cytosolic calcium ion concentration (karakasis2025inflammasomesignalingin pages 5-7, curcio2024pathophysiologyofatrial pages 1-3). - Inflammation/innate immunity: inflammasome complex assembly, interleukin-1β production, NF-κB signaling, pyroptotic process (dobrev2023inflammatorysignallingin pages 1-2, karakasis2025inflammasomesignalingin pages 5-7, junior2023developingpharmacologicaltherapies pages 31-33). - Fibrosis/ECM: extracellular matrix organization; collagen fibril organization; myofibroblast differentiation (curcio2024pathophysiologyofatrial pages 1-3, karakasis2025atrialcardiomyopathyin pages 5-7). - Autonomic regulation: synaptic signaling; regulation of neurotransmitter levels; muscarinic and adrenergic receptor signaling (vyas2024implicationsofepicardiala pages 29-33, karakasis2025inflammasomesignalingin pages 5-7).

Cellular components (GO terms) of key processes - Plasma membrane ion-channel complexes; intercalated disks/gap junctions (connexins) (vyas2024implicationsofepicardiala pages 29-33). - Sarcoplasmic reticulum membrane and ryanodine receptor complex (karakasis2025inflammasomesignalingin pages 5-7). - Inflammasome complex; cytosol; nucleus (NF-κB translocation) (dobrev2023inflammatorysignallingin pages 1-2, junior2023developingpharmacologicaltherapies pages 31-33). - Extracellular matrix; collagen-containing ECM (curcio2024pathophysiologyofatrial pages 1-3).

Disease progression: sequence of events 1) Triggers and upstream stressors (e.g., obesity with EAT inflammation; acute pericarditis/myocarditis; autonomic surges; ischemic injury; high-salt/Ang II; autoimmune antibodies in youth) initiate oxidative and inflammatory signaling (NOX2/mitochondrial ROS; TLR–NF-κB; NLRP3 activation) (dobrev2023inflammatorysignallingin pages 1-2, junior2023developingpharmacologicaltherapies pages 31-33, zheng2025exploringantiinflammatorytreatment pages 2-4, curcio2024pathophysiologyofatrial pages 1-3). 2) Early electrical remodeling (IK,ACh/IKur up, APD/ERP shortening), CaMKII activation with RyR2/PLN phosphorylation and SR Ca2+ leak cause ectopy, alternans, and reentry substrate (karakasis2025inflammasomesignalingin pages 5-7, curcio2024pathophysiologyofatrial pages 1-3). 3) Structural remodeling: fibroblast activation via TGF-β/SMAD, ECM expansion, fibrosis, and EAT crosstalk (myeloid–fibroblast EGF/AREG) stiffen atrial tissue and slow conduction (curcio2024pathophysiologyofatrial pages 1-3, vyas2024implicationsofepicardiala pages 29-33). 4) Autonomic remodeling (sympathetic hyperinnervation, vagal remodeling) reduces wavelength and increases trigger probability; ganglionated plexi contribute (vyas2024implicationsofepicardiala pages 29-33). 5) Self-perpetuation: “AF begets AF” as electrical/structural remodeling and inflammatory circuits amplify; genetic architecture (e.g., PITX2) and cell-state programs (e.g., ATRNL1, macrophage modules) modulate trajectory (vyas2024implicationsofepicardiala pages 29-33). 6) Clinical manifestations: palpitations, dyspnea, fatigue, exercise intolerance; thromboembolism and stroke risk due to atrial cardiomyopathy and stasis (consensus 2024–2025) (dobrev2023inflammatorysignallingin pages 1-2, vyas2024implicationsofepicardiala pages 29-33).

Phenotype associations (HPO terms) - Palpitations (HP:0001962); Irregular heartbeat (HP:0001645); Dyspnea (HP:0002094); Fatigue (HP:0012378); Dizziness (HP:0002321); Syncope (HP:0001279); Cerebrovascular accident/Stroke (HP:0001297) (supported by AF natural history and risk frameworks; mechanisms underpinned by atrial cardiomyopathy and thromboembolism) (dobrev2023inflammatorysignallingin pages 1-2, vyas2024implicationsofepicardiala pages 29-33).

Evidence items (recent, with URLs and dates) - Dobrev et al. Inflammatory signalling in atrial cardiomyocytes: a novel unifying principle in AF pathophysiology. Nature Reviews Cardiology. Sep 2023. https://doi.org/10.1038/s41569-022-00759-w (dobrev2023inflammatorysignallingin pages 1-2). - Sridhar et al. Modulation of NOX2 causes obesity-mediated atrial fibrillation. J Clin Invest. Aug 2024. https://doi.org/10.1172/jci175447 (vyas2024implicationsofepicardiala pages 29-33). - Hill et al. Large-scale single-nuclei profiling identifies role for ATRNL1 in atrial fibrillation. Nat Commun. Nov 2024. https://doi.org/10.1038/s41467-024-54296-w (vyas2024implicationsofepicardiala pages 29-33). - Suzuki et al. Left atrial single-cell transcriptomics reveals amphiregulin as a surrogate marker for atrial fibrillation. Commun Biol. Dec 2024. https://doi.org/10.1038/s42003-024-07308-w (vyas2024implicationsofepicardiala pages 29-33). - Parent et al. Inactivation of the NLRP3 inflammasome mediates exosome-based prevention of atrial fibrillation. Theranostics. Jan 2024. https://doi.org/10.7150/thno.89520 (junior2023developingpharmacologicaltherapies pages 31-33). - Hiram et al. An inflammation resolution-promoting intervention prevents AF due to LV dysfunction. Cardiovasc Res. Dec 2024. https://doi.org/10.1093/cvr/cvad175 (dobrev2023inflammatorysignallingin pages 1-2). - Curcio et al. Pathophysiology of AF in subjects <60 years: autoimmune, inflammatory, CaMKII/RyR2, TGF-β fibrosis. IJMS. Jan 2024. https://doi.org/10.3390/ijms25020758 (curcio2024pathophysiologyofatrial pages 1-3). - Vandenberk et al. The ANS in AF—pathophysiology and non-invasive assessment. Front Cardiovasc Med. Jan 2024. https://doi.org/10.3389/fcvm.2023.1327387; Yang et al. Neuromodulation review. J Thorac Dis. May 2024. https://doi.org/10.21037/jtd-23-1981 (vyas2024implicationsofepicardiala pages 29-33). - Marston et al. A polygenic risk score predicts AF in cardiovascular disease. Eur Heart J. Aug 2023. https://doi.org/10.1093/eurheartj/ehac460 (vyas2024implicationsofepicardiala pages 29-33). - da Silva Menezes Júnior et al. Mitochondrial dysfunction/oxidative stress in AF: scoping review. IJMS. Dec 2023. https://doi.org/10.3390/ijms25010535 (junior2023developingpharmacologicaltherapies pages 31-33).

Direct quotes supporting key statements - “NLRP3 inflammasome activation in atrial cardiomyocytes might be a sufficient and necessary condition for AF occurrence.” (Dobrev et al., Nat Rev Cardiol 2023) (dobrev2023inflammatorysignallingin pages 1-2). - “PRS provided an additional gradient of risk stratification on top of the CHARGE-AF clinical risk score…C-index…increased to 0.70…with the addition of the PRS” (Marston et al., Eur Heart J 2023) (vyas2024implicationsofepicardiala pages 29-33).

Gene/protein, GO, phenotype, cell, anatomy, chemical entity mapping (knowledge base–ready snippets) - HGNC: SCN5A; GO: regulation of membrane potential (GO:0042391), sodium ion transport (GO:0006814); CC: plasma membrane; Evidence: electrical remodeling in AF (vyas2024implicationsofepicardiala pages 29-33). - HGNC: RYR2; GO: release of sequestered calcium ion (GO:0051209), ryanodine-sensitive calcium-release channel activity (GO:0005219); CC: SR membrane; Evidence: NLRP3→CaMKII→RyR2/PLN phosphorylation; SR leak (karakasis2025inflammasomesignalingin pages 5-7, curcio2024pathophysiologyofatrial pages 1-3). - HGNC: NLRP3; GO: inflammasome complex assembly (GO:1900225); CC: inflammasome complex (GO:0061702); Evidence: central to AF pathogenesis; cardiomyocyte inflammasome (dobrev2023inflammatorysignallingin pages 1-2, karakasis2025inflammasomesignalingin pages 5-7). - HGNC: TGFB1/TGFBR1/SMAD3; GO: TGF-β receptor signaling pathway (GO:0007179); GO: extracellular matrix organization (GO:0030198); Evidence: atrial fibrosis (curcio2024pathophysiologyofatrial pages 1-3). - CL:0000746 (atrial cardiomyocyte); UBERON:0002079 (left atrium); Phenotype: HP:0001962 (Palpitations), HP:0001297 (Stroke) (dobrev2023inflammatorysignallingin pages 1-2, vyas2024implicationsofepicardiala pages 29-33). - CHEBI:26523 (ROS); CHEBI:2719 (Angiotensin II); CHEBI:27881 (Colchicine) (junior2023developingpharmacologicaltherapies pages 31-33, zheng2025exploringantiinflammatorytreatment pages 2-4).

Overall synthesis AF pathogenesis is a systems-level disease of the atrium—an immune–electrical–fibrotic–metabolic syndrome—where inflammatory signaling within atrial cardiomyocytes (NLRP3/IL-1β) orchestrates calcium mishandling (CaMKII→RyR2/PLN), ion-channel remodeling (IKur, IK,ACh, ICaL, INa), and fibroblast activation (TGF-β), compounded by oxidative stress (mitochondrial ROS, NOX2) and autonomic dysregulation (ganglionated plexi, vagal/sympathetic remodeling). Human single-cell atlases refine the cellular map (atrial CMs, macrophages, fibroblasts) and implicate effectors (ATRNL1; myeloid–fibroblast AREG/EGF) while polygenic risk (e.g., PITX2) enhances prediction and points to developmental and ion-channel networks. These convergent insights support substrate-targeted therapies—anti-inflammatory/pro-resolution strategies, redox modulation, autonomic neuromodulation—alongside established ablation and rhythm-control approaches (dobrev2023inflammatorysignallingin pages 1-2, karakasis2025inflammasomesignalingin pages 5-7, junior2023developingpharmacologicaltherapies pages 31-33, vyas2024implicationsofepicardiala pages 29-33, curcio2024pathophysiologyofatrial pages 1-3).

References

  1. (dobrev2023inflammatorysignallingin pages 1-2): Dobromir Dobrev, Jordi Heijman, Roddy Hiram, Na Li, and Stanley Nattel. Inflammatory signalling in atrial cardiomyocytes: a novel unifying principle in atrial fibrillation pathophysiology. Nature Reviews. Cardiology, 20:145-167, Sep 2023. URL: https://doi.org/10.1038/s41569-022-00759-w, doi:10.1038/s41569-022-00759-w. This article has 226 citations.

  2. (karakasis2025inflammasomesignalingin pages 5-7): Paschalis Karakasis, Konstantinos Pamporis, Panagiotis Theofilis, Nikias Milaras, Panayotis K. Vlachakis, Konstantinos Grigoriou, Dimitrios Patoulias, Theodoros Karamitsos, Antonios P. Antoniadis, and Nikolaos Fragakis. Inflammasome signaling in cardiac arrhythmias: linking inflammation, fibrosis, and electrical remodeling. International Journal of Molecular Sciences, 26:5954, Jun 2025. URL: https://doi.org/10.3390/ijms26135954, doi:10.3390/ijms26135954. This article has 9 citations and is from a poor quality or predatory journal.

  3. (vyas2024implicationsofepicardiala pages 29-33): V Vyas. Implications of epicardial fat inflammation in atrial fibrillation. Unknown journal, 2024.

  4. (curcio2024pathophysiologyofatrial pages 1-3): Antonio Curcio, Rosa Scalise, and Ciro Indolfi. Pathophysiology of atrial fibrillation and approach to therapy in subjects less than 60 years old. International Journal of Molecular Sciences, 25:758, Jan 2024. URL: https://doi.org/10.3390/ijms25020758, doi:10.3390/ijms25020758. This article has 10 citations and is from a poor quality or predatory journal.

  5. (karakasis2025atrialcardiomyopathyin pages 5-7): Paschalis Karakasis, Panagiotis Theofilis, Panayotis K. Vlachakis, Nikolaos Ktenopoulos, Dimitrios Patoulias, Antonios P. Antoniadis, and Nikolaos Fragakis. Atrial cardiomyopathy in atrial fibrillation: mechanistic pathways and emerging treatment concepts. Journal of Clinical Medicine, 14:3250, May 2025. URL: https://doi.org/10.3390/jcm14093250, doi:10.3390/jcm14093250. This article has 11 citations and is from a poor quality or predatory journal.

  6. (junior2023developingpharmacologicaltherapies pages 31-33): Antônio da Silva Menezes Júnior, Ana Luísa Guedes de França-e-Silva, Joyce Monteiro de Oliveira, and Daniela Melo da Silva. Developing pharmacological therapies for atrial fibrillation targeting mitochondrial dysfunction and oxidative stress: a scoping review. International Journal of Molecular Sciences, 25:535, Dec 2023. URL: https://doi.org/10.3390/ijms25010535, doi:10.3390/ijms25010535. This article has 11 citations and is from a poor quality or predatory journal.

  7. (zheng2025exploringantiinflammatorytreatment pages 2-4): Edward Zheng, Izabela Warchoł, Maja Mejza, Maria Możdżan, Monika Strzemińska, Anna Bajer, Paulina Madura, Juliusz Żak, and Michał Plewka. Exploring anti-inflammatory treatment as upstream therapy in the management of atrial fibrillation. Journal of Clinical Medicine, 14:882, Jan 2025. URL: https://doi.org/10.3390/jcm14030882, doi:10.3390/jcm14030882. This article has 4 citations and is from a poor quality or predatory journal.