Atrial Fibrillation

Complex MONDO:0004981 Cardiovascular Disease Cardiac Arrhythmia

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.

4
Pathophys.
6
Phenotypes
5
Genes
7
Treatments
5
Subtypes
14
References
2
Deep Research
◆

Subtypes

5
Paroxysmal Atrial Fibrillation
Episodes terminate spontaneously within 7 days.
Persistent Atrial Fibrillation
Episodes last longer than 7 days or require intervention.
Long-standing Persistent Atrial Fibrillation
Continuous AF for more than 12 months.
Permanent Atrial Fibrillation
AF accepted as permanent rhythm.
Valvular Atrial Fibrillation
AF associated with mitral stenosis or mechanical valves.
⚙

Pathophysiology

4
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 link
Cardiac Conduction link
Show evidence (2 references)
PMID:39146015 SUPPORT
"NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden."
This demonstrates that electrical remodeling including altered action potential duration is a key pathophysiological mechanism in AF.
PMID:38255832 PARTIAL
"Atrial fibrillation (AF) is an arrhythmia that affects the left atrium, cardiac function, and the patients' survival rate."
Confirms AF affects atrial electrical function and is influenced by electrophysiological mechanisms.
Atrial Structural Remodeling
Atrial fibrosis and dilation create substrate for AF maintenance. Fibrosis disrupts normal conduction and creates reentrant circuits.
Cardiac Fibroblast link
Show evidence (1 reference)
PMID:38255832 PARTIAL
"it is influenced by a complex interplay of autoimmune, inflammatory, and electrophysiological mechanisms."
Inflammatory mechanisms contribute to structural remodeling including fibrosis that maintains AF substrate.
Pulmonary Vein Triggers
Ectopic beats originating from pulmonary vein myocardial sleeves commonly trigger AF episodes. These foci have distinct electrophysiology.
Atrial Thrombus Formation
Loss of atrial contraction leads to blood stasis, particularly in the left atrial appendage, promoting thrombus formation and embolic stroke.
Show evidence (1 reference)
PMID:38255832 NO_EVIDENCE
"Atrial fibrillation (AF) is an arrhythmia that affects the left atrium, cardiac function, and the patients' survival rate."
AF affects cardiac function including atrial contraction, which contributes to thromboembolism risk and impacts patient survival.
●

Phenotypes

6
Cardiovascular 3
Palpitations FREQUENT Palpitations (HP:0001962)
Show evidence (1 reference)
PMID:35873859 SUPPORT
"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.
Irregular Pulse VERY_FREQUENT Arrhythmia (HP:0011675)
Stroke OCCASIONAL Stroke (HP:0001297)
Major complication due to thromboembolism
Ear 1
Dizziness OCCASIONAL Vertigo (HP:0002321)
Respiratory 1
Dyspnea FREQUENT Dyspnea (HP:0002094)
Show evidence (1 reference)
PMID:35873859 SUPPORT
"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 1
Fatigue FREQUENT Fatigue (HP:0012378)
Show evidence (1 reference)
PMID:26318825 SUPPORT
"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.
🧬

Genetic Associations

5
KCNQ1 (Risk Factor)
KCNE2 (Risk Factor)
KCNJ2 (Risk Factor)
SCN5A (Risk Factor)
PITX2 (Risk Factor)
Show evidence (2 references)
PMID:39146015 PARTIAL
"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 by upregulation of paired-like homeodomain transcription factor 2 (PITX2)."
Demonstrates PITX2 plays a mechanistic role in AF pathophysiology, supporting its genetic association with AF risk.
PMID:35980763 SUPPORT
"In patients with cardiovascular conditions, AF PRS is a strong independent predictor of incident AF that provides complementary predictive value when added to a validated clinical risk score and NT-proBNP."
Polygenic risk score including PITX2 and other loci significantly predicts AF risk, validating genetic contributions to AF susceptibility.
💊

Treatments

7
Anticoagulation
Action: Pharmacotherapy NCIT:C15986
Agent: warfarin ↗ apixaban ↗ rivaroxaban ↗ dabigatran ↗
Warfarin or DOACs to prevent stroke based on CHA2DS2-VASc score.
Show evidence (1 reference)
PMID:37573616 SUPPORT
"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.
Rate Control
Action: Pharmacotherapy NCIT:C15986
Agent: metoprolol ↗ diltiazem ↗ digoxin ↗
Beta blockers, calcium channel blockers, or digoxin.
Rhythm Control
Action: Pharmacotherapy NCIT:C15986
Agent: amiodarone ↗ flecainide ↗ sotalol ↗
Antiarrhythmic drugs (amiodarone, flecainide, sotalol).
Catheter Ablation
Action: radiofrequency ablation therapy MAXO:0001395
Pulmonary vein isolation for rhythm control.
Cardioversion
Electrical or pharmacological restoration of sinus rhythm.
Left Atrial Appendage Closure
Alternative to anticoagulation in selected patients.
Risk Factor Modification
Weight loss, blood pressure control, sleep apnea treatment.
🌍

Environmental Factors

5
Hypertension
Most common modifiable risk factor
Show evidence (1 reference)
PMID:27057292 SUPPORT
"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.
Obesity
Associated with atrial remodeling
Show evidence (2 references)
PMID:39146015 SUPPORT
"Obesity is linked to an increased risk of atrial fibrillation (AF) via increased oxidative stress."
Establishes obesity as a major risk factor for AF through oxidative stress mechanisms.
PMID:39146015 SUPPORT
"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.
Obstructive Sleep Apnea
Strong bidirectional relationship
Show evidence (1 reference)
PMID:29657903 SUPPORT
"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.
Alcohol
Holiday heart syndrome
Hyperthyroidism
Reversible cause
{ }

Source YAML

click to show 
name: Atrial Fibrillation
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-02-27T12:00:00Z'
category: Complex
parents:
- Cardiovascular Disease
- Cardiac Arrhythmia
disease_term:
  preferred_term: atrial fibrillation
  term:
    id: MONDO:0004981
    label: atrial fibrillation
has_subtypes:
- name: Paroxysmal Atrial Fibrillation
  description: Episodes terminate spontaneously within 7 days.
- name: Persistent Atrial Fibrillation
  description: Episodes last longer than 7 days or require intervention.
- name: Long-standing Persistent Atrial Fibrillation
  description: Continuous AF for more than 12 months.
- name: Permanent Atrial Fibrillation
  description: AF accepted as permanent rhythm.
- name: Valvular Atrial Fibrillation
  description: AF associated with mitral stenosis or mechanical valves.
pathophysiology:
- 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:39146015
    reference_title: "Modulation of NOX2 causes obesity-mediated atrial fibrillation."
    supports: SUPPORT
    snippet: "NOX2 inhibition normalized atrial action potential duration and abrogated
      obesity-mediated ion channel remodeling with reduced AF burden."
    explanation: This demonstrates that electrical remodeling including altered
      action potential duration is a key pathophysiological mechanism in AF.
  - reference: PMID:38255832
    reference_title: "Pathophysiology of Atrial Fibrillation and Approach to Therapy in Subjects Less than 60 Years Old."
    supports: PARTIAL
    snippet: "Atrial fibrillation (AF) is an arrhythmia that affects the left atrium,
      cardiac function, and the patients' survival rate."
    explanation: Confirms AF affects atrial electrical function and is
      influenced by electrophysiological mechanisms.
- name: Atrial Structural Remodeling
  description: >
    Atrial fibrosis and dilation create substrate for AF maintenance.
    Fibrosis disrupts normal conduction and creates reentrant circuits.
  cell_types:
  - preferred_term: Cardiac Fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  evidence:
  - reference: PMID:38255832
    reference_title: "Pathophysiology of Atrial Fibrillation and Approach to Therapy in Subjects Less than 60 Years Old."
    supports: PARTIAL
    snippet: "it is influenced by a complex interplay of autoimmune, inflammatory,
      and electrophysiological mechanisms."
    explanation: Inflammatory mechanisms contribute to structural remodeling
      including fibrosis that maintains AF substrate.
- name: Pulmonary Vein Triggers
  description: >
    Ectopic beats originating from pulmonary vein myocardial sleeves
    commonly trigger AF episodes. These foci have distinct electrophysiology.
- 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:38255832
    reference_title: "Pathophysiology of Atrial Fibrillation and Approach to Therapy in Subjects Less than 60 Years Old."
    supports: NO_EVIDENCE
    snippet: "Atrial fibrillation (AF) is an arrhythmia that affects the left atrium,
      cardiac function, and the patients' survival rate."
    explanation: AF affects cardiac function including atrial contraction, which
      contributes to thromboembolism risk and impacts patient survival.
phenotypes:
- name: Palpitations
  category: Cardiovascular
  frequency: FREQUENT
  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
    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: Irregular Pulse
  category: Cardiovascular
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
- name: Fatigue
  category: Systemic
  frequency: FREQUENT
  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
    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
    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: Dizziness
  category: Neurological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Dizziness
    term:
      id: HP:0002321
      label: Vertigo
- name: Stroke
  category: Neurological
  frequency: OCCASIONAL
  notes: Major complication due to thromboembolism
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
genetic:
- name: KCNQ1
  association: Risk Factor
- name: KCNE2
  association: Risk Factor
- name: KCNJ2
  association: Risk Factor
- name: SCN5A
  association: Risk Factor
- name: PITX2
  association: Risk Factor
  notes: Major GWAS locus
  evidence:
  - reference: PMID:39146015
    reference_title: "Modulation of NOX2 causes obesity-mediated atrial fibrillation."
    supports: PARTIAL
    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 by upregulation of paired-like homeodomain
      transcription factor 2 (PITX2)."
    explanation: Demonstrates PITX2 plays a mechanistic role in AF
      pathophysiology, supporting its genetic association with AF risk.
  - reference: PMID:35980763
    reference_title: "A polygenic risk score predicts atrial fibrillation in cardiovascular disease."
    supports: SUPPORT
    snippet: "In patients with cardiovascular conditions, AF PRS is a strong independent
      predictor of incident AF that provides complementary predictive value when added
      to a validated clinical risk score and NT-proBNP."
    explanation: Polygenic risk score including PITX2 and other loci
      significantly predicts AF risk, validating genetic contributions to AF
      susceptibility.
environmental:
- name: Hypertension
  notes: Most common modifiable risk factor
  evidence:
  - reference: PMID:27057292
    reference_title: "Atrial Fibrillation and Hypertension: Mechanistic, Epidemiologic, and Treatment Parallels."
    supports: SUPPORT
    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.
- name: Obesity
  notes: Associated with atrial remodeling
  evidence:
  - reference: PMID:39146015
    reference_title: "Modulation of NOX2 causes obesity-mediated atrial fibrillation."
    supports: SUPPORT
    snippet: "Obesity is linked to an increased risk of atrial fibrillation (AF) via
      increased oxidative stress."
    explanation: Establishes obesity as a major risk factor for AF through
      oxidative stress mechanisms.
  - reference: PMID:39146015
    reference_title: "Modulation of NOX2 causes obesity-mediated atrial fibrillation."
    supports: SUPPORT
    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
  notes: Strong bidirectional relationship
  evidence:
  - reference: PMID:29657903
    reference_title: "Obstructive Sleep Apnea as a Risk Factor for Atrial Fibrillation: A Meta-Analysis."
    supports: SUPPORT
    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: Alcohol
  notes: Holiday heart syndrome
- name: Hyperthyroidism
  notes: Reversible cause
treatments:
- name: Anticoagulation
  description: Warfarin or DOACs to prevent stroke based on CHA2DS2-VASc score.
  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
    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.
- name: Rate Control
  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
- name: Rhythm Control
  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
- name: Catheter Ablation
  description: Pulmonary vein isolation for rhythm control.
  treatment_term:
    preferred_term: radiofrequency ablation therapy
    term:
      id: MAXO:0001395
      label: radiofrequency ablation therapy
- name: Cardioversion
  description: Electrical or pharmacological restoration of sinus rhythm.
- name: Left Atrial Appendage Closure
  description: Alternative to anticoagulation in selected patients.
- name: Risk Factor Modification
  description: Weight loss, blood pressure control, sleep apnea treatment.
datasets:
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.