Atrial Fibrillation · Falcon

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

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