Epicardial Adipose Tissue Arrhythmogenesis

Definition

Epicardial adipose tissue (EAT) is the visceral fat depot located between the myocardium and the visceral pericardium, enclosed within the pericardial sac and sharing coronary blood supply with the heart. No fascial barrier separates EAT from adjacent myocardium, enabling direct structural and paracrine crosstalk. EAT promotes cardiac arrhythmias through three interlocking pathways: (1) structural infiltration creating anatomical conduction barriers; (2) potential electrotonic coupling via gap junctions; (3) a paracrine secretome of adipokines and extracellular vesicles that remodel ion channels, gap junctions, and promote fibrosis. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)

Key Concepts

EAT Anatomy

• EAT originates from the splanchnopleuric mesoderm via epicardial progenitor epithelial-to-mesenchymal transition; distinct from paracardial adipose tissue (PAT), which derives from thoracic mesenchyme, lies outside the pericardium, and does not share coronary circulation. PAT is not an equivalent substitute in research models. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• EAT is predominantly located along the atrioventricular and interventricular grooves, extending around the atria and coronary arteries; can cover virtually the entire cardiac surface. Average EAT = ~20% of total heart weight; increases with BMI after age 40. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• EAT is a complex microenvironment of adipocytes, preadipocytes, fibroblasts, immune cells, adrenergic and cholinergic nerve cells, and blood vessels. EAT is a source of catecholamine biosynthesis including (nor)epinephrine. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)

Pathway 1 — Structural Infiltration and Conduction Barrier

• Adipocytes infiltrate the myocardium in two patterns: (a) thin compact cords penetrating between cardiac bundles, and (b) fibro-fatty infiltration — adipocytes surrounded by dense fibrotic areas after inflammatory remodeling. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• Infiltrated adipose tissue creates an anatomical barrier to the activation wavefront, forcing it along a "zigzag" path — as in post-MI conduction slowing (de Bakker model). The resulting activation delay and discontinuous conduction produce fractionated electrograms and the substrate for re-entry. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• In sheep post-MI model: intramyocardial adiposity → myocardial discontinuity, decreased conduction velocity, reduced electrogram amplitude, increased arrhythmia risk, and lateralisation of Cx43 in adjacent myocytes. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• In CAD patients (epicardial mapping): local conduction slowing, electrogram fractionation, and Cx40 lateralisation colocalize with high local EAT volume. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• Fibro-fatty infiltration is more arrhythmogenic than adipose alone (De Coster computer modelling): greater percentage of non-conductive tissue needed to induce arrhythmia with fat alone vs. fat + fibrosis. Atrial fibro-fatty replacement is more extensive in persistent than paroxysmal AF — emphasising its role in AF maintenance. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)

Pathway 2 — Electrotonic Coupling (Hypothetical)

• Both white adipocytes (mouse) and cardiomyocytes express Cx43; white adipocytes are functionally coupled to each other via Cx43. Whether EAT adipocytes electrically couple to cardiomyocytes remains unproven in humans. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• Predicted membrane potential gradient: cardiomyocyte RMP ≈ −90 mV; white adipocyte ≈ −30 mV; fibroblasts/macrophages −10 to −30 mV. If coupling occurs:
  • Slight depolarisation (RMP −75 to −65 mV): increased excitability ("superexcitability") (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
  • Further depolarisation (RMP −65 to −55 mV): partial Na⁺ channel inactivation → decreased upstroke velocity → reduced conduction velocity, increased risk of block and re-entry (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
  • Extreme depolarisation: complete Na⁺ channel inactivation; propagation dependent on ICa,L (very slow) (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• Analogous coupling demonstrated between cardiomyocytes and fibroblasts (rabbit heart), between cardiomyocytes and myofibroblasts (inducing spontaneous diastolic depolarization and ectopic activity), and between cardiomyocytes and macrophages. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)

Pathway 3 — Paracrine Secretome: Electrical Remodeling

• The EAT secretome comprises soluble factors (growth factors, cytokines, bioactive lipids) and extracellular vesicles (EVs) carrying proteins, lipids, mRNAs, miRNAs, lncRNAs, and circRNAs that can be transferred to adjacent cardiomyocytes. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• EVs from AF patients' epicardial fat contain pro-inflammatory/profibrotic cytokines and profibrotic microRNAs; incubation with hiPSC-CM sheets for 7 days shortened APD80 and induced sustained rotors (Shaihov-Teper 2021). (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• EAT secretome prolongs APD90 in rabbit atrial cardiomyocytes, with a less negative RMP, increased late INa and ICa,L, and decreased IK1. EAT secretome reduces IKr in H9c2 rat cardiomyocytes. 24h sheep EAT incubation of hiPSC-CMs extends field potential duration. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• In silico study (De Coster): secretome-induced APD prolongation created more complex spiral wave dynamics in a 2D monolayer and full human atria model. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)

Adipokines: Ion Channel Remodeling

• TNF-α: Reduces Ito (transient outward K⁺) in rat ventricular myocytes → APD prolongation. Also reduces Cx40 expression and slows conduction velocity in guinea pig hearts. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• IL-1β: Decreases Ito → APD prolongation in rat hearts; prolongs field potential duration in hiPSC-CMs; increases spontaneous diastolic SR Ca²⁺ release → DAD risk and triggered activity; downregulates/degrades Cx43 in post-MI mouse models. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• IL-6: Modulates ICa,L (dose- and duration-dependent increase or decrease); downregulates SERCA2a activity and expression → Ca²⁺ handling dysregulation; reduces Cx40 and Cx43 expression in HL-1 mouse atrial myocytes. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• FABP4 (fatty acid-binding protein-4): Reduces intracellular systolic peak Ca²⁺ in rat cardiomyocytes. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)

Pathway 3 — Paracrine Secretome: Profibrotic Adipokines

• Activin A (TGF-β superfamily): highly present in EAT secretome; induces collagen 1 deposition in rat atria; effect neutralised by activin A antibody. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• Visfatin (NAMPT): Secreted by adipocytes and macrophages; promotes cardiac fibroblast proliferation and increased collagen synthesis. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• TGF-β1: Induces fibroblast-to-myofibroblast switch → ECM production, fibroblast proliferation, collagen synthesis; cardiac overexpression in mice → interstitial fibrosis. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• Leptin: Secreted by EAT adipocytes; stimulates collagen I in cardiac myofibroblasts. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• MCP-1 (CCL2): Secreted by EAT adipocytes and immune cells; enhances myofibroblast activation, fibroblast proliferation, collagen expression. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• IL-6: IL-6 infusion in rats → increased collagen volume fraction. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• MMPs (MMP-1, -2, -8, -9): Secreted at high levels by EAT; TNF-α induces excessive MMP secretion → ECM remodeling. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)

Lipotoxicity Pathway

• Lipid overload of cardiomyocytes overwhelms mitochondrial FFA oxidation → accumulation of toxic ceramides → mitochondrial and ER dysfunction, Ca²⁺ dysregulation, ROS production. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• ROS-mediated Ca²⁺ overload → delayed afterdepolarizations (DADs) and triggered activity. ROS also alter Cx43-mediated electrical coupling → conduction slowing. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• Cardiac lipid droplets (LDs) buffer against lipotoxicity; when LD capacity is saturated → excess ROS, arrhythmias. Lipid storage diseases are associated with lethal arrhythmias. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)

ECG Correlates of EAT Volume

• P-wave duration: Positively associated with EAT thickness/volume in healthy subjects and morbidly obese patients across multiple studies; reflects slowed atrial conduction. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• P-wave dispersion: Associated with EAT in healthy subjects — implies anisotropic, heterogeneous sinus impulse propagation facilitating re-entry. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• PR interval: EAT volume linearly correlated with longer PR interval in 4 independent studies; highest vs lowest EAT tertile → 10–16 ms longer PR. Prolonged PR independently predicts AF, HF, mortality. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• QRS duration: Strongly associated with EAT volume; highest vs lowest EAT → 6.7 ms longer QRS. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• Fragmented QRS (fQRS): Associated with increased EAT in hypertensive patients and healthy subjects; EAT >4.5 mm predicted fQRS with 75% sensitivity/58% specificity. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• Tpeak–Tend (TpTe) interval: Increased with higher EAT, along with increased QT dispersion — repolarisation heterogeneity predicting SCD/mortality. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)

EAT Volume and Arrhythmia Risk

• EAT volume is positively related to AF incidence, duration, and recurrence. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high; sources/obesity-cv-aha-2021, rating: very high)
• EAT on the ventricular free walls correlates with frequency of premature ventricular contractions. Paracardial + EAT sum is positively related to ventricular arrhythmias in patients with HF. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• EAT infiltrations into ventricular myocardium → fibrosis → re-entrant ventricular tachycardia circuits. (sources/obesity-cv-aha-2021, rating: very high)

Contradictions / Open Questions

• EAT and QTc discrepancy: In vitro EAT secretome clearly prolongs APD (via decreased IKr, decreased Ito, increased late INa/ICaL) suggesting QTc prolongation would be expected. However, 3 of 4 observational ECG studies show no QTc association with EAT; only one small study (n=216) reported a negative correlation (less QTc with higher EAT, opposite direction). The net effect of secretome-induced APD changes on surface QTc in humans remains unresolved. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• EAT adipocyte-cardiomyocyte electrotonic coupling: Mechanistically plausible given Cx43 co-expression, but entirely unproven in humans or intact heart preparations. All evidence is extrapolated from fibroblast-myocyte and macrophage-myocyte coupling studies. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• EAT as cause vs. consequence of AF: The obesity-EAT-AF relationship may be bidirectional: AF itself may increase EAT fibrosis (demonstrated in sheep model), meaning fibro-fatty infiltration may both cause and result from AF. The primary direction of causality is not established in humans. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• Specific secretome components: The adipokine(s) responsible for the APD-prolonging effects of EAT secretome in experimental systems remain unidentified. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)
• No interventional RCT data: All evidence for EAT as an arrhythmogenic substrate is observational (ECG associations) or experimental (animal/cell models). No RCT has demonstrated arrhythmia reduction with EAT volume reduction as a primary endpoint. (sources/epi-adipose-arrhythmia-jacc-2021, rating: high)

Connections

• Related to concepts/Visceral-Adiposity — EAT as the cardiac ectopic fat depot within the broader visceral adiposity framework
• Related to entities/Atrial-Fibrillation — EAT as structural and paracrine AF substrate
• Related to concepts/Electrical-Remodeling — adipokine-mediated ion channel and connexin downregulation
• Related to concepts/Cardiac-Action-Potential — APD prolongation, altered RMP, Na⁺ channel inactivation by EAT coupling/secretome
• Related to concepts/Cardiac-Repolarization — TpTe interval, QT dispersion as EAT ECG correlates
• Related to concepts/Torsades-de-Pointes — APD prolongation and repolarisation heterogeneity from EAT secretome
• Related to entities/Obesity — BMI → EAT accumulation → arrhythmogenic substrate
• Related to concepts/OSA-Arrhythmogenic-Substrate — OSA worsens EAT; shared AF substrate mechanisms
• Related to concepts/Atrial-Cardiomyopathy — EAT listed as a therapeutic target in 2025 ESC AtCM consensus
• Related to sources/epi-adipose-arrhythmia-jacc-2021
• Related to sources/obesity-cv-aha-2021

Sources

• sources/epi-adipose-arrhythmia-jacc-2021
• sources/obesity-cv-aha-2021