What is the electrophysiology of early afterdepolarizations (EADs)?

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Last updated: September 11, 2026 • View editorial policy

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Electrophysiology of Early Afterdepolarizations (EADs)

Early afterdepolarizations are abnormal depolarizations occurring during late phase 2 or early phase 3 of the cardiac action potential, triggered by reactivation of L-type calcium channels before the membrane has adequately repolarized, in the setting of prolonged action potential duration. 1, 2

Core Electrophysiological Mechanism

EADs arise from a fundamental imbalance between inward and outward currents during the repolarization phase of the action potential. The critical requirement is action potential prolongation combined with either increased inward currents or decreased repolarizing potassium currents 1, 2.

Primary Ionic Mechanisms

The electrophysiology involves two potential pathways:

1. L-type Calcium Channel Reactivation (Primary Mechanism)

  • The membrane must remain at plateau voltages long enough for L-type calcium channels to recover from inactivation
  • Reactivation occurs before the membrane has returned to a sufficiently negative potential (typically between -10 to -40 mV)
  • This creates a "window current" where calcium channels can reopen during the prolonged plateau 1, 3
  • The L-type calcium channel plays a unique and essential role in creating the nonlinear dynamics necessary for EAD formation 4

2. Sodium-Calcium Exchange Current

  • Spontaneous calcium release from the sarcoplasmic reticulum can activate a depolarizing sodium-calcium exchange current
  • This provides an alternative mechanism for generating the inward current that produces the afterdepolarization 1, 2

Conditions Required for EAD Formation

Action potential prolongation is the prerequisite, caused by:

  • Increased inward currents:

    • Late sodium current (INa-L)
    • L-type calcium current (ICa-L)
    • Sodium-calcium exchange current (NCX)

  • Decreased repolarizing currents:

    • Reduced potassium currents (particularly IKr and IKs)
    • This represents "reduced repolarization reserve" 1, 2, 4

Voltage and Timing Characteristics

EADs occur at specific voltage ranges during the action potential:

  • Phase 2 EADs: Develop at the end of a prolonged plateau at takeoff potentials between -10 and -30 mV 5
  • Phase 3 EADs: Occur during later repolarization at takeoff potentials around -60 mV 5

The timing is critical—EADs demonstrate cycle-length dependence, becoming more prominent at slower heart rates when action potentials are longer 5. This explains why bradycardia facilitates EAD formation in long QT syndromes.

Dynamical Systems Perspective

Recent advances reveal that EADs represent a nonlinear dynamical phenomenon involving quasi-equilibrium states and bifurcations 4. The system requires:

  1. Formation of a quasi-equilibrium state at plateau voltage
  2. Sufficient instability in this state to allow oscillations
  3. The L-type calcium channel creating the necessary nonlinear behavior for these oscillations 4

The trajectory of the action potential must pass through an oscillatory regime where the balance of currents permits repetitive depolarizations 6. Interventions that shift the trajectory away from this oscillatory regime (such as Ito suppression) can prevent EADs without eliminating the underlying oscillatory structure 6.

Clinical Arrhythmogenic Significance

EADs serve as the trigger for torsades de pointes ventricular tachycardia in conditions with QT prolongation 1, 2, 7. The sequence involves:

  1. EAD formation in myocardial cells (particularly M-cells with longest action potential duration)
  2. Generation of a premature ventricular complex when the EAD reaches threshold
  3. Heterogeneous repolarization creating substrate for reentry
  4. Initiation of polymorphic VT/VF 1, 7

Common Clinical Scenarios

EADs are the mechanism underlying arrhythmias in:

  • Drug-induced QT prolongation (particularly IKr blockers) 1, 7
  • Congenital long QT syndrome (ion channel mutations) 1, 7
  • Acquired conditions causing action potential prolongation (electrolyte abnormalities, particularly hypokalemia and hypomagnesemia) 1

Critical Distinction from Delayed Afterdepolarizations

Unlike delayed afterdepolarizations (DADs), which occur after complete repolarization and result from calcium overload, EADs occur during the repolarization phase itself 1, 2. DADs are favored by tachycardia and catecholamines, while EADs are favored by bradycardia and action potential prolongation—opposite rate dependencies 5.

Key Pitfalls in Understanding EAD Electrophysiology

  • Not all action potential prolongation produces EADs—the specific balance of ionic currents and the presence of oscillatory dynamics are required 4
  • QT prolongation alone is insufficient for arrhythmogenesis—heterogeneity of repolarization across the myocardium is also necessary 7
  • The role of calcium is complex—while L-type calcium channel reactivation is critical, sarcoplasmic reticulum calcium release can also contribute via NCX activation 1, 3

References

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