1. Reentry (the most common mechanism)

• Unidirectional block. A premature beat meets tissue that is still refractory in one direction.
• Slow conduction. The impulse travels slowly through a channel of surviving myocytes, which gives the blocked region time to recover.
• Re-excitation. The impulse returns and re-enters through the recovered tissue, closing the loop.

2. Triggered activity

• Early afterdepolarizations (EADs) arise before full repolarization. They occur when repolarization is prolonged, as in acquired long QT syndrome. Drug causes include sotalol and erythromycin, and low potassium also contributes. The result is torsades de pointes.
• Delayed afterdepolarizations (DADs) arise after repolarization is complete, typically from intracellular calcium overload. Examples are digitalis toxicity, catecholamine excess, and catecholaminergic polymorphic VT, which comes from gain-of-function RyR2 mutations.
• Braunwald's Heart Disease, Ch. 62

3. Abnormal automaticity

Common clinical settings

• Acute MI. Goldman-Cecil lists adrenergic tone, intracellular electrolyte disturbance, free fatty acids and oxygen free radicals as contributors. It states that "micro-re-entry likely is the most common electrophysiologic mechanism of early-phase arrhythmias," though enhanced automaticity and triggered activity also occur - Goldman-Cecil Medicine, Ventricular Arrhythmias.
• Chronic ischemic scar. This is the most common cause of sustained monomorphic VT.
• Cardiomyopathies. Dilated, hypertrophic and arrhythmogenic RV cardiomyopathy all produce scar or fibrosis.
• Channelopathies. These include long QT, Brugada syndrome and CPVT.
• Drugs and metabolic causes. Digitalis and QT-prolonging agents are examples, as are hypokalemia and hypomagnesemia.
• Idiopathic VT with a structurally normal heart. Examples are outflow tract VT (triggered activity or automaticity) and fascicular VT (reentry within the Purkinje system). Harrison's notes that scar-related reentrant VTs carry a risk of sudden death, whereas idiopathic VT is more benign.

Why it matters

ECG appearance

Recent evidence check

Step by step

1. Normal timing. During the plateau (phase 2) the inward L-type Ca²⁺ current (I_Ca,L) is balanced by outward K⁺ currents (I_Kr, I_Ks). Phase 3 follows, when K⁺ efflux dominates and the membrane returns to rest. The Na⁺ channels are inactivated during all of this, and I_Ca,L inactivates as the plateau ends.
2. Repolarization is delayed. Outward K⁺ current is reduced (the "repolarization reserve" is lost), or inward current persists (the late Na⁺ current is increased). Examples are K⁺-channel block, long QT mutations, low extracellular K⁺, and calmodulin kinase II (CaMKII) activation, which enhances late Na⁺ and Ca²⁺ currents.
3. The membrane stays depolarized for too long. Medical Physiology describes the key point: "I_Na remains inactivated because the cell is so depolarized." But "I_Ca has had enough time to recover from inactivation and, because the cell is still depolarized, triggers a slow, positive deflection in V_m known as an early afterdepolarization" - Medical Physiology, Ch. 21. Because the cell is still at plateau-range voltage, the recovered Ca²⁺ channels can reopen. This is called reactivation.
4. Sodium-calcium exchange adds to it. Ca²⁺ entry and release from the sarcoplasmic reticulum (SR) activate the Na⁺/Ca²⁺ exchanger (NCX). NCX is electrogenic and brings in net inward current, which further prolongs the action potential and sustains the depolarizing oscillation. Goodman & Gilman says EAD triggered upstrokes "probably reflect inward current through Ca²⁺ channels or possibly the NCX and/or Na⁺ channels" - Goodman & Gilman, Ch. 34.
5. Repolarization resumes or a beat fires. Eventually I_K grows and pulls the membrane back to rest. If the EAD is large enough to reach threshold, it triggers an extrasystole (a premature ventricular contraction).

Why EADs are more likely in some conditions

• Slow heart rate. There is more time at plateau, and class III drugs cause EADs at slow rates. This is why bradycardia and the post-pause beat precede torsades.
• Low K⁺ or Mg²⁺. Low extracellular K⁺ reduces outward K⁺ current, which delays repolarization further.
• Drugs that block I_Kr. Examples are sotalol, quinidine and erythromycin.
• Cell type. Purkinje cells and mid-myocardial M cells have intrinsically longer action potentials, so they develop EADs more readily than epicardial cells.
• Phase of the EAD. Phase 2 EADs occur at potentials positive to about -30 mV, and phase 3 EADs occur at more negative potentials. Phase 2 EADs mainly involve I_Ca,L reactivation, while phase 3 EADs involve NCX and other mechanisms.

From one cell to arrhythmia

Contrast with DADs

What is right

• Repolarization is prolonged, so the membrane stays at depolarized voltages for longer than normal.
• Channels that were inactivated recover from inactivation while the cell is still depolarized.
• Those channels then reopen and generate an inward current. That inward current produces the EAD.

What needs correcting

Corrected summary

Normal role

• Ca²⁺ removal. Braunwald's Heart Disease says NCX extrudes most of the Ca²⁺ that entered through I_Ca,L. A very small fraction is removed by the plasma membrane Ca²⁺-ATPase (PMCA). The SR Ca²⁺-ATPase (SERCA) takes up the rest into the SR. This lets the cell relax in diastole.
• Energy source. NCX uses the inward Na⁺ gradient, which the Na⁺/K⁺-ATPase maintains, to drive Ca²⁺ out. Goodman & Gilman describes this as antiport: 3 Na⁺ in for 1 Ca²⁺ out.
• Electrogenic. Three Na⁺ carry three positive charges in, while one Ca²⁺ carries two positive charges out. The net result is one positive charge entering per cycle. In forward mode, NCX therefore produces an inward (depolarizing) current. Braunwald adds that NCX "almost always functions to extrude Ca²⁺, resulting in a net inward current" (Braunwald's Heart Disease, Na⁺/Ca²⁺ Exchanger).
• Reverse mode. The exchanger can also run backward, bringing Ca²⁺ in and removing Na⁺. This happens when the cell is strongly depolarized or intracellular Na⁺ is high. Fishman's describes NCX as operating in either forward or reverse mode (Fishman's Pulmonary Diseases and Disorders). Reverse mode is brief in a normal cardiac action potential.

Role in delayed afterdepolarizations (DADs)

1. Ca²⁺ overload (from digitalis, catecholamines, ischemia, or RyR2 gain-of-function in CPVT) makes the SR leak or spontaneously release Ca²⁺ after repolarization.
2. The rise in cytosolic Ca²⁺ activates NCX in forward mode to remove it.
3. NCX brings in 3 Na⁺ for each Ca²⁺ it removes, so there is a net inward current.
4. This depolarizes the membrane after repolarization is complete. That is the DAD, and if it reaches threshold it triggers a premature beat.

Role in early afterdepolarizations (EADs)

• During a prolonged plateau, Ca²⁺ is already elevated and SR release can occur late in the action potential.
• NCX then provides inward current at the plateau and prolongs the action potential. This favors L-type Ca²⁺ channel reactivation, which is the main EAD driver.
• Goodman & Gilman says EAD upstrokes "probably reflect inward current through Ca²⁺ channels or possibly the NCX and/or Na⁺ channels." This points to NCX as a contributor in some EADs, especially phase 3 EADs, and not as the sole cause.
• Fuster and Hurst describes a priming effect. NCX provides an electrogenic inward current that helps EADs form and prolongs the action potential. This is the mechanism behind the biphasic effect of β-adrenergic stimulation on EADs.
• Braunwald also shows EADs in mice with heterozygous knockout of NCX, so the exchanger is not strictly required for every EAD.

Summary