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Cardiac Electrophysiology and Arrhythmia Pathogenesis

Q: What is the exact electrophysiological mechanism underlying a re-entrant excitation loop (reentry)?

The mechanism of a re-entrant loop (reentry) is based on unidirectional conduction block. Orthodromic conduction — an impulse fails to travel down a damaged refractory pathway but propagates through an adjacent healthy pathway.Retrograde return — upon reaching distal tissues, the impulse travels backward toward the damaged area.Circuit closure — by the time the impulse returns, the damaged tissue has recovered from refractoriness and conducts the impulse in the reverse direction. As a result, the impulse re-enters the non-damaged tissue, forming a continuous circular pathway of excitation.

For medical students2 min readUpdated 2026-10-10

Arrhythmias are heart rhythm disorders caused by abnormalities in automaticity and conduction. Their pathogenesis is driven by altered ion currents in myocardial cells, which distort the normal action potential and disrupt synchronized myocardial contraction. Understanding these mechanisms is essential for selecting appropriate antiarrhythmic therapy.

Resting membrane potentialApproximately –90 mV in Purkinje fibers and around –55 mV in pacemaker cells.

Conduction velocityMaximum in the bundle of His (up to 5 m/s); minimum in the AV node (0.02–0.05 m/s).

Antiarrhythmic drugsClassified into 4 main classes based on their effects on specific ion channels and receptors.

Proarrhythmic effectAntiarrhythmic medications can paradoxically provoke new or worsen existing rhythm disturbances.

Conduction System and Its Regulation

The heart functions in a coordinated manner thanks to a strict hierarchy of pacemakers. The sinoatrial (SA) node sets the normal heart rate, while the atrioventricular (AV) node acts as a secondary pacemaker (generating 40–60 impulses per minute).

The AV junction performs a critical filtering function. Conduction velocity in its penetrating fibers drops to 0.02–0.05 m/s. This allows impulses to pass in only one direction (antegradely) and protects the ventricles from overload during rapid atrial rates. The fibrous skeleton between the chambers acts as an electrical insulator, preventing retrograde re-entry of impulses.

The signal then travels down the bundle of His, where conduction velocity is maximal (1.5–5 m/s), and spreads into the Purkinje fibers. These terminal branches contain myosin and can contract along with the working myocardium, ensuring a powerful systole.

Neural regulation is mediated by the autonomic nervous system:

Parasympathetic (n. vagus): via $M_2$ muscarinic receptors, it inhibits automaticity and conduction. The right vagal branch controls the SA node, and the left branch controls the AV node. The ventricles lack parasympathetic innervation.
Sympathetic: via $eta_1$ adrenergic receptors, it increases automaticity and accelerates conduction, affecting the entire myocardium.

Purkinje Fiber Action Potential

The electrophysiological model of a conduction system cell comprises five phases, each driven by specific ion fluxes:

Phase 0 (Rapid depolarization): Upon reaching threshold potential (–60 mV), fast voltage-gated $Na^+$ channels open. An avalanche influx of $Na^+$ shifts the membrane potential to +35 mV. The duration of this phase determines conduction velocity.
Phase 1 (Early repolarization): A transient outward $K^+$ current.
Phase 2 (Plateau): A slow inward $Ca^{2+}$ current maintains membrane depolarization, preventing rapid repolarization.
Phase 3 (Final repolarization): Massive outward $K^+$ efflux returns the cell to its resting potential (–90 mV).
Phase 4 (Spontaneous diastolic depolarization): Slow inward $Na^+$ and $K^+$ currents. The slope of this phase determines cellular automaticity.

Nodal Characteristics and Refractoriness

In SA and AV nodal cells, impulse generation relies on different mechanisms. The resting membrane potential is higher (around –55 mV), rendering most fast sodium channels inactivated. Phases 0 and 4 are mediated by inward calcium currents. This current is triggered by an initial sodium influx via specialized non-selective cationic channels—$I_f$ channels (funny channels)—which form the basis of normal pacemaker automaticity.

To protect the heart from tetanic contractions and pathological impulse circulation (reentry), an effective refractory period (ERP) exists. It spans phases 0, 1, 2, and early phase 3. During this time, the cell is entirely unexcitable and cannot conduct another propagated action potential.

Arrhythmia Pathogenesis and Pharmacotherapy

Arrhythmias arise in the setting of hypoxia, metabolic derangements, or endocrine disorders (e.g., thyrotoxicosis). Based on their mechanism, they are classified into blocks (decreased conduction), extrasystoles (increased automaticity), and re-entrant circuits (reentry due to conduction abnormalities).

To treat tachyarrhythmias, 4 main classes of drugs are used:

Class I: Sodium channel blockers (affect phases 0 and 4, decrease conduction velocity).
Class II: $eta$-blockers (exert non-competitive action, inhibit adenylyl cyclase).
Class III: Potassium channel blockers (prolong phase 3 and the ERP).
Class IV: Non-dihydropyridine calcium channel blockers (decrease nodal automaticity).

For bradyarrhythmias and heart blocks, agents that accelerate the heart rate are used, such as muscarinic antagonists and $eta$-agonists.

Mnemonic

Action potential phases and ions: 0 — Sodium (inward, conduction), 2 — Calcium (inward, plateau), 3 — Potassium (outward, repolarization). Phase 4 (automaticity) — mediated by $I_f$ channels.

Frequently asked questions

What subclasses are distinguished within Class I antiarrhythmic drugs, and which specific agents belong to them?

Class I antiarrhythmic drugs (sodium channel blockers) are divided into three subclasses: IA, IB, and IC. This classification is based on binding kinetics to sodium channels, effects on cardiac electrophysiological parameters, and clinical indications. Specific drug agents for each subclass are not listed in the provided material.

What is the exact electrophysiological mechanism underlying a re-entrant excitation loop (reentry)?

The mechanism of a re-entrant loop (reentry) is based on unidirectional conduction block.

Orthodromic conduction — an impulse fails to travel down a damaged refractory pathway but propagates through an adjacent healthy pathway.
Retrograde return — upon reaching distal tissues, the impulse travels backward toward the damaged area.
Circuit closure — by the time the impulse returns, the damaged tissue has recovered from refractoriness and conducts the impulse in the reverse direction.

As a result, the impulse re-enters the non-damaged tissue, forming a continuous circular pathway of excitation.

What is the mechanism underlying the proarrhythmic action of antiarrhythmic drugs?

The proarrhythmic effect of antiarrhythmic medications stems from their ability to paradoxically trigger rhythm disorders via two main pathways:

Vagolytic mechanism — blockade of vagal tone increases SA nodal automaticity and facilitates AV nodal conduction, potentially worsening ventricular arrhythmias.
Effects on reentry — depression of conduction velocity can paradoxically shorten the circuit path length. Propagation through a 'shorter loop' occurs faster, accelerating re-entrant tachycardia.

Risk factors include underlying structural heart disease and electrical instability.

Why is the AV node called a 'filter'?

Conduction velocity in its penetrating fibers is minimal (0.02–0.05 m/s). This delays excessive impulses during atrial tachycardias, allowing only antegrade transmission and protecting the ventricles from overload.

What is the effective refractory period (ERP)?

It is the time frame (phases 0, 1, 2, and early 3) during which a cell cannot generate a new propagated action potential. Prolonging the ERP protects the myocardium from premature beats and circus movement tachycardias (reentry).

How does the SA nodal action potential differ from that of Purkinje fibers?

In pacemaker cells, the resting membrane potential is less negative (–55 mV), fast sodium channels are inactive, and depolarization and automaticity are driven by calcium currents and $I_f$ channel activity.

Go deeper

Detailed mechanism of action for each of the 4 classes of antiarrhythmic drugs
Use of supplementary agents in arrhythmias (adenosine, cardiac glycosides, potassium, and magnesium preparations)
The role of fibrous tissue in the electrical insulation of atria from ventricles
Clinical-pathogenetic correlation: linking developmental mechanisms to specific arrhythmia types