Cardiac electrophysiology and how arrhythmias arise

How each heartbeat is an electrical wave, how that wave goes wrong, and why drugs that fix rhythm can also cause new problems.

Updated Nov 12, 2026

Each heartbeat starts as an electrical impulse that spreads through the heart in a fixed order, driven by ion channels in each cell. Arrhythmias arise when impulses start in the wrong place or at the wrong rate, or when they circle back on themselves. Understanding the action potential, refractoriness and the main mechanisms explains how antiarrhythmic drugs act, and why they can also provoke arrhythmias.

Key points

Ventricular muscle cells fire a long action potential: fast sodium entry (phase 0), a calcium plateau (phase 2) and potassium-driven repolarisation (phase 3).
Sinus and AV nodal cells depend on calcium channels and a pacemaker current (If, through HCN channels), so they are slowed by beta blockers, verapamil, diltiazem and ivabradine.
The refractory period protects the heart from re-excitation; drugs that lengthen it can stop re-entry but may also prolong the QT interval.
Three mechanisms: abnormal automaticity, triggered activity from afterdepolarisations, and re-entry around a circuit.
Inherited channel diseases (long QT, Brugada, CPVT) show the same mechanisms in pure form.
Every antiarrhythmic can cause arrhythmias (proarrhythmia), so treatment aims at symptoms and outcomes, not a perfect ECG.

The action potential and the ECG

At rest a ventricular cell sits at a negative voltage held by potassium channels (IK1). Phase 0 is a rapid upstroke as sodium channels open; phase 1 is brief early repolarisation; phase 2 is a plateau where L-type calcium entry triggers calcium release from the sarcoplasmic reticulum and contraction; phase 3 is repolarisation through delayed rectifier potassium currents (rapid IKr, from hERG/KCNH2, and slow IKs, from KCNQ1); phase 4 is rest. On the surface ECG, the P wave is atrial depolarisation, the PR interval mostly reflects AV node delay, QRS is ventricular depolarisation (sodium-dependent), and the QT interval spans ventricular depolarisation plus repolarisation. Sodium channel blockers widen QRS; IKr blockers lengthen QT; AV nodal blockers lengthen PR.

Pacemaker cells and refractoriness

Sinus and AV nodal cells have no stable resting potential: in phase 4 they drift upward through the funny current (If) and calcium currents until they fire, with an upstroke carried by calcium rather than sodium. Sympathetic stimulation steepens this drift and speeds the rate; vagal acetylcholine flattens it. After each beat a cell cannot fire again for a while (effective refractory period), because sodium channels must recover from inactivation. In muscle this recovery follows repolarisation; in nodal tissue it lasts beyond it. Refractoriness keeps the wave moving forward and is the main lever antiarrhythmic drugs pull.

Mechanisms of arrhythmia

Enhanced or abnormal automaticity: the sinus node or other cells fire too fast, or injured muscle develops its own pacemaker activity (ischaemia, catecholamines, hypokalaemia, stretch).
Early afterdepolarisations: oscillations during phases 2–3 when repolarisation is long, as with IKr blockers, bradycardia or low potassium; they trigger torsades de pointes.
Delayed afterdepolarisations: after repolarisation, when cells are overloaded with calcium that is released spontaneously, as in digoxin toxicity or CPVT.
Re-entry: an impulse finds a circuit with a one-way block and a slow pathway, then keeps circling (AV nodal re-entry, accessory pathways, atrial flutter, ventricular tachycardia around a scar). Drugs break it by slowing conduction further until it blocks, or by lengthening refractoriness.

Inherited arrhythmia syndromes

These channel diseases teach the mechanisms directly.

Long QT syndrome (Romano-Ward): autosomal dominant, most often from variants in KCNQ1, KCNH2 or SCN5A; slow repolarisation favours early afterdepolarisations and torsades. QT-prolonging drugs and low potassium or magnesium add risk.
Brugada syndrome: often from loss-of-function variants in the sodium channel gene SCN5A; ventricular arrhythmias and sudden death, usually at rest or during sleep, more often in men and in people of Asian ancestry. Some antiarrhythmics, psychiatric drugs and electrolyte disturbances can unmask it.
Catecholaminergic polymorphic VT (CPVT): variants in RYR2 or CASQ2 disturb calcium release in myocytes; exercise or emotional stress triggers ventricular tachycardia through delayed afterdepolarisations. Beta blockers are the base of treatment, and flecainide can be added.

Principles of clinical use

Antiarrhythmic drugs have narrow margins. The first questions are whether the rhythm is dangerous or only symptomatic, and whether a reversible cause (ischaemia, low potassium or magnesium, thyroid disease, a drug) can be fixed. For atrial fibrillation, the main decisions are stroke prevention with anticoagulation according to risk, and rate control (beta blocker, verapamil, diltiazem or digoxin) versus rhythm control (cardioversion, flecainide in structurally normal hearts, amiodarone, sotalol, dofetilide, or catheter ablation). Anticoagulation before and after cardioversion lowers the risk of stroke. Adenosine briefly blocks the AV node and stops most re-entrant supraventricular tachycardias. Unstable rhythms are treated electrically, and implantable defibrillators prevent sudden death in high-risk patients.

Proarrhythmia

The same actions that stop an arrhythmia can start another. Sodium channel blockers slow conduction and can create re-entry, especially in scarred hearts: in the CAST trial, flecainide and encainide given after a heart attack increased deaths. IKr blockers such as sotalol, dofetilide and many non-cardiac drugs (some antibiotics, antipsychotics and antiemetics) prolong QT and can cause torsades. Risk rises with female sex, bradycardia, low potassium or magnesium, high drug levels and combinations of QT-prolonging drugs. Intravenous magnesium sulfate is used for torsades.

Test yourself

Think of the answer, then tap the question to see it.

Which ion current drives phase 0 in ventricular muscle, and which drives it in the sinus node?

Sodium current in ventricular muscle; calcium current in sinus and AV nodal cells, which is why calcium channel blockers slow the nodes.

What are early afterdepolarisations and which arrhythmia do they trigger?

Voltage oscillations during a prolonged phase 2 or 3, favoured by long QT, slow rates and low potassium; they trigger torsades de pointes.

What two conditions does a re-entry circuit need?

A one-way (unidirectional) block and conduction slow enough that tissue ahead has recovered when the impulse returns.

What happens in catecholaminergic polymorphic VT?

Variants in RYR2 or CASQ2 disturb calcium release, so exercise or stress causes delayed afterdepolarisations and ventricular tachycardia.

What did the CAST trial show about sodium channel blockers after a heart attack?

Flecainide and encainide suppressed ectopic beats but increased mortality, a key example of proarrhythmia in scarred hearts.

Add to my cards (5)

Example drugs

Connections

← All of pharmacology

Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: Romano-Ward syndrome (MedlinePlus Genetics (U.S. National Library of Medicine), 2026); Brugada syndrome: MedlinePlus Genetics (MedlinePlus Genetics (U.S. National Library of Medicine), 2026); Catecholaminergic polymorphic ventricular tachycardia: MedlinePlus Genetics (MedlinePlus Genetics (U.S. National Library of Medicine), 2026).

Spotted a mistake?We are always improving for the community. Tell us what is wrong and our team will review it.Report a mistake

Representative model, for educational purposes only.