The Cardiac Action Potential: From Ion Channels to the ECG

Phase 0 through Phase 4 in pacemaker and non-pacemaker cells — the ion channel kinetics, refractory periods, antiarrhythmic drug targets, and species differences that connect molecular electrophysiology to the surface ECG.

Introduction: The Electrical Foundation of Every Heartbeat

Every heartbeat begins not with contraction but with electricity — a precisely orchestrated sequence of ion movements across the cardiac myocyte membrane. The cardiac action potential is fundamentally different from the neuronal action potential: it lasts 200–400 milliseconds (versus 2–3 ms in neurons), it has a distinctive plateau phase, and in pacemaker cells it fires spontaneously without any external stimulus.

This article traces the cardiac action potential from Phase 0 through Phase 4, explaining which ions move when, which channels open and close, how refractory periods protect the heart from re-entrant arrhythmias, and — critically for the clinician — where antiarrhythmic drugs intervene. By the end, you will understand why lidocaine works for ventricular tachycardia, why sotalol prolongs the QT interval, and why cats are so sensitive to sodium-channel blockers.

Phase 0: Rapid Depolarisation — The Sodium Surge

Non-Pacemaker Cells (Ventricular and Atrial Myocytes)

Phase 0 is initiated when the membrane potential reaches threshold (approximately −60 to −70 mV). Voltage-gated Na⁺ channels (Na_v1.5 in cardiac muscle) open rapidly, allowing a massive influx of Na⁺ ions down their electrochemical gradient. The membrane potential shoots from the resting −90 mV to approximately +20 to +30 mV in under 2 milliseconds. This is the fastest depolarisation in the body.

The Na⁺ channels have two gates: an activation gate (m gate) that opens rapidly with depolarisation, and an inactivation gate (h gate) that closes more slowly. The brief period when BOTH gates are open — and Na⁺ conductance is maximal — is only about 0.5 ms. The rapid upstroke of Phase 0 produces the QRS complex on the surface ECG.

Pacemaker Cells (SA and AV Nodes)

Pacemaker cells have FEW fast Na⁺ channels. Instead, Phase 0 depolarisation is carried by L-type Ca²⁺ channels (Ca_v1.2/1.3) — a slower current that produces a less steep upstroke. This is why the SA node action potential has a gradual, 'rounded' Phase 0 compared to the sharp spike of ventricular myocytes. The slower conduction velocity through the AV node (0.05 m/s vs 1–4 m/s in Purkinje fibres) is a direct consequence of Ca²⁺-dependent Phase 0 — and it is this delay that gives the ventricles time to fill after atrial contraction.

Phase 1: Early Repolarisation — The Notch

Immediately after the peak of Phase 0, a brief, partial repolarisation occurs — visible as a small 'notch' after the QRS in some leads, most prominently in epicardial recordings. This is mediated by the transient outward K⁺ current (I_to), which activates rapidly and inactivates within 5–10 ms. The I_to current is responsible for the 'spike-and-dome' morphology of the cardiac action potential — the notch between Phase 0 and the plateau of Phase 2.

Species differences in I_to expression are clinically significant. Dogs and humans have robust I_to and a pronounced Phase 1 notch. Cats have much less I_to, giving their ventricular action potentials a smoother contour. Guinea pigs have essentially no I_to — their action potentials lack Phase 1 entirely. This is one reason guinea pig cardiac electrophysiology is a poor model for canine arrhythmias.

Phase 2: The Plateau — Calcium's Moment

Why the Heart Has a Plateau (and Skeletal Muscle Doesn't)

Phase 2 is the defining feature of the cardiac action potential — a sustained depolarisation lasting 200–300 ms during which the membrane potential hovers near 0 mV. This is achieved by a delicate balance between inward Ca²⁺ current (I_Ca,L via L-type channels) and outward K⁺ currents (I_Kr and I_Ks — the rapid and slow delayed rectifiers).

The physiological purpose of the plateau is twofold: (1) it prevents tetanic contraction by ensuring the refractory period lasts almost as long as the contraction itself, and (2) the Ca²⁺ that enters during Phase 2 triggers Ca²⁺-induced Ca²⁺ release (CICR) from the sarcoplasmic reticulum — the actual source of most contractile Ca²⁺. This process is called excitation-contraction coupling (E-C coupling).

The ST Segment on the ECG

During Phase 2, all ventricular myocytes are depolarised to approximately the same potential → no voltage gradient → isoelectric ST segment. ST-segment elevation or depression indicates that some myocytes are at a different potential than others — the hallmark of myocardial ischaemia, injury, or infarction (rare in dogs but well-described in cats with hypertrophic cardiomyopathy and coronary arteriosclerosis).

Phase 3: Repolarisation — Restoring the Gradient

Phase 3 begins when the outward K⁺ currents (I_Kr and I_Ks) overcome the inactivating Ca²⁺ current. The membrane potential falls back toward the K⁺ equilibrium potential (−90 mV). As repolarisation proceeds, the Na⁺ channel inactivation gates (h gates) begin to reopen — the channels transition from inactivated → resting, becoming available for the next action potential.

The T wave on the surface ECG represents Phase 3. Because repolarisation proceeds from epicardium to endocardium (opposite to depolarisation), the T wave is normally concordant with the QRS in most leads (both positive or both negative). T-wave inversion in leads where the QRS is positive suggests abnormal repolarisation — ischaemia, electrolyte disturbance, or ventricular hypertrophy.

Phase 4: The Resting Potential — and Pacemaker Exception

Non-Pacemaker Cells: Stable Resting Potential

Phase 4 in ventricular and atrial myocytes is a stable −90 mV resting potential maintained by the inward rectifier K⁺ current (I_K1). I_K1 is unique among potassium channels — its conductance is HIGHEST at very negative potentials and DECREASES with depolarisation. This 'anomalous rectification' means it clamps the resting potential near E_K but turns off during the plateau so it does not short-circuit Phase 2.

The Na⁺/K⁺-ATPase pump (the 'sodium pump') continuously extrudes 3 Na⁺ for every 2 K⁺ it imports, maintaining the transmembrane gradients. This pump is electrogenic — each cycle moves one net positive charge out of the cell, contributing approximately −4 mV to the resting potential.

Pacemaker Cells: The Unstable Phase 4 — Autorythmicity

SA and AV nodal cells have virtually no I_K1. Instead, they express the 'funny current' (I_f), a mixed Na⁺/K⁺ current that activates on HYPERPOLARISATION (the opposite of most voltage-gated channels, hence 'funny'). As the membrane potential falls below approximately −50 mV at the end of repolarisation, I_f activates and carries net inward (depolarising) current, slowly bringing the membrane toward threshold. This spontaneous Phase 4 depolarisation is the molecular basis of cardiac automaticity.

Refractory Periods: The Heart's Anti-Arrhythmia Safeguard

The cardiac action potential is unique among excitable tissues in having a very long refractory period — almost as long as the contraction itself. This prevents summation and tetanic contraction, which would be catastrophic for a pump that must alternately fill and empty.

Antiarrhythmic Drug Targets: The Vaughan-Williams Classification Mapped to Phases

Species Differences in Cardiac Electrophysiology

The feline heart has a SHORTER action potential duration than the canine heart because cats express proportionally more I_Kr (rapid delayed rectifier K⁺ current). This makes cats MORE susceptible to QT-prolonging drugs — a given degree of I_Kr blockade produces a proportionally greater prolongation of repolarisation in a shorter action potential. Cisapride, a prokinetic agent with I_Kr-blocking properties, can cause fatal torsades de pointes in cats even at therapeutic doses.

From Action Potential to ECG: The Temporal Correlation

The surface ECG is the algebraic sum of all the action potentials occurring in the heart at a given moment. The key temporal correlations are:

• P wave: Phase 0 of atrial myocyte action potentials — atrial depolarisation.
• PR segment: Conduction through the AV node (slow Ca²⁺-dependent Phase 0 of nodal cells) — the isoelectric plateau of atrial cells.
• QRS complex: Phase 0 of ventricular myocyte action potentials — rapid Na⁺-dependent depolarisation spreading through the ventricles.
• ST segment: Phase 2 (plateau) of ventricular myocytes — all cells depolarised, no voltage gradient.
• T wave: Phase 3 (repolarisation) of ventricular myocytes — the epicardial-to-endocardial repolarisation gradient.
• U wave (if visible): Thought to represent repolarisation of Purkinje fibres or afterdepolarisations — prominent in hypokalemia.

Clinical Antiarrhythmic: A Deeper Look at Drug Targets and Arrhythmia Mechanisms

Mechanisms of Arrhythmogenesis — Why the Rhythm Goes Wrong

Cardiac arrhythmias arise from three fundamental mechanisms: (1) ABNORMAL AUTOMATICITY — a latent pacemaker cell (e.g., in the Purkinje fibres) develops enhanced Phase 4 depolarisation, spontaneously firing and usurping the SA node. Catecholamines (via β1 receptors → cAMP → increased I_f and I_Ca) enhance automaticity in subsidiary pacemakers. (2) TRIGGERED ACTIVITY — afterdepolarisations that reach threshold and trigger an extra beat. Early afterdepolarisations (EADs) occur during Phase 2–3 (prolonged AP → L-type Ca²⁺ channels reactivate → triggered upstroke); they are the substrate for torsades de pointes in long QT syndromes. Delayed afterdepolarisations (DADs) occur during Phase 4 (Ca²⁺ overload → spontaneous SR Ca²⁺ release → Na⁺/Ca²⁺ exchanger generates a transient inward current → depolarisation → triggered beat). Digoxin toxicity is the classic DAD-mediated arrhythmia. (3) RE-ENTRY — the commonest mechanism of sustained arrhythmias. Re-entry requires: a unidirectional block in one pathway, slow conduction through an alternative pathway, and recovery of excitability in the blocked pathway just as the impulse returns. This creates a circus movement — the 're-entrant circuit.' The wavelength of the circuit = conduction velocity × refractory period. Antiarrhythmics terminate re-entry by prolonging the refractory period (Class III), slowing conduction (Class I), or both.

Reverse Use-Dependence — Why Sotalol Can Be Pro-Arrhythmic at Slow Rates

Class III drugs (sotalol, dofetilide) block I_Kr — the rapid delayed rectifier K⁺ current. However, this blockade exhibits 'reverse use-dependence': the drug blocks I_Kr MORE effectively at SLOW heart rates and LESS effectively at FAST rates. This is the opposite of what you want — at fast rates (when arrhythmia protection is most needed), the drug is less effective; at slow rates (e.g., during sleep), the drug excessively prolongs repolarisation, creating the substrate for EADs and torsades de pointes. This is the major limitation of pure Class III agents.

Amiodarone — The 'Dirty Drug' That Works

Amiodarone is unique among antiarrhythmics — it has Class I, II, III, and IV effects simultaneously. It blocks Na⁺ channels (Class I, especially inactivated state — use-dependent), non-competitively blocks β-adrenergic receptors (Class II), blocks I_Kr, I_Ks, and I_K1 K⁺ currents (Class III — prolongs APD in all cardiac tissues), and blocks L-type Ca²⁺ channels (Class IV). This broad-spectrum action makes amiodarone the most effective antiarrhythmic available in human medicine. However, in dogs it causes dose-dependent hepatotoxicity (vacuolar hepatopathy, elevated ALT) and is rarely used. In cats, intravenous amiodarone can cause fatal anaphylactoid reactions — it is essentially contraindicated. The search for a safe, effective broad-spectrum antiarrhythmic for veterinary patients continues.

The Cardiac Conduction System: Anatomy Meets Electrophysiology

The specialised conduction system ensures that the electrical impulse reaches every ventricular myocyte within approximately 60 ms — a feat of biological engineering that produces the coordinated, efficient contraction the heart requires. Understanding its anatomy and electrophysiology illuminates why certain arrhythmias occur where they do.

The SA Node — The Primary Pacemaker

The sinoatrial node is a crescent-shaped collection of specialised pacemaker cells (~10,000 cells) located at the junction of the cranial vena cava and the right atrial appendage. Its blood supply is the SA nodal artery (a branch of the right coronary artery in the dog). SA node cells are SMALL (5–10 μm), have sparse contractile machinery, and express the full repertoire of pacemaker currents — I_f, I_Ca,T, I_Ca,L, and minimal I_K1. Inherent firing rate: ~100–120 bpm in the denervated dog SA node, modulated downward by vagal tone (acetylcholine → M2 receptors → Gi → reduced cAMP → reduced I_f and I_Ca → slower Phase 4 depolarisation) and upward by sympathetic tone (noradrenaline → β1 receptors → Gs → increased cAMP → increased I_f and I_Ca → faster Phase 4).

The AV Node — The Gatekeeper

The atrioventricular node sits in the triangle of Koch, bounded by the coronary sinus, the septal leaflet of the tricuspid valve, and the tendon of Todaro. It serves two critical functions: (1) DELAY — conduction velocity is only ~0.05 m/s in the AV node vs ~1 m/s in atrial muscle. This ~100 ms delay ensures atrial contraction is complete before ventricular systole begins. The slow conduction is due to Ca²⁺-dependent action potentials (few Na⁺ channels) and high intercellular resistance (few gap junctions). (2) FILTER — the AV node protects the ventricles from excessively rapid atrial rates. At atrial rates >300 bpm (dogs) or >400 bpm (cats), the AV node exhibits decremental conduction — each successive impulse finds the node progressively more refractory until conduction fails. This is why atrial fibrillation in dogs typically produces a ventricular response of 140–180 bpm, not 400–600 bpm.

The Purkinje System — The Rapid Distribution Network

The bundle of His penetrates the fibrous cardiac skeleton and divides into right and left bundle branches. The left bundle further divides into anterior and posterior fascicles. The terminal Purkinje fibres are the LARGEST cardiac cells (up to 100 μm diameter) with abundant gap junctions (connexin 40 and 43) → conduction velocity of 2–4 m/s — the fastest in the heart. Purkinje cells can also act as subsidiary pacemakers — their intrinsic rate is ~30–40 bpm (ventricular escape rhythm). The orderly sequence of activation: septum (left to right) → apex → free walls → base (last to depolarise, first to repolarise — explaining the normal T wave polarity).

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