Cardiac Action Potential & Pacemaker

The cardiac action potential (AP) is the electrical signature of every heartbeat, and its shape differs fundamentally between working myocardium and nodal tissue. Mastering the ionic basis of each phase unlocks antiarrhythmic pharmacology, ECG interpretation, channelopathies, and accessory-pathway physiology — one of the densest high-yield clusters in NEET PG Physiology.

Two fundamental AP types

The heart has two electrically distinct cell populations. The distinction is the single most tested concept in this topic.

Feature	Fast-response (ventricular/atrial myocyte, Purkinje)	Slow-response (SA & AV node)
Resting/maximal diastolic potential	−85 to −90 mV (stable)	−55 to −60 mV (unstable, drifts up)
Phase 0 upstroke ion	Fast Na⁺ influx (Naᵥ1.5)	L-type Ca²⁺ influx (Caᵥ1.2)
Upstroke velocity (dV/dt)	Rapid (~200–500 V/s)	Slow (~1–10 V/s)
Conduction velocity	Fast	Slow (AV delay)
Threshold	−70 mV	−40 mV
Phase 4	Flat (no spontaneous depol.)	Spontaneous depolarisation (automaticity)
Plateau (phase 2)	Prominent	Absent/poorly developed
Major refractory determinant	Na⁺ channel recovery	Ca²⁺ channel recovery (time-dependent)

High-yield: In nodal (slow-response) tissue there is no functional fast Na⁺ channel — the entire AP, including the upstroke, depends on the slow inward Ca²⁺ current. This is why Class IV (verapamil, diltiazem) and adenosine act predominantly at the SA and AV nodes.

Phases of the ventricular (fast-response) action potential

The classic five-phase ventricular AP (numbered 0–4):

Phase 4 (resting) → Phase 0 (depolarisation) → Phase 1 (initial repolarisation) → Phase 2 (plateau) → Phase 3 (repolarisation) → back to Phase 4

Phase	Name	Dominant current	Direction	Channel
0	Rapid upstroke	I_Na	Inward	Naᵥ1.5 (fast Na⁺)
1	Early repolarisation	I_to	Outward	Transient outward K⁺
2	Plateau	I_Ca-L vs I_Kr/I_Ks	Balanced	L-type Ca²⁺ in, delayed K⁺ out
3	Repolarisation	I_Kr, I_Ks	Outward	Delayed rectifier K⁺
4	Resting potential	I_K1	Outward	Inward rectifier K⁺

• Phase 0: Voltage-gated fast Na⁺ channels open at threshold (≈ −70 mV), producing a steep upstroke; they inactivate within ~1–2 ms.
• Phase 1: Na⁺ channels close; transient outward K⁺ current (I_to) causes a small notch (prominent in epicardium — basis of the Brugada/J-wave).
• Phase 2 (plateau): The hallmark of cardiac muscle. Inward Ca²⁺ through L-type channels balances outward K⁺. Ca²⁺ entry triggers calcium-induced calcium release (CICR) from the sarcoplasmic reticulum via ryanodine receptors → contraction. The long plateau means the absolute refractory period nearly equals the contraction, preventing tetany.
• Phase 3: L-type Ca²⁺ channels inactivate while delayed rectifier K⁺ currents (I_Kr fast, I_Ks slow) dominate → repolarisation.
• Phase 4: I_K1 (inward rectifier) maintains the stable resting potential near E_K (−90 mV). The Na⁺/K⁺ ATPase and Na⁺/Ca²⁺ exchanger restore gradients.

High-yield: I_Kr is encoded by hERG (KCNH2) — blocked by many drugs (drug-induced long QT) and mutated in LQT2. I_Ks is encoded by KCNQ1 — mutated in LQT1. Loss-of-function of Naᵥ1.5 (SCN5A) → LQT3 / Brugada, depending on gating effect.

Pacemaker (slow-response) action potential

Nodal cells have no stable resting potential. After repolarisation they spontaneously drift toward threshold — this is automaticity. Phases are described as 4, 0, 3 (no distinct 1 or 2).

Phase 4 spontaneous depolarisation → reaches −40 mV threshold → Phase 0 Ca²⁺-driven upstroke → Phase 3 K⁺ repolarisation → repeat

Ionic basis of phase 4 (diastolic depolarisation):

1. I_f — the "funny" current: Activated by hyperpolarisation, carried mainly by Na⁺ (with some K⁺) through HCN4 channels. It is the dominant initiator of pacemaker depolarisation and is the target of ivabradine.
2. Decay of I_K (progressively less outward current).
3. I_Ca-T (T-type Ca²⁺) in the later part of phase 4.
4. The terminal upstroke (phase 0) uses I_Ca-L (L-type).

High-yield: The funny current (I_f) is activated by hyperpolarisation and is increased by sympathetic stimulation (cAMP shifts its activation), accelerating heart rate. Ivabradine selectively blocks I_f, slowing the SA node without affecting BP, contractility, or AV conduction — useful in stable angina and HFrEF.

Pacemaker hierarchy

Pacemaker	Intrinsic rate (bpm)
SA node (dominant)	60–100
AV node / junction	40–60
His–Purkinje / ventricle	20–40

The fastest pacemaker (SA node) sets the rate and suppresses slower foci by overdrive suppression. If the SA node fails, lower pacemakers take over (escape rhythms) — hence the slower rates seen in junctional and ventricular escape.

Autonomic modulation

The autonomic nervous system tunes three properties: rate (chronotropy), conduction (dromotropy), and contractility (inotropy).

Effect	Sympathetic (β₁, via cAMP)	Parasympathetic (M₂, vagus → Gi)
Heart rate (chronotropy)	↑ (steeper phase 4, ↑I_f, ↑I_Ca)	↓ (↑I_K, ↓I_f) — positive
AV conduction (dromotropy)	↑	↓ (AV block at high tone)
Contractility (inotropy)	↑ (↑Ca²⁺ entry)	Slight ↓ (atria)

• Sympathetic (noradrenaline/adrenaline → β₁ → Gs → ↑cAMP): Steepens the slope of phase 4 by enhancing I_f and I_Ca-T, raising heart rate. Also speeds AV conduction.
• Vagal (acetylcholine → M₂ → Gi → ↓cAMP + opens GIRK/I_K(ACh)): Hyperpolarises nodal cells and flattens the phase-4 slope. The right vagus predominantly supplies the SA node (slows rate); the left vagus predominantly supplies the AV node (slows conduction/AV block).

High-yield: Vagal stimulation hyperpolarises the SA node by opening acetylcholine-sensitive K⁺ channels (I_K(ACh)/GIRK) — this both lowers the maximal diastolic potential and reduces the phase-4 slope, so it takes longer to reach threshold.

AV nodal conduction delay

The AV node is the only normal electrical connection between atria and ventricles (the rest is insulated by the fibrous annulus). Its slow upstroke (Ca²⁺-dependent) produces the physiological AV delay (~0.1 s), represented by the PR interval (0.12–0.20 s) on the ECG.

Functions of the delay:

• Allows complete atrial emptying ("atrial kick") before ventricular systole.
• Acts as a frequency filter / gatekeeper — protects the ventricle from very fast atrial rates (e.g., limiting ventricular rate in atrial fibrillation/flutter via decremental conduction).

The AV node also shows decremental conduction and a long refractory period, making it the rate-limiting structure and a target for rate control with β-blockers, non-dihydropyridine CCBs, and digoxin (vagotonic).

Refractory periods

• Absolute refractory period (ARP): No stimulus, however strong, can elicit an AP — spans phases 0, 1, 2, and part of 3. Due to inactivated Na⁺ channels.
• Effective refractory period (ERP): Slightly longer; a stimulus may cause local depolarisation but not a propagated AP.
• Relative refractory period (RRP): A stronger-than-normal stimulus can trigger an AP (late phase 3) — vulnerable to re-entry; an early stimulus here (R-on-T) can precipitate VF.

High-yield: The long plateau gives cardiac muscle a refractory period almost as long as the contraction itself, so cardiac muscle cannot be tetanised — essential for rhythmic pumping.

Antiarrhythmic drugs mapped to AP phases (Vaughan-Williams)

Class	Mechanism	Effect on AP	Examples
IA	Moderate Na⁺ block + K⁺ block	↓ phase 0, ↑ duration/QT	Quinidine, procainamide, disopyramide
IB	Weak/fast Na⁺ block	↓ duration; acts on ischaemic tissue	Lignocaine, mexiletine, phenytoin
IC	Strong Na⁺ block	Marked ↓ phase 0, ↑↑ QRS	Flecainide, propafenone
II	β-blockade	↓ phase 4 slope (nodes), ↑ PR	Metoprolol, esmolol
III	K⁺ channel block	↑↑ phase 3 duration, ↑ QT/ERP	Amiodarone, sotalol, dofetilide
IV	L-type Ca²⁺ block	↓ nodal phase 0/4, ↑ PR	Verapamil, diltiazem

Mnemonic for classes: "Some Block Potassium Channels" = Sodium (I), Beta (II), Potassium (III), Calcium (IV). For Class IB agents acting like phenytoin/lignocaine: "Lettuce Met Phenny" (Lignocaine, Mexiletine, Phenytoin).

High-yield: Class IC drugs (flecainide) are contraindicated post-MI / in structural heart disease — the CAST trial showed increased mortality. Adenosine (ultra-short half-life ~10 s) transiently blocks the AV node via A₁ receptors → I_K(ACh) — drug of choice to terminate paroxysmal SVT (AVNRT/AVRT).

Wolff-Parkinson-White (WPW) & accessory-pathway physiology

In WPW an accessory pathway (bundle of Kent) bypasses the AV node, directly connecting atrium to ventricle. Because it lacks the AV node's protective decremental conduction, it conducts rapidly.

ECG triad: short PR (<0.12 s), delta wave (slurred QRS upstroke), wide QRS. The delta wave is ventricular pre-excitation via the fast accessory pathway before the AV-node impulse arrives.

Arrhythmia mechanics:

• Orthodromic AVRT (most common): down AV node, up the accessory pathway → narrow QRS tachycardia.
• Antidromic AVRT: down the accessory pathway, up the AV node → wide QRS.

High-yield: In WPW with atrial fibrillation, AV-nodal blockers (digoxin, verapamil, adenosine, β-blockers) are dangerous — they block the node and shunt all conduction down the accessory pathway, accelerating ventricular rate → VF. Treat with procainamide / ibutilide (or DC cardioversion). Mnemonic for what to avoid: "ABCD" = Adenosine, Beta-blockers, Calcium blockers, Digoxin.

Triggered activity & re-entry (brief)

• Early afterdepolarisations (EADs): Occur in phase 2/3, favoured by prolonged AP/QT (bradycardia, hypokalaemia, hypomagnesaemia, Class IA/III) → torsades de pointes. Treat with IV magnesium.
• Delayed afterdepolarisations (DADs): Occur in phase 4 from Ca²⁺ overload (digoxin toxicity, catecholamines) — driven by the Na⁺/Ca²⁺ exchanger.
• Re-entry requires unidirectional block + slow conduction + an excitable circuit — the basis of most clinical tachyarrhythmias.

Recently asked / exam angle

• "Phase 0 of the SA nodal action potential is due to?" → L-type Ca²⁺ influx (not Na⁺).
• "Funny current is activated by?" → Hyperpolarisation; carried by HCN channels; blocked by ivabradine.
• "Drug acting on the funny current?" → Ivabradine (slows SA node only).
• "Plateau phase ion?" → Ca²⁺ in vs K⁺ out; CICR via ryanodine receptor.
• "hERG / KCNH2 channel carries?" → I_Kr (rapid delayed rectifier K⁺); LQT2.
• "Acetylcholine slows the heart by?" → opening I_K(ACh)/GIRK + reducing phase-4 slope.
• "WPW with AF — avoid which drug?" → AV-nodal blockers (ABCD).
• "Why can't cardiac muscle be tetanised?" → long refractory period due to plateau.
• "Most rapid intrinsic pacemaker?" → SA node (60–100 bpm).
• "Resting membrane potential maintained by?" → I_K1 (inward rectifier).
• "PR interval represents?" → AV nodal conduction delay (0.12–0.20 s).
• Image-based delta wave / short PR → diagnose WPW.

Rapid revision

1. Fast cells (atria, ventricle, Purkinje): phase 0 = fast Na⁺; stable −90 mV resting potential.
2. Slow cells (SA/AV node): phase 0 = L-type Ca²⁺; unstable −60 mV with automaticity.
3. Funny current (I_f, HCN4): activated by hyperpolarisation, initiates phase 4; target of ivabradine.
4. Plateau (phase 2): Ca²⁺ in balances K⁺ out → triggers CICR → contraction → long refractory period (no tetany).
5. Phase 4 of fast cells & resting potential = I_K1 (inward rectifier).
6. Phase 3 repolarisation = delayed rectifier K⁺ (I_Kr/hERG fast, I_Ks/KCNQ1 slow).
7. Pacemaker hierarchy: SA 60–100 > AV 40–60 > ventricle 20–40; fastest dominates (overdrive suppression).
8. Sympathetic (β₁/cAMP): steepens phase 4 → ↑ rate; vagal (M₂/GIRK): flattens phase 4 + hyperpolarises → ↓ rate.
9. AV delay (PR interval 0.12–0.20 s): allows atrial kick and limits ventricular rate in AF/flutter.
10. Vaughan-Williams: I = Na⁺, II = β-block, III = K⁺ (↑QT), IV = Ca²⁺; adenosine = AV-node DOC for SVT.
11. WPW = bundle of Kent: short PR + delta wave + wide QRS; in AF avoid ABCD (Adenosine, Beta-blockers, CCB, Digoxin) → use procainamide/cardioversion.
12. EAD → torsades (give Mg²⁺); DAD → digoxin toxicity (Ca²⁺ overload via Na⁺/Ca²⁺ exchanger).