Cardiac Action Potential & Conduction

A cardiac action potential is the transient, regenerative change in transmembrane voltage that triggers contraction in a single myocardial cell. Two functionally distinct kinds exist. Fast-response (working) action potentials occur in atrial and ventricular contractile cells and in Purkinje fibers; they have a very negative, stable resting potential and a rapid upstroke driven by voltage-gated Na⁺ channels. Slow-response (pacemaker) action potentials occur in the Sinoatrial Node and Atrioventricular Node; they lack a true stable resting potential, depolarize spontaneously, and their upstroke is driven mainly by Ca²⁺ channels rather than Na⁺ channels. The defining feature that distinguishes cardiac muscle electrically from skeletal muscle and neurons is the plateau phase: after the initial upstroke, the membrane potential remains depolarized near 0 mV for roughly 200–300 milliseconds before repolarizing, rather than snapping back within a millisecond or two. This plateau is caused by a near-balance between inward Ca²⁺ current (which also triggers contraction, via Excitation-Contraction Coupling) and outward K⁺ currents. The long plateau produces a correspondingly long absolute refractory period, which is not an accident — it is the safety feature that prevents the heart from being re-excited and thrown into a sustained tetanic contraction, which would be fatal because the heart would never relax to refill with blood. Coordinating all of this is the cardiac conduction system, a hierarchy of self-excitable and conduction-specialized tissue: the SA node (the dominant, fastest pacemaker), internodal atrial pathways, the AV node (which imposes a deliberate delay), the bundle of His, its left and right bundle branches, and the Purkinje fiber network. Adjacent myocardial cells are electrically joined by gap junctions (channels built from connexin proteins, chiefly connexin-43 in ventricle and connexin-40 in the conduction system), which allow current — and thus depolarization — to pass directly from cell to cell. This makes the myocardium behave as a functional syncytium: although anatomically made of discrete cells, it conducts electrically as if it were one continuous sheet.

1. The pacemaker (SA nodal) action potential — how automaticity arises SA nodal cells never rest at a fixed negative potential. Instead, after each action potential repolarizes to about −60 mV, the membrane potential drifts slowly and spontaneously back upward toward threshold. This is called the pacemaker potential or phase 4 slow depolarization, and it is the electrical basis of automaticity. Three currents drive it:

• Iꜰ, the "funny current" — a slowly activating inward current carried by Na⁺ and K⁺ through HCN (hyperpolarization-activated, cyclic-nucleotide-gated) channels, switched on as the membrane repolarizes below about −50 mV. It is "funny" because, unusually, it activates on hyperpolarization rather than depolarization.
• T-type (transient) Ca²⁺ current, activating late in phase 4 and helping accelerate the final approach to threshold.
• Declining outward K⁺ current (Iₖ) — as the delayed-rectifier K⁺ channels that repolarized the previous action potential progressively close, their outward "braking" current wanes, unmasking the net inward currents.

Once the membrane depolarizes to threshold (roughly −40 mV), L-type Ca²⁺ channels open, producing the upstroke (phase 0) — note this is a slow, Ca²⁺-based upstroke, not the fast Na⁺ spike of working muscle, because SA nodal cells have few functional fast Na⁺ channels (they are largely inactivated at this depolarized resting range). Repolarization (phase 3) follows as L-type Ca²⁺ channels inactivate and delayed-rectifier K⁺ channels open, driving the potential back down — and the cycle repeats. Autonomic input tunes the rate: sympathetic norepinephrine (via β₁ receptors, cAMP, PKA) increases Iꜰ and I_Ca, steepening phase 4 and raising heart rate; parasympathetic acetylcholine (via M₂ receptors) opens Iₖ,ACh channels and inhibits Iꜰ, flattening phase 4 and slowing (or even briefly halting) the rate.

2. The ventricular (working muscle) action potential — five phases

Step by step: at rest, the inward-rectifier channels (Iₖ1) keep the ventricular cell's membrane close to the K⁺ equilibrium potential, roughly −90 mV, because the resting membrane is highly K⁺-permeable and only slightly permeable to other ions. An arriving impulse (from a neighboring cell via gap junctions) depolarizes the membrane past threshold (~ −70 mV), opening voltage-gated fast Na⁺ channels; Na⁺ rushes in down its steep electrochemical gradient, producing the explosive phase 0 upstroke that overshoots to about +20 mV within roughly 1–2 milliseconds. These Na⁺ channels then rapidly inactivate (a time- and voltage-dependent conformational change), producing a small phase 1 notch as a transient K⁺ current (Iₜₒ) briefly predominates. The signature plateau (phase 2) now follows: L-type Ca²⁺ channels, which activated more slowly during the upstroke, remain open, allowing a sustained trickle of Ca²⁺ into the cell. This inward Ca²⁺ current is almost exactly counterbalanced by a slowly increasing outward flow of K⁺ through delayed-rectifier channels (I_Kr, the "rapid" component, and I_Ks, the "slow" component), holding the membrane potential nearly flat near 0 mV for hundreds of milliseconds. This is also the electrical signal that triggers calcium-induced calcium release from the sarcoplasmic reticulum, coupling the action potential to contraction (detailed under Excitation-Contraction Coupling). Eventually the L-type Ca²⁺ channels inactivate while I_Kr and I_Ks continue to grow, tipping the balance decisively outward; phase 3 repolarization proceeds, accelerating as Iₖ1 reactivates near the resting potential and rapidly restores the cell to its stable −90 mV baseline (phase 4). Because fast Na⁺ channels remain inactivated throughout most of phases 0–2 and can only recover (return to a closed-but-available state) once the membrane has substantially repolarized during phase 3, the cell is absolutely refractory — no stimulus, however strong, can trigger a second action potential — for almost the entire duration of the plateau. A brief relative refractory period follows during phase 3, in which a stronger-than-normal stimulus can trigger a weaker, slower action potential. This long refractory period, roughly matched to the duration of mechanical contraction, is precisely why cardiac muscle cannot be tetanized: the muscle relaxes and the chambers can refill before the tissue becomes excitable again.

3. The conduction pathway — how the impulse is distributed Once the SA node fires, the impulse must reach every ventricular myocyte in a controlled sequence. The pathway is: 1. SA node (in the wall of the right atrium, near the entrance of the superior vena cava) fires spontaneously (~ 60–100 beats/min intrinsic rate, the fastest of all pacemaker tissues, which is why it normally sets the whole heart's rhythm). 2. The impulse spreads cell-to-cell through atrial myocardium (conduction velocity ~0.3–1 m/s) and along specialized internodal tracts, depolarizing both atria (~0.09 s to traverse the atria) and producing the P wave of the ECG. 3. The impulse converges on the AV node, the only normal electrical connection between atria and ventricles (the fibrous cardiac skeleton electrically insulates the rest of the atria from the ventricles). Conduction through the AV node is deliberately slow, only about 0.05 m/s, because AV nodal cells have small diameter, few gap junctions, and rely on the slower Ca²⁺-based upstroke rather than fast Na⁺ channels. This produces the AV nodal delay, roughly 0.1 second, corresponding to the PR interval on the ECG. 4. This delay is not wasted time — it allows the atria to finish contracting and empty their blood into the ventricles before ventricular contraction begins, maximizing ventricular filling. 5. The signal then enters the bundle of His, crosses the fibrous skeleton, and splits into right and left bundle branches running down either side of the interventricular septum. 6. Finally it spreads through the Purkinje fiber network, specialized conducting cells with very large diameter, few myofibrils, and abundant gap junctions, giving the fastest conduction velocity in the heart — up to ~4 m/s. This rapid distribution ensures the ventricular apex and free walls are activated almost simultaneously, so the ventricles contract essentially as a single unit, squeezing blood upward and out through the semilunar valves (the physiological logic underlying The Heart & Cardiac Cycle).

Voltage clamp reveals the pacemaker current (Trautwein & DiFrancesco). In the 1960s, Wolfgang Trautwein and colleagues applied voltage-clamp techniques (adapted from Hodgkin and Huxley's squid axon work) to isolated sinoatrial node tissue and showed that, unlike nerve or skeletal muscle, SA nodal cells never truly rest — their membrane conductance changes continuously even at "resting" potentials, consistent with a slowly activating current driving spontaneous depolarization. The current itself was characterized in detail in the late 1970s and 1980s by Dario DiFrancesco, who used single-cell and multicellular voltage-clamp recordings from rabbit SA node to isolate a current activated by hyperpolarization (opposite to the behavior of most voltage-gated channels), carried by both Na⁺ and K⁺, and blocked by cesium ions. Because its behavior was so unlike any previously known current, DiFrancesco named it the "funny" current (Iꜰ). Direct pharmacological confirmation came later: ivabradine, a selective Iꜰ blocker, slows heart rate in intact animals and humans without affecting contractility or blood pressure much — exactly the prediction if Iꜰ specifically controls the rate of phase 4 depolarization. This drug is now used clinically to treat inappropriate sinus tachycardia and chronic heart failure, itself strong functional evidence for the mechanism.

Patch clamp dissects the ventricular plateau (Noma, Reuter, and colleagues). The plateau's dependence on L-type Ca²⁺ current was established through voltage-clamp experiments on isolated ventricular myocytes in the 1970s–80s (Harald Reuter and others), showing a slow inward current, separate from the fast Na⁺ current, that was carried by Ca²⁺ (blocked by Ca²⁺ channel antagonists such as verapamil and enhanced by raising extracellular Ca²⁺), and that its time course matched the duration of the plateau. Akinori Noma and others used single-channel patch-clamp recording (the technique developed by Erwin Neher and Bert Sakmann, for which they won the Nobel Prize in 1991) on cardiac cells to resolve individual L-type Ca²⁺ channel openings and individual delayed-rectifier K⁺ channel openings, directly confirming that the plateau reflects a dynamic balance of two opposing currents rather than a single "held-open" state.

Optical mapping visualizes the spreading wavefront. More recent evidence for the conduction pathway comes from optical mapping experiments: isolated, perfused hearts are loaded with voltage-sensitive dyes whose fluorescence changes with membrane potential, and high-speed cameras record the wave of depolarization sweeping across the epicardial and endocardial surfaces in real time. These studies (building on earlier work with multi-electrode arrays by researchers such as Durrer and colleagues in the 1970s, who mapped activation times across the human heart during cardiac surgery) directly visualize what electrophysiology predicted: the impulse originates at the SA node, spreads across the atria, pauses at the AV node, and then activates the ventricular endocardium from apex toward base almost simultaneously via the Purkinje network — matching the measured conduction velocities and explaining the normal shape and timing of the ECG waveform.

Gap junctions as the anatomical substrate for the syncytium. Werner Forssmann and later electron microscopists identified intercalated discs — dense junctional complexes at the ends of cardiac myocytes — and within them, gap junction plaques. Functional confirmation came from dye-coupling experiments: fluorescent tracer molecules injected into one cardiac myocyte were shown to pass rapidly into neighboring cells, but not across regions where connexin channels were pharmacologically blocked (e.g., with heptanol) or genetically deleted (connexin-43 knockout mice), which show markedly slowed conduction and increased arrhythmia susceptibility — direct evidence that gap junctions, not simple extracellular current spread, are what makes the myocardium a functional syncytium.

Example 1 — Calculating total AV delay's contribution to stroke volume. A cardiologist is evaluating a patient whose ECG shows a prolonged PR interval of 260 ms (normal 120–200 ms), a first-degree AV block. Assume normal atrial systole takes 100 ms to fully empty into the ventricle once the atrial impulse arrives, and normal PR interval is 160 ms.

• In a healthy heart: SA node fires → atrial depolarization begins almost immediately → 160 ms later, ventricles depolarize. Since atrial contraction (mechanical) lags atrial depolarization (electrical) by ~ a short delay, and atrial systole (~100 ms) fits comfortably within the 160 ms PR interval, atrial contraction completes before ventricular contraction begins — full "atrial kick" is delivered.
• In this patient: PR interval is 260 ms, meaning the AV node delay itself is prolonged (the atria depolarize normally, but conduction through the AV node is unusually slow — often due to fibrosis, ischemia, or increased vagal tone slowing Ca²⁺-channel-dependent conduction). Since 260 ms still exceeds the 100 ms needed for atrial systole to complete, the atrial kick is still delivered before ventricular contraction, so stroke volume is preserved in simple first-degree block — it is usually asymptomatic.
• Contrast: if the delay lengthens further (progressing toward second- or third-degree block), the atrial impulse may not reach the ventricle at all for one or more beats, atrial and ventricular contraction become dissociated in timing, and the atrial kick's contribution to ventricular filling (normally about 20–30% of end-diastolic volume) is lost intermittently, reducing stroke volume and cardiac output — explaining why higher-grade AV blocks, unlike first-degree block, often produce symptoms (dizziness, syncope) and may require a pacemaker.

Example 2 — Reading an ectopic pacemaker scenario. A resting person has an intrinsic SA node rate of 75 beats/min. Suppose the SA node is damaged by a small infarct. The intrinsic firing rates of the remaining pacemaker tissues are:

Because cardiac pacemaker hierarchy works on the principle that the fastest intrinsic rhythm suppresses (overdrives) all slower ones (via a mechanism called overdrive suppression, in which the higher rate keeps Na⁺/K⁺-ATPase activity elevated in the slower cells, hyperpolarizing them and delaying their own spontaneous depolarization), losing the SA node does not silence the heart — it reveals the next-fastest pacemaker.

• The AV node becomes the new pacemaker, at an intrinsic rate of ~40–60 beats/min ("junctional rhythm").
• On the ECG, this typically shows a normal-looking QRS complex (ventricles still activated via the normal His-Purkinje pathway) but no normal P wave preceding it (or an inverted/retrograde P wave, since the atria are now depolarized backward from the AV node), because atrial depolarization is no longer initiated from the SA node.
• Clinically, this patient would show a resting heart rate around 45–55 beats/min — bradycardia — with preserved (if reduced) cardiac output, since the AV node can still drive the ventricles through the intact conduction system; symptoms depend on whether this rate meets metabolic demand.
• If the AV node also failed, a still slower ventricular ("idioventricular") rhythm of 15–40 beats/min would take over, usually too slow to sustain adequate cardiac output without medical intervention such as an artificial pacemaker.

:::warning[Do not confuse the SA node's role as "fastest pacemaker" with an assumption that it is the only site capable of automaticity.] Every cell in the AV node, bundle of His, and Purkinje system is also capable of spontaneous depolarization; the SA node simply normally fires fastest and suppresses the others via overdrive suppression. If it is damaged, slowed, or its signal fails to reach the ventricles (as in complete heart block), a lower "latent pacemaker" will take over at its own, slower intrinsic rate — the heart does not simply stop, but it may beat dangerously slowly.

Dario DiFrancesco's identification of the "funny current" transformed cardiac electrophysiology from a phenomenological description ("nodal cells drift to threshold") into a precise molecular mechanism. Working first in Cambridge and Milan, DiFrancesco used voltage-clamp recordings from isolated rabbit sinoatrial node preparations, painstakingly separating the small, slowly activating inward current from the much larger currents active at the same voltages. He showed the current activated on hyperpolarization — backwards from the textbook expectation for excitable membranes — and was carried by a mixed Na⁺/K⁺ permeability through what would later be identified as HCN (hyperpolarization-activated cyclic nucleotide-gated) channels. His decades of subsequent work connected this current to autonomic control of heart rate (showing that cAMP directly binds HCN channels to shift their activation, explaining sympathetic acceleration without requiring protein phosphorylation) and, crucially, to a clinically useful drug target: selective Iꜰ blockade as a way to reduce heart rate without weakening contraction, realized in the drug ivabradine.

Understanding pacemaker and working-cell action potentials underlies essentially all of clinical cardiac electrophysiology. Antiarrhythmic drugs are classified by the ion channel or receptor they target based directly on this mechanism: Class I drugs block Na⁺ channels (slowing phase 0 upstroke and conduction velocity), Class II are beta-blockers (reducing sympathetic drive to Iꜰ and I_Ca in nodal tissue), Class III block K⁺ channels (prolonging the plateau and refractory period, e.g., amiodarone), and Class IV block L-type Ca²⁺ channels (slowing AV nodal conduction, e.g., verapamil, used to control ventricular rate in atrial fibrillation by exploiting the AV node's protective "gatekeeper" role). Artificial pacemakers are engineered replacements for a failed SA or AV node, delivering rhythmic electrical stimuli that exploit the same excitability threshold mechanism described here. Implantable cardioverter-defibrillators detect the electrical chaos of ventricular fibrillation (essentially, breakdown of the ordered conduction pathway into disorganized re-entrant circuits) and deliver a shock that simultaneously depolarizes the whole myocardium, resetting all cells to a common refractory state so that organized SA-node-driven rhythm can resume. In agriculture and comparative physiology, understanding conserved ion channel mechanisms (HCN channels, L-type Ca²⁺ channels) across vertebrate hearts underlies veterinary cardiology and toxicology (e.g., predicting how pesticides or plant toxins that block cardiac ion channels affect livestock). In basic and translational research, patient-derived induced pluripotent stem cell-derived cardiomyocytes are now used to model inherited arrhythmia syndromes (such as long QT syndrome, caused by mutations in the very K⁺ or Na⁺ channel genes described here) and to screen new drugs for unwanted cardiac ion channel side effects before they reach clinical trials.

Ask the tutor: How does this electrical sequence translate into the mechanical events and pressure changes of the cardiac cycle?