Physiology · Unit 3: The heart and circulation

Cardiac Action Potentials and the ECG

Why does a ventricular cell stay depolarised for a fifth of a second, how does a pacemaker cell fire with no resting potential, and how does the electrocardiogram turn the heart's spreading wave into lines on paper? This lesson builds the ventricular and sinoatrial action potentials from their currents, with the dog, frog and mouse experiments behind them, follows calcium from the plateau to contraction, and traces the wave through the AV node. Afterwards you can read rate, intervals, a rate-corrected QT and a frontal-plane axis from an ECG, and predict what raised extracellular potassium does to the resting potential, conduction and the tracing.

Once excited, a ventricular muscle cell stays depolarised for a few hundred milliseconds, roughly a hundred times as long as a nerve spike. That plateau sets how much calcium enters, keeps beats from fusing, and shows on the skin as the stretch between the QRS complex and the T wave. This lesson goes further than circulation and the heart, from currents to the tracing.

A long plateau keeps the ventricle from summing its twitches

Teaching values for a human or other large-mammal ventricular cell, from recent reviews (mouse and rat ventricular action potentials are much shorter, with little plateau): phase 4, rest, sits near -90 mV, held close to the potassium equilibrium potential (EK) by the inward-rectifier current IK1. In phase 0, sodium channels (Nav1.5) open once the membrane is depolarised to threshold. Sources differ on the peak: one review gives about +30 mV, another an overshoot of +40 to +60 mV with a maximum rate of rise near 400 V per s. How the spike is made is in the action potential. Phase 1 is a small notch as sodium channels inactivate and a transient outward potassium current, Ito, flows.

Phase 2, the plateau, lasts about 200 ms and is a balance. The L-type calcium current (ICaL, through Cav1.2) flows in; the delayed-rectifier potassium currents IKr (the hERG channel) and IKs flow out, like a tug of war with the rope held near the middle. In phase 3 the L-type channels close and the potassium currents win. Several potassium currents can repolarise the cell, so losing one to a gene variant or a drug is partly covered, a margin called the repolarisation reserve. In isolated cells and some cut wedge preparations, mid-wall (M) cells have the longest action potentials, then endocardial, then epicardial; whether this ordering holds in the intact, well-coupled heart is debated.

While the membrane is depolarised, sodium channels stay inactivated and the cell is refractory: a second stimulus cannot fire it. The refractory period lasts nearly as long as the action potential and so covers most of the twitch. A skeletal muscle fibre, with its brief action potential, can be restimulated during a twitch and summed into tetanus (skeletal muscle mechanics); a ventricular cell cannot, so the ventricle refills between beats.

The classic experiment: what carries the plateau?

The fast sodium current inactivates within milliseconds, so what keeps a ventricular cell depolarised for hundreds? Perhaps a slowly inactivating sodium current. G. W. Beeler Jr. and Harald Reuter tested this in dog ventricular muscle under voltage clamp (Journal of Physiology, 1970): a conditioning depolarisation inactivated the fast sodium system, and they recorded the inward current left.

A slow inward current remained. It persisted in sodium-free solution, was unaffected by tetrodotoxin (a fast sodium channel blocker) and by magnesium, and was very sensitive to external calcium. Its threshold was near -35 mV in Tyrode solution, and its inactivation time constants ran from 40 to 700 ms between -35 and +50 mV, slow enough to span a plateau. They concluded that calcium carries it.

Ruled out: the tetrodotoxin-sensitive sodium channel as the carrier. Not shown: the channel protein (later Cav1.2), human cells, or that the plateau is calcium current alone; and voltage in a multicellular strip is never perfectly uniform. Nor was this the first cardiac calcium current: Reuter had reported a calcium-dependent slow inward current in Purkinje fibres in 1967.

Pacemaker cells have no resting potential

A sinoatrial (SA) node cell never rests. After each action potential its voltage falls to a maximal diastolic potential, the most negative point of the cycle, then drifts upward in phase 4 diastolic depolarisation to threshold. L-type calcium channels carry its slow upstroke, and there is no plateau.

Several currents drive the drift; two are best known. The funny current (If), carried mainly by HCN4 channels, is activated by hyperpolarisation and carries both sodium and potassium, a net inward current at diastolic voltages. How far If is activated at the end of each action potential helps set the steepness of phase 4 and so the rate. A calcium clock of local calcium releases from the sarcoplasmic reticulum (SR) in late diastole adds inward current through the sodium-calcium exchanger. In the coupled-clock model, built mostly from rabbit cells, the two clocks entrain each other. Other currents also contribute, including a low-threshold L-type calcium current (Cav1.3) and the decay of potassium current left from the action potential. How much each contributes is still debated.

Intrinsic rates form a hierarchy: the SA node is fastest; in a standard textbook account, AV node cells fire about 40 to 60 per min and His-Purkinje cells about 15 to 40. The resting sinus rate is usually below the node’s intrinsic rate because vagal tone slows it. The fastest site leads, exciting each slower one before its own ramp reaches threshold.

Autonomic nerves act on the ramp. Noradrenaline at beta-adrenergic receptors raises cyclic AMP, which increases If and steepens phase 4. Acetylcholine at muscarinic M2 receptors lowers cyclic AMP and If, and also opens a G-protein-gated potassium channel that makes the maximal diastolic potential more negative (GPCRs and G proteins; reflex control is in regulating arterial pressure). A simple description of the timing:

cycle length = (threshold - maximal diastolic potential) / slope of phase 4 + action potential duration

In a made-up example, a ramp from -60 to -40 mV at 0.05 mV per ms takes 400 ms; with a 200 ms action potential the cycle is 600 ms, 100 per min. Double the slope: 400 ms, 150 per min.

Pacemaker slope and heart rate⚙ original · interactive
  • diastolic ramp (phase 4)
  • action potential (shape and height schematic)
  • threshold
  • maximal diastolic potential (MDP)
  • one tick per beat
  • the lesson’s made-up example (cycle 800 ms)
Autonomic input
Values used in the rule
Ramp time = (threshold − MDP) / slope
Action potential duration (fixed in this sketch)
400 ms
Cycle length = ramp time + action potential
Rate = 60,000 ms per min / cycle length
R-R on paper at 25 mm per s (1 small square = 0.04 s, 1 large = 0.20 s)
Check from the paper: 1,500 / small squares, 300 / large squares

Hutter and Trautwein’s numbers are frog values: they recorded from sinus venosus fibres of the isolated frog heart, where vagal stimulation moved the mean maximal diastolic potential from about −55 to −65 mV (largest shift 23 mV) and suppressed the ramp, and sympathetic stimulation steepened the ramp with the threshold unchanged. They are not mammalian sinoatrial values, and the sliders here are not fitted to them.

Illustrative sketch, not an ionic model and not a measurement. In this sketch (made up for the sketch unless the lesson gives it): one pacemaker cell; the lesson’s simple description, cycle length = (threshold − maximal diastolic potential) / slope of phase 4 + action potential duration, with a straight ramp; a fixed 400 ms action potential, and the lesson’s made-up example of −60 mV, −40 mV and 0.05 mV per ms, are the lesson’s; the sympathetic doubling of the slope is the lesson’s made-up doubling, but the vagal factor 0.8, the 10 mV shift and all slider ranges are invented; threshold is taken as unchanged by autonomic input (as Hutter and Trautwein found for sympathetic stimulation in the frog; the lesson does not say for vagal); the spike’s height and shape are drawn schematically; the window starts at the end of an action potential; every firing gives one beat of a regular rhythm, so R-R equals the cycle length.

Rule to keep: cycle length = (threshold − maximal diastolic potential) / slope of phase 4 + action potential duration, and rate = 60,000 ms per min / cycle length; a steeper ramp shortens the cycle, a more negative maximal diastolic potential or a less negative threshold lengthens it.

The modern experiment: deleting HCN4 in the adult mouse

If the funny current were the whole pacemaker, removing it should stop the heart. Hcn4-mutant mouse embryos lost about 85 percent of If (Stieber and colleagues, 2003) but died, so Mirko Baruscotti, Dario DiFrancesco and colleagues (PNAS, 2011) deleted Hcn4 in the adult mouse heart with a tamoxifen-inducible, cardiac-specific system. In isolated SA node myocytes, If fell by about 70 percent and spontaneous rate by about 60 percent, and the residual If still responded to beta-adrenergic stimulation. In the intact mice, they report, heart rate fell by about half and AV block developed.

Rate fell by about half and the mice died within about five days; the rhythm did not stop at once. In this model, loss of HCN4 disrupted adult rate and AV conduction. An earlier adult knockout (Herrmann and colleagues, EMBO Journal, 2007) also removed most sinoatrial If but gave recurrent sinus pauses, with no slowing of baseline rate and normal acceleration under sympathetic stimulation, so the phenotype differs between models. Neither result shows that If alone makes the rhythm, and a mouse heart beats several times faster than a human’s. In humans, Schulze-Bahr and colleagues (2003) found a heterozygous HCN4 deletion (1631delC) in one person with sinus node dysfunction; in COS-7 cells the mutant gave If-like currents insensitive to cyclic AMP.

Calcium in, more calcium out

Calcium entering through L-type channels at the dyad, where a T tubule meets the junctional SR, raises calcium in that narrow space and opens the SR’s ryanodine receptors (RyR2), which release far more: calcium-induced calcium release (CICR). The Fabiatos’ skinned-cell evidence is in muscle and movement. Why does this positive feedback not run away? Release is under local control: each cluster of RyR2 responds mainly to the L-type channels next to it, so total release is graded with the L-type current, and release at each site shuts off before the SR empties, by mechanisms still being studied. The fraction of SR calcium released per beat varies with SR load and the trigger. Calcium then returns to the SR through the pump SERCA and leaves the cell through the sodium-calcium exchanger (NCX), and the muscle relaxes.

The release channel matters in people: Priori and colleagues (2001) found RyR2 mutations in four of twelve probands with catecholaminergic polymorphic ventricular tachycardia, an inherited arrhythmia. Contractility, the strength of contraction at a given filling, rises with sympathetic drive as protein kinase A phosphorylates Rad, a protein that inhibits the L-type channel (relieving the inhibition, so more calcium enters), and phospholamban (releasing its brake on SERCA, so the SR holds more). PKA also phosphorylates troponin I, which speeds relaxation; see cAMP and PKA and, for the loop, the cardiac cycle.

The wave pauses at the AV node, and the ECG adds up the wave

Excitation crosses the atria to the atrioventricular (AV) node, normally the only electrical path into the ventricles, pauses, then runs quickly through the bundle of His, the bundle branches and the Purkinje fibres. In perfused rabbit hearts, optical mapping found a step delay of more than 40 ms at the junction of atrium and node, a delay that grew with rapid atrial pacing. Refractory periods in the same rabbit work were about 81 ms in atrium, 90 ms in AV node and 185 ms in His bundle.

The electrocardiogram (ECG) is the summed extracellular field of many cells, recorded from the skin: not one cell’s action potential and not contraction. A depolarisation front moving toward a positive electrode gives an upward deflection. Willem Einthoven set out leads I (right arm to left arm), II (right arm to left leg) and III (left arm to left leg) as a triangle. The P wave records atrial depolarisation, the QRS complex ventricular depolarisation and the T wave ventricular repolarisation; atrial repolarisation is hidden in the QRS. The PR interval, from the start of P to the start of QRS, contains the AV delay. In healthy adults at rest PR typically runs 0.12 to 0.20 s and QRS lasts under 0.12 s.

The textbook account of the upright T wave is that the epicardium repolarises first. Mapping studies question how large that transmural gradient is: in nine perfused pig hearts, repolarisation differed by only about 14 ms across the wall, against 66 ms from left to right and 51 ms from apex to base. Gradients along several axes probably shape the T wave, and how much each matters is still debated.

AV block, read as conduction patterns: in first-degree block every P wave conducts, after a longer delay. In Mobitz I (Wenckebach) the PR lengthens beat by beat until one P fails, then restarts, as a rate-dependent delay like the rabbit step would produce. In Mobitz II the PR stays constant and a P suddenly fails, usually from block below the node. In third-degree block no P conducts, and a slower escape pacemaker drives the ventricles. First-degree and Mobitz I block can be found in healthy endurance athletes and are usually attributed to high vagal tone.

Worked problem: reading one tracing

Illustrative numbers, adult human resting ECG at 25 mm per s: 1 small square = 1 mm = 0.04 s; 1 large square = 5 mm = 0.20 s. Assume a regular rhythm.

  1. Rate. R-R = 4 large squares = 0.80 s. Rate = 60 s per min / 0.80 s = 75 per min (check: 300 / 4 = 75).
  2. Intervals. PR = 4 small squares = 0.16 s; QRS = 2 small squares = 0.08 s.
  3. QT corrected for rate. QT = 9 small squares = 0.36 s. QT shortens as rate rises, so it is corrected to a 1 s cycle:

Bazett: QTc = QT / square root of RR. Fridericia: QTc = QT / cube root of RR (RR in s)

Bazett: 0.36 / 0.894 = 0.40 s. Fridericia: 0.36 / 0.928 = 0.39 s. At 120 per min (R-R 0.50 s) with QT 0.30 s: Bazett 0.30 / 0.707 = 0.42 s; Fridericia 0.30 / 0.794 = 0.38 s. Both leave QT unchanged at R-R = 1 s and drift apart as rate rises. Bazett’s is widely described as overcorrecting at fast rates; his 1920 formula came from a small group of healthy people.

  1. Axis. The mean QRS axis is the average frontal-plane direction of ventricular depolarisation. With the standard hexaxial angles (lead I 0 degrees, lead II +60, aVF +90, aVL -30), net QRS is positive in I and aVF, so the axis lies between 0 and +90 degrees. QRS is isoelectric in aVL, so the axis is perpendicular to it, at +60 or -120 degrees; the quadrant picks +60. Check: lead II should show the largest positive QRS.

Answer: 75 per min, PR 0.16 s, QRS 0.08 s, QTc 0.40 s (Bazett) or 0.39 s (Fridericia), axis about +60 degrees.

Potassium moves the resting potential and reshapes the ECG

Because IK1 dominates the resting ventricular membrane, the resting potential follows EK. The Nernst equation (membrane transport) at 37 C gives 61.5 mV per tenfold ratio. With intracellular potassium at 140 mmol per L:

EK = 61.5 mV x log10([K]outside / [K]inside)

At 4 mmol per L outside, EK = 61.5 x (-1.544) = -95 mV. At 7 mmol per L, EK = 61.5 x (-1.301) = -80 mV, assuming the resting potential tracks EK, an approximation.

Predictions, from models, isolated hearts and animal preparations: a modest depolarisation brings cells nearer threshold, so conduction first speeds. With larger rises, more sodium channels sit inactivated, phase 0 slows and conduction slows; propagation fails only far higher. Raised potassium also increases potassium conductance, so action potentials shorten and repolarisation becomes more synchronous: the classic early ECG change is tall, peaked T waves, although in people the potassium level at which ECG changes appear varies widely. Slower conduction then broadens and flattens the P wave and widens the QRS. Low extracellular potassium does the reverse to duration, lengthening the action potential by reducing outward current through potassium channels and the sodium-potassium pump. Regulation of plasma potassium is in water, sodium and potassium.

Design problem

Hutter and Trautwein (Journal of General Physiology, 1956) recorded with intracellular microelectrodes from the isolated, beating frog heart while stimulating its nerves. Vagal stimulation stops the beat. Does the vagus (A) make the pacemaker membrane more negative, (B) stop the ramp at the same diastolic potential, or (C) block spread of excitation out of the pacemaker? Which recordings tell these apart, what is the control tissue, and what would sympathetic stimulation do?

One way to do it

Record maximal diastolic potential and ramp slope in sinus venosus fibres (the frog’s pacemaker region) during vagal stimulation. A predicts a more negative diastolic potential; B the same potential with a flat ramp; C normal pacemaker activity with a silent atrium. As control, record auricle fibres, which have a stable diastolic potential, to ask whether any hyperpolarisation is general.

Their data: in 28 experiments the sinus fibres’ mean maximal diastolic potential went from 55 to 65.4 mV in magnitude (about -55 to -65 mV; largest shift 23 mV), the ramp was suppressed, and auricle fibres did not change. Hypothesis A fits. Sympathetic stimulation steepened the pacemaker potential with threshold unchanged.

Ruled in: both autonomic limbs act directly on the pacemaker potential. Not shown: which ion carries the change, or how a mammalian SA node behaves; mammalian atrial muscle, unlike this frog auricle, does respond to acetylcholine. Extensions: vary external potassium to test the permeability idea, or block muscarinic receptors (Loewi’s frog hearts are in transmitter systems).

How we measure it

Voltage clamp of cardiac preparations

Hold the membrane at a chosen voltage with a feedback amplifier and record the current needed to keep it there. Changing the voltage protocol, the bath ions or a blocker such as tetrodotoxin separates one current from another, as Beeler and Reuter did in dog ventricle. In multicellular strips the voltage is not perfectly uniform, which limits precision.

Intracellular microelectrode recording

Push a fine glass pipette filled with salt solution into a single cell and record its membrane potential through each beat. It shows the shape of the action potential, the maximal diastolic potential and the slope of the pacemaker ramp, and how nerve stimulation changes them.

Electrocardiography

Record voltage differences between electrodes on the skin as excitation spreads through the heart, on paper moving at a standard speed. The tracing is a summed extracellular signal of many cells; its timing gives rate and conduction intervals, and the size and polarity of QRS across the limb leads give the mean electrical axis.

Inducible tissue-specific knockout mice

Flank a gene with recombination sites and delete it only in one tissue, and only when a drug such as tamoxifen is given. This avoids embryonic death and tests what the gene does in the adult, as in the cardiac Hcn4 knockout.

Finish line

Test yourself

8 questions

Practice and MCAT-style, with explained answers.

Next · Lesson 6

The Cardiac Cycle and Pressure-Volume Loops

Plot ventricular pressure against volume and every heartbeat draws a loop. Which corner moves when the arteries tighten?

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← Lesson 4 · Smooth Muscle and the Myogenic Response

Willem Einthoven

Willem Einthoven

Built the string galvanometer, which recorded the heart's currents faithfully from the body surface, and set out leads I, II and III as the sides of a triangle from which the frontal-plane electrical axis can be calculated. He received the Nobel Prize in Physiology or Medicine for 1924.

Einthoven, a physiologist at Leiden in the Netherlands, started from an instrument that was too sluggish. In 1887 Augustus Désiré Waller had recorded the human heart's electrical activity with a capillary electrometer, in which a mercury meniscus moves with voltage. The records were real but distorted by the lag of the mercury. Einthoven first analysed such records with mathematical corrections and then built an instrument that would not need them. In his string galvanometer a very fine conducting thread hung between the poles of a strong electromagnet; current through the thread deflected it, and its shadow was photographed on moving paper. Because the thread was so light, it followed the heart's fast changes. He then fixed where the electrodes go. Leads I, II and III join the right arm, left arm and left leg as the sides of a triangle, and the deflections in two leads give the direction of the heart's mean electrical axis in the frontal plane. That geometry is still how the frontal axis is read today.

✓ verbatim Einthoven's Nobel lecture, The string galvanometer and the measurement of the action currents of the heart (1925), at NobelPrize.org; Barold, Cardiac Electrophysiology Review 7:99-104 (2003), on Einthoven's triangle and the electrical axis.
G. W. Beeler Jr. and Harald Reuter

G. W. Beeler Jr. and Harald Reuter

Showed under voltage clamp in dog ventricular muscle that a slow inward current, left after the fast sodium current is inactivated, depends on external calcium and not on sodium, and concluded that calcium carries the current that sustains the plateau.

By the 1960s the fast sodium current of heart muscle was known to inactivate within a few milliseconds, yet a ventricular action potential lasts hundreds. Something had to keep charge flowing inward. Harald Reuter had already reported, in Purkinje fibres in 1967, a slow inward current that depended on external calcium. With G. W. Beeler Jr. he turned to dog ventricular muscle and the voltage clamp. They held the membrane at a depolarised level long enough to inactivate the fast sodium system, then stepped the voltage and measured what remained. A slow inward current survived sodium-free solution and tetrodotoxin but rose and fell with external calcium, and its inactivation was slow enough to span a plateau. Their 1970 paper concluded that calcium carries it. Seven years later the same pair used such measurements to build a mathematical model of the ventricular action potential. Models of that kind, now built from human cells, are how investigators test whether blocking one current lengthens the whole action potential.

✓ verbatim Beeler and Reuter, Membrane calcium current in ventricular myocardial fibres, Journal of Physiology 207:191-209 (1970); Beeler and Reuter, Reconstruction of the action potential of ventricular myocardial fibres, Journal of Physiology 268:177-210 (1977).
Otto F. Hutter and Wolfgang Trautwein

Otto F. Hutter and Wolfgang Trautwein

Recorded with intracellular microelectrodes from the beating frog heart while stimulating its nerves, and showed that the vagus hyperpolarises and flattens the pacemaker potential of sinus venosus fibres while sympathetic stimulation steepens it.

Otto Loewi had shown in the 1920s that the vagus slows the frog heart by releasing a chemical. In the 1950s Hutter and Trautwein, and at the same time José del Castillo and Bernard Katz, set out to see what vagal stimulation did to the voltage of a single pacemaker cell. Hutter and Trautwein did so with glass microelectrodes, then a young technique, pushed into fibres of the isolated, spontaneously beating frog heart. In the sinus venosus, the frog's pacemaker region, each fibre showed a slow depolarisation during diastole; in the auricle, the voltage between beats stayed flat. When they stimulated the vagus, the sinus fibres' ramp was suppressed and their diastolic potential moved more negative, by up to 23 mV, while auricle fibres did not change. Sympathetic stimulation did the opposite to the ramp: it rose faster, with the threshold unchanged. Their 1956 paper put both autonomic effects on the pacemaker membrane itself. Which ions were responsible was a further question. Later work found a potassium channel that acetylcholine opens through a G protein.

✓ verbatim Hutter and Trautwein, Vagal and sympathetic effects on the pacemaker fibers in the sinus venosus of the heart, Journal of General Physiology 39:715-733 (1956), open access.
Dario DiFrancesco

Dario DiFrancesco

With H. F. Brown and S. J. Noble described a current in rabbit sinoatrial tissue that is activated by hyperpolarisation and increased by adrenaline, later called the funny current, and was an author of the 2011 adult mouse Hcn4 knockout that tested its role.

In 1979 H. F. Brown, Dario DiFrancesco and S. J. Noble reported in Nature that a current in rabbit sinoatrial node tissue was increased by adrenaline, which suggested how sympathetic nerves speed the heart. The current behaved oddly. It switched on when the membrane was made more negative, the reverse of most voltage-gated currents, and it carried both sodium and potassium, so it flowed inward at diastolic voltages. It became known as the funny current, If. DiFrancesco, working in Milan, spent the following decades on its properties and its control by cyclic AMP. After the HCN channel genes were cloned in the late 1990s, HCN4 was identified as the main isoform in the sinoatrial node, and the question became testable in an animal. In 2011 Mirko Baruscotti, DiFrancesco and colleagues deleted Hcn4 in the hearts of adult mice. Heart rate fell by about half and AV block developed, but the rhythm did not stop at once, a result that keeps If central to rate control without making it the only pacemaker mechanism.

✓ verbatim DiFrancesco, The role of the funny current in pacemaker activity, Circulation Research 106:434-446 (2010); Baruscotti and colleagues, Proceedings of the National Academy of Sciences 108:1705-1710 (2011).
Test yourself
Question 1 of 8 Score 0 / 0

In a human ventricular myocyte, which current carries most of the inward charge that holds the plateau (phase 2)?
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Simulations

  • Pacemaker slope and heart rate · Original interactive — Biochemistrypedia (Deppmann Lab).

Scientist profiles & quotes

  • Willem Einthoven — Einthoven's Nobel lecture, The string galvanometer and the measurement of the action currents of the heart (1925), at NobelPrize.org; Barold, Cardiac Electrophysiology Review 7:99-104 (2003), on Einthoven's triangle and the electrical axis.
  • G. W. Beeler Jr. and Harald Reuter — Beeler and Reuter, Membrane calcium current in ventricular myocardial fibres, Journal of Physiology 207:191-209 (1970); Beeler and Reuter, Reconstruction of the action potential of ventricular myocardial fibres, Journal of Physiology 268:177-210 (1977).
  • Otto F. Hutter and Wolfgang Trautwein — Hutter and Trautwein, Vagal and sympathetic effects on the pacemaker fibers in the sinus venosus of the heart, Journal of General Physiology 39:715-733 (1956), open access.
  • Dario DiFrancesco — DiFrancesco, The role of the funny current in pacemaker activity, Circulation Research 106:434-446 (2010); Baruscotti and colleagues, Proceedings of the National Academy of Sciences 108:1705-1710 (2011).

Quotes are verbatim from the cited source. Profile text is original to this site and was checked against the sources cited.

Images & figures

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Like I'm five

Your heart makes its own tiny electrical sparks. A small patch of cells fires by itself, over and over, like a clock, and the spark spreads across the heart and makes it squeeze. Each heart cell stays switched on for a while after it fires and cannot fire again until its squeeze is nearly over, so squeezes never pile up. Stickers on your chest can pick up the spark and draw it as a wiggly line.
High school

Human heart muscle cells fire action potentials, but each lasts a few hundred milliseconds because calcium flows in while potassium flows out, holding the cell in a plateau. During that time the cell cannot fire again, so beats cannot merge into one long cramp. Pacemaker cells in the sinoatrial node have no steady resting voltage: they drift up to threshold and fire, and sympathetic nerves make the drift faster while the vagus nerve makes it slower. The wave pauses at the atrioventricular node, then races through the ventricles. An ECG records the summed wave from the skin: P for the atria depolarising, QRS for the ventricles depolarising, T for the ventricles repolarising.
College

In ventricular myocytes, Nav1.5 carries the phase 0 upstroke from about -90 mV, Ito makes the phase 1 notch, and the roughly 200 ms plateau is a balance of inward L-type calcium current (Cav1.2) against outward IKr and IKs; IK1 holds phase 4 near EK. The long refractory period prevents tetanus. Sinoatrial cells have a maximal diastolic potential instead of a resting potential, a diastolic ramp driven by the hyperpolarisation-activated funny current (HCN4) and by local SR calcium release acting through the sodium-calcium exchanger, and an L-type calcium upstroke. Beta-adrenergic cAMP raises If and steepens the ramp; acetylcholine at M2 receptors lowers If and opens G-protein-gated potassium channels, hyperpolarising the cell. Calcium entry at the dyad triggers graded calcium-induced calcium release from RyR2, and PKA phosphorylation of Rad (relieving its inhibition of the L-type channel) and of phospholamban raises contractility, while phosphorylation of troponin I speeds relaxation. On the ECG, PR contains the AV delay, QRS is ventricular depolarisation, QT approximates ventricular action potential duration, and the mean QRS axis comes from the hexaxial leads. Raised extracellular potassium depolarises the resting potential, shortens the action potential and eventually slows conduction.
Graduate

A simple description of pacemaker rate is cycle length = (threshold - maximal diastolic potential) / diastolic slope + action potential duration, so autonomic control can act on slope (If, the calcium clock) or on the starting voltage (the G-protein-gated potassium current). In adult mouse sinoatrial myocytes, inducible Hcn4 deletion cut If by about 70 percent and spontaneous rate by about 60 percent without abolishing beta-adrenergic acceleration (Baruscotti and colleagues, 2011; an earlier adult knockout by Herrmann and colleagues, 2007, gave sinus pauses with baseline rate and acceleration preserved), which fits a coupled-clock model in which membrane and calcium clocks entrain each other (Lakatta and colleagues, 2010, mostly rabbit data). At the dyad, CICR stays stable because release is locally controlled at separate release units, graded with ICaL, and shut off at each site before the SR empties (how release terminates is still studied); the fraction released varies with SR load. For the ECG, Bazett (QT divided by the square root of RR) and Fridericia (QT divided by the cube root of RR) agree at RR = 1 s and diverge at fast rates, where Bazett gives larger values. The resting potential follows EK = 61.5 log10([K]o / [K]i) mV at 37 C to a first approximation, which is why raised extracellular potassium depolarises cells, first speeding and then slowing conduction as sodium channels inactivate. Open questions include how much of the human sinoatrial rate depends on If versus calcium cycling, and what sets the upright T wave, given that mapping in perfused pig hearts and open-chest dogs found little transmural dispersion of repolarisation.
Two Augustus Wallers

The Waller who recorded the first human electrocardiogram, in 1887 in London, was Augustus Désiré Waller. With a capillary electrometer wired to electrodes on the body, he showed that the beating human heart produces a voltage that can be picked up at the surface, and he published it in the Journal of Physiology that year. He is easily confused with his father, Augustus Volney Waller, who described in frogs how a cut nerve degenerates beyond the cut, the process now called Wallerian degeneration. Same name, two people, two fields.

— Waller, A demonstration on man of electromotive changes accompanying the heart's beat, Journal of Physiology 8:229-234 (1887).
A correction from a small sample

Henry Cuthbert Bazett's 1920 paper on the time relations of the electrocardiogram analysed recordings from a small group of healthy people and related QT to the square root of the cycle length. A century later his correction is still the best known, although it was fitted to so few hearts. Larger data sets and other formulas, such as Fridericia's cube-root form, give different corrected values at fast and slow rates. A corrected QT is therefore always a number from a particular formula, and a report should say which.

— Roguin, Pacing and Clinical Electrophysiology 34:384-388 (2011), a historical review of Bazett; Bazett, An analysis of the time-relations of electrocardiograms, Heart 7:353-370 (1920).
Potassium during a sprint

Plasma potassium is not fixed even in healthy people. In a study of trained athletes cited in a 2017 review, short maximal exercise raised plasma potassium to an average of about 8.2 mmol per L at its peak, and it fell back with a half-time of about 25 s after exercise stopped. No arrhythmias were apparent, although ECGs were not recorded. Working muscle releases potassium with its action potentials, and the catecholamines of exercise stimulate the sodium-potassium pump, which may be part of why these hearts showed no apparent trouble.

— Weiss, Qu and Shivkumar, Electrophysiology of hypokalemia and hyperkalemia, Circulation: Arrhythmia and Electrophysiology 10:e004667 (2017), and Medbo and Sejersted, Journal of Physiology (1990), the athlete study it cites.

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