Medical Physiology, 3rd Edition

Electrophysiology of Cardiac Cells

The cardiac action potential starts in specialized muscle cells of the sinoatrial node and then propagates in an orderly fashion throughout the heart

The cardiac action potential originates in a group of cells called the sinoatrial (SA) node (see Fig. 21-1), located in the right atrium. These cells depolarize spontaneously and fire action potentials at a regular, intrinsic rate that is usually between 60 and 100 times per minute for an individual at rest. Both parasympathetic and sympathetic neural input can modulate this intrinsic pacemaker activity, or automaticity (see pp. 397–398).

Because cardiac cells are electrically coupled through gap junctions (Fig. 21-3A), the action potential propagates from cell to cell in the same way that an action potential in nerve conducts along a single long axon. A spontaneous action potential originating in the SA node will conduct from cell to cell throughout the right atrial muscle and spread to the left atrium. The existence of discrete conducting pathways in the atria is still disputed. About one tenth of a second after its origination, the signal arrives at the atrioventricular (AV) node (see Fig. 21-1). The impulse does not spread directly from the atria to the ventricles because of the presence of a fibrous atrioventricular ring. Instead, the only available pathway is for the impulse to travel from the AV node to the His-Purkinje fiber system, a network of specialized conducting cells that carries the signal to the muscle of both ventricles.


FIGURE 21-3 Conduction in the heart. A, An action potential conducting from left to right causes intracellular current to flow from fully depolarized cells on the left, through gap junctions, and into cell A. Depolarization of cell A causes current to flow from cell A to cell B (IAB). Part of IAB discharges the capacitance of cell B (depolarizing cell B), and part flows downstream to cell C. B, Subthreshold depolarization of cell A decays with distance. C, The speed of conduction increases with greater depolarization of cell A (blue versus red curve) or with a more negative threshold.

The cardiac action potential conducts from cell to cell via gap junctions

The electrical influence of one cardiac cell on another depends on the voltage difference between the cells and on the resistance of the gap junction connecting them. A gap junction (see p. 205) is an electrical synapse (see Fig. 21-3A) that permits electrical current to flow between neighboring cells. According to Ohm's law, the current flowing between cell A and the adjacent cell B (IAB) is proportional to the voltage difference between the two cells (ΔVAB) but inversely proportional to the electrical resistance between them (RAB):

image (21-1)

When RAB is very small (i.e., when the cells are tightly coupled), the gap junctions are minimal barriers to the flow of depolarizing current.

Imagine that several interconnected cells are initially all at their normal resting potentials (see Fig. 21-3B). An action potential propagating from the left of cell A now injects depolarizing current into cell A. As a result, the cell depolarizes to VA, which is now somewhat positive compared with VB. Thus, a small depolarizing current (i.e., positive charges) will also move from cell A to cell B and depolarize cell B. In turn, current flowing from cell B will then depolarize cell C. By this process, the cells closest to the current source undergo the greatest depolarization.

Imagine that the injected current, coming from the active region of the heart to the left, depolarizes cell A just to its threshold (see Fig. 21-3C, red curve) but that cell A has not yet fired an action potential. At this instant, the current passing from cell A to cell B cannot bring cell B to its threshold. Of course, cell A will eventually fire an action potential and, in the process, depolarize enough to inject enough current into cell B to raise cell B to its threshold. Thus, the action potential propagates down the chain of cells, but relatively slowly. On the other hand, if the active region to the left injects more current into cell A (see Fig. 21-3C, blue curve)—producing a larger depolarization in cell A—the current passing from cell A to cell B will be greater and sufficient to depolarize cell B beyond its voltage threshold for a regenerative action potential. However, at this instant, the current passing from cell B to cell C is still not sufficient to trigger an action potential in cell C. That will have to wait until the active region moves closer to cell C, but the wait is not as long as in the first example (red curve in Fig. 21-3C). Thus, the action potential propagates more rapidly in this second example (blue curve in Fig. 21-3C).

In principle, we could make the action potential propagate more rapidly down the chain of cells in two ways. First, we could allow more ion channels to open in the active region of the heart, so that depolarizing current is larger (blue curve in Fig. 21-3C). Second, we could lower the threshold for the regenerative action potential (“more negative threshold” in Fig. 21-3C), so that even the small current represented by the red curve is now sufficient to trigger cell B.

Just as in a nerve axon conducting an action potential, the intracellular and extracellular currents in heart muscle must be equal and opposite. In the active region of the heart (to the left of cell A in Fig. 21-3B), cells have reached threshold and their action potentials provide the source of current that depolarizes cells that are approaching threshold (e.g., cells A and B). As cell A itself is depolarizing to and beyond threshold, its Na+ and Ca2+ channels are opening, enabling these cations (i.e., positive charge) to enter. The positive charge that enters cell A not only depolarizes cell A but also produces a flow of positive charge to cell B—intracellular current. This flow of positive charge discharges the membrane capacitance of cell B, thereby depolarizing cell B and releasing extracellular positive charges that had been associated with the membrane. The movement of this extracellular positive charge from around cell B toward the extracellular region around cell A constitutes the extracellular current. The flow of intracellular current from cell A to cell B and the flow of extracellular current from around cell B to around cell A are equal and opposite. It is the flow of this extracellular current in the heart that gives rise to an instantaneous electrical vector, which changes with time. Each point on an electrocardiogram (ECG) is the sum of the many such electrical vectors, generated by the many cells of the heart.

Cardiac action potentials have as many as five distinctive phases

The initiation time, shape, and duration of the action potential are distinctive for different parts of the heart, reflecting their different functions (see Fig. 21-2). These distinctions arise because the myocytes in each region of the heart have a characteristic set of channels and anatomy. Underlying cardiac action potentials are four major time-dependent and voltage-gated membrane currents (Table 21-1): imageN21-1

TABLE 21-1

Major Cardiac Membrane Currents That Are Time Dependent and Voltage Gated








Na+ current

Nav1.5 (voltage-gated Na+ channel)



Local anesthetics


Ca2+ current

Cav1.2 (L-type Ca2+ channel)






Kv4.3 + KChIP2




Repolarizing image

Kv11.1 (HERG) + miRP1*




Repolarizing image

Kv7.1 (KvLQT1) + minK*



L-768, 673
Benzopyran chromanol






G protein–activated IK,ACh

Kir3.4 (GIRK4)*




ATP-sensitive current, KATP

Kir6.1 + SUR1 or SUR2*
Kir6.2 + SUR1 or SUR2*




If (Na+ + K+)

Pacemaker current





*These are heteromultimeric channels.

GIRK, G protein–activated inwardly rectifying K+ channel; HERG, human ether-à-go-go–related gene (related to Kv family of K+ channel genes); KChIP2, Kv channel–interacting protein 2; TEA, tetraethylammonium; TTX, tetrodotoxin.


Cardiac Ion Channels

Contributed by W. Jonathan Lederer

The number of distinct ion channels found in heart cells has grown dramatically with the development of new tools. While the cellular and organ-level function follows the presentation in the text and this webnote, important subtleties in the detailed function can depend on the additional channel subtypes that may be expressed at varying levels and that can change under stress or during disease. For example, heart cells express not only the “cardiac” sodium channel (Nav1.5) but also other sodium channel types (e.g., Nav1.4, which is normally found in skeletal muscle; see Table 7-1). In addition to the L-type Ca2+channel, cardiac myocytes may also express the T-type Ca2+ channel (see Table 7-2). In many diseases, the expression of the T-type Ca2+ channel increases. Ventricular and atrial myocytes may express K+channels in a diversity much greater than described in the text. Moreover, the array of K+ channels often changes in disease processes. eFigure 21-1 lists some of the prominent channels and how they contribute to the cardiac action potential.


EFIGURE 21-1 Membrane currents that underlie the cardiac action potential. The action potential time course is shown at top left with typical currents shown below on the left. The time course of inward (blue) and outward (green) currents is shown. The components of each channel type shown are presented on the right. (From George AL Jr: J Clin Invest 123:75–83, 2013.)


George AL Jr. Molecular and genetic basis of sudden cardiac death. J Clin Invest. 2013;123:75–83.

1. The Na+ current (INa) is responsible for the rapid depolarizing phase of the action potential in atrial and ventricular muscle and in Purkinje fibers.

2. The Ca2+ current (ICa) is responsible for the rapid depolarizing phase of the action potential in the SA node and AV node; it also triggers contraction in all cardiomyocytes.

3. The K+ current (IK) is responsible for the repolarizing phase of the action potential in all cardiomyocytes.

4. The pacemaker current (If) is responsible, in part, for pacemaker activity in SA nodal cells, AV nodal cells, and Purkinje fibers.

Besides these four currents, channels carry numerous other currents in heart muscle. In addition, two electrogenic transporters imageN21-2 carry current across plasma membranes: the type 1 Na-Ca exchanger (NCX1; see pp. 123–124) and the Na-K pump (see pp. 115–117).


Cardiac Currents Carried by Electrogenic Transporters

Contributed by W. Jonathan Lederer

In addition to the channels listed in Table 21-1, numerous other channels are present in heart muscle. The distribution of this large array of time- and voltage-dependent membrane currents (see Table 21-1) differs in each of the different cardiac cell types. In addition, there are yet other membrane channels (not shown in Table 21-1) that are responsible for “background” currents that we have not discussed, that are not gated by voltage, and that are not time dependent. These background currents can be modulated by diverse factors and help to shape the action potential.

In addition to all of the channels, cardiac cells have two electrogenic transporters that also carry current across the plasma membranes: the Na-Ca exchanger and the Na-K pump.

Na-Ca Exchanger

The Na-Ca exchanger (NCX; see pp. 123–124 and 126) is an electrogenic transporter that normally moves three Na+ ions into the cell in order to extrude one Ca2+ ion, using the electrochemical gradient for Na+as an energy source for transport. Under these conditions, the Na-Ca exchanger produces an inward or depolarizing current (i.e., a net inward movement of positive charge). However, if this electrochemical gradient reverses, as it transiently does early during the cardiac action potential (due to the positive Vm), the Na-Ca exchanger may be able to reverse and mediate entry of Ca2+ and a net outward current. Later during the cardiac action potential, the Na-Ca exchanger returns to its original direction of operation (i.e., Ca2+ extrusion and inward current). During the plateau phase of the action potential, the inward current mediated by the Na-Ca exchanger tends to prolong the action potential.

Na-K Pump

The Na-K pump is also an electrogenic transporter, normally moving two K+ ions into the cell for every three Na+ ions that it transports out of the cell, using ATP as an energy source (see pp. 115–117). Therefore, this pump produces an outward or hyperpolarizing current. Cardiotonic steroids (such as digoxin and ouabain) inhibit the Na-K pump and thereby cause an increase in [Na+]i. This inhibition also reduces the outward current carried by the pump and therefore depolarizes the cell.

Traditionally, the changes in membrane potential (Vm) during the cardiac action potential are divided into separate phases, as illustrated in Figure 21-4A for cardiac action potentials from the SA node and in Figure 21-4B for those from ventricular muscle.


FIGURE 21-4 Phases of cardiac action potentials. The records in this figure are idealized. IKINaICa, and If are currents through K+, Na+, Ca2+, and nonselective cation channels, respectively.

Phase 0 is the upstroke of the action potential. If the upstroke is due only to ICa (see Fig. 21-4A), it will be slow. If the upstroke is due to both ICa and INa (see Fig. 21-4B), it will be fast.

Phase 1 is the rapid repolarization component of the action potential (when it exists). This phase is due to almost total inactivation of INa or ICa and may also depend on the activation of a minor K+ current not listed previously, called Ito (for transient outward current).

Phase 2 is the plateau phase of the action potential, which is prominent in ventricular muscle. It depends on the continued entry of Ca2+ or Na+ ions through their major channels and on a minor membrane current due to the Na-Ca exchanger NCX1. imageN21-2

Phase 3 is the repolarization component of the action potential. It depends on IK (see Table 21-1).

Phase 4 constitutes the electrical diastolic phase of the action potential. Vm during phase 4 is termed the diastolic potential; the most negative Vm during phase 4 is the maximum diastolic potential. In SA and AV nodal cells, changes in IKICa, and If produce pacemaker activity during phase 4. Purkinje fibers also exhibit pacemaker activity but use only If. Atrial and ventricular muscle have no time-dependent currents during phase 4.

The Na+ current is the largest current in the heart

The Na+ current (see Table 21-1) is the largest current in heart muscle, which may have as many as 200 Na+ channels per square micrometer of membrane. These channels are abundant in ventricular and atrial muscle, in Purkinje fibers, and in specialized conduction pathways of the atria. This current is not present in SA or AV nodal cells.

The channel that underlies INa is a classic voltage-gated Na+ channel, with both α and β1 subunits (see pp. 182–185). The unique cardiac α subunit (Nav1.5) has several phosphorylation sites that make it sensitive to stimulation by cAMP-dependent protein kinase (see p. 57). imageN21-3


Cardiac Na+ Channels

Contributed by W. Jonathan Lederer, Emile Boulpaep, Walter Boron

The channel that underlies INa is a classic voltage-gated Na+ channel, with both an α and β1 subunit (see p. 187 and Fig. 7-12A). The cardiac α subunit differs from the brain α subunit in having a long cytoplasmic loop connecting the first and second repeats of its six membrane-spanning segments. This long loop has several phosphorylation sites, and it conveys a unique quality to the cardiac channel: phosphorylation by cAMP-dependent protein kinase (protein kinase A, or PKA; see p. 57stimulates the cardiac channel, but inhibits the brain channel.

At the negative resting potentials of the ventricular muscle cells, the Na+ channels are closed. However, these channels rapidly activate (in 0.1 to 0.2 ms) in response to local depolarization produced by conducted action potentials and produce a massive inward current that underlies most of the rapid upstroke of the cardiac action potential (phase 0 in Fig. 21-4B). If Vm remains at a positive level, these channels close in a time-dependent process known as inactivation. This process, which is slower than activation but still fairly rapid (half-time, ~1 ms), is partly responsible for the rapid repolarization of the action potential (phase 1). At the potentials maintained during the plateau of the cardiac action potential—slightly positive to 0 mV during phase 2—a very small but important component of this current remains (INa,late). The sustained level of INa helps prolong phase 2. imageN21-4


Late Na+ Current

Contributed by W. Jonathan Lederer

Although the primary purpose of INa in ventricular and atrial myocytes is to support the rapid depolarization of the membrane potential during the upstroke of the cardiac action potential and to provide the inward current needed for rapid conduction, there are other aspects of its function. A small residual fraction of the INa channels may incompletely inactivate or exist in a distinct kinetic mode following phase 1 of the action potential. This enables these channels to contribute current, now dubbed INa,late, that lingers long into phases 2 and 3 of the ventricular and atrial action potentials. Both the inward current and the Na+ influx attributed to INa,late can contribute to changes in myocyte behavior that are proarrhythmic. Since many disease conditions enhance INa,late there is an intense effort to identify and test therapeutic agents that block INa,late with minimal impact on the early or normal INa (Maier and Sossalla, 2013). The specific post-translational modifications of the Na+ channel protein subunits that underlie the late Na+channel state remain unknown but are under active investigation.


Maier LS, Sossalla S. The late Na current as a therapeutic target: Where are we? J Mol Cell Cardiol. 2013;61:44–50.

In cardiac tissues other than the SA and AV nodes, the regenerative spread of the conducted action potential depends in large part on the magnitude of INa (see Fig. 21-3C). The depolarization produced by the Na+ current not only activates INa in neighboring cells but also activates other membrane currents in the same cell, including ICa and IK. For example, unlike in skeletal muscle, in which the action potential duration is relatively short, in cardiac myocytes the depolarization—initiated by Nav1.5—activates the L-type cardiac Ca2+ channel (Cav1.2; see next section), which greatly prolongs the depolarizing phase of the cardiac action potential due to its long-duration opening events. Local anesthetic antiarrhythmic drugs, such as lidocaine, work by partially blocking INa.

The Ca2+ current in the heart passes primarily through L-type Ca2+ channels

The Ca2+ current (ICa; see Table 21-1) is present in all cardiac myocytes. The L-type Ca2+ channel (Cav1.2; see pp. 190–193) is the dominant one in the heart. T-type Ca2+ channels, with different biophysical and pharmacological properties, are also present but in smaller amounts.

In the SA node, the role of ICa, like that of the other time- and voltage-dependent membrane currents, is to contribute to pacemaker activity. In both the SA and AV nodes, ICa is the inward current source that is responsible for the upstrokes (phase 0) of the SA and AV nodal action potentials. Because the nodal cells lack the larger INa, their upstrokes are slower than those in atrial and ventricular muscle (compare A and B of Fig. 21-4). Therefore, the smaller ICa discharges the membrane capacitance of neighboring cells in the SA and AV nodes less rapidly, so that the speed of the conducted action potential is much slower than that of any other cardiac tissue. This feature in the AV node leads to an electrical delay between atrial contraction and ventricular contraction that permits more time for the atria to empty blood into the ventricles.

Although it is smaller, ICa sums with INa during the upstroke of the action potentials of the ventricular and atrial muscle and the Purkinje fibers. In this way, it increases the velocity of the conducted action potential in these tissues. Like INaICa produces virtually no current at very negative potentials because the channels are closed. At more positive values of Vm, the Ca2+ channels rapidly activate (in ~1 ms) and, by a completely separate and time-dependent process, inactivate (half-time, 10 to 20 ms). imageN21-5 A small ICa remains during phase 2 of the action potential, helping to prolong the plateau. In atrial and ventricular muscle cells, the Ca2+ entering via L-type Ca2+ channels activates the release of Ca2+ from the sarcoplasmic reticulum (SR) by calcium-induced Ca2+ release (see pp. 242–243). Blockers of L-type Ca2+ channels—therapeutic agents such as verapamil, diltiazem, and nifedipine—act by inhibiting ICa.


Time Course of Ca2+ Current in Ventricular Muscle

Contributed by W. Jonathan Lederer

In Figure 21-4B, the lower panel (red trace) illustrates the time course of the Ca2+ current during an action potential in a ventricular myocyte.

During phase 4, at rest, where Vm is maximally negative, the Ca2+ channels are mostly closed and ICa is a very small inward current. Following the depolarization produced by the very fast Na+ channel during phase 0, the Ca2+ channels activate (in ~1 ms), producing the rapid downstroke of the red ICa record in Figure 21-4B.

Next, by a completely separate and time-dependent process, the Ca2+ channels inactivate at positive potentials (half-time, 10 to 20 ms), producing the slower decay of inward current toward the end of phase 1 in Figure 21-4B. Along with the inactivation of the Na+ channels and the opening of the Kv4.3 channels that underlie Ito, the inactivation of Ca2+ channels contributes to the small repolarization that defines phase 1 (see Fig. 21-4B). Note that, for both activation and inactivation, the cardiac Ca2+ channels are about an order of magnitude slower than cardiac Na+ channels.

During phase 2 of the action potential, a small ICa remains, helping to prolong the plateau. This phase is represented by the flat portion of the red ICa record displaced below the dashed zero-current line in Figure 21-4B.

During phase 3, as Vm returns to negative potentials, two things happen to Ca2+ channels. First, the still-active Ca2+ channels (which were activated by positive Vm values) will go through a process of deactivation (caused by negative Vm values). Second, the Ca2+ channels that had been inactivated during phase 2 now begin to recover from inactivation. The net effect is that a minuscule Ca2+ current remains during phase 4 … which takes us back to the beginning of this discussion.

The repolarizing K+ current turns on slowly

Cardiac action potentials last two orders of magnitude longer than action potentials in skeletal muscle because the repolarizing K+ current turns on very slowly and—in the case of atrial myocytes, Purkinje fibers, and ventricular myocytes—with a considerable delay. The repolarizing K+ current (IK; see Table 21-1) is found in all cardiac myocytes and is responsible for repolarizing the membrane at the end of the action potential (phase 3 in Fig. 21-4A, B). Two currents underlie IK—a relatively rapid component (image) carried by heteromeric HERG/miRP1 channels and a relatively slow component (image) carried by heteromeric KvLQT1/minK channels (see Box 7-3). imageN21-6 The IK membrane current is very small at negative potentials. With depolarization, it slowly activates (20 to 100 ms) but does not inactivate. In SA and AV nodal cells, it contributes to pacemaker activity by slowly deactivating at the diastolic voltage.


Cardiac K+ Currents

Contributed by W. Jonathan Lederer, Emile Boulpaep, Walter Boron

Table 21-1 lists five K+ currents:

• Ito—the transient outward current—occurs during phase 1 of the action potential. Along with the inactivation of the Na+ channels and (a bit later) the inactivation of Ca2+ channels, Ito contributes to the small repolarization that defines phase 1 (see Fig. 21-4B). The Shaker-type K+ channel (see pp. 193–196) Kv4.3 carries Ito.

• image—the rapid repolarizing K+ current—is the current arising from heteromultimeric channels composed of HERG and miRP subunits.

• image—the slow repolarizing K+ current—arises from different heteromultimeric channels composed of KvLQT1 and minK subunits. In older terminology, the delayed-rectifier K+ current is the sum of image and image.

• image—the inward-rectifying current that prevails at the resting potential. The channels are members of the Kir family (KCNJ genes). The channels close during phase 0, and re-open at the end of phase 3.

• GIRK—the G protein–activated, inwardly rectifying K+ channels (also part of the Kir family; see pp. 197–198)—open in response to ACh. Like many K+ channels, the GIRK channels are comprised of two different GIRK subunits clustered as tetramers.

• KATP—the K+ channels inhibited by intracellular ATP (like GIRKs, part of the IR family of K+ channels; see pp. 197–198)—contribute to the background K+ current. The KATP channel is a tetramer comprised of two different subunits, as is the case for the GIRK K+ channels and the channels that give rise to the image and image currents.

In addition to IK, several other K+ currents are present in cardiac tissue.

Early Outward K+ Current (A-type Current)

Atrial and ventricular muscle cells have some early transient outward current (Ito). This current is activated by depolarization but rapidly inactivates. It contributes to phase 1 repolarization and is analogous to the A-type currents (see p. 193) seen in nerves. A Kv4.3 channel mediates the A-type current in heart and certain other cells.

G Protein–Activated K+ Current

Acetylcholine activates muscarinic receptors and, through the βγ subunits of a G protein, activates an outward K+ current mediated by GIRK K+ channels (see pp. 197–198). This current is prominent in SA and AV nodal cells, where it decreases pacemaker rate by cell hyperpolarization. When activated, this current also slows the conduction of the action potential through the AV node.

KATP Current

ATP-sensitive K+ channels (KATP; see p. 198), activated by low intracellular [ATP], are present in abundance and may play a role in electrical regulation of contractile behavior. These channels are octamers, consisting of four subunits (Kir6.1 or Kir6.2) forming the pore of an inward-rectifier channel and four sulfonylurea receptors (SUR1 or SUR2).

The If current is mediated by a nonselective cation channel

The pacemaker current (If) is found in SA and AV nodal cells and in Purkinje fibers (see Fig. 21-4A, blue curve). The channel underlying this current is a nonspecific cation channel called HCN (for hyperpolarization activated, cyclic nucleotide gated; see pp. 162–165), with HCN4 being dominant in the adult heart. Because the HCN channels conduct both K+ and Na+, the reversal potential of If is around −20 mV, between the Nernst potentials for K+ (about −90 mV) and Na+ (about +50 mV). The HCN channels have the unusual property (hence the subscript f, for “funny” current) that they do not conduct at positive potentials but are activated by hyperpolarization at the end of phase 3. The activation is slow (100 ms), and the current does not inactivate. Thus, If produces an inward, depolarizing current as it slowly activates at the end of phase 3. The If current is not the only current that contributes to pacemaker activity; in SA and AV nodal cells, ICa and IK also contribute significantly to the phase 4 depolarization.

Different cardiac tissues uniquely combine ionic currents to produce distinctive action potentials

The shape of the action potential differs among different cardiac cells because of the unique combination of various currents—both the voltage-gated/time-dependent currents discussed in the preceding four sections and the “background” currents—present in each cell type. imageN21-7 In Chapter 6, we introduced Equation 6-12, which describes Vm in terms of the conductances for the different ions (GNaGKGCaGCl) relative to the total membrane conductance (Gm) and the equilibrium potentials (ENaEKECaECl):

image (21-2)


Contribution of Ionic Currents to the Action Potential

Contributed by W. Jonathan Lederer

Equation 21-2 gives Vm in terms of the weighted conductances of the various ions. Another, less general, way of expressing this concept is the Goldman-Hodgkin-Katz (GHK) equation, which we introduced in Chapter 6. The GHK equation (given as Equation 6-9 and reproduced here) relates Vm to the cellular permeability to different ions (PNaPKPCl), as well as to the intracellular and extracellular concentrations of these ions:


Several assumptions underlie the GHK equation, including that (1) the voltage varies linearly with distance through the membrane (constant-field assumption), (2) the ions move independently of one another, (3) the ions are driven only by their electrochemical gradients, (4) the permeabilities are constant, and (5) the total membrane current is zero (i.e., the individual ionic currents sum to zero and Vm is constant). Although we derived this GHK equation with these assumptions—which are not strictly true during the action potential—the equation nevertheless embodies the notion that changes in permeabilities and concentrations of specific ions will affect the shape of the action potential.

Therefore, as the relative contribution of a particular membrane current becomes dominant, Vm approaches the equilibrium potential for that membrane current (Table 21-2). How fast Vm changes during the action potential depends on the magnitude of each of the currents (Equation 21-2). Not only does each current independently affect the shape of the action potential, but the voltage- and time-dependent currents interact with one another because they affect—and are affected by—Vm. Other important influences on the shape of the cardiac action potential are the membrane capacitance of each cell and the geometry of the conduction pathway (e.g., AV node, bundle of His, ventricular muscle) as the action potential propagates from cell to cell in this functional syncytium via gap junctions. Therefore, it is easy to understand, at a conceptual level, how a particular cell's unique complement of ion channels, the properties of these channels at a particular instant in time, the intracellular ion concentrations, and the cell's geometry can all contribute to the shape of an action potential. imageN21-8

TABLE 21-2

Equilibrium Potentials


















pH = 7.1

pH = 7.4







Mathematical Modeling of the Heart

Contributed by W. Jonathan Lederer

In this chapter and throughout the text, reference is often made to mathematical models and the way they are used to test interpretations of data and to integrate specific experimental findings into a larger physiological context. This approach is used increasingly in teaching, drug testing, and experimental investigations, and will be used in the future in personalized medicine. In heart and other organs, tissues, and cells, the primary weakness of mathematical models is model validation: How do we know that the choice of unknown or uncertain variables placed into the mathematical model is optimal and unprejudiced? This selection is now being done through optimization programs and approaches that, if successful, can be used to improve personalized medicine. Courses are available to begin the application of “systems biology” methods for all.

Powerful resources are available on the Web. The Virtual Cell is a modeling environment for physicians, scientists, and students who seek to investigate quantitative relationships in biology. This is a National Institutes of Health–funded resource and can be accessed and used without charge. Importantly, there is a growing community of users who share their models and modeling code.


Sarkar AX, Christini DJ, Sobie EA. Exploiting mathematical models to illuminate electrophysiological variability between individuals. J Physiol. 2012;590(Pt 11):2555–2567.

Sobie EA, Lee YS, Jenkins SL, Iyengar R. Systems biology—biomedical modeling. Sci Signal. 2011;4:tr2.

Sobie EA, Sarkar AX. Regression methods for parameter sensitivity analysis: Applications to cardiac arrhythmia mechanisms. Conf Proc IEEE Eng Med Biol Soc. 2011;2011:4657–4660.

VCell—The Virtual Cell. [Accessed August 2015].

The SA node is the primary pacemaker of the heart

The Concept of Pacemaker Activity

The normal heart has three intrinsic pacemaking tissues: the SA node, the AV node, and the Purkinje fibers. The term pacemaker activity refers to the spontaneous time-dependent depolarization of the cell membrane that leads to an action potential in an otherwise quiescent cell. Any cardiac cell with pacemaker activity can initiate the heartbeat. The pacemaker with the highest frequency will be the one to trigger an action potential that will propagate throughout the heart. In other words, the fastest pacemaker sets the heart rate and overrides all slower pacemakers. Thus, cardiac pacemakers have a hierarchy among themselves, based on their intrinsic frequency. Two fundamental principles underlie pacemaker activity. The first is that inward or depolarizing membrane currents interact with outward or hyperpolarizing membrane currents to establish regular cycles of spontaneous depolarization and repolarization. The second is that in a particular cell, these currents interact during phase 4 within a narrow range of diastolic potentials: between −70 and −50 mV in SA and AV nodal cells, and between −90 and −65 mV in Purkinje fibers.

SA Node

The SA node is found in the right atrium and is the primary site of origin of the electrical signal in the mammalian heart (Table 21-3). It is the smallest electrical region of the heart and constitutes the fastest normal pacemaker, with an intrinsic rate of about 60 beats/min, or faster in an individual at rest. SA nodal cells are stable oscillators whose currents are always varying with time. imageN21-9 The interactions among three time-dependent and voltage-gated membrane currents (ICaIK, and If) control the intrinsic rhythmicity of the SA node. The sum of a decreasing outward current (IK; green curve in Fig. 21-4A) and two increasing inward currents (ICa and If; red and blue curves in Fig. 21-4A) produces the slow pacemaker depolarization (phase 4) associated with the SA node. The maximum diastolic potential (i.e., the most negative Vm) of the SA nodal cells, which occurs during phase 4 of the action potential, is between −60 and −70 mV. As Vm rises toward the threshold of about −55 mV, ICa becomes increasingly activated and eventually becomes regenerative, producing the upstroke of the action potential. This depolarization rapidly turns off (i.e., deactivates) If, and the whole process begins again. imageN21-10

TABLE 21-3

Electrical Properties of Different Cardiac Tissues






SA node

Primary pacemaker


↑ Conduction velocity
↑ Pacemaker rate

↓ Pacemaker rate
↓ Conduction velocity

Atrial muscle

Expel blood from atria


↑ Strength of contraction

Little effect

AV node

Secondary pacemaker


↑ Conduction velocity
↑ Pacemaker rate

↓ Pacemaker rate
↓ Conduction velocity

Purkinje fibers

Rapid conduction of action potential
Tertiary pacemaker


↑ Pacemaker rate

↓ Pacemaker rate

Ventricular muscle

Expel blood from ventricles


↑ Contractility

Little effect


Action Potential of the Sinoatrial Node

Contributed by W. Jonathan Lederer

Figure 21-4A illustrates the phases of the SA node action potential and the underlying currents.

During phase 0 of the action potential, ICa activates regeneratively (see red record in bottom panel of Fig. 21-4A, specifically the rapid downstroke), producing a rapid upstroke of Vm. Underlying ICa are both T-type and L-type Ca2+ channels.

At the transition between phases 0 and 3, ICa then begins to inactivate, a feature that begins the repolarization process. Note that phases 1 and 2 are not seen in the SA node because the inactivation of ICacombines with the slow activation of IK to bring about the phase 3 repolarization of the action potential.

As Vm approaches the maximum diastolic potential at the beginning of phase 4, three slow changes in membrane current take place that underlie phase 4 pacemaker activity:

1. IK deactivates slowly with time (over hundreds of milliseconds), producing a decreasing outward current (see green record in middle panel of Fig. 21-4A, specifically the slow decline of outward current during phase 4).

2. ICa contributes inward (i.e., depolarizing) current in the following way. Even though Vm has become more negative at the end of phase 3, Vm is still positive enough to keep ICa partially activated (albeit to only a small extent) from the previous action potential. Additionally, at the end of phase 3, Vm is still negative enough to cause ICa to recover slowly from inactivation (remember that recovery from inactivation and activation of ICa are independent processes). Thus, as ICa recovers from inactivation over hundreds of milliseconds, there is a small, increasingly inward ICa that tends to depolarize the SA nodal cells during phase 4 (see red record in lower panel of Fig. 21-4A, specifically the slow downstroke of inward current during phase 4).

3. If slowly activates as Vm becomes sufficiently negative at the end of phase 3. The result is a slowly growing inward (i.e., depolarizing) current (see blue record in middle panel of Fig. 21-4A, specifically the rather rapid downstroke of inward current during phase 4).

Thus, during phase 4, the sum of a decreasing outward current (IK) and two increasing inward currents (ICa and If) produces the slow pacemaker depolarization associated with the SA node.

As Vm rises from about −65 mV toward the threshold of about −55 mV during the pacemaker depolarization, ICa becomes increasingly activated and eventually becomes regenerative, producing the rapid upstroke of the action potential … which takes us back to the beginning of this discussion. Note that the turning off of If tends to oppose the rapid upstroke of Vm during phase 0. However, the activation of ICaoverwhelms the turning off of If.


Control of Pacemaker Activity

Contributed by W. Jonathan Lederer

The interactions of three membrane currents (IfICa,L [L-type Ca2+ channel current], and IK) contribute to pacemaker activity in SA node and AV node in heart as presented in the text. Two other inward currents are considered possible contributors to pacemaker activity under normal conditions, ICa,T and INCX (the T-type Ca2+ channel current and the Na-Ca exchanger current, respectively). Mathematical models imageN21-8 and experimental evidence support the roles that these mechanisms could play in influencing pacemaker activity under normal conditions. Active investigations by many laboratories seek to determine the extent to which these additional mechanisms may influence normal and pathological pacemaker activity. The Na-Ca exchanger–dependent contribution has been dubbed the Ca2+ clock. The essence of the “clock” is the time-dependent subcellular Ca2+ release (Ca2+ sparks) from the SR in SA and AV nodal cells. When this occurs the subcellular Ca2+ sparks activate an inward (depolarizing) INCX.

The membrane currents discussed in the previous paragraph are under the control of local and circulating agents (e.g., acetylcholine, epinephrine, and norepinephrine) and are also targets for therapeutic agents designed to modulate the heart's rhythm (e.g., Ca2+ channel blockers and β-adrenergic blockers).

AV Node

The AV node, located just above the AV ring, is the secondary site of origin of the electrical signal in the mammalian heart. Normally, the AV node may be excited by an impulse reaching it by way of the specialized atrial conduction pathways (see below). Like that of the SA node, the intrinsic rhythmicity of the AV node depends on the interaction of three time-dependent and voltage-gated currents: IKICa, and If. Electrically, the SA and AV nodes share many properties; they have similar action potentials, pacemaker mechanisms, and drug sensitivities and a similarly slow conduction of action potentials. Because the intrinsic pacemaker rate of the AV node is slower (~40 beats/min) than that of the SA node, it does not set the heart rate; its pacemaker activity is considered secondary. However, if the SA node should fail, the AV node can assume control of the heart and drive it successfully.

Purkinje Fibers

The His-Purkinje fiber system originates at the AV node with the bundle of His and splits to form the left and right bundle branches (see Fig. 21-1). The right bundle conducts the electrical signal to the right ventricle, and the left bundle conducts the signal to the left ventricle. The anatomy of the left bundle is variable, but this bundle frequently divides into two main branches—the left anterosuperior fascicle (or hemibundle) and the left posteroinferior fascicle.

Purkinje fiber cells have the slowest intrinsic pacemaker rate (20 beats/min or less). Thus, Purkinje fiber cells become functional pacemakers only if the SA and AV pacemakers fail, and are considered tertiary pacemakers. On the other hand, the bundle of His and the Purkinje fibers are an effective conduction system within the ventricles because they conduct action potentials more quickly than any other tissue within the heart (Table 21-4).

TABLE 21-4

Conduction Velocity in Different Cardiac Tissues



SA node


Atrial pathways


AV node


Bundle of His


Purkinje system


Ventricular muscle


The action potential of the Purkinje fibers depends on four time- and voltage-dependent membrane currents: INa (not present in the SA and AV nodal cells), ICaIK, and If. The maximum diastolic potential is about −80 mV. From that negative Vm, these cells produce a very slow pacemaker depolarization (phase 4) that depends on If. imageN21-11 Because of their low rate of pacemaker depolarization and therefore the uncertainty of reaching the threshold for triggering of an action potential, Purkinje fiber cells are unreliable as pacemakers. Normally, the action potential passing through the AV node activates the Purkinje fiber cells, resulting in a rapid upstroke (phase 0), mediated by INa and ICa. Because INa is large, Purkinje fibers conduct action potentials rapidly.


Action Potential of the Purkinje Fiber

Contributed by W. Jonathan Lederer

As pointed out in the text, the action potential of the Purkinje fibers depends on four time- and voltage-dependent membrane currents:

• INa (not present in the SA and AV nodal cells)

• ICa

• IK

• If

As in ventricular muscle, the maximum diastolic potential of Purkinje fibers (−80 mV) is sufficiently negative that little if any INa remains active during phase 4 of the action potential (see orange curve in middle panel of Fig. 21-4B for ventricular muscle).

In contrast to the SA and AV nodes, in Purkinje fibers the maximum diastolic potential also is sufficiently negative that little if any ICa remains active during phase 4 of the action potential (see red curve in lower panel of Fig. 21-4A for the SA node).

Also in contrast to the SA and AV nodal cells, in Purkinje fiber cells IK deactivates quickly and does not appear to contribute to pacemaker depolarization during phase 4 of the action potential (see green curve in middle panel of Fig. 21-4A for the SA node).

However, at the more negative values of Vm prevailing in Purkinje fiber cells, If activates more fully than in SA or AV nodal cells during phase 4 of the action potential (see blue curve in middle panel of Fig. 21-4A for the SA node). The time-dependent activation of If produces an inward (i.e., depolarizing) current that underlies the depolarization of pacemaker activity. However, this pacemaking happens at a very low rate, so that the pacemaker activity of the Purkinje cells does not normally determine the “heart rate” of the ventricles.

Normally, the Purkinje fiber cells are activated by the conducted action potential that passes through the AV node. The rapid upstroke (phase 0) is mediated by INa and ICa. The rapid repolarization (phase 1) occurs because of the inactivation of INa and the activation of Ito (see Table 21-1 and p. 485). The plateau (phase 2) mainly reflects a small maintained inward current via INa and ICa. Finally, the repolarization (phase 3) begins with the activation of IK.

As is the case for the other pacemaker tissues in the heart, the intrinsic rhythmicity of the Purkinje fibers is the target of therapeutic agents, neurohormones, and physiological changes (e.g., changes in heart rate).

Atrial and ventricular myocytes fire action potentials but do not have pacemaker activity

The resting potential of atrial and ventricular myocytes is substantially more negative (about −80 mV) than the maximum diastolic potential of SA and AV node pacemaker cells (see Fig. 21-1).

Atrial Muscle

Within each atrium, the action potential spreads among cardiac myocytes via a direct cell-to-cell pathway. The atrial action potential depends on three primary time- and voltage-dependent membrane currents: INaIK, and ICa. There is no normal spontaneous (i.e., pacemaker) activity in atrial muscle. It has been proposed that atrial muscle has four special conducting bundles (see Fig. 21-1). One, Bachmann's bundle (anterior interatrial myocardial band), is interatrial and conducts the cardiac action potential from the SA node to the left atrium. Three other internodal pathways—the anterior, middle, and posterior internodal pathways—appear to conduct the action potential from the SA node to the AV node. Therefore, the first step in propagation of the cardiac action potential is the depolarization of the atria, following a general axis from right to left and downward (Fig. 21-5, step 1).


FIGURE 21-5 Sequence of depolarization in cardiac tissue.

If the conduction path through the AV node is blocked, the ventricles will not be activated electrically and will not contract. The spontaneous activity that can arise in the Purkinje fiber cells may provide the necessary electrical signal to activate the ventricles, but this activation occurs normally only at a very low rate, and Purkinje fiber pacemaker activity is fairly unreliable.

Ventricular Muscle

After the action potential reaches the AV node, it travels to the His-Purkinje fiber network and out into the ventricular muscle. The only normal electrical access between atrial muscle and the ventricles is the AV node. Because of this single electrical connection between the atria and the ventricles, there is a well-defined and orderly sequence of electrical activity through the rapidly conducting His-Purkinje network to the ventricles. Within the ventricular muscle, the action potential conducts from cell to cell. Steps 2 to 6 in Figure 21-5 summarize the sequence of events in ventricular activation, which is completed in ~100 ms:

Step 2: The septum depolarizes from left to right.

Step 3: The anteroseptal region depolarizes.

Step 4: The myocardium always depolarizes from the endocardium (the cells lining the ventricles) toward the epicardium (cells on the outer surface of the heart). The left ventricle depolarizes at the apex while the Purkinje fibers are still in the process of conducting the action potential toward the base of the left ventricle.

Step 5: Depolarization spreads from the apex toward the base, carried by the Purkinje fibers. This spread to the base begins even as the signal in the apex is still spreading from the endocardium to the epicardium. The last region to depolarize is the posterobasal region of the left ventricle.

Step 6: The ventricles are fully depolarized.

Ventricular muscle has three major time- and voltage-gated membrane currents: INaICa, and IK (see Fig. 21-4B). Ventricular muscle has no If, and healthy ventricular muscle cells show no pacemaker activity. Starting from a resting potential of −80 mV, the rapid upstroke of the ventricular action potential results from the activation of INa by an external stimulus (e.g., an impulse conducted to the muscle by a Purkinje fiber or by a neighboring ventricular muscle cell). The Ca2+ current is of particular importance to ventricular muscle because it provides the Ca2+ influx that activates the release of Ca2+ from the SR. The rapid repolarization (phase 1), the plateau (phase 2), and the repolarization (phase 3) all appear to be governed by mechanisms similar to those found in the Purkinje fibers. imageN21-11 However, the plateau phase is prolonged in ventricular muscle because the inward and outward currents are rather stable during that time (green, orange, and red curves in Fig. 21-4B).

Once a ventricular muscle cell is activated electrically, it is refractory to additional activation. This effective refractory period arises because the inward currents (INa and ICa) that are responsible for activation are largely inactivated by the membrane depolarization (see Fig. 21-4B). The effective refractory period is the same as the absolute refractory period in nerve and skeletal muscle. During the effective refractory period, an additional electrical stimulus has no effect on the action potential. At the end of the plateau, the cell begins to repolarize as IK increases in magnitude. As ICa and INa begin to recover from inactivation, the relative refractory period begins. During this period, an additional electrical stimulus can produce an action potential, but a smaller one than usual. Refractoriness provides the heart with a measure of electrical safety because it prevents extraneous pacemakers (which may arise pathologically) from triggering ectopic beats. An extrasystolic contraction would make the heart a less efficient pump. Refractoriness also prevents tetanus (see p. 241), a feature observed in skeletal muscle. Tetanus of the heart would mean perpetual systole and no further contractions.

Acetylcholine and catecholamines modulate pacemaker activity, conduction velocity, and contractility

In principle, three mechanisms can slow the firing rate of the SA node (i.e., negative chronotropic effect). First, the steepness of the depolarization during phase 4 can decrease, thereby lengthening the time necessary for Vm to reach threshold (Fig. 21-6A, blue curve). In this way, diastole is longer and the heart rate falls. Second, the maximum diastolic potential can become more negative (see Fig. 21-6B, green curve). In this case, Vm starts phase 4 at a more negative potential and thus takes longer to reach threshold, assuming that the steepness of the phase 4 depolarization has not changed. Third, the threshold for the action potential can become more positive (see Fig. 21-6C, purple curve). Assuming no change in either the maximum diastolic potential (i.e., starting point) or the steepness of the phase 4 depolarization, Vm requires a longer time to reach a more positive threshold. Obviously, a combination of these three mechanisms would have an enhanced effect. Conversely, the SA nodal cells can use each of these three mechanisms in the opposite sense to increase their firing rate (positive chronotropic effect).


FIGURE 21-6 Modulation of pacemaker activity.


The vagus nerve, which is parasympathetic (see p. 339), releases acetylcholine (ACh) onto the SA and AV nodes and slows the intrinsic pacemaker activity by all three mechanisms discussed in the preceding paragraph. First, ACh decreases If in the SA node (see Table 21-1), reducing the steepness of the phase 4 depolarization (see Fig. 21-6A). Second, ACh opens GIRK channels, increasing relative K+ conductance and making the maximum diastolic potential of SA nodal cells more negative (see Fig. 21-6B). Third, ACh reduces ICa in the SA node, thereby reducing the steepness of the phase 4 depolarization (see Fig. 21-6A) and also moving the threshold to more positive values (see Fig. 21-6C). All three effects cooperate to lengthen the time for the SA node to depolarize to threshold; the net effect is to lower the heart rate.

The effects of ACh on currents in the AV node are similar to its effects on those in the SA node. However, because the pacemaker normally does not reside in the AV node, the physiological effect of ACh on the AV node is to slow conduction velocity. The mechanism is an inhibition of ICa that also makes the threshold more positive for AV nodal cells. Because it is more difficult for one cell to depolarize its neighbors to threshold, conduction velocity falls. imageN21-12


Effect of Acetylcholine on Purkinje Fiber Conduction Velocity

Contributed by W. Jonathan Lederer

As noted in the text, ACh slows conduction in both the SA and AV nodes. Purkinje fibers are the third (and slowest) group of cells in the heart with intrinsic pacemaker activity. Recent reports suggest that ACh also decreases the intrinsic activity of Purkinje fibers, presumably via a reduction of If.


Sympathetic innervation to the heart is plentiful, releasing mostly norepinephrine. In addition, the adrenal medulla releases epinephrine into the circulation. Catecholamines, which act through β1-adrenergic receptors, produce an increase in heart rate by two mechanisms. First, catecholamines increase If in the nodal cells, thereby increasing the steepness of the phase 4 depolarization (i.e., opposite to the effect in Fig. 21-6A). Second, catecholamines increase ICa in all myocardial cells. The increase in ICa in the SA and AV nodal cells steepens the phase 4 depolarization (i.e., opposite to the effect in Fig. 21-6A) and also makes the threshold more negative (i.e., opposite to the effect in Fig. 21-6C). Note that catecholamines do not appear to change the maximum diastolic potential. They do, however, produce shorter action potentials as a result of the actions they have on several specific currents.

In atrial and ventricular muscle, catecholamines cause an increase in the strength of contraction (positive inotropic effect) for four reasons. First, the increased ICa (i.e., Ca2+ influx) leads to a greater local increase in [Ca2+]i and also a greater Ca2+-induced Ca2+ release (see pp. 242–243) from the SR. Second, the catecholamines increase the sensitivity of the SR Ca2+-release channel to cytoplasmic Ca2+ (see p. 230). Third, catecholamines also enhance Ca pumping into the SR by stimulation of the SERCA Ca pump (see p. 118), thereby increasing Ca2+ stores for later release. Fourth, the increased ICa presents more Ca2+ to SERCA, so that SR Ca2+ stores increase over time. The four mechanisms make more Ca2+ available to troponin C, enabling a more forceful contraction (Box 21-1).

Box 21-1

Vagal Maneuvers

If a patient has an atrial tachycardia, such as atrial flutter or atrial fibrillation, electrical impulses from the AV node and above may pummel the ventricles and drive them at a very high rate. The ventricular rate may become so high that the effectiveness of the ventricles' pumping is hindered. Because all impulses activating the ventricles must pass through the AV node, use of ACh to slow impulse conduction through the AV node can slow the ventricular rate. Thus, so-called vagal maneuvers, which increase parasympathetic activity, can also decrease ventricular rate. One example is the release from a Valsalva maneuver. During a Valsalva maneuver, one makes a forced expiratory effort against a closed airway (e.g., grunting while lifting a heavy object), raising intrathoracic pressure. Subsequently, opening of the airway allows intrathoracic pressure to fall, so that the now-increased transmural pressure stretches the aorta, stimulating the aortic baroreceptors and triggering a reflex activation of the vagus nerve (see p. 534). Alternatively, massage of the bifurcation of the carotid artery in the neck directly stretches the wall of the carotid sinus, thereby stimulating the baroreceptors. Therefore, by either maneuver, the baroreceptor output signals brainstem centers to stimulate the vagus nerve, thereby slowing the heart.

Digitalis compounds (see p. 117) may also be used to treat supraventricular tachycardias because these drugs may increase vagal tone and decrease sympathetic tone, thereby slowing the conduction of atrial impulses through the AV node. Patients with congestive heart failure may have a low baseline vagal tone and a high baseline sympathetic tone. In these patients, digitalis-like drugs increase myocardial contractility (see p. 530) and cardiac output, causing a reflex increase in vagal tone. imageN21-17


How Does Digitalis Increase Vagal Tone?

Contributed by Emile Boulpaep, Walter Boron

The effect of digitalis drugs to increase vagal tone is probably indirect. Digitalis compounds increase myocardial contractility (see p. 530), which increases cardiac output. The resulting increase in effective circulating volume (see pp. 554–555) relieves high-pressure (see pp. 534–536) and low-pressure baroreceptor reflexes (see pp. 546–547), thereby increasing parasympathetic tone and having the opposite effect on sympathetic tone.