Cardiac Electrophysiology and the Electrocardiogram

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. 21-3 A ), 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.

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. 21-3 A ) 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 ( I _AB ) is proportional to the voltage difference between the two cells (Δ V _AB ) but inversely proportional to the electrical resistance between them ( R _AB ):

When R _AB 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. 21-3 B ). An action potential propagating from the left of cell A now injects depolarizing current into cell A. As a result, the cell depolarizes to V _A , which is now somewhat positive compared with V _B . 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. 21-3 C , 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. 21-3 C , 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. 21-3 C ). Thus, the action potential propagates more rapidly in this second example (blue curve in Fig. 21-3 C ).

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. 21-3 C ). Second, we could lower the threshold for the regenerative action potential (“more negative threshold” in Fig. 21-3 C ), 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. 21-3 B ), 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 Ca ²⁺ 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 ): N21-1

TABLE 21-1

Major Cardiac Membrane Currents That Are Time Dependent and Voltage Gated

CURRENT	NAME	CHANNEL PROTEIN	HUMAN GENE SYMBOL	REVERSAL POTENTIAL OF CURRENT (mV)	INHIBITORS
I Na	Na + current	Nav1.5 (voltage-gated Na + channel)	SCN5A	+60	TTX Local anesthetics
I Ca	Ca 2+ current	Cav1.2 (L-type Ca 2+ channel)	CACNA1C	+120	Nifedipine Verapamil
I K	I to	Kv4.3 + KChIP2	KCND3 + KCNIP2	−100	Tedisamil
	Repolarizing	Kv11.1 (HERG) + miRP1 *	KCNH2 + KCNE 2	−100	Ba 2+ Cs + TEA Dolfetilide E4031
	Repolarizing	Kv7.1 (KvLQT1) + minK *	KCNQ1 + KCNE1	−100	HMR1556 L-768, 673 Benzopyran chromanol
		Kir2.1 Kir2.2	KCNJ2 KCNJ12	−100	Ba 2+ ML133
	G protein–activated I K,ACh	Kir3.4 (GIRK4) *	KCNJ5	−100
	ATP-sensitive current, K ATP	Kir6.1 + SUR1 or SUR2 * Kir6.2 + SUR1 or SUR2 *	KCNJ8 + ABCC8 or ABCC9 KCNJ11 + ABCC8 or ABCC9	−100	Glibenclamide
I f (Na + + K + )	Pacemaker current	HCN4	HCN4	−35	Cs +

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.

* These are heteromultimeric channels.

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Cardiac Ion Channels

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 Ca ²⁺ channel, cardiac myocytes may also express the T-type Ca ²⁺ channel (see Table 7-2 ). In many diseases, the expression of the T-type Ca ²⁺ 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.

Reference

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

• 1

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

• 2

  The Ca ²⁺ current ( I _Ca ) 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 ( I _K ) is responsible for the repolarizing phase of the action potential in all cardiomyocytes.

• 4

  The pacemaker current ( I _f ) 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 N21-2 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 ).

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

Phase 0 is the upstroke of the action potential. If the upstroke is due only to I _Ca (see Fig. 21-4 A ), it will be slow. If the upstroke is due to both I _Ca and I _Na (see Fig. 21-4 B ), 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 I _Na or I _Ca and may also depend on the activation of a minor K ⁺ current not listed previously, called I _to (for t ransient o utward current).

Phase 2 is the plateau phase of the action potential, which is prominent in ventricular muscle. It depends on the continued entry of Ca ²⁺ or Na ⁺ ions through their major channels and on a minor membrane current due to the Na-Ca exchanger NCX1. N21-2

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

Phase 4 constitutes the electrical diastolic phase of the action potential. V _m during phase 4 is termed the diastolic potential; the most negative V _m during phase 4 is the maximum diastolic potential. In SA and AV nodal cells, changes in I _K , I _Ca , and I _f produce pacemaker activity during phase 4. Purkinje fibers also exhibit pacemaker activity but use only I _f . 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 I _Na is a classic voltage-gated Na ⁺ channel, with both α and β ₁ 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 ). N21-3

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. 21-4 B ). If V _m 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 ( I _Na,late ). The sustained level of I _Na helps prolong phase 2. N21-4

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 I _Na (see Fig. 21-3 C ). The depolarization produced by the Na ⁺ current not only activates I _Na in neighboring cells but also activates other membrane currents in the same cell, including I _Ca and I _K . 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 Ca ²⁺ 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 I _Na .

The Ca ²⁺ current in the heart passes primarily through L-type Ca ²⁺ channels

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

In the SA node, the role of I _Ca , like that of the other time- and voltage-dependent membrane currents, is to contribute to pacemaker activity. In both the SA and AV nodes, I _Ca 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 I _Na , their upstrokes are slower than those in atrial and ventricular muscle (compare A and B of Fig. 21-4 ). Therefore, the smaller I _Ca 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, I _Ca sums with I _Na 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 I _Na , I _Ca produces virtually no current at very negative potentials because the channels are closed. At more positive values of V _m , the Ca ²⁺ channels rapidly activate (in ~1 ms) and, by a completely separate and time-dependent process, inactivate (half-time, 10 to 20 ms). N21-5 A small I _Ca remains during phase 2 of the action potential, helping to prolong the plateau. In atrial and ventricular muscle cells, the Ca ²⁺ entering via L-type Ca ²⁺ channels activates the release of Ca ²⁺ from the sarcoplasmic reticulum (SR) by calcium-induced Ca ²⁺ release (see pp. 242–243 ). Blockers of L-type Ca ²⁺ channels —therapeutic agents such as verapamil, diltiazem, and nifedipine—act by inhibiting I _Ca .

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 ( I _K ; 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. 21-4 A, B ). Two currents underlie I _K —a relatively rapid component ( ) carried by heteromeric HERG/miRP1 channels and a relatively slow component ( ) carried by heteromeric KvLQT1/minK channels (see Box 7-3 ). N21-6 The I _K 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.

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

The I _f current is mediated by a nonselective cation channel

The pacemaker current ( I _f ) is found in SA and AV nodal cells and in Purkinje fibers (see Fig. 21-4 A , blue curve). The channel underlying this current is a nonspecific cation channel called HCN (for h yperpolarization activated, c yclic n ucleotide 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 I _f 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, I _f produces an inward, depolarizing current as it slowly activates at the end of phase 3. The I _f current is not the only current that contributes to pacemaker activity; in SA and AV nodal cells, I _Ca and I _K 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. N21-7 In Chapter 6 , we introduced Equation 6-12 , which describes V _m in terms of the conductances for the different ions ( G _Na , G _K , G _Ca , G _Cl ) relative to the total membrane conductance ( G _m ) and the equilibrium potentials ( E _Na , E _K , E _Ca , E _Cl ):

Therefore, as the relative contribution of a particular membrane current becomes dominant, V _m approaches the equilibrium potential for that membrane current ( Table 21-2 ). How fast V _m 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— V _m . 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. N21-8