What provides a graphic representation of all the action potentials occurring in the heart?

The Cardiac Action Potential

The cardiac action potential (Fig. 55-1) is a recording of a cell’s membrane potential,Vm, versus time. During each cardiac cycle, ions move back and forth across the cardiomyocyte cell membrane, thereby changingVm. The cardiac action potential, which reflects the integrated behavior of numerous individual ionic currents, is largely dominated by the movement of Na+, Ca2+, and K+ ions. These ions traverse the cell membrane through ion-selective pores formed by assemblies of integral membrane-spanning proteins and accessory proteins. The behavior of these ionic pathways is highly regulated, and permeation of specific ions is influenced by multiple factors, the most prominent of which are changes in membrane potential (i.e., voltage gating), ligand binding, second messengers such as cyclic adenosine monophosphate, and post-translational modification. Channel function and, by extension, action potential behavior are dynamically tuned in response to normal physiologic factors, especially heart rate. However, a number of pathologic stressors influence channel activity, including acquired syndromes that are associated with cardiac hypertrophy and failure, as well as an ever-growing number of congenital diseases. Regardless of the underlying pathology, the effects on action potential behavior may trigger arrhythmic activity.

The cardiac action potential is divided into phases, each reflecting the major ionic movements that take place. In working cardiomyocytes, such as ventricular or atrial myocytes, theresting membrane potential during diastole, or phase 4 of the cardiac action potential, is determined by the baseline ionic and charge gradients that exist across the sarcolemmal membrane. These gradients are generated by pumps and transporters, the most important of which is the Na+, K+-ATPase. This energy-requiring electrogenic pump, which is the major target of ouabain-like compounds such as digoxin, extrudes three Na+ ions from the intracellular compartment in exchange for two K+ ions, thereby resulting in directionally opposite gradients of Na+ ions (outside > inside) and K+ ions (inside > outside). Under resting conditions, a subset of membrane channels highly permeable to K+ is open, but those that allow for the passage of other ions such as Na+ or Ca2+ are only minimally permeable. As a consequence, the concentration gradient promotes the movement of potassium ions from inside to outside of the cell, until the resulting excess of negative charge within the cell balances the diffusional forces and an electrochemical equilibrium is established. The equilibrium potential for a given ion is calculated by theNernst equation, where Eeq is the equilibrium potential, R is the universal gas constant, T is the absolute temperature, z is the valence of the ionic species, and F is Faraday constant:

Eeq=RTzFln([X] out[X]in)

If the cell membrane wereonly permeable to K+ ions, at the measured concentrations of intracellular and extracellular K+, the resting membrane potential would be approximately −100 mV. However, because of the slight but measurable permeability to other ionic species, which have Nernst potentials that are less negative than that for K+, the actual resting membrane potential in a typical ventricular cardiac myocyte is closer to −85 mV.

Phase 2—The Action Potential Plateau

Cardiac action potentials have uniquely long periods of time during which the potential remains depolarized near 0 mV (plateau). Relatively few channels are open during the plateau, and thus the total membrane conductance is low. The high resistance of the membrane during the plateau acts like thick electrical insulation around a wire; it allows rapid propagation of the action potential with little dissipation. The plateau phase is maintained by a finely tuned balance between two types of inward Ca2+ currents and at least four types of outward K+ currents. Ultimately, K+ currents dominate, and the membrane potential is driven back toward EK.

Two Ca2+ currents, the low voltage-activated, transient Ca2+ current (ICa.T, T-type, ICaV3.2) and the high voltage-activated, long-lasting Ca2+ current (ICa.L, L-type, ICaV1.2) admit the Ca2+ needed to initiate contraction. In the normal heart, ICaV3.2 is found predominantly in atrial pacemaker cells, Purkinje fibers, and coronary artery smooth muscle. These Ca2+ channels rapidly activate at about –50 mV, peak at –20 mV, inactivate with time, are blocked by Ni2+ and a novel Ca2+ channel blocker, mibefradil, but are insensitive to dihydropyridines. ICaV3.2 is only one fifth the size of ICaV1.2 and thus contributes relatively little to the Ca2+ influx of excitation–contraction coupling.11

In contrast to ICaV3.2, ICaV1.2 is the dominant Ca2+ current found in virtually all cardiac cells in all species.12 ICa.L is activated at –30 mV, reaches its peak conductance at +10 mV within 3 to 5 msec, inactivates over hundreds of milliseconds, and is sensitive to block by dihydropyridines (nifedipine), benzothiazepines (diltiazem), and phenylalkylamines (verapamil).6 These channels carry inward current throughout the plateau phase and are required for coupling membrane excitability to myocardial contraction.

The terminal portion of the plateau is sustained by inward current through the electrogenic Na+/Ca2+ exchanger as Ca2+ is transported out of the cell at a ratio of 1 Ca2+ ion per 3 Na+ ions.13 This electrogenic current is capable of providing inward current up to 50% of the size of ICaV1.2. During the action potential upstroke, the exchanger brings in Ca2+ ions, increasing contractility. As the chief means of extruding Ca2+ ions, the exchanger also modulates the Ca2+ content of the sarcoplasmic reticulum.14

Phases of the Cardiac Action Potential

The cardiac transmembrane action potential consists of five phases:phase 0, upstroke or rapid depolarization;phase 1, early rapid repolarization;phase 2, plateau;phase 3, final rapid repolarization; andphase 4, resting membrane potential and diastolic depolarization (Fig. 34.2andeFig. 34.1). These phases are the result of passive ion fluxes moving down their electrochemical gradients established by active ion pumps and exchange mechanisms. Each ion moves primarily through its own ion-specific channel. The following discussion explains the electrogenesis of each of these phases.

EFIGURE 34.1. Demonstration of action potentials recorded during impalement of a cardiac cell.Upper row, Shown are a cell (circle), two microelectrodes, and stages during impalement of the cell and its activation and recovery. Both microelectrodes are extracellular (A), and no difference in potential exists between them (0 potential). The environment inside the cell is negative, and the outside is positive, because the cell is polarized. One microelectrode has pierced the cell membrane (B) to record the intracellular resting membrane potential, which is −90 mV with respect to the outside of the cell. The cell has depolarized (C), and the upstroke of the action potential is recorded. At its peak voltage, the inside of the cell is approximately +30 mV with respect to the outside of the cell. The repolarization phase (D) is shown, with the membrane returning to its former resting potential (E).

Pharmaceutical drugs

Antidysrhythmic drugs are often categorized using the Vaughan–Williams classification system, which is based on their mechanism of activity. The Vaughn–Williams classes are as follows:

Class I: Sodium channel blockers

Class II: Beta-adrenergic blockers

Class III: Potassium channel blockers

Class IV: Calcium channel blockers

Class V: Other or unknown mechanism of action: These include the actions of magnesium, digoxin, and adenosine.

What Causes the Long Action Potential and Plateau in Cardiac Muscle?

At least two major differences between the membrane properties of cardiac and skeletal muscle account for the prolonged action potential and the plateau in cardiac muscle. First, theaction potential of skeletal muscle is caused almost entirely by the sudden opening of large numbers offast sodium channels that allow tremendous numbers of sodium ions to enter the skeletal muscle fiber from the extracellular fluid. These channels are calledfast channels because they remain open for only a few thousandths of a second and then abruptly close. At the end of this closure, repolarization occurs, and the action potential is over within about another thousandth of a second.

In cardiac muscle, the action potential is caused by opening of two types of channels: (1) the samevoltage-activated fast sodium channels as those in skeletal muscle; and (2) another entirely different population ofL-type calcium channels (slow calcium channels), which are also calledcalcium-sodium channels. This second population of channels differs from the fast sodium channels in that they are slower to open and, even more importantly, remain open for several tenths of a second. During this time, a large quantity of both calcium and sodium ions flows through these channels to the interior of the cardiac muscle fiber, and this activity maintains a prolonged period of depolarization,causing the plateau in the action potential. Furthermore, the calcium ions that enter during this plateau phase activate the muscle contractile process, whereas the calcium ions that cause skeletal muscle contraction are derived from the intracellular sarcoplasmic reticulum.

The second major functional difference between cardiac muscle and skeletal muscle that helps account for both the prolonged action potential and its plateau is that immediately after the onset of the action potential, the permeability of the cardiac muscle membrane for potassium ionsdecreases about fivefold, an effect that does not occur in skeletal muscle. This decreased potassium permeability may result from the excess calcium influx through the calcium channels just noted. Regardless of the cause, the decreased potassium permeability greatly decreases the efflux of positively charged potassium ions during the action potential plateau and thereby prevents early return of the action potential voltage to its resting level. When the slow calcium-sodium channels do close at the end of 0.2 to 0.3 second, and the influx of calcium and sodium ions ceases, the membrane permeability for potassium ions also increases rapidly. This rapid loss of potassium from the fiber immediately returns the membrane potential to its resting level, thus ending the action potential.

9.3.2 Relation of the action potential to the surface electrocardiogram

The cardiac action potential has been investigated elucidated using traditional patch clamp and sharp electrode techniques in single cells and myocardial wedge preparations. However, the main clinical tool used to investigate patients is the 12-lead surface ECG. The power of the ECG to diagnose arrhythmia conditions is augmented by various tools including provocation with drugs (adrenaline or sodium-channel blockers such as ajmaline) or exercise, signal averaging, and prolonged recording (e.g., Holter monitoring) (Fig. 9.4).

Each vector (or lead) of the surface ECG reflects the summation of many individual action potentials. It is predominantly influenced by atrial and ventricular myocardium, as the specialized conduction tissue is comparatively very small in mass. The p wave represents atrial depolarization, the QRS complex begins with depolarization of ventricular muscle, and its width reflects the time taken for all muscle to depolarize. The ST segment corresponds to the plateau phase and shifts from the baseline (i.e., ST elevation or depression) reflect voltage gradients from epicardium to endocardium (with the largest contribution from the middle or M cells) and are commonly caused by ischemia (which tends to affect endocardium first due to the nature of coronary blood supply) or infarction. The T wave represents the repolarization phase.

Importantly, the QT interval (measured between the beginning of the earliest Q wave and the end of the latest T wave) does not solely measure the repolarization phase of the action potential, but in fact it measures the entire of the depolarization–repolarization period. Slowed conduction in cardiomyopathy, for example, leads to QRS prolongation (e.g., left bundle branch block), which also therefore prolongs the QT interval. LQTS can only be diagnosed in the absence of structural heart disease or coronary artery disease.

Electrical Activation During Sinus Rhythm

The cardiac action potential originates from the sinus node, located high in the right atrium (Fig. 9-1). Its cells depolarize spontaneously and initiate the spontaneous depolarization of action potentials at a regular rate from the sinus node. This rate depends on various conditions, such as atrial stretch and sympathetic activation, but is usually between 60 and 100 beats per minute (bpm) at rest. Myocytes are electrically coupled to each other through gap junctions. These structures consist of connexin molecules and allow direct intercellular communication.1 Gap junctions do not have a preferential direction of conduction, but because the action potential starts in the sinus node, it spreads from there through the atria. Evidence suggests specialized conduction pathways in the atrium, but their (patho) physiologic relevance is still disputed.

In the human heart, spreading of the action potential through the atria takes approximately 100 msec, after which the impulse reaches the AV node (see Fig. 9-1). In the normal heart the AV node is the only electrical connection between the atria and ventricles, because a fibrous ring (anulus fibrosus) is present between the remaining parts of the atria and ventricles. The AV nodal tissue conducts the electrical impulses very slowly; indeed, it takes approximately 80 msec for these impulses to travel from the atrial side to the ventricular side of the AV node. This delay between atrial activation and ventricular activation has functional importance because it allows optimal ventricular filling. Its slow conduction renders the AV node sensitive to impaired conduction and even complete conduction block, an important indication for ventricular pacing. As with other locations in the heart, conduction in the AV node has no preferential direction. Consequently, impulses can also be conducted retrogradely through the AV node, a condition that can occur when the ventricles are electrically stimulated.

From the AV node, the electrical impulse reaches the His bundle, the first part of the specialized conduction system of the ventricles called the Purkinje system. Within this system the electrical impulse is conducted approximately four times faster (3-4 m/sec) than in the working myocardium (0.3-1 m/sec). This difference results because Purkinje cells are longer and have a higher content of gap junctions.1-5

The intraventricular conduction system can be regarded as a trifascicular conduction system consisting of the right bundle branch (RBB) and two divisions of the left bundle branch (LBB). The RBB proceeds subendocardially along the right side of the interventricular septum until it terminates in the Purkinje plexuses of the right ventricle; the LBB also has a short subendocardial route.

It seems that the bifascicular vision of structure of the LBB is oversimplified.6 The general picture that now emerges is that the left ventricular Purkinje network is composed of three main, widely interconnected parts, depending on the anterior subdivision, the posterior subdivision, and a centroseptal subdivision of the left main bundle. This third medial or centroseptal division supplies the midseptal area of the left ventricle and arises from the LBB, from its anterior or posterior subdivision, or both. The fascicles continue in a network of subendocardially located Purkinje fibers. In the left ventricle, Purkinje fibers form a network in the lower third of the septum and free wall, which also covers the papillary muscles.4,7 In humans the bundles are present only underneath the endocardium, whereas other species (e.g., ox, sheep, goat) have networks of Purkinje fibers across the entire ventricular wall.8,9

It is important to note that the His bundle as well as the right and left bundle branches and their major tributaries are electrically isolated from the adjacent myocardium. The only sites where the Purkinje system and the normal working myocardium are electrically coupled are the Purkinje-myocardial junctions. The exits of the Purkinje system are located in the subendocardium of the anterolateral wall of the right ventricular (RV) and the inferolateral left ventricular (LV) wall4,10 (see Fig. 9-1). This area of exit corresponds with the area of the ventricular muscle that is activated earliest.2-5,11,12 The distribution of the Purkinje-myocardial junctions is spatially inhomogeneous, and the junctions themselves have varying degrees of electrical coupling.13

Endocardial activation of the right ventricle starts near the insertion of the anterior papillary muscle 10 msec after onset of LV activation11 (Fig. 9-2). After activation of the more apical regions, the activation of the ventricular working myocardium occurs predominantly from apex to base, both in the septum and in the LV and RV free wall. Further depolarization occurs centrifugally from endocardium to epicardium as well as tangentially.11,12 The earliest epicardial breakthrough occurs in the pretrabecular area in the right ventricle, from which there is an overall radial spread toward the apex and base. The last part of the right ventricle that becomes activated is the AV sulcus and pulmonary conus. Overall, the posterobasal area of the left ventricle (or an area more lateral) is the last part of the heart to be depolarized (see Fig. 9-2).

The time between arrival of the impulse in the His bundle and the first ventricular muscle activation is approximately 20 msec,4 whereas total ventricular activation lasts 60 to 80 msec, corresponding to a QRS duration of 70 to 80 msec.11 These numbers illustrate the important role of the Purkinje fiber system in the synchronization of myocardial activity. This role results from the system's unique propagation properties and its geometrically widespread distribution. During normal orthodromic excitation, fast propagation over long fibers, together with wide distribution of Purkinje-myocardial junctions, induces a high degree of coordination between distant regions of the myocardium.

Estrogen

Estrogen affects cardiac action potential duration and the associated long QT-related arrhythmogenesis through numerous different mechanisms. Several studies have shown that 17β-estradiol can inhibit the inward rectifier potassium current (IK1) and the delayed and rapid rectifier potassium currents IKs and IKr [113–115]. Estradiol inhibits IKr both directly by blocking the KCNH2/HERG channel and indirectly by increasing the transcription of the β-subunit KCNE2 [116]. Thereby, estradiol exerts a synergistic effect when combined with IKr-blocking drugs [117]. Similarly, the inhibition of IKs by estradiol is caused by a downregulation of the mRNA levels of KCNE1, the β-subunit to the ion channel conducting IKs [35].

Beyond the potassium currents, estradiol affects the regional expression and function of the L-type calcium channel (ICa,L) and the sodium–calcium exchanger (NCX). Studies in rabbits revealed a higher density of ICa,L and INCX in cardiomyocytes from the ventricular base than from the apex in female—but not in male—hearts, thus enhancing a proarrhythmic dispersion of repolarization. This regional difference could be reproduced by incubation of isolated ventricular cardiomyocytes from female hearts with estrogen: Here, an estrogen-induced upregulation of mRNA, proteins, and current densities was observed in basal but not in apical cardiomyocytes [118,119]. The increase of ICa,L was mediated by a genomic mechanism, e.g., an estrogen receptor binding to the promoter region of the gene encoding for the L-type Ca2+ channel [119]. By increasing ICa,L, estradiol enhances the propensity to develop EADs [51]. In summary, estradiol prolongs cardiac repolarization (particularly at slow heart rates) and increases the likelihood of drug-induced arrhythmias, exerting a proarrhythmic synergic effect with concomitant QT-prolonging drugs (Figs. 73.4 and 73.5).

Electrical Cells

The heart is a muscular pump controlled by regular electrical discharges from specialized muscle cells in the conduction system (Chapter 61). The molecular basis for the electrical activity of the heart is the activation of specific ion-conducting channels (Fig. 52-1). Coordinated activation and inactivation of cardiac ion channels regulate the membrane potential of the cardiac cells, thereby resulting in a rapid sequence of depolarization followed by repolarization. This electrical activity, which is manifested on the body surface as the electrocardiogram (ECG), is known as the action potential, and it is responsible for activating the contraction of the cardiac muscle. At a typical heart rate of 70 beats per minute, the heart beats about 100,000 times per day, or 37 million beats a year, corresponding to 3 billion beats over a lifespan of 80 years. Failure to propagate the signal throughout the heart (e.g., heart block), or abnormal rhythms (arrhythmias) that are either too slow (bradycardia) or too fast (tachycardia), can result in death (Chapter 62).

FIGURE 52-1. Cardiac action potential and ion channels.

Myocardial contraction begins when sodium channels open and positively charged sodium ions flow into the cell and cause membrane depolarization (phase 0). During phases 1, 2, and 3, calcium ions flow into the cell through l-type calcium channels, while potassium flows out of the cell through voltage-gated potassium channels. These three phases correspond to the myocardial contraction, which corresponds to the QRS complex on the surface electrocardiogram (ECG). The sodium-potassium adenosine triphosphatase (NKA) helps return the system to its resting state.

C. Phase 1—Transient Outward Current

Phase 1 of the cardiac AP is the transient and relatively small repolarization phase that immediately follows the upstroke of the AP. The size of phase 1 repolarization varies between species and also between different regions of the heart within a given species. Thus, APs recorded from the outer (epicardial) layer of ventricular cells display a more prominent phase 1, whereas APs recorded from the inner (endocardial) layer of ventricular cells display a small phase 1 repolarization (Liu et al., 1993). Phase 1 is also very large in Purkinje fibers and in atrial cells, but is largely absent in nodal cells.

Identification of the specific current or currents responsible for phase 1 repolarization has been controversial. It is now clear that the primary ion responsible for most of the phase 1 repolarization is K+ (Kenyon and Gibbons, 1979), although a Cl− component does appear to contribute to phase 1 repolarization (Bouron et al., 1991; see later).

Phase 1 repolarization is largely due to a transient outward current (Ito). Ito turns on rapidly with depolarization (i.e., beginning during the final portion of the AP upstroke) and is only active at very depolarized potentials; the threshold for activation is approximately –30 mV (Fig. 3). Thus, Ito has a characteristic transient shape—the rapid activation of this current is followed by inactivation during the AP plateau. Because of its voltage dependence and time course, Ito significantly overlaps (and opposes) the inward Ca2+ current (which is the primary depolarizing current during the plateau phase, see later).

This current (Ito) is actually composed of at least two separate currents (Ito1 and Ito2), which are carried through two physically distinct channels (Tseng and Hoffman, 1989). One of the currents (Ito1) is a K+ current that is independent of the internal Ca2+ concentration ([Ca2+]i) and is sensitive to the K+ channel blocker 4-aminopyridine (4-AP). This component of Ito is very similar to the IA current recorded in nerve fibers. The second component of Ito (Ito2) is Ca2+ dependent and less sensitive to 4-AP, but is more sensitive to another K+ channel blocker, tetraethylammonium ion (TEA+). It is thought that Ito2 is, at least in part, a Ca2+ -activated Cl− channel (Harvey, 1996).

Under physiological conditions, the first Ito component, Ito1, is by far the larger of the two components. Thus, irrespective of the exact nature of Ito2, the efflux of K+ (through Ito1 channels) appears responsible for the vast majority of phase 1 repolarization. The second component (Ito2) may become more important when intracellular levels of Ca2+ become too high. Thus, under Ca2+ overload conditions, Ito2 would be activated and shorten the AP duration, thereby indirectly abbreviating the duration of Ca2+ current, resulting in a reduced Ca2+ influx. Thus, activation of Ito2 by intracellular Ca2+ likely acts as a negative feedback mechanism to reduce calcium overload.