RfBachmanifs bundle

Right bundle branch sinus node

Internodal paihways

AV node

Bundle of His

division Anterior division

Purkinje fibers

Posterior

Left bundle branch

FIGURE 9-1. The cardiac conduction system. (AV, atrioventricular.)

Following initiation of the electrical impulse from the SA node, the impulse travels through the internodal pathways of the specialized atrial conduction system and Bach-mann's bundle (Fig. 9-1).1 The atrial conducting fibers do not traverse the entire breadth of the left and right atria; as impulse conduction occurs across the internodal pathways, and when the impulse reaches the end of Bachmann's bundle, atrial depolarization spreads as a wave, conceptually similar to that which occurs upon throwing a pebble into water. As the impulse is conducted across the atria, each depolarized cell excites and depolarizes the surrounding connected cells, until both atria have been completely depolarized. Atrial contraction follows normal atrial depolarization.

Following atrial depolarization, impulses are conducted through the AV node, located in the lower right atrium (Fig. 9-1).1 The impulse then enters the bundle of His, and is conducted through the ventricular conduction system, consisting ofthe left and right bundle branches. The left ventricle requires a larger conduction system than the right ventricle due to its larger mass; therefore, the left bundle branch bifurcates into the left anterior and posterior divisions (also commonly known as "fascicles"). The bundle branches further divide into the Purkinje fibers, through which impulse conduction results in ventricular depolarization, after which ventricular contraction occurs.

The Ventricular Action Potential

The ventricular action potential is depicted in Figure 9-2. Cardiac myocyte resting membrane potential is usually 70 to 90 mV, due to the action of the sodium-potassium adenosine triphosphatase (ATPase) pump, which maintains relatively high extracellular sodium concentrations and relatively low extracellular potassium concentrations. During each action-potential cycle, the potential of the membrane increases to a threshold potential, usually 60 to 80 mV. When the membrane potential reaches this threshold, the fast sodium channels open, allowing sodiumions to rapidly enter the cell. This rapid influx of positiveions creates a vertical upstroke of the action potential, such that the potential reaches 20 to 30 mV. This is phase 0, which represents ventricular depolarization. At this point, the fast sodium channels become inactivated, and ventricular repolarization begins, consisting of phases 1 through 3 of the action potential. Phase 1 repolarization occurs primarily as a result of an efflux of potassi-umions (Fig. 9-2)2 During phase 2, potassiumions continue to exit the cell, but the membrane potential is balanced by an influx ofcalcium and sodium ions, transported through slow calcium and slow sodium channels, resulting in a plateau. During phase

3, the efflux of potassiumions greatly exceeds calcium and sodium influx, resulting in the major component of ventricular repolarization. During phase 4, sodiumions are actively pumped out of the myocyte via the sodium-potassium ATPase pump, resulting in restoration of ion concentrations to their resting values. An understanding of the ionic fluxes that are responsible for each phase of the action potential facilitates understanding of the effects of specific drugs on the action potential. For example, drugs that primarily inhibit ion flux through sodium channels influence phase 0 (ventricular depolarization), while drugs that primarily inhibit ion flux through potassium channels influence the repolarization phases, particularly phase 3.

The Electrocardiogram

The ECG is a noninvasive means of measuring the electrical activity of the heart. The relationship between the ventricular action potential and the ECG is depicted in Figure 9-2. The P wave on the ECG represents atrial depolarization (atrial depolarization is not depicted in the action potential shown in Figure 9-2, which shows only the ventricular action potential). Phase 0 of the action potential corresponds to the QRS complex; therefore, the QRS complex on the ECG is a noninvasive representation of ventricular depolarization. The T wave on the ECG corresponds to phase 3 ventricular repolarization. The interval from the beginning of the Q wave to the end of the T wave, known as the QT interval, is used as a noninvasive marker of ventricular re-polarization time. Atrial repolarization is not displayed on the ECG, because it occurs during ventricular depolarization and is obscured by the QRS complex.

Ekg And Cardiac Action Potential

FIGURE 9-2. The ventricular action potential depicting the flow of specificions responsible for each phase. The specific phases of the action potential that correspond to the absolute and relative refractory periods are portrayed, and the relationship between phases of the action potential and the ECG are shown. (Ca, calcium; K, potassium; Na, sodium.) (From Ref. 2.)

FIGURE 9-2. The ventricular action potential depicting the flow of specificions responsible for each phase. The specific phases of the action potential that correspond to the absolute and relative refractory periods are portrayed, and the relationship between phases of the action potential and the ECG are shown. (Ca, calcium; K, potassium; Na, sodium.) (From Ref. 2.)

Several intervals and durations are routinely measured on the ECG. The PR interval represents the time of conduction of impulses from the atria to the ventricles through the AV node; the normal PR interval in adults is 0.12 to 0.2 seconds. The QRS duration represents the time required for ventricular depolarization, which is normally 0.08 to 0.12 seconds in adults. The QT interval represents the time required for ventricular repolarization. The QT interval varies with heart rate—the faster the heart rate, the shorter the QT interval, and vice versa. Therefore, the QT interval is corrected for heart rate using Bazett's equation, which is:

where QTc is the QT interval corrected for heart rate, and RR is the interval from the onset of one QRS complex to the onset of the next QRS complex, measured in seconds (i.e., the heart rate, expressed in different terminology). The normal QTc interval in adults is 0.36 to 0.44 seconds.

Refractory Periods

After an electrical impulse is initiated and conducted, there is a period of time during which cells and fibers cannot be depolarized again. This period of time is referred to as the absolute refractory period (Fig. 9-2), and corresponds to phases 1, 2, and approximately one-third of phase 3 repolarization on the action potential. The absolute refractory period also corresponds to the period from the Q wave to approximately the first half of the T wave on the ECG (Fig. 9-2). During this period, if there is a premature stimulus for an electrical impulse, this impulse cannot be conducted because the tissue is absolutely refractory. However, there is a period of time following the absolute refractory period during which a premature electrical stimulus can be conducted, and is often conducted abnormally. This period of time is called the relative refractory period (Fig. 9-2). The relative refractory period corresponds roughly to the latter two-thirds of phase 3 repolarization on the action potential and to the latter half of the T wave on the ECG. If a new (premature) electrical stimulus is initiated during the relative refractory period, it can be conducted abnormally, potentially resulting in an arrhythmia.

Mechanisms of Cardiac Arrhythmias

O In general, cardiac arrhythmias are caused by: (a) abnormal impulse formation, (b) abnormal impulse conduction, or (c) both.

Abnormal Impulse Initiation

Abnormal initiation of electrical impulses occurs as a result of abnormal automaticity. If the automaticity of the SA node decreases, this results in a decreased rate of impulse generation and a slow heart rate (sinus bradycardia). Conversely, if the automaticity of the SA node increases, this results in an increased rate of generation of impulses and a rapid heart rate (sinus tachycardia). If other cardiac fibers become abnormally automatic, such that the rate of initiation of spontaneous impulses exceeds that of the SA node, or premature impulses are generated, other types of tachyarrhythmias may occur. Many cardiac fibers possess the capability for automaticity including the atrial tissue, the AV node, the Purkinje fibers, and the ventricular tissue. In addition, fibers with the capability of initiating and conducting electrical impulses are present in the pulmonary veins. Abnormal atrial automaticity may result in premature atrial contractions or may precipitate atrial tachycardia or atrial fibrillation (AF); abnormal AV nodal automaticity may result in "junctional tachycardia" (the AV node is also sometimes referred to as the AV junction). Abnormal automaticity in the ventricles may result in ventricular premature depolarizations (VPDs) or may precipitate ventricular tachycardia (VT) or ventricular fibrillation (VF). In addition, abnormal automaticity originating from the pulmonary veins is a precipitant of AF.

Automaticity of cardiac fibers is controlled in part by activity of the sympathetic and parasympathetic nervous systems. Enhanced activity of the sympathetic nervous system may result in increased automaticity of the SA node or other automatic cardiac fibers. Enhanced activity of the parasympathetic nervous system tends to suppress automaticity; conversely, inhibition of activity of the parasympathetic nervous system increases automaticity. Other factors may lead to abnormal increases in automaticity of extra-SA nodal tissues, including hypoxia, atrial or ventricular stretch (as might occur following long-standing hypertension or after the development of heart failure), and electrolyte abnormalities such as hypokalemia or hypomagnesemia.

Abnormal Impulse Conduction

The mechanism of abnormal impulse conduction is traditionally referred to as reentry. Re-entry is often initiated as a result of an abnormal premature electrical impulse (abnormal automaticity); therefore, in these situations, the mechanism of the arrhythmia is both abnormal impulse formation (automaticity) and abnormal impulse conduction (re-entry). In order for re-entry to occur, three conditions must be present. There must be: (a) at least two pathways down which an electrical impulse may travel (which is the case in the majority of cardiac fibers); (b) a "unidirectional block" in one of the conduction pathways (this "unidirectional block" is often a result of prolonged refractoriness in this pathway, or increased "dispersion of refractoriness," defined as substantial variation in refractory periods between cardiac fibers); and (c) slowing of the velocity of impulse conduction down the other conduction pathway.

The process of re-entry is depicted in Figure 9-3.4 Under normal circumstances, when a premature impulse is initiated, it cannot be conducted in either direction down either pathway because the tissue is in its absolute refractory period from the previous impulse. A premature impulse may be conducted down both pathways if it is only slightly premature and arrives after the tissue is no longer refractory. However, when refractoriness is prolonged down one of the pathways, a precisely-timed premature beat may be conducted down one pathway, but cannot be conducted in either direction in the pathway with prolonged refractoriness because the tissue is still in its absolute refractory period (Fig. 9-3).4 When the third condition for re-entry is present, that is, when the velocity ofimpulse conduction in one is slowed, the impulse traveling forward down the other pathway still cannot be conducted. However, because the impulse in one is traveling more slowly than normal, by the time it circles around and travels upward along the other pathway, sufficient time has passed so the pathway is no longer in its absolute refractory period, and now the impulse may travel upward in that pathway. In other words, the electrical impulse "re-enters" a previously stimulated pathway in the reverse (retrograde) direction. This results in circular movement of electrical impulses; as the impulse travels in this circular fashion, it excites each cell around it, and if the impulse is traveling at a rate faster than the intrinsic rate of the SA node, a tachycardia occurs in the tissue in question. Re-entry may occur in numerous tissues, including the atria, the AV node, and the ventricles.

FIGURE 9-3. The process of initiation of re-entry. There are two pathways for impulse conduction, slowed impulse conduction down pathway A, and a longer refractory period in pathway B. A precisely timed premature impulse usually initiates re-entry; the premature impulse cannot be conducted down pathway B, because the tissue is still in the absolute refractory period from the previous, normal impulse. However, because of dispersion of refractoriness (i.e., different refractory periods down the two pathways), the impulse can be conducted down pathway A. Because conduction down pathway A is slowed, by the time the impulse reaches pathway B in a retrograde direction, the impulse can

FIGURE 9-3. The process of initiation of re-entry. There are two pathways for impulse conduction, slowed impulse conduction down pathway A, and a longer refractory period in pathway B. A precisely timed premature impulse usually initiates re-entry; the premature impulse cannot be conducted down pathway B, because the tissue is still in the absolute refractory period from the previous, normal impulse. However, because of dispersion of refractoriness (i.e., different refractory periods down the two pathways), the impulse can be conducted down pathway A. Because conduction down pathway A is slowed, by the time the impulse reaches pathway B in a retrograde direction, the impulse can be conducted retrogradely up the pathway, because the pathway is now beyond its refractory period from the previous impulse. This creates re-entry, in which the impulse continuously and repeatedly travels in a circular fashion around the loop.

Prolonged refractoriness and/or slowed impulse conduction velocity may be present in cardiac tissues for a variety of reasons. Myocardial ischemia may alter ventricular refractory periods or impulse conduction velocity, facilitating ventricular re-entry. In patients with past myocardial infarction, the infarcted myocardium is dead and cannot conduct impulses. However, there is typically a border zone of tissue which is damaged and in which refractory periods and conduction velocity are often deranged, facilitating ventricular re-entry. In patients with left-atrial or LV hypertrophy as a result of long-standing hypertension, refractory periods and conduction velocity are often perturbed. In patients with heart failure due to LV dysfunction, ventricular refractoriness and conduction velocity are often altered due to LV hypertrophy, collagen deposition, and other anatomic and structural changes.

Vaughan Williams Classification of Antiarrhythmic Drugs

The Vaughan Williams classification of antiarrhythmic drugs, first described in 19705 and subsequently further expanded,6,7 is presented in Table 9-1. This classification is based on the effects of specific drugs on ventricular conduction velocity, repolar-ization/refractoriness, and automaticity. Class I drugs, which are the sodium channel blocking agents, primarily inhibit ventricular automaticity and slow conduction velocity. However, due to differences in the potency of the drugs to slow conduction velocity, the class I drugs are subdivided into class IA, IB, and IC. The class IC drugs have the greatest potency for slowing ventricular conduction, the class IA drugs have intermediate potency, and the class IB drugs have the lowest potency, with minimal effects on conduction velocity at normal heart rates. Class II drugs are the adrenergic P-receptor inhibitors (P-blockers), class III drugs are those that inhibit ventricular repolarization or prolong refractoriness, and class IV drugs are the calcium channel blockers (CCBs) diltiazem and verapamil.

The Vaughan Williams classification of antiarrhythmic drugs has been criticized for a number of reasons. The classification is based on the effects of drugs on normal, rather than diseased, myocardium. In addition, many of the drugs may be placed into more than one class. For example, the class IA drugs prolong repolarization/refract-oriness, either via the parent drug8,9 or an active metabolite,1 and therefore also may be placed in class III. Sotalol is also a P-blocker, and therefore fits into class II. Amiodarone inhibits sodium and potassium channels, is a noncompetitive inhibitor of P

receptors, and inhibits calcium channels, and therefore may be placed into any of the four classes. For this reason, drugs within each class cannot be considered "interchangeable." Nonetheless, despite attempts to develop mechanism-based classifications that better distinguish the actions of antiarrhythmic drugs,11 the Vaughan Williams classification continues to be widely used because of its simplicity and the fact that it is relatively easy to remember and understand.

Table 9-1 Vaughan Williams Classification of Antiarrhythmic Agents3

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