Possible role of ionic changes in the appearance of arrhythmias

Pharmac. Ther. B, Vol. 2, pp. 787-810, 1976. Pergamon Press. Printed in Great Britain

Specialist Subject Editor:

L . SZEKERES

POSSIBLE ROLE OF THE APPEARANCE

IONIC CHANGES IN OF ARRHYTHMIAS

LEONARD S. GETTES Cardiovascular Division, College of Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, USA

1. I N T R O D U C T I O N An appreciation of the role of ionic currents in the genesis of the action potential of excitable tissues, was made possible by the development of the microelectrode and the technique of voltage clamping. As a result of these techniques, Hodgkin and Huxley (1952b) were able to describe mathematically the characteristics of the Na ÷ inward current responsible for depolarization and the K ÷ outward current responsible for repolarization in the squid axon. H o w e v e r , our understanding of the ionic currents responsible for the cardiac action potential is still incomplete. The uncertainties in this area can be attributed to the small size of cardiac fibers and their three dimensional geometry which render uniform changes in transmembrane voltage more difficult to achieve and sustain than in the squid axon and make more difficult the interpretation of experimental data (Johnson and Lieberman, 1971). In spite of the unresolved problems and controversial issues outlined in the articles of Beeler and Reuter (1970a), Johnson and Lieberman (1971), and Trautwein (1973), there is general agreement that Na ÷, Ca 2÷, CI-, and K ÷ each carry an electrical charge across the cell membrane which combine to generate the cardiac action potential. The purpose of this article is to consider the characteristics of the ionic currents which may be important in the genesis of cardiac arrhythmias. The many studies which form the basis of our present understanding of the cardiac action potential will not be reviewed in detail. For this purpose, the reader is referred to the monograph by Hoffman and Cranefield (1960), the volume edited by DeMello (1972) and the review paper of Trautwein (1973), and Reuter (1973), as well as the critique of many of these studies by Johnson and Lieberman (1971). This section is divided into three parts: (1) a general discussion of the characteristics of the ionic currents and their relationships to the action potentials of the various types of cardiac fibers; (2) a consideration of those features of the ionic currents which are particularly germane to an understanding of cardiac arrhythmias and (3) an analysis of some of the changes in ionic currents which may result from myocardial ischemia and contribute to the genesis of the associated arrhythmias.

2. C H A R A C T E R I S T I C S OF T H E IONIC C U R R E N T S R E S P O N S I B L E FOR T H E A C T I O N P O T E N T I A L The ability of an ion to cross from one side of the membrane to the other depends upon the membrane conductance of the ion (g) and the electrical driving force of the ion which is the difference between the equilibrium potential for the particular ion (Ei) and t h e membrane potential (Era). This interaction is described in its simplest form by the ohmic relationship expressed by eqn (1). I = g(Em - E,).

(1)

The equilibrium, or reversal potential of the ion in question, El is determined by the 787

788

L . S . GETFES

ratio of the intracellular ([ ]i) to extracellular ([ ]o) ionic concentration and is expressed by the Nernst equation, eqn (2).

R T . [ ]i E, = - i f - m [ ]o"

(2)

Ionic conductance is determined by variables which are both voltage and time dependent. The time dependency reflects the kinetics whereby the ionic channels within the membrane open and close following a change in mambrane voltage. 2.1. DEPOLARIZING CURRENTS 2.1.1. The Rapid Inward Current The accurate determination of the rapid inward current has been difficult to achieve using voltage clamp techniques because of the difficulties in obtaining rapid, homogeneous changes in cardiac transmembrane voltage and because the time course of the current associated with the discharge of membrane capacitance is similar to the rapid inward current. Since the rapid inward current is responsible for the rapid depolarization of the cardiac cells, studies of the upstroke of the action potential have provided indirect information concerning the rapid inward current (Weidmann, 1955; Brady and Woodbury, 1960; Gettes and Reuter, 1974). In addition, recent improved voltage clamp techniques (Beeler and Reuter, 1970a; New and Trautwein, 1972a) have permitted direct studies. The similarity of the reversal potential of the rapid inward current to the calculated equilibrium potential for Na + (Trautwein, 1973), the sensitivity of the rapid inward current and maximum rate of rise, ( d V / d t ) .... of the action potential upstroke to changes in extracellular Na ÷ concentration (Brady and Woodbury, 1960; and Weidmann, 1955) and the ability to block the current with tetrodotoxin (Dudel et al., 1976b; Beeler and Reuter, 1970a) indicate that as in nerve, the rapid inward current is carried by Na ÷ ions. The reversal or equilibrium potential for Na ÷ current is + 25-+ 40 mV (Trautwein, 1973). During diastole, when the resting membrane potential is between - 8 0 and -90 mV, the difference between ENa and Era, i.e. the electrical driving force, is 120-130 mV. However, no net Na ÷ inward current occurs when the membrane potential is - 90 mV because the membrane conductance for Na ÷, (gN,) is 0. Sodium conductance begins to rise when the membrane is depolarized to approximately - 6 0 m V , the threshold for the Na ÷ inward current. Sodium then rapidly crosses the membrane depolarizing the cell. The magnitude of the rapid inward current and (dV/dt)max of the action potential upstroke is determined by the membrane potential prior to depolarization. It is greatest when the resting potential is more negative than - 70 mV, decreases along an S-shaped curve as the membrane potential prior to depolarization becomes less negative and approaches 0 when this is approximately - 4 0 mV, (Fig. 1) (Weidmann, 1955; Trautwein and Schmidt, 1960; Beeler and Reuter, 1970a; Haas et al., 1971; Gettes and Reuter, 1974). This curve describes the steady state 'inactivation' of the Na ÷ current and can be shifted along the voltage axis by changes in external Ca 2+ concentration and by antiarrhythmic drugs (Weidmann, 1955b; Beeler and Reuter, 1970; Gettes and Reuter, 1974; Chen et al., 1975). The time required for the Na ÷ current to become fully activated is less than 1 msec. Following activation the current is inactivated with a time constant of approximately 10 msec (Trautwein, 1973). A third important kinetic variable is the time required for the current to recover its ability to be reactivated following an activation-inactivation cycle. In cardiac muscle and Purkinje fibers, as in squid axons, the time constants for activation, inactivation and reactivation are voltage dependent (Weidmann, 1955a). H o w e v e r , unlike the squid axon, the time constant for reactivation (Figs 2 and 3) in cardiac muscle is longer than the time constant for inactivation (Haas et al., 1971;

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I~G. 2. Illustration of experiment to determine recovery of (dVldt)m.x in guinea-pig papillary muscle. Action potentials traced in solid lines are those recorded at basic driving rate of 0.5/sec. Those traced in broken lines are premature action potentials. Note that (d V/dt)=x, shown as the differentiated upstroke spikes below the action potentials, decreases in early premature responses arising from the same resting potential and that the decrease is more pronounced and more prolonged following a decrease in resting potential to -68 mV (bottom panels). Reprinted with permission from Gettes and Reuter (1974).

G e t t e s and Reuter, 1974). R e a c t i v a t i o n like inactivation, is altered by c h a n g e s in external Ca 2÷ c o n c e n t r a t i o n ( G e t t e s and Reuter, 1974) and antiarrhythmic drugs (Chen et al., 1975). T h e v o l t a g e and kinetic characteristics of the rapid inward N a ÷ current and the other current s y s t e m s are s h o w n in Table 1. 2.1.2. The S l o w Inward Current

In addition to the rapid inward current, a s l o w e r d e p o l a r i z i n g inward current has b e e n d e m o n s t r a t e d in atrial, ventricular and Purkinje fibers of a variety of s p e c i e s (Reuter, 1967; R o u g i e r et al., 1969; Garnier et al., 1969; M a s h e r and P e p p e r , 1969; O c h i , 1970; B e e l e r and R e u t e r , 1970a b; V i t e k and Trautwein, 1971; N e w and T r a u t w e i n , 1972a, b). T h e current is thought to be carried primarily by Ca 2÷ b e c a u s e it is s e n s i t i v e to c h a n g e s ] ' F I B Vol. 2, N o . 4 - - 1

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FIG. 3. Top: Relationship between (d V/dr)re,, of guinea-pig papillary muscle and the interval from the end of a non-premature (conditioning) response to the onset of a premature (test) response (the test interval--abscissa) at the various resting membrane potentials indicated beside each curve. Data derived from experiment shown in Fig. 2. Bottom: relationship between the magnitude of the slow, Ca 2+ sensitive inward current (Ic,) to the duration of repolarizing clamp steps from + 2 mV to the different potential levels indicated beside each curve. Experiment performed in pig ventricular trabecula bathed in Tyrode solution containing tetrodotoxin 2 x 10 5 g/ml. In both graphs the curves are drawn as single exponentials and the time constants of recovery are indicated by the arrows. Reprinted with permission from Gettes and Reuter (1974) (Fig. 2 and 12). TABLE 1. Characteristics o[ the Ionic Currents

Type Threshold Reversal potential mV Activation r msec* Inactivation r msec* Deactivation ~- msec Reactivation ~- msec* Contribution to action potential

Na

Ca

CI

x,

x2

K2

depol - 60 + 40 - 1 ~ 2-10 -20-100 upstroke

depol - 35 + 60 5-20 30-300 -30-300 upstroke and plateau

repol - 10 - 17 to - 50f 10 60-130 -1000-2000 notch in P fiber

repoi - 50 - 80 1000 -200-300 -plateau

repol - 50 - 80 2000 ---plateau

repol - 100 - 100 50-250 -2000 -spontaneous depolarization

* Voltage dependent. I Probably represents a multi-ionic potential, depol = depolarizing, repol = repolarizing, r = time constant, P = Purkinie. References: (1) Noble and Tsien, 1969a, b; (2) Beeler and Reuter, 1970a, b; (3) New and Trautwein, 1972a, b; (4) Fozzard and Hiroaka, 1973; (5) Trautwein, 1973; (6) Gettes and Reuter, 1974. in e x t e r n a l C a 2+ c o n c e n t r a t i o n ( B e e l e r a n d R e u t e r , 1 9 7 0 b ; N e w a n d T r a u t w e i n , 1972a). I t is b l o c k e d b y m a n g a n e s e , l a n t h a n u m a n d v e r a t r u m , b u t n o t b y t e t r o d o t o x i n ( R o u g i e r et al., 1969; B e e l e r a n d R e u t e r , 1 9 7 0 b ; V i t e k a n d T r a u t w e i n , 1971; K o h l h a r d t et al., 1972; R e u t e r , 1973) a n d is e n h a n c e d b y e p i n e p h r i n e ( R e u t e r , 1966; V a s s o r t et al., 1969; C a r m e l e i t a n d V e r e e c k e , 1969). A s will b e d i s c u s s e d b e l o w , t h e c u r r e n t m a y c o n t r i b u t e t o t h e a c t i o n p o t e n t i a l s p i k e , is i m p o r t a n t in t h e m a i n t e n a n c e o f t h e p l a t e a u , p a r t i c u l a r l y i n v e n t r i c u l a r f i b e r s , a n d is c a p a b l e o f s l o w l y d e p o l a r i z i n g f i b e r s i n w h i c h t h e r a p i d N a ÷ s y s t e m is i n a c t i v a t e d o r b l o c k e d b y t e t r o d o t o x i n ( s e e b e l o w ) . T h e c h a n n e l t h r o u g h w h i c h t h e c u r r e n t f l o w s is n o t s p e c i f i c f o r C a 2÷ s i n c e o t h e r b i v a l e n t c a t i o n s s u c h a s S r ~÷, B a 2+, a n d M g 2÷ m a y a l s o i n d u c e a s l o w d e p o l a r i z a t i o n ( V e r e e c k e a n d C a r m e l e i t , 1971; K o h l h a r d t et al., 1973a, b). T h e s l o w c u r r e n t h a s a t h r e s h o l d o f - 35 m V ( B e e l e r a n d R e u t e r 1 9 7 0 b ; N e w a n d T r a u t w e i n , 1972a). L i k e t h e r a p i d i n w a r d c u r r e n t , i t s m a g n i t u d e is d e p e n d e n t o n t h e t h e m e m b r a n e p o t e n t i a l p r i o r t o d e p o l a r i z a t i o n ( F i g . I) ( N e w a n d

Possible role of ionic changes in the appearance of arrhythrnias

791

Trautwein, 1972a). The kinetics of this current are voltage dependent. The current is activated with a time constant of a p p r o x i m a t e l y 10 msec and is inactivated with a time constant that ranges between 30 and several hundred m s e c within the m e m b r a n e potential range of - 8 0 - 0 m V (Beeler and Reuter, 1970b; N e w and Trautwein, 1972a). Unlike the rapid current system the time course of the r e c o v e r y f r o m inactivation (Fig. 3) coincides with the time constant of inactivation (Gettes and Reuter, 1974).* 2.2. REPOLARIZING CURRENTS 2.2.1. The Transient Current T h e r e are two m a j o r repolarizing current systems: an early transient current, which is sensitive to changes in extracellular C1- concentrations (Dudel et al., 1967a; Trautwein, 1973; F o z z a r d and Hiraoka, 1973) and a slow, time dependent outward current system thought to depend primarily on K ÷ (Noble and Tsein, 1972; Trautwein, 1973). The early transient current, like the inward currents, depends on the m e m b r a n e potential prior to depolarization (Fig. 1). It is fully active when the m e m b r a n e potential prior to depolarization is more negative than - 7 0 mV and b e c o m e s progressively inactivated at less negative m e m b r a n e potentials. The current is activated with a time constant of approximately 1 0 m s e c and is inactivated with a time constant of a p p r o x i m a t e l y 100msec. The reactivation of this current system ranges between 500 msec and 2 sec as the m e m b r a n e potential prior to depolarization ranges between - 8 0 and - 4 5 mV (Fozzard and Hiraoka, 1973). Thus, this current which is probably responsible for notch which follows the Purkinje fiber action potential spike, is diminished at driving rates greater than 1-2/sec. 2.2.2. The D e l a y e d Currents This current s y s t e m is thought to be comprised of three c o m p o n e n t s Ix~, L2, and It2 and to be responsible for the Purkinje fiber plateau (h~ and L2) and for spontaneous diastolic depolarization (It2) (Noble and Tsien, 1968, 1969a, b; H a u s w i r t h et al., 1972b). These currents are carried primarily by K ÷ and have in c o m m o n a phase of inward going or anomalous rectification. H o w e v e r , they differ in the voltage range over which they are activated (Fig. 4). I~2 is activated between - 100 to - 60 mV (Noble and Tsien, 1968). That is, in a m e m b r a n e potential range which is subthreshold for the inward currents. The time course of activation is m e m b r a n e potential dependent. At m e m b r a n e potentials less negative than - 5 0 mV, the activation time constant is approximately 250 msec. At m e m b r a n e potentials within the range of the action potential plateau, the current is activated with a time constant of less than 50 msec. Because of this short time constant, it is felt that Ix2 does not contribute to the maintenance of the plateau except in action potentials of short duration (Noble and Tsien, 1969b). Following repolarization, the current is deactivated with a time constant of about 2 sec (Noble and

0.5

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--50

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FIG. 4. Steady state activation of slow outward currents in Purkinje fiber. Note that the activation of I~2(S®) is complete at membrane potentials below the activation threshold of the plateau currents (Xl and x2). Reprinted with permission from Noble and Tsien (1969). *Since submitting this chapter, Kohlhardt et al., (Pflugers Archiv 335: 1-17, 1975) have reported that the recovery from inactivation of the slow inward current proceeded more slowly than the inactivation of that current. The causes for this discrepancy are not readily apparent.

792

L . S . GETTES

Tsien, 1968, 1972). It is the decay of this current which is believed to be a major factor contributing to diastolic depolarization in pacemaker fibers. L1 is activated between - 5 0 and 0 mV while Ix2 is activated within a slightly more positive potential range (Fig. 4) (Noble and Tsien, 1969a, b). Thus, these components are not activated at potentials within the range of activation of It2. Ix1 is activated with a time constant of approximately 1 sec. Following repolarization, it is deactivated with a time constant of 200-300 msec (Noble and Tsien, 1969b). Ix2 is activated with a time constant of severa$ seconds and is not thought to contribute to the plateau of normal action potentials. It is possible that this current system contributes to the plateau of very long lasting action potentials and those action potentials with plateau positive to 0 mV. The slow repolarizing currents have also been demonstrated in atrial and ventricular myocardial fibers when long voltage clamps are employed (Brown and Noble, 1969; Beeler and Reuter, 1970a; McGuigan, 1970; de Hemptinne, 1971), but are not believed to contribute in a significant way to the normal action potentials of the ventricular myocardium (Giebisch and Weidmann, 1971), which are of shorter duration than Purkinje action potentials and probably do not contribute to the atrial action potentials which are of even shorter duration. 2.3. IONIC CURRENTS RESPONSIBLE FOR THE VARIOUS CARDIAC ACTION POTENTIALS An appreciation of the ionic specificity, voltage dependency and kinetics of the currents described above help to explain some of the features of the action potentials from the various cardiac fibers. 2.3.1. Purkin]e Fibers In fibers which do not have pacemaker characteristics, the diastolic potential behaves as a K ÷ electrode and varies as expected by the Nernst relationship when the extracellular K ÷ concentration is above 3 m u (Weidmann, 1956; Brady and Woodbury, 1960; Hoffman and Cranefield, 1960). Below an extracellular K ÷ of 3 mu, the resting potential deviates from the value predicted by the Nernst equation. When the cell is depolarized by electrical activity in adjacent cells to - 6 0 mV, the Na ÷ channels open and the cell rapidly depolarizes. The maximum upstroke of the action potential ranges between 500 and 1000 V/sec (Hoffman and Cranefield, 1960). The maximum rate of rise and the amplitude of the action potential spike depend upon the membrane potential prior to depolarization and on the extracellular Na ÷ concentration (Weidmann, 1955a). As the cell is depolarized, the current systems attributed to Ca 2÷, CI- and K ÷ are activated. The peak of the action potential is followed by an initial period of rapid repolarization which lasts approximately 20 msec and is attributed to the transient C1current. This current repolarizes the cell to the range of - 20 mV and is then exceeded by a second depolarizing current which results from the activation of the slow inward Ca 2÷ sensitive current and the inward rectification of Ix~. The inward rectification decreases with time, eventually becoming an outward current which overcomes the declining slow inward current and initiates slow repolarization. As K ÷ leaves the cell it accumulates in the extracellular compartments, increases the permeability to K ÷ ions (Weidmann, 1956), terminates the plateau and initiates rapid repolarization which is accompanied by a recharging of membrane capacitance. Following repolarization, the K ÷ current which is activated during depolarization is deactivated. The decrease in K ÷ conductance associated with this deactivation, combined with a constant inward current is responsible for the diastolic depolarization characteristics of Purkinje. fibers having pacemaker characteristics (Trautwein and Kassebaum, 1961; Vassalle, 1966; Noble and Tsien, 1972). 2.3.2. Ventricular Myocardial Fibers The action potentials of ventricular myocardial fibers differ from those of Purkinje fibers in several important ways: (1) the maximum rate of depolarization is slower; (2)

Possible role of ionic changes in the appearanceof arrhythmias

793

the plateau duration is shorter; and (3) spontaneous diastolic depolarization usually does not occur (Hoffman and Cranefield, 1960). The relationship of maximum rate of depolarization of the action potential to the maximum inward current and membrane capacitance is expressed by eqn (3). INa = - C . ( d V / d t )

....

(3)

Where Cm = membrane capacitance. Thus, the slower maximum rate of rise would occur if the maximum inward current were smaller, if the membrane capacitance were greater, or if a larger portion of the total membrane capacitance were discharged than in Purkinje fiber (Trautwein, 1973). Because of the slower maximum rate of rise, the slower inward current system activated during the upstroke may contribute to the peak of the action potential. This factor may explain the observation that in atrial and ventricular fibers of a variety of species, the magnitude of the action potential spike does not vary directly as a function of the extracellular Na ÷ concentration (Coraboeuf and Otsuka, 1956; Deleze, 1959; Brady and Woodbury, 1960) but does vary as extracellular calcium is altered (Surawicz and Gettes, 1968; Reuter, 1973). The shorter duration of the ventricular action potential plateau may be due to its dependence on the inactivation of the slow inward current system (Beeler and Reuter, 1970b; New and Trautwein, 1972a, b) rather than on the activation of the slow outward current (Giebisch and Weidmann, 1971). Further evidence supporting this conclusion is that the time required for the plateau of a premature ventricular action potential to regain the duration of the preceding non-premature action potential corresponds to the reactivation of the slow inward current (Gettes and Reuter, 1974). The absence of spontaneous diastolic depolarization in ventricular fibers suggests that a current system similar to IK2 either does not exist in ventricular fibers or that its voltage and time dependent characteristics are different. Under certain circumstances spontaneous diastolic depolarization can be demonstrated in ventricular fibers (see below). These observations suggest that either a decreasing outward current or an increasing inward current can be induced by appropriate stimuli during diastole.

2.3.3. S A N o d a l a n d A V J u n c t i o n a l F i b e r s The action potentials of the AV and SA nodal cells differ from those of working myocardial and Purkinje cells in that the maximum rate of rise of the upstroke is slower, the overshoot is less positive and the maximum repolarization potential is less negative (Hoffman and Cranefield, 1960). In addition these action potentials are insensitive to tetrodotoxin, which blocks the rapid inward Na ÷ current, but are sensitive to manganese and veratrum which block the slow Ca 2÷ sensitive inward current (Lenfant et al., 1972; Zipes and Mendez, 1973; Benitez et al., 1973). These observations suggest that these action potentials may be 'slow channel' action potentials and as such do not depend on the rapid inward Na ÷ current. Other evidence in support of the slow channel hypothesis has been obtained by analysis of the effects of acetylcholine on these action potentials (Paes de Carvahlo et al., 1969) and of injection of rapid and slow channel blockers into the arteries supplying the SA node and AV junction (Urthaler and James, 1973; Zipes and Fischer, 1974). 'Slow channel' action potentials have also been demonstrated in atrial, ventricular and Purkinje fibers bathed in Na ÷ free solutions or depolarized by K ÷ or current to a level at which the rapid Na ÷ system is inactivated (Engsffeld et al., 1961; Reuter and Scholz, 1968; Carmeleit and Vereecke, 1969; Papanno, 1970; Imanishi, 1971; Cranefield et al., 1972, 1974; Aronson and Cranefield, 1973; Tritthart et al., 1973; Reuter, 1973; Katzung~ 1974; Imanishi and Surawicz, unpublished), and in embryonic myocardial cells (Shigenobu and Sperelakis, 1972; Sperelakis, 1972). These findings indicate that the slow inward current system is capable of inducing a propagated depolarization in cardiac cells.

794

L . S . GETTES

3. CHARACTERISTICS OF IONIC CURRENTS WHICH MAY PARTICIPATE IN ARRHYTHMIA GENESIS Disorders in cardiac rhythm are traditionally considered as abnormalities of impulse formation and/or impulse conduction and the tachyarrhythmias are generally considered to reflect abnormal pacemaker activity or re-entry. Finally, re-entrant arrhythmias are thought to occur when changes in conductance and refractoriness are such that unidirectional block occurs and a re-entry circuit is established. This section will consider those features of the ionic currents responsible for inducing changes in pacemaker activity, conduction and refractoriness which may contribute to the development of arrhythmias. 3.1. CHANGES IN PACEMAKERACTIVITY Spontaneous activity can be depressed by an increase in extracellular K + (Hoffman and Cranefield, 1960; Surawicz and Gettes, 1963; Gettes and Surawicz, 1968), acetylcholine (Hoffman and Cranefield, 1960; Paes de Carvahlo, 1969) and antiarrhythmic drugs (Rosen and Hoffman, 1973). This effect can usually be attributed to an increase in K ÷ conductance during diastole, although the possibility of a decrease in inward current has not been excluded in all instances. A variety of stimuli will induce or enhance diastolic depolarization. These include hyperthermia (Coraboeuf and Weidmann, 1954), myocardial fiber stretch (Kaufmann and Theophile, 1967), changes in extracellular electrolyte concentration, particularly changes in K + (Fig. 5) and Ca 2÷, (Mueller, 1965; Surawicz and Gettes, 1968), depolarizing currents (Trautwein and Kassebaum, 1961; Imanishi, 1971; Cranefield et aL, 1974; Katzung, 1974; Imanishi and Surawicz, unpublished), drugs particularly the digitalis glycosides (Vassalle et aL, 1962; Kassebaum, 1963; Rosen et al., 1973a, b; Saunders et aL, 1973; Hashimato and Moe, 1973; Ferrier et al., 1973a, b) and the beta-stimulating catecholamines (Kassebaum and Van Dyke, 1966; Hauswirth et al., 1969) and some bivalent cations such as Ba 2÷ (Antoni and Oberdisse, 1965; Masher, 1973) and Sr 2+ (Vereecke and Carmeleit, 1971). Although an increase in diastolic depolarization can be attributed to a net increase in inward current, experiments designed specifically to determine whether in each instance this net increase is due to a decrease in outward current or an increase in inward current have not been performed. Catecholamines are thought to induce pacemaker activity by shifting the activation range of IK2 in a depolarizing direction (Hauswirth et al., 1969). They also increase the slow inward Ca 2÷ sensitive current (Reuter, 1966; Carmeleit and Vereecke, 1969; Vassort et al., 1969; Papanno, 1970). There are several features regarding the enhancement of automaticity which may have particular significance in arrhythmia genesis: (1) atrial and ventricular myocardial fibers which normally do not spontaneously depolarize during diastole may be converted into spontaneously discharging fibers (Mueller, 1965; Kaufmann and Theophile, 1967; Masher, 1973); (2) acetylstrophanthidin and ouabain are capable of inducing subthreshold depolarization in Purkinje fibers (Rosen et aL, 1973a, b; Ferrier et al., 1973a, b) which may reach threshold and produce a propagated response or may AControl

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~ " ~

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Possible role of ionic changes in the appearance of arrhythmias

795

cause an area of conduction block. These depolarizations are prevented or abolished by increasing extracellular K ÷, decreasing extracellular Ca 2÷ and by Mn 2÷ and are potentiated by lowering K ÷ and by increasing Ca 2÷. Ferrier et al. (1973b) have concluded that they may be caused by the slow inward current; (3) depolarization of the membrane to levels less negative than -40 mV by the injection of d.c. current is capable of inducing spontaneous depolarizations (Imanishi, 1971; Cranefield et al., 1974; Katzung, 1974; Imanishi and Surawicz, unpublished) (Fig. 6). The slope resistance of the membrane increases during the spontaneous depolarization, suggesting a decrease in membrane conductance (Imanishi and Surawicz, unpublished). These depolarizations are prevented by increasing extracellular K ÷ and lowering extracellular Ca 2÷ and by inhibitors of the slow inward current (Katzung, 1974; Imanishi and Surawicz, unpublished). It has been concluded that the spontaneous depolarizations are probably due to both a decrease in K ÷ outward current and to an inward current, probably carried by Ca 2+.

10"4A I 20 mV

I

- 85 mV

Fro. 6. Effect of 4sec depolarizing current pulses on guinea-pig papillary muscle. Depolarizations below - 40 mV do not induce spontaneous activity. However, when the fiber is depolarized to approximately - 2 0 mV, repetitive spontaneous activity occurs. Printed by permission of Iminishi and Surawicz (article in preparation).

3.2. SLOWED DEPOLARIZATION The rate at which the cell depolarizes is a major determinant of conduction velocity. Thus, it is appropriate to emphasize those features of the depolarizing currents which may be important in the genesis of conduction abnormalities and the development of re-entry circuits. As reviewed above, the magnitude of the rapid inward current and of (dV/dt)=~ of the action potential upstroke is both voltage and time dependent. (dV/dt)m~ and conduction velocity will be decreased in partially depolarized fibers. An increase in extracellular K ÷ decreases resting membrane potential and slows (dV/dt)=~, of the action potential. This accounts for the slowing of intraventricular conduction, widening of the QRS complex and ventricular asystole associated with hyperpotassemia (Gettes et al., 1962; Surawicz and Gettes, 1963, 1968; Ettinger et al., 1974). (dV/dt)m,x and conduction velocity will also be decreased in fibers which develop spontaneous diastolic depolarization and thereby lower the membrane potential at the onset of rapid depolarization (Singer et al., 1967). This mechanism is thought to account for conduction blocks into and out of spontaneously depolarizing ectopic centers (Singer et al., 1967; Friedman et al., 1973a, b) and is one mechanism for 'protection' afforded parasystolic foci (Steffens and Gettes, 1974). The characteristics of the recovery of (dV/dt)=~ following a preceding depolarization will determine the conduction velocity in premature beats. The recovery time becomes longer as the membrane potentials at the onset of depolarization become less negative (Figs. 2 and 3). Thus (dV/dt)mx in premature responses arising from an incompletely repolarized fibers will be less than predicted from the steady state membrane potential-(dV/dt)=~ relationship (Fig. 7). In addition (dV/dt)=~ of premature responses arising from fully repolarized fibers will be less than (d V/dt)=,~ of

7~

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membrane potential at onset of action potential (mV)

FIG. 7. Curves relating (d V/dt)m.x of guinea-pig papillary muscle action potentials to membrane potential at the onset of depolarization. The filled triangles are steady state values obtained when the papillary muscle, stimulated at a rate of 0.25/sec, was depolarized by adding KCl to the perfusate (insert upper). The open circles indicate non-steady state values obtained in the same fiber from premature action potentials initiated during the phase of incomplete repolarization of the preceding non-premature response (insert lower). Reprinted with permission from Gettes and Reuter (1974). the preceding non-premature response for an interval f r o m the end of the non-premature action potential to the onset of the p r e m a t u r e action potential (i.e. the diastolic interval), which will b e c o m e progressively longer as the resting m e m b r a n e potential b e c o m e s progressively less negative (Figs. 2 and 3). ( d V / d t ) m ~ and conduction velocity m a y be slowed by metabolic inhibitors (McDonald and M a c L e o d , 1972), possibly by hypoxia (Trautwein et al., 1954; Parsad and Callaghan, 1971), and by drugs such as quinidine (Weidmann, 1955b). H o w e v e r , it is not clear whether these agents exert their effects by altering the steady state relationship of (d V / d t ) . . . . the kinetics of (d V/dt)max or act independently of alterations in these parameters. Acetylcholine slows depolarization of the AV nodal fibers. This effect has been attributed to a decrease in the slow inward current thought responsible for the upstroke of the action potential in these fibers (Paes de Carvahlo, 1969). As indicated above, the slow inward current system is also capable of depolarizing cardiac fibers in which the rapid N a ÷ system is inactivated. Cranefield et al. (1971a, b 1972) and Wit et al. (1972a, b) have shown that the very slow conduction (0.05 m/sec) in K ÷ depolarized Purkinje fibers which they attribute to the effects of slow channel depolarization can cause uni- or bidirectional blocks, summation, and re-entry. 3.3. REFRACTORINESS

The refractory period is the interval necessary for the fiber to r e c o v e r its ability to depolarize after a preceding depolarization. It depends upon the time required for the cell to repolarize to a re-excitable m e m b r a n e potential following a depolarization and is therefore determined by the duration of the action potential plateau and the r e c o v e r y characteristics of the depolarizing currents. In most fibers, the refractory period terminates when the cell repolarizes to approximately - 6 0 mV (Hoffman and Cranefield, 1960). It is n o t e w o r t h y however, that in fibers of the AV node and in those surrounding the SA node, the refractory period is usually longer than the duration of the action potential (Merideth et al., 1968; Strauss and Bigger, 1972). Plateau duration is altered by a variety of factors including rate, temperature, hypoxia, changes in extracellular electrolyte concentrations, drugs, electrotonic interaction and premature stimulation. S o m e of the factors influence Purkinje and

Possible role of ionicchangesin the appearanceof arrhythmias

797

ventricular fibers differently. Increasing the rate shortens the plateau duration and refractory period in both Purkinje and ventricular fibers (Hoffman and Cranefield, 1960) but the effect is more pronounced in Purkinje fibers (Moore et al., 1965; Gettes and Surawicz, 1968). An increase in extracellular K ÷ concentration also shortens plateau duration in both fiber types but again the effect is more pronounced in Purkinje fibers (Gettes and Surawicz, 1968), probably due to the more direct dependence of the Purkinje fiber plateau upon changes in K ÷ conductance. A decrease in extracellular K ÷ concentration shortens the plateau but prolongs the phase of rapid repolarization in ventricular and Purkinje fibers (Gettes et al., 1962, 1968). Whether the total action potential duration and refractory period become shorter or longer depends upon which of these opposing actions predominate. An increase in extracellular Ca 2÷ concentration shortens while a decrease prolongs plateau duration (Surawicz and Gettes, 1968). This effect is the opposite of that expected by the anticipated changes of the slow inward current system and most likely reflects the interaction between the external Ca 2÷ concentration and the Na ÷ and K ÷ current systems (Hauswirth et al., 1969). An increase in extracellular Na ÷ concentration prolongs plateau duration (Arita and Surawicz, 1973). Hypoxia (Trautwein et al., 1956; McDonald and MacLeod, 1973a) and digitalis (Hoffman and Singer, 1964; Mandel et al., 1972) shorten action potential duration presumably by their influence on the metabolic factors regulating active ionic transport (MacLeod and Parsad, 1969; McDonald and MacLeod, 1973a, b; Langer, 1972) and the resultant changes in intracellular ionic concentrations. The various antiarrhythmic drugs have variable effects on plateau duration but most have in common the property of prolonging the refractory relative to action potential duration (Gettes, 1971; Bassett and Hoffman, 1972). This effect most likely represents the change in the voltage dependency and reactivation characteristics of the depolarizing currents.(Weidmann, 1955b; Chen et al., 1975). The effects of electrotonic interaction have been investigated by Mendez et al. (1969) and by Sasyniuk and Mendez (1971). These investigators showed that the plateau duration of action potentials proximal to an area of conduction block, induced by pressure or occurring naturally at the Purkinje-papillary muscle junction, were markedly shortened and promoted the development of re-entry. The effects of electrotonic interaction have also been demonstrated in AV nodal cells (Mendez and Moe, 1966; van Cappelle et al., 1972). These studies provide evidence that the duration of the action potential is influenced by electrical events in adjacent cells. Prematurity also effects action potential duration. These effects cannot be attributed only to the change in the intra-stimulus interval since, in both Purkinje fibers and ventricular fibers, the action potential durations of early premature responses differ from the action potential duration of steady state responses having the same intrastimulus intervals (Gettes et al., 1972). In the Purkinje fiber, as indicated above, the slow outward current (Ix,), activated during the plateau, deactivates with the time constant of 200-300 msec following rapid repolarization and provides a 'background' of outward repolarizing current which affects the premature action potential. The duration of a premature action potential will progressively decrease as it arises in progressively closer proximity to the plateau of the preceding non-premature action potential (Gettes et al., 1972; Hauswirth et al., 1972a), since the earlier the premature action potential, the less complete will be the deactivation of the outward current and the greater the 'background' outward, repolarizing current. In ventricular myocardial fibers, the plateau duration of a premature action potential can be correlated to the reactivation of the slow inward current systems (Gettes and Reuter, 1974). As a result, the duration of the premature action potential in ventricular fibers, as in Purkinje fibers, will vary as a function of the proximity of the onset of the premature action potential to the end of the preceding non-premature action potential. If this interval is longer than the recovery time for the slow inward current system, i.e. 100-150 msec, the action potential duration will be equal or, for unexplained reasons, slightly longer than the duration of the preceding non-premature action potential

798

L . S . GE'ITES

(Gettes et al., 1972). If the premature response or the first response following a sudden change of rate originates within 100-150msec of the end of the preceding nonpremature action potential, i.e. within the period of incomplete reactivation of the slow inward current system, the duration of the premature action potential and of the refractory period will shorten progressively (Gettes et al., 1972; Janse et al., 1969). The duration of the action potential preceding the premature response also influences the duration of the premature action potential (Gettes et al., 1972). This factor is important because (1) the magnitude of currents generated during the plateau will differ in action potentials having different durations; and (2) the proximity of a premature to a non-premature response will also differ in action potentials of varying durations. The durations of the Purkinje fiber action potentials vary depending upon their location within the conduction system (Mendez et al., 1969; Myerburg et al., 1970). The responses to a premature stimulus will therefore arise in closer proximity to the longer action potential than to the shorter ones. As a result of this difference in proximity, the relationship between the end of the premature action potentials may be the reverse of their relationships in the non-premature action potentials. This is illustrated in the upper two panels of Fig. 8. As a rule, the duration of the Purkinje fiber action potential is longer than that of the ventricular fiber action potential (Hoffman and Cranefield, 1960) but the difference between the two at the Purkinje muscle junction is small (Mendez et al., 1969; Myerburg et al., 1970). An early premature stimulus will fall in closer proximity to the end of the Purkinje fiber action potential than to the end of the ventricular fiber action potential. As shown in Fig. 8, the resultant Purkinje premature action potential may be of shorter duration than the ventricular action potential and thus the normal sequence of the recovery of excitability in the two types of fibers may be reversed. A premature response arising during the relative refractory period which includes the vulnerable period, i.e. from the apex to the end of the T wave on the electrocardiogram propagates through incompletely repolarized fibers. This may cause: (1) a slowed rate of depolarization due to the voltage dependency and recovery characteristics of the rapid inward current; (2) a shortened refractory period due to the characteristics of the slow outward current in Purkinje fibers and the slow inward current in ventricular fibers. These changes may induce alterations of sequence of the recovery of excitability and areas of conduction block which, in turn, will cause changes in electrotonic interactions. It is reasonable to assume that these events contribute to the re-entry arrhythmias which may follow such premature stimulation (Smirk, 1960; Surawicz et al., 1967; Surawicz, 1971). 4. CLINICAL CORRELATES OF C E L L U L A R CHANGES 4.1. ROLE OF ELECTROLYTECHANGES IN PRODUCTION AND TREATMENTOF ARRHYTHMIAS It is possible to envision disturbances of cardiac rhythm resulting from changes in any of the electrolytes which contribute to the ionic currents responsible for the action potentials of various cardiac fibers. However, in the clinical situation changes in serum K ÷ are responsible for most electrolyte-induced abnormalities in cardiac rhythm. Furthermore, K ÷ salts are clinically effective anti-arrhythmic agents. This relative uniqueness may be attributed to the fact that the changes in serum K ÷ concentration encountered clinically cause significant changes in depolarization, repolarization and pacemaker activity in the various cardiac cells whereas clinically encountered changes in concentrations of Na ÷, Cl- and Ca 2+ exert less profound effects on these electrophysiologic parameters. 4.1.1. P o t a s s i u m As indicated above, the resting potentials in atrial, ventricular and Purkinje fibers behave as a K + electrode and depend upon the ratio of intracellular to extracellular K +

Possible role of ionic changes in the appearance of arrhythmias

CL

799

0

APD ~ 595 CL ~150

5°I

56~ 34~150rnv'

APD ~ 580

500rnsec

rnV

P-V 190

L~I. 500msec.

- 41

FIG. 8. Effect of a premature stimulus on durations of simultaneously recorded Purkinje fiber action potentials of the pig moderator band driven at basic rate of 0.87/sec (above) and on the duration of simultaneously recorded Purkinje and ventricular fiber action potentials driven at a basic rate of l/sec (below). In the simultaneously recorded Purkinje fiber action potentials above, CL = cycle length, APD = action potential duration. In the non-premature response the duration of the upper action potential is 15 msec greater than that of the lower while in the premature response the duration of the upper action potential is 30 msec less than that of the lower. In the simultaneously obtained Purkinje and ventricular action potentials below, P - V = the difference (msec) between the Purkinje and ventricular action potential durations. In the non-premature responses the duration of the Purkinje action potential (above) exceeds that of the ventricular action potential (below) by 190 msec, while in the premature response, it is 41 msec less than the duration of the ventricular action potential. Note that the calibrations in the upper and lower portions of the figure are different. Reprinted with permission from Gettes et aL (1972), (Figs. 5 and 10).

c o n c e n t r a t i o n . T h e r e s t i n g p o t e n t i a l varies as e x p e c t e d b y the c a l c u l a t e d K ÷ e q u i l i b r i u m p o t e n t i a l as the e x t r a c e l l u l a r p o t a s s i u m varies w i t h i n the clinically e n c o u n t e r e d r a n g e of 2 - 8 m E q / l ( G e t t e s e t al., 1962). I n a d d i t i o n , c h a n g e s in e x t r a c e l l u l a r K ÷ c a u s e c h a n g e s in K ÷ c o n d u c t a n c e ( W e i d m a n n , 1956) w h i c h i n f l u e n c e a c t i o n p o t e n t i a l p l a t e a u d u r a t i o n a n d the slopes of rapid r e p o l a r i z a t i o n , a n d s p o n t a n e o u s diastolic d e p o l a r i z a t i o n . It is the c o m b i n a t i o n of these c h a n g e s w h i c h a c c o u n t for b o t h the a r r h y t h m o g e n i c a n d a n t i - a r r h y t h m i c effects of c h a n g e s in p o t a s s i u m c o n c e n t r a t i o n . T h e t y p e of r h y t h m d i s t u r b a n c e p r o d u c e d or a b o l i s h e d b y c h a n g e s in s e r u m K ÷ d e p e n d s n o t o n l y o n the K ÷ c o n c e n t r a t i o n , b u t also o n s e v e r a l o t h e r f a c t o r s i n c l u d i n g : (1) the rate of c h a n g e of the K ÷ c o n c e n t r a t i o n ; (2) the differing s e n s i t i v i t y of the v a r i o u s c a r d i a c fibers to the c h a n g e s in K÷; (3) the p l a s m a c o n c e n t r a t i o n of o t h e r e l e c t r o l y t e s ; (4) the u n d e r l y i n g state of the m y o c a r d i u m ; (5) the i n t e r a c t i o n of c h a n g e s in K + with n e u r o g e n i c f a c t o r s ; a n d (6) with c a r d i o - a c t i v e drugs. T h e s e c o n s i d e r a t i o n s h a v e b e e n d i s c u s s e d in detail in i

.

.

800

L.S. GETrES

several recent reviews (Surawicz, 1966, 1967; Surawicz and Gettes, 1971; Fisch et al., 1966; Fisch, 1973). (a) H y p e r p o t a s s e r n i a . An increase in extracellular K + decreases the resting potential, shortens the action potential plateau, speeds rapid repolarization, and depresses spontaneous diastolic depolarization in fibers of the His-Purkinje system. Although the changes in repolarization cause the earliest electrocardiographic manifestations of hyperpotassemia, (peaking of the T wave and shortening of the QT interval), and occur at a K + concentration of approximately 6 mEq/l, it is the changes resulting from the decrease in resting potential and the decrease in spontaneous diastolic depolarization which are more important in the arrhythmogenic and anti-arrhythmic effects of hyperpotassemia. When the K + concentration is between 6 and 9 m E q / l , the decrease in resting potential causes a decrease in the rate of depolarization and a slowing of intra-atrial, atrio-ventricular, and intra-ventricular conduction. These changes are manifested on the ECG by a widening and decrease in amplitude of the P wave, and by prolongation of the PR interval and QRS duration (Surawicz, 1967b). When the K ÷ concentration is greater than 9 mEq[l conduction through the His-Purkinje system is prolonged as reflected by the prolongation of the H - V interval (Ettinger et al., 1974). These differences in K + concentration at which the various changes occur illustrate the differences of sensitivity of the various fiber types of the increase in K +. The atrial cells are more sensitive than the ventricular fibers which themselves are more sensitive than the cells of the His-Purkinje system. Thus, intra-atrial conduction may be abolished at K ÷ concentrations which still permit atrio-ventricular and intra-ventricular conduction. When this occurs, impulses arising in the SA nodal fibers, the least sensitive of the various fiber types to an increase in extracellular K + may travel to the ventricles presumably through specialized atrial conducting fibers. This may result in sino-ventricular conduction in the presence of sino-atrial block (Vassalle and Hoffman, 1965; Bellet and Jedlicka, 1969). The effect of hyperpotassemia on atrio-ventricular conduction in the clinical situation is variable and both an increase and decrease in atrio-ventricular conduction have been reported (Bettinger et al., 1956). The variability in the effect is attributed to the fact that: (1) A - V conduction is probably optimal at a K ÷ concentration of about 6 mEq/l (Paes de Carvalho and Langan, 1963); (2) the rate of K ÷ increase as well as its magnitude contributes to the changes in A-V conduction (Fisch et al., 1966); and (3) there exists a rather complicated interaction between K ÷ and acetylcholine which contribute to the changes in A - V (Fisch et al., 1966). Nonetheless, experimental evidence suggests that slowing in A-V conduction consistently occurs when K + is greater than 7-8 mEq/l (Fisch et al., 1966; Cohen et al., 1971). Hyperpotassemia may cause ventricular standstill or ventricular fibrillation (Surawicz, 1967a). In the experimental preparation, cardiac standstill may occur from two mechanisms (Surawicz and Gettes, 1963). When K ÷ elevation occurs slowly, intraventricular conduction becomes progressively depressed. This results in a generalized widening of the QRS complex (Fig. 9) although shifts in electrical axis have also been reported (Ewy et al., 1971). Ultimately the ventricular myocardium loses its excitability. An increase in the threshold of excitability may also contribute to this p h e n o m e n o n (Fig. 10) (Surawicz et al., 1965; Gettes et al., 1969). When K + is elevated rapidly, suppression of pacemaker cells may occur before conduction abnormalities become apparent (Surawicz and Gettes, 1963; Surawicz et al., 1967) and cardiac standstill may occur. Ventricular fibrillation may occur when ventricular conduction becomes so slow that some fibers recover their excitability before depolarization through the entire ventricle is completed thereby permitting re-entry to occur (Surawicz, 1967a). The rapid intravenous administration of K ÷ salts has been successfully employed to treat a variety of supraventricular and ventricular tachyarrhythmias (Bettinger et al., 1956). This effect is due most likely to the suppression of spontaneous diastolic

Possible role of ionic changes in the appearance of arrhythmias E.P.

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FIG. 9. Electrocardiograms recorded from a 40 year old woman during an Addisonian crisis. Tracing B was recorded 6 hr after A. Note the diffuse widening of the QRS complex in A and the gradual shift in electrical axis from A-C. This gradual shift suggests that the QRS complex in A is supraventricular and that an intraventricular conduction disturbance is associated with the hyperpotassemia and byponatremia. The three lower tracings are strips of lead II. In A, the P wave is absent and a 2 : 1 conduction block occurs. In B, the P wave is present and the PR interval is prolonged. The rate is slightly faster in A than in B. It is possible, but not proven, that the rhythm disturbance in A is due to sino-atrial block with 1 : 1 and then 2 : 1 sino-ventricular conduction. In C, the PR interval is normal. The ST and T abnormalities may be attributed to the combination of hypokalemia and hypocalcemia.

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802

L.S. GETrES

depolarization in ectopic foci resulting from the increase in K ÷ conductance during diastole. An additional possible mechanism may be related to the observation that an increase in extracellular K + decreases the difference of action potential duration in Purkinje and ventricular myocardial fibers (Gettes and Surawicz, 1968). The administration of K ÷ salts may also cause subtle changes of conduction into or out of a re-entry zone. In patients with A-V block, the administration of K ÷ salts may cause either an improvement or a deterioration of A-V conduction (Bettinger et al., 1956). (b) H y p o p o t a s s e m i a . A decrease in extracellular K ÷ to within clinically applicable concentrations results in a more negative resting potential, shortens the action potential plateau, slows the slope of rapid repolarization and increases the slope of spontaneous diastolic depolarization. The effects on repolarization and diastolic depolarization are similar to those of digitalis. It is not surprising therefore, that hypopotassemia should potentiate the tachyarrhythmia induced by digitalis. However, even in the absence of digitalis, hypopotassemia promotes supra-ventricular and ventricular arrhythmias and A-V conduction disturbances (Davidson and Surawicz, 1967). In the isolated heart, a decrease in extracellular K ÷ to less than 1 mEq/l invariably induces A-V conduction disturbances, atrial and ventricular premature beats, and ventricular fibrillation (Gettes et al., 1966). 4.1.2. Calcium An increase in extracellular Ca 2÷ shortens action potential plateau, which is associated with shortening of the QT interval on the electrocardiogram. It also increases slightly the rate of diastolic depolarization of pacemaker fibers and increases the excitability threshold (Surawicz and Gettes, 1965, 1971). In the experimental animal, hypercalcemia increases QRS duration and produces ectopic beats and ventricular fibrillation. Clinically, severe hypercalcemia may be associated with prolongation of the QRS complex and of the PR interval. Occasionally, higher degrees of A-V block may occur. Although it is postulated that patients with hypercalcemia may develop ventricular fibrillation, direct evidence confirming this relationship is not available. A decrease in extracellular Ca ~÷ lengthens the action potential and prolongs the QT interval on the electrocardiogram (Surawicz and Gettes, 1965, 1971), but is not associated with arrhythmias. On the contrary, hypocalcemia induced by the infusion of Na2 EDTA has been found effective in suppressing ventricular ectopic beats in about 50 per cent of both digitalized and non-digitalized patients (Surawicz et al., 1959). The effect of changes in Ca 2÷ concentration depend on the serum concentration of K ÷ and vice versa. Increasing serum Ca 2÷ restores the resting membrane potential (Hoffman and Cranefield, 1960) and abolishes the intraventricular conduction disturbances induced by hyperpotassemia. In experimental animals, the A-V conduction disturbances and ventricular arrhythmias, including ventricular fibrillation, induced by perfusion with low K ÷ solution can be abolished and prevented by simultaneously lowering the Ca 2+ concentration of the perfusate (Gettes et al., 1966). However, the ionic concentrations of both potassium and calcium required to demonstrate this interaction are not compatible with life. 4.1.3. S o d i u m and Chloride While alterations of Na ÷ and CI- concentrations are capable of altering electrophysiologic properties of single fibers, clinically observed changes in the plasma concentrations of the ions are not associated with arrhythmias. However, it is possible that hyponatremia if present, may contribute to the QRS widening and intraventricular conduction disturbances associated with hyperpotassemia (Fig. 9) (Ewy et al., 1971). Moreover, the administration of sodium salts reverses the intraventricular conduction disturbances associated with hyperpotassemia (Garcia-Palmieri, 1962) or with quinidine toxicity (Bellet et al., 1959) and may prevent the associated ventricular fibrillation or standstill. This effect reflects the dependence of the upstroke of the action potential and therefore conduction velocity on the extracellular sodium concentration.

Possible role of ionic changes in the appearance of arrhythmias

803

4.1.4. Magnesium Hypermagnesemia (3-5 mm/l) causes atrio-ventricular and ventricular conduction disturbances (Surawicz and Gettes, 1971). These observations suggest that the effects of Mg 2÷ on depolarization are similar to those of potassium. Changes in Mg 2÷ concentration also alters repolarization in a manner which is similar to Ca ~÷ (Surawicz and Gettes, 1965). It has been suggested that the electrophysiology effects of magnesium are significantly influenced by the associated concentrations of Ca z÷ and K ÷ (Watanabe and Dreifus, 1972). There is no conclusive evidence implicating alterations in Mg 2÷ concentration per se in the genesis of cardiac arrhythmias. However, there is evidence to suggest that hypomagnesemia decreases the dose of digitalis required to induce ectopic tachyarrhythmias in both experimental animals and in man (Sellers et al., 1970; Belier et al., 1974), and that the infusion of Mg 2÷ salts is effective in suppressing ectopic beats and tachyarrhythmias in both digitalized and non-digitalized patients (Szekely, 1946; Szekely and Wynne, 1951). It has been postulated that these effects of Mg 2÷ may be due to changes in transmyocardial K ÷ kinetics caused by the action of Mg 2÷ on the N a - K activated ATPase system (Seller et al., 1970). 4.2. PATHOPHYSIOLOGY OF ISCHEMIA-RELATED ARRHYTHMIAS Occlusion of a coronary vessel causes an inhomogeneous decrease in coronary blood flow (Griggs and Nakamura, 1968; Becker et al., 1973) resulting in a complex series of inter-related biochemical, mechanical and electrophysiological changes which contribute to the development of arrhythmias. As detailed in a recent review (Gettes, 1974), the decrease in myocardial flow causes myocardial hypoxia which induces anaerobic metabolism, lactic acid production and acidosis. The combination of hypoxia and acidosis results in a decrease in intracellular and an increase in extracellular K ÷ concentrations as well as changes in other electrolyte concentrations, fatty acids and ATP. The rapid development of hypoxia, acidosis and hyperpotassemia in the ischemic zone stimulates sympathetic and parasympathetic nerve endings and depresses contractibility. This latter factor leads to a decrease in myocardial perfusion and a worsening of mycardial ischemia. The information obtained in the single cell can not explain the many factors that lead to cardiac arrhythmias in this clinical setting. For instance, it is difficult to assess the full effects of electrotonic interaction by studies of single cells. It is also difficult to study the effects of ischemia in isolated, bathed preparations. Nonetheless, a consideration of those characteristics of the ionic currents which may contribute to ischemia induced changes in pacemaker activity, conduction and refractoriness illustrate the possible clinical significance of the concepts derived from single cell studies. 4.2.1. Changes in Pacemaker Activity (a) Depression. Parasympathetic stimulation will lead to the accumulation of acetylcholine in the parasympathetic nerve endings which are concentrated about the SA node, atrial and AV junction. This will decrease the rate of spontaneous depolarization of the cells in the sinus node and AV junction (Hoffman and Cranefield, 1960; Paes de Carvahlo et al., 1969) and cause bradycardia. This effect has been attributed to the acetylcholine induced increase in K ÷ conductance (Hoffman and Cranefield, 1960; Ware and Graham, 1967) and possibly a decrease in inward current (Paes de Carvahlo, 1969). A rapid increase in extracellular K ÷ may also decrease spontaneous activity by increasing K ÷ conductance during diastole (Surawicz and Gettes, 1963). However, the contribution of this mechanism to ischemia-related bradycardia is of unknown significance. (b) Enhancement. Sympathetic stimulation will lead to accumulation of norepinephrine in the ischemic myocardium and an increase in circulating catecholamines which will increase the rate of induce spontaneous depolarization in cells of the specialized

8~

L . S . GENES

conducting system. This effect may. be particularly important in the surviving Purkinje fibers located in the subendocardial region of the ischemic zone (Friedman et al., 1973a, b). The depolarization of fibers which occurs as a result of the changes in extracellular and intracellular K ÷ concentration, and possibly as a result of the metabolic consequences of ischemia (McDonald and MacLeod, 1973a, b) may enhance or induce spontaneous activity by (1) creating a battery between cells depolarized to different degrees and producing a flow of DC current which may enhance diastolic depolarization of cells within a specialized conducting system (Trautwein and Kassebaum, 1961); and (2) by lowering the membrane potential to the threshold of the slow inward depolarizing current (approximately - 40 mV) which, in combination with the effect of the catecholamines liberated from the ischemic myocardium, may result in repetitive spontaneous 'slow channel' depolarizations. These several mechanisms may be responsible for some of the ectopic beats and tachyarrhythmias associated with myocardial ischemia. 4.2.2. Slowed Conductance The acetylcholine liberated as a result of parasympathetic stimulation will lead to slowing of the action potential upstroke in cells of the AV junction (Cranefield et al., 1958; Paes de Carvahlo et al., 1967). This mechanism combined with the K ÷ induced depolarization discussed below probably contributes to the delay in AV conduction which not infrequently occurs in association with myocardial infarctions. The decrease in resting membrane potential which occurs as a result of the K ÷ changes will result in a decreased rate of depolarization in the action potential and a slowing of conduction due to the voltage dependent characteristics of rapid Na + inward current system. Conduction abnormalities might also result from a K ÷ induced increase in the diastolic threshold of excitability (Gettes et al., 1969). A decrease in resting potential will result in the slowed recovery of the inward current system. Thus the rate of depolarization of premature action potentials and the conduction velocity of premature response will be even slower than in the non-premature response. In cells depolarized to levels of - 4 0 mV, the Na + system will be totally inactivated. In these cells a propagated depolarization may result from the slow inward Ca 2÷ sensitive current system, particularly when this current is increased by the sympathetic catecholamines liberated from the ischemic area. The slow conduction velocity in such responses (Wit et al., 1972a, b; Cranefield et al., 1971a, b, 1973) probably contributes to the marked slowing of conduction which occurs within the ischemic zone (Bagdonas et al., 1961; Scherlag et al., 1970; Boineau and Cox, 1973; Cox et al., 1973; Ettinger et al., 1973; Surawicz, 1974). 4.2.3. Changes in Refractoriness Hypoxia and an increase in extracellular K ÷ shorten the action potential duration and would be expected to shorten the refractory period. The catecholamines may also shorten action potential duration (Giotti et al., 1973). The action potential duration of early premature action potentials will be shortened because of the deactivation and reactivation characteristics of the plateau currents. The voltage dependency of the recovery of the slow inward current system will contribute to greater shortening of the plateau of those premature action potentials which arise from partially depolarized fibers. These changes may contribute to the increase in inhomogeneity of the recovery of excitability which accompanies myocardial ischemia (Han, 1969) and which, in combination with the changes in conduction referred to above, may be responsible for the development of re-entrant arrhythmias, particularly ventricular fibrillation (Cranefield et al., 1973b; Surawicz, 1971). 5. SUMMARY In this chapter, abnormalities of cardiac rhythm have been discussed in relationship to the ionic currents responsible for the action potential of the various cardiac cells.

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C o n c e p t s r e g a r d i n g (1) t h e specific ionic c u r r e n t s a n d t h e i r c o n t r i b u t i o n to t h e a c t i o n p o t e n t i a l ; a n d (2) the c h a r a c t e r i s t i c s of t h e s e c u r r e n t s w h i c h m a y b e i m p o r t a n t in t h e g e n e s i s o f c a r d i a c a r r h y t h m i a s h a v e b e e n r e v i e w e d . T o i l l u s t r a t e t h e clinical s i g n i f i c a n c e of t h e s e c h a r a c t e r i s t i c s , s o m e o f t h e e f f e c t s of m y o c a r d i a l i s c h e m i a on t h e s e ionic c u r r e n t s a n d t h e i r r e l a t i o n s h i p to t h e d e v e l o p m e n t o f a r r h y t h - n i a s h a v e b e e n considered. W i t h i n t h e l a s t d e c a d e , o u r u n d e r s t a n d i n g of the r e l a t i o n s h i p s b e t w e e n the ionic c u r r e n t s a n d a r r h y t h m i a g e n e s i s h a s b e e n g r e a t l y e n h a n c e d b y (1) t h e m o r e c o m p l e t e e l u c i d a t i o n o f the ionic s p e c i f i c i t y o f t h e c u r r e n t s r e s p o n s i b l e f o r t h e a c t i o n p o t e n t i a l ; (2) t h e a p p r e c i a t i o n o f the significance o f the s l o w i n w a r d c u r r e n t s y s t e m n o t o n l y in e x c i t a t i o n c o n t r a c t i o n c o u p l i n g ( B a s s i n g t h w a i g h t e a n d R e u t e r , 1972) a n d in t h e m a i n t e n a n c e o f the a c t i o n p o t e n t i a l p l a t e a u , b u t also as the p r o b a b l y m a j o r c u r r e n t s y s t e m r e s p o n s i b l e f o r t h e a c t i o n p o t e n t i a l s o f S A a n d A V n o d a l cells a n d as a c a u s e o f s l o w d e p o l a r i z a t i o n in atrial, v e n t r i c u l a r a n d P u r k i n j e fibers; a n d (3) t h e g r e a t e r u n d e r s t a n d i n g of t h e k i n e t i c c h a r a c t e r i s t i c s o f t h e v a r i o u s c u r r e n t s y s t e m s . A s a l l u d e d to b y W e i d m a n n (1974) it is r e a s o n a b l e to e x p e c t t h a t w i t h i n the n e x t d e c a d e w e will o b t a i n a b e t t e r u n d e r s t a n d i n g of: (1) the i m p o r t a n c e o f e l e c t r o t o n i c i n t e r a c t i o n o n t h e a c t i o n p o t e n t i a l , p a r t i c u l a r l y in t r a n s i t i o n a l cells in the p e r i - n o d a l r e g i o n s a n d at t h e P u r k i n j e - p a p i l l a r y j u n c t i o n s ( M e n d e z et al., 1969); (2) t h e c o n t r i b u t i o n o f e l e c t r o g e n i c p u m p s to the r e s t i n g m e m b r a n e p o t e n t i a l a n d p r o d u c t i o n o f t h e p l a t e a u ( H a a s , 1972); (3) the s i g n i f i c a n c e o f t h e a c c u m u l a t i o n o f i o n s w i t h i n i n t r a c e l l u l a r clifts ( M a u g h a n , 1973); (4) the c h a r a c t e r i z a t i o n o f t h e ionic c h a n n e l s w i t h i n the m e m b r a n e (Hille, 1970); a n d (5) t h e r e l a t i o n s h i p b e t w e e n m i c r o - s t r u c t u r e of t h e v a r i o u s cells a n d t h e i r e l e c t r i c a l c h a r a c t e r i s t i c s ( L e g a t o , 1973). A s t h e k n o w l e d g e d e r i v e d f r o m i s o l a t e d p r e p a r a t i o n s is a p p l i e d to the c l i n i c a l s i t u a t i o n a n d as e x p l a n a t i o n s f o r c l i n i c a l l y o b s e r v e d p h e n o m e n a a r e s o u g h t in i s o l a t e d p r e p a r a t i o n s , o u r u n d e r s t a n d i n g o f t h e ionic f a c t o r s r e s p o n s i b l e f o r c a r d i a c a r r h y t h m i a s will b e c o m e more complete. Acknowledgment--The author acknowledges with grateful appreciation the many discussions with Professor

Borys Surawicz and our co-workers which contributed to the development of the ideas expressed in this review. Thanks are also due to Professor Surawicz for his critique of the manuscript. Support for some of the studies reviewed was provided by N.I.H. grant HL 13321. REFERENCES ANTON1, H. and OBERDISSE, E. (1965) Elektrophysiologische Untersuchungen uber die Barium-induzierte Schrittmacher-Aktivtat im isolierten Saugetier-myokard. P/liigers Archiv. 28,1: 259-272.

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KAUFMANN, R. and THEOPHILE, U. (1967) Automatic-Fordernde Dehnungseffekte an Purkinje-Faden, Papillarmuskeln und Vorhoftrabekelm yon Rhesus-Affen. P/liigers Archiv. 297: 174-289. KERZNER, J., WOLF, M., KOSOWSKY, B. D. and LOWN, B. (1973) Ventricular ectopic rhythms following vagal stimulation dogs with acute myocardial infarction. Circulation 47: 44-50. KOHLHAgOT, M., HASSTERT, H. P. and KRAUSE, H. (1973a) Evidence of non-specificity of the Ca channel in mammalian myocardial fiber membranes. Substitution of Ca by Sr, Ba or Mg as charge carriers. P/tagers Archiv. 342: 125-136. KOHLHARDT, M., HERDEY, A. and KUBLER, M. (1973b) Interchangeability of Ca ions and Sr ions as charge carriers of the slow inward current in mammalian fibers. P/lagers Archly. 344: 149-158. KOHLHARDT, M., BAUER, B., KRAUSE, H. and FLECKENSTEIN, A. (1972) Differentiation of the transmembrane Na and Ca channels in mammalian cardiac fibers by the use of specific inhibitors. P/liigers Archiv. 335: 309-322. LANGER, G. A. (1972) Effects of digitalis on myocardial ionic exchange. Circulation 46: 180-187. LEGATO, M. J. (1973) Ultrastructure of the atrial, ventricular, and Purkinje cell with special reference to the genesis of arrhythmias. Circulation 47: 178-189. LENFANT, J., MIRONNEAU, J. and AKA, J. K. (1972) Active repetitive de la fibre sino-auriculaire de grenoville. J. Physiol. Paris 64: 5-18.

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ADDENDUM Since the submission of this chapter a large volume of pertinent literature has accumulated which has not been possible to cite. The monographby P. F. Cranefield entitled The Conduction of the Cardiaclmpulse: The Slow Response and Cardiac Arrhythmias, Futura Publishing Company, Mt. Kisco, New York, 1975 and the monograph by D. Noble entitled The Initiation o[ the Heartbeat, Clarendon Press, Oxford, England, 1975 are of particular interest and importance to the serious student~of cardiac electrophysiology and cardiac arrhythmias.