JACC Vol. 5. No.5 May 1985:22A-34A
22A
Cellular Electrophysiology of Digitalis Toxicity MICHAEL R. ROSEN, MD, FACC New York . New York
The toxic effects of digitalis are attributable in part to poisoning of the enzyme Na + -K + ATPase and in part to the interactions of digitalis with the sympathetic and parasympathetic nervous systems. Additional modifiers of the toxic effects of digitalis include the concentrations of ions such as K + and Cal + , the age of the subject and the extent and type of cardiac disease. At the cellular electrophysiologic level, digitalis toxicity is seen as a depolarization of the membrane with the occurrence-individually or simultaneously-of abnormalities of im-
My purpose in this review is to consider the cellular electrophysiologic mechanisms responsible for digitalis toxicity. I am honored to have been asked to participate in this project commemorating the 200th anniversary of Withering 's account of the foxglove, and also fortunate that the field of cardiac cellular electrophysiology is less than one-fifth as old, thereby facilitating my task . Digitalis is one of the major tools used in the cellular electrophysiologic study of the mechanisms for cardiac arrhythmias. Given the history of varied toxic arrhythmias induced by digitalis clinically and in experimental animal studies , it is not surprising that electrophysiologists and pharmacologists have so frequently used this drug as a means to induce and investigate arrhythmias at the cellular level. As a result , the study of the cellular electrophysiologic mechanisms for arrhythmias and the study of the mechanisms of action of digitalis have proceeded interdependently , with advances in each area benefitting the other. The approach I will use initially in this review will be historic , tracing the experimentation on the cellular mechanisms of digitalis toxicity since the 1950s. I will not attempt to be encyclopedic , but rather will refer to some of the milestones in our understanding of the cellular electrophysiologic mechanisms of digitalis toxicity . Subsequently , From the Departments of Pharmacology and Pediatrics. ColumbiaUniversity College of Physicians and Surgeons. New York. New York. Certain studies referred to in this review were supported by Grants HL-28223. HL·12738 and HL-28958 from the United States Public Health Service. National Heart. Lung, and Blood Institute. Bethesda. Maryland. Address for reprints: Michael R. Rosen. MD. Department of Pharmacology. Columbia University College of Physicians and Surgeons. 630 West 168th Street. New York, New York 10032. © I'l85 by the American College of Cardiology
pulse initiation (including delayed afterdepolarizations and abnormal automaticity) and abnormalities of conduction. The afterdepolarizations result in triggered arrhythmias that differ partially in their characteristics of onset and termination from automatic and reentrant arrhythmias. The cellular electrophysiologic basis for these arrhythmias induced by toxic concentrations of digitalis and their implications with respect to arrhythmogenesis in the in situ heart are explored in detail. (J Am Coli CardioI1985;5:22A-34A)
I shall attempt to relate our understanding of these cellular mechanisms to their role in the occurrence of arrhythmias.
Historic Development To my knowledge, the earliest reports of the cellular electrophysiologic manifestations of digitalis toxicity are those of Woodbury and Hecht ( I) in the frog heart and Fingl et al. (2) in the chick heart. The first of these related the cellular electrophysiologic effects of digitoxin on action potential repolarization (that is, a marked acceleration of the voltage-time course) to the QT interval and T wave changes that occur electrocardiographically . Fingl et al. (2) showed that in the embryonic chick heart , digitoxin initially prolonged and then accelerated repolarization and decreased the amplitude of the action potential , while having no effect on resting; potential. Toxic effects on transmembrane potentiaLs. During the 1950s and 1960s, the toxic effects of digitalis on the transmembrane potentials of tissues from the sinoatrial and atrioventricular (AV) nodes, the His-Purkinje system and the atrial and ventricular myocardium were described in some detail (Fig. I). Various types of digitalis molecules were used, and toxic concentrations were shown to decrease the resting membrane potential of cells in the AV node (3), the Purkinje system (4-8) and the atrial and ventricular myocardium (l ,4-6,9, 10). In ali tissues studied, there were decreases in the amplitude of the action potential (1-11) . In tissues of the atrial and ventricular myocardium, AV node and His-Purkinje system, a decrease in Vmax was also described (3-10). Repolarization, which increased in duration 0735-1097/85/$3.30
ROSEN ELECTROPHYSIOLOGY OF DIGITALIS TOXICITY
JACC Vol. 5, No.5 May 1985:22A- 34A
,
CONTROL
--1'' -
. "'\
J
'",-r:
--.J l'--_ _
OUABAIN
\
"'---
I" J~,---Figure 1. Typical effects of a toxic concentration of digitalis on a canine Purkinje fiber transmembrane potential. Upper panel , Action potential during superfu sion with Tyrode's solution at [K + 10 = 4 mM and temperature = 37°C. The upper trace shows a zero line and the transmembrane potential; the lower trace shows a 200 VIs calibration wave and the electronically differentiated maximal upstroke velocity of phase 0 (V max) ' The lower panel shows the transmembrane potential 30 minutes after the onset of superfusion with ouabain, 2 x 10- 7 M. Note that there is a decrease in the resting potential and action potential amplitude , an acceleration of the voltage-time cour se of repolarization and an increase in the slope of phase 4 depolarization. ln addition, the Vmax is markedly decreased. Calibration bars are 50 mV and 100 ms. (Modified from Hewett KW , Rosen MR [69].)
in His-Purkinje and atrial and ventricular myocardial fibers at low or "therapeutic" concentrations of digitalis (1-5,8,10), decreased in duration at higher concentrations (1-10). This acceleration of repolarization also occurred in fibers of the sinoatrial node (12,13). However, the most characteristic change induced by toxic digitali s concentrations with respect to the initiation of arrhythmias was an increase in the slope of phase 4 depolarization. This was readily demonstrable in Purkinje fibers (4,6-8) and was also described in fibers of the AV node (3), but was not seen in ventricular or atrial muscle (1,4-6,9-12) . Effect on Purkinje versus myocardial fibers. In 1962, Vassalle et al. (6) reported that when Purkinje or ventricular myocardial fibers were exposed to the same concentration of ouabain for the same period of time , the effect on the specialized conducting fibers exceeded that on muscle . Moreover, they found that toxicity developed more rapidly in preparations that were driven than in those that were quiescent, an action also noted by other investigators (14-16). Simply stated, this observation meant that the uptake of
23A
digitalis and its ability to induce toxic effects on the heart was influenced by the number of cardiac impulses; the faster the rate of drive (that is, the greater the number of impulses per unit time), the faster the development of toxicity. The major toxic manifestation described was an increase in the slope of phase 4 depolarization . This gave rise to extrasys toles or sustained rapid rhythm s (6). With longer period s of exposure to digitalis, there were quiescence and inexcitability . Mechanisms of toxic changes in transmembrane potential. The basis of the toxic changes seen in the transmembrane potential as a result of digitali s effect was considered to be the following (6,17,18): digitalis-induced accumulation of potassium extracellularly ([K + 10) by inhibiting the Na + -K + exchange mechanism . The elevation in [K + 10 increased the membrane K + conduct~~Ee, which accelerated repolarization and depressed the ~liihHlU. The reduced intracellular potassium ([K + 1i) and ell!Viiled [K + 10 were also the cause of the reduction in mertlMratle potential (a factor that required more than 20 years to be demonstrated directly using K + -sensitive microelectrodes [19]) . Although active investigation of the cellular electrophysiologic effects of digitali s proceeded through the late 1960s, it was generally assumed that the mechanisms for its toxic manifestations were known ; its depressant effects on the resting and action potential s explained the occurrence of conduction block (l3,20) ? an action that was enhanced at the level of the sinoatrial and AV nodes and the atrium ( 12,21,22) by its abilit y to increase acetylcholine release (23,24). Moreover, the digitalis-induced increase in the slope of phase 4 and the resultant enhanced pacemaker function explained many tachycardias (6,13) . The latter action was understood to be complemented by increased efferent sympathetic activity to the heart (a result of the central nervous system action of digitalis [25-27]), which also served to enhance ectopic impulse initiation . Oscillatory activity. In the early 1970s, several groups (28- 33) working independently discovered that it was not only the effect on normal pacemaker function of digitalis that might modify ectopic impulse initiation , but also the induction of oscillatory activity . As so often is the case when discoveries are made independently in a short time period , each group published its findings with little knowledge of the other groups ' activities and, hence, the oscillation was called a " low amplitude potential" (28,29), a " transient depolarization" (3 1- 33) or , simply, "enhanced diastolic depolarization" (30) . Subsequently, in an effort to simplify the situation , two additional descriptors were suggested (again by investigators working independently) ; these were "delayed afterdepolarizations" (20,34) and " oscillatory afterpotentials" (35). The latter two terms are in use today ; the others have been largely discarded. For the remainder of this presentation, the term I shall use is "delayed after depolarization. "
24A
ROSEN ELECTROPHYSIOLOGY OF DIGITALIS TOXICITY
Figure 2. Comparison of automatic activity (left panels ) and delayed afterdepolarizations (right panels ) in canine Purkinje fibers. Panel A demonstrates an automatic fiber having phase 4 depolarization and a regular rhythm (left) and a driven digitalis-toxic fiber showing what also appears to be phase 4 depolarization (r ight) . At the first arrow , stimulation is discontinued and there is a sequence of oscillations of membrane potential followed by quiescence until the stimulus is reinitiated (second arrow). Several cycles are then required for the oscillations, or delayed afterdepolarizations, to attain their previous amplitude. Calibrations are 20 mY and I s for left and right panels . Panel B, The left panel shows the effects of overdrive pacing on an automatic rhythm. For the first three cycles, the preparation is firing spontaneously. Rapid pacing starts at the first arrow and stops at the second arrow. Note the hyperpolarization that occurs during overdrive pacing and the long period of quiescence after the cessation of pacing. The automatic rhythm then recurs and gradually increases in rate. On the right is the effect of pacing on a digitalistoxic fiber having delayed afterdepolarizations. For the first three cycles, the preparation is paced. Pacing stops at the arrow , and the initial two cycles following the cessation of pacing demonstrate action potentials triggered by delayed afterdepolarizations. There then is a series of dampened oscillations until quiescence occurs. Calibrations: left , 30 mY and 6 s; right, 20 mY and 0.5 s. Panel C , The left panel shows the slope of phase 4 depolarization of an automatic fiber on the vertical axis' and a drive cycle length on the horizontal axis. As drive cycle length decreases, there is a 'g radual decrease in the slope of phase 4 depolarization, reflectingoverdrive suppression. The right panel shows the slope of the ascending limb of a delayed afterdepolarization on the vertical axis and the drive cycle length on the horizontal axis. As drive cycle length 'is shortened, the slope of the afterdepolarization increases.
lACC Vol. 5, No.5 May 1985:22A-34A
A
~
~
UillllillY llL~llllll -l
B
II
~
.J
\\~
I
I I I I_,.-_ _ _ _ _r -_
60
C
-0 30 10
,
.J
\,
~
P
SLOP E ( mV / s)
10
~
\
CO , \0
SL OP E ( ",V
I5
)
._1.,.-•. i , ...
.
, ('
o
•
Digitalis and Delayed Afterdepolarizations Delayed afte rdepo larizations are oscillations in tran smembran e potential that follow full repolarization of the membrane (Fig . 2) . An impo rtant charac teristic o f these afterdepo lari zatio ns is that as the dr ive cycle length of a prep arati on is decreased , the amplitude of the afterdepolarization tend s to increase. and the ir coupling interval to the actio n potenti al that induces them decrea ses with a nearl y linear relation to the dri ve cycle length (Fig . 3) (29,31). As de scribed earlier in this sy mposi um (36) , dela yed afterde polarizations occur as a result of the poi soning of Na + -K + ATPase by d igitalis. The accumulatio n of [Na + ]; in this situation results, in tum , in an increase in [Ca 2 + ];. Th is is secondary to altered functi on of the Na + -Ca 2 + exchange and Ca 2 + release from the sarcoplasmic reticulum and other intracellular stores. The increase in [Ca 2 + ] j trig-
0 ' 0,
b 0
, '00
"~
,i
100 lOO
soo
BCL
( ms )
1000
1000
'00
100 JOe
BCL
soc
1000
1000
(ms )
gers a transient inward current (\) carried in the main by Na " . Th is current is, in fac t, the immediate cau se of the delayed afterdepolarization (37-39).
Delayed afterdepolarizations as basis for cardiac arrhythmias. The major import of the identification of delayed afterdepolarizations was that they provided a far more logical basis than reentry or automaticity for understanding the cau ses of man y digitalis-induced arrhythmias in experimental animals and , by extension , in human subjects. To illustrate, it pre viou sly had been noted in intact animal studies that I ) ectopic ventricular beats-or repetitive ventricular responses (40,4 I) -could be induced by elec trical stimulation during the terminal T wave and the subsequent isoelectric interv al in the heart of digitali s-toxic do gs; 2) there was a cycle length dependency of these ectopic rhythms (in that they were more readil y induced at short premature stimulation cycle lengths); 3) the threshold current require-
ROSEN ELECTROPHYSIOLOGY OF DIGITALIS TOXICITY
JACC Vol. 5. No.5 May 1985:22A-34A
30 DAD amp (mV)
20 10 0
1200
'9;.
~ I 0
1000 DAD·C (ms )
800 600 400 200
V
200 400 600 800 1000 BCl (rns)
Figure 3. Relation of delayed afterdepolarization amplitude (DAD amp) and coupling interval (DAD-C) to the basic cycle length (BCL) of a ouabain-superfused Purkinje fiber. The solid circles represent the first delayed afterdepolarization in a sequence (see Fig. 2A). The open circles represent the second afterdepolarization. Asterisks indicate the delayed afterdepolarizations that attained threshold and initiated a triggered rhythm. (Reprinted from Rosen MR, Danilo P Jr . (47) with permission.)
ment for initiating the ectopic rhythms decreased with increasing toxicity; and 4) the duration of the ectopic rhythms increased with the toxic dose of digitalis. All these descriptors of a digitalis-induced ectopic tachyarrhythmia in the intact animal are consistent with delayed afterdepolarizations in isolated tissue (Table I). Suppression of normal pacemaker mechanisms of specialized conducting fibers. Before there was general aware-
ness of delayed afterdepolarizations, attempts to explain digitalis-induced repetitive ventricular responses had been limited to reentry or automaticity (6,13,40,41). Although it was suggested by some (42-44) that the repetitive ventricular response might represent a form of abnormal automaticity , several factors clouded this interpretation. First was the observation that the automatic mechanisms previously identified in normal specialized conducting fibers of the atrium and ventricle tended to be suppressed by overdrive pacing (Fig. 2) (45). In contrast, the rhythm in digitalis-toxic cardiac fibers and the intact heart occasionally showed an increase in rate as a result of rapid pacing; at other times, there was little effect on rate, and only in a fraction of instances was there suppression (40-42) . Second, intact animal studies had demonstrated a suppression of normal pacemaker function before the onset of digitalistoxic arrhythmias (46), an observation that was corroborated in isolated tissue studies (47) . The implication of these experiments was that, for the most part , the normal pacemaker mechanisms of specialized conducting fibers were suppressed by digitalis and were supplanted by some other mechanism . This was clearly demonstrated by Aronson and Gelles (48) and by Tsien and associates (37-39). They observed not only the cessation of the normal pacemaker current in the presence of digitalis, but its replacement by what Tsien and associates called the iti or transient inward current. Delayed afterdepoIarizations, cycle lengths and tachycardias. The particular characteri stic of delayed afterdepolarization s that makes them so successful a descriptor of many digitalis-induced premature depolarizations and tachycardias is their cycle length dependency . As reviewed in Figure 3 and Table I, when the drive cycle length for a preparation is shortened, so is the coupling interval of the afterdepolarization to the action potential that induces it. At the same time, there is a tendency for the amplitude of the afterdepolarization to increase and for the current required to bring it to threshold to decrease (29). As a result , as drive rate increases, the afterdepolarization will tend more readily
Table 1. Comparison of Digitalis-Induced Repetitive Ventricular Responses in Intact Animals and Delayed Afterdepolarizations in Isolated Tissues Repetitive Ventricular Responses
25A
Delayed Afterdepolarizations
Initiated by premature beat during T wave (after vulnerable period) or early diastole
Initiated most readily at short drive cycle lengths or by premature depolarizations occurring at short coupling intervals
With increasing degree of digitalis toxicity. the electrical current needed to induce repetitive ventricular responses decreases
With increasing degree of digitalis toxicity. the electrical current required to bring delayed afterdepolarizations to threshold potential decreases
With increasing digitalis toxicity, there is a greater likelihood of longer trains of repetitive ventricular responses
With increasing digitalis toxicity. the trains of tachyarrhythmias induced by delayed afterdepolarizations tend to get longer
26A
ROSEN ELECTROPHYSIOLOGY OF DIGITALIS TOXICITY
to attain threshold and will initiate a rhythm whose rate will increase in proportion to the drive rate (Fig. 3). Enhanced automaticity. The foregoing is not meant to imply that all digitalis-induced focal tachyarrhythmias are the result of delayed afterdepolarizations. It appears that a subset is induced by an abnormal automatic mechanism (43,49) that is not overdrive suppressible and the rate of which increases to some extent with the stimulation rate (Fig. 4). It is often difficult to differentiate this rhythm at the cellular level from that induced by delayed afterdepolarizations, and there remains some uncertainty about the relation of the two mechanisms to one another. Other electrophysiologic factors related to digitalis toxicity. Three other factors should be stressed about digitalis-induced delayed afterdepolarizations and the other cellular electrophysiologic manifestations of digitalis toxicity (diminished resting potential, Vmax and accelerated repolarization). The first is that although they have been described and studied using isolated tissues and physiologic saline solutions, they nonetheless occur over a range of digitalis concentrations that mimic the effects of digitalis in vivo. This has been demonstrated in studies of isolated Purkinje and ventricular muscle fibers superfused with the blood of intact digitalis-toxic dogs (28,50). The second factor is that just as intact animal studies (51) have indicated the site of origin of digitalis-toxic ventricular tachycardias to be the specialized conducting system, isolated tissue studies (6) have shown that the cellular electrophysiologic manifestations of digitalis toxicity are far more readily induced (at lower digitalis concentrations and after shorter intervals of superfusion) in specialized conducting than in muscle fibers. Finally, that delayed afterdepolarizations may explain a subset of digitalis-induced tachycardias is suggested by their occurrence in atrial and ventricular fibers of not only the canine (28-33) but also the human (52,53) heart.
Potassium and Calcium Ions as Modifiers of Digitalis Toxicity Before I attempt to relate the cellular electrophysiologic actions of digitalis to cardiac arrhythmias more directly, some additional modifiers of digitalis toxicity should be considered. That there are a number of such modifiers should be intuitively obvious in considering a drug that not only poisons the enzyme system responsible for electrogenic Na + K + pumping, but interacts importantly with ions such as Ca 2 + and K + and with the parasympathetic and sympathetic nervous systems. I am not suggesting that there are not important interactions of digitalis beyond these, but from the point of view of cellular electrophysiology, these are some of the best known and most important. Sodium and potassium. One result of the poisoning of Na + -K + ATPase is that cells commence to accumulate Na + intracellularly, while losing K + to the extracellular envi-
JACC Vol. 5, No, 5 May I985:22A-34A
CL400
""'~ j
)JJJj))
.i.:
CL 300
'iliil/ -:»:»: ~: , I::!
:! , I
: . I, ' ;!
I'
Figure 4. Ouabain-induced enhanced automaticity. The preparation had been superfused with ouabain, 2 x 10- 7 M, for 30 minutes, and then driven sequentially at cycle lengths from 1,000 (top) through 260 (bottom) ms. At the drive cycle lengthof 1,000 ms, cessation of drive is followed by phase 4 depolarization and the onsetof an automatic rhythmwhichgradually increases in rate. The interval between the last driven beat and the first automatic beat is far longer than would be expected for a delayed afterdepolarization (see Fig. 3). As drive cycle length is shortened, there is a shortening of the escape interval for the first automatic beat as well as an acceleration in the rate of the automatic rhythm. Note that during the course of phase 4 depolarization, delayed afterdepolarizations also are seen during the escape interval at cycle lengths of 300 and 260 ms. It is difficult to distinguish whether the spontaneous rhythm at these cycle lengths is initiated by an automatic beat or by a triggered beat secondary to a delayed afterdepolarization. Calibrations: 15 mY and 2 s. (Reprinted from Rosen MR, Danilo P Jr. [49] with permission of the American Heart Association, Inc.) ronment (54). A consequence of these events is that [K."], decreases, [Na +]i and [K + 10 increase and there is a decrease in the resting membrane potential. One result of the increase in [K + ]0 is that the potassium conductance of the membrane increases (55). This, in tum, accelerates repolarization (Fig. 1). The extent to which the [K +]0 is increased depends on its equilibration in the "unstirred layer" adjacent to the outside of the cell membrane. To whatever extent the K + ion is held in that layer (which in tum equilibrates with the larger, bulk extracellular space), the membrane itself will "recognize" this as an elevation of extracellular [K +]. That there is, in fact, a gradient for [K +] between the unstirred layer adjacent to the cell and the bulk phase has been suggested in previous cellular electrophysiologic and ion-sensitive electrode studies of digitalis (19).
JACC Vol. 5, No.5 May 1985:22A-34A
Role of low extracellular K+. Both the extracellular K + concentration before digitalis administration and any changes that are induced or occur spontaneously in [K +]0 during digitalis administration can also modify the effects of digitalis importantly. In the absence of digitalis, if the level of [K +]0 is low (below 3 to 4 mM), there is a tendency for specialized conducting fibers to develop phase 4 depolarization and automatic rhythms (56). Hence, when administered in the presence of a low [K +]0' digitalis is superfused over a preparation that already has a tendency to develop automaticity, and any arrhythmogenic effects of digitalis will be superimposed on this. Moreover, digitalis and K + ions compete for membrane-binding sites, and at low [K +]0 there will be a greater likelihood of increased binding of digitalis to its receptor site (54). Hence, both the inherent arrhythmogenicity of low [K +]0 and the enhanced binding of digitalis in this setting may tend to augment toxicity. Role of high extracellular K+. At high [K + 10 (> approximately 5 mM), there is an increasing competition of K + with digitalis for binding, such that the ability of digitalis to poison Na " -K+ ATPase is diminished (54). Although this action would tend to limit toxicity, the direct electrophysiologic effects of increasing extracellular [K +] have just the opposite effect. As predicted by the Nemst equation (56), elevating extracellular [K +] lowers the membrane potential at rest. It also increases the potassium conductance of the membrane, resulting in accelerated repolarization (55). As a result of the reduced resting potential, action potential amplitude and upstroke velocity are reduced and conduction is slowed. In addition, as stated before, the effect of toxic concentrations of digitalis alone, depleting the intracellular compartment of K + and elevating [K +] extracellularly, has the same end result as elevating [K +] in the bulk phase. Summarizing this very important interaction between K+ and digitalis, we can see that the maintenance of [K +]0 within the physiologic range is the ideal situation for dealing with potential digitalis toxicity. Reducing [K +]0 below this range induces automaticity in its own right and facilitates the binding of digitalis to its receptor; elevating [K + ]m although it will tend to reduce the binding of digitalis, is toxic in its own right in a way that complements digitalis toxicity. K+ and conduction block. In environments of both low [K +]0 and high [K +]0' the combined effect of [K +] and digitalis may induce or enhance conduction block (57). In the former instance, this occurs because in the presence of phase 4 depolarization the action potential is initiated at a low level of membrane potential that, if further diminished, may lead to slowing or block of conduction. In the latter instance, although phase 4 depolarization tends to be suppressed by high [K +]0' the membrane potential is further reduced and its additional reduction (by further elevation of [K+]o or reduction of [K+li, or both) can slow or block conduction.
ROSEN ELECTROPHYSIOLOGY OF DIGITALIS TOXICITY
27A
Calcium. Calcium ion is also important to the occurrence of digitalis toxicity. As mentioned earlier, one of the results of poisoning Na +-K + ATPase is to increase intracellular [Na "] and, with this, to modify the Na " -Ca 2+ exchange. This results in an increase in [Ca 2 +]i. In situations where [Ca2+li is increased markedly (presumably to concentrations greater than those that occur in vivo), there can be electrical uncoupling of cardiac fibers from one another (58). This uncoupling, which also occurs with an increase in [Na +]i (58), results in an increased intercellular resistance and can induce slowing or cessation of conduction (59). Increased intracellular [Ca2+] also serves as the trigger for the transient inward current that induces delayed afterdepolarizations (see foregoing). Elevated extracellular calcium. Changes made in [Ca2+]0 can also alter the effects of digitalis. Elevation of [Ca2 +]0 is associated with a reduction in threshold potential (56). This tends to decrease the excitability of a preparation and to enhance conduction block. Moreover, in the presence of digitalis, elevating [Ca2+]o can augment the transient inward current responsible for delayed afterdepolarizations (37-39,60). All these actions are potentially arrhythmogenic. Reduced extracellular calcium. Reduction of [Ca2+]o tends to increase threshold potential, an effect that would increase excitability (56). Such a reduction of [Ca 2 +]0 would counter the occurrence of conduction block and diminish the magnitude of delayed afterdepolarizations (61), both of which are antiarrhythmic effects. However, the increase in threshold potential increases the likelihood that depolarizing potentials, including delayed afterdepolarizations, might attain threshold and induce an arrhythmia. Therefore, it appears that, as for K +, changes in [Ca2 +]0 both above and below the physiologic level can enhance digitalis toxicity. In summary, the cellular electrophysiologic data relating to the interaction of Ca 2 + and of K + with digitalis suggest that maintenance of physiologic concentrations of both ions would least potentiate arrhythmias. In addition, there is an important interaction between K + and Ca 2 +; namely, elevations in Ca 2 + tend to increase membrane conductance for K + (62). Hence, when K + and Ca 2+ concentrations are altered in the presence of digitalis, one must recall that not only do both ions interact with digitalis, but their important interactions with one another may further modify the effects of digitalis.
Role of Autonomic Nervous System Digitalis and parasympathetic effects. Digitalis also interacts with the parasympathetic and sympathetic nervous systems in ways that can promote toxicity. Parasympathetic effects on the heart alone can induce sinus slowing, sinoatrial block and AV nodal conduction block (56). All these effects appear to result from the actions of the cholinergic
28A
ROSEN ELECTROPHYSIOLOGY OF DIGITALIS TOXICITY
mediator, acetylcholine. By increasing the K + conductance of the cell membrane , acetylcholine alone hyperpolarizes atrial and sinoatrial node fibers (which might induce a modest increase in conduction velocity), and decreases the slope of phase 4 depolarization and the automatic rate of the sinus node (56). Acetylcholine has an additional effect on atrial fibers, causing the suppression of slow inward current carried by Ca H (63). In the regions of the sinus and A V nodes, whose action potentials are largely slow channel-dependent, this action of acetylcholine would tend to depress conduction or block it entirely. The action of digitalis on vagal fibers is such that increased amounts ofacetylcholine are released (23,24). The result of the vagal action of digitalis, then, is seen as an augmentation of the effects of acetylcholine at sites where parasympathetic innervation is densest, that is, supraventricularly. When this indirect action of digitalis is considered in light of its direct effects, which tend to depolarize cardiac cells and depress conduction, then it is apparent that the depressant actions will tend to be additive. Sympathetic effects. There are a number of complex interaction s between digitalis and the sympathetic nervous system. For example, it has been shown that in high concentrations, digitalis may actually be sympatholytic, reducing the sensitivity of the heart to beta-adrenergic catecholamines (22,64 ,65). Of more importance in considering the toxic effects of clinically relevant concentrations of digitalis is its action on the central nervous system to increase efferent sympathetic discharge (66-68) . This results in an increase in catecholamine release at sympathetic terminals , an action that potentiates digitalis toxicity as follows : I have already mentioned that digitalis induces an increase in intracellular [CaH 1 that is responsible for the transient inward current underlying delayed afterdepolarizations, and that also contributes to uncoupling. Through their effect on the betaadrenergic receptor, catecholamines also induce increases in ICaH li (55). As a result , delayed afterdepolarizations that are of subthreshold magnitude in the presence of digitalis alone may attain threshold and induce tachyarrhythmias with the addition of catecholamines (Fig. 5) (69). In contrast, catecholamines alone may hyperpolarize fibers (70,71) and enhance conduction. Nonetheless, it appears that the major interaction of digitalis and catecholamines is arrhythmogenic, potentiating the occurrence of ectopic activity.
Other Variables Related to Digitalis Toxicity Age. Other important variables with respect to digitalis toxicity are age and the presence of disease . Clinical studies (72) have stressed that the very young individual tends not to show digitalis toxicity at serum digoxin levels that are toxic in the older patient. Moreover, toxicity appears to
JACC Vol. 5. No.5 May 1985:22A-34A
A
1M
;1 1\11\ 1\ i.
i
I
~
~ v..... _
t-----4
i~~~j~j~~L _ B
!IOmV
Figure S. Effects of the beta-adrenergic agonist isoproterenol on ouabain-induced delayed afterdepolarizations. Panel A, The upper trace demonstrates a delayed afterdepolarization induced by ouabain, 2 x 10- 7 M. In the presence of isoproterenol, 5 x 10- 6 M (lower trace), the amplitude of the delayed afterdepolarization is increased. Panel B, The upper trace shows a delayed afterdepolarization induced by the effect of the same concentration of ouabain alone in another fiber. In the presence of isoproterenol (lower trace) , there is a triggered action potential. Horizontal bars indicate 1 s. (Modified from Hewett KW, Rosen MR (69).)
occur more readily in the elderly (73). Cellular electrophysiologic studies (74) intended to identify the basis for these observations have demonstrated that for the neonatal canine heart, a higher concentration of digitalis is needed to induce depolarization of the cell membrane and delayed afterdepolarizations than is the case for the mature adult . Moreover, in the old canine heart, toxicity occurs even more readily than in the younger adult (75). Complementary studies (76,77) showing development and age-related changes in digitalis effect have been performed in other animal species as well. It is to be stressed that these studies of agerelated changes in the cellular electrophysiologic manifestations of digitalis toxicity have been performed in animals without cardiac disease , so that the major variable is, in fact, age. It has been suggested (78) that age-related changes in Na + -K + ATPase function and its ability to bind digitalis may be a major factor in the events described here . Presence of cardiac disease. The other important variable I have mentioned is the concurrent presence of cardiac disease (73). In experiments mimicking the clinical situation. tissues from the diseased canine heart have been shown to develop digitalis toxicity more readily than those from the healthy heart . An example of this phenomenon was
JACC Vol. 5, No.5 May 1985:22A-34A
provided by Brennan and Bonn (79) in studies of the effects of digitalis on experimentally infarcted canine hearts.
Digit~lis
ROSEN ELECTROPHYSIOLOOY QF DIGITAUS TOXICITY
A
B
c
Abnormal Conduction SA and AV block. Although a variety of conduction abnormalities have been attributed to digitalis, two that have received prominent attention are atrioventricular (A V) nodal and sinoatrial (SA) block . It is likely that both types of conduction block result largely from the interaction of the "indirect" effect of digitalis, mediated through the parasympathetic nervous system , and the direct effect of digitalis, exerted on the heart itself. It is the suppression of the slow inward current carried by the Ca 2 + ion that in large part explains the ability of vagal stimulation (enhanced , in tum, by digitalis effect) to depress conduction at both nodes (81) , To this is added the direct action of digitalis to depolarize and uncouple cardiac fibers (see earlier). Conduction block in specialized conduction system. There are means other than membrane depolarization and enhanced vagal effect whereby digitalis can induce conduction block . It is likely that, given the differential sensitivity of specialized conducting and myocardial fibers (6) to the toxic effects of digitalis, conduction block will occur most readily in the specialized conducting system (51) . Whereas the cause of block might simply be depolarization of fibers until excitability is lost, there are, as well, more complex effects of digitalis that can depress conduction. One of these is reviewed in Figure 6 . In this experiment, the interaction between the effects of digitalis on phase 4 depolarization and on conduction is reviewed . As a result of these events, bigeminy (panels A and B), concealed conduction (panels A, C and D) and reentry and facilitation of conduction (panel D) can occur. Although a vastly simplified version of the kinds ' of events that might occur in the intact heart, Figure 6 nonetheless helps us understand the complex changes in impulse conduction that can occur as a result of digitalis toxicity. Other complex variations in conduction have been reported as occurring in the presence of toxic digitalis concentrations . For example, Bailey et al. (82) demonstrated functional longitudinal dissociation in canine Purkinje fibers
2
'~~
Toxicity and Cardiac Arrhythmias
In the final section of this review, I shall consider the contribution of digitalis toxicity to cardiac arrhythmias. To do so, I shall use a standard categorization of arrhythmias in widespread use today (80) : that is, I shall consider arrhythmias as resulting from either 1) abnormal conduction or 2) abnormal impulse initiation, with the proviso that some arrhythmias result from their combined effects.
•
29A
o
+
'~
'M=! +
o
+
)~
20
..J mV
lOOms
Figure 6. A canine Purkinje fiber bundle and attached ventricular muscle have been superfused with ouabain, 2 x 10 . 7 M, for approximately 30 minutes. For all panels, the numbers I and 2 indicate the basic drive cycle , and the arrow indicates an induced premature depolarization . Panel A, Both basic drive beats are propagated to the myocardium; the premature depolarization occurs at the peak of a delayed afterdepolarization and is not propagated (that is, there is no myocardial action potentia\) . Panel B, The premature depolarization has been moved earlier and occurs at a higher level of membrane potential. Now, all three action potentials are propagated to the myocardium . Panel C. The premature depolarization has been moved still earlier. The first basic drive beat occurs at a relatively high level of membrane potential and is propagated as is the premature beat. The timing of the delayed afterdepolarization of the premature beat is such that the second basic drive beat occurs at a low level of membrane potential and is not propagated. Panel D is a continuation of Panel C ; the first basic drive beat is not propagated for the same reason as for the last basic drive in Panel C. The premature depolarization (arrow) has been moved still earlier. occurs at a high level of membrane potential and is propagated to the myocardium. This is succeeded by an action potential that reenters the Purkinje system. but does not propagate to the myocardium. However. after it repolarizes. membrane potential is relatively high . As a result. the subsequent basic drive beat is able to propagate to the myocardium. (Reprinted with permission from Rosen MR, et al. Electrophysiology and pharmacology of cardiac arrhythmias . Am Heart J 1975;89:391-9 .)
during superfusion with acetylstrophanthidin . Here, the normal sequence of activation from proximal to distal sites in the Purkinje system was supplanted by either simultaneous activation of proximal and distal sites , or the occurrence of distal before proximal activation .
30A
ROSEN ELECTROPHYSIOLOGY OF DIGITAUS TOXICITY
Thus far, I have reviewed how digitalis may depolarize the membrane and depress conduction as a result of its effect on Na + -K + ATPase, how it may further depress conduction through its effects on phase 4 (as a result of automaticity or delayed afterdepolarizations) and how it may depress conduction still further through its indirect effects mediated by way of the vagus. The changes in [K + 1 and [Ca 2 + 1 mentioned earlier also can contribute to this conduction block . It should be stressed, as well, that the block of conduction may result not only in a bradyarrhythmia, but also when conditions are appropriate, as in Figure 6, in a tachyarrhythmia. Both reentry occuning as a result of circus movement and reflection are possible causes of such tachyarrhythmias (83).
Abnormal ImpuLse Initiation As stated, early studies of digitalis toxicity demonstrated depolarization during phase 4, resulting in enhanced impulse initiation. The initial assumption made was that such impulse initiation was the result of enhancement of automatic pacemaker function by digitalis . As has been discussed in the first section of this review , voltage clamp studies (37-39,48) in the 19708 revealed that digitalis usually "turns off" the normal pacemaker current, suppressing the automatic mechanism. The transient inward current induced by these same toxic concentrations of digitalis is oscillatory in nature and results in the occurrence of delayed afterdepolarizations. With their characteristic cycle length dependency, the afterdepolarizations in turn induce rate-dependent tachycardias, referred to as " triggered " arrhythmias (defined by Cranefield [34] as arrhythmias that obligatorily require a previous action potential and afterdepolarization for their initiation).
Characteristics of afterdepolarization-induced tachycardias. In attempting to relate these events to cardiac arrhythmias Reder and I (84) summarized the characteristics of delayed afterdepolarization-induced tachycardias as follows . I) Delayed afterdepolarizations may induce single premature beats or tachyarrhythmias . If single premature beats occur, they tend to be late in the cardiac cycle. This relate s to the fact that the coupling interval for delayed afterdepolarizations to the impulses that induce them tends to be equal to or slightly less than the drive cycle length (Fig. 3)
(29,31). 2) The occurrence Of an arrhythmia over a wide range of cardiac cycle lengths with a propensity for its occurrence more at short than at long cycle lengths is consistent with delayed afterdepolarizations as the cause . This, too , relates to the relation of delayed afterdepolarization amplitude to drive cycle length (Fig. 3). 3) Shortening of the cycle length of an arrhythmia as the
lACC Vol. 5, No.5 May 1985:22A-34A
cycle length preceding the onset of the arrhythmia diminishes is characteristic of delayed afterdepolarizations. This also relates to the data on coupling interval in Figure 3. 4) The presence of an inverse ratio between an initiating premature beat and a resulting extrasystole, so that a clear pattern of return extrasystoles is evident, suggests that an arrhythmia does not result from delayed afterdepolarizations. This is stated because delayed afterdepolarizations tend to decrease (or sometimes show no change) in their coupling intervals as the coupling intervals of single premature beats decrease (85) . In contrast, reentry would tend more readily to show an inverse ratio between the coupling interval of a premature beat and a following extrasystole (86). 5) The ability of single premature stimuli to shorten the cycle length of a subsequent arrhythmia, while consistent with delayed afterdepolarizations, may not occur (85). This is stated because single premature depolarizations tend far less readily than sustained pacing to modify the cycle length of a delayed afterdepolarization-induced arrhythmia (85) . 6) The requirement for a series of premature stimuli to induce an arrhythmia is more suggestive of delayed afterdepolarizations than is the ability of single premature stimuli to do this. The basis for this is the observation that delayed afterdepolarizations undergo a period of "warm-up"; that is, they require a sequence of 5 to 10 beats at a given cycle length to attain their peak amplitude (29, 3 1). Hence, a single premature beat will tend to induce a smaller delayed afterdepolarization than will a sequence of paced beats at the same cycle length. With this in mind , the occurrence of warm-up over several cycles to an arrhythmia with a stable rate may take place with delayed afterdepolarizations. 7) Termination of delayed afterdepolarization-induced arrhythmias may be sudden or may follow a period of slowing, and termination often is preceded by I to 10 afterbeats (85). Moreover, although termination may be induced by a single premature stimulus, it usually is not (85). 8) Whereas delayed afterdepolarization-induced rhythms usually increase in rate in response to overdrive pacing , approximately 90% can be reproducibly suppressed by overdrive if they are overdriven at cycle lengths less than 200 to 250 ms (85) . 9) Finally, although one can relate a delayed afterdepolarization-induced tachycardia to the pacing cycle lengths that induced it using the linear schema suggested in Figure 3, it must be understood that a number of complex variations on this phenomenon exist. Some of these are explored in Figure 7 . As demonstrated here , if there is an interval during which both the first and second deiayed afterdepolarizations are too small to attain threshold , then over this range of cycle lengths the arrh ythmia may give the appearance of having been overdrive-suppressed. Another complicating factor is that changes in membrane potential may modify
ROSEN ELECTROPHYSIOLOGY OF DIGITALIS TOXICITY
lACC Vol. 5. No.5 May 1985:22A-34A
3lA
Figure 7. Relation between delayed afterdepolarization amplitude (DAD amp) and coupling intetval (DAD CI), on the vertical axis to basic cycle length (BCL) on the horizontal axis. Numbers I and 2 refer to the first and second delayed afterdepolarizations in a sequence (see Fig. 2, Panel A). The arrows refer to the amplitude needed for delayed afterdepolarizations to attain threshold and initiate action potentials. Panel A, As basic cycle length decreases, the coupling intervals for the first (I) and second (2) delayed afterdepolarizations in the sequence also decrease. The amplitude of the afterdepolarizations is such that once the basic cycle length is shortened to 700 ms, the first delayed afterdepolarization attains threshold and initiates an action potential. As the drive cycle length is further decreased and the first delayed afterdepolarization begins to decrease in amplitude, the second afterdepolarization attains threshold and an action potential is seen. As a result, over a wide
range of drive cycle lengths, either the first or the second delayed afterdepolarization reaches threshold and initiates a propagating action potential. If one considers the coupling intervals for the action potentials initiated by these delayed afterdepolarizations, then the first afterdepolarization in the sequence will initiate action potentials at drive cycle lengths of 700 to 400 ms, and the resulting action potentials will have coupling intervals of about 650 to 500 ms. When the drive cycle length becomes sufficiently short that the second delayed afterdepolarization attains threshold (at drive cycle lengths of about 400 to 200 ms), the resultant coupling intervals for the action potentials will be about 800 to 400 ms, that is, about twice the drive cycle length. If this example represented a cardiac arrhythmia that was being overdrive-paced, then at pacing cycle lengths of 700 to 400 ms, there might be a triggered rhythm whose cycle length of 650 to 500 ms decreased with the decrease in drive cycle length. However, at the shorter pacing cycle lengths, there would be a sudden jump to an arrhythmia whose coupling interval was initially 800 ms and then decreased with drive cycle length. In addition, in the range of basic cycle lengths of 400 to 500 ms, where either the first or the second delayed afterdepolarization might reach threshold, the coupling interval for the arrhythmia would tend to be unstable, as indicated by the stippled zone. Panel B, In a different Purkinje fiber, another possibility is seen. Here as the drive cycle length decreases to about 500 ms, the amplitude of the first delayed afterdepolarization becomes subthreshold. The second delayed afterdepolarization does not reach threshold until a cycle length of about 400 ms. Hence, there is a gap of about 100 ms, during which no arrhythmia would occur (dashed line). Considering the implications of this experiment for an arrhythmia, at the longer drive cycle lengths of 700 to 500 ms, an arrhythmia having a coupling interval of 700 to 475 ms would occur. At. drive cycle lengths from 400 to 225 ms (the second delayed afterdepolarization), the coupling interval for the arrhythmia would be about 800 to 450 ms. Hence, we have the same sort of jump from one range of cycle lengths to a second range of cycle lengths in Panel B, as was seen in Panel A with the additional phenomenon of a gap during which no arrhythmia occurs at all. (Reprinted from Rosen M, Reder R [84j with permission.)
the occurrence and amplitude of delayed afterdepolarizations (87,88). Hence, any intervention, such as pacing, if it increases membrane potential to a range at which delayed afterdepolarizations decrease in magnitude, might be expected to alter the occurrence of triggered activity. Delayed afterdepolarizations as a mechanism oftachyarrhythmias. As previously suggested, there is much evidence supporting the idea that delayed afterdepolarizations are an important mechanism for digitalis-induced tachyarrhythmias. I) The characteristics of delayed afterdepolarization-induced rhythms in isolated tissues are quite similar to those of digitalis-induced repetitive ventricular responses in the in situ heart (Table 1) (84).2) The characteristics of onset and offset of some accelerated A V junctional escape arrhythmias in the human heart are more readily explicable by delayed afterdepolarization-induced triggered activity than by reentry or automaticity (89).3) Programmed pacing studies (90,91) in digitalis-toxic dogs have identified a pheno-
menology compatible with triggered activity. 4) Preliminary studies (92-94) using programmed pacing in a small group of human subjects have, likewise, been compatible with triggered activity. 5) Finally, preliminary studies (95) using extracellular electrodes to record diastolic potentials during digitalis toxicity in the intact dog have sugggested that delayed afterdepolarizations may induce the tachycardia. Implications. The latter portion of this discussion is not meant to imply that all digitalis-induced tachycardias are the result of delayed afterdepolarizations and triggered activity. However, it does appear that such activity is important in the genesis of many digitalis-induced tachyarrhythmias. It should be understood, as well, that digitalis-induced delayed afterdepolarizations or triggered activity not only may occur alone, but, as suggested in Figure 6, also may be superimposed on reentrant or automatic mechanisms, further increasing the complexity of arrhythmogenesis during digitalis toxicity.
B
A
25 20 DAD amp (.VI
15 10 5 2.5 1200
DAD 800 CI (.51 400
a
25 ~,
15
\
~
;;o-"Q..~
i
20
~
\\,
"
'.
10
d
1"0.'0.-0 1
'''1
b.'·-01
C/' /;/ A' 111 1 111
,AI
rf!
d
200
pi
600
BCl (msl
1000
200
1000 600 Bel (msl
"-
5 2.5
DAD amp (IlIVI
roo
800 DAD CI (illS I 400
a
32A
ROSEN ELECTROPHYSIOLOGY OF DIGITALIS TOXICITY
I express my gratitude to Andrea Diano for her careful attention to the preparation of this manuscript.
References I. Woodbury LA, Hecht HH. Effects of cardiac glycosides upon the electrical activity of single ventricular fibers of the frog heart, and their relation to the digitalis effect on the electrocardiogram. Circulation 1952;6:172-82. 2. Fingl E, Woodbury LA, Hecht HH. Effects of innervation and drugs upon direct membrane potentials of embryonic chick myocardium. J Pharmacol Exp Ther 1951;104:103-14.
lACC Vol. 5, No.5
May 1985:22A-34A
phanthin treatment on them. Ann Med Exp Bioi Fenn 1959;37(suppl 4):4-9. 24. Madan BR, Khanna NK, Soni RK. Effect of some arrhythmogenic agents upon the acetylcholine content of the rabbit atria. J Pharm Pharmacol 1970;22:621-2. 25. McLain PL. Effects of cardiac glycosides on spontaneous efferent activity in vagus and sympathetic nerves of cats. Int J Neuropharmacol 1969;8:379-87. 26. Gillis RA. Cardiac sympathetic nerve activity. Changes induced by ouabain and propranolol. Science 1969;166:508-10. 27. Eriij D, Mendez R. The modification of digitalis intoxication by excluding adrenergic influences on the heart. J Pharmacol Exp Ther 1964;144:97-103.
3. Watanabe Y, Dreifus L. Electrophysiologic effects of digitalis on A-V transmission. Am J Physiol 1966;211:1461-6.
28. Rosen MR, Gelband H, Hoffman BF.Correlation between effects of ouabain on the electrocardiogram and transmembrane potentials of isolated Purkinje fibers. Circulation 1973;47:65-72.
4. Dudel J, Trautwein W. Elektrophysiologische Messungen zur Strophanthinwirkung am herzmuskel. Arch Exp Pathol Pharmak 1958;232:393-407.
29. Rosen MR, Gelband H, Merker C, Hoffman BF. Mechanisms of digitalis toxicity: effects of ouabain on phase 4 of canine Purkinje fiber transmembrane potentials. Circ Res 1973;47:681-9.
5. Kassebaum DG. Electrophysiological effect of strophanthidin in the heart. J Pharmacol Exp Ther 1963;140:329-38.
30. Davis LD. Effects of changes in cycle length on diastolic depolarization produced by ouabain in canine Purkinje fibers. Circ Res 1973;32:206-14.
6. Vassalle M, Karis J, Hoffman BF. Toxic effects of ouabain on Purkinje fibers and ventricular muscle fibers. Am J Physiol 1962;203:433-9. 7. Coraboeuf E, de Loze C, Boistel J. Action de la digitale sur les potentiels de membrane et d'action du tissu conducteur du coeur de chien etudiee a I' aide de rnicroelectrodes intracellulaires. C R Soc Bioi (Paris) 1953;147:1169-72. 8. Muller P. Kalium und Digitalistoxizitat, Cardiologia 1963;42:176-88. 9. Matsumura M, Takaori S. The effects of drugs on the cardiac membrane potentials in the rabbit. I. Ventricular muscle fibers. Jpn J Pharmacol 1959;8:134-42. 10. Sleator W Jr, Furchgott RF, de GubareffT, Krespi V. Action potentials of guinea pig atria under conditions which alter contraction. Am J Physiol 1964;206:270-82. II. Stutz H, Feigelson E, Emerson J, Bing RD. Effect of digitalis ("Cedelanid") on the mechanical and electrical activity of extracted and nonextracted heart muscle preparations. Circ Res 1954;2:555-64. 12. Toda N, West TC. The influence of ouabain on cholinergic responses in the sino~trial node. J Pharmacol Exp Ther 1966;153:104-13. 13. Hoffman BF, Singer DH. Effects of digitalis on electrical activity of cardiac fibers. Prog Cardiovasc Dis 1964;7:226-60. 14. Koch-Weser J. Myocardial contraction frequency and onset of cardiac glycoside action. Circ Res 1971;28:34-48.
31. Ferrier GR, Saunders JH, Mendez C. Cellular mechanism for the generation of ventricular arrhythmias by acetylstrophanthidin. Circ Res 1973;32:600-9. 32. Saunders J, Ferrier G, Moe G. Conduction block associated with transient depolarizations induced by acetylstrophanthidin in isolated canine Purkinje fibers. Circ Res 1973;32:610-7. 33. Hashimoto K, Moe GK. Transient depolarization induced by acetylstrophanthidin in specialized tissues of dog atrium and ventricle. Circ Res 1973;32:618-24. 34. Cranefield PF. The Conduction of the Cardiac Impulse: The Slow Response and Cardiac Arrhythmias. Mt. Kisco, NY: Futura Press, 1975. 35. Ferrier GR. Digitalis arrhythmias: role of oscillatory afterpotentials. Prog Cardiovasc Dis 1977;19:459-74. 36. Fozzard H, Sheets M. The cellular mechanism of action of cardiac glycosides. J Am Coli Cardiol 1985;5:(suppl):IOA-15A. 37. Tsien RW, Kass RS, Weingart R. Cellular and subcellular mechanisms of cardiac pacemaker oscillations. J Exp Bioi 1979;81:205-15. 38. Kass RS, Lederer WJ, Tsien RW, Weingart R. Role of calcium ions in transient inward current and aftercontractions induced by strophanthidin in cardiac Purkinje fibers. J Physiol 1978;281:187-208.
15. Moran NC. Contraction dependency of the positive inotropic action of cardiac glycosides. Circ Res 1967;21:727-40.
39. Lederer WJ, Tsien RW. Transient inward current underlying arrhythmogenic effects of cardiotonic steroids in Purkinje fibers. J Physiol 1976;263:73-100.
16. Sanyal PN, Saunders PF. Relationship between cardiac rate and the positive inotropic action of ouabain. J Pharmacol Exp Ther 1958;122:499-503.
40. Lown B, Cannon RL III, Rossi MA. Electrical stimulation and digitalis drugs: repetitive response in diastole. Proc Soc Exp BioI Med 1967;126:698-701.
17. Cranefield PF, Hoffman BF. Electrophysiology of single cardiac cells. Physiol Rev 1958;38:41-76.
41. Hagemeijer F, Lown B. Effect of heart rate on electrically induced repetitive ventricular responses in the digitalized dog. Circ Res 1970;27:333-44.
18. Hajdu S, Leonard E. The cellular basis of cardiac glycoside action. Pharmacol Rev 1959;II: 173-209. 19. Miura DS, Rosen MR. The effects of ouabain on the transmembrane potentials and intracellular potassium of canine cardiac Purkinje fibers. Circ Res 1978;42:333-8.
42. Wittenberg S, Gandel P, Hogan PM, Kreuzer W, Klocke FJ. Acceleration of ventricular pacemakers by transient increases in heart rate in dogs during ouabain administration. Circ Res 1972;30:167-76.
20. Roseri MR, Wit AL, Hoffman BF. Cardiac antiarrhythmic and toxic effects of digitalis. Am Heart J 1975;89:391-9.
43. Hogan P, Wittenberg S, Klocke F. Relationship of stimulation frequency to automaticity in the canine Purkinje fiber during ouabain administration. eire Res 1973;32:337-84.
21. Chai CY, Wang HH, Hoffman BF, Wang SC. Mechanisms of bradycardia induced by digitalis substances. Am J Physiol 1967;212:26-34.
44. Wittenberg S. Chronotropic effects of ouabain and heart rate on canine atrium in vivo. Circ Res 1974;34:258-67.
22. Ten Eick RE, Hoffman BF. Chronotropic effect of cardiac glycosides in cats, dogs and rabbits. Circ Res 1969;25:365-78.
45. Vassalle M. The relationship among cardiac pacemakers. Overdrive suppression. Circ Res 1977;41:269-77.
23. Torsti P. Acetylcholine content and cholinesterase activities in the rabbit heart in experimental heart failure and the effect of g-stro-
46. Vassalle M, Greenspan K, Hoffman BF. An analysis of arrhythmias induced by ouabain in intact dogs. Circ Res 1963;13:132-48.
lACC Vol. 5, No.5 May 1985:22A-34A
47. Rosen MR, Danilo P Jr. Digitalis-induced delayed afterdepolarizations. In: Zipes DP, Bailey JC, Elharrar V, eds. The Slow Inward Current and Cardiac Arrhythmias. The Hague: Martinus Nijhoff, 1980:417-35. 48. Aronson RS, Gelles JM. The effect of ouabain. dinitriphenol and lithium on the pacemaker current in sheep cardiac Purkinje fibers. Circ Res 1977;40:517-24. 49. Rosen MR, Danilo P Jr. Effects of verapamil, AHR-2666, tetrodotoxin and lidocaine on digitalis-induced delayed afterdepolarizations. Circ Res 1980;46:117-24. 50. Hashimoto K, Kumura T, Kubota K. Study of the therapeutic and toxic effects of ouabain by simultaneous observations on the excised and blood-perfused sinoatrial node and papillary muscle preparations and the in situ heart of dogs. J Pharmacol Exp Ther 1973;186:463-71.
ROSEN ELECTROPHYSIOLOGY OF DIGITALIS TOXICITY
33A
ouabain- induced delayed afterdepolarizations. J Pharmacol Exp Ther 1984;229:188-92. 70. Cranefield PF, Gadsby De. Isoprenaline increases the potassium permeability of the resting membrane of canine cardiac Purkinje fibers. J Physiol 1981;318:34-5. 71. Boyden PA, Cranefield PF, Gadsby DC. Noradrenaline hyperpolarizes cells of the canine coronary sinus by increasing their permeability to potassium ions. J Physiol 1983;339: 185-206. 72. Hayes CJ, Butler VP Jr, Gersony WM. Serum digoxin studies in infants and children. Pediatrics 1973;52:561-8. 73. Irons GV Jr, Orgain ES. Digitalis-induced arrhythmias and their management. Prog Cardiovasc Dis 1966;8:539-68.
51. Kastor J, Spear J, Moore EN. Localization of ventricular irritability by epicardial mapping. Circulation 1972;45;952-64.
74. Rosen MR, Hordof AJ, Hodess A, Verosky M, Vulliemoz Y. Ouabaininduced changes in electrophysiologic properties of neonatal, young and adult canine cardiac Purkinje fibers. J Pharmacol Exp Ther 1973;194:255-63.
52. Hordof A, Spotnitz H, Mary-Rabine L, Edie R, Rosen M. The cellular electrophysiologic effects of digitalis on human atrial fibers. Circulation 1978;57:223-9.
75. Hewett K, Vulliemoz Y, Rosen MR. Senescence-related changes in the responsiveness to ouabain of canine Purkinje fibers. J Pharmacol Exp Ther 1982;223:153-6.
53. Dangman KH, Danilo P Jr, Hordof AJ, Mary-Rabine L, Reder R, Rosen MR. Electrophysiologic characteristics of human ventricular and Purkinje fibers. Circulation 1982;65:362-8.
76. Goldberg P, Roberts J. Pharmacology. In: Weisfeldt M, ed. The Aging Heart. New York: Raven, 1980:215-46.
54. Lee KS, Klaus W. The subcellular basis for the mechanism of inotropic action of cardiac glycosides. Pharmacol Rev 1971;23: 193-260. 55. Noble D. The Initiation of the Heartbeat. 2nd ed. Oxford: Clarendon, 1979. 56. Hoffman BF, Cranefield PF. Electrophysiology of the Heart. New York; McGraw-Hili, 1960. 57. Fisch e. Relation of electrolyte disturbances to cardiac arrhythmias. Circulation 1973;47:408-19. 58. de Mello WC. Intercellular communication in heart muscle. In: de Mello WC, ed. Intercellular Communication. New York: Plenum, 1977:87-125. 59. Weingart R. The actions of ouabain on intercellular coupling and conduction velocity in mammalian ventricular muscle. J Physiol 1977;264:341-65. 60. Tsien RW, Marban E. Digitalis and slow inward current in heart muscle: evidence for regulatory effects of intracellular calcium on calcium channels. In: Yoshida H, Hagihara Y, Ebashi S, eds. Advances in Pharmacology and Therapeutics II. New York: Pergamon, 1982;217-25. 61. Ferrier GR, Moe GK. Effect of calcium on acetylstrophanthidin-induced transient depolarizations in canine Purkinje tissue. Circ Res 1973;33;508-15. 62. Kass RS, Tsien RW. Control of action potential duration by calcium ions in cardiac Purkinje fibers. J Gen Physiol 1976;67:599-617. 63. Giles W, Noble SJ. Changes in membrane currents in bullfrog atrium produced by acetylcholine. J Physiol (Lond) 1976;261:103-23. 64. Mendez C, Aceves J, Mendez R. Inhibition of adrenergic cardiac acceleration by cardic glycosides. J Pharmacol Exp Ther 1961;131:191-8. 65. Nadeau RA, James TN. Antagonistic effects on the sinus node of acetylstrophanthidin and adrenergic stimulation. Circ Res 1963; 13:388-91. 66. Evans DE, Gillis RA. Effect of ouabain and its interaction with diphenylhydantoin on cardiac arrhythmias induced by hypothalamic stimulation. J Pharmacol Exp Ther 1975;196:577-86. 67. Pace 00, Gillis RA. Neuroexcitatory effects of digoxin in the cat. J Pharmacol Exp Ther 1976;199:583-600. 68. Somberg Je. Bounous H, Levitt B. The antiarrhythmic effects of quinidine and propranolol in the ouabain-intoxicated spinally transected cat. Eur J Pharmacol 1979;54:161-6. 69. Hewett KW, Rosen MR. Alpha and beta adrenergic interactions with
77. Berman W, Ravenscroft P, Sheiner L, Heymann M, Melmon K, Rudolph A. Differential effects of digoxin at comparable concentrations in tissues of fetal and adult sheep. Circ Res 1977;41:635-42. 78. Inturrisi CE, Papaconstantinou Me. Ouabain sensitivity of the Na + -K + -A'TPase from rat neonatal and human fetal and adult heart. Ann NY Acad Sci 1974;242:710-16. 79. Brennan JF, Bonn JR. Effects of ouabain on the electrophysiological properties of subendocardial Purkinje fibers surviving in regions of acute myocardial infarction. Am Heart J 1980;100:201-12. 80. Hoffman BF, Cranefield PF. The physiologic basis of cardiac arrhythmias. Am J Med 1964;670-84. 81. Rosen MR. Interactions of digitalis with the autonomic nervous system and their relationship to cardiac arrhythmias. In: Disturbances in Neurogenic Control of the Circulation. Am Physiol Soc, Bethesda 1981;251-63. 82. Bailey Je. Anderson GJ, Fisch e. Digitalis-induced longitudinal dissociation in canine cardiac Purkinje fibers. Am J Cardiol 1973;32:202-8. 83. Hoffman BF, Rosen MR. Cellular mechanisms for cardiac arrhythmias. Circ Res 1981:49:1-15. 84. Rosen MR, Reder RF. Does triggered activity have a role in the genesis of cardiac arrhythmias? Ann Intern Med 1981;94:794-801. 85. Moak JP, Rosen MR. Induction and termination of triggered activity by pacing in isolated canine Purkinje fibers. Circulation 1984;69:149-62. 86. Pick A. Variants in reciprocal beating; an exercise in deductive interpretation. In: Kulbertus H, ed. Reentry. Lancaster, PA: MTP Press, 1977:3-14. 87. Ferrier GR. Effects of transmembrane potential on oscillatory afterpotentials induced by acetylstrophanthidin in canine ventricular tissues. J Pharmacol Exp Ther 1980;215:332-41. 88. Wasserstrom JA, Ferrier GR. Voltage dependence of digitalis afterpotentials, aftercontractions and inotropy. Am Physiol Soc 1981;H646-53. 89. Rosen MR, Fisch C, Hoffman BF, Danilo P, Lovelace PE, Knoebel SB. Can accelerated atrioventricular junctional escape rhythms be explained by delayed afterdepolarization? Am J Cardiol 1980; 45:1272-84. 90. Gorgels A, Beekman H, Brugada P, Dassen W, Richards D, Wellens H. Extrastimulus-related shortening of the first postpacing interval in digitalis-induced ventricular tachycardia. J Am Coli Cardiol 1983;I:840-57. 91. Zipes DR, Arbel E, Enope RF, Moe GK. Accelerated cardiac escape rhythms caused by ouabain intoxication. Am J Cardiol 1974;33:248-53.
34A
ROSEN ELECTROPHYSIOLOGY OF DIGITALIS TOXICITY
JACC Vol. 5, No.5 May 1985:22A-34A
92. Zipes DR, Foster PR, Trays PI, Pedersen DH. Atrial induction of ventricular tachycardia: re-entry versus triggered automaticity. Am I Cardiol 1979;44: 1-8.
94. Brugada P, Wellens H. The role of triggered activity in clinical arrhythmias. In: Rosenbaum M, Elizari M. Frontiers of Cardiac Electrophysiology. The Hague: Martinus Nijhoff, 1983:195-216.
93. Wellens HJJ, Brugada P, Vanagt EJDM, Rose DL. Barr FW. New studies with triggered automaticity. In: Harrison DC, ed. Cardiac Arrhythmias. A Decade of Progress. Boston: GK Hall Medical, 1981:601-12.
95. Levine JH, Weisfeldt M, BerkhoffD, Franz MR, Guarnieri T. Delayed afterdepolarizations in monophasic action potentials in vivo (abstr). Circulation 1984;70(suppl Il):Il-222.