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Concealment of manifest, and exposure of concealed, ventricular parasystole produced by isoproterenol
Concealment of Manifest, and Exposure of Concealed, Ventriculai Parasystole Produced by lsoproterenol AGUSTIN CASTELlANOS, MD, IVAN J. MENDOZA, MD, RICHARD M. LUCERI, MD, CESAR A. CASTILLO, MD, UAQAT ZAMAN, MD, NADIR SAOUDI, MD, and ROBERT J. MYERBURG, MD
Few studles have dealt with the effects of Isoproterenol on ventricular parasystole. Intravenous lsoproterenol(2 to 4 pg/mln) was admlnlstered to 11 nonmedlcated patlents with ventricular parasystole. At the onset of the drip Infusion, 8 patlents had continuous parasystole, 2 had lntermlttent parasystole, and 1 patlent (In whom lntermlttent parasystole was documented 2 to 5 days earlier) showed no manifest parasystollc actlvlty. In all patients, whose control parasystollc cycle length varled between B80 and 2,530 ms, lsoproterenol caused a decrease of the parasystollc cycle lengths ranging from 12 to 38%. Therefore, lsoproterenol produced a consistent Increase of the parasystollc rate. In 4 patlents, parasystolic activity ceased to be manifest when the concomitantly enhanced (by lsoproterenol) sinus cycle lengths became shorter than 430 ms. This phenomenon reflected a tachy
cardla-dependent parasystollc concealment, presumably as a result of Interference In the parasystollc-ventricular junctlon. In every case, the arrhythmia reappeared at its Initial rate upon stopping the drip Infusion. In no patlent did parasystollc ventricular tachycardla develop. In the patlent without manlfest parasystollc beats, lsoproterenol unmasked the intermittent parasystole that prevlously had been lntrfnslcally manlfest. The latter effect reflected a true exposure, or unmasklng of a latent, rate-independent concealed, parasystollc focus. The flndlngs In this study may explain some of the dlfflcultles and puzzling flndlngs encountered when attempting to dlagnose ventricular parasystde from 24-hour Halter recordings, because ectoplc and sinus cycle lengths can be affected by spontaneously occurring variations In sympathetic dlscharge. (Am J Cardlol 1985;55:1344-1349)
Although much has been written about the various electrocardiographic manifestations of parasystole, less is known about the responses of this arrhythmia to drugs.l12Herein we discussthe effects of isoproterenol on certain types of ventricular parasystole.
Dia@ro~tic criteria: Parasystole wasidentified during the scanning of Holter tapes from 10 ambulatory patients and while obtaining long rhythm strips from a patient in the coronary care unit. The diagnosis of ventricular parasyatole was baaed on criteria previously described.‘4 In all patients, before isoproterenol administration, the ectopic cycle lengths could be measured directly, that is, without any interposed nonparasystolic (einus or extrasystolic) beat, as well 89 with a single interposed nonparasystolic beat.3*4 “Absolute” protection was considered to have been present when single, nonparasyetolic beata that fell in different moments of the cycle did not change the ectopic cycle length.* This finding excluded classic modulated parasystole ~IJwell as parasystole with protection limited to the initial half of the cycle (hereafter called paraaystole with phase 3 protection).3-7 Only 2 types of parasystolee were diagnosed: Contintrous parasystole (8 patients) wascharacterized by interectopic intervals, which were a multiple of ectopic cycle lengths and did not vary by more than 596;marked variations in the coupling intervals; and persistent manifest activity throughout the recording time.epg Intermittent parasystole (3 patients) was characterized by groups of parasystolic beats during which the interectopic intervals were a multiple of the ectopic cycle lengths and the
Methods Clinical information: Eleven nonmedicated patients were studied. No organic heart disease was detected in 5 patients; 3 patients had sick sinus syndrome and 3 had primary conduction system disease. The patients were 21 to 61 years old. Nine were men and 2 were women. The blood pressures were normal in all patients From the Dlvlsion of Cardiology, Dqrtment of Medicine, University ofMiamiSchaolofMediche,Miami,Florlda,andtheUlhrersldedCentral de Venezuela, Caracas, Venezuela. This study was supported In part by Grant 28130 from the Netional Institute of tkalth, Betfmsda, Maryland. Manuscript recehd November 30, 1984; revlsed manuscript received February 4, 1985, accepted February 5,1985. Ad&em far rqrhts: Agustin Castellanos, fXI, Dlviskm of Cmlkkqy (MS), University of Miami School of Medicine, P.O. Box 018980, Mhnl, Florkh 33101. 1344
May
TABLE I
1.1985
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Effects ot lsoproterenol on Ventricular Paraeyetole Maximal IS0 1 ECL (ms)
Maximal IS0 1 ECL(%)
Manifest
1,110
23
Manifest
1,400 1,000 960 1,220 1,120 2,530 1,340
Manifest Manifest Manifest Manifest Manifest
950 740 a45 940 920 1,110 1,620
26 32 :s ;:
Concealed Manifest Manifest Manfiest Concealed Concealed
1,400 1.250 -
Manifest Concealed Manifest
1,210 1,000 -
:: 20
Manifest Manifest Manifest
Type of Parasystole
Control ECL (ms)
1
Continuous
1,440
f
Continuous Continuous Continuous Continuous Continuous Continuous Intermittent Intermittent
Case
i 6 ; 9 :: ECL = ectopic
cycle
length;
IS0 = isoproterenol;
Control PA
PA During Maximal IS0
PA = parasystole.
coupling intervals had marked variations,gJ1 and intervals between the last parasystolic beat of 1 group and the first parasystolic beat of the group that immediately followed, which were not multiples of the ectopic cycle lengths.g-ll Administration of isoproterenol: A drip infusion (2 to 4 pg/min) was given while the patients were continuously monitored using conventional oscilloscopic and electrocardiographic equipment.le In 5 of 10 patients, this was done while Holter recordings were obtained with the same electrode placement as that of the recordings where the arrhythmia was diagnosed.
Results Absence of adverse reactions: No patient developed ventricular tachycardia, sustained or nonsustained. In 1 patient with sick sinus (tachycardiabradycardia) syndrome the drug apparently exposed the patient’s clinical paroxysmal atria1 fibrillation which converted to sinus rhythm, spontaneously, 9 minutes after stopping the drip infusion. One patient complained of palpitations when the sinus rate increased to 1Wmin. This symptom disappeared promptly when isoproterenol was stopped. Effects of isoproterenol on parasystolic rates: The control, directly measured ectopic cycle lengths varied between 2530 and 960 ms (corresponding to rates of 24 to 62/min) (Table I). In 10 patients (8 with continuous and 2 with intermittent parasystole), isoproterenol administration increased the parasystolic rates, since the ectopic cycle lengths decreased by 12 to 36%. An example is shown in Figure 1, where the control ectopic cycle lengths were shortened from 1,440 ms to 1,100 ms (by 23%) during the maximal effects of isoproterenol. The sinus rates also showed variable degree8 of increases, presumably because the differences in clinical settings and in background autonomic tone made the sinus node to respond unequally to isoproterenol. In patients without fast sinus rates, the ectopic cycle lengths could still be measured directly, or with only 1 interposed nonparasystolic beat after the drug was given. However, this was possible mainly during the initial stages of isoproterenol administration, when marked sinus tachycardia did not occur. When sinus tachycardia was induced, it was more likely for manifest parasystolic beats to be followed by parasystolic discharges, which fell during the refractory period of nonparasystolic beats. But even under these circum-
stances, long strips revealed parts during which there was an ectopic cycle length with only a single interposed nonparasystolic beat (Fig. 2). Parasystolic concealment: In 4 patients the sinus rate8 increased so much that they resulted in total parasystolic concealment. Figure 2A shows the ectopic cycle length (1,400 ms) measured directly 15 minutes before isoproterenol. A few minutes after starting the drip infusion (second strip), the ectopic cycle length had a similar duration (1360 ms) despite the presence of an interpolated nonparasystolic beat and an increase in sinus rate. In the third strip, recorded later, the ectopic cycle length had decreased by 32% (to 950 ms). In the fourth strip manifest parasystolic beats were no longer apparent. This was attributed to the fact that the sinus cycle length had become short enough to prevent parasystolic discharges from activating the ventricles. Yet, parasystolic beats reappeared (that is, they again be-
ECL CONTROL
1440 MS
ISOPROTERENOL
3300 MS
1100MS
FKWRE 1. Case 1. lsoproterenol-induced increase in rate of continuous parasystole. The ectopic cycle length (ECL) decreased by 23 % , from 1,440 to 1,100 ms. The top strip shows that despite the marked varlations in coupling intervals, the ectopic cycle lengths had a constant value. Modulation was excluded because nonparasystollc beats that fell in different moments of the cycle failed to affect the ECL. The end of the mlddle strfp (noncontinuous with the top strip) shows the directly-measured ECL. In the bottom strip, 4 parasystolic discharges were unable to produce the QRS complex because they fell during the ventricular effective refractory period.
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CONTROL
ECL :
1I I i
came manifest) when the drip infusion was stopped, since the sinus cycle lengths became progressively longer during their return toward their control values (bottom strip). In 2 of the 4 patients, parasystolic concealment occurred when the sinus cycle lengths became shorter than the shortest (“coupling”) interval (time elapsing between a nonparasystolic beat and an immediately after manifest parasystolic beat) occurring in these patients. Exposure of concealed parasystole: In 1 patient, ventricular parasystole with an ectopic cycle length of 1,300 ms had been documented 3 to 5 days before the day of the study (Fig. 3). However, this patient had not shown evidence of manifest ectopic activity during continuous monitoring for at least 24 hours. In the recording shown in Figure 4, obtained immediately before isoproterenol administration, parasystolic beats were not seen. The sinus cycle lengths ranged from 810 to 360 ms (rates of 74 to 70/min). The tracing in Figure 5, recorded at a slower paper speed at the beginning of the drip infusion, shows intermittent ventricular parasystole occurring when isoproterenol had shortened the sinus cycle length to 620 ms. The interval between 2 consecutive parasystolic beats, which did not change while nonparasystolic beats fell in slightly different moments of the cycle, was considered to represent the ectopic cycle length (decreased, by isoproterenol, from 1,300 ms in Figure 3 to 1,230 to 1,250 ms). In addition, the interval between the last ectopic beat in the first parasystolic series and the first beat in the subsequent series was not a multiple of the assumed ectopic cycle length. The tracing in Figure 6 was recorded after the drip infusion was stopped because of the appearance of clinical atrial fibrillation. Discontinuation of isoproterenol was believed to have resulted in an increase in the ectopic cycle length to 1,325 to 1,370 ms (rates of 44 to 45/min). As in Figure 5, the interval between the last ectopic beat in the first series (top panel) and the first ectopic beat in the next series (bottom panel) was not a multiple of the ectopic cycle length. Furthermore, in each series, the parasystolic rate was unchanged, although 1 or more nonparasystolic beats were interposed within 2 consecutive parasystolic beats. The latter did not fulfill previous electrocardiographic criteria established for the diagnosis of modulation.isp4 The tracing, in Figure 7, recorded a few minutes later, while atrial fibrillation persisted, but with slower ventricular rates, shows (as in Fig. 4) no manifest parasystolic beats. This happened despite the presence of nonparasystolic RR intervals, which were longer than those that previously (Fig. 6) had allowed the parasystole to be manifest.
1400 MS
ISOPROTERENOL 1360 MS
950 MS
CONCEALED AFTERISOPROTERENOL 1400 MS
FtGURE 2. Case 2. Concealment of continuous ventricuiar parasystoie produced by a decrease in the nonparasystolic (sinus) ectopic cycle length (ECL) (increase in rate). Variations in ectopic QRS complexes occurred because the patient changed. position while the recordings were performed.
FIGURE 3. Case 11. Ventricular parasystoie isoproterenoi infusion. The directly rneasued 1,300 ms. Strips are not continuous.
recorded 3 days before ectopic cycle length was
CONTROL (Continuous tracings) “““‘~‘~~~~~‘~~~,‘~~‘~~~~~~~~“~“~~~~~~~~’~~’~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~,,~,~~,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,~,,,,,,,,,,,, 1111,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,I ,,,,,,,,,,, m ,,,,,,,,
Id II
-
-
n
n
h
-
n
I\
-
c
L
-
h
- -
-
FIGURE 4. Case 11. Absence of manifest parasystoiic activity in a patient whose tracings obtained 3 to 5 days earlier had shown intermittent ventricuiar parasystoie (Fig. 3). Sinus rhythm was present before isoproterenoi infusion.
May 1, IS85
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F
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THE AMERICAN
XWRNAL
DF CARDIOLCGY
Volume 55
1347
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,
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6550
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II230 YSIl230 I651 1230 MI11230 MS1
FIGURE 5. Case 11. Ventricular parasystole appearing at a cycle length of 1,230 to 1,250 ms during the maximal rhythm was still present. The interval between the last parasystolic beat in the first series and the first parasystolic a muttiple of the ectopic cycle length that the parasystole had at that moment. F = fusion beat.
Discussion Effects of isoproterenol on parasystolic rate: The increase in parasystolic rate was evident when (and while) the ectopic cycle lengths were measured without any, or with only one, interposed nonparasystolic beat. Because the latter fell in different moments of the ectopic cycle, modulated parasystole3t4J3-22 and parasystole with phase 3 protection could be excluded.5-8 On the other hand, when the sinus (nonparasystolic) rates increased to such a degree that more than 2 nonparasystolic beats fell in between consecutive manifest parasystolic discharges, determination of the ectopic cycle length was less precise. Yet, the degree of inexactitude was still within the limits used to make the diagnosis of parasystole in clinical electrocardiography.lkV-11
Although isoproterenol accelerated the parasystolic rate in all patients, ventricular tachycardia did not occur with the therapeutic doses used. This finding is in keeping with the well known pharmacologic effects of isoproterenol (with the doses used) on automaticity.i2z3 That the automatic rhythms also showed protection supports previous assumptions considering parasystole to be the result of protected automatic activity arising from spontaneous depolarizations in the range of -90 to -70 mV or -60 to -40 mV.’ Oscillatory prepotentials of increasing amplitude may also be implicated, as will be discussed subsequently. In addition to the parasystolic rates being increased by isoproterenol, Nau et a123 found that they were decreased by local anesthetics. They thus considered parasystole to be a result of protected automatic activity arising from high levels of membrane potential.23
CONTINUOUS
TRACINGS
effects of isoproterenol. beat in the next series
Sinus was not
Parasystolic concealment: The absence of manifest parasystolic beats occurring after the sinus rates increased above a given value can be attributed to an isoproterenol-induced improvement of conduction through the zone of protection (region of depressed excitability) surrounding the parasystolic pacemaker. If conduction through this zone improved so much as to result in total abolishment of protection, all incoming nonparasystolic impulses could have reached, thus overdrive suppressing, the automatic pacemaker. Such an assumption implies that isoproterenol in effect caused transient disappearance of parasystolic activity. However, certain findings support another interpretation. For example, in the patients with continuous parasystale, the interval between the last parasystolic beat, before a short period of concealment and the first manifest beat appearing after concealment was a multiple of the ectopic cycle length. Moreover, as previously stated by Nau et al,23 the disappearance of manifest ectopic beats apparently occurred when the progressively decreasing sinus cycle lengths became shorter than the shortest “coupling” interval at which a parasystolic beat could be manifested. Therefore, most likely, the phenomenon was a tachycardia-dependent parasystolic concealment resulting from the impedance to the emergence of parasystolic impulses, that is, from the “interference” created by the fast nonparasystolic impulses, in the ventricular-parasystolic junction. Mechanisms of intermittent ventricular parasystole: Neither exit block of a continuously discharging parasystole nor the late-in-the-cycle loss of protection characteristic of the so-called parasystole with phase 3 protection explained the periods of intermittency that occurred in cases 9,10 and ll.lp5-s Cases 9,10 and 11 had features similar to those of the type of parasystole which Scherf et al’s attributed to “a periodic awakening and vanishing of an active ventricular centre,” presumably due to spontaneous variations CONTINUOUS TRACINGS
11325 MS1 1370 MS11370 F F
MS~1325
ms~1325 F
hEI------
Ifi
TI
1370
1 1370
1
1370
1
1370
]
I390
1 1370
)
1370
1
FIGURE 6. Case 11. Ventricular parasystole occurring after stopping isoproterenol treatment because of the appearance of atrial fibrillate. The interval between the last parasystolic beat in the first series (top) and the first parasystolic beat in the next series (bottom) was not a multiple of the ectoptc cycle length that the parasystole had at that moment. The panels show continuous recordings.
FIGURE
7. Case
11. Disappearance
(possibly
reconcealrnent) of intreatmmt (while atrtal fibrillation was still present). This occurred despite the presence of nonparasystolic RR intervals, which were longer than those that previously (Ftg. 4 and 5) had allowed ths parasystolic beats to become manifest.
termittent pmsystde afterstopplnaIsoproerenol
f348
EFFECTS
OF ISOPROTERENOL
of automatic activity. ~JOJ~ In fact, experiments made with microelectrode techniques show how, in some preparations, automatic activity is preceded by oscillations of increasing amplitude.2s27 Cranefield observed trains (groups) of automatic impulses during which the last impulse of a train was followed by subthreshold oscillations of decreasing amplitude, which gave way to oscillations of increasing amplitude.27 When one of the latter reached threshold, it initiated another train of automatic impulses. 27 The intervals during which the subthreshold oscillations occurred varied in duration.27 Extrapolation of these findings to the surface electrocardiogram explains why the intervals between the last manifest parasystolic beat of 1 group and the first beat of the group immediately following were not multiples of the ectopic cycle length (Fig. 5 and 6). Exposure of concealed parasystole: Occurrence of a marked prolongation of 1 of these intervals, during which the “latent” pacemaker had subthreshold oscillations or was quiescent may explain the long period (more than 24 hours) without manifest parasystolic beats, seen in case 11. Isoproterenol could have exposed the arrhythmia if, by acting on the “latent” pacemaker, it increased the amplitude of subthreshold of oscillations so as to produce trains (groups) of manifest automatic impulses arising from levels of membrane potential in the range of either -90 to -70 mV or -60 to -40 mV.27 Isoproterenol also exposed the zone of depressed excitability (or of entrance block) where protection occurred, thus confirming that isoproterenol had a greater enhancing effect on automaticity than on conduction. We did not prove parasystolic modulation applying previously published electrocardiographic criteria.3T4 Yet if, as postulated by several investigators, all parasystoles are indeed subjected to some degree of electrotonic modulation, then the latter may have been present, but “masked,” in all patients.13-16 Masking, a term used in regulatory integrative comparative physiology, may be extrapolated to clinical electrocardiography to indicate that electrotonically induced variations in ectopic cycle lengths occurred, but were of a lesser magnitude than those attributed to spontaneous fluctuations in automatic activity.24 Furthermore, overt parasystolic modulation may have been present. The intermittent parasystole seen in Figure 6 could theoretically be explained by assuming (at that moment) an ectopic cycle length of 1,500 ms and a biphasic phase response curve with a maximum delay of around 100 ms and a maximum acceleration of around 200 ms. Moreover, it can also be postulated that the long periods of “silence” (Fig. 5 and 6) may have resulted from the development of stable 2:l entrainment and concealment of all ectopic discharges. This is in fact predicted whenever appropriate changes in frequency relations between the parasystolic and sinus pacemakers convert a complex entrainment ratio to a rigidly constant harmonic ratio.14 In the latter case every pacemaker discharge could be forced to occur during the ventricular refractory period, in which case would never become manifest unless, of course, there
is another drastic change in frequency relations. As demonstrated by the biologic model of modulation,16 such periods of silence can cover wide ranges of frequency ratios. Clinical implications: Our findings may explain some of the difficulties and otherwise puzzling findings encountered when attempting to diagnose ventricular parasystole from 24-hour Holter recordings. For example, the association of longer ectopic cycle lengths with slower sinus rates and of shorter ectopic cycle lengths with faster sinus rates could be the result of concordant effects (enhanced automaticity) exerted by spontaneously occurring variations in sympathetic discharge. Unfortunately, these findings can be construed to indicate that parasystole is not present because such “spontaneous” variations of ectopic cycle length preclude this diagnosis. In fact, what may be occurring in these situations is that the parasystolic rate changes with coexisting fluctuations of intrinsic sympathetic activity. Furthermore, transient, otherwise unexplained disappearance (or “pseudointermittency”) of a continuous parasystole during episodes of sinus tachycardia may reflect the tachycardia-dependent inability of a continuously discharging parasystole from activating the ventricular myocardium. Finally, although the mechanisms of true parasystolic intermittency in cases 9,10 and 11 is unclear, the exposure of a (during normal sinus rhythm) concealed parasystole (case 11) probably reflected a drug-related enhancement of automaticity of a “latent” protected (parasystolic) automatic pacemaker. Again, if this were to occur spontaneously because of a sudden surge of sympathetic activity, the clinical manifestation would be the abrupt appearance of an intermittent parasystolic rhythm (by the definition of Scherf et aP). Nevertheless, attractive as these hypotheses are, they require future prospective studies (including the induction of non-cathecolamine-related changes in sinus or paced atrial cycle lengths) to corroborate them. References 1. Castellanos
A, Molelro F, Keyden D, Myerburg RJ. Evolvln~n~~ ths elecbocardiogaphic diils of ventricular parasystde. : ME, Wellens IUJ, eds. Tachycardias: Mechanism, Diagkxls and Treatment. Philadelphia: Lee B Febiger, 1984;287-306. 2. Kayden D. Lucerl FM. Zaman L. Molelro F. Mverbura RJ. Castellanos A. Me&anisins and lmpiications df ventricul& Ijarasysiole~in inferior myocardial infarction (abstr). PACE 1983;6:323. 3. Castellanos A. Lucerl RY. Molelro F, Kayden DS. Trohman RD. Zaman L, Myerburg dJ. Annihilation, entraiketit and modulation of ventricular stolic rhythms. Am J Cardiol 1984;54:317-322. 4. lizxl , Aldarlz AE, Acunzo RS. Halpem MS, Davldenkl JM, Ellzarl MV, Roserhum MB. Modulation of perasystollc activity by nonparfisystolic beak Circulation 1982;66:482-469. 5. Cehen H, w R, Pkk A. lntermlttent perasy-stole-mechanism of ection. Circulation 1973;48:761-774. Ick A. The electrophysiologic basis of paraeystole and its variants. In: 8. r Wellens HJJ, Lie KI, Janse MJ. eds. The Conduction System of the Heart. Structure, Function and Clinical Implications. Leiden: HE Stenfert Kroese BV. +976;143-162. 7. Ceetellenae A, +atrkle VY, Bun9 RJ, Bhe~s DS, Myerburg RJ. A search Lg modulation In intermittent ventricular parasystole. PACE 1980;3:730. Castellanos
M arbu
A, Casllllo CA, Medlna-Ravel1
V, Molelro
F, Betlcovlls
BV,
RJ. Electronic pacemaker models of parasystole. PACE 1982; 5:!37-36. 0. Bched D, Bchett A. Extrasystoies and Allied Anhylhrnlas. New York: @une 8 stratton. 1953; 297-301. D. Boyd LJ. Three unusuel cases of peraeystole. Am Heart J 10. Bcherf 1950339:650-663. 4. S&h D, Scholl A, Reld EC, Chamsal Do. Intermittent parasystole. Cer-
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,*.
13. 14. 15. 16. 17. 18. 19. 20.
da
1957;30:217-228. z-GrmzaIas A. Sympathomimatic treatment. In: Gayer? A, Cosln J, eds. Dkgtcsk and Treatment of cardiac &&ythmii. New Yak: persrrmOn F’ress, 1980:967-973. Jaltfe J, Mea GK. Effect of electrotonic potent&Is on pacemaker activity of canine Pwkinje fibers in relation to parasystole. Circ Res 1976;39: 801-808. ~aK.JsllhJ,~WJ,UooB.Amathematicalmodelofparasystole and its applkatkn to clinical arrhythmtas. Circulation 1977;56:968-979. JoSo J, Mea GK. A biologic model of parasystote. Am J Cardiol 1979; 43761-772. Antzatavttch C, Jaltfo J, Mea OK. Ekctrotonk modutaticn of tracemaker acttvtty. Ftather biological and matharnstkal observatkns on tha behavior of modulated parasystole. Circulatkn 198266: 1225 1232. J&la J. Antzebvttch C. Mea GK. The case for modulated oorasvstok. PACE . 1982;5:911-926. Rowethat JE, Fanfar OR. Contribution of varkble entrance and exit block in protected fo$ to arrhythmogenesis in isotated ventricular tissues. Circulation l903;67:1-6. J&fe~ J, AntzaIavKch C. Pacem&er amihilatkmz dkgtcetk and Mapeutk implications. Am Heart J 1980;100:128-130. GWmeur RF Jr, Ztpea DP. Cellular basis for cardiac arrhythmias. Cardkl
21. 22. 23.
24. 26.
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Clin 1963;1:3-11. Furuaa A, Shkdo G, Makuuchl H, Sa@aa Y, Matark H, Takayanagi K, houa H. Apparent suppression of ventrtcular perasystok by cerdlac pacing. Jpn Haart J 1979;20643-851. Furuaa A, Yatuao H, Sal~usa M. Effects of intervening beats on ectopic cycle length in a patient with ventricutar parasystole. Jpn Heart J 1981; 22:201-209. Nau GJ, Atdarlz AE, Acuruo RS. Etfzarl MV, Roaanbaum MS. Clinical studies on the mechanism of ventricular arrhythmias. In: Rosenbaum MB, Elk& MV, eds. Frontiers of Cardiac Etectrcphysiokgy. Boston: Martinus Nijtwff, 1963;239-273. Qndar PH, Moare-Ede MC. Li t-d& masking of circadian temperature m&advlty rhylhms in squirre k monkeys. Am J Physkl 1983;245:927-
Waat TC. Effects of chronotropk influences on s&thresMd oscillations in the sko-atrtal node. In: Paes De &valho A. GeMall WC, Hoffman SF, eds. The Specialized Tissues of the Heart. New York Elsevkr, 1961; 81-94. 26. vaadlaYcerdiac er pdentlals at different extra- and intr@lul~ K concentrations. kl 1965;208:770-775. 27. Cranaflekt PF. The Cmctuctkn of the Cardiac Impulse. New York Futura. 1975;239-243.
Few studles have dealt with the effects of Isoproterenol on ventricular parasystole. Intravenous lsoproterenol(2 to 4 pg/mln) was admlnlstered to 11 nonmedlcated patlents with ventricular parasystole. At the onset of the drip Infusion, 8 patlents had continuous parasystole, 2 had lntermlttent parasystole, and 1 patlent (In whom lntermlttent parasystole was documented 2 to 5 days earlier) showed no manifest parasystollc actlvlty. In all patients, whose control parasystollc cycle length varled between B80 and 2,530 ms, lsoproterenol caused a decrease of the parasystollc cycle lengths ranging from 12 to 38%. Therefore, lsoproterenol produced a consistent Increase of the parasystollc rate. In 4 patlents, parasystolic activity ceased to be manifest when the concomitantly enhanced (by lsoproterenol) sinus cycle lengths became shorter than 430 ms. This phenomenon reflected a tachy
cardla-dependent parasystollc concealment, presumably as a result of Interference In the parasystollc-ventricular junctlon. In every case, the arrhythmia reappeared at its Initial rate upon stopping the drip Infusion. In no patlent did parasystollc ventricular tachycardla develop. In the patlent without manlfest parasystollc beats, lsoproterenol unmasked the intermittent parasystole that prevlously had been lntrfnslcally manlfest. The latter effect reflected a true exposure, or unmasklng of a latent, rate-independent concealed, parasystollc focus. The flndlngs In this study may explain some of the dlfflcultles and puzzling flndlngs encountered when attempting to dlagnose ventricular parasystde from 24-hour Halter recordings, because ectoplc and sinus cycle lengths can be affected by spontaneously occurring variations In sympathetic dlscharge. (Am J Cardlol 1985;55:1344-1349)
Although much has been written about the various electrocardiographic manifestations of parasystole, less is known about the responses of this arrhythmia to drugs.l12Herein we discussthe effects of isoproterenol on certain types of ventricular parasystole.
Dia@ro~tic criteria: Parasystole wasidentified during the scanning of Holter tapes from 10 ambulatory patients and while obtaining long rhythm strips from a patient in the coronary care unit. The diagnosis of ventricular parasyatole was baaed on criteria previously described.‘4 In all patients, before isoproterenol administration, the ectopic cycle lengths could be measured directly, that is, without any interposed nonparasystolic (einus or extrasystolic) beat, as well 89 with a single interposed nonparasystolic beat.3*4 “Absolute” protection was considered to have been present when single, nonparasyetolic beata that fell in different moments of the cycle did not change the ectopic cycle length.* This finding excluded classic modulated parasystole ~IJwell as parasystole with protection limited to the initial half of the cycle (hereafter called paraaystole with phase 3 protection).3-7 Only 2 types of parasystolee were diagnosed: Contintrous parasystole (8 patients) wascharacterized by interectopic intervals, which were a multiple of ectopic cycle lengths and did not vary by more than 596;marked variations in the coupling intervals; and persistent manifest activity throughout the recording time.epg Intermittent parasystole (3 patients) was characterized by groups of parasystolic beats during which the interectopic intervals were a multiple of the ectopic cycle lengths and the
Methods Clinical information: Eleven nonmedicated patients were studied. No organic heart disease was detected in 5 patients; 3 patients had sick sinus syndrome and 3 had primary conduction system disease. The patients were 21 to 61 years old. Nine were men and 2 were women. The blood pressures were normal in all patients From the Dlvlsion of Cardiology, Dqrtment of Medicine, University ofMiamiSchaolofMediche,Miami,Florlda,andtheUlhrersldedCentral de Venezuela, Caracas, Venezuela. This study was supported In part by Grant 28130 from the Netional Institute of tkalth, Betfmsda, Maryland. Manuscript recehd November 30, 1984; revlsed manuscript received February 4, 1985, accepted February 5,1985. Ad&em far rqrhts: Agustin Castellanos, fXI, Dlviskm of Cmlkkqy (MS), University of Miami School of Medicine, P.O. Box 018980, Mhnl, Florkh 33101. 1344
May
TABLE I
1.1985
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Effects ot lsoproterenol on Ventricular Paraeyetole Maximal IS0 1 ECL (ms)
Maximal IS0 1 ECL(%)
Manifest
1,110
23
Manifest
1,400 1,000 960 1,220 1,120 2,530 1,340
Manifest Manifest Manifest Manifest Manifest
950 740 a45 940 920 1,110 1,620
26 32 :s ;:
Concealed Manifest Manifest Manfiest Concealed Concealed
1,400 1.250 -
Manifest Concealed Manifest
1,210 1,000 -
:: 20
Manifest Manifest Manifest
Type of Parasystole
Control ECL (ms)
1
Continuous
1,440
f
Continuous Continuous Continuous Continuous Continuous Continuous Intermittent Intermittent
Case
i 6 ; 9 :: ECL = ectopic
cycle
length;
IS0 = isoproterenol;
Control PA
PA During Maximal IS0
PA = parasystole.
coupling intervals had marked variations,gJ1 and intervals between the last parasystolic beat of 1 group and the first parasystolic beat of the group that immediately followed, which were not multiples of the ectopic cycle lengths.g-ll Administration of isoproterenol: A drip infusion (2 to 4 pg/min) was given while the patients were continuously monitored using conventional oscilloscopic and electrocardiographic equipment.le In 5 of 10 patients, this was done while Holter recordings were obtained with the same electrode placement as that of the recordings where the arrhythmia was diagnosed.
Results Absence of adverse reactions: No patient developed ventricular tachycardia, sustained or nonsustained. In 1 patient with sick sinus (tachycardiabradycardia) syndrome the drug apparently exposed the patient’s clinical paroxysmal atria1 fibrillation which converted to sinus rhythm, spontaneously, 9 minutes after stopping the drip infusion. One patient complained of palpitations when the sinus rate increased to 1Wmin. This symptom disappeared promptly when isoproterenol was stopped. Effects of isoproterenol on parasystolic rates: The control, directly measured ectopic cycle lengths varied between 2530 and 960 ms (corresponding to rates of 24 to 62/min) (Table I). In 10 patients (8 with continuous and 2 with intermittent parasystole), isoproterenol administration increased the parasystolic rates, since the ectopic cycle lengths decreased by 12 to 36%. An example is shown in Figure 1, where the control ectopic cycle lengths were shortened from 1,440 ms to 1,100 ms (by 23%) during the maximal effects of isoproterenol. The sinus rates also showed variable degree8 of increases, presumably because the differences in clinical settings and in background autonomic tone made the sinus node to respond unequally to isoproterenol. In patients without fast sinus rates, the ectopic cycle lengths could still be measured directly, or with only 1 interposed nonparasystolic beat after the drug was given. However, this was possible mainly during the initial stages of isoproterenol administration, when marked sinus tachycardia did not occur. When sinus tachycardia was induced, it was more likely for manifest parasystolic beats to be followed by parasystolic discharges, which fell during the refractory period of nonparasystolic beats. But even under these circum-
stances, long strips revealed parts during which there was an ectopic cycle length with only a single interposed nonparasystolic beat (Fig. 2). Parasystolic concealment: In 4 patients the sinus rate8 increased so much that they resulted in total parasystolic concealment. Figure 2A shows the ectopic cycle length (1,400 ms) measured directly 15 minutes before isoproterenol. A few minutes after starting the drip infusion (second strip), the ectopic cycle length had a similar duration (1360 ms) despite the presence of an interpolated nonparasystolic beat and an increase in sinus rate. In the third strip, recorded later, the ectopic cycle length had decreased by 32% (to 950 ms). In the fourth strip manifest parasystolic beats were no longer apparent. This was attributed to the fact that the sinus cycle length had become short enough to prevent parasystolic discharges from activating the ventricles. Yet, parasystolic beats reappeared (that is, they again be-
ECL CONTROL
1440 MS
ISOPROTERENOL
3300 MS
1100MS
FKWRE 1. Case 1. lsoproterenol-induced increase in rate of continuous parasystole. The ectopic cycle length (ECL) decreased by 23 % , from 1,440 to 1,100 ms. The top strip shows that despite the marked varlations in coupling intervals, the ectopic cycle lengths had a constant value. Modulation was excluded because nonparasystollc beats that fell in different moments of the cycle failed to affect the ECL. The end of the mlddle strfp (noncontinuous with the top strip) shows the directly-measured ECL. In the bottom strip, 4 parasystolic discharges were unable to produce the QRS complex because they fell during the ventricular effective refractory period.
1348
EFFECTS
OF ISOPROTERENOL
CONTROL
ECL :
1I I i
came manifest) when the drip infusion was stopped, since the sinus cycle lengths became progressively longer during their return toward their control values (bottom strip). In 2 of the 4 patients, parasystolic concealment occurred when the sinus cycle lengths became shorter than the shortest (“coupling”) interval (time elapsing between a nonparasystolic beat and an immediately after manifest parasystolic beat) occurring in these patients. Exposure of concealed parasystole: In 1 patient, ventricular parasystole with an ectopic cycle length of 1,300 ms had been documented 3 to 5 days before the day of the study (Fig. 3). However, this patient had not shown evidence of manifest ectopic activity during continuous monitoring for at least 24 hours. In the recording shown in Figure 4, obtained immediately before isoproterenol administration, parasystolic beats were not seen. The sinus cycle lengths ranged from 810 to 360 ms (rates of 74 to 70/min). The tracing in Figure 5, recorded at a slower paper speed at the beginning of the drip infusion, shows intermittent ventricular parasystole occurring when isoproterenol had shortened the sinus cycle length to 620 ms. The interval between 2 consecutive parasystolic beats, which did not change while nonparasystolic beats fell in slightly different moments of the cycle, was considered to represent the ectopic cycle length (decreased, by isoproterenol, from 1,300 ms in Figure 3 to 1,230 to 1,250 ms). In addition, the interval between the last ectopic beat in the first parasystolic series and the first beat in the subsequent series was not a multiple of the assumed ectopic cycle length. The tracing in Figure 6 was recorded after the drip infusion was stopped because of the appearance of clinical atrial fibrillation. Discontinuation of isoproterenol was believed to have resulted in an increase in the ectopic cycle length to 1,325 to 1,370 ms (rates of 44 to 45/min). As in Figure 5, the interval between the last ectopic beat in the first series (top panel) and the first ectopic beat in the next series (bottom panel) was not a multiple of the ectopic cycle length. Furthermore, in each series, the parasystolic rate was unchanged, although 1 or more nonparasystolic beats were interposed within 2 consecutive parasystolic beats. The latter did not fulfill previous electrocardiographic criteria established for the diagnosis of modulation.isp4 The tracing, in Figure 7, recorded a few minutes later, while atrial fibrillation persisted, but with slower ventricular rates, shows (as in Fig. 4) no manifest parasystolic beats. This happened despite the presence of nonparasystolic RR intervals, which were longer than those that previously (Fig. 6) had allowed the parasystole to be manifest.
1400 MS
ISOPROTERENOL 1360 MS
950 MS
CONCEALED AFTERISOPROTERENOL 1400 MS
FtGURE 2. Case 2. Concealment of continuous ventricuiar parasystoie produced by a decrease in the nonparasystolic (sinus) ectopic cycle length (ECL) (increase in rate). Variations in ectopic QRS complexes occurred because the patient changed. position while the recordings were performed.
FIGURE 3. Case 11. Ventricular parasystoie isoproterenoi infusion. The directly rneasued 1,300 ms. Strips are not continuous.
recorded 3 days before ectopic cycle length was
CONTROL (Continuous tracings) “““‘~‘~~~~~‘~~~,‘~~‘~~~~~~~~“~“~~~~~~~~’~~’~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~,,~,~~,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,~,,,,,,,,,,,, 1111,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,I ,,,,,,,,,,, m ,,,,,,,,
Id II
-
-
n
n
h
-
n
I\
-
c
L
-
h
- -
-
FIGURE 4. Case 11. Absence of manifest parasystoiic activity in a patient whose tracings obtained 3 to 5 days earlier had shown intermittent ventricuiar parasystoie (Fig. 3). Sinus rhythm was present before isoproterenoi infusion.
May 1, IS85
..,..,-,.....,-...._.
F
--mm-
THE AMERICAN
XWRNAL
DF CARDIOLCGY
Volume 55
1347
F -----s
-_.--
u-.-
.
. . . . . ...” I,..,
..~ ..,,,.,.
,
~
,,
1~ IIJ Y
A
‘.
1
m
1-a
a
f
1
A
aI’
a
1
*w-’
T-
11230 UI 1230 MS11250 MS1
6550
I 1310 x 5 7 1
II230 YSIl230 I651 1230 MI11230 MS1
FIGURE 5. Case 11. Ventricular parasystole appearing at a cycle length of 1,230 to 1,250 ms during the maximal rhythm was still present. The interval between the last parasystolic beat in the first series and the first parasystolic a muttiple of the ectopic cycle length that the parasystole had at that moment. F = fusion beat.
Discussion Effects of isoproterenol on parasystolic rate: The increase in parasystolic rate was evident when (and while) the ectopic cycle lengths were measured without any, or with only one, interposed nonparasystolic beat. Because the latter fell in different moments of the ectopic cycle, modulated parasystole3t4J3-22 and parasystole with phase 3 protection could be excluded.5-8 On the other hand, when the sinus (nonparasystolic) rates increased to such a degree that more than 2 nonparasystolic beats fell in between consecutive manifest parasystolic discharges, determination of the ectopic cycle length was less precise. Yet, the degree of inexactitude was still within the limits used to make the diagnosis of parasystole in clinical electrocardiography.lkV-11
Although isoproterenol accelerated the parasystolic rate in all patients, ventricular tachycardia did not occur with the therapeutic doses used. This finding is in keeping with the well known pharmacologic effects of isoproterenol (with the doses used) on automaticity.i2z3 That the automatic rhythms also showed protection supports previous assumptions considering parasystole to be the result of protected automatic activity arising from spontaneous depolarizations in the range of -90 to -70 mV or -60 to -40 mV.’ Oscillatory prepotentials of increasing amplitude may also be implicated, as will be discussed subsequently. In addition to the parasystolic rates being increased by isoproterenol, Nau et a123 found that they were decreased by local anesthetics. They thus considered parasystole to be a result of protected automatic activity arising from high levels of membrane potential.23
CONTINUOUS
TRACINGS
effects of isoproterenol. beat in the next series
Sinus was not
Parasystolic concealment: The absence of manifest parasystolic beats occurring after the sinus rates increased above a given value can be attributed to an isoproterenol-induced improvement of conduction through the zone of protection (region of depressed excitability) surrounding the parasystolic pacemaker. If conduction through this zone improved so much as to result in total abolishment of protection, all incoming nonparasystolic impulses could have reached, thus overdrive suppressing, the automatic pacemaker. Such an assumption implies that isoproterenol in effect caused transient disappearance of parasystolic activity. However, certain findings support another interpretation. For example, in the patients with continuous parasystale, the interval between the last parasystolic beat, before a short period of concealment and the first manifest beat appearing after concealment was a multiple of the ectopic cycle length. Moreover, as previously stated by Nau et al,23 the disappearance of manifest ectopic beats apparently occurred when the progressively decreasing sinus cycle lengths became shorter than the shortest “coupling” interval at which a parasystolic beat could be manifested. Therefore, most likely, the phenomenon was a tachycardia-dependent parasystolic concealment resulting from the impedance to the emergence of parasystolic impulses, that is, from the “interference” created by the fast nonparasystolic impulses, in the ventricular-parasystolic junction. Mechanisms of intermittent ventricular parasystole: Neither exit block of a continuously discharging parasystole nor the late-in-the-cycle loss of protection characteristic of the so-called parasystole with phase 3 protection explained the periods of intermittency that occurred in cases 9,10 and ll.lp5-s Cases 9,10 and 11 had features similar to those of the type of parasystole which Scherf et al’s attributed to “a periodic awakening and vanishing of an active ventricular centre,” presumably due to spontaneous variations CONTINUOUS TRACINGS
11325 MS1 1370 MS11370 F F
MS~1325
ms~1325 F
hEI------
Ifi
TI
1370
1 1370
1
1370
1
1370
]
I390
1 1370
)
1370
1
FIGURE 6. Case 11. Ventricular parasystole occurring after stopping isoproterenol treatment because of the appearance of atrial fibrillate. The interval between the last parasystolic beat in the first series (top) and the first parasystolic beat in the next series (bottom) was not a multiple of the ectoptc cycle length that the parasystole had at that moment. The panels show continuous recordings.
FIGURE
7. Case
11. Disappearance
(possibly
reconcealrnent) of intreatmmt (while atrtal fibrillation was still present). This occurred despite the presence of nonparasystolic RR intervals, which were longer than those that previously (Ftg. 4 and 5) had allowed ths parasystolic beats to become manifest.
termittent pmsystde afterstopplnaIsoproerenol
f348
EFFECTS
OF ISOPROTERENOL
of automatic activity. ~JOJ~ In fact, experiments made with microelectrode techniques show how, in some preparations, automatic activity is preceded by oscillations of increasing amplitude.2s27 Cranefield observed trains (groups) of automatic impulses during which the last impulse of a train was followed by subthreshold oscillations of decreasing amplitude, which gave way to oscillations of increasing amplitude.27 When one of the latter reached threshold, it initiated another train of automatic impulses. 27 The intervals during which the subthreshold oscillations occurred varied in duration.27 Extrapolation of these findings to the surface electrocardiogram explains why the intervals between the last manifest parasystolic beat of 1 group and the first beat of the group immediately following were not multiples of the ectopic cycle length (Fig. 5 and 6). Exposure of concealed parasystole: Occurrence of a marked prolongation of 1 of these intervals, during which the “latent” pacemaker had subthreshold oscillations or was quiescent may explain the long period (more than 24 hours) without manifest parasystolic beats, seen in case 11. Isoproterenol could have exposed the arrhythmia if, by acting on the “latent” pacemaker, it increased the amplitude of subthreshold of oscillations so as to produce trains (groups) of manifest automatic impulses arising from levels of membrane potential in the range of either -90 to -70 mV or -60 to -40 mV.27 Isoproterenol also exposed the zone of depressed excitability (or of entrance block) where protection occurred, thus confirming that isoproterenol had a greater enhancing effect on automaticity than on conduction. We did not prove parasystolic modulation applying previously published electrocardiographic criteria.3T4 Yet if, as postulated by several investigators, all parasystoles are indeed subjected to some degree of electrotonic modulation, then the latter may have been present, but “masked,” in all patients.13-16 Masking, a term used in regulatory integrative comparative physiology, may be extrapolated to clinical electrocardiography to indicate that electrotonically induced variations in ectopic cycle lengths occurred, but were of a lesser magnitude than those attributed to spontaneous fluctuations in automatic activity.24 Furthermore, overt parasystolic modulation may have been present. The intermittent parasystole seen in Figure 6 could theoretically be explained by assuming (at that moment) an ectopic cycle length of 1,500 ms and a biphasic phase response curve with a maximum delay of around 100 ms and a maximum acceleration of around 200 ms. Moreover, it can also be postulated that the long periods of “silence” (Fig. 5 and 6) may have resulted from the development of stable 2:l entrainment and concealment of all ectopic discharges. This is in fact predicted whenever appropriate changes in frequency relations between the parasystolic and sinus pacemakers convert a complex entrainment ratio to a rigidly constant harmonic ratio.14 In the latter case every pacemaker discharge could be forced to occur during the ventricular refractory period, in which case would never become manifest unless, of course, there
is another drastic change in frequency relations. As demonstrated by the biologic model of modulation,16 such periods of silence can cover wide ranges of frequency ratios. Clinical implications: Our findings may explain some of the difficulties and otherwise puzzling findings encountered when attempting to diagnose ventricular parasystole from 24-hour Holter recordings. For example, the association of longer ectopic cycle lengths with slower sinus rates and of shorter ectopic cycle lengths with faster sinus rates could be the result of concordant effects (enhanced automaticity) exerted by spontaneously occurring variations in sympathetic discharge. Unfortunately, these findings can be construed to indicate that parasystole is not present because such “spontaneous” variations of ectopic cycle length preclude this diagnosis. In fact, what may be occurring in these situations is that the parasystolic rate changes with coexisting fluctuations of intrinsic sympathetic activity. Furthermore, transient, otherwise unexplained disappearance (or “pseudointermittency”) of a continuous parasystole during episodes of sinus tachycardia may reflect the tachycardia-dependent inability of a continuously discharging parasystole from activating the ventricular myocardium. Finally, although the mechanisms of true parasystolic intermittency in cases 9,10 and 11 is unclear, the exposure of a (during normal sinus rhythm) concealed parasystole (case 11) probably reflected a drug-related enhancement of automaticity of a “latent” protected (parasystolic) automatic pacemaker. Again, if this were to occur spontaneously because of a sudden surge of sympathetic activity, the clinical manifestation would be the abrupt appearance of an intermittent parasystolic rhythm (by the definition of Scherf et aP). Nevertheless, attractive as these hypotheses are, they require future prospective studies (including the induction of non-cathecolamine-related changes in sinus or paced atrial cycle lengths) to corroborate them. References 1. Castellanos
A, Molelro F, Keyden D, Myerburg RJ. Evolvln~n~~ ths elecbocardiogaphic diils of ventricular parasystde. : ME, Wellens IUJ, eds. Tachycardias: Mechanism, Diagkxls and Treatment. Philadelphia: Lee B Febiger, 1984;287-306. 2. Kayden D. Lucerl FM. Zaman L. Molelro F. Mverbura RJ. Castellanos A. Me&anisins and lmpiications df ventricul& Ijarasysiole~in inferior myocardial infarction (abstr). PACE 1983;6:323. 3. Castellanos A. Lucerl RY. Molelro F, Kayden DS. Trohman RD. Zaman L, Myerburg dJ. Annihilation, entraiketit and modulation of ventricular stolic rhythms. Am J Cardiol 1984;54:317-322. 4. lizxl , Aldarlz AE, Acunzo RS. Halpem MS, Davldenkl JM, Ellzarl MV, Roserhum MB. Modulation of perasystollc activity by nonparfisystolic beak Circulation 1982;66:482-469. 5. Cehen H, w R, Pkk A. lntermlttent perasy-stole-mechanism of ection. Circulation 1973;48:761-774. Ick A. The electrophysiologic basis of paraeystole and its variants. In: 8. r Wellens HJJ, Lie KI, Janse MJ. eds. The Conduction System of the Heart. Structure, Function and Clinical Implications. Leiden: HE Stenfert Kroese BV. +976;143-162. 7. Ceetellenae A, +atrkle VY, Bun9 RJ, Bhe~s DS, Myerburg RJ. A search Lg modulation In intermittent ventricular parasystole. PACE 1980;3:730. Castellanos
M arbu
A, Casllllo CA, Medlna-Ravel1
V, Molelro
F, Betlcovlls
BV,
RJ. Electronic pacemaker models of parasystole. PACE 1982; 5:!37-36. 0. Bched D, Bchett A. Extrasystoies and Allied Anhylhrnlas. New York: @une 8 stratton. 1953; 297-301. D. Boyd LJ. Three unusuel cases of peraeystole. Am Heart J 10. Bcherf 1950339:650-663. 4. S&h D, Scholl A, Reld EC, Chamsal Do. Intermittent parasystole. Cer-
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13. 14. 15. 16. 17. 18. 19. 20.
da
1957;30:217-228. z-GrmzaIas A. Sympathomimatic treatment. In: Gayer? A, Cosln J, eds. Dkgtcsk and Treatment of cardiac &&ythmii. New Yak: persrrmOn F’ress, 1980:967-973. Jaltfe J, Mea GK. Effect of electrotonic potent&Is on pacemaker activity of canine Pwkinje fibers in relation to parasystole. Circ Res 1976;39: 801-808. ~aK.JsllhJ,~WJ,UooB.Amathematicalmodelofparasystole and its applkatkn to clinical arrhythmtas. Circulation 1977;56:968-979. JoSo J, Mea GK. A biologic model of parasystote. Am J Cardiol 1979; 43761-772. Antzatavttch C, Jaltfo J, Mea OK. Ekctrotonk modutaticn of tracemaker acttvtty. Ftather biological and matharnstkal observatkns on tha behavior of modulated parasystole. Circulatkn 198266: 1225 1232. J&la J. Antzebvttch C. Mea GK. The case for modulated oorasvstok. PACE . 1982;5:911-926. Rowethat JE, Fanfar OR. Contribution of varkble entrance and exit block in protected fo$ to arrhythmogenesis in isotated ventricular tissues. Circulation l903;67:1-6. J&fe~ J, AntzaIavKch C. Pacem&er amihilatkmz dkgtcetk and Mapeutk implications. Am Heart J 1980;100:128-130. GWmeur RF Jr, Ztpea DP. Cellular basis for cardiac arrhythmias. Cardkl
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Clin 1963;1:3-11. Furuaa A, Shkdo G, Makuuchl H, Sa@aa Y, Matark H, Takayanagi K, houa H. Apparent suppression of ventrtcular perasystok by cerdlac pacing. Jpn Haart J 1979;20643-851. Furuaa A, Yatuao H, Sal~usa M. Effects of intervening beats on ectopic cycle length in a patient with ventricutar parasystole. Jpn Heart J 1981; 22:201-209. Nau GJ, Atdarlz AE, Acuruo RS. Etfzarl MV, Roaanbaum MS. Clinical studies on the mechanism of ventricular arrhythmias. In: Rosenbaum MB, Elk& MV, eds. Frontiers of Cardiac Etectrcphysiokgy. Boston: Martinus Nijtwff, 1963;239-273. Qndar PH, Moare-Ede MC. Li t-d& masking of circadian temperature m&advlty rhylhms in squirre k monkeys. Am J Physkl 1983;245:927-
Waat TC. Effects of chronotropk influences on s&thresMd oscillations in the sko-atrtal node. In: Paes De &valho A. GeMall WC, Hoffman SF, eds. The Specialized Tissues of the Heart. New York Elsevkr, 1961; 81-94. 26. vaadlaYcerdiac er pdentlals at different extra- and intr@lul~ K concentrations. kl 1965;208:770-775. 27. Cranaflekt PF. The Cmctuctkn of the Cardiac Impulse. New York Futura. 1975;239-243.