Vol. 280, Issue 3, H1368-H1375, March 2001
Coupling interval from slow to tachycardiac pacing decides
sustained alternans pattern
Shunsuke
Suzuki1,2,
Junichi
Araki1,
Yumiko
Doi1,2,
Waso
Fujinaka1,2,
Hitoshi
Minami1,
Gentaro
Iribe1,
Satoshi
Mohri1,
Juichiro
Shimizu1,
Masahisa
Hirakawa2, and
Hiroyuki
Suga1,3
1 Department of Physiology II and 2 Department of
Anesthesiology and Resuscitology, Okayama University Medical
School, Okayama 700-8558; and 3 National Cardiovascular
Center Research Institute, Suita, Osaka 565-8565, Japan
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ABSTRACT |
We discovered that the coupling beat interval
from a slow to a tachycardiac pacing period considerably affected the
pattern of the beat-to-beat alternation of the tachycardia-induced
sustained contractile alternans. We analyzed the relationship between
the coupling interval and the pattern and amplitude of the alternans in
the isovolumic left ventricle of canine blood-perfused hearts. The
alternans pattern and amplitude varied transiently over the first
30-50 beats and became gradually stable over the first minute in
all 12 hearts. We discovered that stable alternans, even under the same
tachycardiac pacing, had three different strong-weak beat patterns
depending on the coupling interval. A relatively short coupling
interval produced a representative sustained alternans of the strong
and weak beats. A relatively long coupling interval produced a similar
sustained alternans but in a reversed order of even- and odd-numbered
beats counted from the coupling interval. However, sustained alternans
disappeared after 1-3 specific coupling intervals. We conclude
that ventricular pacing rate does not solely determine the pattern and
amplitude of sustained contractile alternans induced by tachycardia.
myocardium; contractility; calcium handling; arrhythmias
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INTRODUCTION |
MECHANICAL ALTERNANS OF
THE HEART, either transient or sustained, consists of alternating
strong and weak beats despite a regular beating rate. This phenomenon
has interested investigators since it was first described in 1872 by
Traube (33). The two mechanisms accounting for the
phenomenon are alternations of end-diastolic volume (11, 15,
21) and cardiac contractility (5, 15, 19, 20). The
former seems secondary to the latter (15, 19, 20).
Cellular mechanisms, such as alternations of the action potential
duration and intracellular Ca2+ handling via the
sarcoplasmic reticulum, seem to cause the contractile alternans
(15).
Various myocardial conditions are known to affect the pattern and
amplitude of the mechanical alternans. Cardiac anoxia, ischemia (27, 34), tachycardia (4), and hypothermia
(16) cause or intensify sustained mechanical alternans.
Administration of epinephrine (4), caffeine (12, 13,
25), and ryanodine (13) diminish or eliminate the
alternans. On the other hand, the same alternans pattern reappeared
even after a premature or delayed beat interrupting the sustained
alternans (17, 29). These results have yielded a general
view that the pattern and amplitude of sustained mechanical alternans
would change with cardiac contractile conditions at the same beating rate.
However, we accidentally observed that the interbeat alternation
pattern and amplitude of the sustained contractile alternans induced by
tachycardiac pacing varied considerably with a single coupling beat
interval between the same slow and tachycardiac pacing periods.
Intriguingly, sustained contractile alternans even disappeared after a
specific coupling interval. No literature has documented these observations.
Therefore, we investigated the relationship between the coupling
interval and the interbeat alternation pattern and amplitude of
sustained contractile alternans in the excised, cross-circulated canine
heart. We produced sustained contractile alternans by an abrupt
increase in regular pacing rate in normal canine hearts. Our results
showed that 1) the alternans pattern and amplitude changed
markedly with the coupling interval in all of the hearts, 2)
the alternans disappeared at 1-3 specific coupling intervals in
each heart, and 3) the even- and odd-numbered order of
strong and weak beats counted from the coupling interval reversed
across these specific coupling intervals. These findings indicate that a more severe sustained contractile alternans under a given
tachycardiac pacing is not always indicative of a worse cardiac
contractile condition.
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METHODS |
Surgical preparation.
We performed the present experiments in the canine excised,
cross-circulated (blood perfused) heart preparation that we have been
using consistently in our laboratory (3, 14, 18, 24, 28,
31). We conducted them in conformity with the "Guiding Principles for Research Involving Animals and Human Beings," endorsed by the American Physiological Society. The surgical procedures were
described in detail elsewhere (14, 18, 24). Briefly, two
mongrel dogs (9-23 kg body wt) were anesthetized with
pentobarbital sodium (25 mg/kg iv) after premedication with ketamine
hydrochloride (20 mg/kg im). Anesthesia was maintained by fentanyl
(200-250 µg/h iv). The dogs were intubated and artificially
ventilated and were then heparinized (10,000 units iv per dog).
We used the larger dog (18 ± 3 kg body wt; means ± SD) as
the metabolic supporter. Its common carotid arteries and right external jugular vein were cannulated and connected to the arterial and venous
cross-circulation tubes, respectively. The chest of the smaller dog
(12 ± 2 kg body wt) was opened midsternally, and the heart was
used as a donor. The arterial and venous cross-circulation tubes were
cannulated into the left subclavian artery and the right ventricle
through the right atrial appendage, respectively, of the donor dog.
In each of the 12 experiments, the heart-lung section was isolated from
the systemic and pulmonary circulation by ligating the azygos vein,
descending aorta, inferior vena cava, brachiocephalic artery, superior
vena cava, and bilateral pulmonary hili. The beating heart,
supported by cross circulation, was then excised from the chest.
Coronary perfusion of the excised heart was never interrupted during
the preparation. We gave indomethacin (5-20 mg iv; donated by
Banyu Pharmaceutical; Tokyo, Japan) to the support dog to prevent
systemic hypotension occasionally elicited by blood cross circulation
(18, 24).
The left atrium was opened, and all of the left ventricular (LV)
chordae tendineae were cut. Complete atrioventricular block was made by
electrical ablation or by injecting 40% formaldehyde through the right
atrium into the region of the His bundle (30). Electrical
pacing was performed with a bipolar electrode placed on the upper
interventricular septum. A thin latex balloon (unstressed volume, ~50
ml) mounted on a rigid connector was fitted into the LV, and the
connector was secured at the mitral annulus. LV pressure was measured
with a miniature pressure gauge (model P-7, Konigsberg Instruments;
Pasadena, CA) inside the apical end of the balloon and processed with a
direct current strain amplifier. The balloon, primed with water without
air bubbles, was connected to our custom-made volume servo pump
(AR-Brown; Tokyo, Japan). LV volume was accurately controlled and
precisely measured with the servo pump. LV epicardial electrocardiogram
(ECG) was recorded with a pair of screw-in electrodes to trigger data
acquisition and identify the onset of contraction.
We monitored and maintained cardiac temperature in an acrylic box by
warming the coiled portion of the arterial cross-circulation tube in a
thermostat bath. In our preliminary experiment, we needed a
tachycardiac pacing rate of 250-300 beats/min to produce sustained contractile alternans at 36-37°C. This suggests that the heart we prepared was reasonably physiological (34). This
condition, however, rapidly deteriorated the contractility of the
heart, probably because the tachycardia-induced increase in oxygen
demand exhausted the coronary reserve (31). Therefore, we
kept cardiac temperature slightly hypothermic (34.2 ± 1.0°C) to
produce stable sustained contractile alternans at a pacing rate under
250 beats/min in the present study.
Mean systemic arterial blood pressure of the support dog (118 ± 16 mmHg) served as coronary perfusion pressure. It was maintained stable in each experiment by slowly transfusing whole blood reserved from the heart donor dog or by infusing 6% hydroxyethyl starch solution and by continuously infusing methoxamine (5-30 mg/h) as
needed. We measured repeatedly arterial pH (7.42 ± 0.07),
PO2 (131 ± 32 mmHg), and
PCO2 (31 ± 8 mmHg) of the support dog and normalized them with supplemental oxygen and intravenous
NaHCO3 as needed.
Pacing stimuli.
We programmed the pacing stimuli with the use of LabView, version 3.1 (National Instruments), on a Power Mac computer, which controlled a
stimulator with an analog-to-digital converter (Lab-NB, National Instruments).
Figure 1 shows two representative set of
pacing stimuli in one heart. We provided a priming period of regular
slow pacing stimuli at intervals of 500 ms (
120 beats/min) in 9 hearts and 450 ms (133 beats/min) in the other 3 hearts. We then
provided a tachycardiac period of regular pacing stimuli at shorter
intervals of 283 ± 24 ms (213 ± 18 beats/min) to
generate sustained contractile alternans. We provided a variable
coupling interval between the slow priming and tachycardiac periods as
a sole independent variable. We performed similar runs only by changing
the coupling interval in steps of 20-50 ms from 200 to 600 ms in
each heart.
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Fig. 1.
Sustained contractile alternans under the same tachycardiac pacing
after two different coupling intervals (CI) after the priming beats at
the same slow pacing rate. Top, pacing stimuli;
middle, electrocardiagram (ECG); and bottom, left
ventricular pressure (LVP). A and B: intervals of
the slow (L) and the tachycardiac (H) stimuli fixed at 500 and 300 ms,
respectively. CI was 400 (A) and 600 (B)
ms. o and e, odd- and even-numbered beats,
respectively, counted after CI.
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Experimental protocol.
We used isovolumic LV contractions throughout this study. Our
preliminary experiment showed that the LV with a large isovolumic volume could not maintain stable sustained contractile alternans. We
eliminated this problem by keeping LV isovolumic volume at a midrange
volume of 12.3 ± 2.4 ml (89 ± 18 g wt), where LV peak isovolumic pressure was <100 mmHg.
We continuously monitored LV pressure through the slow and tachycardiac
pacing periods and recorded it during the last several slow beats, and
both the transient and stable sustained contractile alternans beats for
1-1.5 min. We then returned to the priming period with slow pacing
until LV contractility became stable. Each experiment was completed
within a few hours while the condition of the preparation was stable.
In three experiments, we repeated the entire protocol to check the
reproducibility of the results.
Monophasic action potential.
Monophasic action potential (AP) was recorded simultaneously with a
contact electrode catheter (7) (Langendorff probe, Boston
Scientific) on the anterolateral LV surface near its obtuse margin in
three hearts. We measured the duration of the monophasic AP duration at
the 90% repolarization (APD90) from the onset of the steep
upstroke to the 90% repolarization level. Here, 100% was defined as
the height of the monophasic AP from its diastolic baseline to the
crest of its plateau (10). We measured APD90 in six consecutive beats during stable sustained contractile alternans. The six APD90 values were averaged for three strong and
three weak beats separately.
Data analyses.
LV pressure, volume, ECG, and APD signals were digitized at 2- or 4-ms
intervals with an analog-to-digital converter (Lab-NB, National
Instruments), displayed, and stored on the hard drive of a computer.
Statistics.
Data were presented as means ± SD. Comparisons of the parameters
between the strong and weak beats were made by Student's paired
t-test. A value of P < 0.05 was considered significant.
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RESULTS |
Sustained alternans.
Figure 1 shows simultaneous tracings of LV pacing stimuli, ECG, and
isovolumic pressure in two representative runs in one heart. These two
runs had the same set of the slow pacing interval (500 ms) for the
priming period and the tachycardiac pacing interval (300 ms) but two
different coupling beat intervals (400 and 600 ms). Under tachycardia,
the contractile alternans changed transiently over the first 10-15
s or 30-50 beats. Thereafter, the strong and weak alternation
pattern and amplitude of the peak isovolumic pressure alternans and
hence contractile alternans became gradually stable over 1 min.
The peak pressure alternated remarkably during the initial transient
and successive stable periods of tachycardiac pacing in Fig.
1A, whereas it stopped to alternate after the initial transient period of tachycardiac pacing in Fig. 1B. Similar
results were obtained in all of the hearts. The index of LV
contractility, Emax, was reasonably good
(8.3 ± 3.8 mmHg · ml
1 · 100
g1) (14, 24, 28, 31, 32). Here,
Emax was calculated as LV peak isovolumic
pressure divided by LV volume minus the initial volume obtained as the
LV volume at which peak isovolumic pressure was zero (31,
32). We confirmed occasionally that the sustained contractile
alternans continued stably with the same pattern and amplitude of
interbeat alternation over 10 min.
The valley, or end-diastolic pressure, also alternated during the
contractile alternans. The higher valley pressure followed the higher
peak pressure and the lower valley pressure followed the lower peak pressure.
Coupling interval and alternans.
Figure 2 shows representative
relationships between the coupling interval and the peak isovolumic
pressures of the strong and weak beats in stable sustained contractile
alternans. LV contractilities of the alternans beats were proportional
to these peak pressures because LV volume was constant. Figure
2A shows that both peak and valley pressures of the
alternans beats changed sensitively with coupling interval. However,
the alternans of both peak and valley pressures completely or almost
disappeared at coupling intervals of 210, 300, and 600 ms (arrows on
the abscissa). Furthermore, the order of the strong and weak beats
counted from the coupling interval reversed across a coupling interval
of 300 ms. Above 300 ms, the odd-numbered beats were stronger and the
even-numbered beats were weaker. Below 300 ms, the odd-numbered beats
were weaker and the even-numbered beats were stronger.
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Fig. 2.
Relationship between CI and the alternating peak and
valley pressures of the strong and weak beats of the sustained
contractile alternans.  and  , Peak and valley
pressures, respectively, of even-numbered beats counted after CI.
 and  , Odd-numbered beats. Vertical
dashed lines on the right indicate the slow pacing interval
(A and B, 450 ms); those on the left
indicate the tachycardiac pacing interval (A, 280;
B, 330 ms). The arrows on the abscissas indicate the
specific CI. A and B correspond to type
I and type II of sustained contractile alternans.
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Figure 2B shows that the alternans amplitude of both peak
and valley pressures suddenly diminished at a coupling interval of 375 ms (arrow) and the alternans order reversed across this coupling
interval. At the other coupling intervals, the alternans amplitude of
both peak and valley pressures remained little changed with the
coupling interval. The alternans amplitude remained little changed,
particularly between 250 and 360 ms.
These results in Fig. 2 show the existence of at least one specific
coupling interval in each heart, at which the amplitude of sustained
contractile alternans totally or almost disappeared and across which
the alternans order of strong and weak beats reversed. Such a specific
coupling interval existed between the slow priming and tachycardiac
pacing intervals, which are indicated by the two dashed lines in Fig.
2. We obtained similar results in all of the hearts. The order of
strong and weak beats at the longer or shorter interval than a specific
coupling interval was uncertain among hearts. Unless we counted
carefully the beat number after the coupling interval, we could not
distinguish the sustained contractile alternans of similar patterns and
amplitudes at longer and shorter intervals than the specific coupling interval.
Table 1 summarizes the number of the
specific coupling intervals and the incidence of different types of the
relationship between the coupling interval and the alternation pattern
in all of the hearts. We counted the number of the coupling intervals at which the alternans disappeared or the order of the strong and weak
beats reversed. We classified these relationships into two types.
Type I was that the alternans amplitude of both peak and
valley pressures continuously changed between the specific coupling
intervals as shown in Fig. 2A. Type II was that
the alternans amplitude was relatively stable at all of the coupling
intervals except around the specific coupling intervals as shown in
Fig. 2B. Ten of the twelve hearts belonged to
type I, and the other two belonged to type II.
The most frequent type I case had two specific coupling
intervals between 200 and 600 ms. We could not find any particular
factor to determine these types.
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Table 1.
Relationship between the number of the specific coupling intervals and
the type of alternation of the peak and valley pressures of the
strong and weak beats
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As for the valley pressures, the higher valley pressure always followed
the higher peak pressure; the lower valley pressure always followed the
lower peak pressure. When the peak pressure alternans disappeared at
the specific coupling intervals, the valley pressure alternans also disappeared.
Transition to sustained contractile alternans.
Figure 3 shows the time course of the
peak and valley pressure alternans from the transient to sustained
phases while the coupling interval was increasing in one heart.
Regardless of the coupling intervals, both peak and valley pressure
alternans always started immediately after the coupling interval. The
even and odd order of strong and weak beats in the transient phase of
contractile alternans was retained, while the alternans became
gradually and finally stable by ~1 min of the tachycardiac pacing.
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Fig. 3.
A-F: transition from the transient to
sustained contractile alternans after various CI in one left ventricle.
Left: LVP from slow beats to the 50th beat from the first
tachycardiac beat in slow-speed recording. Right: LVP of the
201st and 202nd beats in high-speed recording. L, slow beat interval;
H, tachycardiac pacing interval.
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As the coupling interval increased, the strong and weak peak pressure
alternans in the sustained period first increased from Fig. 3,
A-C, then decreased from Fig. 3, C
and D, and increased again from Fig. 3,
D-F. The alternans almost disappeared, as shown in
Fig. 3 D, namely, at a specific coupling interval.
Between Fig. 3, D and E, the order of the strong
and weak beats reversed as exemplified in the odd- (o,
201st) and even-numbered (e, 202nd) beats. We obtained
similar results in all of the hearts.
The valley pressure alternans was largely proportional to the peak
pressure alternans in the transient phase of alternans. However, as the
peak pressure alternans became stable, the valley pressure alternans
almost or completely disappeared, as shown in Fig. 3, A,
D, and E, but remained a little in Fig. 3,
B, C, and F. Therefore, a higher
valley pressure did not always precede a proportionally weaker peak
pressure in the next beat.
Action potential duration.
We found that monophasic AP showed little alternans during the
sustained contractile alternans. The APD90 of the strong
and weak beats recorded in stable sustained contractile alternans were
211 ± 3 versus 212 ± 3 ms (12 runs) in one heart, 210 ± 6 versus 209 ± 4 ms (8 runs) in another heart, and 192 ± 5 versus 193 ± 5 ms (13 runs) in a third heart. The difference in
APD90 between strong and weak beats was not significant in
these hearts (Student's paired t-test, P > 0.05).
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DISCUSSION |
New finding.
The most important finding in this study is that the pattern and
amplitude of the strong and weak contractions in sustained contractile
alternans varied markedly with the coupling interval between the same
set of slow priming and the tachycardiac pacing periods. Although
previous investigators have produced sustained contractile alternans by
abruptly increasing the pacing rate (4, 9, 25, 26, 34,
36), no one has recognized the importance of the coupling
interval between the slow priming and tachycardiac pacing periods. We
obtained the present finding while we maintained stable the cardiac
contractile conditions that could affect the severity of sustained
contractile alternans (4, 16, 27, 34).
Ca2+ handling.
The sustained contractile alternans must be the result of alternating
contractility, because we fixed LV volume to exclude the Starling
effect. We speculate that the contractility alternans reflects
alternans of myocardial Ca2+ handling (6, 28, 35,
36). Even an extrasystole affects myocardial Ca2+
handling in successive beats as manifested by postextrasystolic restitution and potentiation (3, 6, 23, 28). These
postextrasystolic effects involve two Ca2+ handling
mechanisms. One is a change in transsarcolemmal Ca2+ influx
in the extrasystole and its gradual recovery over successive beats
(23, 28). The other is a change in Ca2+
recirculation (i.e., uptake and release) via the sarcoplasmic reticulum
(6, 22, 28). However, these changes disappear after
several postextrasystolic beats under pacing at a slow enough rate not
to produce sustained contractile alternans (6, 28, 35,
36). However, sustained contractile alternans occurs by sufficiently tachycardiac pacing even in normal hearts (34, 36). One or both transsarcolemmal and sarcoplasmic
Ca2+ handling mechanisms seem responsible for the sustained
contractile alternans that we observed.
Because there was no significant alternation of APD90,
alternation of the monophasic AP, and hence transsarcolemmal
Ca2+ influx, are not likely to be a main cause of the
sustained contractile alternans in the present study. In intact hearts,
a Ca2+ channel blockade, verapamil, suppressed APD
alternans but kept LV pressure alternans (12). This
suggests that sustained contractile alternans require sarcoplasmic
reticulum Ca2+ handling, but not always transsarcolemmal
Ca2+ influx alternans. This is compatible with the finding
of no significant APD90 alternans during the sustained
contractile alternans in the present study.
We suspect a mechanism to exist by which even a single coupling
interval preceding the tachycardiac pacing decides the pattern and
amplitude of the sustained contractile alternans. Even a single coupling interval affects the excitation-contraction coupling and the
contraction of the several postextrasystolic tachycardiac beats. This
effect in turn may continuously affect the subsequent sustained
contractile alternans. As shown in Figs. 1 and 3, transient contractile
alternans began tachycardiac pacing. The alternans waxed and waned for
the initial 10-15 s or 30-50 beats. The greater amplitude the
transient contractile alternans had, the greater amplitude the stable
contractile alternans had. At a specific coupling interval, the
amplitudes of both transient and sustained contractile alternans were
smaller than at other coupling intervals. This suggests that the
alternans amplitude initiated on the tachycardiac pacing is carried
over to the successive alternans beats without fading out. This
maintenance means that a mechanism for a stronger beat follows a weaker
beat, despite the regular beat intervals under tachycardia. This
mechanism itself is essentially what maintains sustained mechanical
alternans under tachycardia in normal hearts (34).
Simulation.
We examined whether any sustained-contractile-alternans model on the
basis of myocardial Ca2+ handling in the literature could
simulate our present finding. We first used Adler et al.'s model
(1, 2). This model incorporated two Ca2+
handling mechanisms (1, 2). One is a Ca2+
release to myofilaments on depolarization as a function of
Ca2+ in a releasable terminal to affect only the subsequent
beat. The other is a strong Ca2+ buffering capability of
the sarcoplasmic reticulum to affect several subsequent beats. This
model also incorporated transmembrane Ca2+ influx and
efflux. The Adler model successfully simulated sustained contractile
alternans with an abrupt increase in the beating rate, as shown in Fig.
4. Although a step increase in heart rate
from 120 to 240 beats/min generated sustained contractile alternans, the pattern and amplitude of the contractile alternans remained identical despite varied coupling intervals (200-400 ms). Although we recognized that the order of strong and weak beats reversed between
coupling intervals of 300 and 400 ms, no coupling interval existed to
attenuate or eliminate the alternans. The Adler model could not
simulate any diastolic pressure alternans.
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Fig. 4.
Simulation in the model proposed by Adler et al. (Ref.
1, Eqs. 1-12). After the
priming period of 500 ms pacing intervals, pacing intervals were
shortened to 250 ms for the tachycardiac pacing with a variable CI
(arrow). CI was 200 (top), 300 (middle), and 400 (bottom) ms. and ,
Odd-numbered and even-numbered beats, respectively, counted after the
CI. Pattern and amplitude of alternation were unchanged for all CI.
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Freeman et al. (8) presented a different model to simulate
sustained contractile alternans. They used three time constants to
explain the Ca2+ movement between the three compartments,
i.e., the sarcoplasm, a Ca2+ uptake pool, and a
Ca2+ releasable pool (38). They assumed the
Ca2+ uptake time constant to be inversely proportional to
sarcoplasmic Ca2+ (35). However, they assumed
no contribution of transsarcolemmal Ca2+ transport to the
alternans, namely, constancy of the total intracellular Ca2+ among alternans beats. Figure
5 shows our simulation using this Freeman
model. Figure 5A shows sustained contractile alternans generated even by a single extrasystole interrupting the continuous regular beats (400 ms). These extrasystoles after coupling intervals of
250 (upper) and 300 ms (lower) generated different but stable patterns
of alternation of sarcoplasmic Ca2+. However, we were not
able to produce this type of nontachycardiac sustained alternans in our
heart preparation.
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Fig. 5.
Simulation in the model proposed by Freeman et al. (Ref.
8, APPENDIX). Each panel shows
the beat-to-beat amounts of Ca2+ in three compartments:
sarcoplasm, uptake pool, and releasable pool. A:
extrasystole (ES; 250 ms, top, and 300 ms,
bottom) during regular beat intervals (400 ms).
B: step increase from slow pacing intervals (400 ms) to
tachycardiac intervals (300 ms) with a CI (250 ms, top, and
500 ms, bottom). The right-most beats show sarcoplasmic
Ca2+ in the 201st and 202nd beats from the first beat after
CI.
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Figure 5B shows our simulation of sustained contractile
alternans during tachycardia in a protocol similar to our experiment. These coupling intervals of 250 and 500 ms generated sustained contractile alternans and the pattern and amplitude of sarcoplasmic Ca2+ alternans depend on the coupling interval. However,
the alternans waxed gradually after both coupling intervals until the
strong beat increased twofold of the regular beat and the weak beat
faded out completely. Thus the Freeman model as it is cannot
simulate our present observation. This model can neither yield any
obvious end-diastolic Ca2+ alternans. This may be due to
the assumed constancy of the total intracellular Ca2+
throughout the transient and steady-state phases of tachycardia.
A new Ca2+ handling model, including an appropriate
combination of the Adler et al. (1) and Freeman et al.
(8) models, may account for the present finding.
Development of such a model is beyond the scope of the present study,
although such an effort is warranted. The Adler and Freeman models do
not include alternating changes in end-diastolic (valley) pressure and
Ca2+. Additional components like the end-diastolic pressure
and Ca2+ alternans to these models may help simulate our
observation of the valley pressure alternans accompanying the peak
pressure (contractile) alternans. The Adler and Freeman models included
neither alternating changes in Ca2+ sensitivity nor
responsiveness of contractility. A recent study (37)
suggests that there is an interbeat change in the relation between
Ca2+ handling and contractility after an extrasystole. The
addition of such a mechanism to the Adler and Freeman models might lead to a successful simulation, although we have not attempted this.
Limitations.
One may expect that inserting an appropriately coupled extrasystole
could abolish sustained alternans. If this method works, it could be
used to abolish alternans. Although this possibility remains to be
studied, the disappearance of alternans per se may not be beneficial as
long as tachycardia remains. Besides, because we studied isovolumic
contractions in the excised heart, it remains unknown whether the same
phenomenon could occur in ejecting contractions in in situ hearts.
Because we used normal hearts, the same phenomenon remains to be
examined in failing hearts.
In summary, our new finding is the coupling interval-dependent
variation of the pattern and amplitude of the sustained contractile alternans. We were not able to simulate this observation with the
representative Ca2+ handling models reported in the
literature. The cellular mechanism of the phenomenon remains to be
elucidated for better understanding of cardiac sustained contractile
alternans and Ca2+ handling.
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ACKNOWLEDGEMENTS |
We thank Kimikazu Hosokawa for continuous animal care and Banyu
Pharmaceutical for donating indomethacin. We also thank Dr. Terumasa
Morita, Department of Cardiovascular Surgery, for surgical assistance.
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FOOTNOTES |
This study was supported by Grants-in-Aid for Scientific Research
07508003, 09470009, 10558136, 10770307, 10877006, and
12680832 from the Ministry of Education, Science, Sports and
Culture, Cardiovascular Diseases Research Grant 11C-1 from the Ministry
of Health and Welfare, a Cardiac Physiome grant from the Science and
Technology Agency, and research grants from the Suzuken Memorial
Foundation and the Vehicle Racing Commemorative Foundation, all of Japan.
Address for reprint requests and other correspondence: H. Suga,
National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan (E-mail:
hsuga{at}ri.ncvc.go.jp).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 27 December 1999; accepted in final form 26 October 2000.
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REFERENCES |
1.
Adler, D,
Wong AYK,
Mahler Y,
and
Klassen GA.
Model of calcium movements in the mammalian myocardium: interval-strength relationship.
J Theor Biol
113:
379-394,
1985[ISI][Medline].
2.
Adler, D,
Wong AYK,
and
Mahler Y.
Model of mechanical alternans in the mammalian myocardium.
J Theor Biol
117:
563-577,
1985[ISI][Medline].
3.
Araki, J,
Takaki M,
Matsushita T,
Matsubara H,
and
Suga H.
Postextrasystolic transient contractile alternans in canine hearts.
Heart Vessels
9:
241-248,
1994[ISI][Medline].
4.
Badeer, HS,
Ryo UY,
Gassner WF,
Kass EJ,
Cavaluzzi J,
Gilbert JL,
and
Brooks CM.
Factors affecting pulsus alternans in the rapidly driven heart and papillary muscle.
Am J Physiol
213:
1095-1101,
1967.
5.
Braveny, P.
The relation of alternating contractility of the heart to the inotropic effects of rhythm.
Arch Int Physiol Biochem
72:
553-566,
1964[ISI][Medline].
6.
Burkhoff, D,
Yue DT,
Franz MR,
Hunter WC,
and
Sagawa K.
Mechanical restitution of isolated perfused canine left ventricles.
Am J Physiol Heart Circ Physiol
246:
H8-H16,
1984.
7.
Franz, MR,
Burkhoff D,
Spurgeon H,
Weisfeldt ML,
and
Lakatta EG.
In vitro validation of a new cardiac catheter technique for recording monophasic action potentials.
Eur Heart J
7:
34-41,
1986[Abstract/Free Full Text].
8.
Freeman, GL,
Widman LE,
Campbell JM,
and
Colston JT.
An evaluation of pulsus alternans in closed-chest dogs.
Am J Physiol Heart Circ Physiol
262:
H278-H284,
1992[Abstract/Free Full Text].
9.
Gilbert, JL,
Janse MJ,
Lu HH,
Pinkston JO,
and
Brooks CM.
Production and abolition of alternation in mechanical action of the ventricle.
Am J Physiol
209:
945-950,
1965.
10.
Gillis, AM,
Kulisz E,
and
Mathison HJ.
Cardiac electrophysiological variables in blood-perfused and buffer-perfused, isolated, working rabbit heart.
Am J Physiol Heart Circ Physiol
271:
H784-H789,
1996[Abstract/Free Full Text].
11.
Gleason, WL,
and
Braunwald E.
Studies on Starling's law of the heart. VI. Relationships between left ventricular end-diastolic volume and stroke volume in man with observations on the mechanism of pulsus alternans.
Circulation
25:
841-848,
1962[Abstract/Free Full Text].
12.
Hirayama, Y,
Saitoh H,
Atarashi H,
and
Hayakawa H.
Electrical and mechanical alternans in canine myocardium in vivo. Dependence on intracellular calcium cycling.
Circulation
88:
2894-2902,
1993[Abstract/Free Full Text].
13.
Kihara, Y,
and
Morgan JP.
Abnormal Ca
handling is the primary cause of mechanical alternans: study in ferret ventricular muscles.
Am J Physiol Heart Circ Physiol
261:
H1746-H1755,
1991[Abstract/Free Full Text].
14.
Kohno, K,
Takaki M,
Ishioka K,
Nakayama Y,
Suzuki S,
Araki J,
Namba T,
and
Suga H.
Effects of intracoronary fentanyl on left ventricular mechanoenergetics in the excised cross-circulated canine heart.
Anesthesiology
87:
658-666,
1997[ISI][Medline].
15.
Lab, MJ,
and
Seed WA.
Pulsus alternans.
Cardiovasc Res
27:
1407-1412,
1993[Free Full Text].
16.
Lu, HH,
Lange G,
and
Brooks CM.
Comparative studies of electrical and mechanical alternation in heart cells.
J Electrocardiol
1:
7-17,
1968[Medline].
17.
Mahler, Y,
and
Rogel S.
Interrelation between restitution time-constant and alternating myocardial contractility in dogs.
Clin Sci (Colch)
39:
625-639,
1970[ISI][Medline].
18.
Matsubara, H,
Takaki M,
Yasuhara S,
Araki J,
and
Suga H.
Logistic time constant of isovolumic relaxation pressure-time curve in the canine left ventricle. Better alternative to exponential time constant.
Circulation
92:
2318-2326,
1995[Abstract/Free Full Text].
19.
McGaughey, MD,
Maughan WL,
Sunagawa K,
and
Sagawa K.
Alternating contractility in pulsus alternans studied in the isolated canine heart.
Circulation
71:
357-362,
1985[Abstract/Free Full Text].
20.
Miller, WP,
Liedtke AJ,
and
Nellis SH.
End-systolic pressure-diameter relationships during pulsus alternans in intact pig hearts.
Am J Physiol Heart Circ Physiol
250:
H606-H611,
1986.
21.
Mitchell, JH,
Sarnoff SJ,
and
Sonnenblick EH.
The dynamics of pulsus alternans: alternating end-diastolic fiber length as a causative factor.
J Clin Invest
42:
55-63,
1963.
22.
Mohri, S,
Araki J,
Imaoka T,
Iribe G,
Maesako M,
Mizuno J,
Shimizu J,
Matsubara H,
Ohe T,
Hirakawa M,
and
Suga H.
Myocardial mechanical restitution and potentiation partly underlie alternans decay of postextrasystolic potentiation: simulation.
Heart Vessels
14:
82-89,
1999[ISI][Medline].
23.
Morad, M,
and
Goldman Y.
Excitation-contraction coupling in heart muscle: membrane control of development of tension.
Prog Biophys Mol Biol
27:
257-313,
1973.
24.
Nakayama, Y,
Takaki M,
Kohno K,
Araki J,
and
Suga H.
Mechanoenergetics of the negative inotropism of isoflurane in the canine left ventricle.
Anesthesiology
87:
82-93,
1997[ISI][Medline].
25.
Narayan, P,
McCune SA,
Robitaille PML,
Hohl CM,
and
Altschuld RA.
Mechanical alternans and the force-frequency relationship in failing rat hearts.
J Mol Cell Cardiol
27:
523-530,
1995[ISI][Medline].
26.
Noble, RJ,
and
Nutter DO.
The demonstration of alternating contractile state in pulsus alternans.
J Clin Invest
49:
1166-1177,
1970.
27.
Parmley, WW,
Tomoda H,
Fujimura S,
and
Matloff JM.
Relation between pulsus alternans and transient occlusion of the left anterior descending coronary artery.
Cardiovasc Res
6:
709-715,
1972[ISI][Medline].
28.
Shimizu, J,
Araki J,
Mizuno J,
Lee S,
Syuu Y,
Hosogi S,
Mohri S,
Mikane T,
Takaki M,
Taylor TW,
and
Suga H.
A new integrative method to quantify total Ca2+ handling and futile Ca2+ cycling in failing hearts.
Am J Physiol Heart Circ Physiol
275:
H2325-H2333,
1998[Abstract/Free Full Text].
29.
Spear, JF,
and
Moore EN.
A comparison of alternation in myocardial action potentials and contractility.
Am J Physiol
220:
1708-1716,
1971.
30.
Steiner, C,
and
Kovalik ATW
A simple technique for production of chronic complete heart block in dogs.
J Appl Physiol
25:
631-632,
1968[Free Full Text].
31.
Suga, H,
Hisano R,
Hirata S,
Hayashi T,
Yamada O,
and
Ninomiya I.
Heart rate-independent energetics and systolic pressure-volume area in dog heart.
Am J Physiol Heart Circ Physiol
244:
H206-H214,
1983.
32.
Suga, H,
and
Sagawa K.
Instantaneous pressure-volume relationships and their ratio in the excised, supported canine left ventricle.
Circ Res
35:
117-126,
1974[Abstract/Free Full Text].
33.
Traube, L.
Ein Fall von Pulsus bigeminus nebst Bemerkungen über die Leberschwellungen bei Klappenfehlern und über acute Leberatrophie.
Berl Klin Wschr
9:
185-188,
1872.
34.
Weber, KT,
and
Janicki JS.
Interdependence of cardiac function, coronary flow, and oxygen extraction.
Am J Physiol Heart Circ Physiol
235:
H784-H793,
1978.
35.
Wier, WG,
and
Yue DT.
Intracellular calcium transients underlying the short-term force-interval relationship in ferret ventricular myocardium.
J Physiol (Lond)
376:
507-530,
1986[Abstract/Free Full Text].
36.
Wohlfart, B.
Analysis of mechanical alternans in rabbit papillary muscle.
Acta Physiol Scand
115:
405-414,
1982[ISI][Medline].
37.
Wohlfart, B.
[Ca2+]i following extrasystoles in guinea-pig trabeculae microinjected with fluo-3. A comparison with frog skeletal muscle fibres.
Acta Physiol Scand
169:
1-11,
2000[ISI][Medline].
38.
Yue, DT,
Burkhoff D,
Franz MR,
Hunter WC,
and
Sagawa K.
Postextrasystolic potentiation of the isolated canine left ventricle. Relationship to mechanical restitution.
Circ Res
56:
340-350,
1985[Abstract/Free Full Text].
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