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Am J Physiol Heart Circ Physiol
280: H1368–H1375, 2001.
Coupling interval from slow to tachycardiac pacing
decides sustained alternans pattern
SHUNSUKE SUZUKI,1,2 JUNICHI ARAKI,1 YUMIKO DOI,1,2 WASO FUJINAKA,1,2
HITOSHI MINAMI,1 GENTARO IRIBE,1 SATOSHI MOHRI,1 JUICHIRO SHIMIZU,1
MASAHISA HIRAKAWA,2 AND HIROYUKI SUGA1,3
1
Department of Physiology II and 2Department of Anesthesiology and
Resuscitology, Okayama University Medical School, Okayama 700-8558; and
3
National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
Received 27 December 1999; accepted in final form 26 October 2000
myocardium; contractility; calcium handling; arrhythmias
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).
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: [email protected]).
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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.
The costs of publication of this article were defrayed in part by the
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0363-6135/01 $5.00 Copyright © 2001 the American Physiological Society
http://www.ajpheart.org
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Suzuki, Shunsuke, Junichi Araki, Yumiko Doi, Waso
Fujinaka, Hitoshi Minami, Gentaro Iribe, Satoshi
Mohri, Juichiro Shimizu, Masahisa Hirakawa, and
Hiroyuki Suga. Coupling interval from slow to tachycardiac
pacing decides sustained alternans pattern. Am J Physiol
Heart Circ Physiol 280: H1368–H1375, 2001.—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.
COUPLING INTERVAL AND SUSTAINED ALTERNANS
METHODS
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
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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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 ␮g/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)
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COUPLING INTERVAL AND SUSTAINED ALTERNANS
reasonably good (8.3 ⫾ 3.8 mmHg 䡠 ml⫺1 䡠 100 g⫺1) (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
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
Fig. 2. Relationship between CI and the alternating peak and valley
pressures of the strong and weak beats of the sustained contractile
alternans. F and }, Peak and valley pressures, respectively, of
even-numbered beats counted after CI. E 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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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.
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-todigital 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.
COUPLING INTERVAL AND SUSTAINED ALTERNANS
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
No. of Specific Coupling Intervals
Type I
Type II
Total
0
1
2
3
Total
0
0
0
1
2
3
7
0
7
2
0
2
10
2
12
Values are means ⫾ SD for 2 dogs. Type I corresponds to Fig. 2A.
Type II corresponds to Fig. 2B. Specific coupling interval means the
coupling interval at which the alternation disappeared despite the
tachycardiac pacing.
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.
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.
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.
As the coupling interval increased, the strong and
weak peak pressure alternans in the sustained period
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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.
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
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COUPLING INTERVAL AND SUSTAINED ALTERNANS
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, sus-
tained 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 sustainedcontractile-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
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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 evennumbered (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).
COUPLING INTERVAL AND SUSTAINED ALTERNANS
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. E and F, Odd-numbered and even-numbered beats,
respectively, counted after the CI. Pattern and amplitude of alternation were unchanged for all CI.
Fig. 5. Simulation in the model proposed by Freeman et al. (Ref. 8,
2⫹
APPENDIX). Each panel shows the beat-to-beat amounts of Ca
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.
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.
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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.
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.
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
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COUPLING INTERVAL AND SUSTAINED ALTERNANS
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.
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.
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Limitations. One may expect that inserting an appropriately coupled extrasystole could abolish sustained alternans. If this method works, it could be used
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Besides, because we studied isovolumic contractions in
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In summary, our new finding is the coupling interval-dependent variation of the pattern and amplitude
of the sustained contractile alternans. We were not
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The cellular mechanism of the phenomenon remains to
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COUPLING INTERVAL AND SUSTAINED ALTERNANS
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