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Departments of Radiology and Medicine (Cardiology), University of California, San Francisco 94143; and the Medical Service, San Francisco General Hospital, San Francisco, California 94110
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The goal of this
study was to determine whether
Ca2+ plays a role in regulating
tension development kinetics in intact cardiac muscle. In cardiac
muscle, this fundamental issue of
Ca2+ regulation has been
controversial. The approach was to induce steady-state tetanic
contractions of intact right ventricular trabeculae from rat hearts at
varying external Ca2+
concentrations
([Ca2+]) at 22°C.
During tetani, cross bridges were mechanically disrupted and the kinetics of tension redevelopment were assessed from the rate
constant of exponential tension redevelopment
(ktr). There was a relationship between
ktr and external
[Ca2+] that was
similar in form to the relationship between tension and
[Ca2+]. Thus a close
relationship also existed between
ktr and tension (r = 0.88;
P < 0.001); whereas at
maximal tetanic tension (saturating cytosolic
[Ca2+]),
ktr was 16.4 ± 2.2 s
1 (mean ± SE, n = 7), at zero tension (low
cytosolic [Ca2+]),
ktr extrapolated
to 20% of maximum (3.3 ± 0.7 s1). Qualitatively
similar results were obtained using different mechanical protocols to
disrupt cross bridges. These data demonstrate that tension
redevelopment kinetics in intact cardiac muscle are influenced by the
level of Ca2+ activation. These
findings contrast with the findings of one previous study of intact
cardiac muscle. Activation dependence of tension development kinetics
may play an important role in determining the rate and extent of
myocardial tension rise during the cardiac cycle in vivo.
cross-bridge kinetics; activation; rate constant of exponential tension redevelopment; contraction; trabeculae
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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THE GOAL OF THIS STUDY was to determine whether Ca2+ regulates the kinetics of tension development in intact cardiac muscle. In contracting skinned skeletal muscle fibers, Brenner (4) demonstrated that after cross bridges were mechanically disrupted, the kinetics of tension redevelopment were faster with increased levels of activation by Ca2+. This finding has been confirmed in many recent studies (6, 20-22, 25, 28). However, studies in cardiac muscle have produced markedly differing results. Some studies of both intact (11) and skinned (12) cardiac muscle found that tension redevelopment kinetics were not influenced by Ca2+. This raised an important possibility that regulation of contraction by Ca2+ in cardiac muscle may be fundamentally different from that in skeletal muscle. In contrast, other studies in skinned cardiac muscle found that Ca2+ does influence tension redevelopment kinetics (31, 33).
Uncertainty on this important aspect of Ca2+ regulation of cardiac muscle contraction prompted its reevaluation using intact cardiac muscle in the present study. The issue of whether there is an influence of Ca2+ on force redevelopment kinetics may have important physiological implications for contraction of the heart in vivo. Activation-dependent tension-generating kinetics may contribute to determining the rate and extent of myocardial force development during the cardiac cycle (33).
The experimental approach was to produce steady-state tetanic contractions of intact rat right ventricular (RV) trabeculae. During tetani, cross bridges were mechanically disrupted using a protocol similar to that used by Brenner (4) in skeletal muscle. Trabeculae were subjected to a brief period of unloaded shortening followed by rapid restretch to initial muscle length (release-restretch protocol). Tension redevelopment kinetics were assessed from the rate constant of tension redevelopment (ktr) when cytosolic Ca2+ concentration ([Ca2+]) was varied by altering superfusate [Ca2+]. Previous studies raised the possibility that the time course of tension redevelopment may be influenced by the nature of the length change protocol used to disrupt cross bridges (31, 33). Therefore, we measured ktr using three different mechanical protocols: a release-restretch (4), a sustained release (11), and a brief stretch-release protocol (26).
The results of this study showed that ktr varied fivefold over the full range of Ca2+ activation. This demonstrates that regulation of contraction in intact cardiac muscle is similar to that found in skeletal muscle: for both muscle types, the kinetics of the tension-generating processes are influenced by the level of activation.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Trabecula preparation. All experiments were performed at 22°C. LBNF1 rats (~350 g, n = 7) were anticoagulated with heparin (1,000 U/kg ip) and deeply anesthetized with pentobarbital (85 mg/kg ip). Hearts were removed, placed in a dissection dish, and perfused through the aorta with a modified Krebs-Henseleit solution containing (in mM) 116 NaCl, 5 KCl, 1.2 MgCl2, 1.2 Na2SO4, 2 NaH2PO4, 23 NaHCO3, 10 glucose, and CaCl2 as indicated. Solutions were equilibrated with 95% O2-5% CO2 to obtain a pH of 7.4 at 22°C. To minimize spontaneous contractions during dissection, solutions contained an additional 20 mM KCl and [Ca2+] was 0.2 mM.
The RV was opened, and thin unbranched trabeculae running from the RV free wall to the tricuspid valve were isolated as previously described (7). A small cube of the RV wall containing a trabecula was removed; a remnant of the valve was left attached. The dimensions of the trabeculae (in mm) were length 2.4 ± 0.3, width 0.25 ± 0.04, and thickness 0.11 ± 0.02 (mean ± SE, n = 7). Trabeculae were mounted in a muscle bath (25 × 3 × 5 mm) and superfused (at
5 ml/min)
by Krebs-Henseleit solution with 0.5 mM
[Ca2+].
The cube of ventricle was held in a basket made of platinum wire
attached to a strain gauge (model 403; Cambridge Technology, Watertown,
MA); the valve remnant was mounted on a stainless steel hook attached
to a position-sensitive motor (model 300; Cambridge Technology) (3, 7).
To reduce end compliance, we immobilized muscles to their mounts using
a method described by Julian et al. (15, 16). Using loose ties of
10-0 suture, we lightly held the ends of the muscles against two
small stainless steel pins that emerged axially from the basket and
hook mountings. The chamber was briefly drained, and the muscle ends up
to the suture were cemented to their mounts using cyanoacrylate tissue adhesive (Histoacryl Blau, Mellsungen, Germany). This method of attachment was shown to markedly reduce end compliance (16).
Muscles were field stimulated using platinum wire electrodes in the
side walls of the chamber. Stimulation consisted of 4-ms stimulus
pulses; voltage was set to 50% above that giving maximum tension, and
frequency was 0.5 Hz. Muscle length was adjusted to maximize the twitch
tension. The [Ca2+]
was gradually raised to 1.2 mM over 15 min, and stimulated muscles were
allowed to equilibrate for 1 h.
Signals from the tension transducer and motor were digitized at 1,000 Hz and stored in a laboratory computer.
Experimental protocols.
Superfusate [Ca2+] was
lowered to 0.25 mM (the first concentration in the range to be
studied). To allow steady-state tetani to be induced, we inhibited
Ca2+ uptake to the sarcoplasmic
reticulum (SR) with 100 µM cyclopiazonic acid (CPA) (2, 9). CPA is a
specific inhibitor of the SR Ca2+-ATPase (30); it does not
impair tension development by the myofilaments (17) and does not affect
the Ca2+ sensitivity of intact RV
trabeculae (2). After a 30-min equilibration with the drug, twitch
stimulation was interrupted with tetanization at 10 Hz for 7 s. In
seven experiments, during the tetanus (after 4 s of stimulation), cross
bridges were mechanically disrupted using three different methods that
gave similar results. First, cross bridges were disrupted by slackening
the muscle by rapidly decreasing the muscle length by 15-20% for
40 ms and then rapidly restretching to the initial length (length
changes took 1.5 ms to complete)
(n = 4) (4). In one of these
four experiments a second protocol was also used consisting of a rapid
sustained decrease in muscle length (4% of initial length) that
reduced tension close to the baseline (11, 12). Finally, cross bridges were also disrupted by a brief stretch of the muscle (8% increase and then decrease in muscle length over 3 ms) (26). For this protocol,
the muscle length was first reduced to 92%
(n = 3).
Data analysis and statistics. After the length perturbation, the rate constant of monoexponential tension redevelopment (ktr) was determined by fitting the rise of tension according to the following relation
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(1) |
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Tetanization of trabeculae. To induce steady-state contractions in cardiac trabeculae, we tetanized muscles (n = 7) in the presence of CPA (2). Figure 1 shows records of tension during tetani performed at different superfusate [Ca2+]. Increased superfusate [Ca2+] resulted in increased tetanic tension. Figure 2 shows the relationship between tetanic tension and superfusate [Ca2+]. Figure 2 shows that the increase of tetanic tension had saturated at high superfusate [Ca2+]. The maximum tetanic tension at saturating [Ca2+] was 7.8 ± 1.6 g/mm2 (mean ± SE, n = 7).
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Disruption of cross bridges during tetani.
The records in Fig. 1 also show the effects of mechanically disrupting
cross bridges during tetani using a perturbation of muscle length. This
protocol consisted of a release (15% muscle length decrease
sustained for 40 ms) followed by restretch to initial length. This
protocol caused a substantial reduction of tension. After restretch to
the initial muscle length there was a period of tension redevelopment
during which tension recovered close to the level before the length
perturbation.
Time course of tension redevelopment. To investigate the influence of [Ca2+] on cross-bridge turnover kinetics, we quantitated the time course of tension redevelopment after length perturbations at different superfusate [Ca2+] (4). Tension redevelopment records from Fig. 1 are shown with greater temporal resolution in Fig. 3A. The closed circles superimposed on each trace indicate the time at which tension redeveloped to 90% of maximum after the length perturbation. Figure 3A shows that at high superfusate [Ca2+], tension redeveloped to the 90% level sooner than at low superfusate [Ca2+]. Thus the time course of tension redevelopment was influenced by Ca2+ and was faster at high superfusate [Ca2+] compared with low superfusate [Ca2+].
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Effect of Ca2+ on time course of tension redevelopment. The time course of tension redevelopment after the length perturbation was fit to an exponential function (Eq. 1). Figure 3A shows the result of fitting Eq. 1 to the rise of tension at the highest and lowest superfusate [Ca2+] (dotted lines). Figure 3A shows that the fits coincided closely to the data. The time course of tension redevelopment was quantitated from the rate constant of tension redevelopment (ktr) determined from the fits.
Figure 4 shows the relationship between ktr and superfusate [Ca2+] for a subgroup of experiments where cross bridges were disrupted by a brief period of unloaded shortening followed by restretch (n = 4). For each experiment, ktr values were normalized to the maximum value (the maximum ktr at the highest superfusate [Ca2+] was 14.3 ± 2 s1, mean ± SE,
n = 4). Figure 4 shows that for
increases of superfusate [Ca2+] up to 2 mM
there was a steep increase of
ktr. As
superfusate [Ca2+] was
increased beyond 2 mM, there was a shallower rise of
ktr. The
relationship between
ktr and
superfusate [Ca2+]
suggests that increases of cytosolic
[Ca2+] are associated
with faster tension redevelopment kinetics. The form of the saturating
relationship between
ktr and
superfusate [Ca2+] is
similar to the saturating relationship between tension and superfusate
[Ca2+] shown in Fig.
2. This suggests that increased superfusate
[Ca2+] causes both a
rise of tension and faster tension redevelopment kinetics.
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0.069,
P = 0.93). This suggests that the
influence of end compliance due to lack of length control was not
responsible for the close relationship observed between
ktr and tension.
This simple analysis is quantitatively limited by the apparent
nonlinearity of the relationship between relative
ktr and relative
tension. However, it does show qualitatively that the relationship
found between relative
ktr and relative tension is not greatly influenced by muscle length.
Measurement of ktr using different protocols to disrupt cross bridges. Previous studies have used different length change protocols to disrupt cross bridges. Use of different length change protocols has been suggested as a factor that may have contributed to conflicting results regarding the dependence of ktr on Ca2+ in cardiac muscle (31, 33). Therefore, we confirmed our findings using two additional protocols to disrupt cross bridges.
In one of the experiments described above, cross bridges were also disrupted by a rapid and sustained decrease in muscle length (release) (11, 12). In a third protocol, muscles were briefly and rapidly stretched to forcibly detach cross bridges (stretch-release protocol) (n = 3) (26). Examples of tension transients after these protocols are shown in Fig. 6. Figure 6, bottom, shows tension records normalized to the maximum values attained after the mechanical perturbations. The normalized data clearly show that, after cross bridges were disrupted by a release (Fig. 6A) or stretch-release protocol (Fig. 6B), the time course of tension redevelopment was faster under conditions of high extracellular [Ca2+]. This is consistent with the findings shown in Fig. 3 using the release-restretch protocol.
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1,
n = 3) was similar to that found using
the release-restretch protocol (P = 0.3). However, the value of
ktr at maximum
extracellular [Ca2+]
obtained using the release protocol (43 s1,
n = 1) appeared higher. This is
consistent with a previous study that found that
ktr measured
after a release was approximately twice that measured after a
release-restretch protocol (12).
Data using all three mechanical protocols from all experiments are
summarized in Fig. 7. Figure 7 shows that,
taken together, data for all three protocols formed a close
relationship between ktr and tension.
A linear regression fit to all of the data of this study (solid line)
showed a significant positive correlation between
ktr and tension
(r = 0.88, P < 0.001). For all experiments, at
maximal tetanic tension (saturating cytosolic
[Ca2+]),
ktr was 16.4 ± 2.2 s1 (mean ± SE, n = 7). At zero tension (low
cytosolic [Ca2+])
ktr extrapolated
to 20% of maximum (3.3 ± 0.7 s1). These data
demonstrate that in intact cardiac muscle there is activation
dependence of tension redevelopment kinetics. Furthermore, this finding
does not depend on the use of a particular protocol to disrupt cross
bridges.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The major finding of this study was that after mechanical disruption of cross bridges during tetanization of intact cardiac muscle, the kinetics of tension redevelopment were faster when superfusate [Ca2+] was elevated. This finding demonstrates that in intact cardiac muscle, Ca2+ influences the kinetics of the tension-generating process. This finding is consistent with results from studies of skinned skeletal (4, 6, 20, 21, 25, 28) and cardiac muscle (31, 33) but differs from the results of other studies of intact and skinned cardiac muscle (11, 12).
The physiological significance of this finding is that the influence of Ca2+ on the kinetics of the tension-generating processes may contribute to determining the rate and extent of tension development during the cardiac cycle.
Effect of Ca2+ on the kinetics of tension generation. Previous studies in skeletal muscle found that when cross bridges were mechanically disrupted by a brief period of unloaded shortening followed by restretch, the rate constant of tension redevelopment (ktr) was increased from 5- to 10-fold when [Ca2+] was raised from low to saturating levels (4, 6, 20, 21, 25, 28).
Findings in cardiac muscle have been controversial. Studies using skinned cardiac muscle also found that ktr was increased with [Ca2+] (31, 33). In contrast, other studies in intact and skinned cardiac muscle found that ktr was not influenced by Ca2+ (11, 12). These studies raised the possibility that cardiac muscle may be fundamentally different from skeletal muscle in terms of how tension is regulated by Ca2+. The present study has addressed the conflicting findings from these previous reports. We used thin intact rat RV trabeculae that are metabolically stable at high work loads (29), develop stable steady-state tensions during tetanization (2), and had low residual tensions when cross bridges were disrupted with mechanical protocols. We found that, similar to skeletal muscle, in intact cardiac muscle Ca2+ does increase the kinetics of tension redevelopment after cross bridges are mechanically disrupted by a rapid decrease of muscle length followed by restretch. Some of the disparity in previous reports was suggested to arise from differences in the mechanical protocols used to disrupt cross bridges (31, 33). For example, when cross bridges are disrupted by a rapid decrease of muscle length (i.e., without restretch), even though tension declines to zero, cross bridges may remain attached to actin. The presence of a residual fraction of attached cross bridges may influence the level of activation and thus could mask the influence of Ca2+ on ktr. Therefore, in the present study we monitored ktr using several different protocols to disrupt cross bridges. We found there was a similar activation dependence of tension redevelopment kinetics when cross bridges were disrupted using a release-restretch protocol, a release (without restretch), or a brief stretch-release protocol. This suggests that the finding of an influence of Ca2+ on ktr does not depend on the use of a particular mechanical protocol to disrupt cross bridges.Role of Ca2+ in activation of cardiac muscle contraction: relation to ktr. Classically, Ca2+ has been thought to participate in muscle activation by binding onto troponin and causing a structural change in tropomyosin, which then allows myosin cross bridges to undergo cyclic interactions with actin (14, 19, 24, 32). Thus Ca2+ was thought to cause muscle activation by causing increased numbers of cross bridges to cycle with fixed turnover kinetics between attached high-force states and detached low-force states (27). According to this simple recruitment scheme, ktr would not be expected to vary with [Ca2+].
However, this recruitment hypothesis was brought into question by Brenner (4), who found that ktr was influenced by [Ca2+] in skinned skeletal muscle fibers. This finding was interpreted within the framework of a simple two-state cross-bridge model based on that described by Huxley (13). According to this simple model, ktr reflects cross-bridge turnover kinetics. Thus the finding that ktr depends on [Ca2+] suggested that in skeletal muscle Ca2+ activates contraction by regulating cross-bridge turnover kinetics rather than recruiting cross bridges to cycle. However, the mechanism by which [Ca2+] determines ktr remains uncertain. More recent studies suggest that Ca2+ influences ktr by interaction of Ca2+ with regulatory light chains (22, 25) or troponin C (6, 28) and through dynamic modulation of thin-filament regulatory units (6). Recent mathematical models suggest that the Ca2+ dependence of ktr may involve cooperativity between force-bearing cross bridges and the level of activation (5), or coupling between the two processes of Ca2+ binding to the thin filament and force generation (10, 18). Despite this uncertainty regarding mechanism, the finding that ktr is activation dependent in intact cardiac muscle likely has important physiological significance. Thus the broader context of our finding is in terms of a role for Ca2+ in regulating the rate and extent of tension rise during the cardiac cycle (33).Relation to previous studies. There has been only one previous study of ktr in intact cardiac muscle (11). In marked contrast to the findings of the present study, the previous study found that the kinetics of tension redevelopment were not influenced by the level of activation (11). Several differences in experimental design between these two studies should be considered.
First, the present study used rat myocardium, whereas Hancock et al. (11) used ferret myocardium. However, Hancock et al. (12) using skinned rat myocardium also found ktr was not activation dependent. This raises the possibility that some other difference besides species may explain the conflicting findings. Second, the present study was performed at 22°C, whereas Hancock et al. (11) used 27°C. In a preliminary report, de Tombe and Steinen (8) found greater activation dependence of ktr at higher temperature. This suggests that the small temperature difference between the present and previous study of intact myocardium cannot explain the different findings. Third, the present study used CPA to perform tetanization, whereas Hancock et al. (11) used ryanodine. Previous studies found similar tetanic force and cytosolic Ca2+ levels using tetanization with CPA or ryanodine (2). Furthermore, CPA did not affect the function of the contractile proteins (17, 30). These findings suggest that the different pharmacological methods used to tetanize do not account for the different findings between the present study and that of Hancock et al. (11). Fourth, Hancock et al. (11) used feedback control to maintain a central segment of muscle at a constant length. The present study did not use length control. Length control minimizes the shortening of central sarcomeres because of end compliance. End compliance could lead to underestimation of ktr (6, 33). However, in the present study, there was similar activation dependence of ktr in both short and long muscles, even though shorter muscles should be more susceptible to the effects of end compliance. This suggests that problems of end compliance due to lack of length control do not underlie our finding that ktr was activation dependent. This conclusion is consistent with a study by Wolff et al. (33) that noted the relationship between ktr and tension in skinned rat myocardium was similar both with and without sarcomere length control (although a detailed comparison was not presented). Finally, Hancock et al. (11) used a release to mechanically disrupt cross bridges. The present study used three different mechanical protocols to disrupt cross bridges and found similar activation dependence with all three methods. This suggests that in the present study, the finding that ktr was activation dependent does not depend on the use of a particular protocol to disrupt cross bridges. In summary, despite some differences in experimental design, the differing results of the present and previous study of intact cardiac muscle cannot be reconciled. Thus the present study extends the controversy concerning the Ca2+ dependence of ktr to an intact cardiac muscle preparation. However, the present study is consistent with growing evidence that Ca2+ does play a role in modulating the kinetics of tension redevelopment in cardiac muscle. The present results are consistent with studies of skinned cardiac trabeculae (8, 33) and skinned cardiac myocytes (31). Furthermore, when skinned trabeculae were activated to different levels by liberating Ca2+ from a photolabile chelator, then the rate constant for tension development was increased at higher levels of activation (1, 23). In summary, the present study suggests that, qualitatively, cardiac and skeletal muscle are similar in that both display activation-dependent tension redevelopment kinetics.Limitations of study. In the present study, sarcomere lengths were not controlled. However, we found the activation dependence of ktr was not influenced by muscle length. As discussed above, this suggests that problems of end compliance due to lack of length control do not account for our finding that ktr was activation dependent. Future studies of intact cardiac muscle using length control would be valuable.
Incomplete cross-bridge detachment could lead to further underestimation of the influence of Ca2+ on ktr (31, 33). We used three different protocols to disrupt cross bridges. These protocols resulted in a low residual tension, ranging from ~20% using a release-restretch protocol to almost none (~2%) using a brief stretch-release protocol. However, similar results were obtained using each protocol. This suggests that the overall finding of this study is not altered by the presence of small residual tensions after disrupting cross bridges. In conclusion, this study demonstrates that, in contracting intact cardiac muscle after cross bridges are disrupted, the kinetics of tension redevelopment are faster at higher levels of activation. This finding is similar to the behavior observed in skeletal muscle and suggests that for both muscle types activation of contraction by Ca2+ involves an effect on tension-generating kinetics. This conclusion has important implications for myocardial tension development during the cardiac cycle in vivo.| |
ACKNOWLEDGEMENTS |
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The authors are grateful to Drs. Pieter de Tombe and Matthew Wolff for very helpful discussions of this work and to Dr. Fred Julian for discussion of the method to mount trabeculae.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-56257 (to A. J. Baker).
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. §1734 solely to indicate this fact.
Address for reprint requests: A. J. Baker, Cardiology Div., Rm. 5G1, San Francisco General Hospital, San Francisco, CA 94110.
Received 23 January 1998; accepted in final form 5 May 1998.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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, Time at
which tension was redeveloped to 90% of value after length
perturbation.
