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,2
* Unité INSERM U 400, Créteil, France; and
Unité INSERM U 446 Chatenay-Malabry, France
1Correspondence: Unité INSERM U 400, Faculté de Médecine, 8, rue du Général Sarrail 94000 Créteil, France. E-mail: crozatier{at}im3.inserm.fr
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: CK • ventricular function • cell shortening
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2
3)
. Part of the cytosolic MM isoenzyme is associated structurally with myofibrils, the sarcoplasmic reticulum (SR), and sarcolemmal membranes—sites of excitation-contraction coupling. They use phosphocreatine to locally rephosphorylate ADP produced by ATPases, providing enough energy for normal contractile kinetics or SR Ca2+ reuptake (1
, 4
, 5)
. It has been proposed that the CK system with isoenzymes compartmentalized at the sites of energy production or utilization and interconnected through cytosolic CK may provide a specialized system for fast and efficient energy and signal transfer between mitochondria and ATP using organelles.
Engineered mice lacking mitochondrial and cytosolic CK isoforms were developed (6)
. These were viable and apparently healthy. The initial study examined skeletal muscle function. It showed that mutant mice had no alteration in absolute muscle force, but were unable to perform burst activity and exhibited altered Ca2+ transient (6)
. These muscle studies have been extended, suggesting a role for creatine kinase in fatigue (7)
. Cardiac excitation-contraction coupling and contractile function are markedly different from those of skeletal muscle. The Ca2+-induced Ca2+ release mechanism is specific to the heart as it does not present fatigue, owing to high mitochondrial content and oxidative capacity. Isolated perfused heart studies of CK-deficient mice revealed that they develop nearly normal function under the moderate workload that can be achieved ex vivo (8
, 9)
. This suggests that other mechanisms may ensure energy transfer and signal transduction between sites of energy production and energy utilization. Two mechanisms have been proposed: a support by glycolysis of Ca2+ uptake by the SR (10)
and a closer interaction between mitochondria and organelles (11)
. Indeed, it was shown recently using skinned fibers that ATP produced by mitochondria was nearly as effective as CK-supplied ATP to sustain Ca2+ uptake, suggesting that a direct ATP/ADP channeling exists between mitochondria and SR. However, the question remains as to whether these mechanisms may be compensatory for the lack of CK at higher physiological workloads (11)
.
The goal of our work was to examine the cardiac excitation-contraction coupling in CK-deficient mice using isolated cells and fibers as well as the whole heart in vivo. The aim was to gain insight into the direct role of CK in this process, the extent to which alternate pathways could compensate for the enzyme deficit, and whether the absence of compensation of cellular or organ function suggests a specific role for CK in cardiac cell function.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Six- to 8-month-old male control C57BL/6 and CK(-/-) mice were studied according to the recommendations of the Institutional Animal Care Committee (INSERM, Paris, France).
SR function in skinned fibers
Fiber bundles (diameter 140–250 mm) were dissected free from papillary muscles of the left ventricle of control and CK-deficient mice and skinned in a relaxing solution containing 50 µg/ml saponin to permeabilize the sarcolemma as described previously (10)
.
After skinning, the fiber was tied at both ends with a natural silk thread and mounted on stainless-steel hooks between a length adjustment device and a force transducer (AE 801, Aker’s Microelectronics, Horton, Norway). The transducer elements formed the two arms of a Wheatstone bridge and the output signal for recording was amplified. Fibers were immersed in 2.5 ml chambers arranged around a disk in a temperature-controlled bath positioned on a magnetic stirrer. Each solution was well stirred at high speed. All experiments were performed at 22°C.
The protocol used in this study has been described (10)
. At the beginning of each experiment, the fiber was stretched to 20% of the slack length and exposed to activating control solution at pCa 4.5 to obtain the maximal tension (Tmax) and relaxed again in solution at pCa 9. After emptying the SR by a brief application of caffeine (5 mM), loading was carried out in strongly Ca2+-buffered (10 mM EGTA) loading solutions at pCa 6.25 to maintain a constant [Ca2+] near the Ca2+ pump. The SR was loaded with Ca2+ for 3 min under different test conditions: 3.16 mM MgATP alone, 3.16 mM MgATP and 12 mM PCr, or 3.16 mM MgATP in the presence of glycolytic substrates and cofactors (4 mM nicotinamide adenine dinucleotide, 4 mM glyceraldehyde-3-phosphate, 4 mM phosphoenolpyruvate, and 2 mM inorganic phosphate).
After loading was completed, excess EGTA was washed out (solution W) before an application of 5 mM caffeine at low [EGTA] (0.35 mM). The caffeine-induced tension transient was used to calculate the time course of free [Ca2+] close to the myofibrils during the release by taking pCa/tension dependence as an internal calibration (5)
. Data from each fiber were fitted to the Hill equation using linear regression analysis; the pCa for half-maximal tension (pCa50) and the Hill coefficient (nH) were determined. The [Ca2+] at each step of the tension-time integral was recalculated using Labview software (National Instruments Corporation, Austin, TX) to obtain [Ca2+] time integrals (SCa), taken to evaluate SR Ca2+ loading capacity and kinetics.
Cell isolation
All cellular methods were the same as those we used earlier (12)
. Cardiac myocytes were obtained from male Wistar rat hearts (270–300 g) and isolated as before (12)
. After anesthesia, the heart was perfused under a Langendorff column, allowing a retrograde perfusion of the heart for 5 min by a Ca2+ free solution, followed by a 40 min infusion of the same buffer in which collagenase A (1.2 mg/ml) was added. The heart was removed from the column and cut into small (1 mm) pieces in the same Ca2+ free buffer. Cells were filtered, washed, and Ca2+ (1.2 mM) was reintroduced. At the end of this procedure, 
80% of myocytes had a normal architecture, were quiescent, and could be electrically stimulated. Cardiomyocytes were resuspended in a culture medium and placed on Petri dishes coated with laminin (30 µM/ml) for 3 h at 37°C in an incubator with room air supplemented with 5% CO2.
Fluorescence measurements
Before each experiment, the cells were preloaded for 15 min at room temperature with indo 1/AM by incubation in 200 µl culture medium containing 10 µg indo-1/AM, 180 µl bovine serum albumin and 5 µg pluronic acid in 5 µl dimethylsulfoxide. The cells were washed and maintained at room temperature for 40 min in the culture medium before the fluorescence measurements.
Cytosolic Ca2+ measurements were carried out by dual-emission microfluorometry with the indo-1/AM probe (Hamamatsu France). Cells loaded with the fluorescent probe were excited through a 40x oil immersion objective using a 100 W xenon light (neutrally attenuated to avoid bleaching) and filtered at 360 nm. Excitation and emission beams were separated by a 380 nm dichroic filter. Emission spectra were divided in two by a 455 nm dichroic filter. From the halves of the indo-1 emission spectra, two signals were selected by interference filters at 405 and 480 nm. These signals were recorded by photometers and passed to an amplifier. The fluorescence ration F405/F480, which is independent of the probe concentration, was calculated directly from both signals. All optics and photometers for indo-1 were obtained from Nikon-France.
Experimental protocol and fluorimetry data analysis
Electrical pacing was performed using a Harvard stimulator delivering 40 V stimuli 10 ms in duration at a frequency of 1 or 4 Hz. Cells were continuously perfused at a rate of 2 ml/min by the Krebs solution at room temperature. Each cell isolation allowed the seeding of 30 Petri dishes. One to 3 cells could be observed in each field of the microscope. Regular pacings at 1 and 4 Hz were performed at a sampling interval of 20 ms for 2.88 s. This allowed measurement of 2–3 beats at 1 Hz and 10–12 beats at 4 Hz. To compare the four successive beats of a 1 Hz pacing after a 2–3 min interruption in pacing (post-pause beats), an 8.52 s recording was obtained at a lower speed of image acquisition (72 images separated by 120 ms intervals). We had verified that this procedure did not produce significant attenuation of the measured peak of the Ca2+ transient by comparing it with that obtained at the maximal rate of acquisition of the system (20 ms intervals). After recording these pacings, the bath inside the Petri dish was aspirated and replaced by the solution containing isoprenaline 10-7 M. A recording was made during a 4 Hz pacing after 30 s of isoprenaline infusion. Not all interventions were obtained in all cells.
The mean ratio image of each cell was calculated by the average of all points included in the cell area (Fig. 2)
. The 405/480 ratio values were used as indices of Ca2+ concentrations. Two time points were measured: end diastole (at the bottom of the Ca2+ rising) and the peak of the Ca2+ ratio (systolic Ca2+). The Ca2+ transient (or 
ratio) was the difference between these points.
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Cell shortening during systole was measured by video edge detection of the cells. Systolic shortening was expressed in % as (diastolic value-systolic value)/diastolic value * 100.
In vivo evaluation of ventricular function
An echocardiographic examination was performed in CK+/+ and CK-/- mice using a VINGMED CFM750 echocardiograph with a 9 MHz probe. After intraperitoneal (i.p.) anesthetization with ketamine (0.065 mg/g) and xylazine (0.013 mg/g) and bidimensional short axis examination, a TM line was drawn between papillary muscles in order to record instantaneous left ventricular septum-free wall diameter.
Measured parameters were heart rate, end-diastolic diameter, end-systolic diameter, and the % of systolic diameter shortening (%D) defined as (end-diastolic diameter-end-systolic diameter)/end-diastolic diameter * 100.
After recordings in the basal control state, a 0.02 µg/g isoprenaline dose was injected i.p. and physiological parameters were measured at the peak of monitored heart rate.
To obtain heart rate in a more physiological range than that obtained with xylazine-ketamine anesthetization, the same echocardiographic examination was again performed a week later in the same mice under etomidate (35 µg/g, Jansen-Cilag Laboratory) anesthetization, which allowed higher basal heart rates. Aortic blood pressure was measured during control and isoprenaline injection using a fluid-filled polyethylene catheter (x mm internal diameter) inserted into the right carotid artery.
Statistical analysis
Values are means ± SE. In skinned fiber experiments, a one-way analysis of variance was performed, followed by a Bonferroni post hoc test to compare means. Since only one intervention was performed, paired t tests were used in cellular and in vivo experiments to analyze the effect of an intervention; the Student’s t test was used to compare CK-/- with CK+/+ mice.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(upper panels) demonstrates qualitatively the tension-time relationship observed in skinned fibers from control (CK+/+) and CK-deficient (CK-/-) mice in the presence of ATP and glycolytic substrates. It is clear that both the time-to-peak tension after addition of caffeine (Ca2+ release) and the time-to-half relaxation (Ca2+ reuptake/loss to medium) are increased in CK-/- fibers compared with those from CK+/+ mice. Figure 1
(lower panels) shows calculated time constants for the kinetics of Ca2+ release and relaxation. These are derived from the tension-time curves described previously (5)
.
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The time-to-peak Ca2+ is significantly increased in CK-/- compared with CK+/+ mice when ATP is used solely as the fuel source for the SR Ca2+ ATPase. The inclusion of glycolytic intermediates (and/or PCr for CK+/+ fibers) in the incubation medium significantly increases the rate of Ca2+ release in CK+/+ and CK-/- fibers, but this is still significantly delayed in the CK-/- mice. Half-time for the reuptake/loss to medium of Ca2+ is significantly increased in CK-/- mice, although the inclusion of glycolytic intermediates had no effect in this case (or for CK+/+ mice), perhaps indicating a more structural rather than energetic explanation.
Isolated cell experiments
Effect of different pacing rates on Ca2+ transient and cell shortening
When cells were analyzed at regular pacing rates of 1 and 4 Hz, a negative staircase was observed in CK+/+ and CK-/- mice (Fig. 2
, left panels). The Ca2+ transient evaluated as the change in 405/480 ratio between diastole and systole decreased significantly in both groups. Systolic cell shortening was significantly decreased in CK+/+ during the 4 Hz pacing vs. the 1 Hz pacing (Fig. 2
, lower left panel). A decrease in cell shortening was also observed in CK-/- cell but was not statistically significant.
We then analyzed in detail Ca2+ transient and cell shortening during the 1 Hz beats after a 2–3 min pause. Figure 3
shows a typical example of cellular Ca2+ measurements and Fig. 4
shows mean values of the peak of the Ca2+ transient (left panels). In CK+/+ mice, the Ca2+ transient of the post-pause beat (Figs. 3
, 4)
was significantly larger than that of the ensuing beat. There was no significant change of ratio in the two ensuing Ca2+ transients. There was no change in Ca2+ transient in cardiomyocytes obtained from CK-/- mice when post-pause beats were compared to ensuing beats (Figs. 3
, 4)
.
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In contrast to the absence of post-pause Ca2+ transient potentiation observed in CK-/- mice, there was significant systolic shortening potentiation in the post-pause beat of these cells compared with the ensuing beats (Fig. 4
, lower right panel). This potentiation was similar to that observed in CK+/+ mice (Fig. 4
, upper right panel).
To understand why there was a larger systolic shortening in the post-pause beat than in the ensuing beat in the absence of an increase in the Ca2+ transient peak in this beat, we analyzed decay of the Ca2+ transient by measuring the decrease of the 405/480 ratio during the 240 ms after its peak. In CK-/- cardiomyocytes, the value of the ratio decreased by 50.5 ± 6.8% in the post-pause beat. The fall was significantly larger in the ensuing beat (66.1±8.2%; P<0.005 with the post-pause beat), indicating a longer Ca2+ transient in the first vs. the ensuing beat. This behavior is similar to that measured in cardiomyocytes obtained from CK+/+ mice (53.0±7.0% and 76.2+/+ 5.3% in the post-pause and the ensuing beat, respectively; P<0.001).
Thus, there was no post-pause potentiation of the peak of Ca2+ transient in CK-/- cardiomyocytes, but post-pause potentiation of shortening was preserved due to maintenance of the prolongation of Ca2+ transient in the post-pause beat.
Cellular response to isoprenaline
In control mice, a test dose of 10-7 M isoprenaline (Fig. 2
, right panels) increased the Ca2+ transient to 188 ± 28% (P<0.02) and % cell systolic shortening to 240 ± 37% of control (P<0.02). In cardiomyocytes obtained from CK-/- mice, isoprenaline produced a 175 ± 25% increase in Ca2+transient, similar to that of CK+/+ mice. However, % cell systolic shortening was minimal and not significantly increased (136±33% of control, NS).
In vivo evaluation of ventricular function
To evaluate the in vivo consequences of CK deficiency on cardiac work, we measured ventricular function by echocardiographic methods at baseline and under isoprenaline injection using different anesthetic procedures. Results obtained under xylazine-ketamine anesthetization are given in Fig. 5
. The increase in heart rate produced by isoprenaline was similar in CK+/+ and CK-/- mice (+63.1±22.7% and+56.0±6.8%, respectively). End-diastolic diameters were significantly and similarly decreased after isoprenaline injection in both groups (CK+/+: from 4.03±0.14 to 3.32±0.18 mm; CK-/- from 4.03±0.09 to 3.34±0.26 mm; both ps<0.05). End-systolic diameters were significantly decreased in both groups (CK+/+: 2.40±0.11 to 1.38±0.22 mm; CK-/-: 2.29±0.17 to 1.88±0.21 mm; both ps<0.05) but the decrease in end-systolic diameter was larger in CK+/+ mice, leading to a significant increase in % D in CK+/+ mice and an unchanged % D in CK-/- mice (Fig. 5)
.
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Results obtained under etomidate anesthetization were directionally similar (Table 1)
. Basal heart rates were closer to mice physiological values (500 beats/min) and increased similarly in both groups under isoprenaline, although the increase was smaller than under xylazine-ketamine anesthetization (+39.5±14.7% in CK+/+ mice and +25.3±6.8% in CK-/- mice). The % D increased after isoprenaline challenge in both groups, but the increase tended to be smaller (but not significantly) in CK-/- mice (+5.7±1.7%) than in CK+/+ mice (+12.5±1.8%). However, the decrease in systolic and diastolic aortic pressures induced by isoprenaline (Table 1)
was markedly larger in CK-/- (61.6±7.6 mmHg and 48.8±5.0 mmHg, respectively) than in CK+/+ mice (25.6±4.3 mmHg and 19.6±3.3 mmHg, respectively; both ps<0.005).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Modifications of cellular Ca2+ homeostasis
The tight coupling between SR Ca2+ ATPase activity and MM-CK has been demonstrated in in vitro SR vesicles and in situ. Broadly, speaking, cardiac SR Ca2+uptake is more efficient when ATP can be regenerated locally from ADP produced by the SR ATPase than when exogenous ATP is provided (5
, 13
, 14)
. This has been interpreted as impaired diffusion of adenine nucleotides due to highly crowed cytoplasm and ordered cytoarchitectural organization of cardiac cells. ATPase activity is thermodynamically and kinetically controlled by the ATP/ADP ratio close to the active site. The local control of adenine nucleotide concentration thus is of primary importance for rapid Ca2+ uptake and efficient contractile speed. Aside from MM-CK, this local control is shared by glycolytic complexes (10
, 15
, 16)
. Moreover, in cardiac cells, the existence of a direct functional energetic cross-talk between mitochondria and SR brought about by close contact between organelles was recently demonstrated (11)
. The existence of multiple ATP regenerating processes highlights the importance of the local control of adenine nucleotide pools for cellular efficiency.
In skinned fibers, a previous study (10)
used the amplitude of the caffeine-induced tension transient to assess the amount of Ca2+ loaded into the SR, showing that glycolysis could replace the CK system in fueling SR Ca2+ ATPase. In the present study, the marked slowing of the kinetics of caffeine-induced Ca2+ release in CK-deficient mice (Fig. 1)
suggests a slowing of Ca2+ release of the SR. The kinetics more nearly resembles those found in atria than ventricles (17)
, interpreted because of morphological differences between the two tissues. Various factors may contribute to these changes. Adenine nucleotide content is a modulator of the velocity of Ca2+ efflux (18
, 19)
. In the absence of CK, the decrease in ATP/ADP ratio may contribute to a smaller velocity and amount of Ca2+ released. However, a slowing of the kinetics was not observed in control mice when PCr was omitted, suggesting a more complex origin. It is possible that the slowed kinetics of Ca2+release in CK-/- mice that persisted with glycolytic load may originate from the marked cytoarchitectural modifications observed in CK-/- cardiomyocytes (11)
. Other proteins involved in Ca2+ cycling may contribute to the slowing of Ca2+ release in skinned fibers—for instance, FKBP 12.6, a protein that modulates the gating of ryanodine channels (20
, 21)
.
Although in skinned fibers caffeine-induced Ca2+ release kinetics was not markedly improved (Fig. 1)
, in isolated cells, the kinetics of the Ca2+ transient was completely normal. There are thus compensatory pathways other than the glycolytic pathway that allow a normal Ca2+transient in cardiomyocytes of CK-deficient mice. A major difference between skinned fibers and whole cells in these experiments is the absence of functioning mitochondria in the former. Mitochondria have been shown to interact tightly with the SR to rapidly modulate calcium movements (22)
and high-energy phosphates (11)
. In the model of CK-deficient mice, Kassik et al. (11)
recently showed a tighter interaction between mitochondria and organelles. The present study further extends the hypothesis that a cellular remodeling may in part compensate for the absence of CK, perhaps by increasing interactions between mitochondria and ATP-consuming organelles at the level of calcium and energy metabolism.
Frequency-dependent changes in Ca2+ transient and shortening: relations with SR function
Analysis of frequency modulation of cellular function is an indirect approach in the analysis of SR Ca2+ homeostasis at the whole cell level. The cellular response to an increased rate of pacing (1–4 Hz; Fig. 2
) was as expected in CK+/+ mice: Ca2+ transient and systolic shortening significantly decreased when heart rate was increased, corresponding to the negative staircase usually observed in small rodents with an abundant SR (23)
. The response was similar in CK-/- mice, showing a normal adaptation of cardiomyocytes to heart rate changes.
In contrast to the normal cardiomyocyte response to heart rate changes, the response after a pause was different in CK+/+ and CK-/- cardiomyocytes. The peak of Ca2+transient was not increased after a long pause in CK-/- cardiomyocytes (Figs. 3
, 4)
. The absence of post-pause potentiation of Ca2+ transient may be explained by the absence of an increase in SR Ca2+ load during a long pause. However, post-pause potentiation may occur even without changes in SR Ca2+ content (24
, 25)
. Another possible mechanism is an increased rate of Ca2+ release by SR (26)
due to the recovery from refractoriness of ryanodine receptors (26
27
28)
, a process, called adaptation (29
, 30)
, which recovers time dependently (31)
. Thus, after a long pause, the recovery of refractoriness may be completed and induce a larger Ca2+ release than during steady state. An abnormality in the adaptation process of ryanodine receptors may explain the absence of post-pause potentiation of Ca2+ transient in CK-/- cardiomyocytes. In contrast, maintenance of the post-pause shortening can be attributed to the longer duration of Ca2+ transient in the post-pause beat than in the ensuing beat, similarly in CK-/- and in CK+/+ mice (Fig. 3)
, leading to a larger amount of released Ca2+ despite the absence of an increased peak of Ca2+ transient.
In vivo and cellular ß-adrenergic response.
Application of echocardiography to small animals provides a unique way to assess more physiological cardiac function in the basal state and under ß-adrenergic stimulation. In the basal state, ventricular function was normal in CK-/- mice (Fig. 5
, Table 1
). This is similar to what has been shown in isolated hearts from these mice (8)
. However, the increase in ventricular function in response to isoprenaline in vivo was completely blunted in mice under xylazine-ketamine anesthetization (Fig. 5)
. The response was also decreased under etomidate anesthetization but not abolished (Table 1)
. Since aortic pressure decreased more under isoprenaline in CK-/- than in CK+/+ mice, the decrease in afterload was larger in CK-/- mice; thus, the increase in %D should have been larger than in CK+/+. This strongly suggests there is an abnormal ventricular response to ß-adrenergic challenge in mice lacking both isoforms of CK. This is confirmed by the longer end systolic LV diameter in CK-/- than in CK+/+ in the presence of isoprenaline for a smaller aortic systolic pressure (Table 1)
and is in line with the blunted contractile response to isoprenaline of CK-/- cells (Fig. 2)
.
An abnormal adrenergic signal transduction in CK-/- mice could be responsible for these abnormal contractile responses. This possibility is unlikely, however, since the heart rate response in vivo was similar in both types of mice (Fig. 5
and Table 1
) and the Ca2+transient response was similar in CK-/- and CK+/+ mice (Fig. 2)
, suggesting that the abnormality was probably not at the receptor or postreceptor level but at the intracellular level.
Cardiomyopathy could be responsible for this alteration in cardiac response to catecholamines, but this is also unlikely. End-diastolic diameter was larger under etomidate anesthetization in CK-/- but heart rate was slower (Table 1)
; under xylazine-ketamine anesthetization for similar heart rates, end-diastolic diameters were similar in both groups (Fig. 5)
. There was no change in end-diastolic wall thickness (Table 1)
. These mice were shown to have a similar increase in ventricular function in isolated hearts under increased Ca2+ concentration in the perfusate but with a more ‘energetically costly’ increase in cardiac work in terms of high-energy phosphate use (8)
. The energy demand of an in situ heart is larger than that of an in vitro isolated heart. It has been calculated that in vitro work of an isolated mouse heart was only 20% of that maximally achievable in situ (32)
. It is likely that alternate pathways compensating for the absence of CK previously discussed allow a full compensation of ventricular function in the basal state, but when the energy demand is markedly and abruptly increased (such as during ß-adrenergic stimulation), they are unable to compensate for the absence of CK.
In conclusion, the present study shows that in the absence of CK, compensatory pathways (glycolytic pathway and interaction with mitochondria) allow a quasi-normal Ca2+ homeostasis with abnormalities only in beat-to-beat adaptation of the cell Ca2+ transient in isolated cells. In contrast (and more important), although these pathways may appear redundant, allowing a normal in vivo basal cardiac function in CK-deficient mice, they are not sufficient to cope with a large and rapid increase in energy demand produced by ß-adrenergic stimulation. This reveals the specific role of CK at the cardiac muscle level that cannot be compensated for by other pathways.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received for publication October 31, 2001. Accepted for publication December 7, 2001.
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REFERENCES |
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P < 0.01; 
