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J Am Coll Cardiol, 2001; 37:463-469
© 2001 by the American College of Cardiology Foundation
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CLINICAL STUDY: MYOCARDIAL ISCHEMIA

Myocardial perfusion imaging findings and the role of adenosine in the warm-up angina phenomenon

Peter Bogaty, MDa, John G. Kingma, PhD, FACCa, Jean Guimond, MDa, Paul Poirier, MDa, Luce Boyer, RNa, Lyne Charbonneau, RNa and Gilles R. Dagenais, MD, FACCa

a Quebec Heart Institute/Laval Hospital, Laval University, Sainte-Foy, Quebec, Canada

Manuscript received March 15, 2000; revised manuscript received September 18, 2000, accepted October 26, 2000.

Reprint requests and correspondence: Dr. Peter Bogaty, Quebec Heart Institute/Laval Hospital, 2725 Chemin Sainte-Foy, Sainte-Foy, Quebec, Canada G1V 4G5
peter.Bogaty{at}med.ulaval.ca


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

This study examined the roles of myocardial perfusion and adenosine in warm-up angina.

BACKGROUND

In warm-up angina, neither the role of an adenosine-mediated mechanism, as is found in experimental ischemic preconditioning, nor of increased myocardial perfusion is well defined.

METHODS

In substudy A, a single-photon emission computed tomography (SPECT)-thallium-201 exercise test was performed by 12 subjects with ischemic heart disease on three occasions one week apart. The third test was preceded by a warm-up test. The extent of the thallium deficit and its intensity on the third test were compared with the baseline tests controlling for the heart rate-systolic blood pressure product (RPP) at thallium injection. In substudy B, 12 similar subjects did two successive exercise tests at two separate sessions and received the adenosine antagonist, aminophylline (intravenous 5 mg/kg bolus and 0.9 mg/kg/h infusion) at one session, and equivalent saline at the other session. Change in ischemic threshold (RPP at 1 mm ST segment depression) and in maximum ST depression adjusted for RPP were analyzed.

RESULTS

In substudy A, despite a significant attenuation of electrocardiogram indexes of myocardial ischemia between the baseline and third (warmed-up) tests, the thallium extent deficits (20.8 ± 15.1% and 16.8 ± 12.4%) and intensity deficits (41.2 ± 12.6% and 39.3 ± 12.6%) did not differ significantly. In substudy B, the increase in ischemic threshold on re-exercise was unaffected by aminophylline. Adjusted maximum ST depression even decreased to a greater extent on re-exercise with aminophylline (by 51 ± 21%) than with saline (by 32 ± 19%) (p = 0.012).

CONCLUSIONS

While warm-up angina is associated with a significant attenuation of exercise electrocardiogram indexes of ischemia, it is unaccompanied by significant changes in SPECT perfusion and does not appear to be mediated by an adenosine-dependent mechanism since it is not blocked by aminophylline. Thus, its mechanism, which appears distinct from experimental ischemic preconditioning, remains unidentified.

Abbreviations and Acronyms
  CAD = coronary artery disease
  ECG = electrocardiographic, electrocardiogram
  K+-ATP = adenosine triphosphate-sensitive potassium channel(s)
  RPP = heart rate-systolic blood pressure product
  SPECT = single-photon emission computed tomography (or tomographic)
  STD = ST segment depression
  Tl-201 = thallium-201

Warm-up angina is an intriguing phenomenon whereby, in subjects with coronary artery disease (CAD), the angina induced by initial exercise is attenuated, or even disappears, if they briefly slacken or interrupt their exertion before resuming it at the same or an even greater level of intensity (1–7). This attenuation of myocardial ischemia can be objectified using a protocol of two exercise electrocardiographic (ECG) tests separated by a brief rest (4–7). Its underlying mechanism is undefined. This ischemia-sparing phenomenon does not appear to be associated with downregulation or stunning of left ventricular contractile function, variations in adrenergic tone or activation of adenosine triphosphate-sensitive potassium channels (K+-ATP) (7). It has been speculated that it could be analagous to experimental ischemic preconditioning in which, in animal models, brief coronary artery occlusion preceding sustained occlusion, followed by timely reperfusion, can considerably reduce infarct size (8). In humans in a variant of this model, during coronary angioplasty, brief inflations of the balloon catheter before longer inflation attenuate ECG and other manifestations of myocardial ischemia (9,10). In experimental ischemic preconditioning and its human variant, adenosine has been identified as a key mediator, but the role of increased myocardial perfusion through the collateral circulation is controversial (10–16). Therefore, to explore the underlying mechanism and the relationship, if any, with experimental ischemic preconditioning, this study evaluated the roles in warm-up angina of adenosine and of myocardial perfusion, as determined by single-photon emission computed tomography (SPECT) using thallium-201 (Tl-201).


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
This study consisted of two substudies. Substudy A evaluated the role of myocardial perfusion in warm-up angina using SPECT; substudy B examined the role of adenosine using the nonspecific adenosine receptor antagonist, aminophylline. All 21 subjects in this study had to have: 1) stable angina; 2) documentation of CAD with coronary angiography (≥70% coronary artery stenosis) in 13 subjects and with Tl-201 myocardial perfusion imaging (significant reversible hypoperfusion) in 8 subjects; 3) a previous positive ECG exercise test (≥1 mm ST segment depression 80 ms after the J point compared with the baseline ST segment); and 4) a resting ECG without left ventricular hypertrophy, conduction abnormality or ST segment deviation ≥1 mm. All subjects were in normal sinus rhythm. In addition, in order to optimize interpretation of the myocardial perfusion scans, all subjects in substudy A had to have documented normal left ventricular contractility, an effort-induced Tl-201 deficit of at least 10% (see subsequent text) and a redistribution Tl-201 scan within normal limits (not suggestive of prior myocardial infarction). All subjects had previously performed several reproducible exercise tests and were well familiar with this procedure. Each substudy involved 12 subjects; three subjects participated in both substudies. The hospital institutional review board approved both substudies, and all patients gave written informed consent.

Exercise ECG protocol.   In both substudies, beta-blocking and calcium antagonist drugs were stopped at least 48 h and nitrates at least 12 h before testing. No patients were taking digitalis. All tests in substudy A were performed in midmorning in the fasting state and all tests in substudy B in midafternoon at least 2 h postprandially and with no consumption of caffeinated beverages that day. Subjects were instructed to refrain from exercise or unusual exertion and not to smoke that day prior to exercise testing. In both substudies, the symptom-limited modified Bruce protocol was used on a Q65 treadmill linked to a Q4000 monitor (Quinton Instrument Co., Seattle, Washington). The ECG was continuously monitored. A standard 12-lead ECG was taken in the resting, supine and standing positions and then every 30 s during exercise and recovery, which was in the sitting position. Each time, both an averaged and a raw data ECG were obtained. Blood pressure was obtained with a mercury sphygmomanometer every 2 min and at peak exercise. Indications for stopping the exercise test were uncomfortable dyspnea or angina (always aiming for the same discomfort score of 7/10 on a visual scale), a drop in blood pressure >10 mm Hg or a serious arrhythmia. The ECG display screen was shielded such that both subject and medical supervisor were blinded to exercise duration. The same physician supervised all tests. The warm-up protocol involved two successive exercise tests separated by an interval of about 10 min, which depended on subjects’ willingness to re-exercise and return of the ST segment to its original resting baseline (7). The second exercise is referred to as the warmed-up test.

The exercise test was considered positive at first appearance of sustained 1 mm ST segment depression 80 ms after the J point, compared with the resting ECG taken in the standing position just before exercise. The raw data and averaged tracings were examined for consistency requiring three consecutive beats with similar findings. The time of onset of exercise test positivity and the corresponding heart rate-systolic blood pressure product (RPP) or ischemic threshold were noted as was the time of onset of angina. Maximum ST segment depression was noted on raw data and averaged tracings taken at peak exercise. When a warmed-up exercise ECG test was compared with a baseline test, adjusted maximum ST segment depression was also analyzed (7). This was the amount of ST segment depression (STD) at or near peak exercise corresponding to the highest RPP common to both exercises. ST segment recovery time was from end-exercise to the final appearance of 1 mm STD. Since T wave inversion often occurs during recovery and appears to drag down the ST segment, the latter was carefully scrutinized, and, if it rose during recovery to less than 1 mm depression only to subsequently drop down with T wave inversion, this latter change was not considered as recovery time (17). After all patients had been studied, exercise tracings were analyzed independently by two examiners, unaware whether the exercise test was a baseline or a warmed-up test, and differences were resolved by consensus. Only the evaluation of adjusted maximum STD was, of necessity, performed after unblinding.

Substudy A: nuclear imaging protocol and data analysis.   Subjects were studied at three separate sessions one to three weeks apart. At the first session, they performed a single symptom-limited exercise Tl-201 SPECT test. One minute before the anticipated end of exercise, 3.0 mCi (111 MBq) of Tl-201 was injected intravenously and flushed with 10-ml saline. At the second session, they performed another such test except that Tl-201 was administered at the RPP, which was as close as possible to that of the Tl-201 injection at the first session; the test was terminated 1 min later. The Tl-201 exercise tests of these first two baseline sessions established inter-test variability. At the third session, subjects performed the two successive exercise tests of the warm-up protocol with Tl-201 administered at the warmed-up test, again at a RPP that was as close as possible to that at Tl-201 injection in the baseline tests. This warmed-up test was also terminated 1 min after injection. The findings of the warmed-up test were compared with those of the baseline test with the closest RPP at Tl-201 injection. Recovery time was truncated at 2 min in this substudy because of the need to proceed with the scintigraphic imaging protocol. Subjects were then taken by wheelchair within 5 min to the scintigraphic imaging camera.

A 5-min planar anterior view was first obtained within 10 min of injection, followed by SPECT imaging performed on a large field-of-view single head rotation gamma camera with a 0.37-inch thick sodium iodide crystal and 65 photomultiplier tubes (Siemens Orbiter, Chicago, Illinois) equipped with a low energy all-purpose parallel hole collimator. The system was linked to a Siemens Microdelta computer. A 20% energy window centered on the 80 Kev x-ray peak and a 10% window centered on the 167 Kev gamma-ray peak were used. Sixty-four 20-s projections were acquired over a 180° arc, extending from the 45° right anterior oblique to the 45° left posterior position using a circular orbit. Data were stored in a 64 x 64 16-bit (word) matrix. Field-nonuniformity and center-of-rotation offset corrections were performed before reconstruction. A Butterworth filter with 0.4 cutoff and an order of 5.0 was used for processing the raw data after prereconstruction interslice averaging using a 0.25, 0.50, 0.25 weighting array. Sections were reconstructed in short, vertical-long and horizontal-long axes.

Redistribution imaging was performed 4 h after Tl-201 injection using the same parameters of acquisition and reconstruction without reinjection of Tl-201. After reconstruction, all images were checked and realigned, if necessary, for appropriate registration of stress and redistribution images in each plane. Two-dimensional polar map display representing extent and severity of disease were generated for the initial tomograms and delayed tomograms using commercially available software (18,19).

One pixel thick (6 mm) contiguous slices were added together in the three axes to obtain 2 pixel thick (12 mm) slices. After visual inspection and qualitative appreciation of myocardial perfusion defects, the severity of disease was characterized as the ischemic/normal wall ratio obtained from circumferential profiles on the slice showing the most severe Tl-201 perfusion defect (maximum deficit). The extent of the perfusion abnormality was evaluated by the percentage of abnormal myocardium on extent polar map display. These methods of measuring the extent and severity of myocardial ischemia have been validated previously (18–20). All scintigrams were evaluated by a single experienced specialist in cardiac nuclear medicine unaware of the patients’ other clinical data. In all cases, Tl-201 heart/lung uptake ratios were assessed from stress and redistribution planar views to rule out any possible underestimation of disease severity due to diffuse multivessel disease. Subjects were eliminated from analysis after the initial control study if the maximum severity deficit was <20% or the extent deficit was <10% because of the difficulty in such subjects of measuring a possibly significant difference from findings on the warmed-up test.

Substudy B protocol.   In this protocol, subjects came to two exercise test sessions one to four weeks apart. At each session, they performed the two successive ECG exercise tests of the warm-up protocol. The interval between the two tests of the first session was kept identical at the second session. At each session, intravenous access was secured, and, in double-blind fashion and in random order, at one session, aminophylline, the ethylenediamine salt of theophylline, was administered as a 5 mg/kg intravenous bolus over 5 min followed by a 0.9 mg/kg/h intravenous infusion, and, at the other session, equivalent saline was given. The first exercise test was commenced after bolus drug administration and the infusion stopped at the end of the recovery period of the second test. Serum theophylline was measured at that time using a homogeneous enzyme immunological assay (Cedia) on a Hitachi 917 apparatus (Roche Diagnostics, Laval, Quebec). All ECG tracings were analyzed blinded to aminophylline versus saline administration and to the order of the tests, as already described.

Statistical analysis.   Values are expressed as means ± standard deviation. The paired Student t-test was used to compare intrasession and intersession exercise ECG and scintigraphic parameters. Data for substudy B comparing saline to aminophylline were analyzed using a two-way repeated-measures analysis of variance. Relationships between serum theophylline levels and changes in the ischemic threshold and in adjusted maximum STD from the first to the second exercise were evaluated using Pearson’s correlation coefficients. A p value ≤0.05 was considered statistically significant. Data were analyzed using the statistical package SAS (SAS Institute Inc., Cary, North Carolina).


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Substudy A.   The 11 men and one woman of this substudy were aged 55 ± 8 years. Three patients had single-vessel angiographic coronary disease or single-region disease by scintigraphic imaging, and nine patients had multivessel or multiregion disease. Exercise duration and workload achieved in the baseline test used in the comparative analysis were 11.2 ± 2.8 min and 8.9 ± 2.6 metabolic equivalent units, respectively. The ischemic threshold (x10–3) increased from 17.3 ± 3.6 in the baseline test to 20.0 ± 3.9 in the warmed-up test, an increase of 16.5 ± 12.5% (p = 0.002) in 10/12 subjects (Fig. 1). This parameter could not be analyzed in the remaining two subjects because their warmed-up tests were negative, and peak RPP in their warmed-up tests was below the ischemic threshold of their baseline tests. The adjusted maximum STD decreased by 28.9 ± 38.6% from 3.1 ± 1.5 mm in the baseline test to 2.0 ± 1.2 mm in the warmed-up test (p = 0.015) (Fig. 1).



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  		Figure 1 The ischemic threshold and the adjusted maximum (max) ST segment depression in exercises 1 and 2 of the scintigraphic study (substudy A). The ischemic threshold is the heart rate-systolic blood pressure product x 10–3 at the appearance of 1 mm ST segment depression. Adjusted max ST depression is the maximum ST segment depression corresponding to the highest heart rate-systolic blood pressure product common to both exercises. Exercise 1 is the baseline exercise electrocardiogram Tl-201 test, which was used in the analysis, and exercise 2 is the warmed-up Tl-201 test of the third exercise session. Tl-201 = thallium-201.

 
The variability in the ischemic extent score between the two baseline tests was 6.9 ± 3.7% and was established by comparing the extent deficits in the two baseline tests of those subjects (6 of the 12 subjects studied) whose RPPs at Tl-201 injection differed by less than 5% (1.3 ± 1.4%). The mean difference in RPPs at Tl-201 injection between the baseline tests and the warmed-up tests was minor at 3.8 ± 1.9%. Since myocardial oxygen consumption at Tl-201 injection could, thus, be assumed to be quite similar, the myocardial scintigrams of the two tests could be compared. The extent deficit of the baseline test was 20.8 ± 15.1% and was 16.8 ± 12.4% in the warmed-up test (p = 0.11) (Fig. 2). This difference (6.6 ± 5.9%) was within the inter-test variability established by analysis of baseline tests. As for the maximum deficit, there was no significant difference in this scintigraphic parameter between the baseline test (41.2 ± 12.6%) and the warmed-up test (39.3 ± 12.6%) (Fig. 2).



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  		Figure 2 The myocardial Tl-201 percent extent and percent maximum deficit perfusion defects at exercises 1 and 2 in substudy A. Exercise 1 is the baseline exercise Tl-201 test, which was used in the analysis, and exercise 2 is the warmed-up Tl-201 test of the third exercise session. Tl-201 = thallium-201.

 
Substudy B.   The 10 men and 2 women of this substudy were aged 62 ± 7 years. Seven patients had single-vessel coronary disease or single-region disease by scintigraphic imaging, and five patients had multivessel or multiregion disease. All had normal left ventricular contractility. Inter-test time at both sessions was 11 ± 3 min. Serum theophylline was 30.1 ± 10.3 µmol/L. Electrocardiogram exercise parameters are summarized in Table 1. The slightly more prolonged exercise time at exercise 2 compared with exercise 1 was no longer observed with aminophylline. Heart rate-systolic blood pressure product at rest and at peak exercise was higher at exercise 2 compared with exercise 1 with and without aminophylline. Heart rate-systolic blood pressure product at rest tended to be higher with aminophylline than with saline at exercise 1 (p = 0.09) and was higher at exercise 2 (p = 0.04); RPP at peak exercise was higher with aminophylline than it was with saline (p = 0.01). While time to angina was slightly longer at exercise 2 compared with exercise 1 with saline, there was no change with aminophylline. Maximum STD and recovery time both decreased at exercise 2, and this was unaffected by aminophylline. With aminophylline, the ischemic threshold at exercise 1 was 13 ± 16% higher than the level observed with saline (p = 0.016) (Fig. 3). However, whereas the ischemic threshold (x10–3) increased significantly at exercise 2 from 22.1 ± 4.2 to 25.5 ± 5.3 with saline (p < 0.001), a similar increase was also observed from 25.0 ± 5.9 to 28.3 ± 6.1 (p < 0.001) with aminophylline. Nor was there a correlation between serum theophylline levels and any change in ischemic threshold from exercise 1 to exercise 2 (r = 0.02, p = 1.0). The adjusted maximum STD decreased markedly at exercise 2 compared with exercise 1 with saline (2.6 ± 0.8 to 1.8 ± 0.8 mm, p < 0.001) as with aminophylline (2.5 ± 1.0 to 1.3 ± 1.0 mm, p < 0.001) (Fig. 4). Interestingly, the degree of attenuation of this parameter was even greater with aminophylline (51 ± 21% versus 32 ± 19%, p = 0.012). There was no correlation between serum theophylline levels and the change in adjusted maximum STD from exercise 1 to exercise 2 (r = 0.06, p = 0.8).


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  		Table 1 Exercise ECG Parameters in Substudy B

 


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  		Figure 3 Ischemic thresholds of ex 1 and 2 at the 2 ex sessions. Subjects received intravenous saline at one session and intravenous aminophylline at the other session. See Figure 1 and text for definition of the ischemic threshold. *Aminophylline at ex 1 versus saline at ex 1, p = 0.016. ex = exercise.

 


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  		Figure 4 Adjusted maximum (max) ST segment depression of ex 1 and 2 at the saline and aminophylline exercise electrocardiogram sessions. See Figure 2 and text for definition of adjusted maximum ST depression. ex = exercise. *Decrease in adjusted max ST depression from ex 1 to ex 2 with aminophylline compared with decrease with saline, p = 0.012.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The principal findings of this study are: 1) the attenuation of myocardial ischemia observed with repeated exercise is not accounted for by an improvement in myocardial perfusion as determined by Tl-201 SPECT imaging, and 2) this phenomenon does not appear to be mediated by an adenosine-dependent mechanism.

Warm-up angina and myocardial perfusion.   The physiologic basis of warm-up angina is unexplained, and few studies have explored potential mechanisms. Whereas an increase in coronary perfusion has been suggested (1–3,21,22), two studies using serial exercise testing and consecutive cardiac pacing protocols, respectively, and measuring coronary flow with great cardiac vein cannulation and thermodilution did not show increased flow (23,24). Because of the limitations of this technique of evaluating regional myocardial flow, we used Tl-201 SPECT imaging to further characterize this phenomenon. Despite the well-established superior sensitivity of perfusion scintigraphy compared with the exercise ECG for the detection of myocardial ischemia and despite the significant attenuation of the ECG parameters of myocardial ischemia on re-exercise, controlling for estimated myocardial oxygen consumption by correction for RPP, we found no corresponding significant modification of scintigraphic myocardial perfusion findings.

Warm-up angina and adenosine.   It has been suggested that the attenuation of ischemia with repeated exercise is a form of ischemic preconditioning whereby myocardium subjected to brief coronary artery occlusions becomes conditioned to better withstand subsequent more severe ischemia (8). Adenosine has been identified as a key mediator of this phenomenon (11–14). Bamiphylline, a selective A1 adenosine receptor antagonist, does not blunt the warm-up phenomenon (25). However, adenosine might mediate the warm-up phenomenon via receptors other than the A1 receptor subtype. A recent study, using serial exercise testing and blinded administration of aminophylline, a nonselective adenosine antagonist, has suggested that the warm-up phenomenon is not adenosine-dependent (26). Aminophylline was given as a 3-mg/kg bolus without a subsequent intravenous infusion. Exercise did not appear to be truly symptom-limited, and inter-test time was relatively long at 20 min. Myocardial ischemia as judged by maximum STD was modest (1.67 ± 0.59 mm), as was the attenuation of ischemia on re-exercise as judged by the increase in ischemic threshold (about 5%) and, contrary to placebo, there was no longer a significant change in the ischemic threshold and in maximum STD with re-exercise when aminophylline was administered. Thus, the findings of that study were not unequivocal in ruling out an adenosine-dependent warm-up angina mechanism. In our study, the bolus of aminophylline was 5 mg/kg followed by a continuous infusion; exercise was symptom-limited, and inter-test time was about 10 min. More myocardial ischemia was solicited (maximum STD of 2.50 ± 0.98 mm), and there was a significant 15% increase in ischemic threshold on re-exercise. Thus, in our study, a robust dose of aminophylline, considered sufficient to antagonize myocardial adenosine receptors nonselectively, did not block the rise in ischemic threshold nor the decrease in adjusted maximum STD observed with repeated exercise, both of which are characteristic of the warm-up phenomenon. While this does not necessarily rule out any role for adenosine as a mediator of warm-up ischemia, it makes it unlikely that adenosine is a critical mediator of this phenomenon.

In warm-up angina, in contrast with experimental ischemic preconditioning and during coronary angioplasty (27–29), activation of K+-ATP also does not appear to be critically involved (7,30). When this notion is added to the present evidence that adenosine receptor blockade does not blunt the warm-up phenomenon, it strongly suggests that the mechanisms of classic ischemic preconditioning and of warm-up angina are physiologically distinct.

Potential mechanisms.   Interestingly, aminophylline raised the ischemic threshold of the first exercise in our study compared with saline, confirming previous studies (31,32). We also found that its attenuation of adjusted maximum STD was significantly greater than that observed on re-exercise with saline. Thus, contrary to the hypothesis tested, aminophylline appeared to potentiate, not blunt, the warm-up angina effect. The ischemia-sparing effect of aminophylline has been attributed to the blocking of transmural coronary steal from ischemic endocardium to nonischemic epicardium, induced by local adenosine release (33–36). This redistribution of myocardial blood flow effect could also be achieved by aminophylline’s stimulation of {partial}1 receptors (37–39). The unexpected finding that the warm-up angina effect was amplified with aminophylline raises the possibility that the mechanism of warm-up angina might be redistributive transmural myocardial flow from epicardium to endocardium. Such improved perfusion would not be apparent with Tl-201 SPECT that would rather detect modifications in extent and severity of ischemia due to increased collateral flow from adjacent nonischemic myocardium. If such a mechanism accounts for the warm-up phenomenon, it would be necessary to postulate the existence of a local chemical mediator with a half-life of at least several minutes, liberated under the stimulus of the first exercise, responsible for the transmural redistribution of flow and potentiated by aminophylline. An animal model of the warm-up phenomenon, using microspheres to measure transmural distribution of myocardial blood flow, would be necessary to explore this possibility. Finally, aminophylline might also exert an ischemia-sparing effect via its influence on substrate metabolism during exercise (40).

Conclusions.   The mechanism of ischemic attenuation on re-exercise or warm-up angina remains elusive. It does not appear to be explained by improved collateral myocardial perfusion and, in this regard, resembles classic ischemic preconditioning. However, it is unaffected by both adenosine receptor blockade and by blockade of K+-ATP (7,30), suggesting that it is mechanistically distinct from classic ischemic preconditioning. Future work should determine whether transmural myocardial flow redistribution or an ischemia-induced shift in myocardial energy-producing substrate might not account for this intriguing phenomenon.


   Acknowledgments
 
We gratefully acknowledge the dedication and expert technical assistance of Ms. Thérèse Jean of the Nuclear Medicine Department, Ms. Claudette Brochu of the Exercise Testing Laboratory and Mr. Fernand Bertrand, BSc of the Biochemistry Laboratory of Laval Hospital.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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