CLINICAL STUDIES
Attenuation of myocardial ischemia with repeated exercise in subjects with chronic stable angina
Relation to myocardial contractility, intensity of exercise and the adenosine triphosphate–sensitive potassium channel
Peter Bogaty, MDa,
John G. Kingma, Jr., PhD, FACCa,
N.-Michelle Robitaille, MDa,
Sylvain Plante, MD, FACCa,
Serge Simard, MSca,
Lyne Charbonneau, BSca and
Jean G. Dumesnil, MD, FACCa
a Quebec Heart Institute/Laval Hospital, Laval University, Ste-Foy, Quebec, Canada
Manuscript received April 8, 1998;
revised manuscript received July 8, 1998,
accepted July 29, 1998.
Address for correspondence: Dr. Peter Bogaty, Quebec Heart Institute/Laval Hospital, 2725 Chemin Ste-Foy, Ste-Foy, Quebec, Canada G1V 4G5
peter.Bogaty{at}med.ulaval.ca
 |
Abstract
|
|---|
Objectives. This study characterized the attenuation of myocardial ischemia observed with re-exercise to determine whether: 1) a differing exercise intensity modifies this attenuation; 2) it could be explained by contractile down-regulation or stunning; 3) it is mediated by activation of ATP-sensitive potassium channels (K+-ATP).
Background. Subjects with ischemic heart disease (IHD) frequently note less angina with re-exercise after a brief rest. Potential mechanisms of this ‘warm-up’ phenomenon have been little explored.
Methods. IHD subjects with a positive exercise test were studied. Groups I and II (12 subjects each) underwent 2 successive Naughton protocol exercise echocardiography tests (with 1 min instead of 2 min stages for Group II). Group D (10 subjects) had type II diabetes, were on  10 mg daily of the K+-ATP blocker, glibenclamide, and underwent the group I exercise protocol. The ischemic threshold or rate-pressure product at 1 mm ST segment depression, ST depression corresponding to the peak rate-pressure product of the first exercise (maximum ST depression equivalent), and left ventricular wall motion indexes before and immediately after each exercise were analyzed.
Results. Exercise-induced myocardial ischemia with re-exercise was similarly attenuated in groups I, II, and D. The ischemic threshold was raised by nearly 20% with re-exercise (p = 0.001, p = 0.02, and p = 0.02, respectively) and the maximum ST depression equivalent was nearly halved on re-exercise (p = 0.005, p = 0.006, and p = 0.001, respectively). Exercise-induced wall motion dysfunction was attenuated with re-exercise. In group I, wall motion returned to the initial baseline score prior to exercise 2, whereas in the more intense protocol of group II, wall motion dysfunction persisted prior to exercise 2.
Conclusions. Thus, the attenuation of myocardial ischemia observed with re-exercise appears to be independent of the intensity of the exercise protocol and is not explained by down-regulation of myocardial contractility induced by the initial ischemic stimulus. Since results were similar in diabetic subjects on robust doses of glibenclamide, this phenomenon does not appear to be mediated by K+-ATP activation.
|
Abbreviations and Acronyms
| | ECG | = electrocardiogram or electrocardiographic | | ET | = exercise test | | IHD | = ischemic heart disease | | K+-ATP | = adenosine triphosphate–sensitive potassium channel(s) | | LV | = left ventricular | | RPP | = rate–pressure product | | STD | = ST-segment depression | | VD | = vessel disease |
|
Subjects with chronic ischemic heart disease (IHD) frequently describe the phenomenon of "warm-up" or "walk-through" angina. They note that angina provoked by an initial exertion is attenuated and even disappears if they momentarily diminish or stop their exertion before resuming it. The initial exertion appears to have acted as an ischemic conditioning stimulus. This well-known clinical observation has been documented in a number of studies using serial exercise testing or repetitive cardiac pacing (1–10). Although re-exercise is associated with an attenuation of ischemia, the heart rates and blood pressures attained are the same or greater (3,5,7–10). The physiologic basis of this phenomenon is unexplained and very few studies have explored potential mechanisms. An increase in coronary perfusion has been suggested (2,3,5,10,11) but never demonstrated (4,6). Another hypothesis is an adaptive down-regulation of regional myocardial contractile function in the ischemic region, which diminishes ischemia by decreasing oxygen demand (4,9,12,13). Because this latter possibility has not been directly tested, we undertook this study in stable angina subjects coupling serial treadmill exercise with echocardiography. We also sought to characterize the phenomenon of exercise-induced ischemic attenuation as completely as possible electrocardiographically, using two exercise protocols that differed in their rate of increase in intensity. Finally, to test whether this phenomenon might be mediated by a metabolic mechanism through activation of adenosine triphosphate–sensitive potassium channels (K+-ATP) on cardiac myocytes, we also studied diabetic stable angina subjects taking robust chronic doses of the oral hypoglycemic agent and K+-ATP blocker glibenclamide.
|
Methods
|
|---|
Patient selection.
We first studied 24 subjects with stable Canadian Cardiovascular Society class 1 to 2 angina, a previous positive exercise test (ET) (1-mm ST-segment depression [STD] 80 ms after the J point) and significant coronary artery disease documented either angiographically (70% coronary artery stenosis) or with thallium myocardial perfusion imaging (significant reversible hypoperfusion). In addition, these subjects had to have a normal resting electrocardiogram (ECG; minor T-wave abnormality permitted) and normal left ventricular (LV) contractility. All subjects had previously passed several reproducible ETs and were very familiar with this procedure. Beta-adrenergic blocking agents and calcium channel antagonists were stopped 48 h and long-acting nitrates 12 h prior to exercise testing. On the day of study, subjects were instructed not to exercise and to avoid any unusual exertion; they rested for at least 30 min before testing, which was always undertaken in midafternoon at least 2 h postprandially. The study protocol was approved by the hospital ethics committee and written informed consent was obtained from all subjects.
Exercise protocol.
Of the initial 24 subjects, the first 12 (group I) performed two successive Naughton protocol treadmill ETs (protocol I). To determine whether a more rapidly progressive ET protocol would yield similar findings, the next 12 subjects (group II) performed a modified Naughton protocol with 1-min instead of 2-min stages (protocol II). Of the two tests per subject, each was supervised in random order by one of the same two cardiologists, who were always blinded to the findings of the first test. Each subject was also kept unaware of the rationale for the study, of the findings of the first test and could not see the display screen during exercise. Subjects were instructed to exercise to near maximum discomfort whether this was angina, fatigue or dyspnea (score of 7 to 8 of 10 on a visual scale). Other predefined indications for stopping exercise were: a drop in systolic blood pressure >10 mm Hg, a serious arrhythmia or the subject’s desire to stop. Tests were performed on a Q65 treadmill linked to a Q4000 monitor (Quinton Instrument Co., Seattle, Washington). The ECG was continuously monitored. Precordial leads V4, V5 and occasionally V6 were positioned 6 to 8 cm lower than usual to permit optimal echocardiographic imaging. A standard 12-lead ECG was taken in the resting left lateral decubitus position (because this was the position during echocardiographic imaging) and standing positions and then every 30 s during exercise and recovery. Each time both an averaged and a raw data ECG were obtained. The arterial blood pressure was taken with a mercury sphygmomanometer every minute until peak exercise and then three times during recovery. The second ET was promptly undertaken once the following conditions were met: 1) second baseline resting echocardiographic imaging (begun once the ST segment was within 0.5 mm of the initial baseline) was completed; 2) the ST segment had returned to its initial (isoelectric) baseline documented in the left lateral decubitus position prior to the first test; and 3) the subject was willing to re-exercise.
Exercise ECG analysis.
The ET was considered positive at first appearance of 1-mm STD 80 ms after the J point compared with the resting ECG taken in the left lateral decubitus position just prior to exercise. The raw data and averaged tracings were examined for consistency, requiring consecutive beats (three for the raw data and two for the averaged tracings) with similar findings. The time of onset of ET positivity and the corresponding heart rate–systolic blood pressure product (RPP) or ischemic threshold were noted. The time of onset of angina was noted. Maximum STD was noted on raw data and averaged tracings taken just before the end of exercise. All leads exhibiting the criteria of positivity at end exercise were noted. The RPP at peak exercise was noted and the maximum STD corresponding to this RPP on the first test was compared with the STD on the second test corresponding to this same RPP. This analysis could be done in most subjects because the peak RPP on the second test generally equaled or exceeded that of the first test. This parameter is subsequently referred to as the "maximum STD equivalent." Recovery time was the time from the end of exercise to the final appearance of 1-mm STD noted on the 12-lead ECG recovery tracings. After all patients had been studied, their exercise ECG tracings were analyzed blindly and independently by two examiners, resolving differences by consensus. Only the evaluation of the maximum STD equivalent was, of necessity, performed after unblinding.
Echocardiographic protocol.
Two-dimensional echocardiography was performed by the same experienced technician using a Hewlett-Packard Sonos (Andover, Massachusetts) 1000 or 2000 echocardiograph. Images were acquired in the long axis, short axis and apical two- and four-chamber views, and were digitized in the usual manner with a Microsonics Image Vue (Mawah, New Jersey) analyzer if the Sonos 1000 was used or with the incorporated stress test module if the Sonos 2000 was used. Four echocardiographic documents were acquired from each subject: 1) initial baseline prior to the first ET; 2) immediately on termination of the first ET; 3) second baseline prior to the second exercise; and 4) immediately following the second ET. Postexercise imaging was obtained within 90 s of the completion of exercise. Subjects were rehearsed to promptly revert to the same left lateral decubitus position on completion of each ET. Optimal echocardiographic windows were determined for all subjects prior to the first test. The LV wall motion score index (14) was determined for each study independently by two experienced observers, resolving their differences by consensus.
Study in diabetic subjects.
We also studied 10 stable angina subjects with type II diabetes mellitus (group D) who were taking at least 10 mg daily of the oral hypoglycemic sulfonylurea derivative glibenclamide and who had the same eligibility criteria as groups I and II. These subjects underwent serial exercise with protocol I, as group I, except that echocardiography was not performed. They recovered following exercise in the same left lateral decubitus position. Glibenclamide blood levels were measured at the time of exercise testing.
Cross-over echocardiographic study.
Because echocardiographic findings differed in the two exercise protocols, to ascertain whether this was due to the nature of the exercise protocol or to differences in the patient groups, eight subjects (four from the less intense and four from the more intense exercise protocol) were subsequently restudied with cross-over to the other exercise protocol with echocardiographic imaging as described above. Inter-test exercise time was deliberately identical in the two exercise protocols for each subject.
Statistical analysis.
Means and SDs were determined for continuous variables. Mean values of quantitative variables were compared with one-way analysis of variance for unpaired data when normality and variance assumptions were fulfilled and with the Wilcoxon rank-sum test when they were not. A posteriori comparisons were performed with Tukey’s method. Mean values of quantitative variables were compared using paired Student t tests for comparisons between the first and second ETs. To measure relationships between variables, Pearson product–moment correlation coefficients were used as linear relationships were observed. All reported p values were two-sided with results considered significant for p values  0.05. Data were analyzed using the statistical package program SAS (SAS Institute, Cary, North Carolina).
|
Results
|
|---|
Patient characteristics.
Group I was comprised of 10 men and 2 women aged 57 ± 10 years and group II was comprised of 11 men and 1 woman, aged 56 ± 8 years. All 10 group D subjects were men aged 65 ± 6 years. Of the group I subjects, 11 had undergone coronary angiography within 1 year. Five subjects had one-vessel disease (VD), five had two-VD and one had three-VD. The remaining group I subject had a recent scintigraphic study suggesting one-VD. All group II subjects had undergone coronary angiography within the year. Three subjects had one-VD, seven had two-VD and two had three-VD. Seven group D subjects had a recent coronary arteriogram showing one-VD in three subjects, two-VD in one and three-VD in three. The remaining three group D subjects had a scintigraphic study that was suggestive of one-VD in two subjects and two-VD in one subject. Eight group D subjects were on 10 mg glibenclamide daily and the remaining two subjects on 20 mg daily. Glibenclamide serum level was 0.44 ± 0.39 µmol/l (range 0.04 to 1.00) and values were unaccountably skewed. Five subjects had serum levels 0.24 µmol/l and five subjects had serum levels >0.60 µmol/l.
Exercise test results.
The times between the end of ET 1 and the start of ET 2 for groups I, II and D were 13 ± 4 min, 13 ± 2 min and 13 ± 3 min, respectively. For group I, RPP at 1-mm STD or the ischemic threshold was 18% higher in ET 2 and an increase was observed in 11 of the 12 subjects (p = 0.001); for group II, it was 12% higher in ET 2 and an increase was observed in 9 of the 12 subjects (p = 0.02); for group D, it was 16% higher in ET 2 and an increase in threshold was observed in 8 of the 10 subjects (p = 0.02) (Fig. 1). For group I, the maximum STD equivalent of ET 2 (corresponding to the peak RPP of ET 1) was 41% less than maximum STD that occurred in ET 1; it was 2.2 ± 0.6 mm in ET 1 and 1.3 ± 1.0 mm in ET 2 (p = 0.005). This parameter decreased in ET 2 in 9 of the 10 subjects in whom it could be measured. For group II, the maximum STD equivalent decreased 39% in ET 2; it was 2.3 ± 1.0 mm in ET 1 and 1.4 ± 1.1 mm in ET 2 and a decrease was noted in seven of the eight subjects in whom it could be measured (p = 0.006). For group D, the maximum STD equivalent decreased 47%; it was 1.5 ± 0.5 mm in ET 1 and 0.8 ± 0.5 mm in ET 2 and a decrease occurred in all but two subjects (p = 0.001) (Fig. 2). Other ET results are shown in Table 1. In ET 2 compared with ET 1, exercise time, workload achieved metabolic equivalents (METS), time to angina and time to 1-mm STD all increased and recovery time decreased. The RPP at baseline was always higher prior to ET 2 and peak RPP was generally higher in ET 2.
View larger version (17K):
[in this window]
[in a new window]
|
Figure 1 Ischemic thresholds (heart rate x systolic blood pressure at 1-mm STD) in exercises (Ex) 1 and 2 are plotted for each subject in the three study groups. Vertical bars display means and SDs.
|
|
View larger version (19K):
[in this window]
[in a new window]
|
Figure 2 Maximum (Max) STD equivalent in millimeters plotted for each subject in whom it could be measured in exercises (Ex) 1 and 2 in the three study groups. See text for definition of this parameter. Vertical bars display means and SDs.
|
|
The degree of attenuation of ischemic ECG indexes on reexercise was not significantly different among the three groups, and an analysis comparing the five group D subjects with high range glibenclamide levels with the five subjects in the low range did not indicate any differences in the changes from ET 1 to ET 2.
Echocardiographic results.
For group I, LV wall motion score indexes are shown in the left panel of Figure 3 at the four time points—prior to ET 1, just after ET 1, prior to ET 2 and just after ET 2. In this group, ischemia-induced wall motion dysfunction observed with the second exercise was significantly attenuated compared with the dysfunction induced with the first exercise (p = 0.03). Importantly, wall motion returned to initial baseline in 10 of 12 subjects prior to ET 2 in group I. This appears to rule out stunning or contractile down-regulation as the mechanism accounting for ischemic attenuation with re-exercise. However, for group II, which had the more intense exercise protocol, the findings were different (right panel of Fig. 3): LV wall motion at baseline 2 did not return to baseline 1 levels in 7 of 12 subjects; it was significantly perturbed at baseline 2 compared with baseline 1 (p = 0.002). In addition, contrary to group I, wall motion dysfunction was not significantly different in ET 2 compared with ET 1, perhaps because of the added effect of persistent stunning contributing to the dysfunction induced by ET 2. Nonetheless, the degree of contractile dysfunction at ET 2 compared with baseline 2 was less than that at ET 1 compared with baseline 1 (p = 0.047), suggesting that even in this more intense exercise protocol, despite the added stunning effect, there was still an attenuation of dysfunction on reexercise.
View larger version (14K):
[in this window]
[in a new window]
|
Figure 3 Echocardiographic LV wall motion score indexes (means and SDs) at baselines (Rest) and immediately following each exericse (Ex) in groups I and II.
|
|
Cross-over study.
To be certain that the persistent wall motion dysfunction at baseline 2 in group II was due to the intensity of the exercise protocol and not to patient characteristics, a cross-over study of eight subjects was performed. Four of these subjects came from the original, less intense protocol I and all had a normal baseline 2 wall motion score in protocol I; the other four subjects came from the original, more intense protocol II and all had an abnormal baseline 2 wall motion score compared with baseline 1. With the less intense protocol, wall motion score indexes at baselines 1 and 2 were similar (1.10 ± 0.10 vs. 1.15 ± 0.15, respectively; p = NS). However, with the more intense protocol, wall motion score indexes at baselines 1 and 2 were significantly different, with persistent contractile dysfunction at baseline 2 (1.10 ± 0.07 vs. 1.20 ± 0.15, respectively; p = 0.045). This supports the original analysis that the more intense exercise protocol was responsible for the persistent wall motion abnormality prior to reexercise.
Role of adrenergic tone.
To determine whether there might be a relation between the degree of attenuation of ischemia on re-exercise and the increased resting RPP prior to exercise 2 compared with the resting RPP prior to exercise 1, the change in this latter parameter (considered an index of adrenergic tone) was correlated to the change in ischemic threshold and to the change in the maximum STD equivalent. No relation was found.
|
Discussion
|
|---|
This study confirms and extensively characterizes, with exercise ECG and contractile function data, the impressive attenuation of exercise-induced myocardial ischemia that has been observed with repeated exercise (2,3,5,7–10). In addition, its principal findings are that: 1) this phenomenon appears to be independent of the intensity of the exercise protocol; 2) the attenuation of myocardial ischemia is not explained by a down-regulation of cardiac contractile function induced by the initial ischemic stimulus; 3) this phenomenon does not appear to be mediated by a K+-ATP dependent mechanism; and 4) it is not related to adrenergic tone.
Exercise ECG data.
Exercise duration, workload achieved and maximum RPP increased significantly on re-exercise. These improvements were not necessarily due to an attenuation of myocardial ischemia and may have been the consequence of a training or learning effect. However, all subjects were already very familiar with treadmill exercise and had previously passed several reproducible ETs. Moreover, the resting RPP prior to ET 2 was consistently higher than it was prior to ET 1, arguing against the presence of a training effect. Time to angina increased significantly on re-exercise but this variable is subjective. Time to 1-mm STD also increased significantly but might be due to improved hemodynamic conditions on re-exercise rather than to a change in the ischemic threshold. Maximum and total STD and the number of positive leads at peak exercise would not be expected to undergo much modification on re-exercise because subjects performed to a similar symptom-limited end point. Although postexercise STD recovery time was substantially reduced following the second exercise, it is not established as an index of ongoing myocardial ischemia and probably reflects the intensity of exercise-induced ischemia (15,16). However, two quantifiable exercise ECG indicators of myocardial ischemia did markedly improve on re-exercise. First, the RPP at the onset of 1-mm STD, which is considered a valid and relatively constant index of the ischemic threshold (17–19), was almost 20% higher on re-exercise and an increase in the ischemic threshold was observed in over 80% of subjects, as has been found in other studies (7–10). Second, we analyzed a novel parameter that highlights even more strikingly the blunting of ischemia on reexercise. The maximum STD equivalent or STD at ET 2 corresponding to the maximum RPP of ET 1 was less than half the value of maximum STD in ET 1. A decrease in this parameter was observed in over 90% of subjects in whom it could be measured.
Relation to exercise protocol.
This study tested whether the intensity of exercise might affect the degree of attenuation of myocardial ischemia on re-exercise. The very gradual standard Naughton protocol might have simply provided an ongoing warm-up or conditioning stimulus so that, on re-exercise, little or no further attenuation of ischemia might be observed. However, the findings for group I show that this was not the case. On the other hand, a more intensive exercise protocol with a halving of the stages to 1 min might have provided a stronger conditioning stimulus, creating a greater attenuation of ischemia on re-exercise. Alternatively, by allowing less time for achieving steady states during initial exercise, such a protocol might have been less propitious for the blunting of ischemia on reexercise. However, the results indicate that the degree of attenuation of myocardial ischemia is similar regardless of the intensity of the ischemic primer or of ET 2.
Relation to contractile function and the down-regulation hypothesis.
Both exercise protocols similarly showed that LV contractile function on ET 2 compared with its baseline was significantly less perturbed than on ET 1, a finding consistent with the attenuation of symptoms and ECG signs of ischemia.
To our knowledge, this is the first study to evaluate the relation of cardiac contractility to the attenuation of myocardial ischemia observed with re-exercise and to determine whether an ischemia-induced down-regulation or stunning of contractile function rematching oxygen supply and demand could account for the attenuation of ischemia. This hypothesis has been evoked but not directly tested (4,12,13). Okazaki et al. (6) cannulated the great cardiac vein in IHD subjects with isolated significant anterior descending artery stenosis to measure regional coronary flow by thermodilution and also measured oxygen consumption and locally released adenosine while subjects performed two supine ergometric ETs. Although STD occurred later and was attenuated on ET 2, coronary flow did not increase in the ischemic zone. There was also less myocardial oxygen consumption and greater adenosine release in this zone on ET 2. A decrease in contractile function as a result of ET 1 could have accounted for these observations, but the authors did not evaluate this and believed that it was not the responsible mechanism because baseline oxygen consumption before the two tests was similar. However, this observation per se does not rule out a myocardial stunning mechanism (20). Williams et al. (4) subjected IHD patients to two sequential rapid atrial pacings and documented less ischemia during the second pacing as measured by angina, STD and lactate extraction but found comparable coronary flow (similarly using great cardiac vein cannulation and thermodilution) and reduced myocardial oxygen consumption on the second pacing. They suggested that the mechanism was a reduction in regional myocardial contractility although this parameter was not evaluated. The possibility of diminished contractile function also was suggested by the work of Thadani et al. (12), who observed a decrease in cardiac output on the second of two rapid cardiac pacings in angina subjects.
The findings from exercise protocol I in the present study appear to exclude ischemia-induced down-regulation of contractile function as the mechanism accounting for the attenuation of ischemia observed with repeated exercise. In the 12 subjects studied with echocardiography in protocol I, LV wall motion returned to the initial baseline (which was normal in most cases) prior to ET 2 in all but two subjects. However, this was not so with the more intense exercise protocol II. Significant wall motion abnormality persisted prior to ET 2. In this case, down-regulation of contractile function could account for some or all of the attenuation of ECG ischemic parameters and ischemia-induced contractile dysfunction observed with ET 2. By restudying eight patients with cross-over to the other exercise protocol, we determined that it was the intensity of exercise that accounted for the persistent LV dysfunction prior to ET 2. Thus, the findings of exercise protocol I indicate that down-regulation of contractile function cannot explain the attenuation of ischemia observed with re-exercise, although the findings of exercise protocol II do not rule out the contribution of such a mechanism when exercise is more intense. However, if down-regulation or stunning were a contributory mechanism, it might have been expected to result in a greater attenuation of ECG ischemia in protocol II than that observed in protocol I where down-regulation was not observed. Because the degree of ECG ischemic attenuation was similar when the two protocols are compared, it is unlikely that down-regulation or stunning contributes in any significant way to this phenomenon.
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 (4,6–9,21). Our findings are also consistent with experimental data dissociating stunning and classic ischemic preconditioning (22–24).
Relation to K+-ATP.
Activation of sarcolemmal and mitochondrial K+-ATP in cardiac myocytes is implicated in ischemic preconditioning, and the latter can be inhibited with blockade of K+-ATP using the oral hypoglycemic agent glibenclamide (25–29). Therefore, diabetic angina subjects taking robust chronic daily doses of glibenclamide constitute a model to test whether the attenuation of ischemia with repeated exercise may also be attributable to a metabolic mechanism via activation of myocardial K+-ATP. Therapeutic concentrations of glibenclamide have been shown to block vascular K+-ATP in humans (30). However, we found that the degree of attenuation of myocardial ischemia on reexercise was similar in diabetic subjects on glibenclamide and in nondiabetic subjects, suggesting that K+-ATP activation is not the underlying mechanism. This conclusion must be tempered by two caveats: 1) clinical doses of glibenclamide might be insufficient to block K+-ATP in cardiac myocytes effectively and 2) when glibenclamide is used long term, the presence of endogenous countervailing or escape mechanisms from K+-ATP blockade cannot be excluded. However, our findings are in agreement with a recent study in which no modification was found in the degree of attenuation of myocardial ischemia on reexercise when nondiabetic subjects received 10 mg oral glibenclamide acutely (31). The ischemic threshold was not evaluated in the latter study.
Potential limitations.
We compared two exercise protocols but initially used different subjects in each protocol. We also compared diabetic subjects taking glibenclamide with nondiabetic subjects not taking glibenclamide. The findings might appear less strong than if subjects had served as their own controls. However, this is unlikely because findings were consistent in direction and magnitude across the three study groups, which were comparable in age (except for the older diabetic subjects), gender, degree of coronary artery disease and LV function. In addition, subsequent cross-over data in eight subjects confirmed our initial observations. Finally, these results obtained in subjects with conserved LV function might not necessarily be reproducible in the presence of prior large myocardial infarction.
Conclusions.
This study confirms and systematically characterizes the impressive attenuation of myocardial ischemia observed with repeated exercise. Our results suggest that this attenuation is unexplained by stunning or contractile down-regulation, adrenergic tone or K+-ATP activation. Future work should attempt to identify this intriguing endogenous mechanism.
|
Acknowledgments
|
|---|
We gratefully acknowledge the expert technical support of Jocelyn Beauchemin and François Leduc, MD, and the secretarial assistance of Micheline Gingras.
|
Footnotes
|
|---|
Dr. Bogaty was supported in part by a scholarship from the Fonds de la Recherche en Santé du Québec (FRSQ).
|
References
|
|---|
1. Wayne EJ, Graybiel A. Observations on the effect of food, gastric distension, external temperature, and repeated exercise on angina of effort, with a note on angina sine dolor. Clin Sci. 1934;1:287–304
2. MacAlpin RN, Kattus AA. Adaptation to exercise in angina pectoris. Circulation. 1966;33:183–201[Abstract/Free Full Text]
3. Jaffe MD, Quinn NK. Warm-up phenomenon in angina pectoris. Lancet. 1980;2:934–936[Medline]
4. Williams DO, Bass TA, Gewirtz H, Most AS. Adaptation to the stress of tachycardia in patients with coronary artery disease: insight into the mechanism of the warm-up phenomenon. Circulation. 1985;71:687–692[Abstract/Free Full Text]
5. Joy M, Cairns AW, Sprigings D. Observations on the warm up phenomenon in angina pectoris. Br Heart J. 1987;58:116–121[Abstract/Free Full Text]
6. Okazaki Y, Kodama K, Sato H, et al. Attenuation of increased regional myocardial oxygen consumption during exercise as a major cause of warm-up phenomenon. J Am Coll Cardiol. 1993;21:1597–1604[Abstract]
7. Stewart RAH, Simmonds MB, Williams MJA. Time course of "warm-up" in stable angina. Am J Cardiol. 1995;76:70–73[CrossRef][Medline]
8. Maybaum S, Ilan M, Mogilevsky J, Tzivoni D. Improvement in ischemic parameters during repeated exercise testing: a possible model for myocardial preconditioning. Am J Cardiol. 1996;78:1087–1091[Medline]
9. Tomai F, Crea F, Danesi A, et al. Mechanisms of the warm-up phenomenon. Eur Heart J. 1996;17:1022–1027[Abstract/Free Full Text]
10. Ylitalo K, Jama L, Raatikainen P, Peuhkurinen K. Adaptation to myocardial ischemia during repeated dynamic exercise in relation to findings at cardiac catheterization. Am Heart J. 1996;131:689–697[CrossRef][Medline]
11. Rizi HR, Kline RC, Besozzi MC, et al. Walk-through angina phenomenon demonstrated by graded exercise radionuclide ventriculography. Possible coronary spasm mechanisms. Am Heart J. 1982;103:292–294[CrossRef][Medline]
12. Thadani U, Lewis JR, Mathew TM, West RO, Parker JO. Reproducibility of clinical and hemodynamic parameters during pacing stress testing in patients with angina pectoris. Circulation. 1979;60:1036–1044[Free Full Text]
13. Homans DC, Sublett E, Dai X-Z, Bache RJ. Persistance of regional left ventricular dysfunction after exercise-induced myocardial ischemia. J Clin Invest. 1986;77:66–73[Medline]
14. Bourdillon PDV, Broderick TM, Sawada SG, et al. Regional wall motion index for infarct and noninfarct regions after reperfusion in acute myocardial infarction: comparison with global wall motion index. J Am Soc Echocardiogr. 1989;2:398–407[Medline]
15. Bogaty P, Gavrielides S, Mure P, Gaspardone A, Maseri A. The duration and magnitude of ST segment depression during exercise and recovery: a symmetrical relationship. Am Heart J. 1995;12:666–671[CrossRef]
16. Bogaty P, Guimond J, Robitaille N-M, et al. A reappraisal of exercise electrocardiographic indeces of the severity of ischemic heart disease: angiographic and scintigraphic correlates. J Am Coll Cardiol. 1997;29:1497–1504[Abstract]
17. Robinson BF. Relation of heart rate and systolic blood pressure to the onset of pain in angina pectoris. Circulation. 1967;35:1073–1083[Abstract/Free Full Text]
18. Gobel FL, Nordstrom LA, Nelson RR, Jorgensen CR, Wang Y. The rate-pressure product as an index of myocardial oxygen consumption during exercise in patients with angina pectoris. Circulation. 1978;57:549–556[Abstract/Free Full Text]
19. Starling MR, Moody M, Crawford MH, Levi B, O’Rourke RA. Repeat treadmill exercise testing: variability of results in patients with angina pectoris. Am Heart J. 1984;107:298–303[CrossRef][Medline]
20. Ohgoshi Y, Goto Y, Futaki S, Yaku H, Kawaguchi O, Suga H. Increased oxygen cost of contractility in stunned myocardium of dog. Circ Res. 1991;69:975–988[Abstract/Free Full Text]
21. Marber MS, Joy MD, Yellon DM. Is warm-up in angina ischemic preconditioning? Br Heart J. 1994;72:213–215[Free Full Text]
22. Murry CE, Richard VJ, Jennings RB, Reimer KA. Myocardial protection is lost before contractile function recovers from ischemic preconditioning. Am J Physiol (Heart Circ Physiol). 1991;29:H796–H804
23. Matsuda M, Catena TG, Vander Heide RS, Jennings RB, Reimer KA. Cardiac protection by ischaemic preconditioning is not mediated by myocardial stunning. Cardiovasc Res. 1993;27:585–592[Medline]
24. Mitchell MB, Winter CB, Locke-Winter CR, Banerjee A, Harken AH. Cardiac preconditioning does not require myocardial stunning. Ann Thorac Surg. 1993;55:395–400[Abstract]
25. Cole WC, McPherson CD, Sontag D. ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage. Circ Res. 1991;69:571–581[Abstract/Free Full Text]
26. Gross GJ, Auchampach JA. Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res. 1992;70:223–233[Abstract/Free Full Text]
27. Yao Z, Cavero I, Gross GJ. Activation of cardiac KATP channels: an endogenous protective mechanism during repetitive ischemia. Am J Physiol (Heart Circ Physiol). 1993;264:H495–H504[Abstract/Free Full Text]
28. Tomai F, Crea F, Gaspardone A, et al. Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker. Circulation. 1994;90:700–705[Abstract/Free Full Text]
29. Liu Y, Sato T, O’Rourke B, Marban E. Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection? Circulation. 1998;97:2463–2469[Abstract/Free Full Text]
30. Bijlstra PJ, Lutterman JA, Russel FGM, Thien T, Smits P. Interaction of sulphonylurea derivatives with vascular ATP-sensitive potassium channels in humans. Diabetologia. 1996;39:1083–1090[Medline]
31. Correa SD, Schaefer S. Blockade of KATP channels with Glibenclamide does not abolish preconditioning during demand ischemia. Am J Cardiol. 1997;79:75–78[CrossRef][Medline]
This article has been cited by other articles:
|
|
|
|
 
X. Xu, W. Wan, L. Ji, S. Lao, A. S. Powers, W. Zhao, J. M. Erikson, and J. Q. Zhang
Exercise training combined with angiotensin II receptor blockade limits post-infarct ventricular remodelling in rats
Cardiovasc Res,
June 1, 2008;
78(3):
523 - 532.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Noel, J. Jobin, A. Marcoux, P. Poirier, G. R. Dagenais, and P. Bogaty
Can prolonged exercise-induced myocardial ischaemia be innocuous?
Eur. Heart J.,
July 1, 2007;
28(13):
1559 - 1565.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Valensi and G. Slama
Review: Sulphonylureas and cardiovascular risk: facts and controversies
The British Journal of Diabetes & Vascular Disease,
July 1, 2006;
6(4):
159 - 165.
[Abstract]
[PDF]
|
|
|
|
|
|
|
J J Meier, B Gallwitz, W E Schmidt, A Mugge, and M A Nauck
Is impairment of ischaemic preconditioning by sulfonylurea drugs clinically important?
Heart,
January 1, 2004;
90(1):
9 - 12.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Bogaty, P. Poirier, L. Boyer, J. Jobin, and G. R. Dagenais
What Induces the Warm-Up Ischemia/Angina Phenomenon: Exercise or Myocardial Ischemia?
Circulation,
April 15, 2003;
107(14):
1858 - 1863.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F Tomai
Warm up phenomenon and preconditioning in clinical practice
Heart,
February 1, 2002;
87(2):
99 - 100.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A D Kelion, T P Webb, M A Gardner, O J M Ormerod, G L Shepherd, and A P Banning
Does a selective adenosine A1 receptor agonist protect against exercise induced ischaemia in patients with coronary artery disease?
Heart,
February 1, 2002;
87(2):
115 - 120.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Bogaty, J. G. Kingma, J. Guimond, P. Poirier, L. Boyer, L. Charbonneau, and G. R. Dagenais
Myocardial perfusion imaging findings and the role of adenosine in the warm-up angina phenomenon
J. Am. Coll. Cardiol.,
February 1, 2001;
37(2):
463 - 469.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-S. V. Chen, S. C. Body, and S. K. Shernan
Myocardial Preconditioning: Characteristics, Mechanisms, and Clinical Applications
Seminars in Cardiothoracic and Vascular Anesthesia,
July 1, 1999;
3(2):
85 - 97.
[Abstract]
[PDF]
|
|
|
|
Top
Abstract
Methods