The effect of an angiotensin-converting enzyme inhibitor and a K+ATP channel opener on warm up angina
Richard J. Edwards,
Simon R. Redwood,
Pier D. Lambiase and
Michael S. Marber*
Division of Cardiology, KCL, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK
Received 6 November 2003; revised 10 November 2004; accepted 18 November 2004; online publish-ahead-of-print 20 December 2004.
* Corresponding author. Tel:+44 207 922 8191; fax:+44 207 960 5659. E-mail address: mike.marber{at}kcl.ac.uk
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Abstract
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Aims In various models, angiotensin-converting enzyme (ACE) inhibitors and K+ATP channel openers can potentiate and mimic ischaemic preconditioning, respectively. Our aim was to determine whether these characteristics are shared by the phenomenon of warm up in angina, often regarded as a surrogate of ischaemic preconditioning.
Methods and results Twenty patients with ischaemic heart disease were assigned in a double blind, randomized cross-over design to equivalent pressor doses of nicorandil 20 mg bid, enalapril 10 mg bid, losartan 25 mg bid, or placebo for 3 days. Patients underwent three consecutive exercise tolerance tests on each medication separated by a 1-week interval. Each patient underwent 12 exercise tests in total and 13 patients completed the study. On each medication the second exercise was separated from the first by 15 min of rest and the third exercise was performed 90 min after the second to control for training. The time to 0.1 mV ST depression and rate pressure product at 0.1 mV ST depression increased significantly in all groups during exercise two compared with exercise one. Nicorandil reduced angina but did not attenuate this warm up effect. This benefit of first exercise waned by test three with placebo, losartan, and nicorandil, but not with enalapril.
Conclusion In contrast to predictions based on ischaemic preconditioning the magnitude of the warm up was apparently unaltered by nicorandil, losartan, or enalapril, however its duration seemed to be extended by enalapril. Thus ischaemic preconditioning and warm up angina are likely to have differing pharmacological profiles suggesting a diverse underlying mechanism.
Key Words: Angina Exercise ACE-inhibitor K+ATP channel Ischaemic preconditioning
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Introduction
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Warm up angina has been recognized for over 200 years.1 It describes patients with ischaemic heart disease who report exertional angina which forces them to stop and rest but paradoxically are then able to continue walking without further symptoms. These symptoms are accompanied by objective measures on exercise testing, as patients experience less severe angina and a reduction in ST depression at similar workloads during a second exertion.2 It has been suggested that the favourable adaptation during a second episode of angina may be due to an increase in the myocardium's endogenous resistance to ischaemia in a manner akin to the experimental phenomenon of ischaemic preconditioning.3
Ischaemic preconditioning describes how exposure of the myocardium to brief episodes of sub-lethal ischaemia and reperfusion can protect against subsequent myocardial infarction. Preconditioning is receptor-mediated and in animal models bradykinin and adenosine are able to pre-condition the heart in the absence of an initial ischaemic insult.4 The action of angiotensin-converting enzyme (ACE)-inhibitors is in part mediated through the inhibition of bradykinin breakdown.5 It is this effect that has been shown to potentiate the effects of preconditioning in animal and cellular models.6 The protective effects of preconditioning are thought to be in part mediated by the opening of K+ATP channels in the membranes of cardiomyocytes and/or their mitochondria. Nicorandil opens these K+ATP channels and mimics the protective effects of preconditioning in isolated cells and whole animal studies.79
The aim of this study was to examine whether findings from laboratory models of ischaemic preconditioning can be extrapolated to a model of repeat exercise in patients with ischaemic heart disease. This was done by contrasting the effects on warm up angina of a K+ATP channel opener (nicorandil), an ACE-inhibitor (enalapril) with those of placebo and an angiotensin (AT) receptor blocker (losartan). Losartan was chosen to control for the effects of enalapril on the reninangiotensin axis.
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Methods
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Patients
Patients with a positive exercise test (>0.2 mV of planar or down sloping ST depression) and angiographic evidence of significant coronary stenoses were selected on a consecutive basis. Patients were selected from the waiting list and had >70% stenosis in the left anterior descending coronary artery with, or without, other significant stenoses (see Table 1). Patients had to be in sinus rhythm without conduction disturbance or any other abnormality that complicated ECG interpretation, or increased risk of exercise. No patients had evidence of left ventricular hypertrophy, myocardial infarction, heart failure, cardiomyopathy, or valvular heart disease. Diabetic patients on oral hypoglycaemic agents and patients on antihypertensives or digoxin were not included. In patients suitable for the study, anti-anginal medication apart from statins and aspirin were cautiously withdrawn 1 week prior to the first test. Once recruited to the study, patients had to complete two consecutive treadmill tests successfully in order to familiarize themselves with the protocol and the staff. The St Thomas' Hospital research ethics committee approved the study and written informed consent was obtained from each patient.
Exercise protocol
Patients completed four sets of treadmill exercise tests with an interval of 1 week between sets. During each set, patients underwent three consecutive exercise tests on the background of different study medications. All patients were tested at 9 am and were instructed not to undertake strenuous exercise for 24 h, or take solid food or caffeine for 12 h, prior to the test. Exercise tests were performed using the standard Bruce protocol on a Quinton® Q5000 exercise treadmill (Quinton®, Seattle, WA, USA). Twelve-lead ECG tracings were obtained every 20 s and blood pressure recorded at baseline, peak exertion, 0.1 mV ST depression, and every 3 min during the exercise and 2 min during recovery. The second test was separated from the first by a 15-min rest period. A third exercise test was performed after a further 90 min of rest and was used to control for a possible training effect.
For a 3-day period prior to, and on the morning of, each exercise day, patients took tablets with a twice-daily regime. The test formulations were losartan 25 mg bid, enalapril 10 mg bid, nicorandil 10 mg bid, and placebo bid. There was a 3-day wash-out period before the next course of medication. The order of medication was chosen at random, in a cross-over design with neither physician nor patient aware of the assignment.
The level of the ST segment measured 0.08 s after the J point was calculated after signal averaging using the computer-assisted system on the Q5000. ST segment deviation was also checked manually by an investigator blinded to the exercise test to confirm that conduction defects, arrhythmias or a wandering baseline did not affect the computer interpretation. Criteria for terminating the exercise tests were: (i) physical exhaustion, (ii) severe chest pain, (iii) attaining maximal age- related heart rate, (iv) ST depression >0.4 mV, or (v) occurrence of severe dysrhythmias. The primary endpoints were rate pressure product (RPP) at 0.1 mV ST depression and degree of ST depression at equivalent workloads at peak exercise. Exercise duration and time to 0.1 mV ST depression and recovery time to 0.05 mV ST depression were secondary endpoints.
Statistical analysis
All data were entered on to a computerized spreadsheet. A multiple cross-over design was employed and the same patients completed each of the four arms of the study. A multiple regression model was used to compare treatment, visit number, and patient, using least squares. An F-test was applied to compare the mean value of each exercise parameter on the four treatments. A P-value smaller than 0.05 demonstrates significant evidence that the treatment with the highest mean response differed from the treatment with the lowest mean response. A single sample Student's t-test was used to assess whether the mean values on each particular treatment differed between two exercise efforts. Summary statistics are expressed as mean (±SD) unless otherwise stated.
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Results
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We recruited 20 patients with ischaemic heart disease. Seven patients were excluded: one developed intermittent bundle branch block during exertion, three patients did not display evidence of warm up during a second exertion on placebo, and three patients did not reach 0.15 mV ST depression during the second exercise on placebo. The reason for excluding patients without robust warm up angina was that the purpose of this study is to determine the effect of medication on the warm up phenomenon rather than to describe its prevalence and magnitude. No patients withdrew due to clinical deterioration. All but one of the patients were excluded before they contributed any results to the study. Thirteen patients (12 men) successfully completed all four arms of the study. The demographic characteristics of the patients are shown in Table 1. The results summarized in Tables 25 contain the mean values of the variables measured during exercise together with their statistical comparison within each set of sequential tests on a single study medication. Table 6 is of the P-values resulting from the F-test of the mean values, and differences between mean values, for the most clinically relevant exercise parameters obtained on each study medication compared across medications.
No two patients had the same order of medication and there is little evidence of any visit effect, i.e. the results do not seem to change systematically between visits (over and above any treatment effect), data not shown. The bar graphs in Figures 1 and 2 demonstrate the changes in primary endpoints; time to 0.1 mV ST depression and ST depression, at peak exertion.

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Figure 1 Time to 0.1 mV ST segment depression. Bar graphs demonstrate the mean values (±SEM) of the time taken to reach 0.1 mV STD depression, during three sequential exercise tests in four groups. In each group similar patterns exist: first, there is an 1020% improvement in time taken to reach this milestone compared with initial exertion. This improvement is significant and consistent. This time wanes by Ex 3 in placebo, nicorandil, and losartan groups, whilst in the enalapril group there is still a significant increase in performance compared with initial exertion.
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Figure 2 ST segment depression at equivalent workloads. Bar graphs demonstrate the mean values (±SEM) of ST depression at equivalent workloads, during three sequential exercise tests in four groups. Again during Ex 2, there is an 25% decrease in ST depression compared with Ex 1. This protective effect wanes by Ex 3, in placebo, nicorandil, and losartan groups, whilst in the enalapril group there is still a significant decrease in ST depression compared with initial exertion.
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In the placebo group (Table 2), time to 0.1 mV ST depression increased significantly during the second exercise test (Ex 2) compared with the first (Ex 1) (50±39 s), whilst the difference was smaller and non-significant when Ex 1 was compared with the third (Ex 3) (15±51 s). This pattern was repeated in the nicorandil group (Table 3) (58±43 and 8±49 s) and the losartan group (Table 4) (112±97 and 49±60 s) respectively. In keeping with the other interventions the enalapril group (Table 5) also had an increase in time to 0.1 mV ST depression during Ex 2 compared with Ex 1 (86±52 s). However, in contrast to the other interventions, the tolerance to exercise-induced ischaemia seen during Ex 2 was also apparent and significant during Ex 3 (83±64 s).
RPP at 0.1 mV ST depression, in the placebo group, also improved significantly during Ex 2 compared with Ex 1 (1456±1016 beats/min . mmHg) and again the difference was small between Ex 1 and Ex 3 (107±2059 beats/min . mmHg). For nicorandil the difference between Ex 2Ex 1 and Ex 3Ex 1 was (2580±2013 and 1249±1931 beats/min . mmHg) and for Losartan (2610±2234 and 1255±1360 beats/min . mmHg), respectively. In the enalapril group the RPP at 0.1 mV ST depression was increased during Ex 2 compared with Ex 1 by 2526±2190 beats/min . mmHg but in contrast to the other groups the protective effect was sustained significantly through to Ex 3 with a 2281±2502 beats/min . mmHg difference.
At the equivalent peak times there was a 0.61±0.68-mV and 0.11±0.76-mV reduction in ST segment depression during Ex 1 compared with Ex 2 and Ex 3 in the placebo group. For nicorandil it was 0.50±0.51 and 0.04±0.33 mV and for losartan 0.46±0.34 and 0.09±0.31 mV. In the enalapril group, as in the other groups, there was a significant reduction in ST segment depression during Ex 2 (0.7±0.44 mV), but in contrast to the other groups the protective window was maintained to Ex 3. Furthermore, even though patients exercised for a greater duration, the degree of ST shift at peak exercise was lower during Ex 2 in placebo, nicorandil, and losartan groups but not in the enalapril group.
These patterns of performance on sequential exercise on a single medication are confirmed by comparison of the values between medications. The column Ex 2Ex 1 of Table 6 shows that the mean increase in performance on second vs. first effort is similar for all four treatments. However, medication does influence the difference in performance on third vs. first effort as measured by RPP at 0.1 mV ST depression, time to 0.1 mV ST depression, and degree of ST depression at equivalent workloads. Inspection of Tables 25 shows that this results from a persistence to Ex 3, on enalapril, of the enhanced exercise performance usually only seen on Ex 2, an effect not seen in the placebo, losartan, and nicorandil groups.
Despite a greater level of cardiac work the recovery time to 0.05 mV ST depression was also reduced during Ex 2 in all groups, suggesting that warm up results in a more rapid resolution of ischaemia. At baseline, in all groups, there was a tendency for the heart rate to be greater at the beginning of Ex 2 when compared with Ex 1 and Ex 3.
Consistent with its anti-anginal properties, in the nicorandil group there was a significant enhancement (P<0.05) in time to, and RPP at, 0.1 mV ST depression during Ex 1, compared with all other groups, suggesting that therapeutic concentrations of nicorandil had been achieved.
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Discussion
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The objective of this study was to investigate whether drugs that trigger ischaemic preconditioning also attenuate warm up angina. There were two important findings. First, a patient's ability to warm up during a second exertion was not influenced by the use of nicorandil, losartan, or enalapril. In all groups the time to, and RPP at, 0.1 mV ST depression was increased during the Ex 2 compared with Ex 1. Exercise duration was greater during second exertion in all groups and yet the degree of ST depression at peak exertion and recovery times were consistently reduced during the Ex 2. Secondly, in the ACE-inhibitor group, the window of protection was prolonged. During Ex 3 in placebo, nicorandil, and losartan groups time to 0.1 mV ST depression and RPP at 0.1 mV STD reverted to levels seen during Ex 1. Whilst in the enalapril group, the protective effect of warm up was maintained.
The study protocol recorded 18 descriptors of exercise during a total of 12 exertions. The complexity of the resultant analyses makes multiple comparisons necessary and therefore has an inherent risk of a type I statistical error. We have attempted to minimize the risk of such false positive findings by limiting our analysis to ST shift at peak exertion and time to, and RPP at, 0.1 mV ST segment depression. Nonetheless some of the positive findings may be specious and this needs to be heeded when interpreting the results.
Warm up angina and ischaemic preconditioning
First effort, warm up, or first hole angina describe the ability of patients with ischaemic heart disease to exercise to angina, rest, and then continue exertion with few or no symptoms. The relationship between warm up angina and ischaemic preconditioning has been a subject of interest.3 They share several common features and it has been suggested that warm up angina may represent a clinical surrogate of ischaemic preconditioning. Both require a short episode of ischaemia followed by reperfusion/rest to trigger protection. During the phase of protection, the myocardium is less susceptible to ischaemic damage, measured by a reduction in ST shift in the case of warm up, and infarct size in the case of classical preconditioning.10 Both phenomena have memory such that the heart remains in a protected state for about 1 h after the initiating ischaemia but protection disappears altogether by 2 h.1114 In addition, although initially ischaemia preconditioning can be renewed by further ischaemic stimuli, tolerance eventually occurs.15
Bradykinin and adenosine are important agonists in the initiation of ischaemic preconditioning.16 Binding of these ligands triggers an intracellular signalling cascade which activates protein kinase C and mitogen-activated protein kinases.4 There is some evidence that a distal effector, responsible for delaying cell death, is the opening of K+ATP channels in the sarcolemmal and/or mitochondrial membrane.17 Our study is the first to examine the role of the K+ATP opener nicorandil, and also an inhibitor of bradykinin breakdown, the ACE-inhibitor enalapril, on warm up during exercise.
Nicorandil
Nicorandil was developed as an anti-anginal medication, it has two moieties, a nitrate and a K+ATP opener, and it is the latter moiety that may be responsible for it's preconditioninglike effects.18 However, it should also be mentioned that the nitrate moiety has been shown to induce delayed preconditioning in animals and man.19,20 Experimental studies have demonstrated that infarct size is reduced in animals exposed to a lethal episode of ischaemia following pre-treatment with nicorandil.18,21,22 Similar results are found in isolated cell models of ischaemia,23 as well as in isolated human atrial trabeculae exposed to K+ATP openers.24 Much excitement has been generated by this compound; when added to aggressive anti-anginal treatment for unstable angina, it reduces myocardial ischaemia, non-sustained ventricular, and supraventricular arrhythmia.25 Nicorandil can also block the protective effects of initial balloon inflation during coronary angioplasty, a finding that does not occur with nitrates.26
In our study, nicorandil did not mimic the warm up effect. This observation suggests that opening of K+ATP is not an essential event in triggering warm up angina. It is unlikely that the dose of nicorandil used was insufficient to trigger opening of K+ATP. We used the maximum recommended dose and a regime that makes tolerance unlikely.27 Furthermore, consistent with its anti-ischaemic properties, patients taking nicorandil had less ST depression at a given workload and the time to 0.1 mV ST depression was increased by 9, 11, and 10% when Ex 1, Ex 2, and Ex 3 tests were compared with their placebo counterpart.
Other groups have examined the role of K+ATP channel blockers but with disparate findings. One group demonstrated no effect of these compounds28 whilst Tomai et al.29 demonstrated inhibition of the warm up effect in patients pre-treated with glibenclamide. Klepzig et al.30 found that glibenclamide did block preconditioning; whilst glimepiride, a less cardio-specific sulfonylurea, did not. The findings in this study suggest that the mechanism of warm up angina is independent of K+ATP channel opening.
ACE-inhibitors
ACE-inhibition causes vasodilatation, and has favourable effects on sodium homeostasis, ventricular wall stress, and remodelling in heart failure. ACE also cleaves bradykinin and ACE-inhibitors therefore result in bradykinin accumulation. Bradykinin up-regulates nitric oxide and increases the bioavailability of prostacyclin causing naturetic, vasodilatory, anti-aggregatory, antithrombotic, antiproliferative, and anti-atherosclerotic effects.31 Recent data also suggest that ACE-inhibitors can potentiate the effects of ischaemic preconditioning through the inhibition of bradykinin breakdown. Animal hearts exposed to ACE-inhibitors prior to an ischaemic episode have a reduced infarct size, decreased reperfusion arrhythmias and improved function compared with controls.3234 Interestingly, the protective effect of ACE-inhibition in the setting of preconditioning is abolished with specific bradykinin receptor blockers;32,35,36 a finding that has also been demonstrated in isolated human trabeculae.6 In an in vivo human model of preconditioning during serial balloon angioplasty, Leesar et al.37 demonstrated that pre-treatment with bradykinin appears to be just as effective as ischaemic preconditioning and suggest that it could be used prophylactically to favourably attenuate ischaemia in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Yellon's group38 have also demonstrated, in a pig coronary angioplasty model of delayed preconditioning, that pre-treatment with ACE-inhibitors can augment a mild ischaemic stimulus such that it induces a protected state 24 h later.
Our hypothesis was that ACE-inhibitors might enhance the degree of warm up during Ex 2. Their inability to enhance the effect of first exercise raises the possibility that the conditioning first exercise has an all or nothing effect. However the protective window was prolonged. In view of the multiple effects of exercise and ACE-inhibition it is difficult to draw specific mechanistic conclusions from this finding. However the prolongation of warm up has direct clinical relevance and provides consistent evidence of ACE-inhibitors' anti-ischaemic properties in patients with coronary heart disease.39
Angiotensin II type 1 receptor blockers
Losartan was chosen primarily to control for the blood pressure lowering and AT II effects of enalapril. However, evidence is emerging that AT II blockers also have anti-ischaemic and preconditioning-like effects. Work by Sato et al.34 demonstrated that AT II blockade can mimic the protective effects of preconditioning using a Langendorf model of myocardial infarction. They showed the protection could be partially blocked by the bradykinin receptor blocker, HOE 140, and they suggest that AT II receptor type 1 blockade induces preconditioning by both a bradykinin-dependent and independent mechanism. Work by Schartz et al.40 also showed that losartan was equivalent to ACE-inhibition at reducing infarct size. The exact mechanism of losartan's ability to pre-condition is not understood and not all studies have consistently demonstrated the protective effect of AT receptor blockade. In this study, losartan had no effect on warm up during exercise, which suggests that the protective effect of warm up is independent of the AT1 receptor.
The mechanism of warm up angina
The body's response to exercise is complex, allowing a number of mechanisms potentially contributing to warm up angina. Amongst these mechanisms, changes in systemic vascular resistance, and delayed, and reduced pulse wave reflectance are likely to dominate. Evidence that such alterations persist after first exercise is evidenced by the fact that heart rate and systolic blood pressure had not completely normalized at the start of Ex 2 on some of the medications.
Warm up angina has traditionally been explained by an increase in blood flow to the ischaemic territory through vasodilatation of the diseased artery and/or subtended vascular bed, and/or through enhanced recruitment of collateral vessels. This study does not rule out such a mechanism based on improved endothelial function increasing coronary flow reserve following first exercise. However, we have previously demonstrated that the existence of coronary collaterals is not essential to the warm up effect.41 In support of mechanisms other than ischaemic preconditioning contributing to warm up, a number of observations suggest warm up angina is not wholly dependent on an ischaemic preconditioning-like phenomenon. For example, Bogaty and colleagues42 have recently shown that an attenuated, though definite, warm up effect follows exercise of an intensity below the threshold needed to induce ischaemia. Tomai et al.43 were unable to demonstrate that adenosine receptor blockade interfered with the benefit of first effort. Furthermore, Kelion et al.44 failed to show that adenosine receptor activation could protect the heart against exercise-induced ischaemia, whilst another investigator was unable to prevent the warm up effect with glibenclamide.28 These results, in combination with our findings, suggest that mechanisms other than preconditioning are responsible for the warm up effect.
The mechanisms that underlie warm up angina are not yet clearly understood.41 Nonetheless following an episode of exercise-induced angina there are documented and significant reductions in angina severity, exercise limitation, ST-segment depression, and dysrhythmia. Whilst our findings cast further doubt on the role of ischaemic preconditioning in warm up angina they also suggest that ACE-inhibition has the unexpected advantage of prolonging the benefit following exercise-induced angina. Furthermore, we have shown that these benefits continue despite anti-anginal drugs and agents commonly used to prevent further cardiovascular events. Such findings reinforce the need to understand the mechanisms underlying the warm up effect to ensure that this natural phenomenon is harnessed to the patient's benefit.
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Acknowledgements
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This study was supported by the British Heart Foundation FS/97084. We thank Merck Sharp and Dohme for an unrestricted grant to cover patients' travel costs and for the supply of placebo.
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