CLINICAL STUDY
Exercise-induced ischemia initiates the second window of protection in humans independent of collateral recruitment
Pier D. Lambiase, BA, MRCP*,
Richard J. Edwards, BSc, MRCP*,
Michael R. Cusack, BSc, MRCP*,
Clifford A. Bucknall, MD, FRCP*,
Simon R. Redwood, MD, MRCP, FACC* and
Michael S. Marber, PhD, FRCP, FACC*,*
* Department of Cardiology, King’s College London, The Rayne Institute, St. Thomas’ Hospital, London, United Kingdom
Manuscript received April 29, 2002;
revised manuscript received October 15, 2002,
accepted November 19, 2002.
* Reprint requests and correspondence: Prof. Michael S. Marber, Department of Cardiology, King’s College London, The Rayne Institute, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK.
mike.marber{at}kcl.ac.uk
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Abstract
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OBJECTIVES: This study was designed to examine if exercise-induced ischemia initiated late preconditioning in humans that becomes manifest during subsequent exercise and serial balloon occlusion of the left anterior descending coronary artery (LAD).
BACKGROUND: The existence of late preconditioning in humans is controversial. We therefore compared myocardial responses to exercise-induced and intracoronary balloon inflation–induced ischemia in two groups of patients subjected to different temporal patterns of ischemia.
METHODS: Thirty patients with stable angina secondary to single-vessel LAD disease underwent percutaneous coronary intervention (PCI) after two separate exercise tolerance test (ETT) protocols designed to investigate isolated early preconditioning (IEP) alone or the second window of protection (SWOP). The IEP subjects underwent three sequential ETTs at least two weeks before PCI. The SWOP subjects underwent five sequential ETTs commencing 24 h before PCI.
RESULTS: During PCI there was no significant difference in intracoronary pressure–derived collateral flow index (CFI) between groups (IEP = 0.15 ± 0.13, SWOP = 0.19 ± 0.15). In SWOP patients, compared with the initial ETT, the ETT performed 24 h later had a 40% (p < 0.001) increase in time to 0.1-mV ST depression and a 60% (p < 0.05) decrease in ventricular ectopic frequency. During the first balloon inflation, peak ST elevation was reduced by 49% (p < 0.05) in the SWOP versus the IEP group, and the dependence on CFI observed in the IEP group was abolished (analysis of covariance, p < 0.05). The significant attenuation of ST elevation (47%, p < 0.005) seen at the time of the second inflation in the IEP patients was not seen in the SWOP patients.
CONCLUSIONS: Exercise-induced ischemia triggers late preconditioning in humans, which becomes manifest during exercise and PCI. This is the first evidence that ischemia induced by coronary occlusion is attenuated in humans by a late preconditioning effect induced by exercise.
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Abbreviations and Acronyms
| | ANCOVA | = analysis of covariance | | ANOVA | = analysis of variance | | ATP | = adenosine triphosphate | | CFI | = collateral flow index | | ECG | = electrocardiogram | | ETT | = exercise tolerance test | | HR | = heart rate | | IEP | = isolated early preconditioning | | iNOS | = inducible nitric oxide synthase | | LAD | = left anterior descending coronary artery | | PCI | = percutaneous coronary intervention | | RPP | = rate pressure product | | SWOP | = second window of protection |
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It is now established that ischemic preconditioning is a biphasic phenomenon with a first window of protection developing within minutes of a brief ischemic insult but lasting only 1 to 2 h and a second window of protection (SWOP) developing between 12 and 24 h but lasting for 3 to 4 days (1,2). The SWOP, also known as late or delayed preconditioning, has important therapeutic implications because, unlike the first window, it can protect against both myocardial stunning and infarction (3). Furthermore, contrary to the first window or early preconditioning, tolerance does not occur, because repeated triggers prolong the effect (4). Thus, despite a lesser magnitude of cardioprotection, the second window has a number of advantages over the first window of preconditioning. Hence, evidence that the SWOP exists in humans would provide a major impetus to the development of therapies for maintaining the heart in a continuously preconditioned state. Unfortunately, the existence and relative importance in patients of a SWOP after brief ischemia remain controversial. Nonetheless, the recent observation of pharmacologically triggered late protection in humans implies its presence (5).
Despite a number of studies suggesting that warm-up angina may be a clinical surrogate of early preconditioning, there have been only two studies investigating the existence of a late warm-up effect as a surrogate of late preconditioning (6,7). These studies, which measured ischemic thresholds in patients undergoing serial exercise tolerance tests (ETTs) separated by 24 h, reached opposite conclusions. This may in part be due to the fact that both failed to control for collateral flow and neither performed a third exercise test on the first day to demonstrate the disappearance of early preconditioning and to exclude improvements in exercise performance resulting from training. Furthermore, neither study attempted to reproduce observations in animals by examining the effect of late preconditioning on myocardial ischemia induced by controlled coronary artery occlusion.
Despite these disparate findings with protocols designed to induce late preconditioning, clinical data from our group and others agree that early preconditioning, initiated by either exercise or percutaneous coronary intervention (PCI), occurs in patients and is independent of collateral recruitment (8,9). Because, in animal studies, the initiation of early preconditioning presages late preconditioning, our aim was to investigate their relationship in a homogeneous group of patients with an isolated and discrete stenosis within the left anterior descending coronary artery (LAD) in whom distal collateral support was measured.
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Methods
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Subjects and groups.
Patients with stable angina due to isolated LAD disease, with a normal resting electrocardiogram (ECG) and normal left ventricular function, were allocated to two groups. The first group, designed to investigate isolated early preconditioning (IEP group), underwent serial exercise treadmill tests at least 14 days before PCI. The second group, designed to investigate the SWOP (SWOP group), underwent serial exercise testing 24 and 4 h before PCI. The patients were carefully matched for proximity of the LAD stenosis and exercise performance to angina. The effects of early and late preconditioning on ischemia induced during serial balloon inflations were examined by comparing these two groups of patients (Fig. 1). Calcium antagonists, angiotensin-converting enzyme inhibitors, nicorandil, ß-blockers, long-acting nitrates, and sulfonylureas were discontinued for at least 48 h before exercise and/or PCI. The theoretical risk associated with abrupt cessation of ß-adrenoceptor blockers required patients to reduce their dose by 50% for 48 h before stopping medication completely. Patients receiving long-acting L-type calcium channel blockers were instructed to stop their medication seven days before exercise and/or PCI. In addition, for the 48 h before exercise and/or PCI, patients were discouraged from activities likely to induce angina or require the symptomatic relief of short-acting nitrates. The St. Thomas’ Hospital research ethics committee approved the study, and written informed consent was obtained from each patient.
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Figure 1 Study protocol. Patients were divided into two groups: isolated early preconditioning (IEP) and second window of protection (SWOP). In the IEP group, serial exercise tests were performed at least 14 days before elective percutaneous coronary intervention for single-vessel left anterior descending coronary artery disease. In the SWOP group, exercise was 24 h and 4 h before PCI. Solid rectangle = treadmill exercise tolerance test. Cross-hatched rectangle = 180-s intracoronary balloon inflation.
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Exercise protocol.
All patients were exercised at 9 AM and instructed not to take caffeine for 24 h before their test. In both groups of patients, the first test was considered the baseline test, and the second 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. The SWOP patients underwent an additional pair of ETTs, separated by 15 min of rest, 4 h before PCI (Fig. 1).
The ETTs were performed using the standard Bruce protocol on a Quinton Q5000 exercise treadmill (Quinton, Seattle, Washington). Twelve-lead ECG tracings were obtained every 20 s, and blood pressure was recorded at baseline, peak exertion, 0.1-mV ST depression, every 3 min during exercise, and every 2 min during recovery. 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 a blinded investigator to ensure that the computer interpretation was not affected by conduction defects, arrhythmias, or a wandering baseline. The lead with the greatest ST segment deviation was used for subsequent analysis. The ventricular ectopic beat frequency was also recorded. Chest pain severity was recorded every minute using a subjective scale of 0 to 10 (0 = no pain; 10 severe pain). Criteria for terminating the exercise tests were as follows: 1) physical exhaustion; 2) severe chest pain; 3) attainment of maximal age-related heart rate (HR); 4) ST depression >0.4 mV; or 5) occurrence of severe dysrhythmias (supraventricular arrhythmias causing hemodynamic compromise or ventricular tachycardia). The primary end point was time to 0.1-mV ST depression. Secondary end points were rate pressure product (RPP) at 0.1-mV ST depression, exercise duration, and ventricular ectopic frequency during the last minute of exercise.
PCI protocol.
The measurement of pressure-derived collateral flow index (CFI)
The CFI was measured by the physiologic derivation of collateral flow from coronary occlusion pressure (Poccl) according to Pijls et al. (10). An 0.014-in. pressure sensing wire (PressureWire RADI Medical Systems, Uppsala, Sweden) was set at zero and calibrated before being passed through the coronary guiding catheter. Pressure traces recorded from the guide catheter and pressure sensing wire were verified for concordance in the aortic root. The pressure wire was then passed into the distal LAD beyond the target lesion. The CFI was calculated from the mean coronary occlusion pressure (Poccl, mm Hg), coronary sinus pressure (CS, mm Hg), and the aortic pressure (Pao, mm Hg) using the equation: (Poccl – CS)/(Pao – CS).
Each patient underwent two intracoronary balloon inflations of 180 s duration separated by at least 5 min of reperfusion. The balloon was deflated prematurely only if the patient experienced one of the following: 1) severe chest pain; 2) systolic blood pressure drop of >30 mm Hg; or 3) sustained ventricular tachycardia or complex ectopy (couplets, early ventricular ectopy with the R-wave falling on or within 40 ms of a T-wave, or sustained ventricular bigeminy). Between inflations, the balloon was withdrawn from the lesion site, with continuous monitoring of distal coronary artery pressure. Nitrates and opiates were withheld until completion of the protocol; if necessary, benzodiazepines were used to sedate the patient.
Assessment of myocardial ischemia
A 12-lead surface ECG was recorded before and every 30 s during inflation and reperfusion. Maximal ST segment deviation during PCI was derived from anonymized ECGs by a blinded reviewer. Chest pain severity was scored by the patient at 60-s intervals during balloon occlusion on an analogue scale from 0 to 10 (0 = no pain; 10 severe pain). Ectopic beat frequency and the occurrence of any ventricular tachycardia or fibrillation were recorded. The diagnosis and quantification of arrhythmias conformed to the Lambeth conventions.
Statistical analysis.
One-way or two-way repeated-measures analysis of variance (ANOVA) were used to analyze continuous variables, as appropriate. Post hoc contrasts between groups at an individual time point, or within a group at different time points, were performed with a Student t test for unpaired or paired data using the Bonferroni correction. A chi-square test was used for comparison of categorical variables between groups. Analysis of covariance (ANCOVA) was employed to assess the differences between least-square regression lines. Data are expressed as mean ± SE. A p value <0.05 was considered statistically significant.
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Results
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Patient characteristics and clinical data.
There were no statistically significant differences in the characteristics of the patients within the IEP and SWOP groups with respect to age, gender, prevalence of cardiovascular risk factors, and use of anti-anginal and lipid-lowering drugs (Table 1). The proximity and severity of LAD stenoses were also similar.
Exercise ECG.
The main findings on exercise are summarized in Table 2. All the patients achieved at least 0.15 mV of ST segment depression on first exercise. There were no significant differences between the groups in times to ischemia during exercise 1.
The data obtained during the series of exercise tests on the first day in the SWOP group parallel the changes in the IEP group. On day 1, the second compared to the first effort in the SWOP group showed an enhanced duration to 0.1-mV ST depression (29% increase, p < 0.005) and RPP at 0.1-mV ST depression (18% increase, p < 0.005). This effect had declined on the third effort 90 min later. This is consistent with our previous reported findings in early preconditioning (8). Patients in the SWOP group underwent further exercise the following day (Fig. 1). However, the fourth effort performed 24 h after the first effort showed a return of the enhanced exercise time (increased by 40% compared with effort 1, p < 0.001) and RPP at 0.1 mV of ST depression; an improvement usually associated with second effort. This effect was maintained on the fifth and final exercise test performed 15 min later. There was no evidence of a further significant improvement in the time to 0.1-mV ST depression or RPP on the fifth effort compared with the fourth effort. Thus, although patients usually benefit from recent exertion, as seen comparing the first and second efforts in both groups, this benefit was not seen between the fourth and fifth effort despite identical rest periods and exertion protocols. This effect was not associated with any difference in that rate of change of HR and systolic pressure from baseline to 1-mm ST depression between ETT 1 and 4 (0.13 [±0.01] beats/min/s and 0.11 [±0.03] mm Hg/s on ETT 1, respectively and 0.13 [±0.02] beats/min/s and 0.11 [±0.02] mm Hg/s on ETT 4, respectively). There was a 60% reduction in the incidence of ventricular ectopics at peak exercise on ETT 2 in the SWOP group, mirroring the findings in the IEP patients. However, this effect was carried over to ETT 4 and 5, 24 h later, indicating that protection against dysrhythmia on exercise is also a manifestation of SWOP.
PCI.
There were no significant differences in either the location or severity of the LAD stenoses between groups. Furthermore, the CFI was equivalent in both groups at 180 s of balloon inflation. There were no significant changes in the mean or peak CFI between the two balloon occlusions in each group (Table 3).
A number of important differences between the two groups were identified during the PCI protocol. First, the peak amplitude of ST segment elevation on inflation 1 was 49% less in the SWOP group than the IEP group (p = 0.03). Second, the significant attenuation of ST segment elevation seen on second inflation in the IEP group (47% reduction, p < 0.005, ANOVA), and reported by others and us previously, was not seen in the SWOP group (Figs. 2 and 3). These differences in objective measures of ischemia were also reflected in subjective chest pain scores, with a reduction in symptoms on second coronary artery occlusion occurring only in the IEP group.
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Figure 2 Pattern of ST-segment deviation in the second window of protection (SWOP). Panels A and B are representative electrocardiograms (ECGs) taken from a patient in the SWOP group with a collateral flow index of 0.2. Panel A shows the appearance of precordial ECG leads V4 and V5 at 5 min of exercise on efforts 1 to 4 (see Fig. 1). In this particular example, the attenuation of ST depression seen on exercise treadmill test (ETT) 2 versus ETT 1 is less marked, though still apparent, on ETT 3. A similar trend was seen in the group data (Table 2). However, on ETT 4, performed 24 h after ETT 1, the attenuation of ST depression is at least as marked as on ETT 2. Panel B is from the surface 12-lead ECG recorded after 180 s of the first and second intracoronary balloon occlusions. In contrast to patients in the IEP group, there is no attenuation of ST elevation on the second balloon occlusion. Furthermore, in the grouped data (Table 2) the magnitude of ST elevation on first inflation is less than in the IEP group.
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Figure 3 ST-segment elevation during the first and second intracoronary balloon occlusions of the left anterior descending coronary artery in early and late preconditioning groups. With increasing duration of ischemia, the attenuation of ST elevation seen on the second compared with the first occlusion is apparent only in the early preconditioning group. In addition, the absolute magnitude of ST elevation on occlusion 1 is less in the SWOP than in the IEP group (see Table 2). Two-way repeated-measures analysis of variance was performed with post-hypothesis testing to compare the degree of ST elevation between inflations 1 and 2 at 30-s intervals, having examined the effects of time, treatment, and group. *p < 0.05,  p < 0.01 for occlusion 1 versus occlusion 2.
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The possibility remains that these altered patterns of symptoms and measures of myocardial ischemia are related to differences in the amount or pattern of collateral recruitment caused by recent exercise-induced ischemia in the territory rendered ischemic by balloon occlusion. However, this explanation is not supported by the relationship between CFI and peak amplitude of ST elevation on first balloon occlusion (Fig. 4). The regression lines in the IEP and SWOP groups differ significantly (p < 0.05 by ANCOVA). However, on the second occlusion the IEP group regression line gradient changes such that it is no longer significantly different from that of the SWOP group. Therefore, myocardial ischemia, as measured by ST segment deviation, was less marked in the SWOP group through mechanisms independent of collateral flow. The significantly shallower slope of the SWOP group (Fig. 4) suggests that factors distinct from collateral flow contributed to the amplitude of ST-segment change.
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Figure 4 The relationship between maximal ST elevation and collateral flow index (CFI) during the first intracoronary balloon occlusion. ST elevation is negatively related to collateral flow in the isolated early preconditioning (IEP) group (p < 0.01). However, this dependence is less marked in the second window of protection (SWOP) group. Moreover, when collateral support is poor (CFI < 0.25), ST elevation is less marked in the SWOP group (Table 2).
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Thus, for all durations of ischemia examined, the depth of ischemia as measured by ST elevation is less 24 h after exercise, and this is not related to augmentation of collateral flow.
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Discussion
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This is the first clinical study to conclusively demonstrate that 24 h after exercise-induced myocardial ischemia there is an enhanced resistance to further ischemia caused by both exercise and coronary artery occlusion. The time course, degree of protection, and independence from collateral recruitment are consistent with late preconditioning. Because exercise performance to angina returned to baseline on an intermediate third exercise test, this phenomenon is not due to training. We have therefore documented that the appearance of a first window of protection, which fades by 90 min, is followed by the appearance of a second window at 24 h.
The use of ST-segment deviation.
Surrogate models of early preconditioning, in common with the model we describe here, are heavily reliant on the use within a single patient of ST-segment deviation as a measure of ischemic severity. Based on experiments in mice with, and without, an ablation in the gene encoding the sarcolemmal adenosine triphosphate (ATP)-sensitive potassium channel, it is now clear that opening of this channel during early ischemia accounts for ST-segment shift (11). Intracellular ATP markedly reduces the probability that this channel will open (12). Thus, ST-segment deviation is at least in part an indirect measure of intracellular ATP depletion during ischemia. It is therefore perhaps not surprising that in animal experiments the changes in ST deviation with repeated bouts of myocardial ischemia have been shown to be a reliable and true measure of the presence or absence of ischemic preconditioning, providing the sarcolemmal ATP-dependent potassium channel is allowed to open normally (13,14). We therefore believe, as do other investigators, that within an individual patient the amplitude of ST segment shift is a reliable index of severity of ischemia. In clinical studies, ST-segment changes correlate with both metabolic and myocardial functional parameters during myocardial ischemia (15–18). Indeed, the change in chest pain score between inflations mirrors the changes in ST elevation in each group, thus providing two clinical end points that demonstrate the effect of late preconditioning on severity of ischemia during PCI (19).
The relative magnitude of early and late protection.
Using ST-segment shift as a readout of the severity of ischemia, Billinger et al. (20) reported that the increase in CFI measured on serial balloon occlusions accounts for only 30% of the reduction in ST elevation. The implication was that early preconditioning is responsible for up to 70% of the protection observed in a similar PCI model. This observation is in keeping with those made within our study in the IEP group. However, an interesting change occurs in the pattern of the relationship between peak CFI and maximal amplitude of ST elevation in patients in the SWOP group. As the square of the correlation coefficients indicates, the individual variation in collateral flow could explain 42% and 2% of the variation in ST elevation in the IEP and SWOP groups, respectively. This difference between the two groups is most likely due to collateral flow–independent reduction in ST elevation by the SWOP which is manifest most clearly in the hearts with more severe ischemia due to a lower CFI. Because these patients had evidence of late preconditioning on exercise testing immediately before PCI, it is likely that this phenomenon "carried over" to PCI. The fact that there is a significant reduction in the degree of ST elevation between occlusions in these patients is compatible with animal data that show that acute preconditioning may not add significantly to SWOP (21). This may be due to the fact that in the SWOP-protected heart, ischemia severity is sufficiently attenuated that it fails to reach the threshold necessary to trigger early preconditioning, although it seems 5 min of ischemia may be sufficient to add to late preconditioning in one animal model (22). Thus, our use of 180-s rather than 120-s coronary occlusions (5) should have resulted in a suprathreshold preconditioning stimulus. However, a recent study suggests that even 180 s is close to threshold in patients older than 65 years (23).
Mechanisms of myocardial protection initiated by exercise.
Exercise is recognized as an independent factor in cardioprotection. Epidemiologic studies have demonstrated that it diminishes cardiovascular risk by enhancing lipid metabolism, reducing obesity, and increasing insulin sensitivity (24). A number of the physiologic effects of exercise could account for its myocardial protective properties. In in vivo animal models with normal coronary arteries, exercise (25) can induce cardioprotection in a manner analogous to that of more classical triggers of late protection such as hyperthermia and myocardial ischemia-reperfusion. Thus, there may be physiologic changes triggered by exercise that act independently of the myocardial ischemia that we documented. This is consistent with the emerging debate that surrounds the mechanistic relationship between warm-up angina and early preconditioning (26). Heat shock protein production secondary to hyperthermic or ischemic stress is established as one of the mechanisms of protection activated during delayed preconditioning (27,28). There is evidence from animal studies that coronary endothelial levels of constitutive nitric oxide synthase are elevated after exercise (29), which can trigger inducible nitric oxide synthase (iNOS) induction and thus delayed preconditioning (30). These mechanisms match the time course of the protection demonstrated in this clinical study. Indeed, Bolli (31) has demonstrated that the delayed infarct sparing effects of exercise, nitric oxide donors (nitroglycerin and S-nitroso-N-acetylpenicillamine), and  1-opioid agonists are completely abrogated in iNOS–/– knockout mice. Moreover, Leesar et al. (5) have demonstrated that exogenous nitric oxide donors can trigger late preconditioning in patients with coronary artery disease.
Study limitations.
Inherent within the interpretation of our study are a number of assumptions. We have concluded that the increased exercise performance on efforts 4 and 5 in the SWOP group is a manifestation of late preconditioning. This assumption is based upon the similarity in CFIs between groups. Although CFI is a valid determinant of myocardial ischemia during balloon inflation, it may not precisely reflect collateral recruitment during exercise, which may have differed between efforts 1 and 4 in the SWOP group. If this was the case, the reduced measures of myocardial ischemia on exercise, but not coronary artery occlusion, may not have been due to a late preconditioning-like effect. However, Bogaty et al. (32) have shown that the attenuation of ST depression during warm-up angina of early preconditioning is not associated with significant changes in the extent or intensity of single-photon emission computed tomography with sestamibi deficits on perfusion imaging. There is no significant difference in the rate of change of HR and systolic pressure to 1-mm ST depression between ETT 1 and 4. This supports the contention that regional blood flow did not differ significantly in the LAD territory on ETT 1 and 4 as these are determinants of collateral flow and MVO2. A myocardial perfusion study during late preconditioning would need to be undertaken to fully address this question.
Similarly, we found it difficult to control for other possible interfering effects such as silent myocardial ischemia between exercise efforts and PCI. However, because exercise performance to angina was similar, such episodes are likely to have been balanced between groups and not have contributed to the late preconditioning effect.
The characteristics of the patients as listed in Table 1 show a tendency for hypertension to be more prevalent in the late preconditioning group. This may also have contributed to a tendency to an increased use of calcium antagonists, lipid-lowering drugs, and perhaps nitrates in this patient group. Because these therapies were discontinued for at least 48 h before exercise or PCI, we think it is unlikely that intergroup differences in these anti-anginal agents contributed to our results. In addition, any contribution, as a result of incomplete washout, would have been to increase performance on efforts 1, 2, and 3 rather than on exercise 4; as was observed. Nonetheless, it is possible that this intergroup imbalance contributed to our findings in an unspecified manner.
This study shows that a delayed preconditioning effect can be demonstrated in humans which attenuates myocardial ischemia caused by either increased demand on exercise or reduced supply on intracoronary occlusion by a balloon. This effect is able to increase ischemic thresholds during exercise by as much as 42% and reduce the ST elevation caused by coronary artery occlusion by 49%. These observations support the concept that a clinically significant degree of ischemic protection is induced 24 h after myocardial ischemia. This phenomenon may enable adjunctive therapies to reduce the symptoms and manifestations of coronary artery disease.
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Footnotes
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This study was supported by the British Heart Foundation FS/97084 and FS/2001016.
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M. Saha, S. R. Redwood, and M. S. Marber
Exercise training with ischaemia: is warming up the key?
Eur. Heart J.,
July 1, 2007;
28(13):
1543 - 1544.
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A. M. N. Kabir, J. E. Clark, M. Tanno, X. Cao, J. S. Hothersall, S. Dashnyam, D. A. Gorog, M. Bellahcene, M. J. Shattock, and M. S. Marber
Cardioprotection initiated by reactive oxygen species is dependent on activation of PKC{varepsilon}
Am J Physiol Heart Circ Physiol,
October 1, 2006;
291(4):
H1893 - H1899.
[Abstract]
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P. D. Thompson
Exercise Prescription and Proscription for Patients With Coronary Artery Disease
Circulation,
October 11, 2005;
112(15):
2354 - 2363.
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S. G. De Hert, F. Turani, S. Mathur, and D. F. Stowe
Cardioprotection with Volatile Anesthetics: Mechanisms and Clinical Implications
Anesth. Analg.,
June 1, 2005;
100(6):
1584 - 1593.
[Abstract]
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H. Jneid, M. Chandra, M. Alshaher, C. A. Hornung, X.-L. Tang, M. Leesar, and R. Bolli
Delayed Preconditioning-Mimetic Actions of Nitroglycerin in Patients Undergoing Exercise Tolerance Tests
Circulation,
May 24, 2005;
111(20):
2565 - 2571.
[Abstract]
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M. Juhaszova, C. Rabuel, D. B. Zorov, E. G. Lakatta, and S. J. Sollott
Protection in the aged heart: preventing the heart-break of old age?
Cardiovasc Res,
May 1, 2005;
66(2):
233 - 244.
[Abstract]
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C. Penna, G. Alloatti, S. Cappello, D. Gattullo, G. Berta, B. Mognetti, G. Losano, and P. Pagliaro
Platelet-activating factor induces cardioprotection in isolated rat heart akin to ischemic preconditioning: role of phosphoinositide 3-kinase and protein kinase C activation
Am J Physiol Heart Circ Physiol,
May 1, 2005;
288(5):
H2512 - H2520.
[Abstract]
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D. B. Buxton
Cytokines and Late Preconditioning
Cardiovasc Res,
October 1, 2004;
64(1):
6 - 8.
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A. Crisafulli, F. Melis, F. Tocco, U. M. Santoboni, C. Lai, G. Angioy, L. Lorrai, G. Pittau, A. Concu, and P. Pagliaro
Exercise-induced and nitroglycerin-induced myocardial preconditioning improves hemodynamics in patients with angina
Am J Physiol Heart Circ Physiol,
July 1, 2004;
287(1):
H235 - H242.
[Abstract]
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M E Faircloth, S R Redwood, and M S Marber
Ischaemic preconditioning and myocardial adaptation to serial intracoronary balloon inflation: cut from the same cloth?
Heart,
April 1, 2004;
90(4):
358 - 360.
[Abstract]
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Y. Nishino, T. Miura, T. Miki, J. Sakamoto, Y. Nakamura, Y. Ikeda, H. Kobayashi, and K. Shimamoto
Ischemic preconditioning activates AMPK in a PKC-dependent manner and induces GLUT4 up-regulation in the late phase of cardioprotection
Cardiovasc Res,
February 15, 2004;
61(3):
610 - 619.
[Abstract]
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A. N. DeMaria, O. Ben-Yehuda, D. Berman, G. K. Feld, B. H. Greenberg, J. D. Knoke, K. U. Knowlton, W. Y. W. Lew, and S. Tsimikas
Highlights of the year in JACC 2003
J. Am. Coll. Cardiol.,
December 17, 2003;
42(12):
2156 - 2166.
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