CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY
Frequency and clinical significance of ischemic preconditioning during percutaneous coronary intervention
Warren K. Laskey, MD, FACC*,* and
Dana Beach, RN*
* Division of Cardiology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
* Reprint requests and correspondence: Dr. Warren K. Laskey, Cardiac Catheterization Laboratory, National Naval Medical Center, 8901 Wisconsin Avenue, Bethesda, Maryland 20889, USA.
warrenlaskey{at}earthlink.net
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Abstract
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OBJECTIVES: We sought to examine the short- and long-term clinical consequences of ischemic preconditioning (IP) during percutaneous coronary intervention (PCI).
BACKGROUND: Ischemic preconditioning has been demonstrated in animal models to significantly diminish the extent of myocardial necrosis consequent to coronary occlusion. Surrogate markers of ischemic injury (ST segment shift, lactate release, creatine kinase release) in humans have been shown to be similarly diminished with IP elicited during PCI. There are no studies of the frequency of inducibility of IP during PCI, nor are there longer-term data on the clinical relevance of IP.
METHODS: A total of 382 patients underwent elective PCI employing a previously validated protocol to elicit IP. Procedural, in-hospital, and one-year outcomes were recorded.
RESULTS: Ischemic preconditioning was elicited in 80% of patients and was associated with a significant reduction in the likelihood of in-hospital adverse cardiac events (IP group, 12.1%; non-IP group, 44.1%; p < 0.0001). Women and diabetic patients were less likely to exhibit IP. By one year, patients failing to manifest IP were at significantly greater risk of post-discharge death or non-fatal myocardial infarction (MI) (non-IP group, 25.9%; IP group, 11.1%; p < 0.002). Failure to manifest IP was significantly and independently associated with an increased risk of death or non-fatal MI by one year.
CONCLUSIONS: Clinically relevant short- and long-term cardioprotection can be found in association with IP during PCI. In-hospital adverse ischemic events are significantly diminished in patients with IP, as are the risks of death or non-fatal MI at one year. Failure to elicit IP during PCI serves as an independent marker of increased risk of future ischemic events.
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Abbreviations and Acronyms
| | AE | = adverse clinical event | | CI | = confidence interval | | CK-MB | = creatine phosphokinase-MB fraction | | ECG | = electrocardiogram/electrocardiograph(ic) | | IP | = ischemic preconditioning | | MI | = myocardial infarction | | PCI | = percutaneous coronary intervention |
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Since the original description in 1986 by Murry et al. (1), ischemic preconditioning (IP) has been the subject of intense investigation. Although this seminal study, performed in a canine model, demonstrated the powerful effect of IP on the extent of myocardial necrosis consequent to coronary artery occlusion, similar observations have been reported in other species (2–4) as well as with the use of surrogates for post-ischemic injury (5,6). Although an analogous cardioprotective phenomenon has been suggested in the clinical literature, these studies have, of necessity, been limited to retrospective, inferential analyses (7–9) or the use of surrogate end points after controlled coronary occlusion during percutaneous coronary intervention (PCI) (10–19). There are no data in the clinical literature addressing the frequency of the ability to elicit IP in an unselected population of patients undergoing PCI nor are there data relating the ability to elicit IP during PCI to subsequent cardiovascular outcomes. Therefore, we performed a pro-spective, longitudinal study in a series of patients undergoing PCI using a previously validated protocol in order to demonstrate the frequency of the ability to induce IP and to compare clinical outcomes at one year in patients with and without induced IP.
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Methods
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The patient population for the present study was comprised of all patients undergoing elective PCI from January 1997 through June 2001 by a single operator (W.L.) using a validated IP protocol (vide infra). Patients were excluded from consideration for the following: acute ST segment elevation myocardial infarction (MI) (n = 10); an abnormal baseline electrocardiogram (ECG) (e.g., significant ST segment depression, left bundle-branch block precluding analysis of the ST segment shift during PCI) (n = 13); ischemic chest pain within 12 h of PCI (n = 10); absence of supporting evidence of myocardial ischemia (n = 26); ongoing administration of intravenous nitroglycerin (n = 5); refusal to grant permission to obtain clinical follow-up at one year (n = 6); inability to successfully complete the PCI (n = 4) (in these 4 patients persistent ST changes after the first inflation precluded continuation of the protocol); hemodynamic instability at any time during the PCI (n = 3); in-lab death (n = 1); and participation in an extant investigational protocol (n = 30). The final dataset was comprised of 382 patients.
The protocol for the induction of IP during PCI has been described and validated by our group (10,16,17) and others (11–15,18,19). A 90-s period of balloon occlusion of the target artery is followed by a 5-min period of unobstructed reperfusion. A subsequent 90-s balloon occlusion at an identical inflation pressure is then performed. The calibrated ST segment response is assessed from either the surface ECG (n = 306), using the leads that best correspond to the distribution of the target artery and reporting the maximal ST segment shift, or the electrogram recording, using the intracoronary guide wire (n = 76). In the present investigation, the visual analog scale for pain assessment (10,16) was not employed. Ischemic preconditioning was considered present when the magnitude of ST segment elevation at the completion of the second inflation was reduced by at least 33% of the magnitude of the ST segment elevation recorded during the first inflation. This cutoff represents the lower limit of the 95% confidence interval (CI) of the mean magnitude of ST segment reduction reported in 10 recently published studies of IP during PCI (10–19).
Definitions and variables analyzed.
In-lab significant adverse clinical events (AEs) were defined as evolving Q-wave MI, emergent coronary artery bypass surgery, side-branch occlusion, significant (greater than National Heart, Lung, and Blood Institute class B) dissection, distal embolization, slow or no reflow, or abrupt vessel closure. In-hospital AEs were defined as post-procedural death, urgent coronary artery bypass surgery, and either Q-wave MI or a significant increase (2 x normal) in the post-procedural creatine phosphokinase-MB fraction (CK-MB) obtained by 12 h post procedure. Troponin levels were not routinely assessed during this time period.
One-year clinical follow-up was obtained (99% of discharged patients) by telephone interview conducted by an individual not directly involved in the PCI (D.B.) and included assessment of vital status and recurrent cardiovascular events (death or MI). The diagnosis of MI was confirmed in 80% of the events reported as such by review of the pertinent hospital records. Consent for follow-up was obtained in accordance with the requirements of the Institutional Review Board of the University of Maryland, Baltimore.
Data analysis.
Summary data are expressed as mean ± SD or median and interquartile intervals for continuous variables and percentages for categorical variables. Inter-group comparisons were performed using an unpaired t test for continuous, normally distributed variables and the Mann-Whitney U test for non-parametric data. Pre- and post-PCI ST segment shifts were compared using Wilcoxon signed rank statistics. Contingency table analyses were used for the comparison of categorical variables. The product limit method was used to estimate time-dependent outcome (death or non-fatal MI) rates. Log-rank statistics were used in the comparison of these time-dependent outcomes between the IP and non-IP groups. Finally, after satisfying proportionality assumptions, Cox proportional hazards analysis controlling for those covariates demonstrating an association with outcome on univariate analysis was used to examine the relationship of IP to outcomes at one year. Hazard ratios and their 95% CI are reported. Statistical significance was achieved when p < 0.05. All analyses were performed using Statview, version 5.0 (SAS Institute, Inc., Cary, North Carolina).
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Results
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The clinical and angiographic characteristics of the study population are typical for patients undergoing elective contemporary PCI (Table 1). The mean age was 64 years. Seventy-six percent were male. Forty-four percent were undergoing PCI, having presented with an acute coronary syndrome. Twenty-four percent exhibited significantly decreased left ventricular systolic function (ejection fraction <40%). Thirty-one percent were diabetic subjects requiring oral hypoglycemics and/or supplemental insulin for control. Thirty-three percent had clinically significant co-morbidity. Overall, stent implantation was performed in 66% of patients (IP: 65%; non-IP: 68%; p = NS); the remainder underwent conventional balloon angioplasty (IP: 35%; non-IP: 32%; p = NS). All patients were discharged receiving a daily dose of aspirin and, in the case of stent implantation, ticlopidine or clopidogrel for at least one month. Overall glycoprotein IIb/IIIa antagonist use was 25% (IP: 23%; non-IP: 26%; p = NS).
Ischemic preconditioning, as previously defined, was elicited in 80% of patients. Differences between patients manifesting IP and those without IP are summarized in Table 1. Patients who failed to manifest IP were more likely to be older, female, and diabetic. As seen in Table 2 and Figure 1, the decrease in ST segment elevation from Inflation 1 to Inflation 2 was significantly greater in patients with IP (mean change in IP group, 5.7 ± 1.7 mV; mean change in non-IP group, 0.1 ± 0.6 mV; p < 0.0001). Notably, although many patients without IP exhibited ST segment elevation during the initial balloon inflation, the magnitude of this shift was significantly less than that seen in the IP group (Table 2).
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Figure 1 (A) (left panel) Histogram depicting the distribution of ST segment shift (mV) during the first inflation in patients manifesting ischemic preconditioning (IP). The median (25th, 75th percentile) values were 10.0 (9.0, 12.0) mV. In all panels, the number of patients is indicated on the y-axis. (Right panel) Histogram depicting the distribution of ST segment shift (mV) during the second inflation in patients manifesting IP. Notice the overall shift to the left of the distribution indicating a significant reduction in the magnitude of ST segment elevation during Inflation 2. The median (25th, 75th percentile) values were 5.0 (4.0, 6.0) mV. (B) (left panel) Histogram depicting a bimodal distribution of ST segment shift (mV) during the first inflation in patients failing to manifest IP. Notice the overall leftward shift compared with A, indicating a reduced extent of ST segment elevation. The median (25th, 75th percentile) ST segment shift was 6.0 (2.0, 8.0) mV. (Right panel) Histogram depicting the distribution of ST segment shift (mV) during the second inflation in patients failing to manifest IP. The distributions are virtually superimposable, indicating no overall change from the first to second inflations. The median (25th, 75th percentile) ST segment shift was 6.0 (2.0, 8.0) mV.
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As can be seen in Figure 1B, there was a non-uniform distribution of the ST segment responses during the first inflation in the non-IP group. There were no identifiable clinical or demographic features that distinguished patients with <2 mV of ST segment deviation from those with >2 mV of ST segment deviation. Importantly, the proportion of patients with surface ECG recordings was similar in the IP (81%) and non-IP groups (76%; p = NS). When patients in the non-IP group with <2 mV of ST segment elevation during the first inflation (Fig. 1B) were excluded from analysis, the magnitude of ST segment elevation in the IP group (10.4 ± 1.7 mV) remained significantly higher than in the non-IP group (7.8 ± 1.5 mV; p < 0.001).
Overall in-lab procedural success (angiographic success without in-lab AE) was achieved in 95% of patients, and in-hospital procedural success (in-lab procedural success without in-hospital AE) was achieved in 81%. The vast majority (>95%) of in-hospital AEs was the result of a post-procedural increase in CK. The frequency of CK-MB release in patients with IP (11.4%) was significantly lower than in patients without IP (41.5%; p < 0.0001). As seen in Table 2, there was a non-significant trend toward lower in-lab procedural success in patients without IP. However, in-hospital procedural success was significantly lower in patients failing to manifest IP, reflecting the increased AE rate in this group (IP group 12.1%; non-IP group 44.1%; p < 0.0001).
At one year, the overall event rate of death/non-fatal MI was 14.1% (95% CI: 10.6%, 17.6%). There were fewer post-discharge adverse events (death/non-fatal MI) in the IP group (cumulative event rate in IP group, 11.1%; cumulative event rate in non-IP group, 25.9%; p < 0.002). As depicted in Figure 2, patients failing to manifest IP during PCI were at significantly greater risk of death/MI over the year after the procedure (log-rank p = 0.001). This increased risk was apparent as early as 50 days after PCI and continued to increase over the follow-up period. These results were unchanged when the group of non-IP patients with <2 mV ST segment deviation during the first inflation were excluded from analysis (log-rank p = 0.0004). Furthermore, there was no significant difference in the rates of death/non-fatal MI between non-IP patients with <2 mV ST segment deviation during the first inflation and those with >2 mV ST segment deviation ( 2 = 0.68, p = 0.4).
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Figure 2 Kaplan-Meier plot of the estimated rates of freedom from death or non-fatal MI during the year after hospital discharge. There was a highly statistically significant reduction in event-free survival (log-rank p = 0.001) in patients failing to manifest ischemic preconditioning (IP) during PCI.
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When the analysis was restricted to mortality at one year, a significantly increased risk was again seen in the patients failing to manifest IP despite the small number of deaths in each group (6 deaths in the IP group; 10 deaths in the non-IP group; log-rank p < 0.001). Using Cox proportional hazards regression, the reduction in the mortality risk at one year associated with IP was highly significant (hazard ratio 0.12; 95% CI 0.03, 0.38).
The importance of the ability to elicit IP during PCI was confirmed on multivariate analysis after adjusting for the covariates recorded in Table 1. Using Cox proportional hazards analysis, the statistically significant independent predictors of death or non-fatal MI at one year were presentation with an acute coronary syndrome and multivessel coronary artery disease, whereas the use of beta-blockers and the ability to elicit IP were associated with a diminished risk of death or MI (Table 3).
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Discussion
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In this report we describe, for the first time, the incidence and clinical significance of the ability to induce IP during elective PCI. Ischemic preconditioning could be elicited in 80% of patients using a standardized protocol. The frequency of post-procedural cardiac enzyme elevation was significantly lower in patients manifesting IP. Importantly, the risks of death and death/non-fatal MI at one year were reduced by 85% and 55%, respectively, in patients manifesting IP. Multivariate analysis confirmed (the absence of) IP as an independent predictor of death/MI at one year after PCI.
Since the original description of IP by Murry et al. (1), this potent cardioprotective phenomenon has been validated in numerous animal models, thereby underscoring its biologic importance. Despite extensive investigations into the cellular and molecular basis of IP, there is no consensus at present on the precise mechanism(s) whereby myocytes develop tolerance to more ischemia (20). Increasing attention has focused on the mitochondrial adenosine triphosphate-dependent potassium channel as a "final common pathway" (20–22), and numerous agonists are believed to mediate their respective preconditioning effect via this mechanism (23). However, the molecular bases for pharmacologically induced versus physiologically induced IP may be distinct (24).
In contrast to the experimental literature, there is considerable debate over the clinical relevance of IP in humans (23,25). As no study in humans can rigorously duplicate the experimental situation (brief ischemia followed by prolonged ischemia with the intention to result in myocardial necrosis), the clinical literature has resorted to the use of surrogate markers and end points. Thus, the PCI model of coronary occlusion (brief myocardial ischemia) has been extensively validated in the clinical literature, whereas the use of ST segment deviation (in contrast to myocardial necrosis) has served as a surrogate marker of ischemic injury. Additional surrogates of ischemic injury approaching quantification of myocyte necrosis (but short of histopathologic confirmation) include analysis of myocardial-specific proteins (26,27), transmyocardial lactate release (10,15), and regional myocardial contractile function (18). However, all such studies in humans have been limited to the short-term sequelae of IP. Retrospective observational studies (7–9), in which IP was inferred from patient interviews of survivors of MI, have suggested a potential clinical significance of IP in terms of "hard" cardiovascular outcomes.
Ischemic preconditioning could not be elicited in 20% of the patients undergoing the described protocol. On further analysis, only female gender and diabetic status were significantly associated with the failure to induce IP. The suggestion of an increased failure rate in older patients may reflect the fact that either the variation in ages in each group was insufficient to detect such an effect or that substantially older patients, that is, >75 years, were under-represented in this series. We have previously reported on the failure to elicit IP when PCI is performed within 12 h of an anginal episode (16), which is why these patients were excluded from participation. An intriguing observation not previously reported is that many of the non-IP patients exhibited ST segment elevation during the first balloon inflation. The magnitude of the response was, however, significantly lower than that seen in IP patients during the first inflation. Thus, patients failing to manifest IP may still maintain the capacity to manifest myocardial ischemia.
The absence of IP conferred increased short- and long-term risk after PCI. As we have previously shown (26), the likelihood of post-procedural CK elevation was significantly decreased in patients manifesting IP. However, the increased risk of death/MI at one year associated with the failure to induce IP was independent of the association between IP and CK elevation (and in-hospital AE) and suggests a different mechanism whereby IP may confer long-term benefit. Although older patients, diabetic patients, and women were less likely to manifest IP, none of these potential confounders were independently associated with death/non-fatal MI at one year. That IP remained significantly, and inversely, associated with the risk of death/non-fatal MI at one year affirms the clinical significance of this phenomenon.
The failure to elicit IP during PCI (inability of ischemic myocardium to "protect" itself) may reflect profound and deleterious alterations in myocardial metabolism during low-flow ischemia. Although a considerable literature has accumulated on the metabolic alterations in preconditioned myocardium (28), no information is currently available on the metabolic features of myocardium that fails to manifest IP. The inability of ischemic myocardium to "down-regulate" its metabolic machinery (23) may predispose such tissue to be particularly vulnerable to repetitive or prolonged ischemia. The clinical consequences of such vulnerability would be reflected in a higher risk of death or non-fatal MI.
The present study was a prospective, observational cohort analysis designed to assess the inducibility of IP in clinical practice. Although a randomized design may have allowed for a more equal distribution of variables in the two groups, the strong relationship between IP and event-free survival on multivariate analysis provides additional support for our conclusions. This study did not take into account the effects, if any, of delayed preconditioning (20,29). That a significant ischemic response to the first balloon inflation was noted in 80% of our patients argues strongly against an undetected effect of delayed preconditioning. If the latter were to obtain, the magnitude of ST shift during the initial balloon inflation would have been considerably less (30).
In summary, IP can be elicited in 80% of patients undergoing elective PCI. The absence of IP is strongly associated with the risk of death/non-fatal MI within the year after PCI. The ability to elicit IP confers a significantly diminished risk of death or non-fatal MI at one year.
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Abstract
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