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Circulation. 1997;95:2500-2507

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(Circulation. 1997;95:2500.)
© 1997 American Heart Association, Inc.

Articles

Preconditioning of Human Myocardium With Adenosine During Coronary Angioplasty

Presented at the 45th Annual Scientific Session of the American College of Cardiology, Orlando, Fla, March 24 to 28, 1996.

Massoud A. Leesar, MD; Marcus Stoddard, MD; Mirza Ahmed, MD; John Broadbent, MD; Roberto Bolli, MD

From the Division of Cardiology, University of Louisville (Ky).

Correspondence to Roberto Bolli, MD, Division of Cardiology, University of Louisville, Louisville, KY 40292. E-mail r0bolli01{at}ulkyvm.louisville.edu

Abstract

Background It is unknown whether adenosine can precondition human myocardium against ischemia in vivo.

Methods and Results Thirty patients were randomized to receive a 10-minute intracoronary infusion of adenosine (2 mg/min) or normal saline; 10 minutes later, they underwent percutaneous transluminal coronary angioplasty (PTCA; three 2-minute balloon inflations 5 minutes apart). In control patients, the ST-segment shift on the intracoronary ECG was significantly greater during the first inflation than during the second and third inflations, consistent with ischemic preconditioning. In contrast, in adenosine-treated patients, there were no differences in ST-segment shift during the three inflations. The ST-segment shift was significantly smaller in the adenosine-treated group compared with the control group during all three inflations. The reduction in ST-segment shift afforded by adenosine during the first inflation (-72% versus first inflation in control subjects) was greater than that afforded by ischemic preconditioning in control subjects (-52% during the third versus first inflation). Measurements of chest pain score paralleled those of ST-segment shift. Adenosine had no effect on baseline regional wall motion as determined by quantitative two-dimensional echocardiography. Thus, intracoronary infusion of adenosine before PTCA rendered the myocardium remarkably resistant to subsequent ischemia. Judging from the intracoronary ECG, the protection provided by adenosine was even superior to that provided in control subjects by the ischemia associated with the first two balloon inflations. Infusion of adenosine had no major adverse effects in patients undergoing PTCA of the left anterior descending or circumflex arteries.

Conclusions Adenosine preconditions human myocardium against ischemia in vivo. Pretreatment with adenosine is remarkably effective (even more effective than ischemic preconditioning) and could be used prophylactically to attenuate ischemia in selected patients undergoing PTCA of the left anterior descending coronary artery. Whether adenosine can be safely infused into the right or the circumflex coronary artery in the presence of a temporary pacemaker remains to be established.


Key Words: adenosine • ischemia • angioplasty

Brief episodes of ischemia render the myocardium more resistant to subsequent ischemic episodes, a phenomenon that has been termed ischemic preconditioning.1 A considerable body of experimental evidence suggests a central role of adenosine as an endogenous mediator of ischemic preconditioning. Liu et al2 were the first to propose that preconditioning is mediated by the release of adenosine from ischemic myocytes (as a result of ATP breakdown) and by the consequent activation of adenosine A1 receptors. This hypothesis was based on the demonstration in rabbit hearts that preconditioning could be blocked by adenosine receptor antagonists and conversely could be mimicked by adenosine or adenosine A1 receptor agonists.2 3 The adenosine hypothesis has been subsequently supported by studies in dogs4 5 6 and pigs.7 In contrast, endogenous adenosine does not appear to be necessary for ischemic preconditioning to occur in rat hearts, although exogenous adenosine can precondition rat myocardium.8 9 Thus, there appear to be important species differences with respect to the role of adenosine in ischemic preconditioning.

To date, the only data supporting a role of adenosine in preconditioning human myocardium have been obtained in isolated, in vitro preparations. Studies of human atrial trabeculae10 and cultured human ventricular cardiomyocytes11 exposed to simulated ischemia and reperfusion have concluded that adenosine mediates the development of a state resembling ischemic preconditioning in these preparations. These in vitro models of substrate-free hypoxia involving atrial myocardium or cultured ventricular myocytes obviously differ in several major respects from the clinical setting of ischemia occurring in the intact working ventricle. To the best of our knowledge, evidence that adenosine can precondition human myocardium in vivo is still lacking.

Several recent studies12 13 14 15 16 have shown that in the course of percutaneous transluminal coronary angioplasty (PTCA), the severity of myocardial ischemia during balloon inflation decreases with subsequent inflations, suggesting the development of ischemic preconditioning. The mechanism for this form of preconditioning during PTCA is unknown. We reasoned that if the adenosine hypothesis is applicable to humans, then pretreatment with adenosine before the first balloon inflation should induce a state of preconditioning similar to that induced by ischemia itself. The present investigation was conducted to test this hypothesis. Specifically, the goals of this study were to determine whether intracoronary infusion of adenosine before PTCA mitigates the manifestations of ischemia observed during balloon inflation and, if so, whether the magnitude of the protection afforded by adenosine is equivalent to the magnitude of the protection afforded in control patients by the ischemic preconditioning associated with the first two balloon inflations.

Methods

Study Population
The patient population consisted of 30 subjects referred for PTCA of an isolated obstructive lesion (internal diameter reduction >70% by visual assessment) in the proximal two thirds of a major coronary artery. Patients were prospectively selected on the basis of the following criteria: (1) no angiographically visible collateral vessels, (2) no history or ECG evidence of prior myocardial infarction in the territory supplied by the vessel undergoing PTCA, (3) no conduction defects on the ECG, (4) no evidence of left ventricular (LV) hypertrophy on the echocardiogram, and (5) no baseline ST-segment abnormalities on the surface or intracoronary ECG. Thirteen patients were admitted with a diagnosis of unstable angina; the remaining 17 had clinically stable angina pectoris (Table 1Down). The average interval between the last episode of angina and PTCA was 7.1±1.1 days in control subjects and 8.0±1.2 days in adenosine-treated patients. No patient had angina pectoris in the 72 hours before PTCA. On the LV angiogram, the ejection fraction was 59±1% in control patients and 56±2% in adenosine-treated patients (Table 1Down). This study was approved by the Institutional Review Board on July 17, 1995; informed consent, through an institutionally approved human investigation form, was obtained from all patients.


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  		Table 1. Clinical Features of the Two Groups of Patients

Experimental Protocol
In this single-blind study, patients were randomly allocated to a control or an adenosine-treated group. The control group consisted of 15 patients (9 men and 6 women, ranging in age from 40 to 77 years; mean age, 58±3 years); the adenosine-treated group consisted of 15 patients (8 men and 7 women, ranging in age from 41 to 76 years; mean age, 56±3 years; Table 1Up). All patients were being treated with aspirin (325 mg/d) for >=48 hours before PTCA; 26 patients (13 control and 13 adenosine-treated patients) were receiving long-acting nitrates, 15 (7 control and 8 adenosine-treated) were receiving ß-blockers, and 9 (5 control and 4 adenosine-treated patients) were receiving calcium channel antagonists for >=48 hours before PTCA (Table 1Up). Antianginal medications were not discontinued before the procedure. Four patients (2 control and 2 adenosine-treated patients) received intravenous nitroglycerin before and throughout PTCA, and 13 (7 control and 6 adenosine-treated patients) received intracoronary nitroglycerin (Table 1Up). All patients were studied after an overnight fast and were premedicated with midazolam (1 mg IV 10 minutes before the procedure).

PTCA was performed by a standard technique by use of the femoral approach. After placement of the guiding catheter and performance of baseline coronary angiography, a bolus of 10 000 IU heparin was administered intravenously; additional boluses of heparin were given during the procedure to achieve an activated clotting time of >300 seconds. Nonionic contrast medium (Iopamidol, Squibb, Inc.; 796 mOsm/kg) was used in all patients. After venous cannulation, a 5F bipolar temporary transvenous pacemaker was advanced under fluoroscopic guidance to the right ventricular apex and set to demand mode for heart rate backup. A 2.2F Tracker coronary-infusion catheter (SciMed Life System) was advanced over a 0.014-in guide wire (Traverse Wire, Advanced Cardiovascular Systems) into the proximal portion of the coronary artery for selective intracoronary infusion of adenosine or saline. Adenosine (Adenocard, Fujisawa Pharmaceutical Co) was dissolved in sterile normal saline (20 mg in 50 mL) and infused at a rate of 2 mg/min over 10 minutes. The control group received an equivalent volume of vehicle (normal saline). After infusion of adenosine or vehicle, the Tracker catheter was removed. After a 10-minute drug-free period, the lesion was crossed with a 0.014-in guide wire. PTCA was performed with Advanced Cardiovascular Systems or Medtronic balloon dilatation catheters ranging in diameter from 2.5 to 3.5 mm. Balloon sizes were determined by examination of the normal regions of the coronary artery adjacent to the stenosis. After the balloon was positioned across the lesion, patients underwent three balloon inflations, each lasting 120 seconds, interspersed with 5-minute periods of reperfusion during which the balloon was deflated and withdrawn proximal to the lesion with the guide wire remaining across the lesion. Balloon inflation pressures ranged from 5.0 to 8.0 atm. Five minutes after the end of the third inflation, the study protocol was terminated, and decisions regarding further inflations or other interventional procedures were made on an individual basis.

Assessment of Myocardial Ischemia
Lead V5 of the electrocardiographer (model M1700 A, Hewlett-Packard, Inc) was connected to the coronary guide wire. The intracoronary ECG (derived from the guide wire) along with the remaining 11 standard surface leads were recorded continuously at a paper speed of 50 mm/s during the three balloon inflations and at selected times after deflation. All ECG recordings were analyzed by a cardiologist who had no knowledge of the study protocol. At all time points, the ST-segment shift was measured 80 ms after the J point. The sums of the absolute values of the ST-segment shifts from baseline on the surface ECGs and on the intracoronary ECGs were calculated separately and expressed in millimeters (1 mm=0.1 mV).

Assessment of Chest Pain
At the beginning of the procedure, patients were informed that they may develop chest pain during balloon inflations. At the end of each inflation, the intensity of the cardiac pain was assessed with a visual-analog scale.17 Patients were asked to put a mark on a 100-mm scale marked from no symptoms (0) to the most severe symptoms (100). The intensity of the chest pain was measured in millimeters from 0 to the subject’s mark.

Echocardiographic Studies
To assess the effect of adenosine on LV systolic function, two-dimensional echocardiograms were performed serially in 15 patients (8 control and 7 adenosine-treated subjects) at baseline and immediately after adenosine or saline infusion. The methods have been previously described in detail.18 19 Briefly, two-dimensional images of the left ventricle were obtained from the apical four- and two-chamber views with a phased-array echocardiographic machine (SONOS 1500 or 2500, Hewlett-Packard, Inc) and a 2.5-MHz transducer. The images were recorded on 1/2-in videotape for subsequent review and analysis. With the use of a commercially available microcomputer system (GTI, Freeland), the echocardiograms were analyzed qualitatively and quantitatively for the development of regional LV wall motion abnormalities. Quantitative analysis was performed by use of a centerline method that constructs 100 equidistant chords perpendicular to a line centered between digitized LV end-diastolic and end-systolic endocardial borders.20 One hundred equidistant chords perpendicular to the centerline were constructed between boundaries, and the shortening of every 10th chord was determined before and after adenosine or saline infusion. Individual chordal shortening was averaged for all the chords within the LV segments subserved by the artery infused with adenosine or saline; this quantity provided an overall measure of wall motion in the territory that received the intracoronary infusion. A similar method was used to measure wall motion in the segments that did not receive the intracoronary infusion. Values for individual patients were then averaged to obtain mean chordal shortening for the entire group. LV ejection fraction was calculated by the modified Simpson method.21 The echocardiographic studies were analyzed by an echocardiographer (M.S.) who had no knowledge of the treatment.

Statistical Analysis
All data are reported as mean±SEM. ST-segment shifts and chest pain score were analyzed with a two-way repeated measures ANOVA. Post hoc contrasts between groups at various time points or between time points within one group were performed with Student’s t tests for unpaired or paired data, as appropriate, with the Bonferroni correction.22 Chordal shortening and ejection fraction were compared before and after treatment with paired Student’s t tests. The remaining continuous or dichotomous variables were compared between the two groups by use of unpaired Student’s t tests or {chi}2 tests, respectively.

Results

Fifteen patients in the control group and 15 in the adenosine-treated group met the criteria detailed earlier and had technically adequate intracoronary and surface ECGs associated with complete resolution of ischemia between balloon inflations. Complete resolution of ischemia was defined as chest pain resolution and return of the ST segment on the intracoronary and surface ECGs to within 1 mm of baseline during the 5 minutes that elapsed between the first, second, and third balloon inflations. Table 1Up outlines the clinical features of the control and adenosine-treated patients. There were no significant differences between the two groups.

Coronary Angioplasty
Table 2Down summarizes the anatomic and hemodynamic features of the study population. PTCA was successfully performed in all 30 patients; coronary stenosis was reduced from 81±3% to 20±1% in the control group and from 86±2% to 17±1% in the adenosine-treated group. The balloon pressure was similar in the control and adenosine-treated groups (Table 2Down). Heart rate and arterial blood pressure did not differ between the two groups during the three inflations (data not shown). The rate-pressure product was also similar (Table 2Down). There was no ECG or enzymatic evidence of myocardial injury in any patient.


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  		Table 2. Anatomic and Hemodynamic Features of the Two Groups of Patients

ECG Manifestations of Myocardial Ischemia
All patients exhibited ST-segment elevation except one adenosine-treated patient with PTCA of the LAD, who exhibited ST-segment depression. In the control group, the ST-segment shift was significantly greater during the first balloon inflation than during the second and third inflations on both the intracoronary ECG (25±3 versus 16±2 and 12±1 mm, respectively; Fig 1Down) and the surface ECG (15±3 versus 9±2 and 8±1 mm, respectively; Fig 2Down). In contrast, in the adenosine-treated group, there were no differences in the ST-segment shift during the first, second, and third balloon inflations on either the intracoronary ECG (7±1, 7±1, and 6±1 mm, respectively; Fig 1Down) or the surface ECG (6±1, 5±1, and 6±1 mm, respectively; Fig 2Down).



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  		Figure 1. Individual (left) and average (right) values of ST-segment shifts on the intracoronary ECG at the end of the first, second, and third balloon inflations in control and adenosine-treated patients. In control patients, the ST-segment shifts decreased progressively between the first, second, and third inflations. In contrast, in adenosine-treated patients, the ST-segment shifts were similar during all three inflations. During all three inflations, the ST-segment shifts were less in adenosine-treated compared with control patients. The ST-segment shift was less in adenosine-treated patients during the first inflation than in control patients during the third inflation. Values are mean±SEM.



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  		Figure 2. Individual (left) and average (right) values of ST-segment shifts on the surface ECG at the end of the first, second, and third balloon inflations in control and adenosine-treated patients. In control patients, the ST-segment shifts decreased between the first and second inflations. In contrast, in adenosine-treated patients, the ST-segment shifts were similar during all three inflations. During the first inflation, the ST-segment shift was less in adenosine-treated than in control patients. Values are mean±SEM.

On the intracoronary ECG, the ST-segment shift was significantly smaller in the adenosine-treated group than in the control group during each of the three inflations (7±1 versus 25±3 mm [-72%], P<.001, during the first inflation; 7±1 versus 16±2 mm [-56%], P<.001, during the second; and 6±1 versus 12±1 mm [-50%], P<.02, during the third) (Fig 1Up). The effect of adenosine was so pronounced that during the first inflation, there was little overlap between treated and control patients (Fig 1Up). The intracoronary ST-segment shift recorded during the first inflation in the adenosine group was significantly (P<.01) less than that recorded during the third inflation in the control group (Fig 1Up); as a result, the reduction in ST-segment shift afforded by adenosine during the first inflation (-72% compared with the first inflation in control patients) was greater than that afforded by ischemic preconditioning during the third inflation in the control group (-52% compared with the first inflation in this group).

On the surface ECG, the ST-segment shift was significantly smaller in the adenosine-treated group than in the control group during the first inflation (6±1 versus 15±3 mm, respectively; P<.05) but did not differ significantly between the two groups during the second and third inflations (5±1 versus 9±2 mm and 6±1 versus 8±1 mm, respectively; P=NS; Fig 2Up). The fact that the effects of adenosine on the ST-segment shifts were less striking on the surface than on the intracoronary ECG likely reflects the greater sensitivity of the latter for detecting ischemia in the perfusion bed of the PTCA artery.23

The effect of adenosine on ST-segment shifts was independent of the presence of unstable angina. Indeed, when the analysis was restricted to the 17 patients with stable angina pectoris, the results were similar to those obtained in the entire cohort. For example, during the first, second, and third balloon inflations, the intracoronary ST-segment shift averaged 24±2, 16±2, and 10±2 mm, respectively, in the 9 control patients with stable angina pectoris and 6±1, 6±1, and 5±1 mm, respectively, in the 8 adenosine-treated patients with stable angina pectoris. For corresponding inflations, the values in the treated patients were significantly (P<.05) less than those in the control patients.

Chest Pain
In the control group, the severity of chest pain was significantly greater during the first inflation than during the second and third inflations (74±4 versus 59±4 and 40±4 mm, respectively; Fig 3Down). In contrast, in the adenosine-treated group, the chest pain score did not differ significantly during the first, second, and third inflations (28±6, 25±6, and 24±6 mm, respectively; Fig 3Down). The chest pain score was significantly smaller in the adenosine-treated group than in the control group during all three balloon inflations: -62% (P<.01) during the first inflation, -58% (P<.01) during the second, and -40% (P<.05) during the third (Fig 3Down).



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  		Figure 3. Individual (left) and average (right) values of chest pain score during the first, second, and third balloon inflations in control and adenosine-treated patients. In control patients, the chest pain score decreased progressively from the first to the third inflation. In contrast, in adenosine-treated patients the chest pain score did not change significantly during the three inflations. During all three inflations, the chest pain score was significantly less in adenosine-treated compared with control patients. Values are mean±SEM.

The effect of adenosine on the severity of chest pain was independent of the presence of unstable angina. Indeed, in the 17 patients with stable angina pectoris, the chest pain score was significantly less in the adenosine-treated group than in the control group during all three inflations: -76% (P<.001) during the first inflation, -72% (P<.001) during the second, and -56% (P<.01) during the third.

Echocardiographic Data
To determine whether the cardioprotection observed with adenosine was secondary to a negative inotropic effect, two-dimensional echocardiograms were obtained in 15 patients (8 control and 7 adenosine-treated patients). LV ejection fraction did not change significantly before and after the intracoronary infusion of normal saline (65±2% and 68±2%, respectively) or adenosine (67±3% and 70±3%, respectively). Qualitative analysis also showed no changes in regional LV wall motion before and after treatment. These findings were corroborated by the results of the quantitative analysis performed with the centerline method. In the control group, chordal shortening in the segments that received the infusion of normal saline averaged 5.6±0.3 mm before the infusion and 5.4±0.3 mm after the infusion; in the segments that did not receive the infusion of normal saline, chordal shortening averaged 6.2±0.3 mm before the infusion and 6.8±0.3 mm after the infusion. In the adenosine-treated group, chordal shortening in the segments that received the infusion of the nucleoside averaged 6.3±0.3 mm before the infusion and 6.2±0.3 mm after the infusion; in the segments that did not receive the infusion of the nucleoside, chordal shortening averaged 6.7±0.3 mm before the infusion and 7.2±0.3 mm after the infusion. Thus, administration of adenosine had no appreciable effect on either global LV function or regional LV wall motion.

Adverse Effects of Adenosine
All patients receiving adenosine developed mild transient chest pain during the infusion of the nucleoside, which resolved promptly after the end of the infusion. In no patient was the discomfort severe enough to warrant discontinuation of the infusion. In the early phase of the study, one patient receiving adenosine into the right coronary artery developed AV block (resulting in pacemaker rhythm), which was associated with a mild asymptomatic drop in systolic blood pressure; these effects resolved promptly after discontinuation of the adenosine infusion. After this episode, no patient undergoing PTCA of the right coronary artery was enrolled in the study. In the remaining patients, the infusion of adenosine did not produce any changes in heart rate, PR interval, or blood pressure (data not shown). Thus, in patients undergoing PTCA of the LAD or circumflex arteries, the administration of adenosine was well tolerated.

Discussion

The two major findings of this study can be summarized as follows. First, intracoronary infusion of adenosine before PTCA renders the myocardium remarkably resistant to subsequent ischemia, as indicated by the fact that during the first balloon inflation, the magnitude of the intracoronary ST-segment shift was decreased by 72% and the chest pain score by 62% in adenosine-treated compared with control patients. This protective effect was observed between 10 and 30 minutes after the end of the infusion, at a time when adenosine was no longer present. Second, the protection afforded by adenosine is at least equivalent if not superior to that afforded by ischemic preconditioning. This second conclusion is supported by three lines of evidence: (1) in contrast to control patients in whom the ST-segment shift and the severity of chest pain decreased progressively between the first and third balloon inflations, in adenosine-treated patients there was no decrease in either the ST-segment shift or the severity of chest pain during the second or third inflation compared with the first, suggesting that the myocardium was already "maximally" preconditioned during the first inflation; (2) the surface ECG ST-segment shift noted in adenosine-treated patients during the first inflation was not greater than that noted in control patients during the third inflation, suggesting that the preconditioning effect of adenosine was not weaker than that of the first two episodes of ischemia in control patients; and (3) on the more sensitive intracoronary ECG, the ST-segment shift recorded during the first inflation in the adenosine group was significantly less than that recorded during the third inflation in the control group (and the chest pain showed similar differences), suggesting that the protection provided by adenosine may have actually been greater than that provided by ischemic preconditioning in control patients, even after two balloon inflations. The protective effects of adenosine cannot be ascribed to a negative inotropic action because the infusion of adenosine produced no changes in regional LV wall motion.

Taken together, these results indicate that pretreatment with adenosine mimics ischemic preconditioning in patients undergoing PTCA, a finding consistent with the concept that endogenous adenosine mediates ischemic preconditioning in humans. Previous studies have demonstrated that adenosine mimics ischemic preconditioning in experimental animals1 2 3 4 5 6 7 8 9 and in isolated human myocardium or myocytes subjected to substrate-free hypoxia.10 11 However, to the best of our knowledge, this is the first demonstration that adenosine preconditions human myocardium against ischemia in vivo.

Preconditioning During PTCA
We elected to use PTCA as a clinical setting to test the hypothesis that adenosine induces a preconditioning-like state in humans for several reasons. PTCA offers the opportunity to pretreat patients and to examine the effects of fixed durations of ischemia under relatively controlled conditions. Our results in control patients confirm previous studies12 13 14 15 16 in which less ST-segment shift and less subjective anginal discomfort were noted during the second and/or third balloon inflations compared with the first, a pattern consistent with the development of ischemic preconditioning. The fact that in the setting of PTCA, the reduction in ischemia during the second balloon inflation can be blocked by glibenclamide16 further corroborates the notion that it is due to ischemic preconditioning through the opening of ATP-sensitive K+ channels. Finally, recent data demonstrate that the magnitude of the ST-segment shift accurately reflects the presence and magnitude of the protection afforded by ischemic preconditioning.24 To minimize the influence of potentially confounding variables, we excluded patients with prior myocardial infarction, abnormal baseline ECGs, LV hypertrophy, or angiographically visible collaterals.

The severity of chest pain was assessed with a visual-analog scale, a well-accepted method for the evaluation of pain perception17 that has been widely used because of its simplicity and reliability.15 16 25 In the present study, the changes in the chest pain score paralleled those in the ST-segment shift, thereby corroborating the results obtained with the intracoronary and surface ECGs.

In this study, the protection afforded by adenosine appeared to be even greater than that afforded by ischemic preconditioning, judging from the ST-segment shifts on the intracoronary ECG (Fig 1Up) and the chest pain score (Fig 3Up). This could be due to the fact that the amount of endogenous adenosine released in the interstitial compartment during a 2-minute coronary occlusion is probably less than that which occurs during an intracoronary infusion of 20 mg over 20 minutes. Studies in dogs26 indicate that a 5-minute infusion of adenosine 140 µg·kg-1·min-1 IV produces increases in interstitial adenosine levels comparable to those produced by 5 minutes of coronary occlusion. In our study, the duration of coronary occlusion was 2 minutes, which should have resulted in lower interstitial adenosine levels compared with a 5-minute occlusion. On the other hand, because coronary flow in a major epicardial artery is, at the most, 2% to 3% of cardiac output, a 140–µg·kg-1·min-1 IV infusion should result in coronary arterial blood levels of adenosine equivalent to those produced by a 200- to 300-µg/min IC infusion, which is much lower than the rate of infusion used in our investigation. Thus, it is likely that in our study the interstitial levels of adenosine achieved during the intracoronary infusion were much higher than those achieved during the first balloon inflation.

Previous Studies of the Role of Adenosine in Ischemic Preconditioning in Humans
Although the adenosine hypothesis of preconditioning has been extensively tested in experimental animals,27 clinical information is still lacking. Two previous studies have examined the role of adenosine as a mediator of ischemic preconditioning in human myocardium in vitro. Walker et al10 found that isolated human right atrial trabeculae submitted to 90 minutes of simulated ischemia (substrate-free hypoxia with rapid pacing) could be preconditioned by a 3-minute period of simulated ischemia followed by 12 minutes of reoxygenation. This protective effect was blocked by the adenosine receptor antagonist 8-p-sulphophenyl theophylline and conversely could be induced by the adenosine A1 receptor agonist R-phenyl-isopropyl adenosine. Using monolayer cultures of quiescent human ventricular cardiomyocytes, Ikonomidis et al11 found that 20 minutes of simulated ischemia (anoxia with a low volume of buffer) protected against a subsequent prolonged (90-minute) simulated ischemic episode. Adenosine receptor antagonists blocked this protection, whereas pretreatment with adenosine provided similar protection. Although the results of these studies10 11 support a role of adenosine in mediating ischemic preconditioning in human myocardium, the numerous important differences between substrate-free hypoxia of atrial trabeculae or cultured ventricular myocytes in vitro on the one hand and ischemia of the intact heart in vivo on the other require that the adenosine hypothesis be explored in the clinical setting.

Only one previous study has examined the effect of adenosine on ischemic preconditioning in the intact human heart. In a recent report, Kerensky et al28 found that a bolus of 100 µg IC adenosine given just before balloon inflation failed to decrease the severity of ischemia during the first inflation (as assessed by the ST-segment shift and the chest pain score) compared with control patients but prevented the decrease in ST-segment shift between the first and second inflations that was noted in control patients. Neither control nor adenosine-treated patients exhibited a reduction in chest pain during the second inflation compared with the first.28 Our results differ substantially from that report. In our study, pretreatment with adenosine effected a marked reduction in both ST-segment shift and chest pain score during the first inflation compared with control patients. These indexes of ischemia decreased further during the second and third inflations in control but not in adenosine-treated patients, probably because a near-maximal protection had already been achieved with the infusion of adenosine. The reasons for the discrepancy between our results and those of Kerensky et al probably relate to the different experimental protocols. We used a 200-fold greater dose of adenosine (20 mg versus 100 µg). We allowed a 10-minute period for preconditioning to develop after adenosine infusion, whereas Kerensky et al gave the bolus of adenosine just before the first inflation. We measured ST-segment shifts 80 ms after the J point at the end of a 120-second inflation, whereas these authors measured ST-segment shifts 40 ms after the J point and 60 seconds after the beginning of the inflation (which lasted 90 seconds). Finally, we excluded patients with prior myocardial infarction in the PTCA territory, whereas in the study by Kerensky et al, 19% of the patients suffered a myocardial infarction an average of 6.7 days before PTCA.

Dosage and Safety of Adenosine
Except for a study in recipients of cardiac transplantation,29 no previously published report has used an intracoronary infusion rate of adenosine as high as 2 mg/min. Unlike previous studies that focused on the vascular effects of adenosine, however, the aim of the present investigation was to activate the A1 receptors on the cardiac myocytes. Our choice of the dosage of adenosine (2 mg/min for 10 minutes) was based on previous experimental results4 6 and on the notion that a large fraction of the intravascular nucleoside is taken up by red cells and endothelial cells and therefore does not reach the myocytes.30 31 In dogs, a 5-minute intracoronary infusion of adenosine at 400 µg/min fails to precondition against infarction,4 indicating that this dose is insufficient to produce a high enough interstitial concentration to mimic ischemic preconditioning. However, a 10-minute intracoronary infusion at 400 µg/min does precondition the canine heart6 ; corrected for the human heart size, this infusion rate corresponds to {approx}1.5 mg/min.

Infusion of adenosine at 2 mg/min into the LAD and left circumflex artery did not cause major adverse effects in the present study. The chest pain associated with adenosine was mild and resolved promptly after the end of the infusion. Adenosine had no effect on regional wall motion. Our results are consistent with those of other investigators29 who infused adenosine into the LAD at incremental doses up to 2.2 mg/min in patients who had received cardiac transplantation 1 to 3 years earlier and noted no bradycardia and only minimal changes in blood pressure. Therefore, it appears that adenosine can be safely infused into the LAD at a rate of 2 mg/min. Infusion of adenosine into the right or a dominant left circumflex artery, however, may result in bradyarrhythmias and/or hypotension unless ventricular pacing is used. Further studies with larger patient groups are needed to evaluate the safety of infusing adenosine into the right or the left circumflex artery in the presence of a temporary ventricular pacemaker.

Study Limitations
A limitation of this study is the use of a single-blind design. However, it is unlikely that this had an important impact on the results because (1) objective ECG end points were used, (2) the ST-segment shift was measured by a cardiologist who was blind to the treatment, and (3) the magnitude of the differences between control and treated patients was greater than could be explained by bias alone. Although the administration of antianginal agents could potentially have confounded the results, the two groups of patients were comparable with respect to concomitant therapy (aspirin, nitrates, calcium channel blockers, ß-blockers; Table 1Up); therefore, any effect of these drugs should have been similar in the two groups.

We assessed the severity of myocardial ischemia on the basis of the ST-segment shift and the anginal pain severity. The surface and intracoronary ECGs represent highly sensitive, well-accepted, and simple methods for the evaluation of myocardial ischemia during PTCA.12 13 14 15 16 23 32 33 34 For example, Labovitz et al33 found that during PTCA, ST-segment changes always precede LV systolic dysfunction. Because ST-segment shifts were measured sequentially in the same patient, any variable that differed among patients cannot explain the lack of change in ST-segment shifts in adenosine-treated patients during subsequent balloon inflations. More importantly, Shattock et al24 recently demonstrated that the ST-segment shift accurately reflects the presence of ischemic preconditioning. In that study, pigs were subjected to two brief (8-minute) coronary occlusions interspersed with 8 minutes of reperfusion and then to a long (60-minute) coronary occlusion that caused myocardial infarction. The ST-segment shift recorded during the first 3 minutes of ischemia decreased with subsequent occlusions so that it was considerably less during the third occlusion than during the first. This decrease in ST-segment shift was associated with a profound reduction in infarct size and was independent of any changes in collateral perfusion. Furthermore, in this model, pretreatment with adenosine or conversely blockade of adenosine receptors induces a decrease or an increase, respectively, in the ST-segment shift, which is paralleled by changes in infarct size (J.M. Downey, personal communication). These experimental data24 strongly support the concept that the ST-segment shift provides a reliable index of preconditioning.

We assessed adenosine-induced protection during a short (2-minute) coronary occlusion. Although the drug was protective in this setting, it is possible that it would be ineffective with longer occlusions. Pretreatment with intracoronary adenosine decreases infarct size after a 60-minute coronary occlusion in dogs.6 As discussed, there is good correlation in experimental animals between the decrease in ST-segment shift recorded during the first 3 minutes of a 60-minute coronary occlusion and the reduction in infarct size measured after the 60-minute occlusion, implying that the ST-segment shift recorded early in an ischemic episode predicts the degree of injury incurred during the subsequent hour of ischemia.24

Practical Implications
Aside from their conceptual and pathophysiological importance, our results may have practical implications. The infusion of adenosine was well tolerated and may find a useful application in PTCA. Specifically, the notion that a brief infusion of adenosine renders the myocardium resistant to subsequent ischemia could be applied to increase the safety of PTCA in high-risk patients, including those with left main coronary disease, severe triple-vessel disease, large regions of myocardium at risk, severely depressed LV function, and unstable angina with hemodynamic compromise. Alleviation of myocardial ischemia during balloon inflation may allow not only expansion of the patient population currently deemed eligible for PTCA but also prolongation of the inflation period, which could improve the immediate angiographic results.35 36 37 38 In this context, a recent randomized study38 has demonstrated the high clinical success of prolonged balloon inflations compared with standard short inflations. Furthermore, adenosine preconditioning should substantially reduce the patient discomfort during balloon inflation, as was found in our study. In those instances in which PTCA is complicated by acute closure requiring emergency surgery, the protection provided by adenosine preconditioning may retard the development of necrosis and allow more time for revascularization. When complications (eg, dissections) requiring placement of intracoronary stents develop, adenosine preconditioning may provide an opportunity to perform these "bailout" procedures with less hemodynamic instability. In view of these considerations, pretreatment with adenosine may become a routine prophylactic measure in selected patients undergoing PTCA of the LAD. Whether adenosine can be safely infused into the right or the circumflex coronary artery in the presence of a temporary pacemaker remains to be established.

Acknowledgments

This work was supported in part by NIH R01 grants HL-43151 and HL-55757 (Dr Bolli), AHA Kentucky Affiliate grant KY-96-GS-39 (Dr Leesar), and an Alliant Community Trust Grant (Dr Leesar). This study was supported by the Medical Research Grant program of the Jewish Hospital Foundation, Louisville, Ky.

Received August 19, 1996; revision received December 6, 1996; accepted December 16, 1996.

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