(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.
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 1
). 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 1).
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.
|
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 1
). 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 1).
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 1). 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 
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 1 outlines the clinical features of the
control and adenosine-treated patients. There were no
significant differences between the two groups.
Coronary Angioplasty
Table 2 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 2). 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 2). There was no ECG or enzymatic
evidence of myocardial injury in any patient.
|
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 1) and the surface ECG (15±3 versus 9±2 and 8±1
mm, respectively; Fig 2). 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 1) or the surface ECG (6±1, 5±1, and 6±1 mm,
respectively; Fig 2).
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|
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 1). The effect of
adenosine was so pronounced that during the first inflation,
there was little overlap between treated and control patients (Fig 1).
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 1); 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 2).
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 3). 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 3). 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 3).
|
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 1) and the chest pain score (Fig 3). 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
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 1); 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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K. W. Mahaffey, J. A. Puma, N. A. Barbagelata, M. F. DiCarli, M. A. Leesar, K. F. Browne, P. R. Eisenberg, R. Bolli, A. C. Casas, V. Molina-Viamonte, et al. Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: Results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) Trial J. Am. Coll. Cardiol., November 15, 1999; 34(6): 1711 - 1720. [Abstract] [Full Text] [PDF]
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L. P. Perrault and P. Menasche Preconditioning: can nature’s shield be raised against surgical ischemic-reperfusion injury? Ann. Thorac. Surg., November 1, 1999; 68(5): 1988 - 1994. [Abstract] [Full Text] [PDF]
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M. A. Leesar, M. F. Stoddard, S. Manchikalapudi, and R. Bolli Bradykinin-induced preconditioning in patients undergoing coronary angioplasty J. Am. Coll. Cardiol., September 1, 1999; 34(3): 639 - 650. [Abstract] [Full Text] [PDF]
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F. Tomai, F. Crea, L. Chiariello, and P. A. Gioffre Ischemic Preconditioning in Humans : Models, Mediators, and Clinical Relevance Circulation, August 3, 1999; 100(5): 559 - 563. [Abstract] [Full Text] [PDF]
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F. Grund, H. T. Sommerschild, T. Lyberg, K. A. Kirkeboen, and A. Ilebekk Microembolization in pigs: effects on coronary blood flow and myocardial ischemic tolerance Am J Physiol Heart Circ Physiol, August 1, 1999; 277(2): H533 - H542. [Abstract] [Full Text] [PDF]
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 H.-S. V. Chen, S. C. Body, and S. K. Shernan Myocardial Preconditioning: Characteristics, Mechanisms, and Clinical Applications Seminars in Cardiothoracic and Vascular Anesthesia, July 1, 1999; 3(2): 85 - 97. [Abstract] [PDF]
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F. Tomai, F. Crea, A. Gaspardone, F. Versaci, A. S. Ghini, C. Ferri, G. Desideri, L. Chiariello, and P. A. Gioffre Effects of naloxone on myocardial ischemic preconditioning in humans J. Am. Coll. Cardiol., June 1, 1999; 33(7): 1863 - 1869. [Abstract] [Full Text] [PDF]
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 G. Li, S. Chen, E. Lu, and Y. Li Ischemic preconditioning improves preservation with cold blood cardioplegia in valve replacement patients Eur. J. Cardiothorac. Surg., May 1, 1999; 15(5): 653 - 657. [Abstract] [Full Text] [PDF]
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W. K. Laskey Beneficial Impact of Preconditioning During PTCA on Creatine Kinase Release Circulation, April 27, 1999; 99(16): 2085 - 2089. [Abstract] [Full Text] [PDF]
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A. M. Feldman, D. R. Wagner, and D. M. McNamara AMPD1 Gene Mutation in Congestive Heart Failure : New Insights Into the Pathobiology of Disease Progression Circulation, March 23, 1999; 99(11): 1397 - 1399. [Full Text] [PDF]
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M. Billinger, M. Fleisch, F. R. Eberli, A. Garachemani, B. Meier, and C. Seiler Is the development of myocardial tolerance to repeated ischemia in humans due to preconditioning or to collateral recruitment? J. Am. Coll. Cardiol., March 15, 1999; 33(4): 1027 - 1035. [Abstract] [Full Text] [PDF]
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J. A. Auchampach and R. Bolli Adenosine receptor subtypes in the heart: therapeutic opportunities and challenges Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H1113 - H1116. [Full Text] [PDF]
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 U. Vahlensieck, P. Bokník, I. Gombosová, S. Huke, J. Knapp, B. Linck, J. Neumann, M. C. Deng, H. H. Scheld, H. Jankowski, et al. Inotropic Effects of Diadenosine Tetraphosphate (AP4A) in Human and Animal Cardiac Preparations J. Pharmacol. Exp. Ther., February 1, 1999; 288(2): 805 - 813. [Abstract] [Full Text]
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R. W. Landymore, A. J. Bayes, J. T. Murphy, and J. H. Fris Preconditioning prevents myocardial stunning after cardiac transplantation Ann. Thorac. Surg., December 1, 1998; 66(6): 1953 - 1957. [Abstract] [Full Text] [PDF]
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C. Seiler, M. Billinger, R. Bolli, M. M. Leesar, M. M. Ahmed, M. M. Stoddard, and M. J. Broadbent Adenosine-Induced Preconditioning of Human Myocardium? • Response Circulation, August 25, 1998; 98(8): 824 - 825. [Full Text]
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H. T. Lee, R. Bolli, and M. A. Leesar Adenosine Pretreatment of Human Myocardium and Ischemic Preconditioning • Response Circulation, June 9, 1998; 97(22): 2279 - 2279. [Full Text]
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M. Osada, T. Netticadan, K. Tamura, and N. S. Dhalla Modification of ischemia-reperfusion-induced changes in cardiac sarcoplasmic reticulum by preconditioning Am J Physiol Heart Circ Physiol, June 1, 1998; 274(6): H2025 - H2034. [Abstract] [Full Text] [PDF]
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R. A. Kloner, R. Bolli, E. Marban, L. Reinlib, and E. Braunwald Medical and Cellular Implications of Stunning, Hibernation, and Preconditioning : An NHLBI Workshop Circulation, May 19, 1998; 97(18): 1848 - 1867. [Full Text] [PDF]
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L. P. Perrault, P. Menasche, K. V. Ylitalo, and K. J. Peuhkurinen Ischemic Preconditioning Before Normothermic Retrograde Cardioplegia Ann. Thorac. Surg., December 1, 1997; 64(6): 1874 - 1876. [Full Text]
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