JACC
HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK
QUICK SEARCH:   [advanced]


     

J Am Coll Cardiol, 2005; 45:1775-1780, doi:10.1016/j.jacc.2005.02.061
© 2005 by the American College of Cardiology Foundation
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (59)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ross, A. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ross, A. M.

CLINICAL RESEARCH: CORONARY ARTERY DISEASE

A Randomized, Double-Blinded, Placebo-Controlled Multicenter Trial of Adenosine as an Adjunct to Reperfusion in the Treatment of Acute Myocardial Infarction (AMISTAD-II)

Allan M. Ross, MD, FACC*, Raymond J. Gibbons, MD, FACC{dagger}, Gregg W. Stone, MD, FACC{ddagger}, Robert A. Kloner, MD, PhD, FACC§, R. Wayne Alexander, MD, PhD, FACC||,* for the AMISTAD-II Investigators

* Department of Medicine, George Washington University, Washington, DC
{dagger} Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota
{ddagger} Columbia University Medical Center and The Cardiovascular Research Foundation, New York, New York
§ Keck School of Medicine, Division of Cardiovascular Medicine, University of Southern California and the Heart Institute of Good Samaritan Hospital, Los Angeles, California
|| Department of Medicine, Emory University School of Medicine, Atlanta, Georgia

Manuscript received October 15, 2004; revised manuscript received December 28, 2004, accepted February 14, 2005.

* Reprint requests and correspondence: Dr. R. Wayne Alexander, Department of Medicine, Emory University Hospital, H-153, 1364 Clifton Road NE, Atlanta, Georgia 30322. (Email: ralexan{at}emory.edu).


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 Appendix
 Supplementary data
 References
 
OBJECTIVES: The purpose of this research was to determine the effect of intravenous adenosine on clinical outcomes and infarct size in ST-segment elevation myocardial infarction (STEMI) patients undergoing reperfusion therapy.

BACKGROUND: Previous small studies suggest that adenosine may reduce the size of an evolving infarction.

METHODS: Patients (n = 2,118) with evolving anterior STEMI receiving thrombolysis or primary angioplasty were randomized to a 3-h infusion of either adenosine 50 or 70 µg/kg/min or of placebo. The primary end point was new congestive heart failure (CHF) beginning >24 h after randomization, or the first re-hospitalization for CHF, or death from any cause within six months. Infarct size was measured in a subset of 243 patients by technetium-99m sestamibi tomography.

RESULTS: There was no difference in the primary end point between placebo (17.9%) and either the pooled adenosine dose groups (16.3%) or, separately, the 50-µg/kg/min dose and 70-µg/kg/min groups (16.5% vs. 16.1%, respectively, p = 0.43). The pooled adenosine group trended toward a smaller median infarct size compared with the placebo group, 17% versus 27% (p = 0.074). A dose-response relationship with final median infarct size was seen: 11% at the high dose (p = 0.023 vs. placebo) and 23% at the low dose (p = NS vs. placebo). Infarct size and occurrence of a primary end point were significantly related (p < 0.001).

CONCLUSIONS: Clinical outcomes in patients with STEMI undergoing reperfusion therapy were not significantly improved with adenosine, although infarct size was reduced with the 70-µg/kg/min adenosine infusion, a finding that correlated with fewer adverse clinical events. A larger study limited to the 70-µg/kg/min dose is, therefore, warranted.

Abbreviations and Acronyms
  AMISTAD = Acute Myocardial Infarction Study of Adenosine
  CHF = congestive heart failure
  DSMB = Data Safety Monitoring Board
  ITT = intention to treat
  MI = myocardial infarction
  STEMI = ST-segment elevation myocardial infarction

Minimizing infarct size by restoring flow in the occluded coronary artery is a central objective of acute therapy for ST-segment elevation myocardial infarction (STEMI). Experimental evidence suggests that further infarct size limitation might be achieved by use of drugs to limit irrevocable myocyte necrosis (1). Approaches beneficial in experimental models of acute MI include antioxidants to mitigate reperfusion-associated oxidative stress, rheological agents to improve blood viscosity and microvascular perfusion, oxygen-carrying polymers, anti-inflammatory agents, and strategies to reduce injurious intracellular ion shifts. Clinical trials using these approaches have been either negative (2–7) or mixed (with insulin-glucose-potassium, or magnesium infusion, or sodium hydrogen exchange inhibitors) (8–12). Adenosine, however, may be an important exception as it has consistently provided myocardial protection from ischemic injury in animal models (13–15) and in small clinical studies of STEMI (16–20), myocardial ischemia (21), and coronary artery bypass surgery (22).

In the Acute Myocardial Infarction Study of Adenosine (AMISTAD-I) of 236 thrombolytic-treated patients, a significant 33% relative reduction in infarct size was seen with a 3-h adenosine infusion (70 µg/kg/min) compared with controls (18). Efficacy, however, was limited to patients with anterior infarction, and the trial was underpowered to evaluate clinical benefit. Also, a trend toward an increase in adverse clinical events was present in patients with nonanterior STEMI. The AMISTAD-II trial, therefore, was designed as a larger trial of adenosine as adjunctive therapy to either thrombolytic or mechanical reperfusion in acute anterior STEMI. Both clinical and infarct size end points were evaluated with both the 70-µg/kg/min dose and a lower dose of 50 µg/kg/min.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 Appendix
 Supplementary data
 References
 
Study group.   This double-blinded, placebo-controlled, randomized study was conducted in 13 countries (390 sites) (Appendix), and enrolled 2,118 patients between June 1999 and December 2000. Enrollment required age over 18 years, reperfusion therapy (fibrinolysis or percutaneous intervention) within 6 h of onset of ischemic type pain (≥30 min), and electrocardiographic evidence of anterior STEMI. Electrocardiographic requirements were either ≥2 mm of ST-segment elevation in at least two contiguous precordial leads or (presumed) new left bundle branch block. Informed written consent was provided by all patients. Table 1 lists exclusion criteria.


View this table:
[in this window]
[in a new window]
  		Table 1. Exclusion Criteria
 
Treatment regimen.   Patients selected for reperfusion therapy were randomly assigned to adenosine, 70 µg/kg/min (the AMISTAD-I dose) or 50 µg/kg/min (utilized to evaluate dose-related responses), or to placebo in a 1:1:1 scheme. Study drug infusion (3 h) had to be started within 15 min either of the start of fibrinolysis or before coronary intervention. If severe hypotension, bradycardia, or bronchospasm was observed, the infusion rate could be reduced by decrements of 15%. Aminophylline was permitted for adverse adenosine responses. Other concomitant therapies were permitted at the discretion of the managing physician.

Clinical end points.   The primary clinical efficacy end point (by intention to treat [ITT]) was time from randomization to first occurrence (>24 h after initiating reperfusion) of in-hospital congestive heart failure (CHF), first re-hospitalization for CHF, or death from any cause during six months’ follow-up. For this and other analyses, the principal prespecified comparison was between placebo and the combined adenosine groups. Secondary analyses included comparison of each adenosine dose, separately, versus placebo. Analysis by "treatment per protocol" was also prespecified, and defined as including: study drug infusion started within 15 min of the protocol initiation, at least a full hour’s infusion, and receiving not less than half or more than twice the assigned total dose. Secondary end points included all-cause and cardiovascular mortality within six months and those specific to the infarct size substudy.

Heart failure was judged to be present if two of the following criteria were documented: new pulmonary edema by chest X-ray in the absence of a non-cardiac cause, rales over one-third or greater of the lung fields believed to be due to pulmonary edema, pulmonary capillary wedge pressure >18 mm Hg with cardiac index <2.4 l/min/m2, dyspnea with pO2 <80 mm Hg or O2 saturation <90% without known pre-existing lung disease, and use of loop diuretics to treat presumed pulmonary congestion.

Infarct size substudy.   Infarct size was measured by technetium-99m sestamibi single-photon emission computed tomography imaging between 120 and 216 h after randomization. The raw data were processed at the Nuclear Core Laboratory (Mayo Clinic Foundation, Rochester, Minnesota), which was blinded to treatment. Imaging equipment and image acquisition for each site were quality-controlled using a cardiac phantom as previously described (23). Infarct size was measured as previously described (24) and has been related to: ejection fraction and end-systolic volume (25,26), fibrosis in explanted hearts and myocardial biopsies (27,28), ventricular function after revascularization (29,30), mortality (31,32), and clinical outcome (33,34).

Statistical analyses and sample size estimates.   The primary end point comparison used the Gehan-Wilcoxon rank survival method and assumed a principal event in 16% of the placebo group (10% death and 6% CHF). A sample size of 675 per arm would provide 80% power for detecting a 25% relative difference between pooled adenosine and placebo. The total sample size projected was ~2,100 patients, and 2,118 were enrolled. The Data Safety Monitoring Board (DSMB) (Appendix) was empowered to recommend discontinuation of one adenosine treatment arm (for futility or adverse event frequency) and continuation of the trial with the remaining adenosine arm in a 2:1 randomization scheme.

The infarct size substudy sample estimate assumed a median infarct size of 30% of the left ventricle in placebo-treated patients. To detect a 20% reduction with 80% power would require 175 patients in each group. Infarct size was reported as median (25%, 75% interquartile ranges) and compared by using a model of analysis of covariance on ranks, adjusted for time to therapy and prior history of infarction. Significance for all comparisons was set at the 0.05 level.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 Appendix
 Supplementary data
 References
 
Baseline characteristics and therapy were balanced across the groups (Table 2). The DSMB performed an interim evaluation on the data from 1,010 patients and informed the Steering Committee that the lower dose treatment arm, however, would meet futility criteria. Closure of the low-dose treatment arm would have entailed a statistical penalty. Furthermore, by the time protocol changes could have been implemented, over 75% of the projected enrollment would have been completed. Funding was not available to support the increase in sample size that would have been required to maintain the power of the study. The trial was, therefore, completed with both treatment arms.


View this table:
[in this window]
[in a new window]
  		Table 2. Patient Demographics by Treatment Group
 
Clinical end points.   As analyzed by ITT, the primary end point of survival in the absence of in-hospital CHF or rehospitalization for CHF was 82% in the placebo group, and 84% in the pooled adenosine groups (p = 0.43). Analyzed on a "per protocol" basis, survival free of in-hospital CHF or rehospitalization for CHF was 82% in the placebo group and 85% in the pooled adenosine group. This 17% risk reduction also was not statistically significant (p = 0.16).

When the individual adenosine dose groups were analyzed on an ITT basis, there were no significant differences among the placebo, 50-µg, and 70-µg treatment groups. Mortality occurred in 11.8% of placebo patients versus 10.4% in the 50-µg group (p = 0.37) and in 10.2% of the 70-µg group (p = 0.31 vs. placebo). The specific frequency of the components of the principal end points by both ITT and per protocol are summarized in Table 3.


View this table:
[in this window]
[in a new window]
  		Table 3. Primary Clinical End Points
 
Infarct size substudy.   A total of 266 patients were enrolled in the imaging substudy. Of these, 254 actually underwent imaging, and 243 (91% of those enrolled) had images suitable for quantitative analysis. Figures 1 and 2 display infarct size (% left ventricle). In the placebo group, the median infarct size was 27% (interquartile range 4% to 49%). In the pooled adenosine group, the median infarct size tended to be reduced to 17% (1% to 39%), p = 0.074. Median infarct size in the 50-µg/kg/min adenosine group was 23% (6% to 39%), not significantly different from placebo (p = 0.41). In contrast, median infarct size in the 70-µg/kg/min group was 11% (0% to 37%), representing a significant reduction from that in the placebo group (p = 0.023).



View larger version (17K):
[in this window]
[in a new window]
  		Figure 1 Infarct size measured as a percent of the left ventricle (LV) by technetium-99m single-photon emission computed tomographic imaging in the 243 patients in the infarct size substudy with images suitable for quantitation. The 25th percentile, median, and 75th percentiles are shown for the placebo group, the pooled adenosine group, the 50-µg/kg/min adenosine group, and the 70-µg/kg/min adenosine group. Only the higher adenosine dose group showed a significant reduction in median infarct size relative to placebo (p = 0.023)

 
There was also a significant association between infarct size and the development of in-hospital CHF, rehospitalization for CHF, or death. The median infarct size in the 28 patients who developed one of these end points was 43% (26% to 53%), significantly larger than the 17% (1% to 39%) in the 215 patients without any of these end points (p < 0.001) (Fig. 2).



View larger version (12K):
[in this window]
[in a new window]
  		Figure 2 Infarct size measured as a percent of the left ventricle (LV) by technetium-99m single-photon emission computed tomographic sestamibi imaging in the 28 patients in the infarct size substudy who suffered a primary end point (death, in-hospital congestive heart failure [CHF], or re-hospitalization for CHF), compared with the 215 patients who did not have an end point. The 25th percentile, median, and 75th percentiles are shown for each group. The group with a primary end point had larger infarcts than did those without (p < 0.001).

 
Adverse clinical events.   Adenosine infusion at either dose was associated with a low incidence of adverse clinical events relative to placebo (Table 4). There was a modest increase in adenosine-associated hypotension, which was generally well tolerated. Recurrent MI was observed in 2% of patients in each treatment group, and total cerebrovascular accidents occurred in <1% of each group.


View this table:
[in this window]
[in a new window]
  		Table 4. Adverse Events by Treatment Groups
 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
Appendix
 Supplementary data
 References
 
In the present trial, intravenous adenosine as an adjunct to reperfusion therapy in acute anterior STEMI did not result in an overall reduction in adverse clinical events, although the study medication was well tolerated and resulted in a dose-related reduction in infarct size. The reduction in infarct size in the 70-µg/kg/min dose group seen in this trial is consistent with the first AMISTAD trial in which this dose was used (18). In the current trial, the median infarct size in the 70-µg/kg/min group (11% of the left ventricle) represented a 57% relative reduction from the placebo group median (26%). In AMISTAD-I, the median infarct size in the treated group with anterior STEMI was 15% versus 45% with placebo (a relative reduction of 67%). Thus, these two trials support the contention that a 3-h 70-µg/kg/min adenosine infusion reduces infarct size in patients with anterior STEMI undergoing reperfusion therapy.

Despite the fact that a strong relationship was present between infarct size and the primary clinical end point (death or heart failure), only a weak trend was present toward improvement in clinical outcomes with the pooled adenosine dose regimens. A likely explanation for failure of the trial to demonstrate a clinical benefit was that it was underpowered. The sample size calculation was based on a reduction of events in the pooled adenosine group by 25% compared with placebo. The reduction observed was only 11%. This result in part reflects the modest infarct size reduction in the 50% of patients receiving the lower adenosine dose. There were two reasons for evaluating the lower dose in the present study: a preclinical study had suggested that both low and high doses were equally effective in reducing myocardial infarct size (35), and there was interest in determining if a lower (but effective) dose would further reduce the incidence of bradycardia and hypotension. Moreover, neither adenosine group alone was of sufficient size to make a statistically robust and informative comparison to the placebo group regarding the clinical end point.

As noted, there is a strong body of data from animal models of MI indicating that adenosine and adenosine agonists are myocardial protectants (14,15,36–39). The numerous potential mechanisms have recently been reviewed (40). Although it is known that stimulation of adenosine receptors mimics ischemic preconditioning (15), it is unlikely that this mechanism played a role in the present study, because adenosine was not administered until after coronary artery occlusion. Adenosine has anti-inflammatory effects that may inhibit neutrophil adhesion to endothelium and migration into the myocardium, cytokine release from mononuclear cells, release of oxygen radicals, and cardiomyocyte apoptosis (40). Adenosine also has an anti-platelet effect (41) that may have a role in maintaining infarct artery patency.

Previously, as noted, there has been no consistent clinical evidence that a pharmacologic agent, administered as an adjunct to reperfusion, can actually impact infarct size (1). Now, both AMISTAD-I (18) and AMISTAD-II have shown that adenosine reduces infarct size. These data are also consistent with the results of a small trial of intracoronary infusion of adenosine in patients with acute MI undergoing primary angioplasty (17).

Study limitations.   The major limitation of this study was that the sample size was too small to confirm that the observed adenosine-related reduction in the combined clinical end point was statistically significant.

Conclusions.   This trial adds to previous evidence that a 3-h adenosine infusion at 70 µg/kg/min (but not at the lower 50-µg/kg/min dose) reduces infarct size in anterior MI patients when given in conjunction with reperfusion therapy. The correlation between infarct size and clinical outcome in this study, as well as the trend toward improved clinical outcomes, suggests that a more robustly powered investigation of this relatively safe and inexpensive drug as adjunctive therapy to reperfusion is warranted to demonstrate whether the reduced infarct size achieved with the higher infusion dose translates into enhanced event-free survival.


   Appendix
Top
 Abstract
 Methods
 Results
 Discussion
 Appendix
Supplementary data
 References
 
For a list of AMISTAD-II study investigators and participation sites, please see the June 7, 2005, issue of JACC at www.onlinejacc.org.


   Supplementary data
Top
 Abstract
 Methods
 Results
 Discussion
 Appendix
 Supplementary data
References
 


   Acknowledgments
 
The authors are grateful for the creative and indefatigable editorial assistance of Lynda Prickett Mathews. We also thank William Wheeler, MD, King Jolly, Pharm D, Christy Nolan, and Tim Warneke for their support.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 Appendix
 Supplementary data
 References
 

  1. Kloner RA, Rezkalla SH. Cardiac protection during acute myocardial infarctionwhere do we stand in 2004?. J Am Coll Cardiol 2004;44:276-286.[Abstract/Free Full Text]
  2. The European Myocardial Infarction Project Free Radicals (EMIP-FR) Group Effect of 48-hour intravenous trimetazidine on short- and long-term outcomes of patients with acute myocardial infarction, with and without thrombolytic therapy. A double-blind, placebo-controlled randomized trial Eur Heart J 2000;21:1537-1546.[Abstract/Free Full Text]
  3. Wall TC, Califf RM, Blankenship J, et al. Intravenous fluosol in the treatment of acute myocardial infarction. Results of thrombolysis and angioplasty in myocardial infarction 9 trial Circulation 1994;90:114-120.[Abstract/Free Full Text]
  4. Collaborative Organization for Rheoth RX Evaluation (CORE) Investigators Effects of Rheoth Rx on mortality, morbidity, left ventricular function, and infarct size in patients with acute myocardial infarction Circulation 1997;96:192-201.
  5. Baran KW, Nguyen M, McKendall GR, et al. Double-blind randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction Circulation 2001;104:2778-2783.[Abstract/Free Full Text]
  6. Faxon DP, Gibbons RJ, Chronos NA, et al. The effect of blockade of the CD11/CD18 integrin receptor on infarct size in patients with acute myocardial infarction treated with direct angioplastythe results of the HALT-MI study. J Am Coll Cardiol 2002;40:1199-1204.[Abstract/Free Full Text]
  7. Mahaffey KW, Granger CB, Nicolau JC, et al. COMPLY Investigators Effect of pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to fibrinolysis in acute myocardial infarctionthe COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) trial. Circulation 2003;108:1176-1183.[Abstract/Free Full Text]
  8. Malmberg K, the DIGAMI Study Group Prospective randomized study of intensive insulin treatment on long-term survival after acute myocardial infarction in patients with diabetes mellitus BMJ 1997;314:1512-1515.[Abstract/Free Full Text]
  9. Diaz R, Paolasso EA, Piegas LS, et al. Metabolic modulation of acute myocardial infarction Circulation 1998;98:2227-2234.[Abstract/Free Full Text]
  10. Rupprecht HJ, vom Dahl T, Terres W, et al. Cardioprotective effects of the Na+/H+ exchange inhibitor cariporide in patients with acute anterior myocardial infarction undergoing direct PTCA Circulation 2000;101:2902-2908.[Abstract/Free Full Text]
  11. Theroux P, Chaitman BR, Danchin N, et al. Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Main results of the GUARDIAN trial Circulation 2000;102:3032-3038.[Abstract/Free Full Text]
  12. Woods KL, Fletcher S, Roffe C, et al. Intravenous magnesium sulfate in suspected acute myocardial infarctionresults of the second Leicester Intravenous Magnesium Intervention trial (LIMIT-2). Lancet 1992;339:1553-1558.[CrossRef][ISI][Medline]
  13. Kaminski PM, Proctor KG. Attenuation of no-reflow phenomenon, neutrophil activation, and reperfusion injury in intestinal microcirculation by topical adenosine Circ Res 1989;65:426-435.[Abstract/Free Full Text]
  14. Babbitt DG, Virmani R, Forman MB. Intracoronary adenosine administered after reperfusion limits vascular injury after prolonged ischemia in the canine model Circulation 1989;80:1388-1399.[Abstract/Free Full Text]
  15. Thornton JD, Liu GS, Olsson RA, et al. Intravenous pretreatment with A1-selective adenosine analogue protects the heart against infarction Circulation 1992;85:659-665.[Abstract/Free Full Text]
  16. Garratt KN, Holmes Jr DR, Molina-Viamonte V, et al. Intravenous adenosine and lidocaine in patients with acute myocardial infarction Am Heart J 1998;136:196-204.[CrossRef][ISI][Medline]
  17. Marzilli M, Orsini E, Maraccini P, et al. Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction Circulation 2000;101:2154-2159.[Abstract/Free Full Text]
  18. Mahaffey KW, Puma JA, Barbagelata A, 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 1999;34:1711-1720.[Abstract/Free Full Text]
  19. Quintana M, Hjemdahl P, Solleri A, et al. Left ventricular function and cardiovascular events following adjuvant therapy with adenosine in acute myocardial infarction treated with thrombolysis, results of the ATTenuation by Adenosine of Cardiac Complications (ATTACC) study Eur J Clin Pharmacol 2003;59:1-9.[ISI][Medline]
  20. Assali AR, Sdringola S, Ghani M, et al. Intracoronary adenosine administered during percutaneous intervention in acute myocardial infarction and reduction in the incidence of "no-reflow" phenomenon Cathet Cardiovasc Interv 2000;51:27-31.[CrossRef][ISI][Medline]
  21. Leesar MA, Stoddard M, Ahmed M, et al. Preconditioning of human myocardium with adenosine during coronary angioplasty Circulation 1997;95:2500-2507.[Abstract/Free Full Text]
  22. Mentzer RM, Birjiniuk V, Khuri S, et al. Adenosine myocardial protectionpreliminary results of a phase II clinical trial. Ann Surg 1999;229:643-649.[CrossRef][ISI][Medline]
  23. O’Connor MK, Gibbons RJ. Quantitative myocardial SPECT for infarct sizingfeasibility of a multicenter trial assessed by means of a cardiac phantom. J Nucl Med 1995;36:1130-1136.[Abstract/Free Full Text]
  24. Christian TF, Schwartz RS, Gibbons RJ. Determinants of infarct size in reperfusion therapy for acute myocardial infarction Circulation 1992;86:81-90.[Abstract/Free Full Text]
  25. Christian TF, Behrenbeck T, Pellikka PA, et al. Mismatch of left ventricular function and infarct size demonstrated by technetium-99m isonitrile imaging after reperfusion therapy for acute myocardial infarctionidentification of myocardial stunning and hyperkinesia. J Am Coll Cardiol 1990;16:1632-1638.[Abstract]
  26. Chareonthaitawee P, Christian TF, Hirose K, et al. Relation of initial infarct size to extent of left ventricular remodeling in the year after acute myocardial infarction J Am Coll Cardiology 1995;25:567-573.[Abstract]
  27. Medrano R, Lowry RW, Young JB, et al. Assessment of myocardial viability with 99mTc sestamibi in patients undergoing cardiac transplantation Circulation 1996;94:1010-1017.[Abstract/Free Full Text]
  28. Dakik HA, Howell JF, Lawrie GM, et al. Assessment of myocardial viability with 99mTc-sestamibi tomography before coronary bypass graft surgerycorrelation with histopathology and postoperative improvement in cardiac function. Circulation 1997;96:2892-2898.[Abstract/Free Full Text]
  29. Udelson JE, Coleman PS, Metherall J, et al. Predicting recovery of severe regional dysfunctioncomparison of resting scintigraphy with 201-T1 and 99m Tc-sestamibi. Circulation 1994;89:2552-2561.[Abstract/Free Full Text]
  30. Maes AF, Borgers M, Flameng W, et al. Assessment of myocardial viability in chronic coronary artery disease using technetium-99m sestamibi SPECT J Am Coll Cardiol 1997;29:62-68.[Abstract]
  31. Miller TD, Christian TF, Hopfenspirger MR, et al. Infarct size after acute myocardial infarction measured by quantitative tomographic 99mTc sestamibi imaging predicts subsequent mortality Circulation 1995;92:334-341.[Abstract/Free Full Text]
  32. Burns RJ, Gibbons RJ, Yi Q, et al. The relationships of left ventricular ejection fraction, end-systolic volume index and infarct size to six-month mortality after hospital discharge following myocardial infarction treated by thrombolysis J Am Coll Cardiol 2002;39:30-36.[Abstract/Free Full Text]
  33. Schomig A, Kastrati A, Dirschinger J, et al. Coronary stenting plus platelet glycoprotein IIb/IIIa blockade compared with tissue plasminogen activator in acute myocardial infarction. Stent versus Thrombolysis for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction study Investigators N Engl J Med 2000;343:385-391.[Abstract/Free Full Text]
  34. Kastrati A, Mehilli J, Dirschinger J, et al. Stent versus Thrombolysis for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction (STOPAMI-2) Study Investigators Myocardial salvage after coronary stenting plus abciximab versus fibrinolysis plus abciximab in patients with acute myocardial infarctiona randomised trial. Lancet 2002;359:920-925.[CrossRef][ISI][Medline]
  35. Norton ED, Jackson EK, Virmani R, Forman MB. Effect of intravenous adenosine on myocardial reperfusion injury in a model with low myocardial collateral blood flow Am Heart J 1991;122:1283-1291.[CrossRef][ISI][Medline]
  36. Olafsson B, Forman MB, Puett DW, et al. Reduction of reperfusion injury in the canine preparation by intracoronary adenosineimportance of the endothelium and the no-reflow phenomenon. Circulation 1987;76:1135-1145.[Abstract/Free Full Text]
  37. Forman MB, Velasco CE, Jackson EK, et al. Adenosine attenuates reperfusion injury following regional myocardial ischemia Cardiovasc Res 1993;27:9-17.[Free Full Text]
  38. Yao Z, Gross GJ. A comparison of adenosine-induced cardioprotection and ischemic preconditioning in dogs. Efficacy, time course, and role of KATP channels Circulation 1994;89:1226-1236.
  39. Pitarys CJ, Virmani R, Vildibill HD, et al. Reduction of myocardial reperfusion injury by intravenous adenosine administered during the early reperfusion period Circulation 1991;83:237-247.[Abstract/Free Full Text]
  40. Headrick JP, Hack B, Ashton KJ. Acute adenosinergic cardioprotection in ischemic-reperfused hearts Am J Physiol Heart Circ Physiol 2003;285:H1797-H1818.[Abstract/Free Full Text]
  41. Hata K, Whittaker P, Kloner RA, et al. Brief antecedent ischemia attenuates platelet mediated thrombus in damaged and stenotic canine coronary arteriesrole of adenosine. Circulation 1998;97:692-702.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
E. Velot, B. Haas, F. Leonard, I. Ernens, M. Rolland-Turner, C. Schwartz, D. Longrois, Y. Devaux, and D. R. Wagner
Activation of the adenosine-A3 receptor stimulates matrix metalloproteinase-9 secretion by macrophages
Cardiovasc Res, August 10, 2008; (2008) cvn201v2.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
J. W. Adams, J. Wang, J. R. Davis, C. Liaw, I. Gaidarov, J. Gatlin, N. D. Dalton, Y. Gu, J. Ross Jr., D. Behan, et al.
Myocardial expression, signaling, and function of GPR22: a protective role for an orphan G protein-coupled receptor
Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H509 - H521.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
G. W. Stone
Angioplasty Strategies in ST-Segment-Elevation Myocardial Infarction: Part II: Intervention After Fibrinolytic Therapy, Integrated Treatment Recommendations, and Future Directions
Circulation, July 29, 2008; 118(5): 552 - 566.
[Full Text] [PDF]

Home page
 Eur Heart JHome page
S. Kasama, M. Furuya, T. Toyama, S. Ichikawa, and M. Kurabayashi
Effect of atrial natriuretic peptide on left ventricular remodelling in patients with acute myocardial infarction
Eur. Heart J., June 2, 2008; 29(12): 1485 - 1494.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
G. W. Stone, B. Witzenbichler, G. Guagliumi, J. Z. Peruga, B. R. Brodie, D. Dudek, R. Kornowski, F. Hartmann, B. J. Gersh, S. J. Pocock, et al.
Bivalirudin during Primary PCI in Acute Myocardial Infarction
N. Engl. J. Med., May 22, 2008; 358(21): 2218 - 2230.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
J. L. Strande, A. Hsu, J. Su, X. Fu, G. J. Gross, and J. E. Baker
Inhibiting Protease-Activated Receptor 4 Limits Myocardial Ischemia/Reperfusion Injury in Rat Hearts by Unmasking Adenosine Signaling
J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 1045 - 1054.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
H. Thibault, C. Piot, P. Staat, L. Bontemps, C. Sportouch, G. Rioufol, T. T. Cung, E. Bonnefoy, D. Angoulvant, J.-F. Aupetit, et al.
Long-Term Benefit of Postconditioning
Circulation, February 26, 2008; 117(8): 1037 - 1044.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
P. A. Grayburn and J. W. Choi
Advances in the assessment of no-reflow after successful primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: now that we can diagnose it, what do we do about it?
J. Am. Coll. Cardiol., February 5, 2008; 51(5): 566 - 568.
[Full Text] [PDF]

Home page
 Card Surg AdultHome page
I. George and M. C. Oz
Myocardial Revascularization after Acute Myocardial Infarction
Card. Surg. Adult, January 1, 2008; 3(2008): 669 - 696.
[Full Text]

Home page
 NEJMHome page
R. Ramaraj, M. B. Forman, E. K. Jackson, C. J. Lowenstein, B. Ibanez, G. Cimmino, J. J. Badimon, P. G. Korantzopoulos, J. A. Goudevenos, D. M. Yellon, et al.
Myocardial reperfusion injury.
N. Engl. J. Med., December 6, 2007; 357(23): 2408 - 2408.
[Full Text] [PDF]

Home page
 NEJMHome page
D. M. Yellon and D. J. Hausenloy
Myocardial Reperfusion Injury
N. Engl. J. Med., September 13, 2007; 357(11): 1121 - 1135.
[Full Text] [PDF]

Home page
 Anesth. Analg.Home page
T. J. Gan and A. S. Habib
Adenosine as a Non-Opioid Analgesic in the Perioperative Setting
Anesth. Analg., August 1, 2007; 105(2): 487 - 494.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
C. B. Granger and M. R. Patel
The Search for Myocardial Protection: Is There Still Hope?
J. Am. Coll. Cardiol., July 31, 2007; 50(5): 406 - 408.
[Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
W. E. Stansfield, N. C. Moss, M. S. Willis, R. Tang, and C. H. Selzman
Proteasome Inhibition Attenuates Infarct Size and Preserves Cardiac Function in a Murine Model of Myocardial Ischemia-Reperfusion Injury
Ann. Thorac. Surg., July 1, 2007; 84(1): 120 - 125.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
M. T. Dirksen, G. J. Laarman, M. L. Simoons, and D. J.G.M. Duncker
Reperfusion injury in humans: A review of clinical trials on reperfusion injury inhibitory strategies
Cardiovasc Res, June 1, 2007; 74(3): 343 - 355.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
C.-H. Lee, A. Low, B.-C. Tai, M. Co, M. Y. Chan, J. Lim, Y.-T. Lim, and H.-C. Tan
Pretreatment with intracoronary adenosine reduces the incidence of myonecrosis after non-urgent percutaneous coronary intervention: a prospective randomized study
Eur. Heart J., January 1, 2007; 28(1): 19 - 25.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
H. Funakoshi, T. O. Chan, J. C. Good, J. R. Libonati, J. Piuhola, X. Chen, S. M. MacDonnell, L. L. Lee, D. E. Herrmann, J. Zhang, et al.
Regulated Overexpression of the A1-Adenosine Receptor in Mice Results in Adverse but Reversible Changes in Cardiac Morphology and Function
Circulation, November 21, 2006; 114(21): 2240 - 2250.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
R. A. Kloner, M. B. Forman, R. J. Gibbons, A. M. Ross, R. W. Alexander, and G. W. Stone
Impact of time to therapy and reperfusion modality on the efficacy of adenosine in acute myocardial infarction: the AMISTAD-2 trial
Eur. Heart J., October 2, 2006; 27(20): 2400 - 2405.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
G. Maurer
Adenosine as an adjunct to reperfusion in myocardial infarction
Eur. Heart J., October 2, 2006; 27(20): 2376 - 2377.
[Full Text] [PDF]

Home page
 HeartHome page
S A Harding
The role of vasodilators in the prevention and treatment of no-reflow following percutaneous coronary intervention
Heart, September 1, 2006; 92(9): 1191 - 1193.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
D. T. Mangano, Y. Miao, I. C. Tudor, C. Dietzel, for the Investigators of the Multicenter Study of, and and the Ischemia Research and Education Foundation
Post-Reperfusion Myocardial Infarction: Long-Term Survival Improvement Using Adenosine Regulation With Acadesine
J. Am. Coll. Cardiol., July 4, 2006; 48(1): 206 - 214.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
R. A. Kloner
Moving Preconditioning From Bench to Bedside
J. Am. Coll. Cardiol., July 4, 2006; 48(1): 215 - 216.
[Full Text] [PDF]

Home page
 Cardiovasc ResHome page
R. A. Kloner and S. H. Rezkalla
Preconditioning, postconditioning and their application to clinical cardiology
Cardiovasc Res, May 1, 2006; 70(2): 297 - 307.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
S. R. Dixon, C. L. Grines, and W. W. O'Neill
The Year in Interventional Cardiology
J. Am. Coll. Cardiol., April 18, 2006; 47(8): 1689 - 1706.
[Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
M. B. Forman and E. K. Jackson
Role of Adenosine in Acute Myocardial Infarction
J. Am. Coll. Cardiol., March 21, 2006; 47(6): 1235 - 1236.
[Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
M. V. Cohen and J. M. Downey
AMISTAD Trials: Possible Reasons for Lack of Success
J. Am. Coll. Cardiol., March 21, 2006; 47(6): 1236 - 1236.
[Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
A. M. Ross, R. J. Gibbons, G. W. Stone, R. A. Kloner, and R. W. Alexander
Reply
J. Am. Coll. Cardiol., March 21, 2006; 47(6): 1236 - 1237.
[Full Text] [PDF]

Home page
 JAMAHome page
Additional Information
JAMA, March 15, 2006; 295(11): E1 - E6.
[Full Text] [PDF]

Home page
 Eur Heart J SupplHome page
M. Ferenc and F.-J. Neumann
Efficacy of primary PCI: the microvessel perspective