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(Circulation. 2000;102:3032.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Inhibition of the Sodium-Hydrogen Exchanger With Cariporide to Prevent Myocardial Infarction in High-Risk Ischemic Situations

Main Results of the GUARDIAN Trial

P. Théroux, MD; B.R. Chaitman, MD; N. Danchin, MD; L. Erhardt, MD; T. Meinertz, MD; J.S. Schroeder, MD; G. Tognoni, MD; H.D. White, MD; J.T. Willerson, MD; A. Jessel, MD; for the GUARd During Ischemia Against Necrosis (GUARDIAN) Investigators

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Background—The transmembrane sodium/hydrogen exchanger maintains myocardial cell pH integrity during myocardial ischemia but paradoxically may precipitate cell necrosis. The development of cariporide, a potent and specific inhibitor of the exchanger, prompted this investigation of the potential of the drug to prevent myocardial cell necrosis.

Methods and Results—A total of 11 590 patients with unstable angina or non–ST-elevation myocardial infarction (MI) or undergoing high-risk percutaneous or surgical revascularization were randomized to receive placebo or 1 of 3 doses of cariporide for the period of risk. The trial failed to document benefit of cariporide over placebo on the primary end point of death or MI assessed after 36 days. Doses of 20 and 80 mg every 8 hours had no effect, whereas a dose of 120 mg was associated with a 10% risk reduction (98% CI 5.5% to 23.4%, P=0.12). With this dose, benefit was limited to patients undergoing bypass surgery (risk reduction 25%, 95% CI 3.1% to 41.5%, P=0.03) and was maintained after 6 months. No effect was seen on mortality. The rate of Q-wave MI was reduced by 32% across all entry diagnostic groups (2.6% versus 1.8%, P=0.03), but the rate of non–Q-wave MI was reduced only in patients undergoing surgery (7.1% versus 3.8%, P=0.005). There were no increases in clinically serious adverse events.

Conclusions—No significant benefit of cariporide could be demonstrated across a wide range of clinical situations of risk. The trial documented safety of the drug and suggested that a high degree of inhibition of the exchanger could prevent cell necrosis in settings of ischemia-reperfusion.

Key Words: ischemia • myocardial infarction • cardiopulmonary bypass • necrosis • cariporide

	Introduction

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Current interventions in acute coronary syndromes mainly target the culprit coronary lesion with antithrombotic and reperfusion therapy. Other therapeutic opportunities exist to counteract the cascade of events leading to myocardial infarction (MI) and death. One is direct cell protection.¹ Although many interventions along this line are effective experimentally, none has reached the stage of clinical application.

The sodium-hydrogen exchanger (NHE) was recently identified and cloned, and its role in cell necrosis has been defined.² NHE-1, 1 of 6 isoforms recognized, is ubiquitously distributed in tissue and is the predominant isoform in the myocardium.³ The exchanger rapidly activates during ischemia as the accumulating hydrogen ions interact with a sensor site of the exchanger protein to promote electroneutral transmembrane exchange of H⁺ for Na⁺, promoting cell necrosis by Ca²⁺ exchange for Na⁺.^{2 3 4 5} Cariporide (HOE642A) was recently developed as a powerful and specific inhibitor of the exchanger.⁶ The drug,^{6 7} a benzoylguanidine of 379.46-Da molecular weight, and similar compounds^{8 9} have consistently been associated with cardioprotective effects in various experimental models of ischemia-reperfusion. Pilot studies in humans have been promising.¹⁰ The GUARDIAN trial (GUARd During Ischemia Against Necrosis) was the first large-scale trial to assess the potential protective effect of NHE inhibition in humans.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Study Population
Patients hospitalized for unstable angina (UA) or non–ST-elevation MI (NSTEMI) or undergoing high-risk percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) were candidates for the trial. Signed informed consent was obtained from all patients before enrollment.

Inclusion and Exclusion Criteria
The inclusion criteria for UA/NSTEMI were repetitive or prolonged angina pain at rest within 12 hours with ST-T changes (ST-segment shift >1 mm in 2 contiguous leads, T-wave inversion >1.5 mm in 3 contiguous leads) or elevation of cardiac markers (serum creatine kinase [CK] and/or CK-MB >1.5 times the upper limit of normal [ULN], or troponin I or T greater than the ULN). Patients with angina at rest 12 hours to 4 weeks after an acute MI were also eligible.

PCI criteria were angina at rest within 4 weeks and any approved intervention planned for a lesion with 2 type B or 1 type C characteristic.¹¹ CABG criteria were urgent intervention, repeat CABG, or angina at rest within 4 weeks with 2 of the following features: age >65 years, female sex, diabetes mellitus, ejection fraction <35%, or left main or 3-vessel disease.

Persistent ST elevation, secondary UA, shock, refractory pulmonary edema, hypersensitivity to amiloride (a structurally related compound), noncardiac progressive fatal disease, significant liver or renal dysfunction, pregnancy or potential for pregnancy, and noncompliance were exclusion factors.

Trial Organization
A Steering Committee supervised the scientific conduct of the study, and an independent Data and Safety Monitoring Board (DSMB) oversaw safety and ethical issues. An End-Point Validation Committee and an ECG/MI/Ischemia Core Laboratory located at St Louis University (St Louis, Mo) shared the responsibility of adjudicating all end-point events. A total of 382 clinical centers from 23 countries participated in the study. Data management and study monitoring were conducted by Quintiles Inc (Research Triangle Park, NC). Aventis Inc sponsored the study.

Randomization and Drug Administration
Every 8 hours, 4 parallel groups were given placebo or doses of 20, 80, or 120 mg of cariporide as a 60-minute infusion in 50 mL of normal saline. Protocol-specified dose adjustments were applied for patients with moderate renal impairment. Drug therapy was initiated as soon as possible after admission in patients with UA/NSTEMI and between 15 minutes and 2 hours before PCI or CABG.

The treatment duration varied from 2 to 7 days, covering the period of risk as determined by investigators. Drug discontinuation was recommended after a symptom-free period of 12 to 24 hours with no intervention planned. Discontinuation after 3 doses was allowed with uneventful PCI.

Study End Points
The primary end point consisted of all-cause mortality or MI between randomization and 36 days. Secondary end points included the primary end point at 10 days, events related to left ventricular dysfunction (cardiac mortality, MI, cardiogenic shock, overt congestive heart failure, and life-threatening arrhythmia) at 6 months, and extent of infarction assessed by peak CK-MB elevation. The diagnosis of MI was based on ECG or CK-MB elevation >2 times the ULN in UA/NSTEMI, >3 times the ULN after PCI, and >100 U/L after CABG. A 12-lead ECG was obtained before randomization, after 24 hours, at 10 days (or at discharge), and at 36 days. Serum CK-MB values were determined locally before randomization and after 4, 8, 12, and 24 hours (8, 12, 16, and 24 hours in CABG patients). A 12-lead ECG was requested when chest pain recurred and serial CK-MB when pain lasted 20 minutes.

ECG tracings were analyzed according to Minnesota code with adoption of the Novacode.¹² A Q-wave MI was defined by new Q waves appearing >24 hours after randomization. Estimates of infarct size were obtained with a score of peak CK-MB values during the first 24 hours: 0, CK-MB < ULN; 1, 1- to 2-fold ULN (3-fold in PCI); 2, 2- (3 for PCI) to 5-fold ULN; 3, 5- to 10-fold ULN; and 4, >10-fold ULN. Absolute units per liter were used for CABG (60, 60 to 100, 100 to 200, 200 to 300, and >300 U/L, respectively), as well as a ratio of peak to ULN values, to account for different analytical methods used at various sites. A score of 4 was assigned for cardiovascular death. Patients were seen in-hospital after 36 days and contacted after 6 months.

The ECG/MI/Ischemia Core Laboratory validated all reported ischemic events and screened all case record forms and ECGs for unidentified MIs. Two members of the End-Point Validation Committee adjudicated equivocal cases and database identified events, with final reconciliation by the chairmen when discordant results were achieved.

Statistics
The sample size estimate assumed a primary event rate of 15% with placebo (10% to 15% in UA/NSTEMI and PCI and 20% to 25% in CABG); an entry diagnosis distribution of 40% to 50%, 30% to 40%, and 10% to 20%, respectively; and a 90% power to detect a 25% relative risk reduction in one of the active treatment arms versus placebo at a significance level of 0.017 (0.05/3, accounting for the 3 pairwise comparisons). The first estimate of 2250 patients per dose arm targeting 1200 patients with an end-point event was adjusted to 2875 after a planned blinded event rate reestimate showed a lower than expected event rate.

A nonparametric covariance adjustment analysis was used to calculate probability values and 98% confidence limits for the primary end point.¹³ Predefined covariates were age, sex, entry MI, ST-segment depression, congestive heart failure, diabetes, previous MI, and cerebrovascular or peripheral vascular disease. The homogeneity of these covariates was tested with Fisher and Wilcoxon tests. The square root of the unadjusted ² statistics was calculated, and the time to the first primary end point event was displayed with Kaplan-Meier curves. The same statistics were used for analysis by entry diagnosis. An extended Mantel-Haenszel statistic standardized within strata ranks examined the CK-MB scores. Fisher exact tests were used for safety analyses that were performed in all patients exposed to the drug. Two interim analyses were performed by the DSMB after 288 and 659 subjects, respectively, had experienced investigator-reported primary end-point events. A number of exploratory analyses were planned as part of the phase 2 design of the trial.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Patients
Baseline characteristics were well balanced across the 4 treatment arms (see Table 1). Significant differences were found for age (P=0.01), number of diabetics (P=0.04), sex distribution (P=0.04), previous hypertension (P=0.02), and diagnosis of UA/NSTEMI (P=0.03) between the placebo and 80-mg cariporide groups, as well as for age between the 120-mg cariporide PCI (P=0.03) and 80-mg cariporide CABG groups (P=0.01) and for number of diseased vessels in the UA/NSTEMI group (P=0.01). Treatment was applied in 99% of randomized patients, and a median of 6 doses were administered, 8 with UA/NSTEMI and CABG and 3 with PCI, with no differences between groups.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics

Results and Analysis
The rate of death or MI at 36 days was similar in placebo and cariporide 20- and 80-mg dose groups, and a 10% risk reduction was seen in the 120-mg cariporide group (P=0.122) (Table 2). No effects at any dose existed in UA/NSTEMI. In PCI, a 23% reduction in death or MI (P=0.06) was observed in the 20-mg group, with no effects at higher doses. In CABG patients, no effects existed at the 20- and 80-mg doses, whereas a 25% reduction in death or MI was present with the 120-mg dose of cariporide (P=0.027). Overall mortality was higher in the UA/NSTEMI and CABG groups than in the PCI group and was unaffected by treatment. In CABG patients, the 36-day mortality rate was 5.0% in the 20- and 120-mg groups and 4.2% and 4.3% in the placebo and 80-mg arms, respectively.

View this table: [in this window] [in a new window]   Table 2. Incidence of Death and MI at 36 Days (Primary End Point)

Events were clustered in the first 48 hours in PCI and CABG patients and were more dispersed in UA/NSTEMI patients (Figure). Reductions in risk with PCI and the 20-mg dose of cariporide were 21.1% at 3 days (P=0.12), 22.1% at 10 days (P=0.09), and 16.0% at 6 months (P=0.10). With the 120-mg dose of cariporide in CABG patients, they were 32.3% at 5 days (P=0.007), 28.5% at 10 days (P=0.016), and 19.3% at 6 months (P=0.033).

View larger version (26K): [in this window] [in a new window]   Figure 1. Cumulative rates of death or MI in the 4 study groups. From top to bottom, overall population (all), patients enrolled with diagnosis of unstable angina or myocardial infarction (UA/NQMI), patients enrolled before PCI, and patients enrolled before CABG.

CK-MB distribution scores were similar among the 4 study groups (Table 3). Ratios of peak CK-MB elevation to ULN tended to be lower with increasing doses of cariporide in CABG and were significantly less with the 120-mg dose of cariporide (P=0.02). Rates of Q-wave MI were reduced by 32% across the 3 diagnostic categories with the 120-mg dose (95% CL -52, -0.03, P=0.03), by 34% in the UA/NSTEMI group, by 24% in the PCI group, and by 33% in the CABG group. The rates of non–Q-wave MI were reduced in CABG patients only by 47% (95% CL -66, -16, P=0.005). Patients with an evolving MI at entry had no special benefit. The investigator-reported event rates were 11.8% with placebo and 11.6% with 20 mg, 12.20% with 80 mg, and 11% with 120 mg of cariporide. In CABG, they were 9.8% with placebo and 7.8% with cariporide 120 mg. Treatment effects were of the same magnitude across the various geographic areas (Table 3).

View this table: [in this window] [in a new window]   Table 3. Secondary Analyses

The 6-month composite outcome events related to left ventricular dysfunction were similar between groups, with some decrease in CABG patients with the 120-mg dose of cariporide (P=0.06).

Safety
Adverse events led to drug discontinuation in 4.8% to 6.6% of cariporide patients and in 4.6% of placebo patients, mainly for cardiovascular and central nervous system reasons (Table 4). A dose response was observed for some side effects such as dizziness and altered mental status, which had a very broad definition. No excess effect existed with regard to specific functions such as speech, personality, movement, and symptoms related to the autonomic system. Headache was frequent but appeared related to nitroglycerine use. Most reports (60%) of liver toxicity were based on isolated abnormal liver function tests. A trend to more frequent anemia was observed in the CABG group, with no counterpart in risk of hemorrhage in this group or the PCI group. Dyspnea was reported more frequently in treated patients, with no specific cause identified. There were no or minimal changes in heart rate, blood pressure, ECG time intervals, red and white blood cells, and platelets. Liver and renal function tests showed slight increases in treated patients. Overall, the changes with cariporide were minute with none showing a statistically significant excess.

View this table: [in this window] [in a new window]   Table 4. Safety Data

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The GUARDIAN trial investigated a novel pharmacological approach for direct myocardial cell protection using a phase 2/3 trial addressing safety of cariporide, dose response, and efficacy to prevent death and MI. Three doses were compared with placebo across various conditions at risk on the hypothesis that NHE inhibition would be effective irrespective of the immediate cause of ischemia creating a risk of necrosis. The study documented no benefit of cariporide across these clinical settings. Doses of 20 and 80 mg were ineffective, whereas the 120-mg dose was associated with fewer end-point events in CABG patients. In this subgroup, the risk of nonfatal MI was reduced by 32% (P=0.007) at 36 days and the risk of death or MI by 25% (P=0.03). Although predefined, this analysis should be interpreted cautiously because it applies to 1 of 9 study subgroups and could be due to chance. Thus, no dose response to the drug was observed and there was no effect on mortality; further, the risk reduction in the 20-mg PCI group reached similar proportions, although not statistically significant. Support for a true benefit in CABG patients is provided by the reduction in risk observed during treatment and maintained through 6 months, less CK-MB elevation, a reduction in Q-wave as well as non–Q-wave MIs, and similar benefit observed across different geographic regions and with events adjudicated by investigators. This reduction, if confirmed, would represent clinically significant progress. Accordingly, the discussion focuses on results that could help future investigations of NHE inhibition, such as doses and effective level of inhibition of NHE, clinical situations of interest, timing for administration, benefit during ischemia versus ischemia-reperfusion, and possible weaknesses of the trial design such as the unconventional phase 2/3 design that was selected because of the convincing experimental data, lack of appropriate surrogate markers of efficacy in humans, and phase 1 tolerance data that supplied evidence on maximally tolerated doses. Although provisions had been made to drop 1 or more dosage arms if shown ineffective on interim analyses, such action did not occur. This study could be seen as a negative phase 3 but a strong phase 2 trial. Whether the exercise was excessive or will help reach a quicker consensus regarding the usefulness of Na⁺/H⁺ inhibitors is a matter of speculation at the present time.

Dose Selection
The absence of a dose response, with benefit restricted to the high dose, may suggest undertitration. The dose selection was partly empirical in the absence of data on concentrations of cariporide that fully inhibit NHE activity in human ischemic myocytes. Blood concentrations, degree of inhibition of the exchanger, and infarct size reduction correlated in experimental studies.^{8 10} Furthermore, the IC50 of 72.6 ng/mL of cariporide is similar in rabbit red cells and in human platelets. Given an elimination half-life of 3.5 hours in humans, doses of 80 and 120 mg TID were expected to inhibit NHE activity by 90% to 100% at peak concentrations and 75% to 85% at troughs. Furthermore, the early studies had suggested that doses higher than 120 mg administered within 30 minutes resulted in excessive side effects, such as nausea, flushing, paresthesia, vertigo, diaphoresis, and possibly blood pressure increase. To favor tolerance, higher doses were not used in GUARDIAN, and the infusion period was extended to 60 minutes. The 20-mg dose was introduced to cover the full range of the dose-response curve with the expectation that the dose would be dropped at an interim analysis. Although a weak dose response was seen in some adverse events, close monitoring of 8605 patients exposed to cariporide showed a favorable safety profile with no excess in frequency or severity of adverse events compared with placebo, indicating the maximum tolerated dose had not been reached. Higher doses and/or faster infusion rates could result in more frequent or more serious side effects.

To explore further the issue of optimal dosing, a concentration-efficacy pharmacokinetic model was constructed correlating Kaplan-Meier time-to-event risk of death or MI observed in the trial with cariporide plasma levels predicted from phase 1 and 2 studies. The CABG population served for this analysis because it allowed definition of a period of risk between start of anesthesia and end of surgery. This analysis incorporated the cariporide dosing history, weight, height, sex, and serum creatinine level as main predictors of plasma levels. The model was validated with serial cariporide plasma levels obtained at 5 time points in 269 GUARDIAN patients participating in a pharmacokinetic substudy (PopKin Substudy results, W. Weber and L. Harnisch, unpublished data). The concentration-efficacy analysis revealed a steep onset of reduction in the risk of death/MI with cariporide plasma concentration above a threshold concentration of 550 ng/mL, with a relative risk reduction of 35%. These plasma levels were reached in none of the patients who received the 20-mg dose, in 20% of those who received the 80-mg dose, and in 67% of those who received the 120-mg dose, suggesting that higher dosages and/or dosing modifications that maximize exposure during the period of risk could improve the efficacy of cariporide. Alternatively, optimization of the benefit of NHE inhibition could be achieved by applying other measures for cell protection, such as further minimization of calcium entry by inhibition of the Na⁺-HCO₃^- symporter.¹⁴

Modalities for Benefit
The experimental models that documented infarct size reduction were almost exclusively derived from models of ischemia-reperfusion.⁵ Maximal gain was obtained with drug administered before occlusion or shortly thereafter. Later administration during ischemia or before reperfusion required higher doses for more modest and less reproducible benefit.^{2 5 6 7 8} The GUARDIAN trial optimized these conditions by targeting patient enrollment before occurrence of necrosis. This was best achieved in CABG patients, for whom the drug was administered before global ischemia and during subsequent reperfusion. The situation is more complex in UA/NSTEMI and PCI, where periods of occlusion of variable duration alternate with periods of reperfusion and necrosis caused by complete occlusion or distal embolization of thrombotic material.

The 120-mg dose reduced the rate of Q-wave MI by 25% to 35% in each of the diagnostic entry groups, whereas the rate of non–Q-wave MI was only reduced in CABG patients. These differential findings could be explained by a shift from Q-wave to non–Q-wave MIs but also may be related to different rates of reperfusion in different clinical conditions. Reperfusion is uniformly performed in CABG, whereas MIs in UA/NSTEMI are reperfused only when ST-segment elevation develops and in PCI only when abrupt vessel closure supervenes, a rare event; small infarcts caused by side branch occlusion or distal embolization, often diagnosed by CK-MB or troponin T or I elevation, are not reperfused. Indeed, activity of the exchanger is self-limited during ischemia as an ionic equilibrium is reached between the extracellular and intracellular spaces, but it is intensified on reperfusion by rapid washout of the acidic extracellular fluid.^{2 6} Therefore, the results of the GUARDIAN trial suggest that NHE inhibition will be most useful to buy time to perform reperfusion before necrosis develops. Experimental data have suggested that the time gained could be significant.⁹ Even if NHE inhibition in these circumstances may not completely prevent an infarct, the primary goal of the GUARDIAN trial, it may still significantly reduce infarct size and preserve left ventricular function. Troponin levels were not assessed in the trial because measurements were not widely available among clinical centers when the study was performed.

Conclusions and Outlook Beyond GUARDIAN
Although the GUARDIAN trial failed to show an overall clinical benefit of NHE inhibition, it suggests that proper inhibition of the exchanger in settings of ischemia-reperfusion such as CABG could be beneficial. Furthermore, NHE inhibition may be useful in unexplored situations in which cell protection is warranted, such as evolving MI, cell hibernation and stunning, arrhythmias, apoptosis and left ventricular remodeling. Trials with different study designs are required to investigate these important clinical issues.

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Trial Participants
Steering Committee
Pierre Théroux (Chairman), Bernard R. Chaitman, Nicolas Danchin, Leif Erhardt, Thomas Meinertz, John S. Schroeder, Gianni Tognoni, Harvey D. White, James T. Willerson.

Data and Safety Monitoring Board
Desmond Julian (Chairman), C. Richard Conti, Gordon D. Murray, Marc A. Pfeffer, Knut Rasmussen, Gillian Taylor (statistical analyst).

End-Point Validation Committee
Pierre Théroux and Leif Erhardt (Cochairmen), Ramon Castello, Ariel Cohen, Roland Demeyere, Dan J. Fintel, Gilbert Gosselin, Thomas Ischinger, Seppo Lehto, Jacques H.F. Lenis, Mario Lopez, Roberto Marchioli, Alfredo Meniconi, Guy B. Pelletier.

ECG/MI/Ischemia Classification Laboratory
B.R. Chaitman (Principal Investigator), J.D. Cohen, K. Stocke, I. Gussak, M. Miller.

Sponsor
Aventis, Inc: W.U. Nickel, A. Jessel, A. Akbary, C. Alles, B. Bauer, M. Bruckner, P. Bryers, E. Chi, D. Coppola, H. Donovan, L. Harnisch, B. Hientzsch, B. Katgely, B. Keller, M. Klueglich, H.-J. Lomp, U. Loose, M. Oster, C. Priestley, S. Roy, D. Sauerteig, G. Schulz, A. Steinstraesser, M. Treudler, W. Weber, R. Wesch.

Quintiles, Inc: D. Call, C. Zimmer, C. Durocher, M. Fiola, C. Hahn, M.K. Jolly, L. Langer, S. McDermott, B. McElhinney, R. McGloughlin, K. McLean, K. Redant, J. Rosasco, A. Taber, C. Tyner.

Investigators
Argentina
Hospital Privado, Cordoba, M. Amuchastegui; Clinical Bazterrica, Buenos Aires, C.M. Barrero; Hospital Italiano, Buenos Aires, O. Bazzino; Hospital Durand, E.J. Beck; Sanatorio San Geronimo, Santa Fe, C.A.R. Becker; Sanatorio Allende, Cordoba, J.O. Bono; Clinica Indepenencia, Buenos Aires, G. Bortman; Hospital Espanol, Buenos Aires, G. Bortman; Clinical de la Obra Social del Ministerio de Economia, Buenos Aires, A. Cagide; CEMIC, Buenos Aires, J.J. Fuselli; Hospital Ramos Mej, Buenos Aires, A.L. Girotti; Instituto Medico de Diagnostico y Tratamiento, Santa Fe, M.A. Hominal; Hospital Pirovano, Buenos Aires, J.O. Lazzari; Sanatorio Mitre, Buenos Aires, A.S. Liprandi; Sanatorio Agote, Buenos Aires, J.A. Lowenstein; Hospital de Clinicas, Buenos Aires, A. Jose; Sanatorio Anchorena, Terapia Intensiva, Buenos Aires, E.F. Mele; Hospital Italiano, La Plata, J.A. Plastino; Piso Hospital Argerich, Buenos Aires, M.A. Riccitelli; Hospital Santojanni, Buenos Aires, D. Ryba; Instituto Modelo de Cardiologia, Cordoba, C. Serra; Hospital Israelita, Buenos Aires, H.G. Torres; Instituto del Torax, La Plata, R.G. Torrijos; Hospital Britanico, Buenos Aires, J.E. Ubaldini.

Australia
Gold Coast Hospital, Southport, G. Aroney; Flinders Medical Center, Bedford Park, P. Aylward; Townsville General Hospital, Townsville, B. Bidstrup; Royal Adelaide Hospital, Adelaide, M. Brown; Redcliffe Hospital, Redcliffe, P. Carroll; Royal Brisbane Hospital, Herston, D. Cross; The Alfred Hospital, Prahran, J. Federman; Princess Alexandra Hospital, Woolloongabba, P. Garrahy; Fremantle Hospital, Fremantle, R. Hendriks; Austin and Repatriation Medical Center, Heidelberg, M. Horrigan; Ashford Specialist Center, Ashford, R. Lehman; John Hunter Hospital, Hunter Region, J. Leitch; St Vincent’s Hospital, Fitzroy, A. MacIsaac; Royal North Shore Hospital, St Leonards, G. Nelson; Launceston General Hospital, Launceston, B. Singh; Royal Perth Hospital, Perth, R. Taylor; Sir Charles Gairdner Hospital, Nedlands, P. Thompson; Royal Hobart Hospital, Hobart, A. Thomson; Coffs Harbor Base Hospital, Coffs Harbor, J. Waites.

Austria
Landeskrankenhaus Feldkirch, Feldkirch, H. Drexel; A Krankenhaus der barmherzigen Schwestern vom heiligen Kreuz, Wels, B. Eber; Hanusch Krankenhaus, Vienna, G.B. Gaul; Medizinische Universitätsklinik, Graz, W. Klein; Allgemeines Krankenhaus der Stadt Wien, Vienna, G. Maurer; Krankenanstalt der Gemeinde Wien, Vienna, J. Slany; Wilhelminenspital der Stadt Wien, Vienna, K. Steinbach; A Landeskrankenhaus Bruck an der Mur, Mur, G. Zenker.

Belgium
Hôpital Erasme, Brussels, G. Berkenboom; Clinique Sainte Elisabeth, Namur, P. Bernard; O.L.V. Ziekenhuis, Moortselbaan, Aalst, G. Heyndrickx; AZ Jette VUB, Laarbeeklaan, Brussels, L. Huyghens; UCL Mont-Godinne, Yvoir, E. Schröder; Hartcentrum ZOL, Genk, W. Van Mieghem.

Canada
Foothills Hospital, Calgary, J. Hansen; Royal Alexandra Hospital, Edmonton, W. Hui; Sauve Professional Corporation, Fort McMurray, M. Sauve; Vancouver Hospital & Health, Science Center, Vancouver, A. Fung; Royal Jubilee Hospital, Victoria Heart Institute Foundation, Victoria, P. Klinke; W Surrey Memorial Hospital, Surrey, J. Kornder; M UBC Site, Vancouver, S. Rabki; St Paul’s Hospital, Vancouver, C.R. Thompson; Health Science Center, Winnipeg, E.T. Cuddy; St Boniface General Hospital, Winnipeg, A. Morris; Saint John Regional Hospital, St John, D.R. Mar; Center Hospitalier Regional, Bathurst, F. Shabani; General Hospital Health Science Center, St John’s, B. Rose; QE2 Health Sciences Center, I. Bata; University of Ottawa Heart Institute, Ottawa, R.S.B. Beanlands; Victoria Hospital, London, K.J.C. Finnie; King Street West, Brockville, J. Hynd; St Joseph Hospital, Hamilton, A. Kitching; Thunder Bay Regional Hospital, Thunder Bay, C. Lai; Toronto East General Hospital, Toronto, C. Lefkowitz; Sudbury General Hospital, Sudbury, S.J. Sauve; Ottawa General Hospital, Ottawa, A.T.J. Wielgosz; Laval Hospital, Ste-Foy, P. Bogaty; Cite de la Santé, Laval, G. Boutros; Clinique de Cardiologie de Levis, Levis, F. Delage; Institut de Cardiologie de Montréal, Montréal, R. Gallo; Hospital Charles-Lemoyne, Greenfield Park, G. Gaudreault; Center Regional de Trois-Rivières, Trois-Rivieres, P. Gervais; Hospital Maisonneuve-Rosemont, Montreal, D. Gossard; Center Hospitalier Le Gardeur, Repentigny, G. Gosselin; Reseau Sante Richelieu-Yamaska, St-Hyacinthe, D. Grandmont; Center Hospitalier Universitaire de Quebec, Quebec, G. Houde; The Montreal General Hospital, Montreal, T. Huynh; Center Hospitalier Regional de Lanaudiere, Joliette, S. Kouz; Hospital Notre Dame, Montreal, P. Laramée; Center Universitaire de Santé de l’Estrie, Sherbrooke, S. Lepage; Sacré-Coeur Hospital, Montreal, J. Nasmith; Hôtel Dieu de St-Jérôme, St-Jérôme, Y. Pesant; Hôtel-Dieu de Montreal, Montreal, D.C. Phaneuf; Center Hospitalier Universitaire de Quebec, Sainte-Foy, J.F. Poulin; Center Hospitalier St-Sauveur, Val D’Or, J. Pouliot; Hospital Ste-Croix, Drummondville, R. Roux; Center Hospitalier Pierre-Boucher, Longueuil, E. Sabbah; The Lakeshore General Hospital, Pointe-Claire, F. Sandrin; Center Hospitalier Universitaire de Quebec, Quebec, B. Tremblay; St Paul’s Hospital, Saskatoon, S.K. Dhingra; Royal University of Saskatchewan, Saskatoon, J. Lopez.

Czech Republic
2. int.klinika FNKV, Prague, P. Gregor; 3. int.klinika VFN, Prague 2, J. Hradec; 2. int Klinika FN, Kralove, V. Pidram; Kardiologie IKEM, Prague 4, J. Sochman; 1. int. klinika FN, Pekarska 53, Brno, J. Toman; 2. int. klinika FN, Pekarska 53, Brno, J. Vitovec, J Spinar; 2. int.klinika VFN Prague, Prague, J. Vojacek.

Denmark
Gentofte Amtssygehus, Helllerup, S.Aggestrup; Kolding Sygehus, Grenå, M. Asklund; Viborg Sygehus, Viborg, H. Bagger; Varde Sygehus, Varde, B.D. Christiansen; Sygehus Fyn, Svenborg, K. Egstrup; Hjørring Sygehus, Hjørring, N. Falstie-Jensen; Roskilde Amts Sygehus Køge, Køge, K. Klarlund; Thisted Sygehus, Thisted, L. Kroll; Nstved Hospital, Nstved, J. Larsen; Kalundborg Sygehus, Kalundborg, H. Madsen; Fredericia Sygehus, Frederica, J. Markenvard; Grenå Centralsygehus, Grenå, H. Rickers; Bispebjerg Hospital, Bakke, Copenhagen, B. Sigurd; Amtssygehuset i Gentofte, Hellerup, C. Torp-Pedersen.

Finland
Kuopio University Hospital, Kuopio, J. Hartikainen; Vaasa Central Hospital, Vaasa, H. Kivelä; Kymeenlaakso Central Hospital, Kotka, E. Koskela; Helsinki University Central Hospital, Helsinki, K. Luomanmäki; Helsinki University Central Hospital, Helsinki, V. Manninen; Jyväskylä Central Hospital, Jyväskylä, J. Melin; Pohjois-Karjala Central Hospital, Joensuu, J. Nurminen; Kanta-Häme Central Hospital, Hämeenlinna, A. Palomaki; Tampere University Central Hospital, Tampere, A. Pasternack; Peijas Hospital, Vantaa, S. Pohjola-Sintonen; Jorvi Hospital, Espoo, R. Sipilä; Turku University Central Hospital, Turku, L.M. Voipio-Pulkki.

France
Hôpital Bichat, Paris, P. Assayag; Center Hospitalier Universitaire, Besançon, J.P. Bassand; Hôpital Laribosiere, Paris P. Beaufils; Hôpital La Cavale Blanche, Brest, J.J. Blanc; CHRU Hôpital Central, Strasbourg, C. Brandt; CHR-Hôpitaux de haut-Leveque, T. Pessac, T. Couffinhal; Hôpital de Brabois-Hopital d’Adultes, Vandoeuvre Les Nancy, N. Danchin; Hôpital Henri Mondor, Creteil, J.L. Dubois-Randé; Hôpital Charles Nicolle, Rouen, H. Eltchaninoff; Hôpital de Purpan, Toulouse, J. Puel; Hôpital Antoine Beclere, Clamart, M. Slama; Hôpital du Bocage, Dijon, J.E. Wolf.

Germany
Universitätsklinikum, Klinik III für Innere Medizin, Cologne (Lindenthal), D. Beuckelmann; Chirurgische Universitätsklinik, Freiburg, F. Beyersdorf; Zentrum Innere Medizin, Universitaet Goettingen, Goettingen, A. Buchwald; Innere Abteilung, Caritas-Krankenhaus, Bad Mergentheim, H.D. Bundschu; Universität Göttingen, Klinik für Thorax, Göttingen, H. Dalichau; Universitätsklinikum, Franz-Volhard-Klinik, Berlin, R. Dietz; Medizinische Hochschule Hannover, Hannover, H. Drexler; Deutsches Herzzentrum Berlin, Abteilung Kardiologie, Berlin, E. Fleck; Universitätsklinik, Klinik für Thorax-und Kardiovaskuläre Erkrankungen, Düsseldorf, E. Gams; Akademisches Lehrkrankenhaus, Med. Klinik II, Kaiserslautern, H.G. Glunz; Innere Medizin III, Medizinische Universitätsklinik, Heidelberg, M. Haas; Chirurgische Klinik der Ruprecht-Karls-Universität Heidelberg, Heidelberg, S. Hagl; Städtisches Klinikum Mannheim, Mannheim, J. Harenberg;. Herzzentrum Bad Krozingen, Bad Krozingen, G.F Hauf; Medizinische Hochschule Hannover, Hannover, A. Haverich; Deutsches Herzzentrum Berlin, Berlin, R. Hetzer; Herzzentrum Lahr/Baden, Lahr, E. Freiherr von Hodenberg; Universitätsklinikum Magdeburg, Magdeburg, J.G.C. Huth; Medizinische Klinik und Poliklinik, Tübingen, K.R. Karsch; Medizinische Klinik, Universitätsklinikum, Magdeburg, H.U. Klein; Städt. Krankenanstalten Idar-Oberstein GmbH, Idar-Oberstein, H.H. Klein; Kerckhoff-Klinik Nauheim, W.P. Klövekorn; Klinik Nordrhein, Nauheim, G. Kober; Winterberg-Klinikum, II Saarbrücken, T. Kunz, K. Zwirner; Universitätsklinik, Innere Medizin-Kardiologie, Marburg, B. Maisch; Universitätskrankenhaus Eppendorf, Hamburg, T. Meinertz; Kerckhoff-Klinik GmbH, Nauheim, V. Mitrovic; Klinik für Herzchirurgie, Philipps-Universität Marburg, R. Moosdorf; Klinik fur Thorax-, Herz- und Gefäßchirurgie, Frankfurt am Main, A. Moritz; Johannes Gutenberg-Universität, Mainz, H. Oelert; Klinikum Grosshadern, Munich, B. Reichart; Medizinische Universität zu Lübeck, Lübeck, G. Richardt; Johannes Gutenberg-Universität, Mainz, H.J. Rupprecht; Klinikum Ludwigshafen, Ludwigshafen, W. Saggau; Medizinische Klinik und Poliklinik, Abteilung für Innere Medizin, Universitätsklinikum Benjamin Franklin, Berlin, H.P. Schultheiss; Deutsches Herzzentrum München, Munich, A. Schoemig; Medizinische Universitätsklinik Lübeck, Lübeck, H.H. Sievers; Universitätsklinikum, I. Medizinische Klinik, Kiel, R. Simon; Klinikum Grosshadern, Medizinische u. Poliklinik I, Munich, G. Steinbeck; Herzchirurgische Klinik am Zentralkrankenhaus KZVA, Augsburg, E. Struck; Universitätsklinikum Rostock, Rostock, W. Urbaszek; Klinikum der Albert-Ludwigs-Universität, Freiburg, A. van de Loo; Universitätsklinikum RWTH, Aachen, J. vom Dahl; Theresienkrankenhaus, Institut fur Klinische Pharmakologie, Klinikum Mannheim, M. Wehling; Klinikum Ludwigshafen, Ludwigshafen, R. Zahn; Klinikum der Johann Wolfgang Goethe Universität, Frankfurt am Main, A.M. Zeiher; Universitätsklinik Leipzig, Leipzig, R. Zotz.

Hungary
Szent Gyorgyi Albert Medical University, Szeged, M. Csanády; DOTE, Department of Cardiology and Pulmology, Medical University Debrecen, Debrecen, I. Édes; National Institute of Cardiology, Budapest, M. Keltai; Zala County Hospital, Zalaegerszeg, B. Mezei; Hiete II, Budapest, Cardiovascular Center, Budapest, I. Préda.

Ireland
University College Hospital, Galway, K. Daly; Limerick Regional Hospital, Limerick, T. Peirce; Mater Misericordiae Hospital, Dublin, D. Sugrue; Mallow General Hospital, Cork, P. Sullivan.

Israel
Bellinson Hospital, Tikva, A. Battler, S. Sclarovsky; Heart Institute, Sheba Medical Center, Tel-Hashomer, B. Rabinowitz; S. Sclarovsky; Shaare.Zedek Hospital, Jerusalem, D. Tzivoni.

Italy
Azienda Ospedaliera, "Vito Fazzi," Lecce, F. Bacca; Ospedale "Mauriziano," Turin, G. Baduini; Ospedale Università di Padova, Padua, S. Dalla Volta; Ospedale Clinicizzato San Donato, Milanese, L. de Ambroggi; Ospedale S. Maria Nuova, Emilia, U. Guiducci; Ospedale "G Mazzini," Teramo, F. Jacovoni; Ospedale Regionale "G. Lancici," Ancona, R. Piva; Ospedale M. Bufalini, Cesena, F. Tartagni; Ospedale S. Bortolo, Vicenza, M. Vincenzi; Ospedale di Borgo Trento, Verona P. Zardini.

Luxembourg
Center Hospitalier de Luxembourg, Barble, C. Delagardelle.

New Zealand
Ashburton Hospital, Ashburton, M. Audeau; Wairau Hospital, Blenheim, D. Durham; Waikato Hospital, Hamilton, D. Friedlander; Denis Nelson Hospital, Nelson, A. Hamer; North Shore Hospital, Auckland, H. Hart; Timaru Hospital, Timaru, D. Jardine, M. Hill; Christchurch Hospital, Christchurch, H. Ikram; Napier Hospital, Napier (Site moved on 26 October 1998 to Healthcare Hawksbay, Hastings), R. Luke, G. Lewis; Rotorua Hospital, Rotorua, K. Logan; Healthcare Hawksbay, Hastings (Until 25 October 1998, site was based at Napier Hospital, Napier), G. Lewis, R. Luke; Hutt Hospital, Lower Hutt, S. Mann; Tauranga Hospital, Tauranga, H. Patel; Whangarei Area Hospital, Whangarei, R. Rankin; Middlemore Hospital, Auckland, M. Williams, D. Scott; Wellington Hospital, Wellington, M. Simmonds; Green Lane Hospital, Auckland, H. White; Dunedin Hospital, Dunedin, G. Wilkins.

Norway
Hjerteavdelingen, Haukeland sykehus, Bergen, H. Bjørnstad; Medisinsk avdeling, Sentralsykehuset i Akershus, Nordbyhagen, J. Erikssen; Hjertemedisinsk avdeling, Ullevål sykehus, Oslo, J. Eritsland; Aker sykehus, Med. avd., Oslo, V. Hansteen.

South Africa
Wilgers Hospital, Pretoria, J.M. Bennett; Somerset Hospital, Cape Town, E. Brice; Addington Hospital, Durban, S. Cassim; Groote Schuur Hospital, Cape Town P.J. Commerford; Medforum Hospital, Pretoria, E.N. Maree; Tygerberg Hospital, Tygerberg, F.J. Maritz; Universitas Hospital, Bloemfontein, J.D. Marx; Wentworth Hospital, Durban, A.S. Mitha; Academic Hospital, Pretoria, D.P. Myburgh; R.K. Khan Hospital, Durban, N. Ranjith; Panorama Medi-Clinic, Cape Town, A. Saaiman; Pretoria Heart Hospital, Pretoria, F.A. Snyders.

Sweden
Thoraxkirurgiska kliniken, Blekingesjukhuset, Karlskrona, B. Åberg; Hjärtmottagningen, Centrallsarettet, Västerås, S. Bandh; Medinmottagningen, Trelleborgs Lasarett, Trelleborg, L. Forslund; Medicinkliniken, Lasarettet, Falun, L. Hagström; Hjärt-lungkliniken, Universitetssjukhuset–MAS, Malmö, O. Hansen; Avd 92 HIA, Medicinkliniken, Göteborg, M. Hartford; Medicinkliniken 2C, Luleå sjukhus, Luleå, F. Huhtasaari; Medicinmottagningen, Sjukhuset, Varberg, J. Jonsson; Medicinkliniken, Länssjukhuset, Sundsvall, B. Moller; Thoraxkirurgiska kliniken, Sahlgrenska Sjukhuset, Göteborg, P. Mykén; Medicinkliniken avd 11, Bodens Sjukhus, Boden, J. Nilsson; Medicinkliniken, Hässleholms Sjukhus, Hässleholm, C. Pater; Medicinkliniken, Hjârtintensiven M84, Huddinge, G. Rasmanis; Medicinkliniken, Bisby lasarett, Visby, F. Rückers; Thoraxkirurgiska kliniken, Akademiska Sjukhuset, Uppsala, J. Thorelius, Thoraxkirurgiska kliniken, Universitets-sjukhuset, Malmö and Lund, L. Thulin); Medicinkliniken, HIA/Hjärtcentrum, Borås Lasarett, Borås, H. Tygesen; Medicinkliniken, Sjukhuset, Ängelholm, D. Ursing; Medicinkliniken, St Görans Sjukhus, Stockholm, L. Wennerstrom.

Switzerland
Stadtspital Triemli, Zürich, O. Bertel; Inselspital, Medizinische Klinik, Bern, M. Fleisch; Ospedale Regionale di Lugano, Sede Ospedale Civico, Lugano, T. Moccetti; Kreisspital, Abteilung Innere Medizin, Bülach, H.P. Voegelin.

The Netherlands
Martini Hospital, Groningen, P.J.L.M. Bernink; Hospital Zeeuws-Vlaanderen, "De Honte," Terneuzen, R. Ciampricotti; University Hospital Maastricht, Maastricht, C. De Zwaan; Canisius Hospital, Nijmegen, D.P. Hertzberger; St. Antonius Ziekenhuis, Nieuwegein, J.H. Kingma; Onze Lieve Vrouwe Gasthuis, Amsterdam, G.J. Laarman; Catharina Hospital, Eindhoven, H.R. Michels; Medisch Spectrum Twente, Enschede, J.C. Poortermans; St. Sophia Ziekenhuis, Zwolle, A.R. Ramdat Missier; Academisch Ziekenhuis Leiden, Leiden, E.E. Van der Wall; Academisch Ziekenhuis Vrije Universiteit, Amsterdam, G. Veen; Beatrix Ziekenhuis, Gorinchem, A.G.R. Visman.

United Kingdom
The Royal Victoria Hospital, Belfast, A.J. Adgey; General Infirmary at Leeds, Wellcome Wing, Leeds, S. Ball; St. Thomas Hospital, London, C.A. Bucknall; Royal Hallamshire Hospital, Sheffield, K. Channer; Wythenshawe Hospital, Manchester, R.D. Levy; Inverclyde Royal Infirmary, Greenock, A. Mackay; The Victoria Infirmary, Glasgow, R.J. Northcote; Belfast City Hospital, Belfast, G. Richardson; Papworth Hospital, Papworth Everard, L.M. Shapiro; Oldchurch Hospital, Romford, J.D. Stephens.

United States
Appleton Heart Institute, Appleton, P. Ackell; VA-Pittsburgh Health Care System, Pittsburgh, Pa, M. Amidi; Clearwater, Fla, M. Amin; Cardiovascular Medicine & Cardiac Arrhythmias, Redwood City, Calif, E. Anderson; University of Texas Health Houston, Tex, H.V. Anderson; East Carolina School of Medicine, Greenville, NC, J. Babb, Clement J. Zablocki; VA Medical Center, Milwaukee, Wis, V.S. Bamrah; University of Utah School of Medicine, Salt Lake City, Utah, W. Barry (coinvestigator: J. Revenaugh); University of Florida Health Sciences Center, Jacksonville, Fla, T. Bass (coinvestigator: M. Zenni); Iowa Heart Center, Des Moines, Iowa, P.A. Bear; Indianapolis, Ind, D. Beckman (coinvestigator: R.J. Kovacs); Cardiovascular Research Institute, Dallas, Tex, M.R. Berk; South Broward Cardiology Consultants, Hollywood, Fla, H. Berlin; VA Greater Los Angeles Healthcare System, Los Angeles, Calif, M.M. Bersohn; Malcolm Medical Research Institute, Slidell, La, V.K. Bethala; Saint John Hospital, Nassau Bay, Tex, R. Bhalla (coinvestigator: M.S. Kumar); St. Louis University, St. Louis, Mo, S. Bitar; University of Louisville, Louisville, Ky, R. Bolli; The Heart and Lung Group of Savannah, Savannah, Ga, R.K. Bottner; Washington Hospital Center, Washington, DC, S. Boyce; Advanced Cardiac Specialists, Gilbert, Ariz, W.M. Breisblatt (coinvestigator: R. Siegel); University of Arizona, Tucson, Ariz, S. Butman; Cardiology Research Associates, Ormond Beach, Fla, J.E. Carley; Midwest Cardiology, Columbus, Ohio, A.T. Chapekis; UCI Medical Center, Orange, Calif, J. Chen; Cardiology Associates of Mobile, Mobile, Ala, R. Chernick; Northern California Medical Associates, Santa Rosa, Calif, P. Coleman; Beth Israel Deaconess Medical Center, Boston, Mass, M. Comunale; Buffalo Cardiology & Pulmonary Associates PC, Williamsville, NY, J.C. Corbelli; Cardiology Associates of Lake Mead, Henderson, Nev, R. Croke (coinvestigator: A. Steljes); Howard University Hospital, Washington, DC, C.L. Curry; East Alabama Cardiovascular Associates, Opelika, Ala, W.R. Davis; The Oregon Clinic, Portland, Ore, D. Dawley; Harbor UCLA Medical Center, Torrance, Calif, R. Detrano; RX Trials, Silver Spring, Md, L. Dibos; NJ Medical School, Newark, NJ, E. Dwyer; SORRA Research Center/ClinSites, Birmingham, Ala, J.T. Eagan, Jr; MediQuest Research Group, Ocala, Fla, R. Feldman; Advanced Clinical Therapeutics, Tucson, Ariz, J. Fernandez; Chicago, Ill, D. Fintel; Mississippi Center for Clinical Research, LLC, Jackson, Miss, J. Fletcher; Johns Hopkins Hospital, Baltimore, Md, G. Gerstenblith; Louisiana State University Medical Center, Shreveport, La, J. Ghali; Southeastern Healthcare Associates, Vidalia, Ga, P.J. Giles; University of Texas, Health Center at Tyler, Tyler, Tex, D. Hector, D. Goulden III; North Shore University Hospital, Manhasset, NY, D. Grossman; Palmetto Clinical Research, Summerville, SC, C.H. Grossman; UCSF Medical Center, San Francisco, Calif, W. Grossman; CAMCARE Health Education and Research Institute, Charleston, WV, S. Grubb (coinvestigator: G.J. Rosencrance); University of Kentucky, Lexington, Ky, J. Gurley; Primary Care Cardiology, Inc, Ayer, Mass, T.C. Hack; Portland Cardiovascular Institute, Portland, Ore, M.V. Hart; Oklahoma Foundation for Cardiovascular Research, Oklahoma City, Okla, J. Harvey; Tyler Cardiovascular Consultants, Tyler, Tex, D.A. Hector II; University of Texas, Tyler, Tex, D. Hector, D. Goulden; Dallas VA Medical Center, Dallas, Tex, S. Heinle; Baylor College of Medicine, Houston, Tex, J.A. Herd; Wright Patterson AFB, Dayton, Ohio, P. Hickle; MetroHealth Medical Center, Cleveland, Ohio, J. Hodgson; Akron General Medical Center, Akron General Hospital/The Heart Center, Akron, Ohio, M.M. Hughes, J. Litman; Massachusetts General Hospital, Boston, Mass, I.K. Jang; Western Cardiology Associates, Denver, Colo, R. Jantz; VA Medical Center, Salem, Va, N. Jarmukli; Galen Medical Group, Chattanooga, Tenn, J.R. Jarrett; Richmond, Va, R. Jesse (coinvestigator: G. Vetrovec); Beverly Hills, Calif, R. Karlsberg; Maine Medical Center, Portland, Me, M.A. Kellett, Jr; Lindner Center at the Christ Hospital, Cincinnati, Ohio, D.J. Kereiakes; Integris Oklahoma Heart Center, Oklahoma City, Okla, R. Kipperman; Boston Medical Center Hospital, Boston, Mass, M.D. Klein; DRAM, Lanham, MD, T. Ko; Bay Area Heart Center, St. Petersburg, Fla, D. Kohl; Jacksonville Center for Clinical Research, Jacksonville, Fla, M.J. Koren; UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, J.B. Kostis; Indianapolis, Ind, R.J. Kovacs (coinvestigator: D. Beckman); Saint John Hospital, Nassau Bay, Tex, M.S. Kumar (coinvestigator: R. Bhalla); Novum, Inc, Washington, DC, B.I. Lee; Seattle VA Medical Center, Seattle, Wash, K.G. Lehmann; Oklahoma Heart Institute, Tulsa, Okla, W. Leimbach; Portland, Ore, S.J. Lewis; Botsford General Hospital, Farmington Hills, Mich, B. Lewis; University of Rochester Medical Center, Rochester, NY, C.S. Liang; Akron General Medical Center, Akron General Hospital/The Heart Center, Akron, Ohio, G. Litman; Port Charlotte, Fla, M. Lopez; Washington VAMC, Washington, DC, D. Lu; The Ohio State University Medical Center, Columbus, Ohio, R.D. Magorien, Jr; Anaheim, Calif, R.P. Makam; Mayo Clinic, Jacksonville, Fla, J.F. Malouf; Wake Heart Associates, Raleigh, NC, J.T. Mann III; San Diego Cardiac Center, San Diego, Calif, D.G. Marsh; VA Medical Center, Decatur, Ga, J.J. Marshall; Cardiology Group of Memphis, Memphis, Tenn, F. McGrew III; Heart Institute of St. Petersburg, St. Petersburg, Fla, M. McIvor; LA-USC Medical Center, Los Angeles, Calif, A. Mehra; Geisinger Clinic, Danville, Pa, F.J. Menapace; Florida Heart Group, Orlando, Fla, M.R. Milunski; Stuckey Research Center, Fort Wayne, Ind, M. Mirro; Montgomery Cardiovascular Associates, Montgomery, Ala, P. Moore; Creighton Cardiac Center, Omaha, Neb, A. Mooss; Midwest Heart Research Foundation, Lombard, Ill, J. Moran; Orange County Research Center, Orange, Calif, J. Neutel (coinvestigator: L. Santora); Arrhythmia Center for Southern Wisconsin Ltd, Milwaukee, Wis, I. Niazi; The Greater Fort Lauderdale Heart Group Research, Fort Lauderdale, Fla, A. Niederman; Mid America Heart Institute, Kansas City, Mo, J. O’Keefe, Jr; William Beaumont Hospital, Royal Oak, Mich, W. O’Neill; La Jolla, Calif, W. O’Riordan; Gabriel Clinic Research Corp, Georgetown, Tex, T. Parker; Cardiac Study Center, Inc, Tacoma, Wash, D. Peizner; San Diego VA Medical Center, San Diego, Calif, W.F. Penny; University of Florida, Gainesville, Fla, C.J. Pepine; Reno Cardiology Research Laboratory, Reno, Nev, P.E. Pool; Rx Trials, Inc, Silver Springs, Md, A. Qazi; Swedish Medical Center, Seattle, Wash, M. Reisman; University of Utah School of Medicine, Salt Lake City, Utah, J. Revenaugh (coinvestigator: W. Barry); CAMCARE Health Education and Research Institute, Charleston, WV, G.J. Rosencrance (coinvestigator: S. Grubb); South Texas Clinical Trials, San Antonio, Tex, D. Ruff; Orange, Calif, L. Santora (coinvestigator: J. Neutel); UC at Davis Medical Center, Davis, Calif, S. Schaefer; Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Ill, G. Schaer; Milwaukee Heart Institute, Milwaukee, Wis, D. Schmidt; VA Medical Center, New York, NY, S. Sedlis; Jackson Memorial Hospital, Miami, Fla, R. Sequeira; Cardiovascular Center of Sarasota, Sarasota, Fla, M.E. Shahawy, Jack D. Weiler; Hospital of the Albert Einstein College of Medicine, Bronx, NY, J. Shirani; Advanced Cardiac Specialists, Phoenix Memorial Hospital, Phoenix, Ariz, R. Siegel (coinvestigator: W.M. Breisblatt); 30 Harrison Street, Suite 250, Johnson City, NY, N. Stamato, Cardiology Associates of Lake Mead, Henderson, Nev, A. Steljes (coinvestigator: R. Croke); Novum, Inc, Seattle, Wash, A. Sytman; Batey Cardiovascular Center, Bradenton, Fla, L. Tami; University of N. Carolina, Chapel Hill, NC, D. Tate; University of Oklahoma, Health Sciences Center, Oklahoma City, Okla, U. Thadani; Pomona Valley Hospital Medical Center, Pomona, Calif, R.T. Trivedi; Washington Hospital Center, Washington, DC, L. Van Voorhees; Cincinnati, Ohio, R. Vester; West Hospital, Richmond, Va, G. Vetrovec (coinvestigator: R. Jesse); Mount Sinai Medical Center, New York, NY, D. Vorchheimer; Dartmouth Hitchcock Medical Center, Lebanon, NH, J. Wahrenberger; Long Island Jewish Medical Center, New Hyde Park, NY, I. Weg; Orlando, Fla, I.R. Weinstein; Androscoggin Cardiology Associates Research, Auburn, Me, R.J. Weiss; University of Minnesota, UMHC, Minneapolis, Minn, C. White; Heart and Vascular Clinic of Northern Colorado, Collins, Colo, T.B. Whitsitt; Iowa Heart Center, Des Moines, Iowa, W.J. Wickemeyer; Washington University School of Medicine, St. Louis, Mo, K. Winters; Baystate Medical Center, Springfield, Mass, A. Wiseman; Cardiology Consultants, Medical Group of the Valley, Tarzana, Calif, J. Work; San Diego, Calif, L.G. Yellen; Bridgeport Hospital, Bridgeport, Conn, S. Zarich;. University of Florida, Jacksonville, Fla, M. Zenni II (coinvestigator: T. Bass); University of Pittsburgh-Medicine, Pittsburgh, Pa, G. Ziady (coinvestigator: Z.M. Jafar); James A. Haley Veterans Hospital, Tampa, Fla, R. Zoble.

Received March 31, 2000; revision received July 28, 2000; accepted August 8, 2000.

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				E. Murphy and C. Steenbergen Mechanisms Underlying Acute Protection From Cardiac Ischemia-Reperfusion Injury Physiol Rev, April 1, 2008; 88(2): 581 - 609. [Abstract] [Full Text] [PDF]

				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]

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

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

				J.-C. Tardif, M. Carrier, D. E. Kandzari, R. Emery, R. Cote, T. Heinonen, M. Zettler, V. Hasselblad, M.-C. Guertin, R. A. Harrington, et al. Effects of pyridoxal-5'-phosphate (MC-1) in patients undergoing high-risk coronary artery bypass surgery: Results of the MEND-CABG randomized study J. Thorac. Cardiovasc. Surg., June 1, 2007; 133(6): 1604 - 1611. [Abstract] [Full Text] [PDF]

				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]

				K. Imahashi, F. Mraiche, C. Steenbergen, E. Murphy, and L. Fliegel Overexpression of the Na+/H+ exchanger and ischemia-reperfusion injury in the myocardium Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2237 - H2247. [Abstract] [Full Text] [PDF]

				N. G. Perez, M. R. Piaggio, I. L. Ennis, C. D. Garciarena, C. Morales, E. M. Escudero, O. H. Cingolani, G. Chiappe de Cingolani, X.-P. Yang, and H. E. Cingolani Phosphodiesterase 5A Inhibition Induces Na+/H+ Exchanger Blockade and Protection Against Myocardial Infarction Hypertension, May 1, 2007; 49(5): 1095 - 1103. [Abstract] [Full Text] [PDF]