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.

OBJECTIVES: The Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial was designed to test the hypothesis that adenosine as an adjunct to thrombolysis would reduce myocardial infarct size. BACKGROUND: Reperfusion therapy for acute myocardial infarction (MI) has been shown to reduce mortality, but reperfusion itself also may have deleterious effects. METHODS: The AMISTAD trial was a prospective, open-label trial of thrombolysis with randomization to adenosine or placebo in 236 patients within 6 h of infarction onset. The primary end point was infarct size as determined by Tc-99 m sestamibi single-photon emission computed tomography (SPECT) imaging 6+/-1 days after enrollment based on multivariable regression modeling to adjust for covariates. Secondary end points were myocardial salvage index and a composite of in-hospital clinical outcomes (death, reinfarction, shock, congestive heart failure or stroke). RESULTS: In all, 236 patients were enrolled. Final infarct size was assessed in 197 (83%) patients. There was a 33% relative reduction in infarct size (p = 0.03) with adenosine. There was a 67% relative reduction in infarct size in patients with anterior infarction (15% in the adenosine group vs. 45.5% in the placebo group) but no reduction in patients with infarcts located elsewhere (11.5% for both groups). Patients randomized to adenosine tended to reach the composite clinical end point more often than those assigned to placebo (22% vs. 16%; odds ratio, 1.43; 95% confidence interval, 0.71 to 2.89). CONCLUSIONS: Many agents thought to attenuate reperfusion injury have been unsuccessful in clinical investigation. In this study, adenosine resulted in a significant reduction in infarct size. These data support the need for a large clinical outcome trial.

Intravenous adenosine and lidocaine in patients with acute myocardial infarction.

OBJECTIVES: A pilot study was designed to assess the safety of combined intravenous adenosine and lidocaine in patients with acute myocardial infarction and to estimate the likelihood of a beneficial effect on final infarct size. BACKGROUND: Adenosine plus lidocaine reduces infarct size in animals, but the safety and efficacy in human beings is unknown. METHODS AND RESULTS: Adenosine (70 microg/kg per minute intravenous infusion) plus lidocaine (1 mg/kg intravenous bolus injection and 2 mg/kg per minute infusion) was given to 45 patients with acute myocardial infarction. Patients underwent immediate balloon angioplasty without preceding thrombolytic therapy. Myocardial perfusion defects were measured with serial technetium 99m sestamibi studies. One patient developed persisting hypotension in conjunction with a large inferolateral myocardial infarction. Transient hypotension in three other patients resolved with a reduction in adenosine. Advanced atrioventricular block was never observed. Other adverse events (including atrial fibrillation, ventricular tachyarrhythmia, bradycardia, and respiratory distress) occurred at low frequencies, as expected for patients with acute myocardial infarction. An initial median perfusion defect of 45% of the left ventricle (60% for anterior infarction, 17% for nonanterior infarction) was observed. At hospital discharge (mean +/- SD = 4.3 +/- 2.1 days) the median value was 12%, and at 8 +/- 4 weeks it was 3% (7% for anterior infarction, 0% for nonanterior infarction); 14 patients had no measurable follow-up. Compared with historical control patients, prehospital discharge measurements were not different but late perfusion defects were improved. CONCLUSIONS: Treatment with intravenous adenosine and lidocaine during acute myocardial infarction has sufficient safety and potential for improved myocardial salvage. Randomized studies are justified.

Safety, tolerance, and efficacy of adenosine as an additive to blood cardioplegia in humans during coronary artery bypass surgery.

Myocardial stunning after heart surgery is associated with increased morbidity and mortality in patients with severe multivessel disease and reduced myocardial function. The purpose of this study was to evaluate the safety, tolerance, and efficacy of adenosine as a cardioprotective agent when added to blood cardioplegia in patients undergoing coronary artery bypass surgery. Sixty-one patients were randomized to standard cold-blood cardioplegia, or cold-blood cardioplegia containing 1 of 5 adenosine doses (100 microM, 500 microM, 1 mM, 2 mM, and 2 mM with a preischemic infusion of 140 microg/kg/min of adenosine). Invasive and noninvasive measurements of ventricular performance and rhythm were obtained preoperatively, prebypass, and then at 1, 2, 4, 8, 16, and 24 hours postbypass. Use of inotropic agents and vasoactive drugs pastoperatively was recorded; blood samples were collected for measurement of nucleoside levels. High-dose adenosine treatment was associated with a 249-fold increase in the plasma adenosine concentration and a 69-fold increase in the combined levels of adenosine, inosine, and hypoxanthine (p <0.05). Increasing doses of the adenosine additive were also associated with lower requirements of dopamine (p = 0.003) and nitroglycerine (p = 0.001). The 24-hour average doses for dopamine and nitroglycerine in the placebo group were 28-fold and 2.6-fold greater than their respective high-dose adenosine treatment cohorts. Finally, the placebo- and 100 microM-adenosine group was associated with a lower ejection fraction when compared to patients receiving the intermediate dose or high-dose treatment. These findings are consistent with the hypothesis that adenosine is effective in attenuating myocardial stunning in humans.

Mechanisms for vagal modulation of ventricular repolarization and of coronary occlusion-induced lethal arrhythmias in cats.

Our goal was to better understand the mechanisms underlying muscarinic receptor actions on the ventricle in vivo. Therefore, we studied the effects of vagal stimulation on ventricular repolarization and of vagal tone on lethal arrhythmias induced by 30 minutes of left anterior descending coronary artery ligation in anesthetized cats. Experimental groups included normal control cats subjected only to coronary ligation and cats pretreated with atropine, pertussis toxin (PTX), or propranolol. All cats received bilateral cervical vagal stimulation (Vstim) at 1, 3, and 5 Hz for 1 minute at 10-minute intervals. Before coronary ligation, Vstim slowed sinus rate, prolonged the PR interval, and lowered blood pressure. Most important from the point of view of electrophysiological function was a vagally induced acceleration of ventricular repolarization in paced and unpaced hearts, which could be explained by the effects of acetylcholine (ie, shortening the subepicardial muscle action potentials). The effect on repolarization was blocked by atropine or PTX but not by propranolol. The extent of sinus slowing and acceleration of repolarization was directly related to the level of functional PTX-sensitive G protein (P < .05). Coronary occlusion was performed during atrial pacing such that the heart rate in all groups was equal. The incidence of ventricular fibrillation (VF) was 10% in the control group and 50% and 54% in atropine and PTX groups, respectively (P < .05). During atrial pacing before coronary occlusion, a vagal index was calculated as percent QTc shortening during Vstim. When the vagal index was 13% to 26%, the incidence of VF during occlusion was zero. When the vagal index was 0% to 12%, VF was 52% (P < .01). Conclusions are as follows: (1) Vstim accelerates ventricular repolarization in cats via a pathway that incorporates a PTX-sensitive G protein and involves an altered gradient between epicardium and endocardium. (2) Removal of vagal tone during ischemia favors VF, as predicted by a vagal index.

An alpha-1-adrenergic receptor subtype is responsible for delayed afterdepolarizations and triggered activity during simulated ischemia and reperfusion of isolated canine Purkinje fibers.

BACKGROUND: We used standard microelectrode techniques to study delayed afterdepolarizations and triggered activity induced by alpha 1-adrenergic stimulation in canine Purkinje fibers in the setting of simulated ischemia and reperfusion. METHODS AND RESULTS: The ischemic environment included 10.8 mM [Ca2+]o, 10 mM [K+]o, 40-50 mm Hg PO2, 20 mM lactate (pH 6.7), and 1 x 10(-7) M phenylephrine. During ischemia, there was the variable occurrence of abnormal automaticity, early afterdepolarizations, and delayed afterdepolarizations. During reperfusion, 100% of preparations manifested delayed afterdepolarizations and 40% manifested triggered activity. Decreasing PO2 to less than 20 mm Hg markedly reduced the incidence of delayed afterdepolarizations and triggered activity, as did increasing PO2 to values of more than 90 mm Hg. WB 4101, an alpha 1-subtype-selective competitive blocker that antagonizes the effects of alpha 1-agonists to induce phosphoinositide metabolism and increase [Ca2+]i, significantly reduced the incidence of delayed afterdepolarizations and triggered activity. In contrast, the alpha 1-subtype-selective blocker chloroethylclonidine, an alkylating agent, had no effect on afterdepolarizations or triggered activity. CONCLUSIONS: Our results indicate that a specific alpha 1-adrenergic pathway is involved in the induction of triggered activity in the setting of ischemia and reperfusion and suggest that interventions used to block this specific pathway have the potential to be antiarrhythmic. They also emphasize the importance of the magnitude of hypoxia in the expression of the arrhythmias.