Today, the most important treatment for protection of ischemic myocardium is early reperfusion therapy. This involves opening the occluded vessel quickly and keeping it open. Important modalities include thrombolysis, percutaneous coronary interventions including angioplasty and stenting, aspirin, heparin, and GP IIb/IIIa inhibitors.

Dr. Kloner and colleagues are studying modalities that may improve upon reperfusion alone. To date, researchers have studied a number of pharmacologic interventions for this purpose. Many of them have failed. These include white blood cell inhibitors, oxygen radical scavengers and complement inhibitors. Studies in the medical literature show negative outcomes for these agents.

However, there have been some positive studies in the medical literature. For example, some investigations have focused on early intravenous beta-blockade for acute myocardial infarction. A number of these trials suggest that early beta-blockade, within the first 3 to 5 hours of acute myocardial infarction, will reduce infarct size, improve left ventricular function and reduce reinfarction rates. Some studies suggest this approach may even improve survival.

Another area of interest is glucose-insulin-potassium. In one recent trial including patients with diabetes mellitus and acute myocardial infarction, this therapy reduced 1-year mortality (18.6% versus 26.1% in control, p = 0.03). This difference persisted and remained significantly improved at 3.4 years. The effect was most evident in patients who were at low cardiovascular risk and had not received previous insulin treatment. In another study of glucose-insulin-potassium in acute myocardial infarction, there was a significant difference in mortality only in patients without acute heart failure.

Dr. Kloner said glucose-insulin-potassium might have an anti-arrhythmic mechanism of action. In experimental models, the treatment produced no change in infarct size.

Adenosine, on the other hand, appears to reduce infarct size in a number of experimental studies. Investigators have also implicated adenosine as one mechanism in the pathway of ischemic preconditioning. In addition, some researchers have suggested that adenosine reduces reperfusion injury. Adenosine has other properties as an antiplatelet agent, and may have anti-inflammatory properties as well.

Two large trials, AMISTAD I and II, both show that adenosine given with or before reperfusion reduces myocardial infarct size in patients with anterior wall myocardial infarcts. In the AMISTAD II study, there was also a trend toward fewer adverse cardiac events. Because of these findings, adenosine deserves additional research and assessment, Dr. Kloner said.

Hypothermia is another modality that may offer additional benefit over early reperfusion alone. Laboratory studies have shown that cooling the heart during ischemia offers profound cardioprotection.

In an experimental rabbit model, Dr. Kloner and co-investigators reduce the temperature of the region at risk in the setting of a coronary artery occlusion. They found a temperature decrease of 4 degrees centigrade slowed the metabolism of the heart and reduced cell necrosis.

Now, researchers are designing clinical trials to evaluate the potential benefit of hypothermia in humans. In one recent study, investigators induced hypothermia using a heat exchange catheter. They found that at temperatures lower than 35 degrees centigrade, patients may have reduced infarct size.

Sodium/hydrogen exchange inhibitors such as cariporide markedly reduced the size of infarct in experimental models. In this study, rabbits received cariporide or placebo 15 minutes before occlusion of the coronary artery.

Some clinical trials now corroborate this experimental data. In one study, patients who received cariporide before angioplasty had smaller infarct size and improved ventricular function. Another study showed cariporide provided some benefit in patients undergoing coronary bypass. There were fewer deaths or re-infarctions in these patients.

Investigators are looking at other potentially cardioprotective agents, such as magnesium. A group of drugs called ATP-sensitive potassium channel (K ATP) openers seem to be very promising. No trials have addressed the use of these drugs in patients with acute myocardial infarct. However, it is likely trials will occur in the future.

Today, the best therapy for these patients includes two parts. The first part is opening the artery quickly with techniques such as thrombolysis or angioplasty and stenting. The second part is keeping the artery open with agents such as aspirin, GP IIb/IIIa inhibitors and low-molecular weight heparin. Beyond these modalities, there may be adjunctive therapies that will further improve outcome.