Can we target metabolism and ion flux as a therapy for coronary artery occlusion?

Michael Marber¹, Gary Lopaschuk^2
1Department of Cardiology, St. Thomas’ Hospital, London UK
²Cardiovascular Research Group, Faculty of Medicine,
University of Alberta, Edmonton, Alberta, Canada

Correspondence: Professor Michael S. Marber, Department of Cardiology, KCL,
St Thomas’ Hospital, Lambeth Place Road, London SE1 7EH, UK. e-mail: mike.marber@kcl.ac.uk

This issue of Heart and Metabolism is dedicated to a discussion of interventions that preserve myocardium following coronary artery occlusion by influencing the changes in metabolism and ion fluxes that accompany ischemia and reperfusion. For such interventions to have a clinical impact they must slow the rate at which myocardium dies following coronary artery occlusion, and/or must limit lethal events occurring when infarct-related artery patency is restored, so-called ‘reperfusion injury’. The underlying premise is that either intra- or postischemic protection saves myocardium, maintaining contractile reserve, thereby limiting maladaptive postinfarction remodeling. The net effect of such protective interventions would be to limit increases in postinfarction end-systolic volume, the most powerful predictor of subsequent mortality.[1] The question therefore is, are there any metabolic or ionic interventions that are able to reduce mortality?

Agents that only slow necrosis
The first compelling problem is that discussed by Drs Sack and Yellon. In the experimental laboratory there are a number of interventions that can slow the rate of myocardial death following coronary occlusion. However, most investigators find that these treatments, which include adenosine and sodium proton exchange inhibitors, must be given before the moment of coronary artery occlusion. One reason why this is necessary is that the amount of collateral support to the ischemic zone is uncertain, and therefore to ensure that the protective substance is in contact with the myocardium it has to be delivered by antegrade flow. Another reason is that these interventions only slow the rate of necrosis, they do not resurrect dead myocytes, and must therefore be present when myocardial necrosis is threatened rather than established. In the clinical arena, where presentation with chest pain and ST-segment elevation is triggered by coronary occlusion, there are few circumstances where such interventions are practical. As Drs Avkiran, Cohen, and Downey point out, it is exactly these sorts of issues that may explain why the GUARDIAN[2] and AMISTAD[3] trials, though negative overall, suggested that treatment with a sodium proton exchange inhibitor or adenosine may still benefit certain subgroups.

Agents that limit reperfusion injury
The concept of reperfusion injury is one that we have always found difficult to grasp. Unfortunately, despite decades of research it remains controversial, with one camp believing that reperfusion merely unmasks myocytes that died during ischemia, and the other camp believing that reperfusion kills myocytes that were still alive at the end of ischemia. The most convincing way to unravel the contribution of reperfusion is to find interventions that limit ultimate infarct size only when given during reperfusion. Unfortunately, most such interventions have yielded dichotomous results, with some investigators finding they do protect and others finding they do not. Recently, however, the observation that the process of apoptosis may continue during reperfusion has provided a target for late intervention. This allows strategies that are closely allied to the treatment of patients presenting with ST elevation, namely reperfusion therapy.
In this issue Drs Sack and Yellon point out that insulin may have antiapoptotic properties thereby enabling it to limit infarct size even when given during reperfusion. Together with Drs Avkiran, Cohen, and Downey they argue it is exactly these properties of insulin that enabled the small pilot ECLA trial of glucose, insulin, and potassium (GIK) to succeed[4] where larger trials such as AMISTAD and ESCAMI failed. Moreover, in the clinical study described in this issue by Drs van Campen, Klein, and Visser, GIK was also shown to improve left ventricular function during the reperfusion phase of myocardial infarction, enabling the detection of viable but stunned or hibernating myocardium. This is a significant finding since it is exactly under these circumstances that dobutamine extends necrosis in animal models.[5]
Hence it is the cheap metabolic strategy of GIK, lacking patent protection, that receives the greatest support from our contributors. The GIK hypothesis is currently being tested in the larger, noncommercial, ECLA 2 full-scale trial. We urge those of you who are interested to visit http://www.ecla.org.ar.

Summary
In patients with acute coronary artery occlusion and ST elevation there is no proven intervention other than reperfusion that definitely reduces the volume of myocardium that undergoes infarction. Further clinical investigation is necessary to determine whether metabolic and other interventions are cardioprotective at reperfusion. Whilst these studies are ongoing, keep taking the aspirin, ßblockers, ACE inhibitors, and statins!

REFERENCES

Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Main results of the GUARDIAN trial. Guard during ischemia against necrosis (GUARDIAN) Investigators.

Theroux P, Chaitman BR, Danchin N, Erhardt L, Meinertz T, Schroeder JS, Tognoni G, White HD, Willerson JT, Jessel A.

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.

Publication Types:

• Clinical Trial
• Randomized Controlled Trial

PMID: 11120691 [PubMed - indexed for MEDLINE]

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.

Mahaffey KW, Puma JA, Barbagelata NA, DiCarli MF, Leesar MA, Browne KF, Eisenberg PR, Bolli R, Casas AC, Molina-Viamonte V, Orlandi C, Blevins R, Gibbons RJ, Califf RM, Granger CB.

Duke Clinical Research Institute, Durham, North Carolina 27715, USA. mahaf002@mc.duke.edu

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.

Publication Types:

• Clinical Trial
• Multicenter Study
• Randomized Controlled Trial

PMID: 10577561 [PubMed - indexed for MEDLINE]

4: Circulation 1998 Nov 24;98(21):2227-34

Related Articles, Books, LinkOut

Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiologicos Latinoamerica) Collaborative Group.

Diaz R, Paolasso EA, Piegas LS, Tajer CD, Moreno MG, Corvalan R, Isea JE, Romero G.

Department of Cardiology, Instituto Cardiovascular de Rosario, Rosario, Argentina.

BACKGROUND: Several trials have been performed in the past using glucose, insulin, and potassium infusion (GIK) for the treatment of acute myocardial infarction (AMI). Because of continuing uncertainty about the potential role of this therapeutic intervention, we conducted a randomized trial to evaluate the impact of a GIK solution during the first hours of AMI. METHODS AND RESULTS: Four hundred seven patients with suspected AMI admitted within 24 hours of symptoms onset were enrolled. In a ratio of 2:1, 268 patients were allocated to receive GIK (high- or low-dose) and 139 to receive control. Phlebitis and serum changes in the plasma concentration of glucose or potassium were observed more often with GIK. A trend toward a nonsignificant reduction in major and minor in-hospital events was observed in patients allocated to GIK. In 252 patients (61.9%) treated with reperfusion strategies, a statistically significant reduction in mortality (relative risk [RR] 0.34; 95% CI: 0.15 to 0.78; 2P=0.008) and a consistent trend toward fewer in-hospital events in the GIK group were observed. CONCLUSIONS: Our results confirm that a metabolic modulation strategy in the first hours of an AMI is feasible, applicable worldwide, and has mild side effects. The statistically significant mortality reduction in patients who underwent a reperfusion strategy might have important implications for the management of AMI patients. It is now essential to perform a large-scale trial to reliably determine the magnitude of benefit.

Publication Types:

• Clinical Trial
• Multicenter Study
• Randomized Controlled Trial

PMID: 9867443 [PubMed - indexed for MEDLINE]