VIEWPOINT
Insulin therapy as an adjunct toreperfusion after acute coronary ischemia
A proposed direct myocardial cell survival effect independent of metabolic modulation
Michael N. Sack, MD, PhD* and
Derek M. Yellon, PhD, DSc, Hon FRCP, FACC ,*
* The Hatter Institute for Cardiology Research, MRC Inter-University Cape Heart Group, University of Cape Town Medical School, Cape Town, South Africa
The Hatter Institute for Cardiovascular Studies, UCL Hospitals & Medical School, London, United Kingdom
Manuscript received June 11, 2002;
revised manuscript received September 23, 2002,
accepted November 19, 2002.
* Reprint requests and correspondence: Prof. Derek M. Yellon, The Hatter Institute and Centre for Cardiology, University College London Hospitals & Medical School, Grafton Way, London WC1E 6DB United Kingdom.
hatter-institute{at}ucl.ac.uk
Reperfusion therapy has become a practical and effective strategy in the salvage of ischemic myocardium. The direct enhancement of cardiac cellular tolerance against ischemic and reperfusion injury should further improve patient outcome in acute coronary syndromes (ACS). This approach has been explored for many decades, and although we await mortality-weighted randomized clinical trials, the infusion of glucose-insulin-potassium (GIK) has shown promise in protecting post-infarct myocardium. The current dogma is that this cardioprotective effect of GIK acts via the modulation of cardiac and circulating metabolites to provide the heart with an optimal metabolic milieu to resist ischemia and reperfusion injury. This concept of metabolic modulation has gained favor in coronary heart disease, and its efficacy currently is being investigated in stable angina using the new class of partial fatty acid oxidation inhibitors, including trimetazidine and ranolazine. We contend that the mitogen insulin, itself, promotes tolerance against ischemic cell death via the activation of innate cell-survival pathways in the heart. To advance this viewpoint, we will present clinical data that support a dose-dependent effect of insulin’s beneficial action in the management of acute myocardial infarction. Furthermore, we present experimental data that identify cell-survival programs that are directly activated by the administration of insulin. Finally, as intravenous insulin therapy is both labor intensive and associated with metabolic perturbations, we propose that the development of pharmaco-therapeutic agents that target downstream cell-survival insulin-activated signaling molecules may be an alternate approach to promote cardioprotection during ACS.
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Abbreviations and Acronyms
| | ACS | | acute coronary syndrome(s) | | AMI | | acute myocardial infarction | | ECLA | | Estudios Cardiologicos Latinoamerica study | | FFA | | free fatty acids | | GIK | | glucose-insulin-potassium | | MI | | myocardial infarction | | pFOX | | partial fatty acid oxidation | | S6K | | p70S6 kinase |
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