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
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Abstract
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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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The concept that the metabolic cocktail, glucose-insulin-potassium (GIK), may protect ischemic cardiomyocytes was initially introduced by Sodi-Pallares in 1962 (1). The further rationale for the use of this metabolic therapy was proposed by Opie (2) in 1970, when he suggested two chief mechanisms: the promotion of cardiac glycolysis and the diversion of free fatty acids (FFA) to adipocytes, with a resultant reduction in cardiac FFA metabolism. A number of early clinical studies with administration of this metabolic cocktail yielded promising results, and a subsequent meta-analysis suggested that GIK therapy might have an important role in reducing in-hospital mortality after acute myocardial infarction (AMI) (3). In the "myocardial reperfusion era" the randomized controlled Estudios Cardiologicos Latinoamerica (ECLA) study suggested that patients who underwent reperfusion therapy had reduced in-hospital mortality after the co-administration of GIK (4). Acceptance of the benefits and the subsequent use of this metabolic cocktail have, however, not been forthcoming, despite almost four decades having passed since such therapy was proposed. The reason for the lack of enthusiasm is multi-factorial and includes the lack of large clinical studies, the poor understanding of the basic mechanisms of how this metabolic cocktail acts, and the complexity in administering this therapeutic cocktail. To adequately address the efficacy of GIK, a large randomized clinical study is now underway (GIK II: http://www.ecla.org.ar). Furthermore, alternate therapeutic strategies to optimize glucose utilization in the management of stable coronary artery disease are being explored (5–7). The most promising appear to be via the promotion of glucose oxidation using the partial fatty acid oxidation (pFOX) inhibitors in the context of stable angina (8,9). However, in our opinion, the use of these alternate "metabolic-modulatory" strategies does not incorporate the putative direct beneficial effects of insulin administration during acute coronary syndromes (ACS). In this regard, research from our laboratories and other laboratories implicates the direct cell survival effects of insulin as a "metabolically independent" component of the GIK cocktail (10–12). The clinical data and a proposed insulin-directed cell survival hypothesis conferring these cardioprotective effects are discussed. Finally, pharmacologic targeting of insulin signaling may be appropriate in future drug development to promote this cardiac tolerant state in the context of ACS.
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The clinical case for GIK in cardioprotection
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The meta-analysis of 1,932 patients randomized to GIK therapy or placebo in the "pre-reperfusion era" demonstrated that GIK therapy could save an additional 49 lives per 1,000 patients treated for AMI (3). Although studies need to be performed, it was assumed that the benefit of this therapy might be less applicable in the current aggressive thrombolysis and acute revascularization era. However, as was shown in the ECLA study, a statistically significant reduction in mortality after AMI was obtained in patients who received concomitant reperfusion treatment with the GIK cocktail (4). It is interesting that, in the one-year follow-up data from the ECLA study, only those subjects who had received the high-dose GIK therapy had a statistical survival advantage over the control group (4). The decision to use a high-dose GIK regimen was based on the pioneering dose-response studies of Rackley and co-workers, who determined the GIK infusion rates that would result in the maximal suppression of FFA levels as well as the maximal myocardial glucose uptake (13). Two additional clinical studies have been performed in the reperfusion era. The first, the Diabetes Mellitus, Insulin Glucose infusion in Acute Myocardial Infarction (DIGAMI) study, was designed to assess the efficacy of glucose and insulin therapy in diabetic patients who presented with AMI (14). Long-term subcutaneous insulin therapy was instituted beyond the acute-infarction period in the non-insulin-dependent diabetic patients (who constituted approximately 80% of the subjects in the DIGAMI study). Despite these differences, the end result was similar to a 29% relative risk reduction for mortality in the patients treated with insulin and glucose. In the second study, Ceremuzynski et al. (15) did not show any beneficial effect of low-dose GIK therapy. Apstein and Opie (16) reviewed the different GIK doses in the ECLA and the Ceremuzynski studies and suggested that the higher insulin dosing in the ECLA study was consistent with the previous pre–reperfusion era studies that showed a benefit of high-dose GIK therapy (reviewed [17]). Collectively, these clinical studies support a role for GIK therapy after an AMI and suggest that the dose of insulin needs to be optimal to confer this benefit. This latter finding supports the metabolic optimization hypothesis as a mechanism underlying the mortality-reducing effects of GIK (13,14). In support of the metabolic hypothesis, clinical studies have demonstrated an anti-anginal effect of newer metabolic modulators in patients with stable angina (6,8,9).
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Experimental data to support a direct cardioprotective effect of insulin
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After the ECLA clinical study, Jonassen and co-workers (18), in an experimental study, compared the temporal effects of administering GIK in an in vivo rat model of myocardial infarction (MI). It is interesting that GIK was demonstrated here to be equally effective in reducing the final infarct size, whether administered during the entire ischemia/reperfusion period or only during the reperfusion period. Moreover, when GIK was administered at reperfusion, the early reperfusion FFA and glucose levels were unchanged compared with those in vehicle-treated controls. This was significantly different from the FFA and glucose levels in the animals treated with GIK throughout the ischemia/reperfusion period (18). To further delineate this observation and to establish the role of insulin at reperfusion, we used the isolated perfused rat heart model of ischemia and reperfusion. Here, insulin was administered alone at reperfusion and demonstrated that an immediate 15-min treatment with insulin resulted in the same reduction in infarct size as insulin administered for a 2-h period after reperfusion (11). Taken together, these data bring into question the exclusivity of the glucose/FFA hypothesis concerning the GIK combination’s cardioprotective effects and implicate an independent cardioprotective effect of insulin, in its own right, during reperfusion.
Although reperfusion is a prerequisite for tissue salvage after an MI, there is a price to pay in terms of distinct reperfusion-associated pathologies (reviewed [19]). One postulated aspect of this pathology is the development of reperfusion-induced myocyte loss beyond that sustained as a consequence of ischemia alone. In this regard, it has recently been suggested that, in addition to necrosis, a component of cell death not previously considered in reperfusion injury—programmed cell death, or apoptosis—may play a biologically significant role (20). Under experimental conditions, an increase in apoptosis has been observed in cardiac reperfusion models, suggesting that the deleterious effects of reperfusion are, at least in part, due to apoptosis (21–23). Taking these data into consideration, we have suggested that insulin may attenuate apoptosis during reperfusion and hence result in cardioprotection (20). We and others have shown that insulin can indeed attenuate such apoptotic processes in a number of tissues (10,12,24).
Because we have demonstrated that insulin appears to have a direct effect on limiting tissue injury during post-ischemic reperfusion, our laboratories have focused on delineating the molecular cell-survival signaling pathways downstream of insulin that could be orchestrating this tolerant phenotype in the heart (schematized in Fig. 1). Initial experiments in cardiomyocytes demonstrated that the administration of insulin at the moment of reoxygenation significantly enhanced myocardial cell viability and reduced the degree of apoptosis compared with vehicle-alone treated control cardiomyocytes (10). As insulin is thought to confer anti-apoptotic effects via the activation of the cell survival pathways shown in Figure 1, we initially used pharmacologic inhibitors of these signaling transduction pathways and demonstrated that tyrosine kinase, PI3 kinase, and p70S6 kinase (S6K) signaling were required for this cardioprotective phenotype to be functional (10,11). In conjunction, the activity of the cell-survival promoting signaling intermediates (i.e., protein kinase B [Akt] and S6K) was induced by the administration of insulin at reperfusion (11). Additionally, we demonstrated that insulin therapy at reperfusion maintained the pro-apoptotic peptide BAD (Bcl-2/Bcl-XL-agonist causing cell death) in an inactive phosphorylated form (11). A recent in vivo study confirmed the anti-apoptotic role of insulin administration at cardiac reperfusion in the rat (12). Here, Gao et al. (12) identified an additional signaling cascade (i.e., endothelial nitric oxide synthase phosphorylation) as a target of insulin activated PI3-kinase and Akt cardioprotective signaling. Collectively, these data support a role for insulin in promoting cell survival at reperfusion putatively via multiple pro-survival and anti-apoptotic signaling events. As shown in Figure 1, current knowledge would support a role of Akt activation in both direct cell survival and glucose metabolism. In contrast, the S6K is implicated in directly promoting cell survival (25) and in inhibiting BAD, which when activated, is known to destabilize mitochondrial membrane integrity and promote apoptosis (26). We postulate that these insulin-modulated signaling molecules may be feasible therapeutic targets for enhancing cardiac tolerance to ischemia in the management of ACS. Recently, experimental data clearly support a role for Akt activation in the attenuation of myocardial ischemic injury (12,27,28). In this context, it has also been shown that the HMG-CoA reductase inhibitors can also activate this intracellular kinase to the benefit of the cell (29–31). Hence, Akt activation may be a reasonable therapeutic target for the design of future agents to protect the myocardium against the consequences of reperfusion-induced injury.
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Figure 1 Schematic of insulin signaling pathways that promote cell survival and facilitate increased glucose uptake. These signaling pathways have recently been reviewed in depth. Akt = protein kinase B; BAD = Bcl-2/Bcl-XL-agonist causing cell death; eNOS = endothelial nitric oxide synthase; PI3K = phosphatidylinositol 3,4,5-trisphosphate; S6K = p70S6 kinase (70-kDa ribosomal protein S6 kinase). The superscripted p denotes the phosphorylation status of BAD and eNOS, respectively.
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Conclusions
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For a number of years clinical data have supported a role of GIK in reducing morbidity and mortality after MI. The encouraging data from the ECLA and the DIGAMI studies suggest that this cardioprotective effect may be achieved over and above benefits obtained with reperfusion therapy alone. Moreover, the recent experimental data with the administration of insulin at reperfusion suggest that the glucose/fatty acid hypothesis may be incomplete and that insulin may exert direct cardiac cell survival effects in the context of ischemia and reperfusion injury. Here, the downstream Akt and S6K signaling intermediates in the insulin pathway may be novel targets to manipulate and promote cardiomyocyte salvage in the management of AMI. An additional possible mechanism of insulin-activated cardioprotection that has not been discussed in this viewpoint is its nitric oxide–mediated vasodilatory effects (32). Finally, we hope that the enhanced understanding of how insulin may directly affect heart muscle tolerance to ischemia will support the recruitment of patients into the mortality-weighted ECLA-GIK II study, the results of which may be of benefit in the future management of AMI.
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Footnotes
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This work was supported by the British Heart Foundation (DMY), The Wellcome Trust (MNS and DMY), The South African Medical Research Foundation (MNS), and the Hatter Foundation, UK (MNS and DMY).
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References
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Abstract
The clinical case for...