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Metabolic modulation of acute myocardial infarction: novel concepts underlying old strategiesDr Rafael Díaz Acute myocardial infarction (AMI) continues to be
the most frequent cause of death in the developed world. Despite
tremendous improvement in the management of AMI during the last
20 years,[1–4] the continuing high morbidity and mortality rates
stimulate the intensive search for different therapeutic options.[5]  Figure 1. Schematic description of myocardial substrate metabolism. GLUT, glucose transporter; HK, hexokinase; G 6-P, glucose 6-phosphate; ADP, adenosine diphosphate; LT, lactate transporter; PDHa, activate dephosphorylated pyruvate dehydrogenase; ETC, electron transport chain; O2, oxygen; Acetyl CoA, acetyl coenzyme A; TCA, tricarboxylic acid; NADH, nicotinamide adenine dinucleotide; FADH2, flavine adenine dinucleotide.[12] During ischemia, severe reductions in blood flow (like in AMI) result in reductions in glucose uptake (extraction is related to coronary flow), greater rates of lactate accumulation, glycogen breakdown, complete contractile dysfunction and, finally, myocardial necrosis and infarction. Circulating free fatty acid (FFA) levels rise dramatically during and following episodes of ischemia.[13–15] This high plasma FFA concentration increases the severity of ischemic damage due to its direct toxic effects[16] and in part due to the inhibitory effects on pyruvate oxidation by inhibiting the pyruvate dehydrogenase (PDH) complex.[17,18] Upon reperfusion, mitochondrial oxidative phosphorylation returns to pre-ischemic levels. However, mechanical contractile work remains transiently impaired, gradually recovering to a pre-ischemic level. This phenomenon, called ‘stunning myocardium’, is characterized by an increased level of oxygen consumption for a specific level of work developed.[12] During myocardial reperfusion there is an overshoot of fatty acid metabolism,[17,19,20] impaired pyruvate oxidation and an increase in glycolysis.[21] High rates of FFA beta-oxidation inhibit pyruvate oxidation via inhibition of the PDH complex. Uncoupling of the accelerated glycolysis and pyruvate oxidation is the major source of net hydrogen ion (H+) production during reperfusion.[22,23] Metabolic intervention with glucose-insulin-potassium (GIK) in AMI Different metabolic interventions have been proposed for the treatment of heart disease and they are all directed at shifting the source of energy towards a carbohydrate substrate by: (1) increasing glycolytic flux; (2) decreasing FFA oxidation and indirectly increasing glucose oxidation and flux through the PDH complex; and (3) directly activating the PDH complex, thereby increasing glucose oxidation.[12] One simple method of stimulating glycolysis and decreasing fatty acid oxidation is by infusing high doses of glucose with insulin. High plasma glucose concentrations and insulin stimulate the uptake of glucose and glycolysis, and produce a marked decrease in circulating FFA, therefore reducing FFA oxidation (dramatically increased during the hyperacute phase of AMI, due to high levels of circulating catecholamines and, occasionally, the use of heparin).[24] Mechanism of action of GIK The high glucose concentration and the addition of insulin produce an immediate shift in the source of metabolic substrate. Glucose uptake increases as it is related to its blood concentration, blood flow and the expression of its carrier GLUT1 and GLUT4 (stimulated by insulin).[25–27] High glucose and activated transporters enhance the glycolytic flux to produce pyruvate. Due to the indirect stimulation of PDH (via the inhibition of FFA beta-oxidation), pyruvate is transformed to acetyl coenzyme A (CoA) that restarts the oxidative metabolism during reperfusion. The decrease in FFA levels and FFA beta-oxidation has salutary effects, avoiding their direct and indirect toxic myocardial effects in the context of ischemia/reperfusion.[19] In summary, the beneficial metabolic effects of high doses of glucose and insulin can be due to: (1) an increase in glycolysis and glycolytically derived ATP; (2) an increase in PDH complex activity due to a decreased plasma FFA and elevated insulin levels, resulting in less lactate and H+ accumulation; and (3) lower accumulation of noxious fatty-acyl CoAs due to lower FFA levels.[12] Limiting the effects of glucose-insulin-potassium (GIK) to exclusively metabolic ones is a somewhat narrow perspective. Potassium itself reverses intracellular ion loss during extreme ischemia. High glucose concentration would produce favorable osmolar changes; fluid volume overload can contribute to a better hemodynamic performance; and insulin effects beyond the metabolic effect (coagulation, apoptosis) can also contribute to the potential beneficial effects of GIK in AMI.[16] Clinical experience with GIK Since it first appeared in the literature in 1962,28 GIK infusion for the treatment of AMI has been empirically adopted by most cardiologists mainly based on its property of avoiding arrhythmias and accelerating the process of ST resolution. However, its impact on clinical outcomes has never been clearly demonstrated. Furthermore, clinical trials during this period did not fulfill the methodological statements accepted by the conceptual model of clinical research which emerged during the 1980s. Trials were done using different inclusion criteria, different dosages and durations of infusion, and different routes of administration, and these were reasons for the conflicting results between different trials, hiding the potential benefit of this approach. Furthermore, meta-analysis was not used until later as a common research tool to collect data and formulate hypotheses. The lack of any trial showing strong and convincingly positive results, and probably also due to the absence of any commercial support, are plausible reasons why the cardiovascular community abandoned GIK during the late 1970s. In 1997, a meta-analysis of prior GIK trials in AMI was published.29 The authors, using appropriate techniques, analyzed only studies that had been properly randomized, excluding those with unacceptable methodological pitfalls. The results showed a 28% (CI: 10–43) reduction of in-hospital mortality, from 21 to 16.1%, P = 0.004). Despite the intrinsic weaknesses and limitations of meta-analysis, the results were the first published data to show the impact of GIK on clinical outcomes in AMI. Most of the studies had been performed before the widespread use of reperfusion. An accompanying editorial called for a large, prospective trial with GIK in the setting of proven treatments and methodological modern standards.[30] In the context of the reperfusion era, three small trials were performed using GIK for the treatment of AMI. The DIGAMI trial used a GIK infusion followed by the long-term administration of subcutaneous insulin in diabetic patients with AMI and showed a trend towards a lower in-hospital mortality and a statistically significant reduction in mortality at 1-year follow-up.[31] The Polish GIK trial in AMI patients within 24 h from the onset of symptoms was prematurely stopped due to a non-significant increase in all-cause in-hospital mortality in the GIK group32 and the ECLA GIK Pilot Trial. The ECLA GIK Pilot Trial In 1994, our group initiated the first step of a large project using metabolic support as an adjunctive therapy for AMI. The first part of this project was published in 1998, called the ECLA GIK Pilot Trial.[33] As a pilot trial, the study was designed to look for safety and feasibility. Patients randomized into the trial were to be recruited within 24 h of symptom onset. Ancillary treatments were left to the discretion of the physician responsible, including the choice of reperfusion therapy. Patients were allocated to GIK or control in a ratio of 2:1. Two GIK concentrations were selected: a high dose that had proved in the past to maximally suppress FFA levels, and a low dose (in an attempt to improve the practical use of this infusion). GIK was shown to have minor, non-lifethreatening and easily managed side effects. Mild phlebitis was more often reported in GIK patients (16.8%) than in controls. However, severe phlebitis occurred in only 2% of GIK patients (most of the population [83%] received the infusion via a peripheral line). Mild increases in glucose and potassium serum concentrations were observed in the GIK group, but in no case did these lead to an increase in morbidity or mortality. Patients allocated to receive GIK (high or low concentrations) showed a non-significant in-hospital trend towards lower mortality, severe heart failure, ventricular fibrillation and a statistically significant decrease in the rate of electromechanical dissociation. The combined endpoint of death — non-fatal severe heart failure and non-fatal ventricular fibrillation — was significantly reduced from 20.1% in the control group to 12.1% in the GIK group (relative risk [RR] 0.56, CI 0.37–0.94, 2P = 0.03). When analyzing the population of those who received and those who did not receive reperfusion therapies (as specified in the protocol), the mortality reduction trend observed in the overall population reached a statistically highly significant value (RR 0.34, CI 0.15–0.77, 2P = 0.008). Using a more specific method of analyzing the data and focusing on hard events, we stratified the endpoints of death, severe heart failure and ventricular fibrillation in the nonreperfused and reperfused populations. A 47% non-significant reduction in all deaths was observed (2P = 0.10). Using the 99% CI, the lower limit of mortality reduction in reperfused patients was still below the unit (RR 0.27, 99% CI 0.08–0.96), being the heterogeneity test significant (c2 = 4.68, P = 0.03), probably reinforcing the concept that GIK produces different outcomes in patients who do or do not undergo a reperfusion strategy. A 30% non-significant reduction in any severe heart failure was observed, which was more pronounced in reperfused patients, and a 56% borderline (P = 0.07) reduction in ventricular fibrillation was detected both in reperfused and non-reperfused patients (Figure 2).  Figure 2. Major in-hospital events stratifying the population into reperfused and non-reperfused patients. Note the statistically significant P-values (P = 0.03) for the heterogeneity test for death, reinforcing the concept that GIK might have more pronounced effects in patients submitted to a reperfusion strategy.[33] As a pilot trial, the ECLA trial was underpowered to assess clinical outcomes, so the efficacy analyses should be cautiously interpreted and used merely as exploratory data. Figure 3 shows the relative risk of in-hospital events in the overall population and in the subgroup of patients who received a reperfusion strategy. Notwithstanding the impressive magnitude of the effect observed in hard endpoints such as mortality, probably more important is the direction of the impact of GIK in different clinical outcomes. The benefit (towards a reduction) is evident in all variables that can be affected by a metabolic strategy (death, severe heart failure and severe arrhythmias), and more pronounced in the subgroup of patients treated with reperfusion therapies.  Figure 3. Relative risk of in-hospital events in the overall population (A) and in the subgroup of patients who received a reperfusion strategy (B). Note the consistent direction of the effect towards a benefit in those events potentially influenced by the GIK infusion, reaching a statistically significant P-value (P = 0.008) for death in the reperfused population. CABG, coronary artery bypass graft; PTCA, percutaneous transluminal coronary angioplasty; KC; killip classification VF, ventricular fibrillation.[33] How should the ECLA GIK Pilot Trial be interpreted? First, the pilot trial was part of a project developed to test a simple therapy that can modulate the metabolic derangement that occurs during the first hours of an AMI. The project is not finished and therefore we should not jump to hasty conclusions. Second, the pilot nature of the GIK trial should only be seen as a platform from which to carry out exploratory analyses of efficacy to formulate hypotheses. With this concept in mind, different conclusions can be reached: • the safety of a GIK infusion during the early hours of an AMI has been proved; • a high-dose infusion of GIK is applicable; • the beneficial trend in outcomes observed in our pilot trial is consistent with previously reported data and strongly supports the rationale for exploring GIK as an adjunctive strategy for the treatment of AMI; • the target population for a large-scale trial using this therapeutic approach should comprise reperfused AMI patients; however, we cannot abandon the possibility that GIK could have an impact in non-reperfused patients. Future directions A novel concept using old therapies has emerged during recent years. During most of the last decade, research was focused on the improvement of reaching and maintaining patent related arteries, aimed at modifying the current natural history of AMI. Myocardial damage after an acute ischemic insult is the final determinant of immediate and long-term prognosis. Looking beyond the occlusive/ thrombotic process and optimizing the energy transfer by manipulating the metabolic pathways soon after an AMI, would probably have a promising impact in limiting myocardial damage. The tremendous amount of basic research knowledge plus the promising results of limited clinical experience together comprise the rationale for a precise methodological endeavor to reliably answer a critical and relevant scientific question. The GIK 2 International Trial has already started and aims to determine the mortality impact of GIK in the current AMI scenario. This non-industrysupported challenge requires the mobilization of hundreds of cardiologist worldwide motivated by scientific curiosity. More than 1000 patients have been randomized to date. We believe this is the best way of testing this hypothesis in order to definitively establish the role of this simple, cheap and potentially life-saving therapy. REFERENCES |
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© 2010 Les Laboratoires Servier