In this study, additional treatment with GIK in patients treated with primary PCI for acute myocardial infarction showed no decrease in enzymatic infarct size and no difference in mean LVEF between GIK and control patients was observed. However, preservation of left ventricular function as determined by a LVEF ≤ 30% was more frequently seen in GIK treated patients. One explanation for the discrepancy between the effects on poor and mean left ventricular function is that the number of patients in our analysis was not sufficient to detect an effect on mean left ventricular ejection fraction. Mean LVEF was 1.3% higher in GIK patients, so and several patients may have been prevented from LVEF ≤ 30%.
Since these results are based on an intention-to-treat analysis in a randomized controlled trial of the effects of GIK, we may have underestimated the effect on preservation of myocardial function. In the control group more patients died, and these patients had a high enzyme release and probably a severely impaired LVEF as well. Nevertheless, our data make it unlikely that GIK has a clinically relevant impact of GIK on enzyme release, but at the same time show an important reduction in the number of patients with a LVEF ≤ 30%. A LVEF ≤ 30% exposes these patients to a high risk of developing heart failure during follow-up, even after successful PCI . We also found a relation between high enzyme release and poor left ventricular function. Possibly the relation between GIK and poor LVEF is related to a selection bias in this sub-analysis. On the other hand it can be hypothesized that GIK mediates effects on LVEF, as measured after 2 to 4 days after admission, that are unrelated to enzymatic infarct size.
In our previous study on the effect of GIK on 30-day mortality, we found a beneficial effect of GIK on outcome in patients who had no signs of heart-failure at admission. Patients with Killip class 1 did not have smaller enzymatic infarct sizes in this analysis. However, the CK-MB curve over the first 96 hours after admission in GIK patients lies below that in controls. Mean LVEF is higher in patients treated with GIK compared to control patients, albeit not significantly (P = 0.12). Even as in the overall population in patients with Killip class 1 treatment with GIK was related with a lower rate of LVEF ≤ 30%.
Previous clinical studies with GIK
Several studies have reported enzymatic infarct size in MI patients treated with GIK, mainly in patients without reperfusion therapy [12, 14]. Clinical studies in the era of reperfusion provided sparse information [1, 19]. In line with our results, the Pol-GIK trial showed that neither the median and maximal CK nor maximal glutamic-oxaloacetic transaminase differed significantly between GIK and control patients . However, the Pol-GIK trial used low-dose GIK and included patients with a lower risk, i.e. no patients with signs of heart failure were included. One study of 32 MI patients treated by thrombolysis found that infusion of GIK resulted in a shorter time to peak CK and a smaller total enzyme release . In line with our results on enzyme release, the REVIVAL trial found no effect of GIK treatment on the myocardial salvage index measured with technetium-99m sestamibi scintigraphy 6 to 8 hours after admission and after 7 to 14 days (0.50 versus 0.48, P = 0.96). In this trial, GIK consisted of 1000 ml 20% glucose with 40 IU of insulin and 64 mmol potassium chloride at a rate of 1.8 ml/hour for 24 hours. However, in the predefined subgroup of patients with diabetes mellitus, a significant difference in salvage index was found (mean difference 0.19, 95% confidence interval 0.01–0.37). In a trial of 37 patients treated with primary PCI, a beneficial effect of GIK on myocardial function was observed . The increase of the LVEF from baseline to 3 months was 12.5% in the GIK group (P = 0.002) versus 6.1% in the placebo group (NS). However, when GIK and placebo were compared directly, the difference between increments in LVEF was not significant. This may have been the result of a combination of small numbers of patients and profound changes in the LVEF during the 3–6 months after PCI for acute MI . In patients with diabetes mellitus and without myocardial ischemia, infusion of insulin and glucose increased the contractile force, i.e. rest LVEF and LVEF during dynamic exercise measured by radionuclide ventriculography . In 32 anterior MI patients, the left ventricular wall motion score index as measured by echocardiography at baseline was 1.87 and it decreased significantly during GIK infusion to 1.76 (P < 0.001) .
In January 2005, the 30-day results of the Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation-Estudios Cardiologicos Latinoamerica (CREATE-ECLA) trial (N = 20201) were published . Infusion of high-dose GIK had no beneficial effect on the overall population, with a mortality rate of 10.0% in the GIK group compared to 9.7% in the control group (P = 0.45). The lack of benefit was also observed in several large subgroups that may benefit in particular from GIK, such as patients treated within 4 hours after symptom onset (N = 8361). Only in patients treated by PCI (N = 1838) was a reduction of 30-day mortality observed, from 6.3% in control patients to 4.8% in GIK patients; but this was not significant. Therefore, in patients treated with a combination of GIK and reperfusion, as in our study, the role of metabolic modulation in mortality and myocardial function needs further investigation.
Several studies on animals have assessed the effects of GIK on infarct size in myocardial infarction, but show conflicting results [5, 9, 11]. A study of pigs showed that hearts treated with GIK had significantly less tissue acidosis, higher wall motion scores and less tissue necrosis . Similar results were obtained in a study of rats, in which the administration of GIK not only before induction of ischemia but also during acute ischemia seemed beneficial for myocardial function . A recent study of diabetic sheep found that GIK improved left ventricular contractility as determined by stroke work efficiency .
Mechanisms of action
We found a relationship between higher enzymatic infarct size and low LVEF. Since we observed an effect of GIK only on LVEF, the preservation of left ventricular function could not be declared a reduction of myocardial necrosis. The potential mechanisms by which GIK might be beneficial include metabolic effects, direct hemodynamic effects, improvement of coronary flow and catecholamine-mediated effects. The main effect of GIK infusion is supposed to be improved delivery of glucose to the ischemic myocardium resulting in a suppression of free fatty acids [28–31]. Treatment with glucose and insulin inhibits lipolysis, thereby decreasing circulating free fatty acid levels, and suppresses fatty acid oxidation. Moreover, in the postischemic myocardium, contractile dysfunction may also be caused by impairment of glucose oxidation and cytosolic proton accumulation, so agents that enhance glucose oxidation in the postischemic heart may also improve contractile function . After prolonged periods of low-flow ischemia, functional recovery is mainly determined by the extent of irreversible ischemic damage. After brief episodes of ischemic damage, oxidative metabolism rapidly returns, well before contractile activity is restored. Therefore GIK treatment is likely to be beneficial when started soon after the onset of ischemia. Protection of ischemic cardiac cell membranes may also improve reflow after reperfusion and protect against the no-reflow phenomenon by reducing cell swelling and microvascular compression . These microvascular protective effects on the coronary circulation are probably similar in patients with and without diabetes mellitus [34, 35]. GIK infusion improved regional myocardial perfusion and function in segments adjacent to the infarct area in patients recovering from an acute MI . Another beneficial mechanism may be the protective effect of GIK on the cell membrane [37–39]. Insulin promotes tolerance against ischemic cell death via the activation of innate cell-survival pathways in the heart . However, in a small study of patients with MI treated with PCI, administration of GIK did not improve the enzymatic antioxidant reserve .
Left ventricular function was measured in 88% of patients. For some patients transferred back to the referring hospitals within 48 hours the measurement was missing. The same goes for patients who died within 48 hours. Therefore the exact relation between LVEF and 30-day mortality cannot be determined. It is unknown whether these missing data have influenced the results. We determined the left ventricular function before discharge and it has been suggested that measurements after long-term follow-up are more predictive[18, 23].