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European Journal of Heart Failure 2002 4(2):181-184; doi:10.1016/S1388-9842(01)00222-7
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© 2002 European Society of Cardiology

Glucose insulin potassium infusion improves systolic function in patients with chronic ischemic cardiomyopathy

Yves Cottina,*, Isabelle Lhuilliera, Laurent Gilsonb, Marianne Zellerc, Caroline Bonneta, Christine Toulouseb, Pierre Louisa, Luc Rochettec, Claude Girardb and Jean-Eric Wolfa

a Cardiology Department University Hospital, Dijon, France
b Anesthesiology Department University Hospital, Dijon, France
c LPPCE, Faculty of Medicine University of Burgundy, Dijon, France

* Corresponding author. Service de Cardiologie, Hôpital du Bocage, Bd de lattre de Tassigny, 21034 Dijon, Cedex, France. Tel.: +33-3-80293311; fax: +33-3-80293333. E-mail address: yves.cottin{at}chu-dijon.fr


   Abstract
Top
 Abstract
1. Background
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: We assessed the effects of glucose–insulin–potassium (GIK) by echocardiography in stable patients with ischemic dysfunction.

Methods: Twelve male patients with stable coronary disease (SCD) and ejection fraction (EF) <45% were studied for systolic function. GIK (glucose 30%, 300 insulin units and KCl 6 g/l) was infused at 1 ml/kg per h over 20 min. Hemodynamic and echocardiographic measurements were recorded at rest (T0), at the end (20 min) of GIK infusion (T + 20), 20 and 40 min after the end of the infusion (T + 40 and T + 60).

Results: At T + 20, a significant decrease in WMSI (wall motion score index) was observed compared with T0 (2.16±0.14 vs. 2.30±0.16: P<0.05). An increase in EF was reported at T + 40 and T + 60 compared with T0 (44.1±7.8% and 53.3±11.6% vs. 35.6±4.5%, respectively: P<0.01). A decrease in WMSI was observed at T + 40 and T + 60 compared with rest (2.02±0.17 and 1.93±0.11 vs. 2.30±0.16, respectively: P<0.01).

Conclusion: Our present work suggests that GIK infusion improves systolic function in patients with SCD and ejection fraction <45%. Further studies are needed to determine if short-term GIK infusion could be useful for therapeutic or diagnostic strategies in these patients.

Key Words: Glucose–insulin–potassium • Echocardiography • Left ventricular function

Received January 10, 2001; Revised May 8, 2001; Accepted August 14, 2001


   1. Background
Top
 Abstract
 1. Background
2. Methods
 3. Results
 4. Discussion
 References
 
Glucose uptake and glycolytic ATP production, are important determinants of viability, especially when the heart is compromised by reduced flow [1,2]. Beneficial effects of glucose–insulin–potassium (GIK) infusion have been demonstrated in patients in the acute phase of myocardial infarction and during cardiac surgery. However, no data are available in patients with stable and severe left ventricular ischemic dysfunction. This study was designed to assess the effects of GIK infusion on systolic and diastolic left ventricular parameters measured by echocardiography in stable patients with severe left ventricular (LV) ischemic dysfunction.


   2. Methods
Top
 Abstract
 1. Background
 2. Methods
3. Results
 4. Discussion
 References
 
Our study group consisted of 12 men aged from 36 to 78 years (mean: age: 58±12 years). All patients presented a severe left LV dysfunction with an ejection fraction (EF) <45% and an average NYHA class of 2.33±0.49. They had an history of myocardial infarction (>6 months) and three vessel disease authenticated by coronary angiography. None of the patients had left main stenosis, valvular heart disease or diabetes mellitus. All patients were in normal sinus rhythm and any cardiac medications were maintained.

After baseline recordings were obtained, GIK solution was given as glucose 30% with 300 insulin units and 6 g of potassium chloride per liter at an infusion rate of 1 ml/kg per h over 20 min.

Blood glucose concentrations, heart rate, systolic and diastolic blood pressure were determined every 20 min during the first 2 h, and every hour during the next 4 h.

Five echocardiography studies were performed on each patient. The first was obtained at rest (T–20), the second before initiation of therapy after 20 min of rest (T0), then after completion of the GIK infusion: 20 min (T+20) and 20 and 40 min after the end of the infusion (T+40 and T+60).

Echocardiography was performed with a Sonos 2500 echocardiographic system (Hewlett-Packard, Andover, MA, USA). The left ventricle volumes were calculated according to the M-mode formula of Teichholz et al., and from that, the ejection fraction (EF) was calculated [3]. The left ventricular shortening fraction (SF) was computed.

Each segment was visually graded using a semiquantitative scoring system, where 1=normal; 2=hypokinetic; 3=akinetic; and 4=dyskinetic. A regional Wall motion score index (WMSI) was defined as the sum of each segment score divided by the number of interpreted segments [4]. Interobserver variability in our laboratory attained 95% concordance for the scoring of 1600 segments and 92% concordance for identifying the presence of contractile reserve of 203 dysfunctional segments, respectively. Intraobserver variability for the scoring was concordant for 95% segments and 95% for the presence of contractile reserve. A 20% reduction in WMSI represents the 95% confidence interval, discriminating a significant difference between normal and abnormal contractile response to low dose dobutamine by two-dimensional echocardiography in our laboratory.

The peak velocity of early rapid filling (E wave) and the peak velocity of atrial filling (A wave) were recorded, and the E to A ratio (E/A) was calculated. The deceleration time (DT) and the LV isovolumic relaxation time (IVRT) were determined. Informed consent was obtained from patients before any procedures were undertaken. The investigation conformed with the principles outlined in the Declaration of Helsinki.

Data were expressed as mean±standard deviation (S.D.). Statistical analysis of dependence vs. time was performed by one-way ANOVA analysis for repeated measurements; when statistical significance was observed, a post-hoc Tukey test was carried out. Statistical significance was considered acceptable for P<0.05.


   3. Results
Top
 Abstract
 1. Background
 2. Methods
 3. Results
4. Discussion
 References
 
The patients were in a stable condition as confirmed by the absence of modification of hemodynamic or echocardiographic parameters between the two studies at rest (T–20 and T0). During GIK perfusion and follow-up period, no serious adverse symptoms were observed in echocardiography, and in particular, no arrhythmia or severe hypotension. No significant hemodynamic changes were observed during GIK infusion or during the follow-up period (Table 1).


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  		Table 1 Hemodynamic parameters and blood sugar at rest, after 20 min of GIK-infusion and 40 min and 60 min after the end of the infusion (values are mean±S.D.)

 
No changes were demonstrated for all diastolic parameters during GIK infusion and follow-up (Table 2). Despite the absence of changes in heart rate or blood pressure, during GIK-infusion a significant improvement in WMSI was observed at T+20 vs. T0 (2.16±0.14 vs. 2.30±0.16: P<0.05) (Fig. 1). In contrast, no significant modification of EF and SF was recorded at the end of the infusion (Table 2). While no modification was noted during GIK infusion, an EF increase after infusion was demonstrated at T+60 and T+40 compared with T0 (44.1±7.8% and 53.3±11.6% vs. 35.6±4.5%, respectively: P<0.01). In addition, an improvement of the WMSI was observed at T+40 and T+60 compared with T0 (2.02±0.17 and 1.93±0.11 vs. 2.30±0.16, respectively: P<0.01). No modification of diastolic parameters was associated with systolic change at any time.


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  		Table 2 Echocardiography parameters at rest, after 20 min of GIK-infusion and 40 min and 60 min after the end of the infusion (values are mean±S.D.)

 


Figure 1
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  		Fig. 1 WMSI evolution at rest, during GIK infusion and follow-up. (*P<0.05 vs. T0, $P<0.01 vs. T0). The dotted line represents a 20% reduction in WMSI calculated from T0 values.

 

   4. Discussion
Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
References
 
The major findings of this study are that short-term GIK infusion: (1) was well tolerated and resulted in no serious adverse reactions in the patients; (2) improved the ejection fraction and wall motion score index.

4.1. GIK and post-ischemia
Several studies have demonstrated the therapeutic benefit of GIK on the post-ischemic heart [5,6]. GIK solution was initially advocated for the treatment of acute myocardial infarction (AMI) as a polarizing agent to promote electrical stability and later as an agent to provide metabolic support. Recently, an important meta-analysis of all GIK trials in AMI showed a mortality reduction of 28% [7]. Moreover, Rogers et al. suggested that GIK infusion at the acute phase of myocardial infarction induces a decrease in free fatty acids, the predominant myocardial energy substrate. This effect was associated with a protective effect on ischemic myocardium, probably by preventing the accumulation of long chain acyl CoA by improving free fatty acid metabolism [8]. During cardiopulmonary bypass, the beneficial effects of GIK on the cardiac index are also established, especially in patients with poor ventricular function [9,10].

4.2. GIK and chronic ischemia
Eberli and coworkers have previously demonstrated an increase in blood flow and a decrease in coronary resistance in ischemic hearts treated with GIK [11]. Moreover, the effects of GIK on myocardial performance have been demonstrated in dogs, without a decrease in systemic vascular resistance [12,13]. In patients, a recent study suggests a direct stimulatory effect of insulin on endothelial production of NO without hemodynamic changes [14].

4.3. Contractile reserve
LV dysfunction is generally studied by pharmacological inotropic stimulation using echocardiography or MRI [15]. In our study, a short-term infusion of GIK has been used, and the maximal effects appeared 40 min after the complete infusion. These findings suggest a metabolic effect of the GIK on the chronic ischemic myocardium. However, improvement in LV function was delayed compared with the changes after dobutamine infusion, and without tachycardia and/or increase in blood pressure.

Recent experimental studies report that insulin given alone improves contractile function during moderate ischemia without increasing O2 consumption [16]. This result reflects an apparent increase in O2 efficiency [17]. Insulin stimulates myocardial glucose metabolism and inhibits fatty acid metabolism [2]. Evidence also suggests that insulin-stimulated glycolytic flux would enhance SR Ca2+ ATPase activity, increase uptake of Ca2+ by the SR; Improving contractile function also suggests that insulin can be internalized by myocardial cells and activates the SR Ca2+ ATPase by binding to SR membranes [18,19]. It is also important to point out that GIK increases arachidonic acid formation, thereby stimulating prostacyclin, a known potent coronary vasodilatator [20].

4.4. Limitations of the study
The study cohort represents a small group of patients. However, the absence of modifications of hemodynamic and echocardiographic parameters at rest confirmed the stable state before GIK infusion. In contrast, a 20% reduction in WMSI was observed only at T+40 and T+60 and confirmed the presence of significant changes without influence of loading conditions over time.

In conclusion, our preliminary observations suggest that GIK results in improved LV systolic function in patients with chronic ischemic cardiomyopathy. Further studies are needed to determine if short-term GIK infusion could be useful for therapeutic or diagnostic strategies in patients with chronic ischemic coronary diseases.


   References
Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. King L.M., Opie L.H. Glucose delivery is a major determinant of glucose utilisation in the ischemic myocardium with a residual coronary flow. Cardiovasc Res (1998) 39:381–392.[Abstract/Free Full Text]
  2. Opie L.H., Owen P. Effect of glucose-insulin-potassium infusions on arteriovenous differences of glucose and of free fatty acids and on tissue metabolic changes in dogs with developing infarction. Am J Cardiol (1976) 38:310–321.[CrossRef][Web of Science][Medline]
  3. Teichholz L.E., Kreulen T., Herman M.V., Gorlin R. Problems in echocardiographic volume determinations: Echocardiographic-angiographic correlations in the presence or absence of asynergy. Am J Cardiol (1976) 37:7–11.[CrossRef][Web of Science][Medline]
  4. Schiller N.B., Shah P.M., Crawford M., et al. Recommendations for quantification of the left ventricle by two-dimensional echocardiography. J Am Soc Echo (1989) 2:358–367.[Medline]
  5. Depré C., Vanoverschelde J.L., Taegtmeyer H. Glucose for the heart. Circulation (1999) 99:578–588.[Free Full Text]
  6. Malmberg K., Ryden L., Efendic S., et al. Randomized trial of insulin-glucose infusion-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol (1995) 26:57–65.[Abstract]
  7. Fath-Ordoubadi F., Beatt K.J. Glucose-insulin-potassium therapy for treatment of acute infarction: an overview of randomized placebo-controlled trials. Circulation (1997) 96:1152–1156.[Abstract/Free Full Text]
  8. Rogers W.J., Stanley A.W., Breinig J.B., et al. Reduction of hospital mortality rate of acute myocardial infarction with glucose-insulin-potassium infusion. Am Heart J (1976) 92:441–454.[CrossRef][Web of Science][Medline]
  9. Girard C., Quentin P., Bouvier H., et al. Glucose and insulin supply before cardiopulmonary bypass in cardiac surgery: a double-blind study. Ann Thorac Surg (1992) 54:259–263.[Abstract]
  10. Lazar H., Philippides G., Fitzgerald C., et al. Glucose–insulin–potassium solutions enhance recovery after urgent coronary artery bypass grafting. J Thorac Cardiovasc Surg (1997) 113:354–362.[Abstract/Free Full Text]
  11. Eberli F.R., Weinberg E.O., Grice W.N., Horowitz G.L., Apstein C.S. Protective effect of increased glycolytic substrate against systolic and diastolic dysfunction and increased coronary resistance from prolonged global underperfusion and reperfusion in isolated rabbit hearts perfused with erythrocyte suspensions. Circ Res (1991) 68:466–481.[Abstract/Free Full Text]
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