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Ann Thorac Surg 2002;73:582-587
© 2002 The Society of Thoracic Surgeons

Original article: cardiovascular

Glucose-insulin-potassium solution improves left ventricular mechanics in diabetes

Tharumenthiran Ramanathan, MBBS*a, Kazuaki Shirota, MDa, Shin Morita, MDa, Takashi Nishimura, MD, PhDa, Yifei Huang, MD, PhDa, Stephen N. Hunyor, MDa

a Cardiac Technology Centre, Department of Cardiology, Royal North Shore Hospital, Sydney, Australia

Accepted for publication September 15, 2001.

* Address reprint requests to Dr Ramanathan, c/o Prof Stephen Hunyor, Cardiac Technology Centre, Block 4, Level 3, Royal North Shore Hospital, St. Leonards, Sydney, NSW 2065, Australia
e-mail: indranrama{at}yahoo.com


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. The mechanism by which glucose-insulin-potassium solutions enhance recovery of left ventricular function after myocardial ischemia in diabetic patients is not well understood. We evaluated the effect of glucose-insulin-potassium on ventriculoarterial coupling and left ventricular mechanics in a chronic ovine model of diabetes.

Methods. Diabetes was induced in 6 sheep with streptozotocin. After 6 months of diabetes, the response of the left ventricular pressure-volume relationship to 60 minutes of intravenous glucose-insulin-potassium solution (1,000 mL of 5% dextrose in water, 100 IU of regular insulin, 90 mmol of KCl at 1.5 mL · kg-1 · h-1) was determined.

Results. Glucose-insulin-potassium solution increased end-systolic elastance 68% (p = 0.01) and improved ventriculoarterial coupling (1.7 ± 0.3 to 1.0 ± 0.1; p < 0.01). Potential energy decreased 35% (p = 0.01), and pressure-volume area decreased 20% (p = 0.01). However, stroke work did not change; therefore stroke work efficiency increased from 50.1% ± 3.5% to 60.2% ± 5.1% (p = 0.01).

Conclusions. Glucose-insulin-potassium solution improves left ventricular contractility and ventriculoarterial coupling in diabetes. Left ventricular mechanics is improved by decreasing total mechanical work without significantly affecting stroke work, resulting in improved stroke work efficiency. Improved efficiency facilitates understanding of the enhanced tolerance to myocardial ischemia afforded by glucose-insulin-potassium solution.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Diabetes mellitus is a major independent predictor of significant morbidity and decreased survival after coronary artery bypass grafting [1]. Interventions that attenuate adverse outcomes in this high-risk group warrant investigation. Recently, there has been a resurgence of interest in glucose-insulin-potassium (GIK) therapy for the ischemic myocardium [2, 3], and there is now evidence that GIK may also have a favorable effect in diabetic patients with myocardial ischemia [4, 5]. The Diabetes Mellitus, Insulin, Glucose Infusion in Acute Myocardial Infarction (DIGAMI) Study [4] demonstrated that insulin-glucose infusion initiated early in the course of myocardial infarction, followed by a multidose insulin regimen, reduced mortality at 1 year 29% compared with conventional therapy. Similarly, in diabetic patients undergoing elective, urgent and emergency coronary artery bypass grafting, Lazar and colleagues [5] showed that GIK therapy commenced at the induction of anesthesia improved myocardial performance and enhanced postoperative recovery.

The mechanism by which GIK enhances recovery of left ventricular (LV) function in diabetic patients after myocardial ischemia is not well understood. Sasso and associates [6] demonstrated that insulin-glucose infusion improves LV ejection fraction in diabetic patients and suggested that this is the result of enhanced ventricular contractility. In addition, experimental and clinical studies have demonstrated improved recovery of LV function when GIK was initiated early or before ischemia [5, 7]. We hypothesized that the benefit of GIK in the diabetic heart may be derived, in part, from its favorable effect on ventricular mechanics and in particular on stroke work efficiency. Inasmuch as the effect of GIK on LV mechanoenergetics in diabetes has not been investigated, we evaluated the impact of GIK on LV contractility, ventriculoarterial coupling, and stroke work efficiency using the time-varying elastance concept [8].


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Six Merino-cross sheep (48 ± 6 kg) were used in this study. Each animal served as its own control. The investigation was approved by the Royal North Shore Hospital Animal Care and Ethics Committee and complied with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (National Institutes of Health publication 85-23, revised 1985).

Induction of diabetes mellitus
Diabetes mellitus was induced with two intravenous doses of streptozotocin (60 mg/kg) administered 5 to 7 days apart [9]. Blood glucose levels were monitored between 8:00 AM and 9:00 AM using a calibrated standard glucometer (Precision Plus, MediSense Inc, Bedford, MA). All 6 animals were determined to be diabetic when the nonfasted blood glucose level consistently exceeded 180 mg/dL. The average baseline blood glucose level was 64.3 ± 2.7 mg/dL and reached 200.9 ± 20.7 mg/dL after the second dose of streptozotocin. The peak insulin level after a 25-g intravenous glucose load was 40.9 ± 25.4 µIU/mL at base line and less than 2.0 µIU/mL when diabetes was established. Hyperglycemia was confirmed weekly in all 6 sheep (207.0 ± 24.0 mg/dL), and untreated diabetes was maintained for 6 months.

Glucose-insulin-potassium dosage
The dose-response studies of Rogers and coworkers [10] demonstrated that a solution of 30% glucose, 50 IU of insulin, and 80 mmol/L potassium administered at a rate of 1.5 mL · kg-1 · h-1 achieved maximal suppression of myocardial free fatty acid uptake rates, as well as maximal increases in myocardial glucose uptake. High-dose GIK solutions (ie, the Rackley regimen) have demonstrated superiority over lower dose solutions [2, 3]. Lazar and colleagues [5] successfully modified the Rackley regimen for diabetic patients undergoing coronary artery bypass grafting (500 mL of 5% dextrose in water with 80 IU of regular insulin and 40 mmol of KCl infused at 30 mL/h). Therefore, we evaluated a modified high-dose GIK regimen: 1,000 mL of 5% dextrose in water with 100 IU of regular insulin and 90 mmol of KCl infused at 1.5 mL · kg-1 · h-1.

Experimental protocol
Six months after induction of diabetes, hemodynamic assessment was undertaken. After baseline measurements, GIK was infused at 1.5 mL · kg-1 · h-1 for 60 minutes, and hemodynamic assessment was repeated.

Hemodynamic assessment
Anesthesia was induced with sodium thiopentone (20 mg/kg) after which the sheep were intubated and mechanically ventilated (Bird model 8, Bird Australia Pty Ltd, Chatswood, NSW, Australia) with 2 L/min of oxygen, 2 L/min of nitrous oxide, and isoflurane 1.4% to 1.8% inspired. Maintenance fluid consisting of Hartmann’s solution was administered through peripheral venous access. The carotid artery and jugular vein were isolated through a transverse incision in the left neck. The jugular vein was cannulated with a 6F Swan-Ganz catheter (Baxter International Inc, Irvine, CA) and an inferior vena cava occlusion catheter (Fogarty 22F, Baxter International Inc). A 5F micromanometer-tipped catheter (Millar Instruments, Houston, TX) and a 6F 12-electrode conductance catheter (Cardiodynamics, Rijinsberg, The Netherlands) were passed from the carotid artery and positioned longitudinally in the LV cavity (confirmed on fluoroscopy and by the volume conductance signals) and used to measure LV pressure and volume [11]. The conductance catheter was connected to a Sigma 5 dual-field signal conditioner-processor (Cardiodynamics). Parallel conductance was obtained from a pulmonary artery injection of hypertonic saline followed by measurement of blood resistivity [12]. Electrocardiogram and LV pressure and volume were displayed and digitized at 200 Hz on a personal computer during steady-state conditions and during transient inferior vena cava occlusion. Ventilation was held at end-expiration during measurements. Data were stored on hard disk and analyzed off-line with custom-designed software [13].

Data analysis
Hemodynamic measurements during steady-state conditions were calculated as the average of 6 to 7 beats. Left ventricular pressure and volume at end-systole and end-diastole, stroke volume, and stroke work were calculated from these data. The end-systolic pressure-volume relationship was assessed from data obtained during transient caval occlusion using an iterative algorithm. Least squares linear regression of the end-systolic pressure-volume points was performed, generating the equation: End-systolic pressure = Ees x (end-systolic volume - V0). The slope of this relationship, end-systolic elastance (Ees), is a load-independent index of LV contractility, and V0 represents the volume-axis intercept of the end-systolic pressure-volume relationship. Ventricular mechanoenergetics were evaluated according to Suga’s method [8] (Fig 1). This approach defines total mechanical energy generated by an ejecting contraction as equivalent to systolic pressure-volume area (PVA), which is the area between the end-systolic pressure-volume relationship, the end-diastolic pressure-volume relationship, and the systolic portion of the pressure-volume loop. Pressure-volume area incorporates both stroke work (SW) and potential energy and is directly related to LV myocardial oxygen consumption. Stroke work represents the energy transferred from the left ventricle to the arterial system and is defined by the area within the pressure-volume loop. Potential energy is the portion of PVA that lies outside the pressure-volume loop and reflects energy used to overcome the inertial properties of the myocardium. Potential energy does not contribute to ejection against arterial pressure and is presumably dissipated as heat during diastole. Stroke work was calculated as SW = [(EDV - ESV) x (ESP - EDP)] and PVA was calculated as PVA = {SW + [0.5 x ESP x (ESV - V0)] - 0.75 x [0.5 x EDP x (EDV - V0)]} where EDV is end-diastolic volume, ESV is end-systolic volume, ESP is end-systolic pressure, and EDP is end-diastolic pressure. The efficiency of energy transfer from the left ventricle to the arterial system (stroke work efficiency) represents the proportion of SW extracted from total mechanical energy generated during contraction and is calculated as the ratio of SW to PVA. Matching between the left ventricle and the arterial system was derived according to the ventriculoarterial coupling framework of Sunagawa and colleagues [14]. Properties of the arterial system (effective arterial elastance, Ea) are represented by the slope of the end-systolic pressure-stroke volume relation whereas LV mechanical properties (Ees) are described by the slope of the end-systolic pressure-volume relationship.



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  		Fig 1. Schematic diagram of the time-varying elastance model. Pressure-volume area = SW + PE. (EDPVR = end-diastolic pressure-volume relation; ESPVR = end-systolic pressure-volume relation; PE = potential energy; LV = left ventricular; SW = stroke work.)

 
Statistical analysis
Data are presented as mean ± standard deviation. Results at baseline and after GIK were compared with paired Student’s t test or the Wilcoxon signed rank test as appropriate. Statistical significance was set at p less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
The hemodynamic effects of GIK are summarized in Table 1. Heart rate, LV pressure, and volume at end-diastole and end-systole did not change significantly. Infusion of GIK did not alter serum potassium level (4.4 ± 0.5 mmol/L baseline versus 4.2 ± 0.2 mmol/L GIK; p = 0.32) or blood glucose level (201 ± 34 mg/dL baseline versus 225 ± 46 mg/dL GIK; p = 0.17).


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  		Table 1. Changes in Hemodynamic Variables After Glucose-Insulin-Potassium Solution

 
Left ventricular contractility and ventriculoarterial coupling
Representative LV pressure-volume loops obtained by transient inferior vena caval occlusion are shown in Figure 2. Infusion of GIK increased the slope (Ees) of the end-systolic pressure-volume relationship by 68% ± 47% (p = 0.01) and V0 increased from -23.9 ± 12.2 mL to 1.0 ± 9.3 mL (p = 0.0004). Effective arterial elastance (Ea) did not change significantly. As a result, the ratio Ea/Ees decreased (p = 0.002).



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  		Fig 2. Representative pressure-volume loops at baseline (A) and after 60 minutes glucose-insulin-potassium infusion (B). Stroke volume is the difference in left ventricular (LV) volume at end-diastole (solid arrow) and end-systole (open arrow). The end-systolic pressure-volume relation connects end-systolic points in multiple loops. The slope of the end-systolic pressure-volume relationship (end-systolic elastance) is a load-independent index of contractility, with a steeper slope reflecting increased contractility.

 
Stroke work, potential energy, pressure-volume area, and stroke work efficiency
Figure 3 shows the acute changes in LV mechanics after 60 minutes of GIK infusion. Pressure-volume area decreased by 20% ± 12% (6,747 ± 1,193 mm Hg · mL at baseline versus 5,290 ± 473 mm Hg · mL with GIK; p = 0.02) without affecting SW (3,364 ± 508 mm Hg · mL at baseline versus 3,175 ± 333 mm Hg · mL with GIK; p = 0.37). Consequently, potential energy decreased from 3,383 ± 748 mm Hg · mL to 2,115 ± 387 mm Hg · mL (p = 0.01), and stroke work efficiency (SW/PVA) improved 21% ± 14%.



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  		Fig 3. Effect of 60 minutes of glucose-insulin-potassium (GIK) infusion on left ventricular mechanoenergetics. *p < 0.05. (B = baseline; PVA = pressure-volume area; SW = stroke work; SW/PVA = stroke work efficiency.)

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
The effect of GIK on ventricular mechanoenergetics in the diabetic heart has not been previously investigated. In this study, we examined the acute effects of GIK on LV contractility, ventriculoarterial coupling, and LV mechanics in a chronic ovine model of diabetes. There were two novel findings: (1) GIK improves LV contractility as well as the optimality of coupling between the left ventricle and the arterial system, and (2) cardiac contraction after GIK infusion wastes less energy yet maintains SW; as a result total mechanical work is reduced and stroke work efficiency is improved.

Previous studies have assessed the effect of insulin-glucose infusions on the diabetic heart using traditional, relatively load-dependent measures of LV systolic function. Infusion of GIK improved cardiac indices of diabetic patients after coronary artery bypass grafting [5], and insulin-glucose infusion increased the LV ejection fraction of diabetic patients at rest and during exercise [6]. Experimental studies in acutely diabetic lambs have demonstrated insulin improves the maximum rate of rise of LV systolic pressure [15]. These studies suggest that GIK may enhance LV contractility; however, the influence of loading conditions cannot be definitively excluded. In the present study, we have demonstrated that GIK improves contractility of the diabetic ventricle based on the load-independent index of contractility, Ees. The mechanism underlying GIK-mediated increases in LV contractility has not been clearly defined. We hypothesize that GIK improves contractility of the diabetic ventricle through modulation of myocardial metabolism. The diabetic myocardium resembles the postischemic myocardium, in that both fail to oxidize glucose adequately and have disproportionately high rates of fatty acid oxidation [16, 17], which corresponds to impaired myocardial performance [18]. Intravenous GIK reverses these defects by stimulating glucose uptake for glycolytic energy production and decreasing myocardial free fatty acid uptake [19]. Enhanced production of adenosine triphosphate by glycolysis may improve contractile function by increasing sarcoplasmic reticular Ca2+ adenosine triphosphatase activity. Conversely, it has been suggested that insulin may be internalized by the myocyte and act much like a catecholamine, augmenting contractile function through direct stimulation of sarcoplasmic reticular Ca2+ adenosine triphosphatase [20]. However, Zhu and associates [21] demonstrated that although GIK improved postischemic LV function, there was no discernible effect on either systolic or diastolic function in the normal porcine heart. They concluded that improvement in postischemic LV function with GIK cannot be attributed to a direct inotropic effect of insulin and may be related to the provision of additional substrate for glycolytic energy production.

Improved LV contractility has important implications for ventriculoarterial coupling, which describes the mechanical relationship between the left ventricle and the arterial system. Ventriculoarterial coupling may be evaluated in the pressure-volume plane using a series elastic chamber model of the cardiovascular system [14]. The ratio of the elastances of the arterial system (Ea) and the left ventricle (Ees) defines coupling between these compartments. Maximum SW occurs when ventricular contractility and Ea are matched (Ea/Ees = 1). Stroke work efficiency is described by the relationship SW/PVA = 1 / [1 + 0.5 (Ea/Ees)] and therefore varies inversely with Ea/Ees [22]. We have demonstrated that GIK decreases the Ea/Ees ratio, indicating improved mechanical coupling between the left ventricle and the arterial system. In agreement with some authors [6, 23], but in contrast with others [24], we found that GIK did not significantly reduce LV end-systolic pressure. Thus, Ea was largely preserved and the GIK-induced decrease in Ea/Ees resulted primarily from increases in LV contractility.

The effect of GIK on the efficiency of energy transfer from the left ventricle to the arterial system was quantified using the ratio of SW to PVA. Suga [8] demonstrated that PVA represents the total mechanical work performed by the left ventricle and is the sum of SW (the energy transferred to the arterial system) and potential energy (energy that is presumably dissipated as heat during the cardiac cycle). In this study, using a chronic ovine model of diabetes, we have shown that GIK improves LV mechanoenergetics. Ventriculoarterial coupling is improved by enhancing LV output impedence (Ees) without increasing arterial input impedence (Ea). The improvement in mechanical coupling between the left ventricle and the arterial system led to a significant decrease in potential energy and therefore in PVA. Stroke work was maintained, and as a result a larger proportion of total mechanical work was transferred to the arterial system, resulting in improved stroke work efficiency. Therefore, after GIK infusion the diabetic ventricle can generate the same SW while performing significantly less total mechanical work. Similarly the inotropic vasodilator, OPC-18790, has been demonstrated to increase energy efficiency in congestive heart failure by improving ventriculoarterial coupling [25]. Although vasodilators also improve stroke work efficiency, by decreasing arterial input impedence without improving contractility, this is achieved at the expense of decreased arterial pressure [22]. Enhanced stroke work efficiency may represent an important mechanism whereby GIK improves LV function in diabetic patients and facilitates understanding of the improved tolerance to ischemia afforded by GIK therapy. During ischemia the total mechanical work generated by the left ventricle is reduced, and the GIK-mediated improved stroke work efficiency enables enhanced preservation of SW despite a reduction in overall LV work.

Importantly, GIK may further improve energy efficiency in the diabetic heart by inducing a shift in energy substrate metabolism from free fatty acid to glucose oxidation. Insulin stimulates glucose uptake, glycolysis, and glucose oxidation. Enhanced production of acetyl-coenzyme A from glucose inhibits fatty acid oxidation. This shift in myocardial substrate utilization may be advantageous because less oxygen is required to produce the same amount of adenosine triphosphate when glucose is oxidized [26]. Endothelial dysfunction of the coronary circulation in diabetic patients reduces the vasodilatory capacity of the vascular bed. Insulin improves endothelial function by upregulation of the nitric oxide pathway, resulting in vasodilation and decreased resistance [27]. This may facilitate the improvement in LV function demonstrated in the present study.

The present results require interpretation within the constraints of several potential limitations. We used a chronic ovine model of type I diabetes whose applicability to diabetic patients with coronary artery disease is unknown. Ischemia in the diabetic heart exacerbates the derangements in myocardial metabolism, causing even greater inhibition of glucose oxidation and acceleration of fatty acid oxidation. Although GIK may reverse the metabolic changes in the ischemic-diabetic heart, whether this leads to an improvement in LV contractility is unknown. We have demonstrated GIK improves contractility based on the load-independent index, Ees. Although changes in preload or afterload do not affect Ees, alterations in level of consciousness or degree of sympathetic activity may do so. In the present study, measurements were taken under light anesthesia and at a stable heart rate to minimize these effects. The GIK-mediated improved stroke work efficiency in the diabetic left ventricle may not reflect a similar change in mechanical efficiency. Mechanical efficiency is the ratio of SW to myocardial oxygen consumption and is the product of stroke work efficiency and the ratio of PVA to myocardial oxygen consumption. Improved LV contractility is traditionally associated with increased oxygen cost and a decrease in the ratio of PVA to myocardial oxygen consumption. Therefore the effect of GIK on mechanical efficiency will depend on the relative changes on stroke work efficiency and the PVA to myocardial oxygen consumption ratio. In this study myocardial oxygen consumption was not directly measured, and the efficiency of energy transfer from myocardial oxygen consumption to mechanical energy (PVA) needs to be established to further evaluate the effect of GIK in the diabetic heart.

In conclusion, we have demonstrated that GIK infusion in the chronically diabetic myocardium improves LV contractility and ventriculoarterial coupling. This enhances the efficiency of energy transfer from the left ventricle to the arterial system. The present investigation indicates that GIK improves LV mechanoenergetics and provides a rationale for the use of GIK initiated before coronary artery bypass grafting or early in the time course of acute myocardial infarction in diabetic patients.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
This study was supported by funding provided by the North Shore Heart Research Foundation. Doctor Ramanathan is a Sir Roy McCaughey Surgical Research Fellow of the Royal Australasian College of Surgeons. We are grateful for the technical assistance of Dr Xing Zheng, Mr Ray Kearns, Mr Gabrial Gomes, Mr Peter Darge, Mr Chi-Ming Lee, and Ms Janelle Wright. In addition we would like to thank Professor John Fletcher, Dr Errol Wilmshurst, and Dr Greg Fulcher for their support.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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