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Cardiovascular Research 2002 55(4):749-756; doi:10.1016/S0008-6363(02)00497-2
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Copyright © 2002, European Society of Cardiology

Left ventricular oxygen utilization efficiency is impaired in chronic streptozotocin-diabetic sheep

Tharumenthiran Ramanathan*, Kazuaki Shirota1, Shin Morita, Takashi Nishimura2, Yifei Huang, Xing Zheng and Stephen Hunyor

Cardiac Technology Centre, Department of Cardiology, Block 4, Level 3, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia

indranrama{at}yahoo.com

* Corresponding author. Tel.: +61-2-9926-8679; fax: +61-2-9901-4097

Received 16 January 2002; accepted 21 May 2002


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: Energy metabolism is altered in the diabetic heart. However, direct in vivo evidence that diabetes impairs energetics at the chamber level is lacking. Therefore, we investigated the effect of diabetes on left ventricular (LV) energetics in a chronic ovine model. Methods: Diabetes was induced in Merino-cross sheep with streptozotocin. Experiments were performed in five animals following 12 months untreated diabetes and six animals served as controls. Open-chest anesthetized sheep were instrumented to determine the LV pressure–volume relationship, oxygen consumption and free fatty acid uptake. Results: Diabetes impaired LV contractility (1.5±0.5 vs. 2.3±0.5 mmHg/ml, P<0.01). Stroke work was preserved but stroke work efficiency (stroke work/pressure–volume area) deteriorated (52±4 vs. 58±3%, P<0.01). Plasma free fatty acid levels increased (1885±1078 vs. 354±203 mmol/l, P<0.01) as did LV free fatty acid uptake (312±278 vs. 90±47 µmol/beat per 100 g LV, P = 0.04). Contractile efficiency decreased (31.9±1.4 vs. 50.0±8.7%, P<0.01) while unloaded oxygen consumption did not change significantly. Therefore, LV oxygen utilization efficiency (stroke work/LV oxygen consumption) was compromised in the diabetic heart (14.9±2.8 vs. 24.3±4.0%, P<0.001). Conclusion: This is the first study to demonstrate that diabetes alters ventricular energetics in vivo. LV oxygen utilization efficiency is impaired as a consequence of decreased contractile efficiency and stroke work efficiency. Impaired efficiency of oxygen utilization may explain in part the increased sensitivity of the diabetic heart to ischemia and the accelerated deterioration of ventricular function in diabetic patients.

KEYWORDS Diabetes; Energy metabolism; Hemodynamics; Oxygen consumption; Ventricular function


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The increased sensitivity of the diabetic heart to ischemia is well described both clinically [1,2] and experimentally [3,4]. However, the underlying mechanisms are not fully elucidated. Under normal physiological conditions myocardial oxygen supply is balanced with oxygen demand. Pathological conditions that decrease myocardial oxygen supply may impair myocardial function or if severe, lead to irreversible tissue damage. Oxygen utilization efficiency critically influences the tolerance of the heart to reduced oxygen supply. Previous studies have demonstrated impaired energy metabolism [5,6] and contractile protein function in the diabetic heart [7]. These investigations suggest that chemomechanical conversion efficiency and therefore oxygen utilization efficiency may be affected by diabetes. However, the potential influence of diabetes on ventricular energetics and oxygen utilization efficiency has not been determined in vivo. To address this issue, the left ventricular pressure–volume relationship and oxygen consumption were simultaneously determined in a chronic ovine model of diabetes. The linear LVVO2–PVA relationship based on the time-varying elastance model of the ventricle is a fully established and widely applied framework to investigate ventricular energetics [8]. The reciprocal of the slope represents the efficiency of chemomechanical conversion by the myocardium (contractile efficiency) and the LVVO2 intercept (unloaded VO2) establishes the energy requirement for basal metabolism and excitation-contraction coupling. We present the first study to investigate the effect of chronic diabetes on LV energy transfer in terms of whole ventricular mechanics coupled with energetics.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
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 US National Institutes of Health (NIH publication 85-23, revised 1996).

2.1 Induction of diabetes mellitus
Diabetes mellitus was induced in 1- to 2-year old Merino-cross sheep with two intravenous doses of streptozotocin (60 mg/kg) administered 5–7 days apart. This induction protocol was adapted from the method used in the pregnant ewe [9] and the resulting diabetic metabolic state has been well characterized in sheep [10]. Blood glucose levels were monitored between 8:00 and 9:00 am using a calibrated standard glucometer (Precision Plus, MediSense, Bedford, MA). Sheep were determined to be diabetic when the non-fasted blood glucose level consistently exceeded 180 mg/dl. The average baseline blood glucose level was 49.7±5.2 mg/dl and reached 207.1±68.7 mg/dl after the second dose of streptozotocin. The peak insulin level following a 25-g intravenous glucose load was 40.6±12.0 µIU/ml at baseline and less than 2.0 µIU/ml when diabetes was established. Hyperglycemia was confirmed weekly (198.8±36.6 mg/dl) and untreated diabetes was maintained for 12 months.

2.2 Surgical preparation
Anesthesia was induced with sodium thiopentone (20 mg/kg) after which sheep were intubated and mechanically ventilated (Bird model 8, Bird Australia, Chatswood, NSW, Australia) with 2 l/min of oxygen, 2 l/min of nitrous oxide and isoflurane 1.4–1.8% inspired. Rectal temperature was monitored and maintained throughout the experiment with warmed intravenous maintenance fluids. A left anterolateral thoracotomy was performed through the fourth intercostal space. The pericardium was opened and the heart suspended in a pericardial cradle. A transit-time ultrasonic flow probe (model 6S, Transonic Systems, Ithaca, NY) was positioned around the proximal left main coronary artery and connected to a flowmeter (model T206, Transonic Systems). The left hemiazygous vein was ligated at its passage through the pericardium and the coronary sinus was cannulated through the proximal left hemiazygous vein stump with a 4-Fr double-lumen fiberoptic oximetry catheter (Baxter International, Irvine, CA). In each experiment the coronary sinus oximetry catheter was calibrated in vivo against a blood oxygen content analyzer (ABL-700, Radiometer, Copenhagen). The carotid artery and jugular vein were isolated through a transverse incision in the left neck. The jugular vein was cannulated with a 6-Fr Swan Ganz catheter (Baxter International, Irvine, CA) and an inferior vena cava occlusion catheter (Fogarty 22-Fr, Baxter International, Irvine, CA). A 5-Fr micromanometer-tipped catheter (Millar Instruments, Houston, TX) and a 6-Fr 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. 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 [11]. EKG, left main coronary artery blood flow, coronary sinus oxygen saturation and LV pressure and volume were displayed and digitized at 200 Hz on a personal computer during steady state conditions and during transient IVC occlusion. Ventilation was held at end-expiration during measurements. Blinding of hemodynamic studies was not possible because animals were recognizable following 12 months handling. Data was stored on hard disk and analysed offline with custom-designed software [12].

2.3 Biochemical analyses
Simultaneous blinded arterial and coronary sinus blood samples were collected and transported on ice to determine free fatty acid uptake. An automated spectrophotometer (Cobas Fara II, F. Hoffman–La Roche, Basel, Switzerland) and the NEFA C kit (Wako Chemicals, Dallas, TX) were used to measure free fatty acid levels in serum.

2.4 Data analysis
Five sheep diabetic for 12 months (three male and two female) and six controls (three male and three female) completed the study. LV pressure and volume at end-systole and end-diastole, stroke volume and stroke work were calculated as the average of steady state data obtained from ten to 20 beats. The end-systolic pressure–volume relationship (ESPVR) 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·(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 ESPVR. Ventricular energetics were evaluated according to Suga's time-varying elastance model [8]. This concept defines total mechanical energy generated by an ejecting contraction as equivalent to systolic pressure–volume area (PVA), which is the area bounded by the ESPVR, the end-diastolic pressure–volume relationship and the systolic portion of the pressure–volume loop. SW represents the energy transferred from the LV to the arterial system and is defined by the area within the pressure–volume loop. SW was calculated as the integral of the pressure–volume loop and PVA was calculated as PVA={SW+[0.5·ESP·(ESV–V0)]–0.75·[0.5·EDP·(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 LV 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. Pressure–volume area is directly related to LVVO2. The unique anatomy of the ovine coronary circulation [13] enables calculation of LVVO2 rather than myocardial oxygen consumption [14]. The ovine left main coronary artery exclusively supplies the LV and there is minimal overlap with the right ventricle [13]. Therefore, LV oxygen consumption per beat was calculated as LVVO2=[(CBF·(SaO2–SvO2)·Hb·1.35)/HR] where CBF is left main coronary artery blood flow, SaO2 is the arterial oxygen saturation, SvO2 is the coronary sinus (venous) oxygen saturation, Hb is hemoglobin and HR is heart rate. The LVVO2–PVA relationship and oxygen utilization efficiency were determined after SW, PVA and LVVO2 were normalized to 100 g LV weight and units converted to J/beat [15]. Oxygen utilization efficiency (%) was calculated as SW/LVVO2. The LVVO2–PVA relationship was generated using least squares linear regression. The reciprocal of the slope represents chemomechanical conversion efficiency or contractile efficiency and the y-intercept represents unloaded VO2. Matching between the LV and the arterial system was derived according to Sunagawa's ventriculoarterial coupling framework [16]. Properties of the arterial system (effective arterial elastance) are represented by the slope of the end-systolic pressure–stroke volume relation while LV mechanical properties (end-systolic elastance) are described by the slope of the end-systolic pressure–volume relationship.

2.5 Statistical analysis
Data are presented as mean±S.D. Comparison between groups was performed with Student's t-test or the Mann–Whitney ranked sum test as appropriate. Assessment of the effect of diabetes on the total pool of LVVO2 and PVA values was evaluated with analysis of covariance (ANCOVA), in a multiple linear regression model with dummy variables coding for control or diabetes [17,18]. Statistical significance was set at P<0.05. Calculations and statistical analyses were performed using Microsoft Excel 7.0 and SPSS 8.0.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Body weight (control: 53±4 kg vs. diabetes: 48±4 kg, P = 0.13) and left ventricular weight (control: 133.9±23.4 g vs. diabetes: 127.9±10.2 g, P = 0.31) did not differ significantly between groups. Hemodynamic variables are presented in Table 1. Heart rate, LV volume and pressure at end-diastole and end-systole were not significantly different.


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  		Table 1 Effect of 12 months’ diabetes on left ventricular hemodynamics

 
3.1 LV contractility, ventriculoarterial coupling and stroke work efficiency
Representative LV pressure–volume loops obtained by transient caval occlusion are shown in Fig. 1. The slope of the end-systolic pressure–volume relationship (Ees) represents a load-independent index of contractility and decreased 34±20% in diabetic sheep (P<0.01). The volume intercept (V0) did not differ significantly between groups (control: –1.4±7.8 ml vs. diabetes: –12.8±24.6 ml, P = 0.14). Diabetes did not alter effective arterial elastance (Ea). Therefore the ratio Ea/Ees increased (P = 0.01) reflecting deterioration in the optimality of matching between the LV and arterial system. Stroke work and pressure-volume area did not differ significantly between control and diabetic groups. However, stroke work efficiency (stroke work/pressure–volume area) decreased 11.5% in diabetic animals (P<0.01).


Figure 1
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  		Fig. 1 Representative pressure–volume loops in control and 12-month diabetic sheep. The slope of the end-systolic pressure–volume relation (ESPVR) is end-systolic elastance, a load-independent index of LV contractility.

 
3.2 Oxygen utilization efficiency
Representative dynamic data recordings are provided in Fig. 2 and mechanoenergetic data are presented in Table 2. Diabetes did not significantly alter mean coronary blood flow (control: 218±59 ml/min vs. diabetes: 280±99 ml/min, P = 0.12) or the arteriovenous oxygen content difference (control: 0.027±0.010 ml O2/ml vs. diabetes: 0.032±0.013 ml O2/ml). However, LV oxygen consumption tended to increase in diabetes (P = 0.065). Consequently, LV oxygen utilization efficiency (stroke work/LVVO2) deteriorated 38.6±16.5% (P<0.001) in diabetic animals compared to control.


Figure 2
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  		Fig. 2 Representative raw data tracing used to derive the pressure–volume and LVVO2–PVA relationships. CBF, coronary blood flow; LVP, left ventricular pressure; LVV, left ventricular volume; SVO2, coronary sinus oxygen saturation.

 

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  		Table 2 Effect of 12 months’ diabetes on left ventricular energetics

 
3.3 Free fatty acid uptake
Arterial free fatty acid levels were significantly higher in diabetic sheep (1885±1078 vs. 354±203 mmol/l, P<0.01). LV free fatty acid uptake was also elevated (diabetes: 312±278 µmol/beat per 100 g LV vs. control: 90±47 µmol/beat per 100 g LV, P = 0.04).

3.4 Contractile efficiency and unloaded VO2
LV oxygen utilization efficiency is determined by unloaded VO2, contractile efficiency and stroke work efficiency. Fig. 3a shows representative LVVO2–PVA relations obtained in control and diabetic animals. The correlation was highly linear in each animal; the median correlation coefficient was 0.958 in the control group and 0.963 in the diabetic group. Although the LVVO2 intercept (unloaded VO2) was not significantly altered, the slope was significantly higher in diabetic hearts (control: 2.0±0.12 vs. diabetes: 3.14±0.74, P<0.01). Therefore contractile efficiency was significantly lower in this group. Comparison of the slopes of the LVVO2–PVA relation between groups was also made by analysis of covariance on the total pool of LVVO2–PVA data. To eliminate inter-individual variability in unloaded VO2, excess LVVO2 was determined by subtracting unloaded VO2 from total LVVO2 for each data point [17]. The obtained correlation was linear in both groups and ANCOVA confirmed a significantly higher slope value in the diabetic group (Fig. 3b). Therefore, the diminished oxygen utilization efficiency observed in the diabetic heart resulted from impaired energy transfer from LVVO2 to mechanical energy and decreased stroke work efficiency.


Figure 3
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  		Fig. 3 (a) Relationships between LVVO2 and PVA in one control (solid squares) and one diabetic (open circles) animal. The LVVO2 above the LVVO2-axis intercept is excess LVVO2 and represents energy used for contraction, whereas the LVVO2 below the LVVO2-axis intercept represents energy expended for excitation-contraction coupling and basal metabolism. (b) The total pool of excess LVVO2 and PVA values from all experiments. The inverse of the slope represents the chemomechanical conversion efficiency of the myocardium. with an increased slope in diabetic sheep reflecting decreased chemomechanical conversion efficiency (P<0.001, ANCOVA).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The effect of diabetes on ventricular energetics has not been previously investigated. In this study, we examined the effect of chronic diabetes on LV oxygen utilization efficiency and the LVVO2–PVA relationship. The principal findings of the present study are that diabetes leads to a deterioration in LV oxygen utilization efficiency as a consequence of decreased chemomechanical conversion efficiency and decreased efficiency of energy transfer from the LV to the arterial system. These findings provide the first direct in vivo evidence of altered ventricular energetics in diabetes and facilitate understanding of the increased sensitivity of the diabetic heart to ischemia.

Experimental studies with animal models of diabetes allow assessment of the direct effect of diabetes on cardiac function in the absence of coronary artery disease. Regan and associates’ initial hemodynamic experiments in the alloxan-diabetic dog [19–21] and alloxan-diabetic Rhesus monkey [22] using load-dependent measures of cardiac function demonstrated preserved cardiac output despite increased chamber stiffness and a reduction in contractile reserve in diabetic animals. Recently, decreased contractility with preserved systolic function has been demonstrated in the streptozotocin-diabetic rat [23] and decreased LV contractility has been reported in genetically diabetic mice [24]. Consistent with these findings, we have demonstrated impaired end-systolic elastance — a load independent index of LV contractility and preserved SW in the streptozotocin-diabetic sheep at 12 months. However, the effect of decreased LV contractility on the efficiency of energy transfer from total mechanical energy generated to stroke work performed (stroke work efficiency) has not been previously determined and depends on the interaction between the LV and vascular loading conditions. Sunagawa quantified this interaction as the ventriculo-arterial coupling ratio (Ea/Ees) [16]. Stroke work efficiency is a monotonically decreasing function of Ea/Ees and can be expressed by the equation: SW/PVA=1/[1+0.5(Ea/Ees)] [25]. We found diabetes increased the ventriculoarterial coupling ratio by decreasing Ees while maintaining Ea. Therefore, in 12-month diabetic sheep stroke work efficiency decreased as a consequence of ventriculoarterial mismatch.

Stroke work efficiency (SW/PVA) and the conversion efficiency of LVVO2 to mechanical energy (PVA/LVVO2) determine LV oxygen utilization efficiency (SW/LVVO2). Suga described the relationship between LVVO2 and PVA as linear with a positive y-intercept. Therefore the slope and the y-intercept of the LVVO2–PVA relation influence LV oxygen utilization efficiency. In the present study, diabetes decreased stroke work efficiency and increased the slope of the LVVO2–PVA relation. Further, despite impaired LV contractility unloaded VO2 was maintained. Taken together, this resulted in impaired LV oxygen utilization efficiency. Hence, the diabetic LV consumes more oxygen to perform a given stroke work. Conversely, if LV oxygen supply is limited, the diabetic LV will fail to perform the required stroke work at an earlier stage than a more efficient ventricle. Impaired LV oxygen utilization efficiency may explain, in part, the increased sensitivity of the diabetic ventricle to ischemia and the accelerated progression of congestive heart failure in diabetic patients.

The increase in the slope of the LVVO2–PVA relation represents a reduction in chemomechanical conversion efficiency. This may reflect either a decrease in the efficiency of conversion of VO2 to ATP (the efficiency of oxidative phosphorylation in synthesizing ATP) or a decrease in the conversion of ATP to mechanical energy (the efficiency of the contractile machinery to generate mechanical energy by hydrolyzing ATP). Biochemical studies have reported reduced ATP production in diabetic heart mitochondria, in part because of decreased pyruvate dehydrogenase activity [26] and oxidative phosphorylation [5,27]. Alterations in contractile proteins may affect the conversion of ATP to mechanical energy. In the rat heart diabetes induces a shift in myosin isoenzymes from V1 to V3 and corresponding decreases in myosin ATPase activity and velocity of contraction [7]. However, the effect of changes in myosin ATPase activity on chemomechanical conversion efficiency is controversial. Goto et al. [17] reported a decrease in chemomechanical conversion efficiency of the hyperthyroid rabbit heart and suggested this may be associated with increased myosin ATPase activity. However, catecholamine administration [15] and myocardial cooling [28] alter myosin ATPase activity but do not change the slope of the LVVO2–PVA relation. Myosin ATPase activity and a shift in myosin isoenzyme distribution is only one of the mechanisms that may control myofilament contraction. Changes in other components of the contractile system may also influence chemomechanical conversion efficiency. Depressed myofibrillar ATPase activity [29] and diminished calcium sensitivity [30] of the myofilaments have been demonstrated in the diabetic heart and may be responsible for the observed decrease in myocyte shortening and tension development. Therefore, these studies suggest efficiency of energy transfer in the myocardium may be altered in diabetes because of disturbances in both energy generation and energy utilization. In the present study, we have demonstrated for the first time that the bioenergetic abnormalities seen at the subcellular level in the diabetic heart translate to decreased chemomechanical conversion efficiency at the chamber level.

The LVVO2 for non-mechanical processes may be estimated from the y-intercept of the LVVO2–PVA relation (unloaded VO2) and represents the energy requirement for basal metabolism and excitation-contraction coupling. Inotropic agents induce an increase in unloaded VO2, which represents increased energy demand for excitation-contraction coupling [15]. In this study unloaded VO2 was maintained despite decreased contractility. We hypothesized this was a result of increased free fatty acid oxidation. Recently, Korvald et al. [18] have demonstrated increased free fatty acid oxidation shifts the LVVO2–PVA relation upward and increases unloaded VO2. The investigators postulated that increased ATP demand for basal metabolism was responsible for a higher unloaded VO2 during free fatty acid loading. The diabetic myocardium is characterized by markedly increased free fatty acid oxidation, which accounts for almost all ATP production [31]. In the present study, chronic diabetes increased free fatty acid uptake and depressed LV contractility. We did not observe a significant change in unloaded VO2 in diabetic animals because the increase in ATP for basal metabolism secondary to increased free fatty acid utilization may have been attenuated by decreased energy demand for excitation-contraction coupling as a result of depressed LV contractility.

We observed a three-fold increase in free fatty acid uptake in diabetic hearts, which suggests increased free fatty acid oxidation as well as intracellular accumulation of fatty acids and triglycerides. Free fatty acid oxidation is increased as a result of alterations in the subcellular control of fatty acids and not simply the result of decreased glucose oxidation and altered circulating substrate and insulin levels [32]. Carnitine palmitoyltransferase 1 is the rate-limiting enzyme involved in mitochondrial free fatty acid uptake and is inhibited by malonyl-CoA [6]. Decreased malonyl-CoA content [26] secondary to increased malonyl-CoA decarboxylase activity and expression [32] may contribute to the observed high rate of free fatty acid oxidation seen in diabetes. In the present study, the decrease in oxygen utilization efficiency was substantially greater than the 11% difference that could be predicted by comparing the phosphate-to-oxygen ratios for free fatty acids and glucose [8,33]. This was due in part to decreased stroke work efficiency and impaired efficiency of energy transfer from ATP to mechanical energy. However, the high free fatty acid load and intracellular accumulation of fatty acids lead to the activation of intracellular futile metabolic cycles, which can increase the energy demand of myocardial metabolism a further 30% [34]. In addition, free fatty acid induced uncoupling of oxidative phosphorylation has been reported to increase oxygen consumption without a concomitant increase in ATP production [35]. Hence increased free fatty acid uptake with concomitant intracellular accumulation of fatty acids and triglycerides may decrease overall chemomechanical conversion efficiency beyond that predicted by the phosphate-to-oxygen ratio.

Our findings require interpretation within the constraints of several potential limitations. We have used a chronic ovine model of type I diabetes whose applicability to patients with diabetes and ischemic heart disease is unknown. Our analysis assumes, as in many prior studies, the linearity of the end-systolic pressure–volume relation. Minor curvilinearity of the ESPVR has been demonstrated in the intact canine heart [36]. Nozawa et al. [37] demonstrated that the LVVO2–PVA relation is the same regardless of whether the end-systolic pressure–volume relation is assumed to be linear or curvilinear. Therefore a significant quantitative error from assumed linearity of the end-systolic pressure–volume relation is unlikely. Variations in sympathetic activity may influence LV contractility and unloaded VO2. In this study, data were collected under light anesthesia and stable heart rate to minimize these effects. Autonomic blockade was not used because of confounding effects on free fatty acid oxidation. Isoflurane depresses myocardial contractility in a dose-dependent manner but has less effect on contractility than halothane and enflurane at equipotent anesthetic concentrations [38]. Importantly isoflurane does not influence oxygen utilization efficiency [39] and a differential effect between control and diabetic animals is unlikely. The small sample size and wide variation in some measures such as body weight and coronary artery blood flow may have obscured potentially significant changes but do not alter the findings of the study.

In conclusion, diabetes impairs oxygen utilization efficiency as a consequence of decreased chemomechanical conversion efficiency and stroke work efficiency. Impaired oxygen utilization efficiency may explain, in part, the increased sensitivity of the diabetic heart to ischemia and the augmented progression to ventricular failure seen in diabetic patients. Therapies aimed at reducing myocardial free fatty acid oxidation and enhancing energy efficiency of the diabetic ventricle may improve cardiovascular outcomes in this high-risk population.

Time for primary review 20 days.


   Acknowledgements
 
Funding from the North Shore Heart Research Foundation supported this study. Dr Ramanathan is a Sir Roy McCaughey Surgical Research Fellow of the Royal Australasian College of Surgeons. Associate Professor Deborah Black, Department of Public Health and Community Medicine, University of New South Wales, performed the statistical analysis contained in this paper. We gratefully acknowledge the technical assistance of Gabrial Gomes, Ray Kearns, Peter Darge and Chi-Ming Lee. In addition we would like to thank Professor John Fletcher for his continuing encouragement and support.


   Notes
 
1 Present address: Department of Cardiothoracic Surgery, St George Hospital, Kogarah NSW 2217, Australia. Back

2 Present address: Department of Cardiothoracic Surgery, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia. Back


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

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