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. Author manuscript; available in PMC: 2011 Dec 1.
Published in final edited form as: J Thorac Cardiovasc Surg. 2010 Jun 12;140(6):1345–1352. doi: 10.1016/j.jtcvs.2010.05.009

Is Hyperglycemia Bad for the Heart During Acute Ischemia?

Louis M Chu 1, Robert M Osipov 1, Michael P Robich 1, Jun Feng 1, Shizu Oyamada 1, Cesario Bianchi 1, Frank W Sellke 1,2
PMCID: PMC2949689  NIHMSID: NIHMS208131  PMID: 20542299

Abstract

Background

This study investigates the impact of diabetes on myocardium in the setting of acute ischemia-reperfusion in a porcine model.

Methods

In normoglycemic (ND) and alloxan-induced-diabetic (DM) male Yucatan pigs, the left anterior descending coronary artery territory was made ischemic, then reperfused. Hemodynamic values and myocardial function were measured. Monastryl blue and triphenyl tetrazolium chloride staining were used to assess size of the areas at risk (AAR) and infarction. Glycogen content was assessed using period acid-Schiff staining. Cell-death and survival signaling pathways were assessed by immunoblotting.

Results

Mean arterial pressure and developed left ventricular (LV) pressure were lower in the DM group (p<0.05). While global LV function was worse in the DM group (p<0.05), regional function in the AAR was improved on the horizontal axis (p<0.05). Mean infarct size was smaller in DM vs. ND (19% vs. 43%, p<0.05), whereas the AAR was similar in both groups (34% vs. 36%, p=0.7). Ischemic myocardium in the DM group displayed more prominent staining for glycogen compared to the ND group. In the AAR, expression of cell survival proteins including phospho-eNOS (0.17±0.04 vs. 0.04±0.01, p<0.05), heat shock protein 27 (0.7±0.2 vs. 0.3±0.1, p<0.05), NF-kB (0.14±0.02 vs. 0.03±0.01, p<0.05), and mTOR (0.35±0.05 vs. 0.15±0.02, p<0.05) were higher in DM animals, whereas in non-ischemic tissue, expression of these proteins was similar or lower in the DM group.

Conclusions

Although type I diabetes worsens global LV function, it is protective in the ischemic area, leading to increased expression of cell survival proteins and decreased infarct size.

INTRODUCTION

In the United States, over 400,000 deaths per year are attributed to acute myocardial infarction (AMI)1. Current treatment of AMI is based on rapid restoration of blood flow to the ischemic area. Unfortunately, this results in additional reperfusion injury to the myocardium via an induced inflammatory response and the release of damaging free radicals2,3. When added to the initial ischemic insult, reperfusion injury increases the incidence of a number of complications, including cardiac dysrhythmias4, myocardial stunning5, and coronary microvascular dysfunction6. Ischemia-reperfusion (I-R) injury results in a combination of necrosis, apoptosis, and autophagy of cardiac myocytes, the severity and onset of which can be modulated by manipulation of certain biochemical pathways via pre- and post-conditioning7. However, the mechanisms by which these pathways protect myocytes are incompletely understood.

On the other hand, it is well known that diabetes mellitus is associated with increased incidence of multi-vessel coronary artery disease, congestive heart failure, and AMI. Both type 1 and type 2 diabetics have significantly poorer clinical outcomes after AMI, with higher rates of repeat intervention, residual ventricular dysfunction, and overall mortality8,9. Surprisingly, experimental studies looking at the sensitivity of the diabetic heart to ischemic injury have been divided, with studies showing both injurious and cardioprotective effects of diabetes10. The majority of these studies, however, utilized either small animal models or in vitro models that do not adequately represent the biochemical and metabolic context that would be seen in patients with acute ischemia. In this study, we used a clinically relevant swine model of type I diabetes to explore the sensitivity of the diabetic heart to ischemia-reperfusion injury in vivo. We found that type I diabetes is cardioprotective against the insult of acute I-R injury and that hyperglycemia may actually be beneficial to the heart in this setting.

MATERIALS AND METHODS

Experimental Design

Sixteen intact male Yucatan mini-swine were divided into two groups: non-diabetic (ND, n=8) and diabetic (DM, n=8). All animals were fed normal chow (S11 Purina, St Louis, MO). Diabetes was induced in DM animals by a single intravenous injection of alloxan (200 mg/kg) at age 15 weeks (Sinclair Research Center, Inc. Columbia, MO). Alloxan-treated animals that maintained blood glucose levels greater than 250 mg/dL were used in the DM group. At twenty weeks of age (5 weeks of exposure to diabetes), animals were subjected to acute ischemia by occluding the left anterior descending coronary artery (LAD) for 60 minutes, followed by release of the LAD and reperfusion for 120 minutes. Hemodynamic and functional measurements were taken at baseline and for every thirty minutes thereafter. Myocardial segmental shortening in the longitudinal axis (parallel to the LAD) and horizontal axis (perpendicular to the LAD) were recorded as well. At the completion of the protocol, the heart was excised, and tissue samples were collected for molecular analyses as described below.

Animals

Swine were housed individually and provided with normal chow and water ad libitum. All experiments were approved by the BIDMC institutional animal care and use committee and conformed to the US National Institutes of Health guidelines regulating the care and use of laboratory animals (NIH publication 5377-3, 1996).

Surgical Protocol

Swine at age 20 weeks were sedated with Telazol (1.5 mg/kg, IM) and weighed prior to endotracheal intubation and ventilation with a volume-cycled ventilator (North American Drager, Telford, PA). Anesthesia was maintained with 2.0% isoflurane (Abbott Laboratories). A 5-French arterial sheath was passed into the right femoral artery via direct cutdown and used for arterial blood sampling and arterial blood pressure monitoring. Arterial blood gas, hematocrit, and core temperature were measured at the start of surgery and every 30 minutes thereafter. Each animal received a one liter bolus of Lactated Ringer's solution followed by continuous infusion (15 ml/kg/hour). A phenylephrine drip (0.25 μg/kg/min) to prevent isoflurane-induced hypotension, heparin (80 units/kg bolus), and lidocaine (1.5 mg/kg bolus) to prevent ventricular dysrhythmia were administered. A median sternotomy was performed. A catheter-tipped manometer (Millar Instruments, Houston, TX) was introduced through the apex of the heart to record left ventricular (LV) pressure. Segmental shortening in the ischemic area-at-risk (AAR) was assessed with a digital ultrasonic crystal measurement system (Sonometrics Corp., London, Ontario, Canada) using four 2-mm digital ultrasonic probes implanted in the subepicardial layer approximately 10 mm apart within the AAR. Cardiosoft software (Sonometrics Corp., London, Ontario, Canada) was used for functional measurements. LAD flow was monitored by a transonics doppler probe. The LAD was occluded 3 mm distal to the origin of the second diagonal branch by a Rommel tourniquet. After 60 minutes, the tourniquet was released and the myocardium allowed to reperfuse for 120 minutes. The LAD was then religated, the ascending aorta was crossclamped, and monastryl blue pigment (Engelhard Corp, Louisville, KY) was injected into the aortic root to demarcate the area at risk. The heart was excised and sectioned into three 1cm-thick slices perpendicular to the LAD from the apex to the point of ligation. Tissue from the slice 1 cm proximal to the apex was used in molecular studies. The remaining tissue was incubated in 1% triphenyl tetrazolium chloride [(TTC), Sigma Chemical Co., St. Louis, MO] solution for 30 min and infarct size was assessed as described below. Ventricular fibrillation (VF) or ventricular tachycardia (VT) events were treated with an extra dose of lidocaine (1.5 mg/kg) and electrical cardioversion with 20–50 J for persistent dysrhythmias.

Measurement of Global and Regional Myocardial Function

Indices of global and regional myocardial function were monitored during the entire experiment: mean arterial pressure (MAP); developed LV pressure (DLVP); positive first derivative of LV pressure (dP/dt); and longitudinal and horizontal segmental shortening in the AAR. These indices were recorded for 10 sequential beats, at baseline and then every 30 minutes thereafter using the Sonometrics Cardiosoft system as previously described11.

Quantification of Myocardial Infarct Size

The LV (including septum) was isolated, cut into 1-cm slices, and immediately immersed in 1% TTC in phosphate buffered saline (Boston Bioproducts, Worcester, MA) at 38°C for 30 minutes. The infarct area (characterized by absence of staining), non-infarcted AAR (characterized by bright red tissue staining), and the non-ischemic ventricle (characterized by purple tissue staining) were photographed and measured. AAR as a percentage of total LV surface area and percent infarction in the AAR were calculated in each individual slice by planimetry (Image J 1.4) using the following equations:

AAR size=(AAR surface area∕LV total surface area)×100
Infarct size=(LV infarct surface area∕LV AAR surface area)×100

Glycogen Staining

Sections of ischemic and non-ischemic myocardium from ND (n =5) and DM (n = 7) animals were placed immediately into 10% formalin and subjected to periodic acid-Schiff staining to assess glycogen content, with amylase-treated sections serving as negative controls. Ischemic areas were evaluated for amount of glycogen by a pathologist in a blinded fashion, and were assigned a score from zero to five, with zero representing complete absence of glycogen and five representing strongest staining for glycogen (non-ischemic myocardium).

Western Blotting

Myocardial samples were homogenized in RIPA buffer (Boston Bioproducts) and total protein concentration determined by BCA assay (Pierce, Rockford, IL). Equal amounts of protein (40 μg) were subjected to SDS-PAGE and immunoblotting as previously described11. Primary antibodies were used according to the manufacturer's recommendation. Levels of Akt, phospho-Akt(Thr308), phospho-Akt(Ser473), phosphorylated endothelial nitric oxide synthase(ser1177) (phospho-eNOS), Erk 1/2, phospho-Erk 1/2(Thr202/Tyr204)), mammalian target of rapamycin (mTOR), phospho-mTOR(Ser2448), stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK), p70S6K1, phospho-p70S6K1(Thr389), 4E-binding protein 1 (4EBP1) and phospho-4EBP1(Thr37/46), NF-kB p65 and phospho-NF-kB p65(Ser536), pyruvate dehydrogenase kinase 1 (PDK1) and phospho-PDK1(Ser241) (Cell Signaling Technology, Beverly, MA), heat shock protein 27 (HSP27), and HSP70 (Stressgen, Ann Arbor, MI) were assessed. Myocardial samples from the non-ischemic and the ischemic territories were assessed separately. Vinculin was used to confirm equal protein loading, and band intensities were normalized to Ponceau staining.

Statistical Analysis

Clinical, hemodynamic, and global and regional LV functional data were analyzed using two-way repeated-measures ANOVA (Systat, San Jose, CA). Post hoc multiple comparison Student-Newman-Keuls test was applied. Myocardial infarct size, glycogen staining, and Western blot densitometry were analyzed using unpaired Student's t-test. Western blot data are presented as density in arbitrary units (AU). Data are reported as mean ± SEM and p<0.05 was considered significant.

RESULTS

Diabetic Swine

There was a significant difference in animal weight between ND and DM animals (ND 22.2±1 kg vs. DM 17±1 kg, p=0.004). The average blood glucose level was significantly higher in the DM group vs. ND group (309±57 mg/dL vs. 37±10 mg/dL, p<0.01). There were no significant differences between groups with respect to arterial blood gas measurements, hematocrit, and core temperature at any time.

Myocardial Infarct Size

The size of the AAR was not significantly different between groups (34% in DM vs. 36% in ND, p=0.7, Figure 1A), whereas the size of the infarct area was smaller in the DM group as compared to the ND group (19% in DM vs. 43% in ND, p<0.05, Figure 1B).

Figure 1.

Figure 1

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Size of AAR as a percentage of LV surface area (p=0.7, A) and necrotic area as a percentage of AAR (B) in ND and DM animals. Shown are representative slices of ND (C) and DM (D) ventricle, with purple arrows pointing to nonischemic area, red arrows to AAR, and gray arrows to infarct area. Data presented as mean ± SEM comparing ND (n=8) and DM (n=8) groups. *P<0.05.

Hemodynamic Parameters

Prior to LAD occlusion, the heart rate (p<0.01) and developed LV pressure (p<0.01 were lower in the DM group as compared to the ND group, while MAP was slightly higher (p=0.3). After occlusion, all three hemodynamic parameters were lower in the DM group. LAD blood flow during the reperfusion period was lower in the DM group(p<0.05) (Figure 2).

Figure 2.

Figure 2

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Hemodynamic and functional data. Heart rate (A), developed left ventricular pressure (DLVP, B), mean arterial pressure (MAP, C), left anterior descending artery blood flow (D), first derivative of LV pressure over time (dP/dt, E), and horizontal segmental shortening (SS) axis (F). Pre = baseline, O1 = 30 minutes occlusion, O2 = 60 minutes occlusion, R1 = 30 minutes reperfusion, R2 = 60 minutes reperfusion, R3 = 90 minutes reperfusion, R4 = 120 minutes reperfusion. Data presented as mean ± SEM comparing ND (n=8) and DM (n=8) groups. †P<0.05.

Global and Regional Myocardial Function

Global systolic LV function as determined from +dP/dt was significantly worse in the DM group as compared to the ND group at all times (p<0.01, Figure 2E). Regional LV function as assessed by percent segmental shortening on the horizontal axis was significantly better in the DM group as compared to the ND group (Figure 2F, p<0.05), while function on the longitudinal axis was not significantly different between groups (not shown).

Glycogen Staining

In the AAR, glycogen content was higher in the DM group compared to the ND group (1.36±0.14 vs. 0.70±0.20, p=0.02, Figure 3).

Figure 3.

Figure 3

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Glycogen staining using period acid-Schiff stain in non-ischemic DM (A), ischemic DM (B), and ischemic ND (C) myocardium, with black arrows indicating intracellular glycogen. Sections shown are representative of all sections assessed. DM (n=7) and ND (n=5) sections were scored in a blinded fashion and glycogen content was compared (D). Data presented as mean ± SEM in arbitrary units (AU). p=0.02.

Protein Expression in the Non-ischemic Territory

Cell Survival Signaling

The expression of total Akt was higher (p<0.01) in the ND group as compared to the DM group, while the expression of phospho-Akt(Ser473) and phospho-Akt(Thr308) was similar between groups (not shown). The ratio of phospho-Akt(Thr 308) to total Akt was significantly higher (p<0.01) in the diabetic group compared to the nondiabetic group (Figure 4A). The expression of PDK1 was lower (p<0.01) in the DM group as compared to the ND group (Figure 4B), while the expression of phospho-PDK1 was similar between groups (ND 0.1±0.01, DM 0.09±0.01, p=0.1). The expression of HSP27 was similar (p=0.3) between groups (Figure 4C), as was the expression of HSP70 (p=0.6, Figure 4D). The expression of phospho-eNOS(Ser1177) tended to be lower in the DM group as compared to the ND group (Figure 4E).

Figure 4.

Figure 4

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Selected cell-survival protein immunblotting results. Ratio of phospho-Akt to total Akt (A), PDK1 (B), HSP 27 (C), HSP 70 (D), phospho-eNOS (E), phospho-NF-kB (F), phospho-mTOR (G), phospho-p70S6K (H), and phospho-4E-BP1 (I)expression was assessed in the ischemic and nonischemic territories of ND (n=8) and DM (n=8) animals. Representative bands are shown, with density expressed as arbitrary units. Data presented as mean ± SEM in arbitrary units (AU). *P<0.05.

The expression of mTOR, phospho-NF-kB p65 (Figure 4F), phospho-mTOR(Ser2448) (Figure 4G), phospho-4E-BP1(Thr37/46) (Figure 4I), NF-kB p65, p70S6K, and 4E-BP1 (not shown), was similar between the groups. Phospho-p70S6K(Thr389) and phospho-NF-kB p65(Ser536) were not detected in either group.

Mitogen-Activated Protein Kinase Signaling

The expression of total Erk 1/2 was similar (p=0.9) between the groups, whereas the expression of phospho-Erk 1/2(Thr202/Tyr204) was lower in the DM group as compared to the ND group (DM 0.03±0.01, ND 0.07±0.02, p=0.04). The expression of phospho-p90RSK(Ser308) was similar (p=0.4) between the two groups (Figure 5B). The expression of SAPK/JNK was lower (p=0.03) in the DM group (Figure 5C).

Figure 5.

Figure 5

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Selected mitogen activated protein kinase immunoblotting results. Ratio of phospho-ERK to total ERK (A), phospho-p90RSK (B), and SAPK/JNK (C) expression was assessed in the ischemic and nonischemic territories of ND (n=8) and DM (n=8) animals. Representative bands are shown, with density expressed as arbitrary units. Data presented as mean ± SEM in arbitrary units (AU). *P<0.05.

Protein Expression in the AAR

Cell Survival Signaling

The expression of total Akt and phospho-Akt(Ser473), and phospho-Akt(Ser 473) was similar between the two groups (not shown), whereas the ratio of phospho-Akt(Thr308) to total Akt tended to be higher in the DM group as compared to the ND group (Figure 4A). The expression of PDK1 (p<0.01, Figure 4B) and phospho-PDK1(Ser241) (DM 0.2±0.01, ND 0.08±0.02, p<0.01) was higher in the DM group. The expression of HSP27 and HSP70 was higher (p<0.05) in the DM group as (figure 4C/D). The expression of phospho-eNOS(Ser1177) was higher (p<0.01) in the DM group (Figure 4E). The expression of mTOR (DM 0.035±0.005, ND 0.017±0.002, p<0.01) and phospho-mTOR(Ser2448) (Figure 4G) was higher in the DM group. The expression of p70S6K (DM 0.09±0.01, ND 0.05±0.02, p<0.01) and phospho-p70S6K(Thr389) (p< 0.02, Figure 4H) were higher in the DM group. The expression of phospho-4E-BP1(Thr37/46) was higher (p<0.01) in the DM group (Figure 4I), whereas the expression of phospho-4E-BP1 tended to be higher (DM 0.3±0.01, ND 0.2±0.02, p=0.07) in the same group. The expression of NF-kB p65 (DM 0.14±0.02, ND 0.03±0.01, p<0.01) and phospho-NF-kB p65(Ser536) (Figure 4F) was also higher in the DM group.

Mitogen-Activated Protein Kinase Signaling

Total ERK 1/2 was more highly expressed in ND animals than DM animals (ND 0.09±0.01, DM 0.04±0.01, p=0.01), but the ratio of phospho-Erk 1/2(Thr202/Tyr204) expression to total Erk 1/2 was higher (p=0.01) in the DM group (Figure 5A). The expression of phospho-p90RSK(Ser308) was higher (p=0.01) in the DM group (Figure 5B). The expression of SAPK/JNK was also higher (p<0.05) in the DM group (Figure 5C).

DISCUSSION

In this study, we examined the effects of type 1 diabetes on LV I-R injury. We previously reported that I-R injury is increased in a porcine hypercholesterolemic model11, and suspected that similar findings would be evident in our type 1 diabetic model. To our surprise, this study demonstrates that experimental type I diabetes is cardioprotective against acute I-R injury, limiting infarct size, improving regional function, and increasing expression of cell survival molecules by at-risk myocytes in a porcine model of myocardial infarction.

It is well documented that patients with type 1 diabetes have worse outcomes after CABG than do non-diabetic patients. However, several studies have shown that the diabetic heart is actually less sensitive to ischemic injury, especially in in vivo models. Chen and associates showed that type I diabetic rat hearts demonstrated enhanced tolerance to ischemia-reperfusion that was abolished by preoperative treatment with insulin12. Ma et al found that capillary density and the expression of cardioprotective proteins including vascular endothelial growth factor (VEGF), eNOS, and phospho-Akt were increased in rats exposed to 2 weeks of diabetes compared to nondiabetic rats, while infarct size and caspase-3, a proapoptotic signal, were decreased13.

Diabetic Swine

Our DM swine achieved fasting blood glucose levels nearly nine times that of ND swine, demonstrating successful induction of type-1 diabetes with alloxan. The mean fasting blood glucose level in ND swine of 37 mg/dL was similar to previously reported values for nondiabetic Yucatan swine (43 mg/dL)14.

Diabetes decreases infarct size and improves regional function

The most striking finding in this study was the significant decrease in infarct size seen in diabetic compared to nondiabetic animals. A possible explanation lies in the regulation of myocardial glucose uptake during cardiac stress. Under resting conditions, metabolism of fatty acids yields 60–70% of the ATP requirement of the heart, but during situations of stress the energy preference shifts to favor utilization of glucose, diminishing the release of damaging free radicals by fatty acid oxidation15. It was thought that, in the insulin-deficient environment of type I diabetes, impaired glucose uptake led to less efficient myocardial metabolism under ischemic conditions. However, recent studies have uncovered alternative pathways that may take over glucose regulation during situations of stress. AMP activated protein kinase (AMPK) has been shown to be an important effector of glycolysis and glucose uptake during cellular stress. In the myocardium, AMPK promotes the translocation of glucose transporter 4 (GLUT-4) to the cell membrane, increasing myocardial glucose uptake and protecting the heart from ischemia16. Hypoxia-induced factor-1α (HIF-1α) has also been found to play a role in glucose metabolism under stress, increasing expression of glucose transporter 1 (GLUT-1) and enzymes involved in glycolysis17. Hyperglycemic, insulin-deficient animals likely utilize these non-insulin dependent pathways to more efficiently metabolize glucose, thus decreasing ischemic damage. The improvement in horizontal contractility seen in the AAR of our diabetic hearts could be due to this increased availability of metabolic substrate for myocardial contraction. It should be noted that blood flow through the LAD during reperfusion was lower in the diabetic group, which could mean decreased delivery of inflammatory mediators and free radicals and decreased reperfusion injury. This difference between groups is one limitation of the current study, but does not explain our Western blotting results.

Diabetic hearts display worsened global function

MAP, DLVP, and dP/dt were all lower in diabetic animals, reflecting worsened global LV function compared to ND animals. Chronic diabetes, through a variety of mechanisms including the accumulation of glycolytic intermediates, the production of toxic intermediates from free fatty acid metabolism, and increased myocardial fibrosis, leads to cellular, structural, and functional changes in the myocardium termed diabetic cardiomyopathy18. In contrast to the AAR, where myocardial stress leads to increased glucose utilization, the nonischemic diabetic left ventricle may preferentially metabolize fatty acids, leading to increased oxidative stress and worsened global LV function.

Glycogen stores in AAR are increased in diabetic hearts

Glycogen staining of myocardium from the AAR revealed a higher amount of glycogen in DM animals compared to ND animals after ischemia-reperfusion. This finding could be interpreted as either decreased utilization or increased availability of glycogen, but given our finding of decreased infarct size in the DM group, the latter scenario is more likely. Previous studies have demonstrated that diabetic myocardium contains more glycogen than non-diabetic myocardium at baseline19. During situations of stress, when glucose is the preferred metabolite, the excess glycogen in ischemic diabetic myocardium could fuel cardioprotective mechanisms, while the glycogen supply in ischemic ND myocardium is exhausted.

Increased expression of cell survival proteins in diabetic hearts

In non-ischemic myocardium, the expression of several proteins involved in cell survival were either similar or lower in diabetic animals compared to controls. Interestingly, the expression of most of these same proteins in the ischemic area was significantly higher in the DM group compared to the control group, indicating that cell survival pathways in ischemic myocardium were more active in these animals. Akt, PDK 1, and eNOS have been shown to reduce ATP breakdown and mitochondrial Ca+ loading, ultimately preconditioning the myocardium against IR injury7. HSP 27 has been shown to protect against IR injury via stabilization of troponin I and T20, and HSP 70 has been found to play a role in late ischemic preconditioning as well21. Phosphorylation and activation of NF-kB is linked with cell survival and inflammation22.

Expression of mTOR, phospho-mTOR, phospho-4EBP1, and p70S6K, a kinase intermediate in the mTOR pathway, was also higher in the ischemic area of DM animals compared to controls. The glucose-dependent mTOR pathway is critical to protein translation, and inhibition of mTOR by rapamycin has been shown to block the protective effects of preconditioning23. The increased glucose in DM animals likely means more available substrate for glucose-dependent mechanisms such as the mTOR pathway.

The same trend was seen when looking at the expression of mitogen-activated proteins involved in cell growth and survival. Erk 1/2, its downstream kinase p90RSK24, and SAPK/JNK25 have all been associated with preconditioning and cardioprotection from I-R injury. It is evident that a host of cell survival and cell growth-related proteins are upregulated in the ischemic area of diabetic animals.

Duration of Hyperglycemia

Several studies in small animal models have found that streptozotocin-induced diabetes exerts contradictory effects on myocardial ischemia in chronic versus acute hyperglycemia, reporting increased infarct size and worsened myocardial function in animals with long-standing disease14. It is also well known that long-term diabetes increases the incidence and complications of MI, and can progress to diabetic cardiomyopathy. A limitation of the current study is that it examines the effects of hyperglycemia at only one time point, relatively early on in the course of diabetes (5 weeks). It is likely that, as the disease progresses, the other previously mentioned biological sequelae of hyperglycemia result in decreased resistance against acute ischemia.

CONCLUSION

Recently, government agencies such as the National Institutes of Health and the Food and Drug administration have been putting greater emphasis on clinically relevant large animal models for preclinical experiments. This is due to the fact that while rodent models of I-R injury and other experiments may give a wealth of information, the findings often do not translate well to patients.

This study provides evidence that type 1 diabetes mellitus and resultant hyperglycemia, though detrimental to global cardiac function and associated with poorer prognosis, are actually cardioprotective against myocardial I-R injury in the short term. This is likely a result of increased availability and utilization of glucose, the heart's preferred energy substrate in times of stress. Thus, the current clinical practice of tightly controlling blood glucose in patients suffering cardiac events may be detrimental to the heart in the acute setting. Recent investigation into AMPK and HIF-1α, potent regulators of glucose uptake in the myocardium, provides possible mechanisms for the cardioprotective properties of hyperglycemia. Additional studies using this model to assess the activity of these enzymes and their targets would help to further elucidate the pathway and possibly develop therapeutic modalities for protection against ischemia.

Ultramini-Abstract.

Diabetes mellitus is a risk factor for poor outcome during cardiac surgery. This study investigates the impact of type 1 diabetes on myocardium in the setting of acute ischemia in a porcine model, and provides evidence that type I diabetes and associated hyperglycemia may be protective against ischemia-reperfusion injury.

Acknowledgements

We thank BIDMC Animal Research Facility and Core Histology Laboratory staff for their efforts.

Disclosures Dr. Frank W. Sellke has research support from Ikaria (Clinton, NJ), Capstone (Tempe, AZ), and Ikaria Pharmaceutical (Seattle, WA), and he is a consultant for Novo Nordisk (Princeton, NJ), Pfizer, and Cubist Pharmaceuticals (Lexington, MA).

Funding Funding for this project was provided to Dr. F.W.S by NHLBI (RO1 HL46716, HL69024, and HL85647), Capstone Corp, and NIH T32-HL076130 (R.M.O, M.P.R) and the Irving Bard Memorial Fellowship (R.M.O, L.M.C, M.P.R).

Footnotes

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