Hyperglycemia upon hospital admission in patients with ST-segment elevation myocardial infarction (STEMI) occurs frequently and is associated with adverse outcomes. It is, however, unsettled as to whether an elevated blood glucose level is the cause or consequence of increased myocardial damage. In addition, whether the cardioprotective effect of exenatide, a glucose-lowering drug, is dependent on hyperglycemia remains unknown. The objectives of this substudy were to evaluate the association between hyperglycemia and infarct size, myocardial salvage, and area at risk, and to assess the interaction between exenatide and hyperglycemia. A total of 210 STEMI patients were randomized to receive intravenous exenatide or placebo before percutaneous coronary intervention. Hyperglycemia was associated with larger area at risk and infarct size compared with patients with normoglycemia, but the salvage index and infarct size adjusting for area at risk did not differ between the groups. Treatment with exenatide resulted in increased salvage index both among patients with normoglycemia and hyperglycemia. Thus, we conclude that the association between hyperglycemia upon hospital admission and infarct size in STEMI patients is a consequence of a larger myocardial area at risk but not of a reduction in myocardial salvage. Also, cardioprotection by exenatide treatment is independent of glucose levels at hospital admission. Thus, hyperglycemia does not influence the effect of the reperfusion treatment but rather represents a surrogate marker for the severity of risk and injury to the myocardium.

In patients with ST-segment elevation myocardial infarction (STEMI), timely treatment with primary percutaneous coronary intervention (PCI) is recommended to restore coronary blood flow and increase myocardial salvage, and thereby to minimize infarct size (1). However, after the opening of an occluded vessel, reperfusion injury may paradoxically cause additional irreversible myocardial damage that may account for as much as 50% of the infarct size (2). The mechanisms behind reperfusion injury have not been fully elucidated, but hyperglycemia, which is observed in approximately half of patients with STEMI upon hospital admission (3), may be unfavorable during reperfusion and has been linked to the subsequent injury (4). Previous studies have demonstrated larger infarct size (58) and poorer prognosis in patients with hyperglycemia upon hospital admission compared with patients without hyperglycemia, both in patients with and without diabetes mellitus (3,5,820). Until now, the impact of hyperglycemia on myocardial salvage has been evaluated in only a limited number of patients (21), and no data exist regarding the relationship between hyperglycemia and area at risk. Thus, the causal role of hyperglycemia in STEMI remains unknown, and whether the association between hyperglycemia and myocardial damage may be attributed to a larger myocardium at risk or is the cause of reperfusion injury leading to decreased myocardial salvage needs to be elucidated. Cardiovascular magnetic resonance (CMR) provides an accurate method for in vivo assessment of infarct size (22,23), area at risk (2427), and myocardial salvage index (28,29).

In a previously published proof-of-concept study (30,31) on patients with STEMI and thrombolysis in myocardial infarction (TIMI) grade 0 or 1 flow before primary PCI, we demonstrated a cardioprotective effect of exenatide. Exenatide is a glucagon-like peptide analog that is known to increase insulin secretion and cellular glucose uptake, and subsequently reduce the level of blood glucose (32). The cardioprotective effect of exenatide may be related to these glucose homeostatic effects (33), and it may be hypothesized that the effect of exenatide depends on the patient’s glucose level upon hospital admission and before undergoing PCI.

The aims of the current study were to evaluate (1) the association between hyperglycemia upon hospital admission and area at risk and myocardial salvage index in STEMI patients, and (2) the interaction between glycemic state upon hospital admission and the cardioprotective effect of exenatide.

Study Population

The patients in this post hoc study participated in a randomized clinical trial comparing intravenous administration of exenatide with placebo in STEMI patients (30). Patients with STEMI were randomized to receive either exenatide or placebo saline solution intravenously 15 min prior to intervention and continued 6 h post-PCI. Exenatide treatment resulted in increased myocardial salvage index, and exenatide also reduced the final infarct size in patients with short system delays; for more details, see the existing publications (30,31). STEMI was defined as ST-segment elevation in two contiguous electrocardiogram (ECG) leads of >0.1 mV in V4–V6 or limb leads II, III, and aVF, or >0.2 mV in leads V1–V3. Patients were not considered for study enrollment if they presented with cardiogenic shock or were unconscious. Similarly, patients with STEMI caused by stent thrombosis, known renal insufficiency, or previous coronary artery bypass graft surgery were excluded from the study. Finally, patients with no subsequent rise in levels of cardiac biomarkers were excluded from the study. All patients eligible for primary PCI were pretreated with aspirin (300 mg orally or 500 mg i.v.), clopidogrel (600 mg orally), and heparin (10,000 units i.v.). On arrival at the catheterization laboratory, a coronary angiography was performed to identify the culprit lesion, and primary PCI was performed according to contemporary guidelines, as previously described (30). All patients were treated with clopidogrel, 75 mg daily for 12 months, and aspirin, 75 mg daily indefinitely. Cardiac biomarkers (troponin T) were measured before intervention and immediately after, 6 h after, 12–18 h after, and on the day after intervention. The proximal location of the culprit lesion was defined as the first segment of the right coronary artery, the left coronary descending artery, and the left circumflex artery. All patients were informed orally and in writing, and all gave their written consent before inclusion. The study was performed according to the Helsinki Declaration guidelines for good clinical practice, and The Danish National Committee on Biomedical Research Ethics approved the protocol. The study was registered at www.clinicaltrial.gov (NCT00835848).

Blood Glucose and Definition of Hyperglycemia

Blood glucose level was measured upon hospital admission at the PCI center before the first angiogram was performed as part of a standard evaluation. For patients without known diabetes, a cutoff value of 8.3 mmol/L (149 mg/dL) was used for the definition of hyperglycemia, whereas for patients with known diabetes a cutoff value of 12.8 mmol/L (231 mg/dL) was used (17). These particular cutoff values were chosen, since they previously have been identified as the most optimal cutoff values for prediction of outcome in STEMI patients undergoing primary PCI for diabetic and nondiabetic patients, respectively (17). Moreover, different cutoff values were used for diabetic and nondiabetic patients, since previous studies (5,17) have demonstrated that the infarct size in nondiabetic patients increases with hyperglycemia, but only with server hyperglycemia among nondiabetic patients. However, a separate analysis was also performed using the same cutoff value independent of the diabetic state (8.3 mmol/L). Hypoglycemia was defined as a blood glucose level of <3.3 mmol/L (60 mg/dL) (11).

Angiography

The angiograms were analyzed for collateral flow to the infarct-related artery according to the Rentrop classification grade (0–3), TIMI flow grade (0–3), and for area at risk according to the APPROACH (Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease) score (34).

CMR

The CMR protocol and image analyses has previously been described in detail (30). In brief, a CMR scan was performed from day 1 to day 7 after the primary PCI (2528), and a second CMR was repeated 3 months ± 3 weeks after the primary PCI. Both scans were performed on a 1.5 Tesla scanner (Avanto; Siemens, Erlangen, Germany) using a 6-channel body array coil. The myocardial area at risk was assessed on the first CMR scan as myocardial edema using a T2-weighted short tau inversion recovery sequence (Fig. 1A). On the second CMR examination, delayed enhancement images were obtained to determine the final infarct size using an ECG triggered inversion-recovery sequence (Fig. 1B). These images were acquired 10 min after intravenous injection of 0.1 mg/kg body weight gadolinium-diethylenetriaminepentaacetic acid (Gadovist; Bayer Schering, Berlin, Germany). Left ventricular (LV) volumes and function were measured from both CMR examinations using an ECG-triggered, balanced steady-state, free precession cine sequence.

Figure 1

Examples of T2-weighted and delayed enhancement images. A delayed enhancement image was used for final infarct size analysis (A), and a T2-weighted image was used for area-at-risk analysis (B). The endocardial and the epicardial borders were manually traced in all short-axis images, and the LV myocardial mass was calculated. Papillary muscles were considered parts of the LV cavity. C: A semiautomatic approach was used to calculate the infarct size. The mean signal intensity was determined automatic in five sectors in each slice. The region with the lowest mean signal intensity was considered “remote” myocardium. A slice-specific threshold was then set as the mean of the remote sector plus 1.8 SDs. In order to take the partial volume effect into account, each pixel within the infarct region was then weighted according to the signal intensity, where the minimal detectable pixel was set as 10%, with weight shown by pink and yellow, respectively. D: The area at risk was defined as the hyperintense area on T2-weighted images. The remote myocardium was determined visually, and the signal intensity within this region was calculated by tracing a region of at least 10 pixels in the middle of the myocardial wall. The signal intensity was then adjusted to the value of the normal + 2 SDs, and the areas of hyperintensity were traced manually.

Figure 1

Examples of T2-weighted and delayed enhancement images. A delayed enhancement image was used for final infarct size analysis (A), and a T2-weighted image was used for area-at-risk analysis (B). The endocardial and the epicardial borders were manually traced in all short-axis images, and the LV myocardial mass was calculated. Papillary muscles were considered parts of the LV cavity. C: A semiautomatic approach was used to calculate the infarct size. The mean signal intensity was determined automatic in five sectors in each slice. The region with the lowest mean signal intensity was considered “remote” myocardium. A slice-specific threshold was then set as the mean of the remote sector plus 1.8 SDs. In order to take the partial volume effect into account, each pixel within the infarct region was then weighted according to the signal intensity, where the minimal detectable pixel was set as 10%, with weight shown by pink and yellow, respectively. D: The area at risk was defined as the hyperintense area on T2-weighted images. The remote myocardium was determined visually, and the signal intensity within this region was calculated by tracing a region of at least 10 pixels in the middle of the myocardial wall. The signal intensity was then adjusted to the value of the normal + 2 SDs, and the areas of hyperintensity were traced manually.

An observer blinded to all clinical data analyzed the images, and for all analyses the endocardial and epicardial borders were manually traced by the incorporation of papillary muscles as part of the LV cavity. The final infarct size was measured using the free software Segment, version 1.8 (http://segment.heiberg.se) (Fig. 1C) (35). The infarct size, defined as the hyperenhanced myocardium on the delayed enhancement images, was determined by an automatic approach, as previously described (35). The infarct size was expressed as a percentage of the total LV mass and as an absolute mass. Using a postprocessing tool (Argus; Siemens, Erlangen, Germany), the area at risk was defined as the hyperintense area on T2-weighted images. A myocardial area was regarded as hyperintense whenever the signal intensity was >2 SDs of the signal intensity in the normal myocardium (Fig. 1D). The salvage index was calculated as follows: (area at risk − infarct size)/area at risk (29). On cine short-axis CMR images, the LV volume was calculated in all 25 phases by manually tracing the endocardial borders using a postprocessing tool (Argus; Siemens). According to the blood pool area, the LV diastolic and systolic frames were then identified; and LV end-diastolic volume, LV end-systolic volume, and LV ejection fraction were calculated.

Statistical Analysis

Patients with normoglycemia and hyperglycemia were compared using the two-tailed χ2 or Fisher exact test for categorical variables and the Student t test or Mann-Whitney U test according to normality for continuous variables. Normality was evaluated by histograms of the standardized residuals. To compare the relationship between the area at risk and the infarct size, a regression analysis was performed, and an ANCOVA was used to test for equality of the regression lines for the patients with normoglycemia and hyperglycemia. Multivariable regression models were performed to adjust for potential confounders using any baseline variable with P < 0.10 for the difference between normoglycemia and hyperglycemia, and diabetes mellitus status was forced into the model owing to the possible interaction with hyperglycemia. Among the nondiabetic patients, the correlation between blood glucose levels upon hospital admission as a continuous variable with area at risk, final infarct size, and myocardial salvage index was also evaluated using linear regression analyses. Since reperfusion injury occurs in the first minutes after reperfusion and TIMI flow grade 0/1 seems pivotal for cardioprotection (4), the patients with pre-PCI TIMI 0/1 flow were also analyzed separately. Exenatide treatment may potentially be a confounder; thus, a separate analysis was performed for patients treated with placebo. To evaluate the association between exenatide treatment and glycemic state upon hospital admission, the patients with TIMI 0/1 flow were stratified according to normoglycemia and hyperglycemia, and the effect of exenatide treatment upon myocardial salvage index was evaluate for each of these groups. Interaction between glycemic state and exenatide treatment in terms of myocardial salvage index was evaluated by ANCOVA. The models were constructed as follows: glycemic state, exenatide/placebo, and glycemic state * exenatide/placebo. A two-sided P value <0.05 was considered statistically significant. All statistical analyses were performed with SPSS software, version 20 (SPSS, Chicago, IL).

Study Population

The patient flowchart is shown in Fig. 2. Blood glucose level upon hospital admission was not available in 41 patients, and a further 44 patients were not considered for study inclusion owing to having aborted STEMI. A total of 92 patients (30%) considered for inclusion in this study were lost to CMR. The patients lost to CMR were older, had shorter system delays, and had better pre-PCI TIMI flow compared with the included patients (Table 1). We included 210 STEMI patients, of whom 25 patients were lost to the first CMR, leaving 185 patients with measurements of both the area at risk and final infarct size. The median blood glucose levels (interquartile range [IQR]) in patients without and with diabetes were 7.9 mmol/L (6.7–9.0 mmol/L) and 11.2 mmol/L (9.2–20.3 mmol/L), respectively. No patients had hypoglycemia upon hospital admission. One hundred twenty-five patients (60%) were in a normoglycemic state upon hospital admission, and 85 patients (40%) were in a hyperglycemic state. Baseline characteristics are presented in Table 2. Patients with hyperglycemia had a higher frequency of pre-PCI TIMI flow 0/1, higher levels of glucose, higher peak troponin T level, higher maximum ST-segment elevation before PCI, higher heart rate at hospital discharge, and shorter time from symptom onset until PCI; they were also more frequently treated with thrombectomy and less frequently randomized to receive exenatide (Table 2). Moreover, these patients tended to have a higher frequency of proximal occlusion (Table 2). Importantly, patients with known diabetes were equally distributed between the two groups (Table 2). The first and second CMRs were performed a median time of 2 days (IQR 1–2 days) and 90 days (IQR 83–95 days) after the STEMI, respectively, with no difference between the groups. A total of 78% of the population underwent the first CMR within 48 h after the STEMI.

Figure 2

Flowchart of patient disposition. CABG, coronary artery bypass graft surgery.

Figure 2

Flowchart of patient disposition. CABG, coronary artery bypass graft surgery.

Table 1

Baseline clinical, angiographic, and procedural characteristics for patients included and lost to CMR

CharacteristicsIncluded (n = 210)Lost to CMR (n = 92)P value
Age, years 61 ± 11 64 ± 12 0.045 
Male 80 75 0.45 
Known diabetes mellitus 10 0.83 
Hypertension 34 43 0.19 
Hypercholesterolemia 49 44 0.53 
Previous PCI 10 0.35 
Preinfarct angina 17 23 0.26 
Preinfarct medical treatment    
 β-Blockers 1.00 
 ACE inhibitors 11 10 0.84 
 Statin 15 18 0.60 
 Aspirin 14 17 0.59 
Hospital admission glucose, mmol/L 8.0 (6.8–9.3) 7.9 (6.7–9.6) 0.87 
Hyperglycemia upon hospital admission 41 44 0.61 
Creatinine, µmol/L 71 (61–86) 71 (58–89) 0.97 
Symptom-to-balloon, min 176 (120–270) 195 (137–265) 0.76 
System delay, min 132 (102–161) 115 (92–145) 0.009 
Maximum ST-segment elevation pre-PCI, mm 3.0 (1.6–5.2) 2.9 (1.5–4.7) 0.69 
LAD infarct location 44 42 0.80 
TIMI flow pre-PCI    
 0/1 68 66  
 2 17 0.043 
 3 15 25  
Proximal culprit location 31 24 0.27 
Bifurcation 0.45 
Collateral flow (Rentrop grade 2/3) 14 13 0.86 
Multiple vessel disease 19 18 0.87 
Visual thrombus 79 74 0.36 
TIMI grade 3 after procedure 94 97 0.42 
Randomized to exenatide 57 45 0.06 
Thrombectomy 56 62 0.31 
Stent    
 No stenting 11 16 0.39 
 Bare metal stent 22 29 
 Drug-eluting stent 67 55  
Treatment with GP IIb/IIIa inhibitor 85 87 0.72 
Peak troponin T, µg/L 4.1 (1.9–7.3) 3.8 (1.7–8.1) 0.74 
CharacteristicsIncluded (n = 210)Lost to CMR (n = 92)P value
Age, years 61 ± 11 64 ± 12 0.045 
Male 80 75 0.45 
Known diabetes mellitus 10 0.83 
Hypertension 34 43 0.19 
Hypercholesterolemia 49 44 0.53 
Previous PCI 10 0.35 
Preinfarct angina 17 23 0.26 
Preinfarct medical treatment    
 β-Blockers 1.00 
 ACE inhibitors 11 10 0.84 
 Statin 15 18 0.60 
 Aspirin 14 17 0.59 
Hospital admission glucose, mmol/L 8.0 (6.8–9.3) 7.9 (6.7–9.6) 0.87 
Hyperglycemia upon hospital admission 41 44 0.61 
Creatinine, µmol/L 71 (61–86) 71 (58–89) 0.97 
Symptom-to-balloon, min 176 (120–270) 195 (137–265) 0.76 
System delay, min 132 (102–161) 115 (92–145) 0.009 
Maximum ST-segment elevation pre-PCI, mm 3.0 (1.6–5.2) 2.9 (1.5–4.7) 0.69 
LAD infarct location 44 42 0.80 
TIMI flow pre-PCI    
 0/1 68 66  
 2 17 0.043 
 3 15 25  
Proximal culprit location 31 24 0.27 
Bifurcation 0.45 
Collateral flow (Rentrop grade 2/3) 14 13 0.86 
Multiple vessel disease 19 18 0.87 
Visual thrombus 79 74 0.36 
TIMI grade 3 after procedure 94 97 0.42 
Randomized to exenatide 57 45 0.06 
Thrombectomy 56 62 0.31 
Stent    
 No stenting 11 16 0.39 
 Bare metal stent 22 29 
 Drug-eluting stent 67 55  
Treatment with GP IIb/IIIa inhibitor 85 87 0.72 
Peak troponin T, µg/L 4.1 (1.9–7.3) 3.8 (1.7–8.1) 0.74 

Data are presented as the mean ± SD, median (IQR), or %, unless otherwise indicated. GP, glycoprotein; LAD, left anterior descending artery.

Table 2

Baseline clinical, angiographic, and procedural characteristics according to glycemic state upon hospital admission

CharacteristicsNormoglycemic
(n = 125 [60%])*Hyperglycemic
(n = 85 [40%])P value
Age, years 61 ± 11 61 ± 10 0.84 
Male 83 75 0.16 
Known diabetes mellitus 0.97 
Hypertension 32 39 0.27 
Hypercholesterolemia 49 48 0.89 
Previous PCI 0.46 
Preinfarct angina 18 17 0.81 
Preinfarct medical treatment    
 β-Blockers 0.79 
 ACE inhibitors 14 0.26 
 Statin 14 17 0.57 
 Aspirin 12 16 0.50 
Hospital admission glucose, mmol/L 6.7 (6.1–7.4) 9.1 (8.4–10.8) <0.001 
Glucose at end of PCI, mmol/L 6.1 (5.4–6.8) 8.2 (7.3–9.9) <0.001 
Time to CMR 1, days 2 (1–2) 2 (1–2) 0.28 
Time to CMR 2, days 89 (80–95) 91 (85–95) 0.53 
Symptom-to-balloon, min 190 (145–275) 165 (120–260) 0.040 
System delay, min 131 (102–165) 132 (101–158) 0.25 
Maximum ST-segment elevation pre-PCI, mm 2.6 (1.3–4.8) 3.5 (2.0–5.5) 0.003 
LAD infarct location 39 48 0.18 
TIMI flow pre-PCI    
 0/1 61 76  
 2 21 12 0.06 
 3 18 12  
Proximal culprit location 27 39 0.07 
Bifurcation 10 0.42 
APPROACH score, % LV (n = 208) 27 (18–29) 28 (22–34) 0.014 
Collateral flow (Rentrop grade 2/3) 15 13 0.71 
Multiple vessel disease 17 20 0.55 
Visual thrombus 78 81 0.64 
TIMI grade 3 after procedure 94 95 0.68 
Randomized to exenatide 65 47 0.011 
Thrombectomy 49 66 0.017 
Stent    
 No stenting 12 10 0.50 
 Bare metal stent 24 31 
 Drug-eluting stent 64 59  
Treatment with GP IIb/IIIa inhibitor 84 86 0.66 
Heart rate at discharge, bpm 73 ± 12 77 ± 13 0.044 
Peak troponin T, µg/L 3.5 (1.6–6.2) 4.4 (2.0–7.9) 0.023 
Acute LVEF 54 (47–59) 52 (45–59) 0.34 
Follow-up LVEF 58 (52–62) 56 (51–65) 0.64 
CharacteristicsNormoglycemic
(n = 125 [60%])*Hyperglycemic
(n = 85 [40%])P value
Age, years 61 ± 11 61 ± 10 0.84 
Male 83 75 0.16 
Known diabetes mellitus 0.97 
Hypertension 32 39 0.27 
Hypercholesterolemia 49 48 0.89 
Previous PCI 0.46 
Preinfarct angina 18 17 0.81 
Preinfarct medical treatment    
 β-Blockers 0.79 
 ACE inhibitors 14 0.26 
 Statin 14 17 0.57 
 Aspirin 12 16 0.50 
Hospital admission glucose, mmol/L 6.7 (6.1–7.4) 9.1 (8.4–10.8) <0.001 
Glucose at end of PCI, mmol/L 6.1 (5.4–6.8) 8.2 (7.3–9.9) <0.001 
Time to CMR 1, days 2 (1–2) 2 (1–2) 0.28 
Time to CMR 2, days 89 (80–95) 91 (85–95) 0.53 
Symptom-to-balloon, min 190 (145–275) 165 (120–260) 0.040 
System delay, min 131 (102–165) 132 (101–158) 0.25 
Maximum ST-segment elevation pre-PCI, mm 2.6 (1.3–4.8) 3.5 (2.0–5.5) 0.003 
LAD infarct location 39 48 0.18 
TIMI flow pre-PCI    
 0/1 61 76  
 2 21 12 0.06 
 3 18 12  
Proximal culprit location 27 39 0.07 
Bifurcation 10 0.42 
APPROACH score, % LV (n = 208) 27 (18–29) 28 (22–34) 0.014 
Collateral flow (Rentrop grade 2/3) 15 13 0.71 
Multiple vessel disease 17 20 0.55 
Visual thrombus 78 81 0.64 
TIMI grade 3 after procedure 94 95 0.68 
Randomized to exenatide 65 47 0.011 
Thrombectomy 49 66 0.017 
Stent    
 No stenting 12 10 0.50 
 Bare metal stent 24 31 
 Drug-eluting stent 64 59  
Treatment with GP IIb/IIIa inhibitor 84 86 0.66 
Heart rate at discharge, bpm 73 ± 12 77 ± 13 0.044 
Peak troponin T, µg/L 3.5 (1.6–6.2) 4.4 (2.0–7.9) 0.023 
Acute LVEF 54 (47–59) 52 (45–59) 0.34 
Follow-up LVEF 58 (52–62) 56 (51–65) 0.64 

Data are presented as mean ± SD, median (IQR), or %, unless otherwise indicated. GP, glycoprotein; LAD, left anterior descending artery; LVEF, LV ejection fraction.

*Blood glucose level <8.3 or 12.8 mmol/L.

†Blood glucose level >8.2 or 12.7 mmol/L.

Hyperglycemia and Area at Risk and Myocardial Salvage Index

STEMI patients with hyperglycemia had a larger area at risk measured by CMR than patients with normoglycemia, with medians of 32% LV (IQR 26–39% LV) and 29% LV (IQR 23–36% LV), respectively (Fig. 3A), as measured by the angiographic APPROACH score (Table 2). As expected, the final median infarct size measured by CMR was also larger in the hyperglycemic patients compared with the normoglycemic patients (11% LV [IQR 6–17% LV] vs. 8% LV [IQR 5–13% LV]) (Fig. 3B). However, the median myocardial salvage index determined by CMR did not differ between the groups (0.71 [IQR 0.64–0.82] and 0.73 [IQR 0.61–0.82], respectively) (Fig. 3C). Using the angiographic APPROACH score to calculate the median myocardial salvage index did not change the result (0.61 [IQR 0.47–0.74] vs. 0.62 [IQR 0.45–0.80], respectively; P = 0.58). The final infarct was not different adjusting for area at risk, since the regression lines for the hyperglycemic and normoglycemic patients were superimposed (Fig. 3D). In a multivariable analysis, hyperglycemia was not independently associated with final infarct size (Table 3).

Figure 3

Impact of hyperglycemia on area at risk, infarct size, and salvage index in patients with STEMI. Box plots (25th percentile, median, and 75th percentile) and whisker (5th and 95th percentile) showing the influence of hospital admission glucose level on CMR-measured myocardial area at risk (A), final infarct size (B), and myocardial salvage index (C). D: Infarct size was also plotted against the myocardial area at risk. There was no difference between the regression lines for patients with normoglycemia and hyperglycemia upon hospital admission (P = 0.82). In both groups, the infarct size correlates with the area at risk (r = 0.80 and r = 0.75, P < 0.001). DM, diabetes mellitus.

Figure 3

Impact of hyperglycemia on area at risk, infarct size, and salvage index in patients with STEMI. Box plots (25th percentile, median, and 75th percentile) and whisker (5th and 95th percentile) showing the influence of hospital admission glucose level on CMR-measured myocardial area at risk (A), final infarct size (B), and myocardial salvage index (C). D: Infarct size was also plotted against the myocardial area at risk. There was no difference between the regression lines for patients with normoglycemia and hyperglycemia upon hospital admission (P = 0.82). In both groups, the infarct size correlates with the area at risk (r = 0.80 and r = 0.75, P < 0.001). DM, diabetes mellitus.

Table 3

Multivariable predictors for final infarct size

r valueP value
Hyperglycemia −0.08 0.31 
Maximum ST-segment elevation pre-PCI 0.36 <0.001 
TIMI flow pre-PCI −0.18 0.028 
Proximal culprit location 0.13 0.09 
Symptom-to-balloon 0.14 0.06 
Thrombectomy 0.06 0.46 
Randomized to exenatide −0.04 0.62 
Heart rate at discharge, bpm 0.33 <0.001 
r valueP value
Hyperglycemia −0.08 0.31 
Maximum ST-segment elevation pre-PCI 0.36 <0.001 
TIMI flow pre-PCI −0.18 0.028 
Proximal culprit location 0.13 0.09 
Symptom-to-balloon 0.14 0.06 
Thrombectomy 0.06 0.46 
Randomized to exenatide −0.04 0.62 
Heart rate at discharge, bpm 0.33 <0.001 

Using a cutoff value of 8.3 mmol/L to define hyperglycemia, patients with hyperglycemia still had a larger median area at risk measured by CMR (29% LV [IQR 22–37% LV] vs. 32% LV [IQR 25–39% LV]; P = 0.049) and the angiographic APPROACH score (27% LV [IQR 19–29% LV] vs. 28% LV [IQR 21–33% LV]; P = 0.036). The association between hyperglycemia and final infarct size seems to be weaker (9% LV [5–13% LV] vs. 10% LV [IQR 6–16% LV]; P = 0.06). The myocardial salvage index did not differ between the groups (0.72 [IQR 0.61–0.82] vs. 0.72 [IQR 0.64–0.83]; P = 0.59). Accordingly, the infarct size was not different adjusting for area at risk (P = 0.57). Among the nondiabetic patients the level of blood glucose upon hospital admission as a continuous variable correlated with final infarct size (r = 0.17; P = 0.018), area at risk by CMR (r = 0.28; P < 0.001), and APPROACH score (r = 0.15; P = 0.042), but not myocardial salvage index (r = 0.07; P = 0.36).

A total of 141 patients had pre-PCI TIMI grade 0/1 flow, of whom 76 (54%) had normal glucose levels upon hospital admission and 65 (46%) had elevated levels. Evaluating only patients with TIMI 0/1 grade flow before undergoing PCI, hyperglycemia was associated with a larger area at risk compared with normoglycemia (33% LV [IQR 27–44% LV] vs. 30% LV [IQR 25–38]; P = 0.042), just as final infarct size tended to be larger (13% LV [IQR 8–18% LV] vs. 10% LV [IQR 7–14% LV]; P = 0.07). However, either the median myocardial salvage index determined by CMR (0.70 [IQR 0.62–0.77] vs. 0.68 [IQR 0.57–0.76]; P = 0.44) or the final infarct size adjusting for the area at risk (P = 0.98) were significantly different between the two groups.

When the patients randomized to receive placebo alone (n = 89) were analyzed, the overall results did not change. Patients with hyperglycemia had a larger myocardium area at risk than normoglycemic with median values of 32% LV (IQR 26–39% LV) and 27% LV (IQR 22–32% LV) (P = 0.008). The final infarct size was numerically larger with a median of 12% LV (IQR 6–17% LV) compared with 9% LV (IQR 5–13% LV) (P = 0.15). The median myocardial salvage index as determined by CMR was 0.70 (IQR 0.60–0.79) for patients with hyperglycemia and 0.69 (IQR 0.58–0.84) for patients with normoglycemia (P = 0.98).

Exenatide and Hyperglycemia

Among patients with TIMI 0/1 grade flow before undergoing PCI, exenatide treatment was associated with a lower blood glucose level upon hospital admission, immediately after the PCI, and 6 h after the PCI (Fig. 4). In patients with normoglycemia, treatment with exenatide resulted in a mean myocardial salvage index determined by CMR of 0.68 ± 0.17 compared with 0.62 ± 0.12 for patients treated with placebo (P = 0.08). Among the patients with hyperglycemia, the myocardial salvage index determined by CMR was 0.73 ± 0.11 for patients treated with exenatide, and 0.64 ± 0.15 for patients treated with placebo (P = 0.017). However, there was no statistically significant interaction between the glycemic state upon hospital admission and treatment allocation (exenatide vs. placebo) with regard to myocardial salvage index (P = 0.71).

Figure 4

Effect of exenatide treatment on blood glucose levels in patients with STEMI and TIMI grade 0/1 flow. The blood glucose level after treatment with exenatide (blue columns) is lower compared with treatment with placebo (green columns), measured upon hospital admission (before PCI), immediately after the PCI, and 6 h after the PCI.

Figure 4

Effect of exenatide treatment on blood glucose levels in patients with STEMI and TIMI grade 0/1 flow. The blood glucose level after treatment with exenatide (blue columns) is lower compared with treatment with placebo (green columns), measured upon hospital admission (before PCI), immediately after the PCI, and 6 h after the PCI.

In the current study, we found that hyperglycemia upon hospital admission in STEMI patients treated with primary PCI is related to a larger myocardium area at risk and final infarct size, without affecting the potential for myocardial salvage. Also, despite the lower blood glucose level in patients treated with exenatide, there was no interaction between glycemic state and exenatide treatment, indicating that the cardioprotective effect of exenatide treatment is independent of glucose level upon hospital admission.

This is the first study to assess the association of glycemic state upon hospital admission with the myocardium area at risk and myocardial salvage in a large cohort of patients with STEMI. Our data suggest that the excessive myocardial damage (58) and adverse prognosis (3,5,819) reported in patients with hyperglycemia are the results of a larger myocardial area at risk, and not of a smaller myocardial salvage. Similarly, since there was no association between hyperglycemia and infarct size when adjusting for the area at risk, the current study demonstrates that the association between hyperglycemia and infarct size is dependent on the size of the area at risk, and hyperglycemic patients can therefore be considered to be at higher risk per se. The patients with hyperglycemia more frequently have anterior infarct location and pre-PCI TIMI flow grade 0/1 and a shorter time from symptom onset until balloon (5,8,17). However, it has previously been demonstrated that the blood glucose level upon hospital admission fails to predict prognosis when adjusted for other predictors including duration of symptoms, TIMI flow, and infarct location (8); likewise, hyperglycemia in the current study failed to predict infarct size in the multivariable analysis. The relationship between hyperglycemia and duration of symptoms might indicate that the early presenters with more pronounced symptoms and faster reaction are at higher risk (36). Importantly, there was no difference in system delay, which is a stronger predictor than time from the onset of symptoms to balloon angioplasty (37,38). Thus, it seems more plausible that hyperglycemia upon hospital admission in STEMI patients is an indicator of increased myocardium area at risk and a marker for the severity of the myocardial damage, rather than being a deteriorating factor in itself.

Cell death owing to lethal reperfusion injury cannot be distinguished from ischemia-induced cell death in vivo, but since it occurs during the reperfusion phase a decrease in myocardial salvage or a larger infarct size adjusted for area at risk would be expected. In this study, hyperglycemia was not related to either of these in the entire cohort of patients with STEMI or in patients with pre-PCI TIMI grade 0/1 flow, which indicates that hyperglycemia does not lead to further irreversible myocardial damage during and after reperfusion with PCI. Thus, our findings suggest that hyperglycemia upon hospital admission is not related to lethal reperfusion injury and does not reduce the potential of salvage. This suggests that hyperglycemia is not directly involved in the death of the myocytes, but is the consequence of metabolic derangements caused by an increased myocardium at risk leading to more extensive myocardial damage. Interestingly, after an acute myocardial infarction the level of serum insulin is not associated with biomarkers reflecting the infarct size and paradoxically is weakly positively correlated with glucose levels (39). Hyperglycemia upon hospital admission is therefore not explained by a decrease in serum insulin level, but may be the result of increased levels of stress hormones leading to greater glucose availability, which may in fact benefit the hibernating myocytes and prevent further apoptosis (40). This may also help to explain the overall disappointing results of previous studies of glucose-lowering therapy in patients with acute coronary syndrome (41). In randomized settings, de Mulder et al. (41) evaluates the effect of insulin treatment on infarct size in patients presenting with STEMI and hyperglycemia, and concluded that glucose-lowering therapy with insulin did not reduce infarct size, but paradoxically tended to increase the infarct size. In contradiction, in the POSTCON II study exenatide therapy resulted in lower glucose levels, an increase in myocardial salvage and decrease in the infarct size adjusted for the area at risk (30). But the cardioprotective effect of exenatide is still not determined and probably involves a direct cardiac action (see below), and the glucose-lowering effect of exenatide is not as dramatic and abrupt as the effect of insulin and does not result in hypoglycemia. Interestingly, Selker et al. (42) reported a reduction in infarct size in patients with suspected acute coronary syndrome and in STEMI patients after prehospital treatment with glucose-insulin-potassium. However, the protective effect of glucose-insulin-potassium treatment is considered to be the cause of increased glucose uptake and improved metabolic support to the ischemic myocardium and not a reduction in the blood glucose level (40,42).

The cardioprotective effects of glucagon-like peptide 1 (GLP-1) and its analogs may be mediated through both cardiac and noncardiac sites of action. GLP-1 receptors have been described in cardiomyocytes, endocardium, vascular endothelium, and smooth muscle cells of rodent hearts (43), and several survival signaling pathways have been proposed to be activated by these receptors (33). However, the expression of GLP-1 receptors in human hearts remains controversial (44). Cardiac as well as noncardiac insulinotropic and insulinomimetic effects, including an increased glucose uptake, might also contribute to the cardioprotective action of GLP-1 analogs. Indeed, we observed a reduced level of glucose before and after the PCI after treatment with intravenous exenatide. However, the cardioprotective effect of exenatide is independent of hyperglycemia upon hospital admission in STEMI patients, but whether the effect is dependent on increased glucose uptake remains unknown.

In contrast to findings in the current study, a previous study by Teraguchi et al. (21) reports a decreased myocardial salvage index in patients with hyperglycemia. The following important differences between that study and ours should be taken into account: 1) Teraguchi et al. (21) did not report data on the area at risk or infarct size, and information regarding pre-PCI TIMI flow is missing, which is an important predictor for myocardial salvage index (45); 2) the time from symptom onset until reperfusion is twice as long in the study by Teraguchi et al. (21) compared with the present study, with means of 375 and 180 min, respectively; and 3) Teraguchi et al. (21) used a cutoff value of 10 mmol/L (180 mg/dL) to identify the patients with hyperglycemia among both diabetic and nondiabetic patients, which does not seem to be optimal in terms of predicting outcome. Eitel et al. (5) demonstrated that a glucose level >7.8 mmol/L is related to larger infarct size in nondiabetic patients, whereas in patients with diabetes a glucose level exceeding 11.1 mmol/L was related to larger infarct size. Similar, Teraguchi et al. (21) found that a glucose level exceeding 10 mmol/L was related to infarct size in nondiabetic patients but not in patients with diabetes. Planer et al. (17) also report different cutoff values for diabetic and nondiabetic patients. In 3,405 STEMI patients, they identified 8.3 and 12.8 mmol/L as the most optimal cutoff values for predicting 30-day mortality in nondiabetic and diabetic patients, respectively (17). Thus, these particular cutoff values were used in the current study, and the findings confirm these values as related to outcome. However, it is still uncertain whether or not to use the same or different cutoff values according to patients with diabetes, but previous observations indicate that the importance of glucose levels in STEMI patients depends on the diabetic state. The current study includes an additional analysis with one definition of hyperglycemia (8.3 mmol/L) without changing the overall results, but the association between hyperglycemia and final infarct size may be weaker. Too few patients with diabetes were included in this study, and it lacks sufficient power to draw any firm conclusions regarding the use of the same or different cutoff values to define hyperglycemia. Using one cutoff value will place most patients with diabetes in the hyperglycemic group, resulting in an inherent bias. Interestingly, Eitel et al. (5) found that hyperglycemia was related to microvascular obstruction by CMR, but the patients were not stratified according to pre-PCI TIMI flow, a pivotal factor for the PCI-induced reperfusion injury (4). Also, there are no data on the area at risk or multivariate analysis; thus, whether hyperglycemia is a cause or a consequence of microvascular obstruction remains unknown. Unfortunately, no data regarding microvascular obstruction were available, since delayed enhancement images were not acquired during the initial scan, which is a limitation to this study.

Study Limitations

Owing to the post hoc nature of our study findings, regarding the association between exenatide and blood glucose levels may only be considered hypothesis generating. Patients in this study were randomized to receive either placebo or exenatide, which could have affected the association between hyperglycemia and myocardial damage, especially since the blood samples were collected after randomization. It is therefore important to underscore that evaluating only the patients treated with placebo did not change the results. Thus, a possible confounding role of exenatide appears unlikely, but using all patients in this substudy increases the statistical power. Area at risk was evaluated by assessing myocardial edema after reperfusion; thus, hyperglycemia may potentially also change the level of myocardial edema. Using CMR has some obvious advantages, as mentioned in the 1Introduction, but also carries inherent limitations owing to contraindications. In the current study, a total of 30% of the patients intended for analysis were lost to CMR, which induces a certain risk of selection bias. Furthermore, the excluded patients and the patients lost to CMR may present some of the most critically ill patients (e.g., patients with renal failure, unconsciousness, or cardiogenic shock), which introduces a risk of selection bias. However, the patients lost to CMR were older, but in contrast had better pre-PCI TIMI flow and shorter system delay; thus, these patients were not sicker, which further limits the risk for selection bias. A relatively wide time window was allowed for the first CMR, but the same time window has been used in previous studies that have validated T2-weighted CMR to delineate area at risk (2528). The majority of the patients underwent the first CMR scan within 48 h (78%), and there was no difference between the groups. Importantly, other estimates of the area at risk, such as by the angiography APPROACH score and ST-segment elevation prior to PCI, were also higher among patients with hyperglycemia, which supports the CMR findings. In the original study, patients were included when they had TIMI flow grade 0/1 before intervention and no other stenosis >70% than the culprit lesion (30). While preprocedural TIMI flow is well-established as a pivotal determinant of reperfusion injury, the role of multivessel disease is more controversial (4). Consequently, in order to increase the statistical power of the present analysis patients with multivessel disease were not excluded. Owing to many statistical comparisons, some significant differences may be observed by chance leading to a risk of type II errors, and the results must be interpreted cautiously and need to be confirmed.

Conclusions

The association between hyperglycemia upon hospital admission and larger infarct size in STEMI patients treated with PCI is explained by a larger myocardial area at risk but not by a reduction in myocardial salvage. Also, cardioprotection by exenatide treatment is independent of hospital admission glucose levels. Thus, we conclude that hyperglycemia does not influence the effect of the reperfusion treatment but rather serves as a marker for the severity of myocardium at risk and injury.

Clinical trial reg. no. NCT00835848, clinicaltrials.gov.

See accompanying article, p. 2209.

Funding. This research was supported by the Danish National Research Foundation for Heart Arrhythmia, the Novo Nordisk Foundation, Danielsen’s Foundation, Rigshospitale's Research Foundation, and the Danish Heart Foundation.

Duality of Interest. H.E.B. is a shareholder in CellAegis Inc. P.C. has received grants from Eli Lilly. T.E. has received grants from and is a member of the advisory board of Eli Lilly. No other potential conflicts of interest relevant to this article were reported.

Authors Contributions. J.L. contributed to the conceptual design, the follow-up of patients, and data quality control; performed the cardiovascular magnetic resonance scan and analysis and angiography; researched the data; performed the general data analysis; and wrote the manuscript, including statistics, tables, and figures. N.V. and W.Y.K. contributed to conceptual design and participated in the cardiovascular magnetic resonance scan protocol and analysis. H.K., E.J., S.H., L.H., K.S., H.E.B., P.C., and M.T. contributed to conceptual design and data analysis and recruitment and enrollment of patients. L.N.-C. contributed to conceptual design, data analysis, data research, and follow-up of patients. T.E. was principal investigator and contributed to conceptual design and data analysis, angiographic data analysis, data research, and recruitment and enrollment of patients. All authors have contributed significantly to the making of the manuscript, to trial design, and to the reviewing and editing of the manuscript. J.L. and T.E. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. Parts of this study were presented at the 25th Transcatheter Cardiovascular Therapeutics Annual Scientific Symposium, San Francisco, CA, 27 October–1 November 2013.

1.
Hamm
CW
,
Bassand
JP
,
Agewall
S
, et al
ESC Committee for Practice Guidelines
.
ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC)
.
Eur Heart J
2011
;
32
:
2999
3054
[PubMed]
2.
Yellon
DM
,
Hausenloy
DJ
.
Myocardial reperfusion injury
.
N Engl J Med
2007
;
357
:
1121
1135
[PubMed]
3.
Kosiborod
M
,
McGuire
DK
.
Glucose-lowering targets for patients with cardiovascular disease: focus on inpatient management of patients with acute coronary syndromes
.
Circulation
2010
;
122
:
2736
2744
[PubMed]
4.
Hausenloy
DJ
,
Erik Bøtker
H
,
Condorelli
G
, et al
.
Translating cardioprotection for patient benefit: position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology
.
Cardiovasc Res
2013
;
98
:
7
27
[PubMed]
5.
Eitel
I
,
Hintze
S
,
de Waha
S
, et al
.
Prognostic impact of hyperglycemia in nondiabetic and diabetic patients with ST-elevation myocardial infarction: insights from contrast-enhanced magnetic resonance imaging
.
Circ Cardiovasc Imaging
2012
;
5
:
708
718
[PubMed]
6.
Jensen
CJ
,
Eberle
HC
,
Nassenstein
K
, et al
.
Impact of hyperglycemia at admission in patients with acute ST-segment elevation myocardial infarction as assessed by contrast-enhanced MRI
.
Clin Res Cardiol
2011
;
100
:
649
659
[PubMed]
7.
Mather
AN
,
Crean
A
,
Abidin
N
, et al
.
Relationship of dysglycemia to acute myocardial infarct size and cardiovascular outcome as determined by cardiovascular magnetic resonance
.
J Cardiovasc Magn Reson
2010
;
12
:
61
[PubMed]
8.
Timmer
JR
,
Hoekstra
M
,
Nijsten
MW
, et al
.
Prognostic value of admission glycosylated hemoglobin and glucose in nondiabetic patients with ST-segment-elevation myocardial infarction treated with percutaneous coronary intervention
.
Circulation
2011
;
124
:
704
711
[PubMed]
9.
Capes
SE
,
Hunt
D
,
Malmberg
K
,
Gerstein
HC
.
Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview
.
Lancet
2000
;
355
:
773
778
[PubMed]
10.
Foo
K
,
Cooper
J
,
Deaner
A
, et al
.
A single serum glucose measurement predicts adverse outcomes across the whole range of acute coronary syndromes
.
Heart
2003
;
89
:
512
516
[PubMed]
11.
Goyal
A
,
Mehta
SR
,
Díaz
R
, et al
.
Differential clinical outcomes associated with hypoglycemia and hyperglycemia in acute myocardial infarction
.
Circulation
2009
;
120
:
2429
2437
[PubMed]
12.
Hoebers
LP
,
Damman
P
,
Claessen
BE
, et al
.
Predictive value of plasma glucose level on admission for short and long term mortality in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention
.
Am J Cardiol
2012
;
109
:
53
59
[PubMed]
13.
Ishihara
M
,
Kagawa
E
,
Inoue
I
, et al
.
Impact of admission hyperglycemia and diabetes mellitus on short- and long-term mortality after acute myocardial infarction in the coronary intervention era
.
Am J Cardiol
2007
;
99
:
1674
1679
[PubMed]
14.
Ishihara
M
,
Kojima
S
,
Sakamoto
T
, et al
Japanese Acute Coronary Syndrome Study Investigators
.
Acute hyperglycemia is associated with adverse outcome after acute myocardial infarction in the coronary intervention era
.
Am Heart J
2005
;
150
:
814
820
[PubMed]
15.
Kadri
Z
,
Danchin
N
,
Vaur
L
, et al
USIC 2000 Investigators
.
Major impact of admission glycaemia on 30 day and one year mortality in non-diabetic patients admitted for myocardial infarction: results from the nationwide French USIC 2000 study
.
Heart
2006
;
92
:
910
915
[PubMed]
16.
Kosiborod
M
,
Rathore
SS
,
Inzucchi
SE
, et al
.
Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes
.
Circulation
2005
;
111
:
3078
3086
[PubMed]
17.
Planer
D
,
Witzenbichler
B
,
Guagliumi
G
, et al
.
Impact of hyperglycemia in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention: the HORIZONS-AMI trial
.
Int J Cardiol
2013
;
167
:
2572
2579
[PubMed]
18.
Stranders
I
,
Diamant
M
,
van Gelder
RE
, et al
.
Admission blood glucose level as risk indicator of death after myocardial infarction in patients with and without diabetes mellitus
.
Arch Intern Med
2004
;
164
:
982
988
[PubMed]
19.
Wahab
NN
,
Cowden
EA
,
Pearce
NJ
,
Gardner
MJ
,
Merry
H
,
Cox
JL
ICONS Investigators
.
Is blood glucose an independent predictor of mortality in acute myocardial infarction in the thrombolytic era?
J Am Coll Cardiol
2002
;
40
:
1748
1754
[PubMed]
20.
Ekmekci
A
,
Cicek
G
,
Uluganyan
M
, et al
.
Admission hyperglycemia predicts inhospital mortality and major adverse cardiac events after primary percutaneous coronary intervention in patients without diabetes mellitus
.
Angiology
2014
;
65
:
154
159
[PubMed]
21.
Teraguchi
I
,
Imanishi
T
,
Ozaki
Y
, et al
.
Impact of stress hyperglycemia on myocardial salvage following successfully recanalized primary acute myocardial infarction
.
Circ J
2012
;
76
:
2690
2696
[PubMed]
22.
Mahrholdt
H
,
Wagner
A
,
Holly
TA
, et al
.
Reproducibility of chronic infarct size measurement by contrast-enhanced magnetic resonance imaging
.
Circulation
2002
;
106
:
2322
2327
[PubMed]
23.
Kim
RJ
,
Fieno
DS
,
Parrish
TB
, et al
.
Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function
.
Circulation
1999
;
100
:
1992
2002
[PubMed]
24.
Aletras
AH
,
Tilak
GS
,
Natanzon
A
, et al
.
Retrospective determination of the area at risk for reperfused acute myocardial infarction with T2-weighted cardiac magnetic resonance imaging: histopathological and displacement encoding with stimulated echoes (DENSE) functional validations
.
Circulation
2006
;
113
:
1865
1870
[PubMed]
25.
Carlsson
M
,
Ubachs
JF
,
Hedström
E
,
Heiberg
E
,
Jovinge
S
,
Arheden
H
.
Myocardium at risk after acute infarction in humans on cardiac magnetic resonance: quantitative assessment during follow-up and validation with single-photon emission computed tomography
.
JACC Cardiovasc Imaging
2009
;
2
:
569
576
[PubMed]
26.
Hadamitzky
M
,
Langhans
B
,
Hausleiter
J
, et al
.
The assessment of area at risk and myocardial salvage after coronary revascularization in acute myocardial infarction: comparison between CMR and SPECT
.
JACC Cardiovasc Imaging
2013
;
6
:
358
369
[PubMed]
27.
Wright
J
,
Adriaenssens
T
,
Dymarkowski
S
,
Desmet
W
,
Bogaert
J
.
Quantification of myocardial area at risk with T2-weighted CMR: comparison with contrast-enhanced CMR and coronary angiography
.
JACC Cardiovasc Imaging
2009
;
2
:
825
831
[PubMed]
28.
Friedrich
MG
,
Abdel-Aty
H
,
Taylor
A
,
Schulz-Menger
J
,
Messroghli
D
,
Dietz
R
.
The salvaged area at risk in reperfused acute myocardial infarction as visualized by cardiovascular magnetic resonance
.
J Am Coll Cardiol
2008
;
51
:
1581
1587
[PubMed]
29.
Eitel
I
,
Desch
S
,
Fuernau
G
, et al
.
Prognostic significance and determinants of myocardial salvage assessed by cardiovascular magnetic resonance in acute reperfused myocardial infarction
.
J Am Coll Cardiol
2010
;
55
:
2470
2479
[PubMed]
30.
Lønborg
J
,
Vejlstrup
N
,
Kelbæk
H
, et al
.
Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction
.
Eur Heart J
2012
;
33
:
1491
1499
[PubMed]
31.
Lønborg
J
,
Kelbæk
H
,
Vejlstrup
N
, et al
.
Exenatide reduces final infarct size in patients with ST-segment-elevation myocardial infarction and short-duration of ischemia
.
Circ Cardiovasc Interv
2012
;
5
:
288
295
[PubMed]
32.
Holst
JJ
.
The physiology of glucagon-like peptide 1
.
Physiol Rev
2007
;
87
:
1409
1439
[PubMed]
33.
Treiman
M
,
Elvekjaer
M
,
Engstrøm
T
,
Jensen
JS
.
Glucagon-like peptide 1—a cardiologic dimension
.
Trends Cardiovasc Med
2010
;
20
:
8
12
[PubMed]
34.
Ortiz-Pérez
JT
,
Meyers
SN
,
Lee
DC
, et al
.
Angiographic estimates of myocardium at risk during acute myocardial infarction: validation study using cardiac magnetic resonance imaging
.
Eur Heart J
2007
;
28
:
1750
1758
[PubMed]
35.
Heiberg
E
,
Ugander
M
,
Engblom
H
, et al
.
Automated quantification of myocardial infarction from MR images by accounting for partial volume effects: animal, phantom, and human study
.
Radiology
2008
;
246
:
581
588
[PubMed]
36.
Nallamothu
BK
,
Bates
ER
,
Herrin
J
,
Wang
Y
,
Bradley
EH
,
Krumholz
HM
NRMI Investigators
.
Times to treatment in transfer patients undergoing primary percutaneous coronary intervention in the United States: National Registry of Myocardial Infarction (NRMI)-3/4 analysis
.
Circulation
2005
;
111
:
761
767
[PubMed]
37.
Lønborg
J
,
Schoos
MM
,
Kelbæk
H
, et al
.
Impact of system delay on infarct size, myocardial salvage index, and left ventricular function in patients with ST-segment elevation myocardial infarction
.
Am Heart J
2012
;
164
:
538
546
[PubMed]
38.
Terkelsen
CJ
,
Sørensen
JT
,
Maeng
M
, et al
.
System delay and mortality among patients with STEMI treated with primary percutaneous coronary intervention
.
JAMA
2010
;
304
:
763
771
[PubMed]
39.
Stubbs
PJ
,
Laycock
J
,
Alaghband-Zadeh
J
,
Carter
G
,
Noble
MI
.
Circulating stress hormone and insulin concentrations in acute coronary syndromes: identification of insulin resistance on admission
.
Clin Sci (Lond)
1999
;
96
:
589
595
[PubMed]
40.
Oliver
MF
,
Opie
LH
.
Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias
.
Lancet
1994
;
343
:
155
158
[PubMed]
41.
de Mulder
M
,
Umans
VA
,
Cornel
JH
, et al
.
Intensive glucose regulation in hyperglycemic acute coronary syndrome: results of the randomized BIOMarker study to identify the acute risk of a coronary syndrome-2 (BIOMArCS-2) glucose trial
.
JAMA Intern Med
2013
;
173
:
1896
1904
[PubMed]
42.
Selker
HP
,
Beshansky
JR
,
Sheehan
PR
, et al
.
Out-of-hospital administration of intravenous glucose-insulin-potassium in patients with suspected acute coronary syndromes: the IMMEDIATE randomized controlled trial
.
JAMA
2012
;
307
:
1925
1933
[PubMed]
43.
Ban
K
,
Noyan-Ashraf
MH
,
Hoefer
J
,
Bolz
SS
,
Drucker
DJ
,
Husain
M
.
Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways
.
Circulation
2008
;
117
:
2340
2350
[PubMed]
44.
Sivertsen
J
,
Rosenmeier
J
,
Holst
JJ
,
Vilsbøll
T
.
The effect of glucagon-like peptide 1 on cardiovascular risk
.
Nat Rev Cardiol
2012
;
9
:
209
222
[PubMed]
45.
Lønborg
J
,
Kelbæk
H
,
Vejlstrup
N
, et al
.
Influence of pre-infarction angina, collateral flow, and pre-procedural TIMI flow on myocardial salvage index by cardiac magnetic resonance in patients with ST-segment elevation myocardial infarction
.
Eur Heart J Cardiovasc Imaging
2012
;
13
:
433
443
[PubMed]