Download Impact of Acute Hyperglycemia on Myocardial Infarct Size

2474
Diabetes Volume 63, July 2014
Jacob Lønborg,1 Niels Vejlstrup,1 Henning Kelbæk,1 Lars Nepper-Christensen,1 Erik Jørgensen,1
Steffen Helqvist,1 Lene Holmvang,1 Kari Saunamäki,1 Hans Erik Bøtker,2 Won Yong Kim,2 Peter Clemmensen,1
Marek Treiman,3 and Thomas Engstrøm1
PHARMACOLOGY AND THERAPEUTICS
Impact of Acute Hyperglycemia
on Myocardial Infarct Size, Area
at Risk, and Salvage in Patients
With STEMI and the Association
With Exenatide Treatment:
Results From a Randomized
Study
Diabetes 2014;63:2474–2485 | DOI: 10.2337/db13-1849
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
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
1Department
Received 5 December 2013 and accepted 26 February 2014.
of Cardiology, Rigshospitalet, Copenhagen University Hospital,
Copenhagen, Denmark
2Department of Cardiology, Aarhus University Hospital, Skejby, Denmark
3Department of Biomedical Sciences and The Danish National Foundation
Research Centre for Heart Arrhythmia, Copenhagen University, Copenhagen,
Denmark
Corresponding author: Jacob Lønborg, [email protected].
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.
Clinical trial reg. no. NCT00835848, clinicaltrials.gov.
© 2014 by the American Diabetes Association. See http://creativecommons.org
/licenses/by-nc-nd/3.0/ for details.
See accompanying article, p. 2209.
diabetes.diabetesjournals.org
to the subsequent injury (4). Previous studies have demonstrated larger infarct size (5–8) and poorer prognosis in
patients with hyperglycemia upon hospital admission
compared with patients without hyperglycemia, both in
patients with and without diabetes mellitus (3,5,8–20).
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 (24–27), 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.
RESEARCH DESIGN AND METHODS
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
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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
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Hyperglycemia and Reperfusion Injury
performed from day 1 to day 7 after the primary PCI (25–
28), and a second CMR was repeated 3 months 6 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 gadoliniumdiethylenetriaminepentaacetic 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.
An observer blinded to all clinical data analyzed the
images, and for all analyses the endocardial and epicardial
Diabetes Volume 63, July 2014
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 2 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
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.
diabetes.diabetesjournals.org
and systolic frames were then identified; and LV enddiastolic volume, LV end-systolic volume, and LV ejection
fraction were calculated.
Statistical Analysis
Patients with normoglycemia and hyperglycemia were
compared using the two-tailed x2 or Fisher exact test for
categorical variables and the Student t test or MannWhitney 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).
RESULTS
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 prePCI 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
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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.
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).
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
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Figure 2—Flowchart of patient disposition. CABG, coronary artery bypass graft surgery.
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).
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Table 1—Baseline clinical, angiographic, and procedural characteristics for patients included and lost to CMR
Included (n = 210)
Lost to CMR (n = 92)
P value
61 6 11
64 6 12
0.045
80
75
0.45
Known diabetes mellitus
8
10
0.83
Hypertension
34
43
0.19
Hypercholesterolemia
49
44
0.53
Previous PCI
7
10
0.35
Preinfarct angina
17
23
0.26
Preinfarct medical treatment
b-Blockers
ACE inhibitors
Statin
Aspirin
8
11
15
14
8
10
18
17
1.00
0.84
0.60
0.59
8.0 (6.8–9.3)
7.9 (6.7–9.6)
0.87
41
44
0.61
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
Characteristics
Age, years
Male
Hospital admission glucose, mmol/L
Hyperglycemia upon hospital admission
Creatinine, mmol/L
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
2
3
68
17
15
66
9
25
0.043
Proximal culprit location
31
24
0.27
Bifurcation
7
5
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
Bare metal stent
Drug-eluting stent
11
22
67
16
29
55
0.39
85
87
0.72
4.1 (1.9–7.3)
3.8 (1.7–8.1)
0.74
Treatment with GP IIb/IIIa inhibitor
Peak troponin T, mg/L
Data are presented as the mean 6 SD, median (IQR), or %, unless otherwise indicated. GP, glycoprotein; LAD, left anterior descending artery.
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 6 0.17 compared with 0.62 6
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 6 0.11 for patients
treated with exenatide, and 0.64 6 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).
DISCUSSION
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
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Table 2—Baseline clinical, angiographic, and procedural characteristics according to glycemic state upon hospital admission
Normoglycemic
(n = 125 [60%])*
Hyperglycemic
(n = 85 [40%])†
P value
61 6 11
61 6 10
0.84
Male
83
75
0.16
Known diabetes mellitus
8
8
0.97
Hypertension
32
39
0.27
Hypercholesterolemia
49
48
0.89
Previous PCI
6
8
0.46
Preinfarct angina
18
17
0.81
Preinfarct medical treatment
b-Blockers
ACE inhibitors
Statin
Aspirin
8
9
14
12
7
14
17
16
0.79
0.26
0.57
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
,0.001
Characteristics
Age, years
6.1 (5.4–6.8)
8.2 (7.3–9.9)
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
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
2
3
61
21
18
76
12
12
0.06
Proximal culprit location
27
39
0.07
Bifurcation
6
10
0.42
Maximum ST-segment elevation pre-PCI, mm
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
Bare metal stent
Drug-eluting stent
12
24
64
10
31
59
0.50
Treatment with GP IIb/IIIa inhibitor
84
86
0.66
73 6 12
77 6 13
0.044
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
Heart rate at discharge, bpm
Peak troponin T, mg/L
Data are presented as mean 6 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.
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 (5–8) and adverse prognosis
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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 CMRmeasured 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.
(3,5,8–19) 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,
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Hyperglycemia and Reperfusion Injury
Diabetes Volume 63, July 2014
Table 3—Multivariable predictors for final infarct size
r value
Hyperglycemia
Maximum ST-segment elevation pre-PCI
TIMI flow pre-PCI
P value
20.08
0.31
0.36
,0.001
20.18
0.028
Proximal culprit location
0.13
0.09
Symptom-to-balloon
0.14
0.06
0.06
0.46
Thrombectomy
Randomized to exenatide
Heart rate at discharge, bpm
20.04
0.62
0.33
,0.001
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
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.
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
diabetes.diabetesjournals.org
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.
Lønborg and Associates
2483
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 INTRODUCTION, 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 (25–28). 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
2484
Hyperglycemia and Reperfusion Injury
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.
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.
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