CLINICAL STUDIES Myocardial Infarction and Acute Coronary Syndromes
Association Between Hyperglycemia
and the No-Reflow Phenomenon in
Patients With Acute Myocardial Infarction
Katsuomi Iwakura, MD,* Hiroshi Ito, MD, FACC,* Masashi Ikushima, MD,* Shigeo Kawano, MD,*
Atsushi Okamura, MD,* Katsuaki Asano, MD,* Tadashi Kuroda, MD,* Koji Tanaka, MD,*
Tohru Masuyama, MD,† Masatsugu Hori, MD,† Kenshi Fujii, MD*
Osaka, Japan
OBJECTIVES We investigated the association between hyperglycemia and the no-reflow phenomenon in
patients with acute myocardial infarction (AMI).
BACKGROUND Hyperglycemia is associated with increased risks of heart failure, cardiogenic shock, and death
after AMI, but its underlying mechanism remains unknown.
METHODS A total of 146 consecutive patients with a first AMI were studied by intracoronary myocardial
contrast echocardiography (MCE) after successful reperfusion within 24 h after symptom
onset. Two-dimensional echocardiography was recorded on day 1 and three months later to
determine the change in the wall motion score (�WMS; sum of 16 segmental scores;
dyskinesia � 4 to normokinesia � 0).
RESULTS The no-reflow phenomenon was found on MCE in 49 (33.6%) of 146 patients; their glucose
level on hospital admission was significantly higher than that of patients who did not exhibit
this phenomenon (209 � 79 vs. 159 � 56 mg/dl; p � 0.0001). There was no difference in
glycosylated hemoglobin or in the incidence of diabetes mellitus between the two subsets. The
no-reflow phenomenon was more often observed in the 75 patients with hyperglycemia
(�160 mg/dl) than in those without hyperglycemia (52.0% vs. 14.1%; p � 0.0001). Patients
with hyperglycemia had a higher peak creatine kinase level (2,497 � 1,603 vs. 1,804 �
1,300 IU/l; p� 0.005) and a lower �WMS (3.7� 4.8 vs. 5.7� 4.3; p� 0.01) than did those
without hyperglycemia. The blood glucose level was an independent prognostic factor for no
reflow, along with age, gender, absence of pre-infarction angina, complete occlusion of the
culprit lesion, and anterior AMI.
CONCLUSIONS Hyperglycemia might be associated with impaired microvascular function after AMI,
resulting in a larger infarct size and worse functional recovery. (J Am Coll Cardiol 2003;41:
1–7) © 2003 by the American College of Cardiology Foundation
Hyperglycemia can be observed in patients with acute
myocardial infarction (AMI), irrespective of a history of
diabetes mellitus (DM) (1–3), and is associated with in-
creased mortality after AMI (3–7). The decrease in blood
glucose, by an insulin-glucose infusion, during the first 24 h
after AMI decreases mortality in patients with DM (7). The
increased mortality in patients with hyperglycemia might be
explained by a larger infarct size (5), a high incidence of
congestive heart failure, and cardiogenic shock (6,8). How-
ever, the underlying mechanisms of these deleterious effects
of hyperglycemia are not well understood.
Impaired microvascular function, or the no-reflow phe-
nomenon, determines functional and clinical outcomes after
AMI (9,10). Myocardial contrast echocardiography (MCE)
has revealed that the no-reflow phenomenon is found in
25% to 30% of patients with AMI, despite successful
coronary recanalization, as shown by angiography (11,12),
and is associated with a larger infarction (11–13), poorer
functional recovery, and more frequent post-AMI compli-
cations (14). This study was conducted to investigate the
association between hyperglycemia and the no-reflow phe-
nomenon in patients with AMI.
METHODS
Study population. Between February 1999 and August
2001, 185 consecutive patients with a first AMI underwent
a primary percutaneous coronary intervention (PCI; angio-
plasty and/or stenting) for arteries exhibiting Thrombolysis
In Myocardial Infarction (TIMI) flow grade 0 or 1 within
24 h after symptom onset, and subsequently, they were
studied by MCE. The diagnosis of AMI was based on
prolonged chest pain lasting �30 min, ST-segment eleva-
tion �2 mm in at least two contiguous electrocardiographic
(ECG) leads, and a more than threefold increase in serum
creatine kinase (CK) levels. Thirty-nine patients were ex-
cluded because of poor echocardiographic images (n � 11),
cardiogenic shock (n � 2), spontaneous recanalization of
the culprit lesion (TIMI flow grade�2) at the time of initial
coronary angiography (n � 19), allergy to ioxaglate (n � 4),
and unsuccessful PCI (n � 3). Therefore, the final study
From the *Division of Cardiology, Sakurabashi Watanabe Hospital; and †Depart-
ment of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka
University, Osaka, Japan.
Manuscript received August 13, 2002; revised manuscript received September 12,
2002, accepted September 20, 2002.
Journal of the American College of Cardiology Vol. 41, No. 1, 2003
© 2003 by the American College of Cardiology Foundation ISSN 0735-1097/03/$30.00
Published by Elsevier Science Inc. PII S0735-1097(02)02626-8
population consisted of 146 patients. The study protocol
was approved by the hospital’s Ethics Committee, and
patients gave written, informed consent.
Study protocol. Just after hospital admission, a 12-lead
ECG was recorded and the blood glucose level was mea-
sured in each patient. All patients underwent two-
dimensional echocardiography with a SONOS 5500 system
(Philips Medical Systems, Andover, Massachusetts). All
patients received an intravenous infusion of nicorandil at 6
mg/h for 24 h after admission (15). Aspirin (243 mg) was
given orally at least 30 min before coronary angiography,
which was performed to find the culprit lesion and collateral
channels. Collateral channels were graded according to the
report by Rentrop (16), and good collateral flow was defined
as grade 2 or 3. We performed coronary angioplasty on the
culprit lesion by using appropriate-sized balloon catheters.
We repeated angioplasty or implanted a stent to reduce the
residual diameter stenosis to �50%. A repeat 12-lead ECG
was obtained during and after each PCI procedure. Coro-
nary reperfusion was achieved in all patients within 90 min
of blood glucose measurement. We did not treat hypergly-
cemia until the PCI procedure was completed and the
patient returned to coronary care unit.
At a mean time of 15 min after the last PCI procedure, we
performed MCE as previously reported (11,14). In brief, we
injected 2 ml sonicated ioxaglate (Hexabrix-320, Tanabe,
Osaka, Japan) containing microbubbles of a mean size of 12
�m into the coronary artery and recorded two-dimensional
echocardiograms. The MCE images, including the parasternal
short-axis view at the mid-papillary muscle level and the apical
two- and four-chamber views, were recorded on videotape. We
measured glycosylated hemoglobin (HbA1c) and total choles-
terol and triglyceride levels on the next day. We performed
echocardiography at a mean period of three months later to
determine the wall motion recovery.
Analysis of echocardiographic data. Two observers
blinded to the patients’ data independently evaluated wall
motion in 16 myocardial segments (17). Wall thickening of
each segment was scored as follows: 4 � dyskinesia; 3 �
akinesia; 2 � severe hypokinesia; 1 � hypokinesia; and 0 �
normokinesia or hyperkinesia. We defined the risk area as
myocardial segments showing dyskinesia, akinesia, or severe
hypokinesia on hospital admission. The wall motion score
(WMS) was calculated as the sum of the scores within the
area at risk. The difference between WMS on admission
and that three months later was defined as �WMS.
An experienced echocardiographer analyzed the MCE
images to determine the presence of the no-reflow phenom-
enon. We defined the no-reflow zone in end-diastolic
images as a contrast perfusion defect after PCI. We quan-
tified the area of no reflow as the ratio of it to the risk area
at baseline. When the ratio exceeded 25%, myocardial
reperfusion was considered incomplete (i.e., no reflow)
(11,14). We have reported the reproducibility of measuring
the size of the contrast defect (11). We also scored the
degree of contrast enhancement within the risk area as
follows: 1 � good enhancement; 0.5 � patchy or endocar-
dial enhancement; 0 � no enhancement (18).
Analysis of patient data. A physician obtained a detailed
clinical history for each study patient. Cardiac symptoms
lasting �30 min were defined as a sign of angina pectoris,
and angina occurring within 48 h before the onset of
infarction was defined as pre-infarction angina (19,20). A
clinical history of risk factors such as DM, hypertension,
hyperlipidemia, and smoking was determined from a patient
interview or medical records. Diabetes mellitus was consid-
ered present if this diagnosis and treatment, including diet,
drugs, or insulin, had been given to the patient or if an
abnormal oral glucose tolerance test or HbA1c �6.5% was
found after admission. We measured fasting blood glucose
in each patient at least twice during the hospital stay, and if
the patient without a history of risk factors or high HbA1c
showed fasting blood glucose �110 mg/dl, we performed a
glucose tolerance test. The patients who showed a high
blood glucose level on admission but who did not fulfill the
aforementioned criteria were classified as not having DM.
Re-elevation of the ST segment was defined as additional
ST-segment elevation on the ECG at reperfusion, com-
pared with that before PCI.
Statistics. All data are expressed as the mean value � SD.
We made comparisons by one-way analysis of variance
(ANOVA) for continuous variables, and significance of
difference was calculated by using the Scheffe´ F test.
Categorical variables were compared by the chi-squared test.
To define hyperglycemia, we constructed receiver-operating
characteristic curves and determined the suitable cutoff
point where sensitivity for the prediction of no reflow is
nearly equal to specificity. The association between hyper-
glycemia and �WMS or contrast enhancement score was
analyzed by analysis of co-variance (ANCOVA), with the
presence or absence of hyperglycemia as a fixed factor and
the peak CK value as a co-variate to adjust the differences in
infarct size. Multivariate logistic regression analysis was
used to identify independent predictors for the development
of the no-reflow phenomenon. Differences were considered
significant at p � 0.05. Statistical analysis was performed
with StatView, version 5.0 (SAS Institute, Cary, North
Carolina).
Abbreviations and Acronyms
AMI � acute myocardial infraction
CK � creatine kinase
DM � diabetes mellitus
ECG � electrocardiogram or electrocardiographic
HbA1c � glycosylated hemoglobin
MCE � myocardial contrast echocardiography
PCI � percutaneous coronary intervention
TIMI � Thrombolysis In Myocardial Infarction
WMS � wall motion score
2 Iwakura et al. JACC Vol. 41, No. 1, 2003
Hyperglycemia and Microvasculature in AMI January 1, 2003:1–7
RESULTS
Patient characteristics. Among the 146 study patients
(mean age 60 � 11 years; 116 men and 30 women), 93 had
the culprit lesion in the left anterior descending coronary
artery, 15 in the left circumflex artery, and 38 patients in the
right coronary artery. The mean time from the symptomatic
onset to coronary reperfusion was 6.9 � 5.7 h. A stent was
implanted in 72 patients. The peak CK level was 2,160 �
1,499 IU/l for the entire group. The blood glucose level on
admission was 176 � 69 mg/dl (range 79 to 549). Blood
glucose on admission was weakly but significantly correlated
with the heart rate on admission (r� 0.28, p� 0.0004) and
with the rate–pressure product (r � 0.30, p � 0.0002), but
not with systolic blood pressure (p � 0.09), suggesting that
the blood glucose level might somehow reflect an adrenergic
drive after AMI.
Diabetes was diagnosed in 41 patients, as described earlier:
25 patients had a previous diagnosis of DM, nine had a high
HbA1c value, and seven were diagnosed on the basis of the
glucose tolerance test. Among 25 patients with a clinical
history of DM, two received insulin, six received gliben-
clamide, three received gliclazide, and one received nateglinide.
The remaining 13 patients were controlled by diet alone.
Among 10 patients receiving oral antidiabetic agents, 9 showed
hyperglycemia on admission, and 4 (3 receiving glibenclamide
and 1 receiving gliclazide) showed no reflow by MCE. An
angiotensin-converting enzyme inhibitor was administered in
133 patients (91.1%) after AMI, and a beta-blocker was used
in 42 patients (28.8%) (Table 1).
The no-reflow phenomenon and blood glucose level. Pa-
tients with AMI were classified into two groups according
to myocardial perfusion patterns; those without no reflow
(n� 97 [66%]) and those with it (n� 49 [34%]). The peak
CK value was higher and �WMS was lower in the no-
Table 1. Clinical Characteristics of the Study Patients
All Patients
(n � 146)
MCE Findings
p Value*
Reflow
(n � 97)
No-Reflow
(n � 49)
Age (yrs) 60 � 11 58 � 11 64 � 11 0.003
Gender (male/female) 116/30 76/21 40/9 0.64
Height (cm) 163 � 8 163 � 7 163 � 8 0.82
Weight (kg) 64.6 � 11.9 64.4 � 12.4 65.3 � 10.8 0.72
Peak creatine kinase (IU/l) 2,160 � 1,499 1,719 � 1,177 3,032 � 1,688 � 0.0001
Blood glucose (mg/dl) 176 � 69 159 � 56 209 � 79 � 0.0001
HbA1c (%) 5.7 � 1.3 5.6 � 1.3 5.9 � 1.3 0.12
Total cholesterol (mg/dl) 199 � 45 201 � 44 194 � 47 0.38
Triglycerides (mg/dl) 113 � 91 119 � 99 100 � 72 0.26
Risk factors (%)
Diabetes mellitus 28.1 23.7 36.7 0.10
Hypertension 50.0 51.5 46.9 0.28
Hyperlipidemia 40.4 45.3 30.6 0.08
Smoking 66.4 72.2 55.1 0.06
Symptom onset to reflow time (h) 6.9 � 5.7 7.2 � 6.2 6.3 � 4.4 0.41
Incidence of pre-infarction angina (%) 43.2 47.4 20.4 0.14
Killip class (I/II/III) 132/12/2 95/2/0 37/10/2 0.03
Hemodynamic data on admission
Systolic blood pressure (mm Hg) 138 � 27 136 � 29 141 � 23 0.34
Heart rate (beats/min) 80 � 18 77 � 17 85 � 20 0.01
Rate–pressure product 11,155 � 3,903 10,684 � 3,635 12,148 � 4,290 0.04
Hemodynamic data after PCI
Systolic blood pressure (mm Hg) 124 � 24 126 � 25 121 � 21 0.32
Heart rate (beats/min) 83 � 12 83 � 12 85 � 13 0.24
Rate–pressure product 10,483 � 3,052 10,383 � 2,718 10,695 � 3,684 0.57
ST-segment re-elevation (%) 38.4 34.0 46.9 0.13
Stent implantation (%) 49.3 46.4 55.1 0.32
Anterior wall MI (%) 63.7 53.6 83.7 0.0002
TIMI flow grade 0 on initial CAG (%) 76.7 70.1 89.8 0.005
Good collateral channels† (%) 29.5 28.1 32.7 0.57
WMS on admission 14.9 � 5.6 13.8 � 5.4 17.0 � 5.4 0.0009
�WMS 4.7 � 4.7 5.6 � 4.6 2.8 � 4.4 0.0006
Medication after AMI
ACE inhibitor (%) 91.1 92.8 87.8 0.59
Beta-blocker (%) 28.8 25.8 34.7 0.26
*P values for the differences between reflow and no reflow by MCE. †Good collateral channels indicate collateral flow graded as 2 or 3. Data are presented as the mean value �
SD or number or percentage of patients.
ACE � angiotensin-converting enzyme; AMI � acute myocardial infarction; CAG � coronary angiogram; HbA1c � glycosylated hemoglobin; MCE � myocardial contrast
echocardiography; MI � myocardial infarction; PCI � percutaneous coronary intervention; TIMI � Thrombolysis in Myocardial Infarction trial; WMS � wall motion score
on echocardiogram.
3JACC Vol. 41, No. 1, 2003 Iwakura et al.
January 1, 2003:1–7 Hyperglycemia and Microvasculature in AMI
reflow group (3,032 � 1,688 vs. 1,719 � 1,177 IU/l, p �
0.0001 and 2.8 � 4.4 vs. 5.6 � 4.6, p � 0.0006, respec-
tively). The patients with no reflow showed a significantly
higher blood glucose level on admission than did those
without it (209 � 79 vs. 159 � 56 mg/dl; p � 0.0001).
There were no differences in HbA1c or in the frequency of
DM between the two groups (no reflow vs. reflow: 5.9 �
1.3% vs. 5.6 � 1.3%, p � 0.12 and 36.7% vs. 23.7%, p �
0.10, respectively). Also, there were no differences in DM
therapy received before hospital admission between the two
groups. Patients with no reflow showed a higher heart rate
and a larger rate–pressure product on admission, although
no differences were observed in these values after successful
PCI. There were no differences in medication (angiotensin-
converting enzyme inhibitor and beta-blocker) after AMI
between the two subsets (Table 1).
We defined hyperglycemia as a blood glucose level
�160 mg/dl, which was the optimal cutoff point to differ-
entiate the patients showing no reflow, based on the
receiver-operating characteristic curve analysis. The mean
blood glucose level of the 75 patients (51.4%) with hyper-
glycemia on admission was 221 � 69 mg/dl. There were no
significant differences in age, gender, time from symptom
onset to coronary reperfusion, or coronary risk factors,
except for DM, between the patients with and those
without hyperglycemia (Table 2). Although the heart rate
on admission was significantly higher in patients with
hyperglycemia, no differences were observed in the hemo-
dynamic data between the two subsets after PCI. There
were no differences in medication between the two groups.
Re-elevation of the ST-segment was more frequently ob-
served in patients with hyperglycemia. The incidence of no
reflow was significantly higher in patients with hyperglyce-
mia than in those without it (52.0% vs. 14.1%; p� 0.0001).
Patients with hyperglycemia also showed a lower contrast
enhancement score than did those without it, even after
adjusting for differences in the peak CK value (0.6 � 0.4 vs.
0.9 � 0.3; p � 0.0001 by ANCOVA). The hyperglycemia
group also showed a significantly higher peak CK value
(2,497 � 1,603 vs. 1,804 � 1,300 IU/l; p � 0.0001) and a
Table 2. Clinical Characteristics of Patients With or Without Hyperglycemia
With Hyperglycemia
(>160 mg/dl)
Without Hyperglycemia
(<160 mg/dl) p Value
No. of patients 75 71
Age (yrs) 61 � 10 58 � 11 0.10
Gender (male/female) 57/18 59/12 0.28
Peak creatine kinase (IU/l) 2,497 � 1,603 1,804 � 1,300 0.005
No reflow on MCE (%) 52.0 14.1 � 0.0001
Blood glucose (mg/dl) 221 � 69 128 � 18 � 0.0001
HbA1c (%) 6.2 � 1.6 5.1 � 0.5 � 0.0001
Total cholesterol (mg/dl) 194 � 45 204 � 45 0.23
Triglycerides (mg/dl) 109 � 103 117 � 78 0.59
Risk factors (%)
Diabetes mellitus 45.3 9.9 � 0.0001
Hypertension 49.3 50.7 0.86
Hyperlipidemia 40.0 40.8 0.92
Smoking 62.7 70.4 0.32
Symptom onset to reflow time (h) 6.1 � 4.9 7.8 � 6.3 0.06
Incidence of pre-infarction angina (%) 44.0 42.3 0.83
Killip class (I/II/III) 64/9/2 68/3/0 0.03
Hemodynamic data on admission
Systolic blood pressure (mm Hg) 139 � 25 137 � 29 0.66
Heart rate (beats/min) 82 � 20 77 � 16 0.12
Rate–pressure product 11,579 � 4,203 10,732 � 3,558 0.20
Hemodynamic data after PCI
Systolic blood pressure (mm Hg) 124 � 23 124 � 25 0.98
Heart rate (beats/min) 87 � 18 81 � 12 0.04
Rate–pressure product 10,834 � 3,286 10,133 � 2,778 0.17
ST-segment re-elevation (%) 49.3 26.8 0.005
Stent implantation (%) 45.3 53.5 0.32
Anterior wall MI (%) 66.7 60.6 0.44
TIMI flow grade on initial CAG (%) 80.0 73.2 0.33
Good collateral channels* (%) 29.3 30.0 0.93
WMS on admission 14.8 � 5.6 14.9 � 5.6 0.94
�WMS 3.7 � 4.8 5.7 � 4.3 0.01
Medication after AMI
ACE inhibitor (%) 88.7 93.3 0.53
Beta-blocker (%) 28.0 29.6 0.83
*Good collateral channels indicate collateral flow graded as 2 or 3. Data are presented as the mean value � SD or number or
percentage of patients.
Abbreviations as in Table 1.
4 Iwakura et al. JACC Vol. 41, No. 1, 2003
Hyperglycemia and Microvasculature in AMI January 1, 2003:1–7
smaller �WMS (3.7 � 4.8 vs. 5.7 � 4.3; p � 0.01). The
hyperglycemia group showed a significantly lower �WMS,
even after adjusting for differences in the peak CK value (p
� 0.009 by ANCOVA) (Fig. 1).
Determinants of the no-reflow phenomenon. We per-
formed multivariate logistic regression analysis to determine
the independent factors related to the development of the
no-reflow phenomenon. Along with the blood glucose level
on admission and HbA1c, we used the following variables:
age, gender, coronary risk factors, Killip class, pre-infarction
angina, location of infarction, elapsed time from symptom
onset t