Association between hyperglycemia and the no-reflow phenomenon inpatients with acute myocardial infarction

Study protocol

Just after hospital admission, a 12-lead ECG was recorded and the blood glucose level was measured 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. Coronary reperfusion was achieved in all patients within 90 min of blood glucose measurement. We did not treat hyperglycemia 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 μm 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 (HbA_1c) and total cholesterol 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 ΔWMS.

An experienced echocardiographer analyzed the MCE images to determine the presence of the no-reflow phenomenon. We defined the no-reflow zone in end-diastolic images as a contrast perfusion defect after PCI. We quantified 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 endocardial 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 considered 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 HbA_1c≥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 HbA_1cshowed 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, compared 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 Scheffé 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 hyperglycemia and ΔWMS 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).

The no-reflow phenomenon and blood glucose level

Patients 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 ΔWMS was lower in the no-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, respectively). 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 HbA_1cor 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 differentiate 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 hyperglycemia 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 hemodynamic 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 observed in patients with hyperglycemia. The incidence of no reflow was significantly higher in patients with hyperglycemia 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 smaller ΔWMS (3.7 ± 4.8 vs. 5.7 ± 4.3; p = 0.01). The hyperglycemia group showed a significantly lower ΔWMS, even after adjusting for differences in the peak CK value (p = 0.009 by ANCOVA) (Fig. 1).

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Figure 1

Relationship between peak creatine kinase (CK) value and Δ wall motion score (WMS) in patients with or without hyperglycemia. Both patients with hyperglycemia (open circles)and those without it (solid squares)showed a weak but significant relationship between peak CK and ΔWMS (r = 0.35, p = 0.002 and r = 0.28, p = 0.04, respectively). The hyperglycemia group showed a significantly lower ΔWMS, even after adjusting for differences in peak CK (p = 0.009 by analysis of covariance).

Determinants of the no-reflow phenomenon

We performed 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 HbA_1c, we used the following variables: age, gender, coronary risk factors, Killip class, pre-infarction angina, location of infarction, elapsed time from symptom onset to reperfusion, ST-segment re-elevation after reperfusion, WMS on admission, presence of good collateral channels, TIMI grade at initial coronary angiography, and use of stenting.

The blood glucose level is one of the independent predictive factors for no reflow, along with age, male gender, absence of pre-infarction angina, complete occlusion (TIMI flow grade 0) of the infarct-related artery, and anterior AMI (Table 3). Diabetes and HbA_1cwere not selected as independent predictive factors. Among these factors, the blood glucose level had the highest Wald’s chi-square value, followed by anterior wall AMI, complete occlusion, and male gender, indicating that the blood glucose level is the strongest factor to predict the no-reflow phenomenon. Even in the model using only the factors that were significant predictors in the univariate logistic analysis (i.e., age, blood glucose, gender, smoking, Killip class, location of infarction, ST-segment re-elevation, WMS on admission, and initial TIMI grade), we obtained the same results, except that the absence of pre-infarction angina was not a significant factor. When we used the incidence of hyperglycemia (≥160 mg/dl) instead of the blood glucose level, we also obtained the same result, with a 12.1 risk ratio of hyperglycemia for the no-reflow phenomenon (95% confidence interval 2.7 to 61.2).

Study limitations

Although all patients underwent coronary reperfusion within 90 min after blood glucose measurement at hospital admission, we do not know how the blood glucose level had changed before coronary reperfusion. We also did not investigate how long hyperglycemia persisted before reperfusion. We did not perform the glucose tolerance test in all patients without a history of DM or a high HbA_1cvalue, and the incidence of DM in the hyperglycemia group (45.3%) might be underestimated. However, several previous reports have demonstrated that >40% of patients with AMI, but without DM, had hyperglycemia on admission (3,8), as in the present study. We did not measure serum catecholamine levels, free fatty acids, blood viscosity, or red-cell deformability, which might be useful to clarify the relationship between the blood glucose level and infarct size. We could not successfully analyze the effects of the sulfonylurea agents, which might affect microvascular integrity, because of the small number of patients receiving these drugs.

The present study was based on a retrospective analysis of the patients and was only a descriptive study in which we established an association between hyperglycemia and the no-reflow phenomenon. Prospective studies are required to determine the effect of hyperglycemia on the no-reflow phenomenon, independent of the infarct size and the effect of controlling blood glucose levels on this phenomenon.