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J Am Coll Cardiol, 2000; 36:731-738
© 2000 by the American College of Cardiology Foundation
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CLINICAL STUDY

Hyperinsulinemia during oral glucose tolerance test is associated with increased neointimal tissue proliferation after coronary stent implantation in nondiabetic patients

A serial intravascular ultrasound study

Tsutomu Takagi, MDa, Kiyoshi Yoshida, MD, FACC*, Takashi Akasaka, MDa, Shuichiro Kaji, MDa, Takahiro Kawamoto, MDa, Yasuhiro Honda, MDa, Atsushi Yamamuro, MDa, Takeshi Hozumi, MDa and Shigefumi Morioka, MDa

a Division of Cardiology, Kobe General Hospital, Minatojima Nakamachi, Kobe, Japan
* Division of Cardiology, Department of Internal Medicine, Kawasaki Medical University, Kurashiki, Japan

Manuscript received August 6, 1999; revised manuscript received March 15, 2000, accepted April 26, 2000.

Reprint requests and correspondence: Tsutomu Takagi, Division of Cardiology, Kobe General Hospital, Minatojima Nakamachi 4-6, Chuo-ku, Kobe, Japan
tx-tkg{at}ka2.so-net.ne.jp


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

The purpose of this study was to determine whether hyperinsulinemia during the oral glucose tolerance test is associated with increased neointimal tissue proliferation after coronary stent implantation in nondiabetic patients.

BACKGROUND

Although hyperinsulinemia induces increased vascular smooth muscle cell proliferation in experimental models, it has not been determined whether hyperinsulinemia is associated with increased neointimal tissue proliferation after coronary stent implantation.

METHODS

Serial (postintervention and six-month follow-up) intravascular ultrasound (IVUS) was used to study 67 lesions treated with Palmaz-Schatz stents in 55 nondiabetic patients. Cross-sectional images within stents were taken at every 1 mm, using an automatic pullback, and a neointimal index was calculated as the ratio between the averaged neointimal area and averaged stent area. All patients underwent a 75-g oral glucose tolerance test. Plasma glucose (PG) and immunoreactive insulin (IRI) levels were measured at baseline and 1 and 2 h after the glucose load. The sum of PGs ({Sigma}PG) and the sum of IRIs ({Sigma}IRI) were calculated. Body mass index (BMI), lipid levels, and glycosylated hemoglobin levels were measured.

RESULTS

There were 27 patients with normal glucose tolerance, and 28 patients with impaired glucose tolerance (IGT). The neointimal index in patients with IGT was greater than that in patients with normal glucose tolerance (42.9 ± 14% vs. 24.9 ± 8.3%, respectively, p < 0.0001). Linear regression analysis showed that the neointimal index at follow-up correlated well with {Sigma}PG (p < 0.0001), fasting IRI (p < 0.0001), {Sigma}IRI (p < 0.0001), triglyceride level (p = 0.018), and BMI (p < 0.0001). Multiple regression analysis revealed that {Sigma}IRI (p = 0.0002) and {Sigma}PG (p = 0.0034) were the best predictors of the greater neointimal index at follow-up.

CONCLUSIONS

Serial IVUS assessment shows that hyperinsulinemia during an oral glucose tolerance test is associated with increased neointimal tissue proliferation after coronary stent implantation in nondiabetic patients.

Abbreviations and Acronyms
  BMI = body mass index
  DM = diabetes mellitus
  HbA1c = glycosylated hemoglobin level
  IGT = impaired glucose tolerance
  IRI = immunoreactive insulin level
  IVUS = intravascular ultrasound
  MLA = minimal lumen area
  MLD = minimal lumen diameter
  NIDDM = non-insulin-dependent diabetes mellitus
  OGTT = oral glucose tolerance test
  PG = plasma glucose level
  VSMC = vascular smooth muscle cell

Although Palmaz-Schatz stent implantation has been shown to reduce restenosis rates compared with balloon angioplasty, in-stent restenosis remains a significant clinical problem, especially in patients with diabetes mellitus (DM) (1–4). Recent human histological studies demonstrated that early thrombus formation and acute inflammation are followed by neointimal tissue proliferation in the chronic stage after coronary stent implantation (5,6). Using serial intravascular ultrasound (IVUS) analysis, Hoffmann et al. (7) found that stents did not recoil and that in-stent restenosis was the result of neointimal tissue proliferation. Kornowski et al. (8) reported that exaggerated neointimal hyperplasia in stented lesions was the main reason for increased restenosis in patients with DM. Increased neointimal growth after coronary stent implantation in DM may result from mitogens that stimulate vascular smooth muscle cell (VSMC) proliferation (9).

Hyperinsulinemia is attributed to insulin resistance, a condition associated with impaired glucose tolerance (IGT) and non-insulin-dependent DM (NIDDM). Hyperinsulinemia and insulin resistance have been implicated as possible common risk factors for coronary artery disease and NIDDM (10). It has been reported that hyperinsulinemia induces greater VSMC proliferation in experimental models (11,12). Hyperinsulinemia in nondiabetic patients is potentially related to greater neointimal tissue proliferation, but the relationship between hyperinsulinemia and neointimal tissue proliferation after coronary stent implantation is unclear. Therefore, we attempted to evaluate the relationship between hyperinsulinemia and neointimal tissue proliferation after coronary stent implantation in nondiabetic patients by means of serial IVUS studies.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Study patients.   From January 1997 through December 1997, a total of 118 patients with 144 lesions underwent elective coronary stent implantation using Palmaz-Schatz coronary stents (Johnson & Johnson) at Kobe General Hospital. We studied 67 lesions from 55 nondiabetic patients. Exclusions in this study included 1) patients with previously treated DM (oral hypoglycemic agents or insulin); 2) patients with a fasting plasma glucose level ≥7.0 mmol/liter (126 mg/dl); 3) patients with plasma glucose level ≥11.1 mmol/liter (200 mg/dl) 2 h after 75 g oral glucose load; 4) ostial lesions or bifurcational lesions; 5) lesions with reference vessel diameter <2.75 mm; 6) lesions treated with more than two stents; and 7) lesions with averaged stent area <6 mm2 as measured by postinterventional IVUS. There were 48 men and 7 women (mean age 60 ± 7 years). Written informed consent was obtained from each patient.

Baseline investigation.   Blood pressure, body height and body weight were measured before the angiographic procedure. Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared. All patients underwent a 75-g oral glucose tolerance test (OGTT) 3 ± 2 days before coronary stent implantation. After fasting overnight, each patient supplied blood samples at baseline and 1 and 2 h after the glucose load. Plasma glucose levels (PG) were measured by the enzymatic method with the use of a Glucose Analyzer 1140 (Kyoto Daiichi Kagaku, Kyoto, Japan), and immunoreactive insulin levels (IRI) were measured by radioimmunoassay with the use of Insulin Riabead II (Dainabot, Tokyo, Japan). The sum of plasma glucose ({Sigma}PG = fasting PG + 1 h PG + 2 h PG) and the sum of insulin levels ({Sigma}IRI = fasting IRI + 1 h IRI + 2 h IRI) were calculated. Glucose tolerance status was based on World Health Organization criteria (13).

Blood chemistry analyses, including glycosylated hemoglobin (HbA1c) levels and lipid levels, were performed at the same time. The HbA1c was measured with the use of a Hi-Auto A1c HA-8121 (Kyoto Daiichi Kagaku, Kyoto, Japan). Total cholesterol and triglyceride levels were measured by the enzymatic method. High-density lipoprotein (HDL) cholesterol levels were measured in plasma after precipitation of low-density lipoprotein (LDL) and very-low-density lipoprotein. The LDL cholesterol concentrations were calculated using the following formula: LDL cholesterol = total cholesterol –HDL cholesterol –(triglyceride/5) (14).

Implantation of palmaz-schatz stent.   Palmaz-Schatz stents were implanted according to standard protocols. The IVUS was used to guide high-pressure adjunctive balloon inflation to achieve targeted stent expansion. The targeted stent expansion was a minimal stent area of ≥80% of the average of the proximal and distal reference lumen cross-sectional areas by IVUS as well as complete stent–vessel wall apposition. All patients received 160 mg of aspirin and 200 mg of ticlopidine. The duration of ticlopidine treatment was four weeks.

Serial intravascular ultrasound imaging.   The IVUS imagings were performed at postintervention (after the final balloon inflation) and at follow-up (6.3 ± 0.6 months after the stent implantation). After administration of 1 to 2 mg of intracoronary isosorbide dinitrate, a 30-MHz, 3.2F IVUS catheter (Cardiovascular Imaging System, Sunnyvale, California) was advanced to the distal site in the coronary artery beyond the target lesion. Continuous images of the coronary artery from beyond the target lesion to the aorto-ostial junction were obtained as the ultrasound catheter was slowly withdrawn at 0.5 mm/s using a motorized pullback device. The IVUS images were recorded on a 0.5-in. sVHS video tape for offline analysis. The IVUS examinations were considered suitable for analysis if images were free from apparent ultrasound artifacts such as oblique catheter positioning or nonuniform rotational distortion.

Quantitative IVUS measurements.   With the use of computer-assisted planimetry (Tape-Measure, Indec System, Capitola, California), quantitative IVUS measurements were performed by a single individual who was blinded to the results of OGTT. The IVUS recordings after stent implantation and at follow-up were replayed on a video screen, and cross-sectional images within stents were selected at every 1 mm (given a pull-back speed of 0.5 mm/s, each 2 s of video playback corresponds to 1 mm of axial length). Fourteen to 16 image slices were selected from each stent. After digitizing individual image slices, the stent cross-sectional and lumen cross-sectional areas were measured, and the neointimal area was calculated as the difference between the stent area and lumen area (Fig. 1). In cases with in-stent restenosis at follow-up, IVUS imagings were performed before the interventional procedure. When the tissue encompassed the catheter, the lumen was assumed to be the physical size of the imaging catheter. Therefore, 1.0 mm was the smallest minimal lumen diameter (MLD), and 0.8 mm2 was the smallest lumen cross-sectional area that could be measured before intervention (15). Because it was difficult to measure the stent area accurately in the image slice at the central articulation, the image slice at this point was excluded from the analysis. All measurements were averaged over the number of selected slices. The neointimal index was calculated as the ratio between averaged neointimal area and averaged stent area. Reproducibility of the IVUS measurements has been previously reported (16).



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  		Figure 1 Representative planar intravascular ultrasound images of Palmaz-Schatz stent at follow-up are shown. Each is duplicated, and the duplicate is labeled. In patient without glucose intolerance (left), the stent area measured 6.4 mm2, and the lumen area measured 4.6 mm2. Thus, there was 1.8 mm2 of neointimal tissue proliferation and the neointimal index was 28%. In patient with impaired glucose tolerance (right), the stent area measured 6.3 mm2, and the lumen area measured 2.2 mm2. Thus, there was 4.1 mm2 of neointimal tissue proliferation and the neointimal index was 65%.

 
Quantitative angiographic analysis.   Quantitative coronary angiography was performed using an automated edge detection system CMS (Medis Medical Imaging Systems, Leiden, the Netherlands) by a single individual who was blinded to the OGTT results. A contrast-filled, nontapered catheter tip was used for calibration. The MLD, reference diameter, percent diameter stenosis, and the diameter of the maximally inflated balloon were measured. Measurements were taken from multiple projections, and the results from the "worst" views were recorded. A balloon-vessel ratio was calculated by dividing the diameter of an inflated balloon by the coronary reference diameter. Stents were considered restenotic if the quantitative angiographic diameter stenosis at follow-up was ≥50%.

Statistical analysis.   Quantitative data are presented as mean ± SD. Differences in categorical variables were analyzed by the Fisher exact probability test, and differences in continuous variables were compared between the two groups using the Mann-Whitney U-test. Results of IVUS measurements and clinical, angiographic, and procedural characteristics were determined using a lesion-based assessment. Previous studies have shown that stented lesions behave independently with regard to restenosis when multiple lesions are treated in the same patients (17). A two-side value of p < 0.05 was considered statistically significant. Multivariate linear regression analysis was used to determine the best predictors of the neointimal index at follow-up. Univariate predictors of the neointimal index at follow-up with a p value < 0.20 were entered into the multivariate model. The best independent predictors and their correlation coefficients were calculated.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
All patients underwent follow-up angiography as part of the study protocol. Nine of the patients had recurrent symptoms at the time of follow-up, but no patients presented with unstable angina or myocardial infarction.

Baseline characteristics, the results of OGTT, and blood chemistry analyses are shown in Table 1. Twenty-seven patients with 34 stents had normal glucose tolerance, and 28 patients with 33 stents had abnormal glucose tolerance. The BMI in patients with IGT was significantly greater than that in patients with normal glucose tolerance. There was no difference between the two groups in the incidence of other coronary risk factors. There was no patient with renal dysfunction in this study. Although no difference was seen in fasting PG between the two groups, 1- and 2-h PG and {Sigma}PG in the IGT group were significantly greater than those in the normal glucose tolerance group. Fasting IRI, 1-h IRI, 2-h IRI, and {Sigma}IRI were significantly greater in patients with IGT than in patients with normal glucose tolerance. No differences existed in lipid levels and HbA1c levels between the two groups.


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  		Table 1 Baseline Characteristics, Results of Oral Glucose Tolerance Test and Lipid Analysis

 
Angiographic and procedural characteristics are shown in Table 2. No differences were seen between the two groups in target vessel, lesion location, or modified ACC/AHA lesion classifications (18). No differences occurred in preinterventional reference vessel diameters, MLD, or lesion lengths between the two groups. There were no differences in final balloon diameters, balloon-to-artery ratio, or final balloon inflation pressure between the two groups. Postprocedural residual dissections were present in two cases (6%) in the normal glucose tolerance group versus one case (3%) in the IGT group (p > 0.9999). Neither slow flow nor thrombus formation occurred after stent implantation in this study. There were 14 stents with restenosis identified by follow-up angiography: 4 (13%) of the 34 stents in the normal glucose tolerance group and 10 (30%) of the 33 stents in the IGT group (p = 0.0772). Focal in-stent restenosis was present in two cases in the normal glucose tolerance group versus one in the IGT group, and diffuse in-stent restenosis was present in two cases in the normal glucose tolerance group versus nine in the IGT group (p = 0.1758).


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  		Table 2 Angiographic and Procedural Characteristics

 
Results of serial IVUS measurements are shown in Table 3. No significant differences in stent area were seen between the two groups at postintervention or at six months’ follow-up. However, the lumen area at follow-up in the IGT group was significantly smaller than that in the normal glucose tolerance group. This was also true for the minimal lumen area (MLA) within stent. The neointimal area and neointimal index at follow-up in the IGT group were significantly greater than those in the normal glucose tolerance group. This was also true for the neointimal area and neointimal index in the image slices with MLA.


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  		Table 3 Results of Serial Intravascular Ultrasound Analysis

 
Results of univariate linear regression analysis are shown in Table 4 and Figure 2. Greater BMI, {Sigma}PG, fasting IRI, {Sigma}IRI, and triglyceride values were all associated with a greater neointimal index at follow-up. However, the neointimal index was not associated with the HbA1c level, the cholesterol levels, or any of the angiographic or procedural factors. As shown in Table 5, multiple linear regression analysis revealed that {Sigma}IRI and {Sigma}PG were significant predictors of the greater neointimal index at follow-up.


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  		Table 4 Linear Regression Analysis of Predictors of the Neointimal Index at Follow-up

 


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  		Figure 2 Relation between insulin levels (top panel) and plasma glucose levels (bottom panel) and neointimal index.

 

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  		Table 5 Multiple Regression Analysis of Predictors of the Neointimal Index at Follow-up

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Using serial IVUS analysis, the present study on nondiabetic patients demonstrated that 1) greater neointimal tissue proliferation occurred in patients with IGT defined by OGTT than in patients with normal glucose tolerance, and 2) {Sigma}IRI and {Sigma}PG after the glucose load were significant predictors of the greater neointimal growth at six months’ follow-up after coronary stent implantation.

Previous studies.   Several studies using B-mode ultrasound in humans reported that hyperinsulinemia is associated with greater intimal medial thickening of the carotid artery (19,20). After vascular injury, including coronary intervention, hyperinsulinemia is potentially associated with greater neointimal tissue proliferation. However, no previous reports evaluated the relationship between hyperinsulinemia and neointimal tissue proliferation following coronary stent implantation. A recent angiographic analysis reported that hyperinsulinemia after the glucose load is associated with greater late lumen loss after balloon angioplasty (21,22). Several IVUS studies have indicated that late lumen loss after intervention in nonstented lesions is primarily determined not by cellular proliferation, but by the direction and magnitude of arterial remodeling (23,24). Meanwhile, IVUS study has demonstrated that chronic stent recoil is minimal and that the late lumen loss and in-stent restenosis are the results of neointimal tissue proliferation (7). Komatsu et al. (5) and Farb et al. (6) have demonstrated that in long-term stents (>30 days after stent implantation) the histological success or failure was determined by degree of neointimal growth within the stents. Therefore, the present study is the first to demonstrate that hyperinsulinemia is associated with an increase in neointimal tissue proliferation that may contribute to restenosis after coronary intervention.

Hyperinsulinemia and insulin resistance.   Although we found a strong relationship between hyperinsulinemia and neointimal tissue proliferation after coronary stent implantation, further investigation is necessary to determine whether hyperinsulinemia itself induces greater neointimal tissue proliferation. Physiological concentrations of insulin are known to stimulate proliferation of cultured VSMC and fibroblasts (10,11). Though insulin itself is a weak mitogen, it can potentiate the expression of the more potent mitogens (such as platelet-derived growth factor and insulin-like growth factor) (25,26). In addition, in vivo studies have demonstrated that an intra-arterial injection of insulin induces atheroma growth in the injected artery (27,28). These findings suggest that insulin has an atherogenic action.

However, according to a recent review of 25 prospective studies correlating insulin levels with heart disease, epidemiological evidence does not support the notion that hyperinsulinemia is a major risk factor for heart disease (29). The available evidence suggests that it is insulin resistance, per se, and not hyperinsulinemia, that is associated with atherosclerosis, thrombogenesis, hypertension, obesity, and DM (30). A recent investigation using B-mode ultrasound reported that the intimal medial thickness of the carotid artery is related to reduced insulin sensitivity but not to insulin levels (31). It is plausible that the relationship between hyperinsulinemia and increased neointimal tissue proliferation is not associated with the atherogenic action of insulin, but is based on the association between insulin resistance and atherosclerosis (32). In this study, we did not measure insulin resistance directly. Although hyperinsulinemia often indicates insulin resistance, the two are not necessarily identical. Further study is necessary to evaluate the relationship between insulin resistance directly assessed by the intravenous glucose tolerance test and neointimal tissue proliferation after coronary stent implantation. However, previous reports cannot rule out the possibility that the compensatory hyperinsulinemia directly related to insulin resistance plays a direct or indirect role in the pathogenesis of atherosclerosis (33).

As shown in Table 5, multiple regression analysis revealed that {Sigma}PG was also a significant predictor of neointimal index at follow-up. Because hyperinsulinemia and hyperglycemia link together in patients with IGT, it is difficult to eliminate the effects of hyperglycemia as an important promoter of increased neointimal tissue proliferation after coronary stent implantation. Hyperglycemia can promote neointimal tissue proliferation not only through compensatory hyperinsulinemia, but also through its effects on endothelial dysfunction, dysregulation of growth factor expression, advanced glycosylation end products, and abnormal extracellular matrix composition (9).

Study limitations.   The present study has some intrinsic limitations. The first is that it is a single center study with a relatively small number of study patients. Second, we excluded patients with DM. Insulin response to a glucose load may be different in patients with DM because of their insulin secretory defect. Moreover, in patients who receive administration of insulin, the effect of exogenous insulin on neointimal tissue proliferation is unclear. Further study in patients with DM is required to evaluate the relationship between hyperinsulinemia and/or insulin resistance and increased neointimal tissue proliferation after coronary stent implantation.

The third limitation is our exclusion of lesions with small reference vessel diameters or small stent areas. Previous studies have reported that the reference vessel diameter and final stent dimensions (either MLD or stent area) were significant predictors of angiographic MLD at six months’ follow-up. A recent study (34) using IVUS has shown that intimal hyperplasia thickness at follow-up is independent of the stent size. If neointimal thickness is a relative constant and is independent of stent size, then there must be a greater encroachment on the lumen dimensions of smaller stents implanted into smaller vessels. Therefore, the effect of hyperinsulinemia on promoting neointimal tissue proliferation may be much more important in smaller stents than in larger ones.

A fourth limitation in this study is that IVUS images at the central articulation were excluded from the analysis. Several angiographic studies and IVUS studies have pointed out that the central articulation is the most frequent site for restenosis in Palmaz-Schatz stents (35,36). However, a recent study (7) using serial IVUS showed that the tendency for increased neointimal tissue accumulation at the central articulation was modest in comparison to the otherwise uniform neointimal tissue accumulation over the length of the stent.

Finally, we used the neointimal index to estimate neointimal tissue accumulation over the stent lengths. Using this index, we could underestimate the focal high-grade in-stent restenosis where the neointimal accumulation is localized. However, aggressive neointimal growth in the diffuse in-stent restenosis, a condition indicated in this study by a greater neointimal index, has been more often associated with a higher frequency of recurrent restenosis after the angioplasty than with focal in-stent restenosis.

Clinical implications.   Treatment strategies designed to limit cellular proliferation may be efficacious in reducing in-stent restenosis. An animal experimental study has shown that pharmacological therapy following coronary stent implantation reduces in-stent restenosis by inhibiting neointimal hyperplasia (37). Several studies have shown that stent implantation combined with radiation vascular therapy reduces in-stent restenosis (38,39). Although patients who experience hyperinsulinemia and/or hyperglycemia after a glucose load do not have clinically significant DM, the present study suggests that they are good candidates for these adjunct therapies following coronary stent implantation to reduce in-stent restenosis.

Conclusions.   Serial IVUS assessment reveals that hyperinsulinemia and hyperglycemia after a glucose load are associated with greater neointimal tissue proliferation after coronary stent implantation in nondiabetic patients.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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