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Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:3302-3310

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:3302-3310.)
© 1997 American Heart Association, Inc.

Articles

Insulin Resistance as an Independent Risk Factor for Carotid Artery Wall Intima Media Thickening in Vasospastic Angina

Kazuya Shinozaki; Yuichi Hattori; Masaaki Suzuki; Yasushi Hara; Akio Kanazawa; Hiroshi Takaki; Motoo Tsushima; ; Yutaka Harano

From the Division of Atherosclerosis, Metabolism, and Clinical Nutrition and the Division of Cardiology (H.T.), Department of Medicine, National Cardiovascular Center, Osaka, and Department of Applied Mathematics (Y. Hattori), Konan University, Kobe, Japan.

Correspondence to Dr Yutaka Harano, Division of Atherosclerosis, Metabolism, and Clinical Nutrition, Department of Medicine, National Cardiovascular Center, 5–7-1, Fujishiro-dai, Suita, Osaka 565, Japan.


*    Abstract
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Abstract Studies have shown the presence of insulin resistance together with compensatory hyperinsulinemia in vasospastic angina as well as obstructive coronary artery disease. There is growing evidence that the development of coronary atherosclerosis may be closely related to systemic atherosclerosis as well as coronary spasm. However, no information is available about the possible relationship between insulin resistance and the existence of carotid atherosclerosis in vasospastic angina without segmental stenosis or luminal irregularities in coronary angiograms. To evaluate the independent effect of insulin resistance on carotid intima media thickening, we performed insulin sensitivity tests (steady-state plasma glucose method) on 40 patients with vasospastic angina and 24 control subjects with angiographically intact coronary arteries. Both oral glucose tolerance tests and lipid analyses were performed. Using B-mode ultrasonography, we assessed intima media thickness and plaque formation of common carotid arteries in these subjects. The steady-state plasma glucose level in the vasospastic angina group was about twofold higher than that of the control group, confirming the presence of insulin resistance in patients with vasospastic angina. The patients with vasospastic angina showed a significant increase in the average intima media thickness of the carotid wall and frequency of plaque formation, although they were comparable to the control subjects in risk factors other than insulin resistance. The intima media thickness was correlated with age (r=.62, P<.001), 2-hour insulin area (r=.45, P<.01), and steady-state plasma glucose level (r=.68, P<.0001) in patients with vasospastic angina. Similar correlations were observed in the control subjects. Multiple regression analyses of data indicated that 67% of the variation in the intima media thickness could be accounted for by age, steady-state plasma glucose level, and cigarette-years in vasospastic angina. In addition, differences in IMT were independently related to vasospastic angina. These results suggest that insulin resistance in association with compensatory hyperinsulinemia may be an important pathogenic factor for the development of coronary artery spasms and systemic early atherosclerosis.


Key Words: vasospasm • atherosclerosis • insulin


*    Introduction
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B-mode high-resolution ultrasonography currently appears to provide the most accurate in vivo assessment of early atherosclerosis, allowing visualization and direct measurement of wall thickness and plaque status.1–3 It is assumed that the atherosclerotic changes in the common carotid artery reflect systemic atherosclerosis, and B-mode ultrasound measurements of intima media wall thickness (IMT) in the carotid artery have proved to be a useful predictor of coronary4–7 as well as cerebrovascular atherosclerotic diseases.8,9 One follow-up study has reported the relationship between coronary artery disease and carotid plaque progression.10 Furthermore, autopsy studies have confirmed the close relationship between carotid and coronary atherosclerosis.11,12

The atherosclerotic process begins during the prediabetic phase, which is characterized by impaired glucose tolerance, hyperinsulinemia, and insulin resistance.13,14 In vitro studies have suggested that alteration of glucose metabolism and insulin action substantially alter the structure and function of the arterial wall and stimulate the initiation and progression of atherosclerosis.15 Epidemiologic studies and retrospective reviews of clinical experience have shown that hyperinsulinemia is a potent cardiovascular risk factor.16–18 The Atherosclerosis Risk in Communities (ARIC) Study showed that higher glucose and insulin concentrations were associated with increased IMT.19 We have recently shown that insulin resistance associated with compensatory hyperinsulinemia is a characteristic feature of vasospastic angina (VAP) as well as obstructive coronary artery disease (CAD).20 On the other hand, clinical studies using intravascular ultrasound have demonstrated that coronary spasm induced by ergonovine is observed in the presence of early atherosclerosis in angiographically intact coronary arteries.21,22 Therefore, a possible interaction may exist between insulin resistance and systemic early atherosclerosis in patients with VAP.

The purpose of this study was to assess common carotid intima to media wall thickness and the occurrence of early atherosclerotic lesion in patients with VAP, compared with subjects with chest pain syndrome. A further effort was made to clarify the relationship between risk factors, especially insulin resistance and accompanied hyperinsulinemia and IMT in VAP.


*    Methods
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Study Subjects
Forty patients with VAP (27 men, 13 women), aged 42 to 69, and 24 control subjects (16 men, 8 women), aged 41 to 72, were studied consecutively at the National Cardiovascular Center, Japan, after informed consent was obtained for the study, which was approved by the Ethical Committee of the Center. All subjects were selected from consecutive patients who were treated at our division between 1993 and 1995 for coronary angiography because of chest pain or clinically suspected coronary artery disease. The control subjects were investigated for atypical chest pain. To avoid possible influences of aging on the insulin sensitivity, three young control subjects under 40 years old (with normal glucose tolerance) were excluded, and control subjects and VAP patients were matched to age. All 24 controls had normal coronary arteries (less than 25% stenosis of the luminal diameter) without spasms (lumen narrowing <50% by ergonovine provocation test). Since diabetes mellitus,23 high blood pressure (BP),24 and obesity25 are known to produce insulin resistance and could be independent risk factors for carotid atherosclerosis, only nonobese, nondiabetic subjects with normotension were chosen to participate in the study. Three control subjects (two with normal glucose tolerance, one with impaired glucose tolerance (IGT)) were treated with calcium-channel-blocking agents. VAP was defined as luminal diameter reduced by >=75% (either spontaneous or ergonovine provocation test) with normal resting angiograms (37 patients showed >=99% spasm) and negative or nondiagnostic exercise tolerance tests. At the time of the study, 31 patients were entirely without continuous medication, and 9 (five with normal glucose tolerance, four with IGT) were undergoing treatment with calcium-channel-blocking agents. Seven patients (five with normal glucose tolerance, two with impaired glucose tolerance) were treated with isosorbide dinitrate in addition to the calcium-channel blockers.

The exclusion criteria that were applied in the selection of the patients were as follows: (1) patients who had diabetes mellitus, hypertension (use of antihypertensive drugs or systolic and diastolic BP greater than 160/95 mm Hg), obesity (body mass index >26.0), familial hypercholesterolemia, or hepatic, renal or endocrine dysfunction; (2) patients who were taking lipid-lowering drugs, beta-adrenergic blocking drugs, or diuretics, which may have adverse effects on carbohydrate and lipid metabolism;26,27 (3) those with a history of valvular disease or macrovascular disease (eg, myocardial infarction, unstable angina, peripheral vascular disease); (4) physically inactive subjects who were unable to perform regular daily life activities.

Baseline Investigation
Metabolic, ultrasonographic, and angiographic studies were performed 3 to 6 months after initial symptoms. Venous blood samples were drawn from each subject after an overnight fast for measurement of plasma glucose, insulin, total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I and B. The LDL cholesterol levels were calculated according to Friedewald's equation: LDL cholesterol (mmol/L)=Total cholesterol-HDL cholesterol-Triglycerides/2.2.28 A 75-g load of glucose (Trelan G 75, Shimizu Company) was administered, and blood samples were drawn at 30, 60, and 120 minutes for determination of plasma glucose and insulin levels. Plasma glucose and insulin response to glucose ingestion were evaluated by calculation of the glucose and insulin areas throughout the 120 minutes of the test period. The definition of glucose tolerance was based on a 2-hour oral glucose tolerance test according to the World Health Organization criteria.29 Glucose was determined by the glucose oxidase method30 and insulin by radioimmunoassay using double antibody.31 Total cholesterol,32 triglyceride,33 HDL cholesterol,34 and apolipoprotein A-I, B35 were determined as described previously. After a 15-minute rest, a mercury sphygmomanometer was used to obtain two values each of systolic and diastolic (phase V Korotokoff sound) BP, and the averages of the two were used for data analyses. Study subjects were classified as nonsmokers if they had never smoked or had stopped smoking at least one year before cardiac catheterization. All the other subjects were classified as smokers. As a cumulative estimate of tobacco consumption, cigarette-years (pieces/dxyr.) was used. Body mass index (BMI) was calculated by using the formula BMI=weight (kilogram)/height (m)2. Plasma catecholamine (epinephrine and norepinephrine) levels were determined by using high-performance liquid chromatography with spectrofluorometric detection.36

Coronary Angiography
Coronary angiograms were obtained in most cases within one month of the metabolic evaluation (0.3±0.2, range 0 to 1.5 months). All antianginal medications were discontinued at least 12 hours before catheterization, with the exception of sublingual nitroglycerin. Coronary angiography was performed by the Judkins technique using a biplane cineangiography system. All patients with VAP had normal coronary angiograms without segmental stenosis or luminal irregularities. Coronary spasm was demonstrated in all VAP patients, during ergonovine-provoked angina in 38 patients, and during spontaneous angina in 2 patients. One mL (0.01 mg) of ergonovine maleate, the most potent of all agents used in provoking coronary spasm,37 was injected into the coronary artery through the catheter. Coronary spasm was defined as total or subtotal (a change in diameter >=75%) vessel occlusion associated with chest pain or ischemic ST changes on the ECG or both. Significant ischemic ECG changes were defined as more than 0.1 mV ST-segment elevation or depression from the control level. If provocation tests were negative, ergonovine maleate (0.01 mg) was administered every 3 minutes until vasospasm was provoked, and the preceding procedure was repeated until the maximal dose reached 0.04 mg.38 If the results were positive, nitroglycerin (0.25 mg) was injected into the coronary artery to relieve the spasm. Twenty-four control subjects had normal or near normal coronary arteries (22 control subjects showed completely normal coronary arteries) and no induction of coronary spasm (<50% of luminal diameter) by ergonovine provocation test.

Insulin Sensitivity Test
Insulin sensitivity tests were performed on all study subjects. The ability of insulin to promote glucose uptake was estimated by the steady-state plasma glucose method using Sandostatin (octreotide acetate; Sandoz)39 originally described by Harano et al.40 An adequate dose of Sandostatin has been used to suppress the endogenous secretion of insulin, glucagon, and growth hormone.41 After an overnight fast, glucose (6 mg/kg/min), KCl (0.5 µ Eq/kg/min), Novolin R40 insulin (7.5 mU/kg in a bolus, followed by a constant infusion at a rate of 0.77 mU/kg/min), and Sandostatin (150 µg/2 hours) were infused simultaneously for 2 hours at a rate 3 mL/kg/h through an antecubital vein via a constant infusion pump. Blood samples were obtained at 0, 30, and 120 minutes for the determination of plasma glucose and insulin. Steady-state plasma glucose (SSPG) and insulin (SSPI) concentrations were obtained at 120 minutes. Under these steady-state conditions, plasma glucose levels are inversely correlated with the rate of glucose disposal and are inversely proportional to the sensitivity to the infused insulin.39

Assessment of Carotid Atherosclerosis
B-mode ultrasound (U sonic model RT 2800 with 7.5 MHz mechanical sector transducer, Yokogawa Medical System) was used to directly image arterial walls of the extracranial carotid arteries. Subjects were examined in the supine position. The transducer was placed in contact with the skin by using coupling gel. Both longitudinal and transverse images were viewed, and three angles of longitudinal views were obtained as anterior oblique, lateral, and posterior oblique in the right and left carotid arteries. All ultrasonographic assessment of carotid arteries was determined by a single trained physician (M.S.) without knowledge of clinical history or risk factor profile.

The IMT as defined by Pignoli et al42,43 was measured as the distance between the lumen-intima interface and the media-adventitia interface on the B-mode ultrasound image: the distance between the bright white line (lumen-intima interface) and the leading edge of the second bright line (media-adventitia interface) of the far wall. The IMT of the common carotid artery was measured at 10, 20, and 30 mm proximal to the bifurcation in anterior oblique views, lateral, and posterior oblique, and always at plaque-free segments. Nine measures were obtained in each arterial segment, and the average value of all measurements (18 IMT values) was used to derive an estimate of the overall IMT in the common carotid arteries. The measurements were done during the scanning from digitized images. Because the intima media thickness of the internal and external carotid arteries and near wall of the common carotid artery were not accessible in all study subjects, only data from the intima media thickness of the far wall of the common carotid artery were considered in this analysis. With the aim of identifying and recording the occurrence of atherosclerotic plaque, the carotid artery was scanned from the distal part of the common carotid artery to approximately 10 mm upward into the internal and external carotid arteries.44 Plaque was considered to be present when a distinct area with more than 50% greater IMT (usually more than 1.2 mm) than neighboring sites could be identified.45 Continuous thickening was not reported as plaque. If the plaque obstructed more than 20% of the lumen diameter, the finding was called a "stenosis." The reproducibility of the IMT measurement was studied by carrying out a repeated scanning within 2 weeks in a randomly chosen subsample of 20 subjects. The second scannings were performed two times independently by the same (M.S.) physician and a different (K.S.) physician. The mean absolute difference±SD between replicated scannings of the IMT was 0.02±0.04 mm and 0.03±0.04 mm for intraobserver and interobserver comparisons, respectively. The correlation coefficients between repeated measurements of the IMT were 0.91 and 0.89 for intraobserver and interobserver analyses, respectively.

Statistical Analysis
Results are expressed as mean±SEM. Statistical analysis was performed with the SAS computer program (SAS Institute).46 Logarithmic transformations were performed on all skewed lipid and lipoprotein variables (triglyceride, LDL cholesterol) to obtain a normal distribution before statistical computations and significance testing were done. Group differences of categorical data were tested by chi-squared analysis with Yate's correction. The plasma glucose and insulin responses during oral glucose tolerance test, SSPG and SSPI, BP, and catecholamine, lipid, and lipoprotein concentrations were compared between groups by using two-way ANOVA and within a group by one-way ANOVA for repeated measures followed by Student's t test with the Bonferroni correction. The relation between continuous factors was assessed with the Pearson or the Spearman correlation coefficient. The Pearson coefficient was used for normally distributed data, and the Spearman coefficient was used for abnormally distributed data. Independent predictive effects of risk factors for IMT were determined by using stepwise multiple regression analysis. Statistical comparisons between groups with and without plaque were performed by Student's t test for unpaired observations. Stepwise discriminant analysis was performed to assess the independent discriminatory power of each risk factor. Variable significant differences in the univariate comparisons (Table 5Down) and systolic BP and cigarette-years were included in the model. Differences were considered significant at P<.05.


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  		Table 5. Stepwise Multiple Regression Analysis of Variables Significantly Associated With Carotid Artery Wall IMT in All Subjects


*    Results
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Subjects' Characteristics
The baseline characteristics of VAP and control subgroups (normal or impaired glucose tolerance) are compared in Table 1Down. The subjects in the four groups were comparable with regard to age, sex, BMI, cumulative tobacco consumption, and BP. Compared with the control subjects with normal glucose tolerance, marked elevation of triglyceride level was observed in patients with VAP, whose levels of HDL cholesterol and apolipoprotein A-I were also significantly lower. There were no significant differences among the groups in the levels of plasma epinephrine, norepinephrine, total cholesterol, LDL cholesterol, or apolipoprotein B.


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  		Table 1. Baseline Characteristics of Study Subjects

Oral Glucose Tolerance Test and Insulin Sensitivity Test
The mean concentrations of fasting plasma glucose and insulin and the 2-hour area in the four subgroups are shown in Table 2Down. In the normal glucose tolerance groups, fasting glucose, insulin, and 2-hour glucose area were slightly but not significantly higher in VAP patients than in the control group. In the IGT groups, the plasma glucose responses and 2-hour glucose areas were significantly higher in the VAP patients than in the control subjects. These results demonstrate that the patients with VAP were relatively glucose intolerant compared with the control groups. In VAP patients with normal or impaired glucose tolerance, 2-hour insulin areas were twice that of the control subjects. When these analyses were repeated with adjustment for age and BMI, similar results were obtained.


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  		Table 2. Results of Oral Glucose Tolerance Test, Steady-State Plasma Glucose and Insulin Levels During Insulin Sensitivity Tests in Vasospastic Angina Compared With Control Subjects

During the insulin sensitivity tests, SSPI levels were not different among the four study groups (Table 2Up). The mean SSPG levels were significantly higher in VAP patients compared with each group of control subjects. These results clearly indicate the presence of an insulin resistance for glucose utilization in patients with VAP. In VAP patients, SSPG levels were positively correlated with age (r=.32, P<.01), BMI (r=.40, P<.001), triglyceride (r=.58, P<.0001), 2-hour glucose area (r=.51, P<.0001), fasting (r=.45, P<.001), and 2-hour insulin area (r=.67, P<.0001). SSPG levels were also inversely correlated with HDL cholesterol (r=-.57, P<.0001) and apolipoprotein A-I (r=-.46, P<.0001) (data not shown).

Analyses of Risk Factor for Intima Media Wall Thickness and Carotid Plaque
IMT of the four subgroups were plotted in Fig 1Down. The average IMT levels were significantly higher in VAP patients with normal glucose tolerance (0.89±0.04 mm) than in the control subjects with normal (0.66±0.03 mm, P<.01) or impaired (0.70±0.04 mm, P<.05) glucose tolerance. The average IMT levels were also remarkably higher in VAP patients with IGT (0.96±0.05 mm) than in the control subjects with normal (P<.0001) or impaired (P<.01) glucose tolerance. However, no differences were found between normal and impaired glucose tolerance in both control and VAP groups.



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  		Figure 1. Scatterplots showing the distribution of intima media wall thickness (IMT) of common carotid arteries in control subjects and patients with vasospastic angina (VAP). Data presented are mean±SE.

Table 3Down shows the simple correlations existing in the control and VAP groups between IMT and cardiovascular risk factors. The statistically most significant findings were that (1) age correlated positively with IMT and (2) 2-hour insulin area and SSPG levels correlated positively with IMT. Triglyceride levels and 2-hour insulin area correlated positively with IMT almost as strongly as did age in all subject group. In addition, a negative correlation of IMT was observed with HDL cholesterol and apolipoprotein A-I in all groups. These results remain unchanged, especially in VAP groups, when all these analyses are performed separately for normal glucose tolerance and IGT group. In normal glucose tolerance groups, IMT levels were positively correlated with age (r=.73, P<.01 in control; r=.67, P<.01 in VAP) and SSPG (r=.74, P<.001 in VAP). In IGT groups, IMT levels were positively correlated with age (r=.68, P<.05 in control; r=.64, P<.01 in VAP), 2-hour insulin area (r=.74, P<.01 in control; r=.62, P<.01 in VAP), and SSPG (r=.67, P<.01 in VAP). Moreover, the relationship between carotid intima media thickness and age, 2-hour insulin area, and SSPG levels remained significant after adjustment for the confounding effect of sex in VAP groups (data not shown).


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  		Table 3. Correlation Coefficients Between Carotid Artery Wall IMT and Baseline Variables in Control, VAP, and All Subjects

Multivariate analyses using stepwise regression models were carried out concerning the IMT with a set of variables selected on the basis of the above correlation analyses (age, 2-hour insulin area, and SSPG) and other recognized risk factors (IGT, cigarette-years, and systolic BP) in VAP patients. Two pairs of such analyses were performed, with SSPG (model 1) and 2-hour insulin area (model 2) as the independent variable (Table 4Down). In model 1, age, SSPG level, and cigarette-years were found to correlate with carotid wall thickness, accounting for 67% of the variability of the IMT. In model 2, age, 2-hour insulin area, and systolic BP were independently associated with the IMT and together explained 62% of the variation in the IMT. In model 2, 2-hour insulin area appeared to be correlated with the severity of carotid wall thickness, but this was less marked (Partial R2=0.094, F statistics=7.84, P=.0082) than that found for SSPG level (Partial R2=0.154, F statistics=13.26, P=.0008). Furthermore, addition of 2-hour insulin area or other lipoprotein variables in model 1 did not significantly increase the value of R2.


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  		Table 4. Stepwise Multiple Regression Analysis of Variables Significantly Associated With Carotid Artery Wall IMT in the VAP Subjects

To evaluate the independent influence of VAP on IMT, we performed stepwise regression analyses in all the study subjects (Table 5Up). We tested the joint contribution of IGT, cigarette-years, systolic blood pressure, and SSPG to the variation of IMT (model 1). In this model, SSPG and age were found to correlate with IMT. On the other hand, addition of VAP in model 1 revealed that VAP itself was independently associated with carotid wall thickness, accounting for 4% of the variation in the IMT (model 2).

Plaques in the carotid arteries were observed more frequently in the VAP patients than in the control subjects (37.5% versus 12.5%, P<.05). None of the patients with VAP and control subjects had stenotic plaque (more than 20% of the luminal diameter) in the carotid arteries. VAP patients with carotid plaque showed markedly higher values in age (62.8±1.4 versus 52.5±1.5, P<.0001), SSPG level (11.2±0.8 versus 8.7±0.5 pmol/L, P<.01), and IMT (1.04±0.04 versus 0.85±0.04, P<.001) compared with patients without carotid plaque. With the exception of these variables, no significant differences were found between the other risk factors and the presence of plaque by univariate analysis. To evaluate the independent association of risk factors with ultrasonographically detected plaque, stepwise discriminant analysis was performed for patients with VAP in relation to carotid plaque. Age (F=15.77, P=.0004), IMT (F=8.71, P=.0054) and SSPG (F=5.46, P=.030) eliminated the power of systolic BP and cumulative tobacco consumption to discriminate between VAP subjects with and without carotid plaque (data not shown).


*    Discussion
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The present study, based on the screened subjects without diabetes, hypertension, and obesity, provided the first evidence that significant thickening of carotid artery intima media complex with frequent plaque formation was observed in VAP without stenotic coronary lesions compared with those free of coronary artery disease. The present data show that SSPG level and 2-hour insulin area during an oral glucose tolerance test were significantly elevated and independently associated with carotid artery wall thickness in patients with VAP. In addition, multivariable analysis show that VAP was independently associated with carotid wall thickness. These findings indicate that insulin resistance, independently of its effect on BP and lipid metabolism, may contribute to the development of contribute to the development of carotid intima media thickening in this population. Two-hour insulin area, although a statistically significant risk factor in univariate analysis, lost its independent contribution in multivariate analysis including both steady-state plasma glucose level and 2-hour insulin area, probably owing to the strong inverse correlation between SSPG and IMT. In multivariate analyses, addition of SSPG levels instead of 2-hour insulin area added about 5% to the ability of the model to explain IMT. In this regard, it seems reasonable to speculate that the hyperinsulinemia that was observed in VAP patients is attributable to a compensatory phenomenon of pancreatic ß-cells to counteract attenuated insulin action for glucose metabolism.

Insulin resistance associated with hyperinsulinemia is thought to contribute to the initiation of early stage atherosclerosis.13,14 Epidemiologic studies and retrospective reviews of clinical reports have shown that hyperinsulinemia is a potent cardiovascular risk factor.16–18 Recently, considerable number of experimental data have accumulated to elucidate the biological and/or cellular bases of association between insulin resistance and atherosclerosis.15 We recently reported that the insulin-mediated glucose metabolism is significantly impaired in patients with angiographically documented obstructive CAD, and a significant correlation was observed between insulin resistance and extent of CAD.47 We have also demonstrated that insulin resistance and compensatory hyperinsulinemia were strongly associated with VAP.20 These findings are in agreement with the recent report on patients with VAP, which has shown that acetylcholine-induced coronary vasoconstriction correlates with hyperinsulinemia and enhanced insulin responses.48

A reduction of endothelium-derived relaxing factor production, probably a result of early intramural atherosclerotic plaque formation, may play a role in vasospasm. Shimokawa et al49 observed in a swine model the early stages of coronary atherosclerosis in lesions in which coronary vasospasm had occurred. Recent clinical studies using intravascular ultrasound have demonstrated the presence of early signs of atherosclerosis at the sites of spasm in vasospastic angina patients with angiographically normal coronary arteries.21,22 Several studies have shown that a defect in insulin-induced stimulation of endothelium-derived relaxing factor release could be one of the factors that contributes to the altered vascular function in insulin-resistant states.50

Investigations of atherosclerosis in human arteries suggest that changes in the carotid IMT, observed with B-mode ultrasonography, may precede the development of atherosclerotic plaques,51 and the accuracy of IMT measurement by ultrasonography has been validated histologically.52 The present study show that, in VAP patients with carotid plaque, the IMT is larger than that in VAP patients without plaque and stepwise discriminant analysis show that age, IMT, and SSPG as the variable significantly associated with carotid plaque. These finding may indicate that thickening of the arterial wall and plaque formations are two contemporaneous or sequential steps of the atherosclerotic process. In several studies, ultrasonographically determined increased IMT of the common carotid artery has been closely associated with cardiovascular risk factor.53 Laakso et al,54 using the euglycemic insulin clamp technique, first demonstrated the presence of insulin resistance in patients with asymptomatic atherosclerosis (stenotic lesion) in the femoral or carotid arteries. We have also reported the close relationship between insulin resistance and atherothrombotic cerebral infarction with angiographically proven carotid artery stenosis.55 Furthermore, in several studies, positive correlations between plasma insulin levels and IMT have been demonstrated. Recently, Agewall et al56 reported the strong and independent correlations between IMT and insulin resistance in patients with no evidence of cardiovascular disease or diabetes mellitus. These results give support to the hypothesis that insulin resistance may be one factor of pathogenetic importance in the development of the initial step as well as the late stage of carotid atherosclerosis.

A separate question is whether the effects of insulin resistance and hyperinsulinemia on intima media wall thickening and plaque formation are mediated through other risk factors such as aging, blood pressure, lipid, and lipoprotein disturbances. The strong relation of age to carotid atherosclerosis is probably an indirect expression of the continuous exposure to various risk factors rather than the results of an intrinsic process of aging. Of interest, glucose tolerance as well as insulin-mediated glucose disposal declines with aging,57 and the age-related increase in IMT and frequency of plaque formation were also well documented. In the present study, systolic BP was shown to be an independent risk factor for intima media thickening in stepwise logistic analysis (Table 4Up, model 2), although the BP span of the investigated groups was relatively narrow, and IMT and systolic BP did not show significant correlations in partial correlation analysis. Among plasma lipids, triglyceride level known to be positively correlated with plasma insulin level or SSPG level, and HDL cholesterol level is inversely correlated, and such correlations were also observed in the present study. An association between carotid artery atherosclerosis and hypercholesterolemia has also been reported.44 The majority of our study subjects had a normal cholesterol level, with no difference between patients with VAP and control subjects.

In the present study, we measured the insulin sensitivity by a SSPG method using Sandostatin. Glucose clamp method is suitable to estimate insulin-mediated glucose utilization at a different concentrations. However, for the comparison of glucose utilization at fixed insulin level, both the glucose clamp and SSPG methods are equivalent, as is shown in the following formula for obtaining glucose clearance: Glucose clearance=A (infusion rate of glucose)/B (SSPG level). In the glucose clamp method, the denominator is fixed (fasting plasma glucose) and the numerator is obtained, whereas in the SSPG method, A is fixed and the denominator (SSPG) is obtained. Therefore, it is generally accepted that the SSPG method permits an accurate assessment of the isolated effect of insulin on glucose metabolism.39,40,58,59 Since our subjects constituted a highly selected group of patients undergoing coronary angiography for the evaluation of chest pain or suspected coronary artery disease, selection bias can never be completely ruled out. The question of whether carotid IMT may represent the initial stage of coronary atherosclerosis remains speculative because no histologic or ultrasonographic proof for the angiographically undetected atherosclerotic lesions of normal coronary arteries was available in the present study. However, previous clinical studies using intravascular ultrasound have demonstrated the presence of coronary artery intima media thickening at the site of spasm induced by ergonovine.21,22

In summary, in this study, we investigated the common carotid intima to media wall thickness and the occurrence of early atherosclerotic lesion in patients with VAP compared with subjects with chest pain syndrome. The results of this study indicate that VAP patients have increased IMT and plaque formation of the carotid artery compared with control subjects and suggest the possibility that such a relation is, in large part, mediated by one or more of the metabolic disorders closely related to VAP, particularly SSPG levels. These results suggest that insulin resistance in association with compensatory hyperinsulinemia may be an important pathogenetic factor for the development of coronary artery spasms and systemic early atherosclerosis.


*    Acknowledgments
 
The authors gratefully acknowledge Drs Masakazu Yamagishi, Yoshio Yasumura, Yasuko Nishioheda, and Hideki Koh for guidance and helpful suggestions. This research was supported by Special Coordination Funds for Promoting Science and Technology (Encouragement System of Center of Excellence) from the Science and Technology Agency of Japan.

Received November 25, 1996; accepted March 17, 1997.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

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