Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation. 1995;92:1749-1757

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shinozaki, K.
Right arrow Articles by Harano, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shinozaki, K.
Right arrow Articles by Harano, Y.

(Circulation. 1995;92:1749-1757.)
© 1995 American Heart Association, Inc.

Articles

Insulin Resistance Associated With Compensatory Hyperinsulinemia as an Independent Risk Factor for Vasospastic Angina

Kazuya Shinozaki, MD; Masaaki Suzuki, MD; Motoyoshi Ikebuchi, MD; Hiroshi Takaki, MD; Yasushi Hara, MD; Motoo Tsushima, MD; Yutaka Harano, MD

From the Division of Atherosclerosis, Metabolism, and Clinical Nutrition (K.S., M.S., M.I., Y. Hara, M.T., Y. Harano) and the Division of Cardiology (H.T.), Department of Medicine, National Cardiovascular Center, Osaka, Japan.

Correspondence to Kazuya Shinozaki, MD, Division of Atherosclerosis, Metabolism, and Clinical Nutrition, Department of Medicine, National Cardiovascular Center, 5-7-1, Fujishiro-dai, Suita, Osaka 565, Japan.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Background It is generally believed that coronary artery spasm plays an important role in the progression of obstructive coronary artery disease. Since insulin resistance together with hyperinsulinemia plays an important role in the pathogenesis of coronary atherosclerosis, we investigated the association of hyperinsulinemia and insulin resistance with vasospastic angina (VAP).

Methods and Results The study population consisted of 60 patients with VAP and 42 control subjects (62 subjects with normal glucose tolerance and 40 with impaired glucose tolerance). Insulin sensitivity was determined by the steady-state plasma glucose (SSPG) method for nondiabetic, normotensive, nonobese subjects (16 control subjects, 16 obstructive coronary artery disease patients, and 16 VAP patients). Compared with the control groups, the 2-hour insulin area (area under the plasma insulin concentration-time curve) during a 75-g oral glucose tolerance test was significantly higher in both VAP groups with normal and impaired glucose tolerance. A high frequency of vasospastic angina was observed in subjects with clustered risk factors for insulin resistance syndrome, suggesting a close association of VAP with this syndrome. In stepwise discriminant analysis, the 2-hour insulin area was significantly associated with VAP independent of other risk factors. SSPG level in VAP was about twofold over control, indicating the presence of insulin resistance in patients with VAP. However, no differences were found between patients with VAP and obstructive coronary artery disease with respect to mean SSPG level.

Conclusions SSPG level was significantly elevated in patients with VAP and obstructive coronary artery disease compared with control subjects. This indicates that hyperinsulinemia is secondary to insulin resistance, both of which are thought to play important roles as risk factors for VAP in the early atheromatous lesion and in the future development of occlusive lesions when chronically present.


Key Words: insulin • apolipoproteins • glucose • vasospasm


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Although several articles have uncovered the causes and predisposing factors for vasospastic angina (VAP), no single cause for spasm has been found. Previous studies have shown that the number of coronary risk factors such as hypertension, hypercholesterolemia, age, and smoking were associated with impairment of endothelium-dependent vasodilation in patients without angiographic evidence of coronary artery disease.1 2 3 4 5 Low apolipoprotein A-I level also has been observed in patients with VAP.6 7 Moreover, decreased intracellular free magnesium and/or increased calcium levels were reported to play an important role in the regulation of vascular tone and development of atherosclerosis.8 9 All these risk factors are believed to induce morphological and functional alterations in the endothelium and/or smooth muscle cells.

Previous studies have shown that endothelial dysfunction is an early event leading to atherosclerosis, preceding occlusive vascular disease in both the experimental primate models10 and human heart transplant recipients.11 A recent clinical study using intravascular ultrasound has demonstrated the presence of early signs of atherosclerosis at the site of focal spasm.12

On the other hand, there is general agreement that insulin resistance underlies all the major coronary risk factors for atherosclerosis: glucose intolerance, hypertension, obesity, and increased VLDL and reduced HDL cholesterol levels. Accumulation of these risk factors is believed to contribute to the development of atherosclerosis.13 14 Several experimental studies have suggested that coronary spasm plays a crucial role in the progression of atheroma.15 In this regard, it is conceivable that VAP may be correlated with impairment of glucose and lipid metabolism.

The present study was designed to examine the possible relation of VAP to insulin resistance in nondiabetic subjects with angiographically assessed vasospasm compared with subjects with chest pain syndrome.


*    Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Study Subjects
Sixty patients with VAP (41 men, 19 women) aged 20 to 71 years and 42 control subjects (24 men, 18 women) aged 27 to 74 years were recruited into this study. All subjects were selected from consecutive patients who entered our division during 1983 to 1993 for coronary angiography because of chest pain or clinically suspected coronary artery disease. The control subjects were investigated for atypical chest pain. All 42 control subjects had normal coronary arteries (>25% stenosis of the luminal diameter) without spasms (luminal narrowing <50% by ergonovine provocation test or spontaneously). Nine control subjects (5 with normal glucose tolerance, 4 with impaired glucose tolerance) were treated with calcium channel blocking agents. VAP was defined as reduced luminal diameter by >=75% (either spontaneous or ergonovine provocation test) with normal resting angiograms (53 patients showed >=99% spasm) and negative or nondiagnostic exercise tolerance tests. Patients who were taking lipid-lowering drugs, ß-adrenergic blocking drugs, or diuretics, which may have adverse effects on carbohydrate and lipid metabolism, were excluded from the study.16 17 At the time of the study, 7 patients were entirely without continuous medication and 53 (33 with normal glucose tolerance, 20 with impaired glucose tolerance) were undergoing treatment with calcium channel blocking agents. Twenty-seven patients (15 with normal glucose tolerance, 12 with impaired glucose tolerance) were treated with isosorbide dinitrate in addition to the calcium channel blocking agents.

Insulin sensitivity was measured in 32 nonobese, normotensive, nondiabetic subjects (16 control subjects, 16 patients with VAP), since insulin resistance may be associated with altered blood pressure18 19 and body mass index (BMI).20 Sixteen nonobese, normotensive patients (8 with normal glucose tolerance, 8 with impaired glucose tolerance) with obstructive coronary artery disease, defined as a reduction >=75% in the luminal diameter of at least one major epicardial coronary artery as determined by coronary angiography, also were studied to compare the results between VAP and obstructive coronary disease. Three patients had three-vessel disease, 5 had two-vessel disease, and 8 had single-vessel disease. All of these patients had a history of effort angina before they underwent coronary angiography. All three groups (control subjects, VAP patients, and obstructive coronary disease patients) were matched for age, BMI, sex ratio, and impaired glucose tolerance.

Those with a history of myocardial infarction, unstable angina, valvular disease, diabetes mellitus, familial hypercholesterolemia, or hepatic, renal, or endocrine dysfunction were excluded from the study. Physically inactive persons unable to perform tasks of regular daily life also were excluded. All subjects gave their informed consent, and the study protocol was approved by the Ethics Committee of the National Cardiovascular Center.

Baseline Investigation
Two weeks before cardiac catheterization, venous blood samples were drawn from each subject after an overnight fast for measurement of plasma glucose, insulin, total cholesterol, triglycerides, HDL cholesterol, and apolipoprotein A-I and B. The LDL cholesterol levels were calculated according to the Friedewald equation: LDL cholesterol (mmol/L)=total cholesterol-HDL cholesterol-triglycerides/2.2.21 A 75-g load of glucose (Trelan G 75, Shimizu Co) 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 (OGTT) according to the World Health Organization criteria. Glucose was determined by the glucose oxidase method22 and insulin by radioimmunoassay using double antibody.23 Total cholesterol,24 triglycerides,25 HDL cholesterol,26 and apolipoprotein A-I and B27 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 Korotkoff sound) blood pressures, and the averages of the two were used for data analyses. Study subjects were classified as nonsmokers if they had never smoked or stopped smoking at least 1 year before cardiac catheterization. All the other subjects were classified as smokers. As a cumulative estimate of tobacco consumption, cigarette-years (cigarettes per dayxyears) was used and BMI calculated from the formula BMI=weight (kg)/height (m)2.

Coronary Angiography
Coronary angiograms were obtained in most cases within 1 month of the metabolic evaluation (0.3±0.2; range, 0 to 2.4 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 with the use of a biplane cineangiography system. All patients with VAP had normal coronary angiograms without segmental stenosis or luminal irregularities. Coronary spasm was demonstrated in 60 patients: during ergonovine-provoked angina in 54 patients and during spontaneous angina in 6 patients. Fifty-six VAP patients (93.3%) had completely normal coronary arteries, and those of the others were nearly normal (<25%). One milliliter (0.01 mg) of ergonovine maleate, the most potent of all agents used in provoking coronary spasm,28 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 >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.29 If the results were positive, nitroglycerin (0.25 mg) was injected into the coronary artery to relieve the spasm. Forty-two control subjects had normal or near-normal coronary arteries (38 control subjects showed completely normal coronary arteries) and no induction of coronary spasm (<50% of luminal diameter) either spontaneously or after ergonovine provocation test.

Insulin Sensitivity Test
Insulin sensitivity tests were performed in 16 control subjects, 16 patients with VAP, and 16 patients with obstructive coronary artery disease. Insulin sensitivity was estimated by the steady-state plasma glucose (SSPG) method30 with the use of Sandostatin, originally described by Harano et al.31 The recently developed cyclic octapeptide Sandostatin, with amino acid sequence (D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr(ol), is an analogue of somatostatin, which inhibits the endogenous secretion of insulin, glucagon, and growth hormone32 and is available commercially. Sandostatin has a longer duration of action than somatostatin and appears to be more potent than the natural compound in its inhibition of gut hormone secretion.32 After an overnight fast, glucose (6 mg/kg per minute), KCl (0.5 µEq/kg per minute), Novolin R40 insulin (7.5 mU/kg in a bolus, followed by a constant infusion at a rate of 0.77 mU/kg per minute), and Sandostatin (150 µg/2 hours) were infused simultaneously for 2 hours at a rate of 3 mL/kg per hour 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, insulin, and free fatty acids. SSPG and insulin concentrations were obtained at 120 minutes. Under these steady-state conditions, plasma glucose levels are inversely correlated with the rate of insulin-mediated glucose disposal and are inversely proportional to insulin sensitivity.30 Plasma catecholamine (epinephrine and norepinephrine) levels were determined using high-performance liquid chromatography with spectrofluorometric detection.33 Fifteen VAP patients were receiving treatment with the calcium channel blocker diltiazem, and 9 were taking nitrate. Ten patients with obstructive coronary disease were receiving diltiazem, and 11 were taking nitrate. Control subjects and patients with VAP were taking no lipid-lowering or ß-adrenergic blocking drugs.

Coronary Risk Factors
The following five risk factors for insulin resistance syndrome were assessed from baseline clinical data.

Hyperinsulinemia The diagnosis of hyperinsulinemia was based on the following laboratory findings: fasting plasma insulin level >110 pmol/L or area under the plasma insulin concentration-time curve (2-hour insulin area) after oral 75-g glucose >800 pmol/L per hour (>2 SD above the mean value of control subjects).

Glucose intolerance The definition of impaired glucose tolerance was based on the 2-hour oral glucose tolerance test according to World Health Organization criteria (plasma glucose levels between 7.8 and 11.1 mmol/L 2 hours after an oral glucose load of 75 g).34

Obesity A patient was classified as obese if his or her BMI exceeded 26 kg/m2 at the time of admission to our hospital.

Hypertension The diagnosis of hypertension was defined as systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg. Normotensive subjects were those with both systolic and diastolic blood pressures below 140 and 90 mm Hg, respectively. Patients were considered to have hypertension if they had been treated with antihypertensive drugs.

Dyslipoproteinemia Hyperlipoproteinemias were defined according to World Health Organization classification.35 The cutoff points were 6.0 mmol/L for total cholesterol and 1.7 mmol/L for triglycerides. The cutoff point for HDL cholesterol was 1.03 mmol/L (the upper limit of the lowest tertile of the baseline HDL cholesterol distribution).

Statistical Analysis
Data are expressed as mean±SEM. Statistical analysis was performed with the SAS computer program (SAS Institute, Cary, NC). The Student t test (continuous variables) was used to test the significance of the differences between two groups. Group differences of categorical data were tested by {chi}2 analysis with Yates' correction. The plasma glucose and insulin responses in the four groups during OGTT, SSPG, and steady-state plasma insulin (SSPI), blood pressure, and lipid and lipoprotein concentrations were compared with one-way ANOVA. Stepwise discriminant analysis was performed to assess the independent discriminatory power of each metabolic risk factor. Variables significantly different in the univariate comparisons (Tables 1Down and 2Down and Fig 3Down) were included in the model. The grouping variable was the presence of vasospastic angina. F statistics and respective probability values are given for each risk factor. Logarithmic transformations were performed on all skewed lipid and lipoprotein variables (triglycerides, LDL cholesterol) to obtain a normal distribution before statistical comparisons and significance testing were performed. Differences with probability values of <.05 were considered statistically significant.


View this table:
[in this window]
[in a new window]
  		Table 1. Clinical Characteristics of Study Subjects


View this table:
[in this window]
[in a new window]
  		Table 2. Blood Pressure, Fasting Plasma Lipid, Lipoprotein, and Apolipoprotein Concentrations in Study Subjects



View larger version (34K):
[in this window]
[in a new window]
  		Figure 3. Bar graphs show 2-hour plasma glucose and insulin areas during 75-g oral glucose tolerance test. VAP indicates vasospastic angina. Significantly different from control subjects with normal glucose tolerance at P<.01, *P<.0001 (ANOVA). Significantly different from control subjects with impaired glucose tolerance at #P<.05, §P<.0001 (ANOVA). Values are mean±SEM.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
Characteristics of the Study Groups
The clinical characteristics of the study subjects are shown in Table 1Up. No statistical differences between control subjects and patients with vasospastic angina were observed in age, sex, cumulative tobacco consumption, or family history of diabetes, hypertension, or coronary artery disease. The groups did not differ significantly in the proportions of hypertensive subjects and smokers. BMI was significantly higher in VAP patients with impaired glucose tolerance compared with both control groups (P<.0001 for control subjects with normal glucose tolerance, P<.01 for control subjects with impaired glucose tolerance). Analysis of dyslipoproteinemia phenotypes showed a significantly increased prevalence of phenotype IV but not phenotypes IIA or IIB.

Plasma Glucose and Insulin Levels
Fig 1Down shows frequency distributions of 2-hour insulin areas in patients and control subjects. Compared with the control group, the distribution of the 2-hour insulin area in the VAP group was skewed toward the higher level: In the VAP group, 76.7% of patients had 2-hour insulin area >800 pmol/L per hour; in the control group, however, only 9.5% of subjects exceeded this limit. Plasma glucose and insulin responses for the four groups during OGTT are shown in Figs 2Down and 3Up. The plasma glucose responses were significantly higher in control (P<.0001) and VAP (P<.0001) subjects with impaired glucose tolerance compared with the control subjects with normal glucose tolerance. These data also demonstrate that patients with VAP were relatively but not significantly glucose intolerant compared with the control groups. Whereas the insulin response was not different between both control groups (normal glucose tolerance, 447.3±32.2 pmol/L; impaired glucose tolerance, 574.8±41.7 pmol/L), VAP patients with normal (950.4±88.0 pmol/L) or impaired (1131.2±118.4 pmol/L) glucose tolerance had 2-hour insulin areas that doubled those in the control subjects. It is interesting to note that patients with VAP were hyperinsulinemic, and the magnitude of the difference in insulin response was greater than that for glucose. The results remained essentially similar after the adjustment of age and/or BMI.



View larger version (28K):
[in this window]
[in a new window]
  		Figure 1. Bar graphs show frequency distribution of 2-hour insulin area in patients with vasospastic angina and in control subjects.



View larger version (18K):
[in this window]
[in a new window]
  		Figure 2. Plots show plasma glucose and insulin responses to a 75-g oral glucose load. Symbols represent control subjects with normal glucose tolerance ({blacktriangleup}, n=25), control subjects with impaired glucose tolerance ({blacksquare}, n=17), vasospastic angina (VAP) patients with normal glucose tolerance ({diamondsuit}, n=37), and VAP patients with impaired glucose tolerance ({bullet}, n=23). Values are mean±SEM.

Blood Pressure, Serum Lipid, Lipoprotein, and Apolipoprotein Levels
Systolic blood pressure was significantly higher in both VAP groups than that of control subjects with normal glucose tolerance (Table 2Up). Diastolic blood pressure also was slightly higher in the VAP groups but was not significant. Compared with the control subjects with normal glucose tolerance, marked elevation of triglyceride level (P<.05) was observed, whereas the levels of HDL cholesterol (P<.01) in the VAP patients with impaired glucose tolerance were significantly lower. Apolipoprotein A-I level was significantly (P<.05) lower in patients with VAP compared with control groups. Although a similar tendency was observed between control subjects and VAP patients with normal glucose tolerance in terms of HDL cholesterol and triglyceride level, none of the differences reached statistical significance. There were no significant differences among the groups in the levels of total cholesterol, LDL cholesterol, or apolipoprotein B. When these analyses were repeated with adjustment for age and/or BMI, similar results were obtained.

Multivariate Analysis
To determine whether independent associations between the 2-hour insulin area and lipid levels and blood pressure existed, multiple regression analysis was performed with 2-hour insulin area, fasting glucose level, 2-hour glucose area, and BMI as the independent variables (Table 3Down). Total cholesterol, triglyceride, and HDL cholesterol levels were significantly associated with 2-hour insulin area, accounting for about 50% of the variance of each lipid and lipoprotein level. Furthermore, none of the other independent variables showed significant correlations with total cholesterol or triglyceride levels. Two-hour insulin area was significantly associated with systolic and diastolic blood pressures (P<.0001). BMI also correlated with HDL cholesterol and diastolic blood pressure.


View this table:
[in this window]
[in a new window]
  		Table 3. Multiple Regression Analysis of Variables Associated With Lipids and Blood Pressure

Cumulative Frequency of Risk Factors
The cumulative frequencies of risk factors for insulin resistance syndrome (hyperinsulinemia, glucose intolerance, obesity, hypertension, and dyslipidemia) in smokers and nonsmokers are shown in Fig 4Down. Because smoking is known to cause vasoconstriction,1 smokers and nonsmokers were analyzed separately. Cumulative frequency of risk factors was higher in patients with VAP than the control group. The number of control subjects decreased progressively with increases in the number of risk factors. Nine percent of smokers with VAP and 10% of nonsmokers with VAP fulfilled all of the diagnostic criteria for insulin resistance syndrome. On the other hand, there were no control subjects with all five risk factors. The subjects showed the following distributions (smokers and nonsmokers, respectively): no risk factors (control subjects, 32% and 41%; VAP patients, 5% and 10%), one risk factor (control subjects, 36% and 29%; VAP patients, 9% and 21%), two risk factors (control subjects, 20% and 18%; VAP patients, 15% and 21%), three risk factors (control subjects, 12% and 6%; VAP patients, 39% and 20%), and four risk factors (control subjects, 0% and 6%; VAP patients, 22% and 10%).



View larger version (57K):
[in this window]
[in a new window]
  		Figure 4. Graphs show cumulative frequencies of five risk factors (hyperinsulinemia, obesity, glucose intolerance, hypertension, and dyslipidemia) for insulin resistance syndrome in current smokers (n=61) and nonsmokers (n=41). VAP indicates vasospastic angina.

Parameters That Best Discriminate Between Patients With Vasospastic Angina and Control Subjects
To examine the independent contribution of 2-hour insulin area and other relevant variables to angiographically assessed VAP, stepwise discriminant analysis was performed in the patients with VAP and the control group (Table 4Down). Two-hour insulin area and apolipoprotein A-I level were independently and significantly associated with VAP. Because coronary risk factors (age, smoking, hypertension, hypercholesterolemia) are associated with endothelial dysfunction and constrictor response to ergonovine, the effects of these confounding factors also were adjusted in the model. Two-hour insulin area remained as a strong discriminant for VAP irrespective of adjustment for these factors. BMI was the only parameter that contributed to discriminant analysis after adjustment for the influence of all these factors.


View this table:
[in this window]
[in a new window]
  		Table 4. Stepwise Discriminant Analysis Between Patients With Vasospastic Angina and Control Subjects

Results of Insulin Sensitivity Test
SSPG levels of the six age- and BMI-matched groups are illustrated in Fig 5Down. There were no significant differences among the groups in the level of blood pressure, plasma epinephrine, or norepinephrine levels. The mean SSPG levels were significantly higher in the VAP patients (normal glucose tolerance, 9.76±1.02 mmol/L; impaired glucose tolerance, 11.93±1.11 mmol/L) compared with each group of control subjects (4.46±0.46 and 6.01±0.45 mmol/L, respectively). The mean SSPG level also was significantly higher in the patients with obstructive coronary disease (normal glucose tolerance, 8.76±0.99 mmol/L; impaired glucose tolerance, 11.32±0.97 mmol/L) compared with each group of control subjects. No differences were found between patients with VAP and obstructive coronary disease with respect to mean SSPG level. SSPI levels were similar among the six groups (control group with normal glucose tolerance, 320.1±26.6 pmol/L; VAP group with normal glucose tolerance, 324.2±21.1 pmol/L; obstructive coronary disease with normal glucose tolerance group, 337.2±31.0 pmol/L; control group with impaired glucose tolerance, 354.4±33.5 pmol/L; VAP group with impaired glucose tolerance, 360.5±27.4 pmol/L; obstructive coronary disease with impaired glucose tolerance group, 357.7±21.3 pmol/L). These results clearly indicate that there is a pathogenetic connection between insulin resistance for glucose utilization and VAP.



View larger version (25K):
[in this window]
[in a new window]
  		Figure 5. Plot of steady-state plasma glucose (SSPG) levels during insulin sensitivity tests in control subjects, patients with vasospastic angina (VAP), and patients with obstructive coronary artery disease (CAD). Probability values were computed by one-way ANOVA.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
This study provided the first evidence that patients with VAP showed insulin insensitivity and suggests that insulin resistance together with compensatory hyperinsulinemia, independent of obesity and hypertension, may contribute to the pathogenesis of coronary vasospasm.

A considerable number of experimental36 and clinical studies37 38 39 have demonstrated a link between hyperinsulinemia and atherosclerotic cardiovascular disease. Although several attempts have been made to determine the risk factors of VAP,3 4 5 6 little attention has been paid to the association of hyperinsulinemia and insulin resistance with coronary vasospasm. Recent studies have demonstrated that coronary spasm induced by ergonovine in humans is related to the presence of early atherosclerotic changes in angiographically intact coronary arteries.40 In the present study, it is important to note that the number of risk factors for insulin resistance syndrome was higher in patients with VAP, and all these variables were both significantly and independently associated with the 2-hour insulin area. We have reported previously that insulin resistance rather than hyperinsulinemia is more positively correlated with hypertension,41 but hyperinsulinemia may play an additional role in the progression of early atheromatous lesions. These results support the hypothesis that insulin resistance together with hyperinsulinemia plays a causative role in the cluster of a series of coronary risk factors and initiation and progression of atheromatous lesions.13

To further evaluate the relation between insulin resistance and VAP while avoiding the dominant effects of other factors, such as blood pressure and obesity, only patients with normal blood pressure and nonobese subjects were included in the study of insulin sensitivity. SSPG levels in patients with vasospastic angina (P<.01 for the subjects with normal glucose tolerance, P<.001 for those with impaired glucose tolerance) were about twice those in control subjects. On the basis of our findings, it seems reasonable to speculate that hyperinsulinemia observed in vasospastic angina is attributable to a compensatory mechanism of ß-cells to inadequate glucose metabolism.

Whether the decrease in insulin sensitivity in the presence of hyperinsulinemia in patients with VAP is primarily associated with coronary vasospasm or is simply a reflection of some other alteration remains unknown. It has been suggested that dysfunction of the endothelium, hyperreactivity of vascular smooth muscle, or both predispose the coronary artery to spasm.42 One explanation for the present observation is that reduction of endothelium-derived relaxing factor (EDRF) production, probably as a result of early intramural atherosclerotic plaque formation, may play a role in vasospasm.43 44 In the early stage of coronary atherosclerosis, injury to the endothelium may cause no morphological alterations but only functional changes in the endothelial cells, which may play an important role in the control of coronary vascular resistance through the production of EDRF.45 Shimokawa et al40 visualized in a swine model the early stages of coronary atherosclerosis in lesions in which coronary vasospasm had occurred. Moreover, this previous experimental report and a clinical study12 using intravascular ultrasound have demonstrated the presence of early signs of coronary atherosclerosis at the site of focal spasm.

Hypertension, hyperlipidemia, and diabetes mellitus attenuate endothelium-dependent relaxation in various blood vessels.46 47 Reaven et al48 reported the presence of insulin resistance in subjects with small, dense LDL particles that may be atherogenic. Other studies have suggested that small, dense LDL particles are a risk factor in the development of atherosclerotic coronary heart disease.49 In our preliminary study, patients with VAP appeared to show these atherogenic lipoprotein profiles. Moreover, chronic hyperinsulinemia may contribute to the development of early atherosclerosis by a direct effect on proliferation of smooth muscle cells.50 These results suggest that the presence of the above-mentioned risk factors are closely associated with insulin resistance and thereby contribute to the altered coronary vascular reactivity in the early stages of atherosclerosis.

As shown in Fig 5Up, insulin resistance also was observed in patients with obstructive coronary disease. For ethical reasons, ergonovine provocation tests were not performed in patients with obstructive coronary disease in the present study. MacAlpin51 and Maseri et al52 reported that most coronary spasms occurred at the site of organic stenosis in patients with coexisting obstructive coronary artery disease. Accordingly, it is conceivable that a relatively major proportion of patients with organic stenosis but not "normal coronary arteries" may be involved in the pathogenesis of VAP. Ginsburg et al53 have demonstrated that maximal contractile responses to ergonovine maleate and histamine were decreased in isolated human coronary artery with advanced atherosclerosis. In fact, in our separate study, very few older subjects (>70 years old) or patients with obstructive coronary artery disease and long-standing (>10 years) diabetes showed positive findings on ergonovine provocation tests.

As suggested previously by Marzilli et al,54 hypoxia of the coronary artery caused by coronary artery spasm may induce dysfunction of the endothelium and dissection of the surface of the atheroma, causing progression of the invasion of serum lipids into the coronary artery wall and finally coronary atherosclerosis. Spasm-induced intramural hemorrhage may be an important factor for acute progression of organic stenosis.15 Recently, Haffner et al55 reported that existence of high insulin concentrations precede the development of numerous coronary risk factors, such as hypertension, decreased HDL concentrations, increased triglyceride concentrations, and non–insulin-dependent diabetes mellitus. All these factors would impair vascular endothelium function and amplify the formation of atherosclerotic lesions.56 Nobuyoshi et al57 have shown in a large number of patients that progression of atheroma has been observed at the sites of coronary spasm (positive for the ergonovine provocation test). These observations support the view that insulin resistance associated with hyperinsulinemia may play an important role in VAP and contribute to the future development of fixed coronary stenosis when chronically persistent. Because VAP does not always precede obstructive coronary disease, more studies are needed to clarify the mechanisms of development of obstructive coronary disease in the insulin-resistant state.

Another possible mechanism is that increased calcium levels and reduced intracellular free magnesium levels, which are closely associated with insulin resistance,8 9 58 may be involved in the pathogenesis of coronary vasospasm. Under the high intracellular calcium levels in smooth muscle cells, insulin action is attenuated due to the inactivation of phosphoserine phosphatase-1 (PP-1),8 while vasoconstriction is exaggerated. Evidence has been reported showing that magnesium, a physiological calcium antagonist, plays an important role in the regulation of vascular smooth muscle tone and development of atherosclerosis.59 60 In vivo and in vitro experiments have shown that insulin can mediate magnesium accumulation in erythrocytes,61 decrease platelet aggregation,62 and stimulate prostaglandin E1 binding and thereby enhance the platelet antiaggregatory action by increasing cAMP levels.63 Magnesium deficiency would lead to increased platelet aggregation through reduction in prostaglandin I2 and an increase in vasoconstrictive prostaglandins such as thromboxane A2 and the lipoxygenase product I2-hydroxyeicosatetraenoic acid.64 Interestingly, magnesium suppresses anginal attacks induced by hyperventilation65 or exercise66 in patients with variant angina. Magnesium affects coagulation and calcium uptake into smooth muscle cells, which are known to be important factors in atherogenesis.59

Previous studies have shown that cigarette smoking is a risk factor for coronary vasospasm,4 and smoking impairs endothelial function dose dependently.67 As shown in Table 1Up and Fig 4Up, cigarette smoking had little impact on risk for VAP in this study. The high frequency of smokers among the control subjects and involvement of subjects who have stopped smoking after the initial symptoms may have influenced our data.

Tasaki et al6 and Shirai et al7 have shown that low levels of apolipoprotein A-I, the major lipoprotein in HDL, is the best discriminator of VAP, although diabetes is not excluded in those studies. A univariate comparison of the control subjects and patients yielded significant probability values for apolipoprotein A-I and 2-hour insulin area (Fig 3Up and Table 2Up). To validate the discriminatory ability, we compared the 2-hour insulin area and other relevant variables by stepwise discriminant analysis (Table 4Up). The corresponding F statistics were >34.6 (P<.0001) and <12.2 (P<.001) for apolipoprotein A-I. These results suggest the superior discriminatory ability of 2-hour insulin area over apolipoprotein A-I for VAP. In addition to the increased 2-hour insulin area and low apolipoprotein A-I, BMI showed discriminatory ability, indicating that these factors may have a strong joint effect on the risk for VAP.

With regard to the mechanism of decreased insulin action in these patients, humoral factors such as amylin, calcitonin gene-related peptide, and/or others may be involved.68 There also remains the possibility that vascular and hemodynamic abnormalities may contribute to decreased insulin sensitivity and secondary hyperinsulinemia. Lillioja et al69 showed that insulin-mediated glucose uptake is correlated inversely with decreased skeletal muscle capillary density. Another study demonstrated that a hemodynamic defect causing reduced skeletal muscle blood flow may contribute to insulin resistance state, such as obesity.70

Limitations
More precise evaluation of physical activity based on the exercise capacity test was not performed for all the subjects. In the present study, in which insulin sensitivity tests were used, 15 patients with VAP and 10 with obstructive coronary artery disease had already been taking the calcium channel blocker diltiazem. In a previous report, Pollare et al71 showed that diltiazem did not affect insulin sensitivity or serum lipid level, whereas we previously showed improvement of insulin sensitivity with the use of a long-acting calcium channel blocker.31 Therefore, it is unlikely that the observed insulin resistance was due to the drug therapy. Since no histological proof for the presence or absence of angiographically undetected atherosclerotic lesions of normal coronary arteries was available in the present study, whether the disruption of endothelial or smooth muscle function may be related to the pathogenesis of vasospasm remains speculative in our study population.

Conclusions
These results suggest that insulin resistance associated with compensatory hyperinsulinemia plays a crucial role in the pathogenetic mechanism in patients with VAP as well as obstructive coronary artery disease. Also, VAP plays an important role in the clinical significance of insulin resistance syndrome and may contribute to the future development of coronary atherosclerosis.


*    Acknowledgments
 
This research was supported by Special Coordination Funds for Promoting Science and Technology (Encouragement System of COE) from the Science and Technology Agency of Japan. The authors gratefully acknowledge Yoich Goto, MD, and Masakazu Yamagishi, MD, for helpful discussions and Yuich Hattori, PhD, for performing the statistical analysis.

Received February 14, 1995; revision received April 19, 1995; accepted May 3, 1995.


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

  1. Vita JA, Treasure CB, Nabel EG, McLenachan JM, Fish D, Yeung AC, Vekshtein VI, Selwyn AP, Ganz P. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation. 1990;81:491-497. [Abstract/Free Full Text]
  2. Egashira K, Inou T, Hirooka Y, Kai H, Sugimachi M, Suzuki S, Kuga T, Urabe Y, Takeshita A. Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans. Circulation. 1993;88:77-81. [Abstract/Free Full Text]
  3. Sato I, Tomita M, Ohe T, Haze K, Shimiomura K. Age-related changes of clinical features and prevalences of coronary risk factors in Japanese patients with vasospastic angina. Chest. 1986;89:12-19. [Abstract/Free Full Text]
  4. Sugiishi M, Takatsu F. Cigarette smoking is a major risk factor for coronary spasm. Circulation. 1993;87:76-79. [Abstract/Free Full Text]
  5. Seiler C, Hess OM, Buechi M, Suter TM, Krayenbuehl HP. Influence of serum cholesterol and other risk factors on vasomotion of angiographically normal coronary arteries. Circulation. 1993;88:2139-2148. [Abstract/Free Full Text]
  6. Tasaki H, Nakashima Y, Nandate H, Yashiro A, Kawashima T, Kuroiwa A. Comparison of serum lipid values in variant angina pectoris and fixed coronary artery disease with normal subjects. Am J Cardiol. 1989;63:1441-1445. [Medline] [Order article via Infotrieve]
  7. Shirai K, Nii T, Imamura M, Kawano T, Mori T, Nakashima Y, Sasaki J, Arakawa K. Low serum apolipoprotein A-I level in patients with vasospastic angina. Am Heart J. 1993;125:320-323. [Medline] [Order article via Infotrieve]
  8. Draznin B. Cytosolic calcium and insulin resistance. Am J Kidney Dis. 1993;21(suppl 3):32-38.
  9. Draznin B, Sussman K, Echel RH, Kao M, Yost Y, Sherman N. Possible role of cytosolic free Ca concentrations in mediating insulin resistance of obesity and hyperinsulinemia. J Clin Invest. 1988;82:1848-1852.
  10. Harrison DG, Armstrong ML, Freiman PC, Heistad DD. Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis. J Clin Invest. 1987;80:1808-1811.
  11. Fish RD, Nabel EG, Selwyn AP, Ludmer PL, Mudge GH, Kloshenbaum JM, Schoen FJ, Alexander RW, Ganz P. Responses of coronary arteries of cardiac transplant patients to acetylcholine. J Clin Invest. 1988;81:21-31.
  12. Yamagishi M, Miyatake K, Tamai J, Nakatani S, Koyama J, Nissen SE. Intravascular ultrasound detection of atherosclerosis at the site of focal vasospasm in angiographically normal or minimally narrowed coronary segments. J Am Coll Cardiol. 1994;23:352-357. [Abstract]
  13. Reaven GM. Role of insulin resistance in human disease. Diabetes. 1989;37:1595-1607. [Abstract]
  14. DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991;14:173-194. [Abstract]
  15. Kuga T, Tagawa H, Tomoike H, Mitsuoka W, Egashira S, Ohara Y, Takeshita A, Nakamura M. Role of coronary artery spasm in progression of organic coronary stenosis and acute myocardial infarction in a swine model: importance of mode of onset and duration of coronary artery spasm. Circulation. 1993;87:573-582. [Abstract/Free Full Text]
  16. Fishman WH. ß-Adrenergic receptor blockers: adverse effects and drug interactions. Hypertension. 1988;11(suppl II):II-21-II-29.
  17. Weinberger MH. Diuretics and their side effects: dilemma in the treatment of hypertension. Hypertension. 1988;11(suppl II):II-16-II-20.
  18. Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, Pedrinelli R, Brandi L, Bevilacqua S. Insulin resistance in essential hypertension. N Engl J Med. 1987;317:350-357. [Abstract]
  19. Pollare T, Lithell H, Barne C. Insulin resistance is a characteristic feature of primary hypertension independent of obesity. Metabolism. 1990;39:167-174. [Medline] [Order article via Infotrieve]
  20. Campbell PJ, Gerich JE. Impact of obesity on insulin action in volunteers with normal glucose tolerance: demonstration of a threshold for the adverse effect of obesity. J Clin Endocrinol Metab. 1990;70:1114-1118. [Abstract]
  21. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifugation. Clin Chem. 1972;18:499-502. [Abstract]
  22. Hoffman WS. A rapid photoelectric method for the determination of glucose in blood and urine. J Biol Chem. 1937;120:52-55.
  23. Hale CN, Randle PJ. Immunoassay of insulin with insulin-antibody precipitate. Biochem J. 1963;88:137-146. [Medline] [Order article via Infotrieve]
  24. Richmond W. Preparation and properties of a cholesterol oxidase from Nacardia sp and its application to the enzymatic assay of total cholesterol in serum. Clin Chem. 1973;19:1350-1356. [Abstract]
  25. Fletcher MJ. A colorimetric method of estimating serum triglycerides. Clin Chim Acta. 1968;22:393-397. [Medline] [Order article via Infotrieve]
  26. Didez LI. Separation and quantitation of subclasses of human plasma high density lipoproteins by a single precipitation procedure. J Lipid Res. 1982;23:1206-1223. [Abstract]
  27. Mancini G, Carbonara AO, Heremans JF. Immunochemical quantitation of antigens by single radial immunodiffusion. Int J Immunochem. 1965;2:235-240.
  28. Kaski JC, Crea F, Meran D, Rodriguez L, Araujo L, Chierchia S, Davies G, Maseri A. Local coronary supersensitivity to diverse vasoconstrictive stimuli in patients with variant angina. Circulation. 1986;74:1255-1265. [Abstract/Free Full Text]
  29. Hackett D, Larkin S, Chierchia S, Davies G, Kaski JC, Maseri A. Induction of coronary artery spasm by a direct local action of ergonovine. Circulation. 1987;75:577-582. [Abstract/Free Full Text]
  30. Harano Y, Hidaka H, Takatsuki K, Ohgaku S, Haneda M, Motoi S, Shigeta Y, Abe H. Glucose, insulin, and somatostatin infusion for the determination of insulin sensitivity in vivo. Metabolism. 1978;27(suppl I):1449-1452.
  31. Harano Y, Kageyama A, Hirose J, Asakura Y, Yokota C, Ikebuchi M, Suzuki M, Omae T. Improvement of insulin sensitivity for glucose metabolism with long-acting Ca channel blocker, amlodipine, in essential hypertensive subjects. Metabolism. 1995;44:315-319. [Medline] [Order article via Infotrieve]
  32. Boden G, Ryan IG, Eisenschmid BL, Shelmet JJ, Owen OE. Treatment of inoperable glucagonoma with the long-acting somatostatin analogue SMS 201-995. N Engl J Med. 1986;314:1686-1689. [Medline] [Order article via Infotrieve]
  33. Nohta H, Mitsui A, Ohkura Y. Spectrofluorometric determination of catecholamines with 1,2-diphenylethylenediamine. Analytica Chimica Acta. 1984;165:171-176.
  34. WHO Study Group. Definition, Diagnosis, and Classification: Diabetes Mellitus. Technical Report Series 727, World Health Organization. 1985:9-25.
  35. Beaumont JL, Carlson LA, Cooper GR, Fejfar Z, Fredrickson DS, Strasser T. Memorandum on classification of hyperlipidemias and hyperlipoproteinemias. Bull World Health Organ. 1970;43:891-898. [Medline] [Order article via Infotrieve]
  36. Stout RW. Insulin and atheroma: 20-year perspective. Diabetes Care. 1990;13:631-654. [Abstract]
  37. Pyörälä K. Hyperinsulinemia as predictor of atherosclerotic vascular disease: epidemiological evidence. Diabetes Metab Rev. 1991;17:87-92.
  38. Rubenstein AH, Seftel HC, Miller K, Bersohn I, Wright AD. Metabolic response to oral glucose in healthy South African White, Indian, and African subjects. Br Med J. 1969;1:748-751.
  39. Rönnemaa T, Laakso M, Pyörälä K, Kallio V, Puukka P. High fasting plasma insulin is an indicator of coronary heart disease in non–insulin-dependent diabetic patients and nondiabetic subjects. Arterioscler Thromb. 1991;11:80-90. [Abstract/Free Full Text]
  40. Shimokawa H, Tomoike H, Nabeyama S, Yamamoto H, Araki H, Nakamura M, Ishii Y, Tanaka K. Coronary artery spasm induced in atherosclerotic miniature swine. Science. 1983;221:560-561. [Abstract/Free Full Text]
  41. Yokota C, Ikebuchi M, Suzuki M, Norioka M, Ikeda K, Shinozaki K, Harano Y. Insulin resistance rather than hyperinsulinemia more closely associated with essential hypertension. Clin Exp Hypertens. 1995;17:523-536.
  42. Lüscher TF, Richard V, Tschudi M, Yang Z, Boulanger C. Endothelial control of vascular tone in large and small coronary arteries. J Am Coll Cardiol. 1990;15:519-527. [Abstract]
  43. Harrison DG, Freiman PC, Armstrong ML, Marcus ML, Heistad DD. Alterations of vascular reactivity in atherosclerosis. Circ Res. 1987;61(suppl II):II-74-II-80.
  44. Jayakody L, Senaratne M, Thomson A, Kappagoda T. Endothelium-dependent relaxation in experimental atherosclerosis in the rabbit. Circ Res. 1987;60:251-264. [Abstract/Free Full Text]
  45. Ross R. The pathogenesis of atherosclerosis: an update. N Engl J Med. 1986;20:488-500.
  46. Lüscher TF, Diederich D, Siebenmann R, Lehmann K, Stulz P, Segesser L, Yang Z, Turina M, Grädel E, Weber E, Bühler FR. Difference between endothelium-dependent relaxation in arterial and in venous coronary bypass grafts. N Engl J Med. 1988;319:462-467. [Abstract]
  47. DeTajeda IS, Goldstein I, Azadza K, Krane R, Cohen RA. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med. 1989;320:1025-1050. [Abstract]
  48. Reaven GM, Chen YDI, Jeppesen J, Maheux P, Krauss RM. Insulin resistance and hyperinsulinemia in individuals with small, dense, low density lipoprotein particles. J Clin Invest. 1993;92:141-146.
  49. Crouse JR, Parks JS, Schey HM. Studies of low density lipoprotein molecular weight in human beings with coronary artery disease. J Lipid Res. 1985;26:566-574. [Abstract]
  50. Stout RW. Development of vascular lesions in insulin-treated animals fed a normal diet. Br Med J. 1970;3:685-687.
  51. MacAlpin RN. Relationship of coronary arterial spasm to sites of organic stenosis. Am J Cardiol. 1980;46:143-153. [Medline] [Order article via Infotrieve]
  52. Maseri A, Severi S, DeNes M, Labbate A, Chierchia A, Marzilli M, Balleatra N, Parodi O, Biagini A, Distante A. `Variant' angina: one aspect of a continuous spectrum of vasospastic myocardial ischemia. Am J Cardiol. 1978;42:1019-1035. [Medline] [Order article via Infotrieve]
  53. Ginsburg R, Bristow MR, Davis K, Dibiase A, Billingham ME. Quantitative pharmacologic responses of normal and atherosclerotic isolated human epicardial coronary arteries. Circulation. 1984;69:430-440. [Abstract/Free Full Text]
  54. Marzilli M, Goldstein S, Trivella MG, Palumbo C, Maseri A. Some clinical considerations regarding the relation of coronary vasospasm to coronary atherosclerosis: a hypothetical pathogenesis. Am J Cardiol. 1980;45:882-886. [Medline] [Order article via Infotrieve]
  55. Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP. Prospective analysis of the insulin-resistance syndrome (Syndrome X). Diabetes. 1992;41:715-722. [Abstract]
  56. Vallance P, Calver A, Collier J. The vascular endothelium in diabetes and hypertension. J Hypertens. 1992;10(suppl 2):S25-S29.
  57. Nobuyoshi M, Tanaka M, Nosaka H, Kimura T, Yokoi H, Hamasaki N, Kim K, Shindo T, Kimura K. Progression of coronary atherosclerosis: is coronary spasm related to progression? J Am Coll Cardiol. 1991;18:904-910. [Abstract]
  58. Paolisso G, Scheen A, D'Onofrio F, Lefebvre P. Magnesium and glucose homeostasis. Diabetologia. 1990;33:511-514. [Medline] [Order article via Infotrieve]
  59. Altura BM, Zhang A, Altura BT. Magnesium, hypertensive vascular diseases, atherogenesis, subcellular compartmentation of Ca2+ and Mg2+ and vascular contractility. Miner Electrolyte Metab. 1993;19:323-336. [Medline] [Order article via Infotrieve]
  60. Altura BT, Brust M, Bloom S, Barbour RL, Stempak JK, Altura BM. Magnesium dietary intake modulates blood lipid levels and atherogenesis. Proc Natl Acad Sci U S A. 1990;87:1840-1844. [Abstract/Free Full Text]
  61. Paolisso G, Sgambato S, Passariello N. Insulin induces opposite changes in plasma and erythrocyte magnesium concentration in normal man. Diabetologia. 1986;29:644-647. [Medline] [Order article via Infotrieve]
  62. Trovati M, Anfossi G, Cavalot F, Massucco P, Mularoni E, Mannuelli G. Insulin directly reduces platelet sensitivity to aggregating agents: studies in vitro and in vivo. Diabetes. 1988;37:780-786. [Abstract]
  63. Kahn NN, Sinha AK. Stimulation of prostaglandin E1 binding to human blood platelet membrane by insulin and the activation of adenylate cyclase. J Biol Chem. 1990;265:4976-4981. [Abstract/Free Full Text]
  64. Nadler JL, Buchanan T, Natarajan R, Antonipillai I, Bergman R, Rude R. Magnesium deficiency produces insulin resistance and increased thromboxane synthesis. Hypertension. 1993;21:1024-1029. [Abstract/Free Full Text]
  65. Miyagi H, Yasue H, Okumura K, Ogawa H, Goto K, Oshima S. Effect of magnesium on anginal attack induced by hyperventilation in patients with variant angina. Circulation. 1989;79:597-602. [Abstract/Free Full Text]
  66. Kugiyama K, Yasue H, Okumura K, Goto K, Minoda K, Miyagi H, Matsuyama K, Kojima A, Koga Y, Takahashi M. Suppression of exercise-induced angina by magnesium sulfate in patients with variant angina. J Am Coll Cardiol. 1988;12:1177-1183. [Abstract]
  67. Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robinson J, Deanfield JE. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993;88:2149-2155. [Abstract/Free Full Text]
  68. Molina JM, Cooper GJS, Leighton B, Olefsky JM. Induction of insulin resistance in vivo by amylin and calcitonin gene-related peptide. Diabetes. 1990;39:260-265. [Abstract]
  69. Lillioja S, Yuong AA, Culter CL, Ivy JL, Abbott WGH, Zawadzki JK, Yki-Järvinen, Christin L, Secomb TW, Bogardus C. Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man. J Clin Invest. 1987;80:415-423.
  70. Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man: a novel mechanism for insulin resistance. J Clin Invest. 1990;85:1844-1852.
  71. Pollare T, Lithell H, Mörlin C, Präntare H, Hvarfner A, Ljunghall S. Metabolic effects of diltiazem and atenolol: results from a randomized, double-blind study with parallel groups. J Hypertens. 1989;7:551-559.[Medline] [Order article via Infotrieve]



This article has been cited by other articles:


Home page
 Eur Heart JHome page
S. Yasuda, S. Miyazaki, M. Kanda, Y. Goto, M. Suzuki, Y. Harano, and H. Nonogi
Intensive treatment of risk factors in patients with type-2 diabetes mellitus is associated with improvement of endothelial function coupled with a reduction in the levels of plasma asymmetric dimethylarginine and endogenous inhibitor of nitric oxide synthase
Eur. Heart J., May 2, 2006; 27(10): 1159 - 1165.
[Abstract] [Full Text] [PDF]

Home page
 Eur. J. Cardiothorac. Surg.Home page
P. K. Mishra
Variations in presentation and various options in management of variant angina.
Eur. J. Cardiothorac. Surg., May 1, 2006; 29(5): 748 - 759.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
K. Shinozaki, A. Hirayama, Y. Nishio, Y. Yoshida, T. Ohtani, T. Okamura, M. Masada, R. Kikkawa, K. Kodama, and A. Kashiwagi
Coronary endothelial dysfunction in the insulin-resistant state is linked to abnormal pteridine metabolism and vascular oxidative stress
J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1821 - 1828.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
F. Samad, M. Pandey, and D. J. Loskutoff
Regulation of tissue factor gene expression in obesity
Blood, December 1, 2001; 98(12): 3353 - 3358.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
K. Shinozaki, Y. Nishio, T. Okamura, Y. Yoshida, H. Maegawa, H. Kojima, M. Masada, N. Toda, R. Kikkawa, and A. Kashiwagi
Oral Administration of Tetrahydrobiopterin Prevents Endothelial Dysfunction and Vascular Oxidative Stress in the Aortas of Insulin-Resistant Rats
Circ. Res., September 29, 2000; 87(7): 566 - 573.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
T. Hammoud, J.-F. Tanguay, and M. G. Bourassa
Management of coronary artery disease: therapeutic options in patients with diabetes
J. Am. Coll. Cardiol., August 1, 2000; 36(2): 355 - 365.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
O. Hirashima, H. Kawano, T. Motoyama, N. Hirai, M. Ohgushi, K. Kugiyama, H. Ogawa, and H. Yasue
Improvement of endothelial function and insulin sensitivity with vitamin C in patients with coronary spastic angina: Possible role of reactive oxygen species
J. Am. Coll. Cardiol., June 1, 2000; 35(7): 1860 - 1866.
[Abstract] [Full Text] [PDF]