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J Am Coll Cardiol, 2000; 36:432-437
© 2000 by the American College of Cardiology Foundation
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CLINICAL STUDIES

Diffuse intimal thickening of coronary arteries in patients with coronary spastic angina

Yuji Miyao, MDa, Kiyotaka Kugiyama, MDa, Hiroaki Kawano, MDa, Takeshi Motoyama, MDa, Hisao Ogawa, MDa, Michihiro Yoshimura, MDa, Tomohiro Sakamoto, MDa and Hirofumi Yasue, MDa

a Department of Cardiovascular Medicine, Kumamoto University School of Medicine, Kumamoto, Japan

Manuscript received July 22, 1999; revised manuscript received February 1, 2000, accepted March 30, 2000.

Reprint requests and correspondence: Dr. Hirofumi Yasue, Department of Cardiovascular Medicine, Kumamoto University School of Medicine, Honjo 1-1-1, Kumamoto City, Japan 860-8556
yasue{at}kumamoto-u.ac.jp


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

The purpose of this study was to evaluate the extent of atherosclerotic changes in angiographically normal coronary arteries using intravascular ultrasound (IVUS) technique in patients with coronary spastic angina.

BACKGROUND

Nitric oxide activity was shown to be decreased in coronary arteries of patients with coronary spastic angina (CSA). Decrease in nitric oxide causes arterial intimal hyperplasia or thickening. However, it remains unclear whether intimal thickening is diffusely present in coronary arteries of patients with CSA.

METHODS

The IVUS study was performed in 26 patients with CSA and with normal coronary angiograms and in 31 control subjects in whom age and gender was matched with those in patients with CSA.

RESULTS

Compared with control subjects, patients with CSA had significantly larger percent intima + media area (%I + M area), intima + media area and maximal intima + media thickness in all of proximal, middle and distal segments (p < 0.01, respectively). Lumen area was comparable between these groups. The presence of spasm was the most powerful independent predictor of increase in percent intima + media area, in multiple-regression analysis with the traditional risk factors as covariates.

CONCLUSIONS

Intimal thickening existed entirely in a coronary artery in patients with CSA and with normal angiograms, independently of other traditional risk factors. The diffuse intimal thickening in the spasm coronary arteries is intimately related with coronary spasm.

Abbreviations and Acronyms
  ACh = acetylcholine
  CSA = coronary spastic angina
  I + M = intima + media
  IVUS = intravascular ultrasound
  LAD = left anterior descending coronary arteries
  LCx = left circumflex coronary arteries
  NO = nitric oxide
  %I + M area = percent intima + media area
  RCA = right coronary arteries

Coronary artery spasm has been shown to play an important role in the pathogenesis of not only variant angina but also ischemic heart disease in general, including other forms of angina pectoris, acute myocardial infarction and sudden death (1,2). We and others have demonstrated that the entire coronary arteries, as well as the localized coronary segments, are hyperreactive to constrictor effects to acetylcholine (ACh) in patients with coronary spastic angina (CSA) and normal coronary angiograms (3,4). Further, spasm frequently occurs in multiple coronary arteries in patients with CSA (5). Recently, we have shown that the endothelial function of not only coronary arteries but also brachial arteries was impaired in patients with CSA (6). Thus, the pathogenetic abnormalities responsible for coronary spasm may not be confined to localized coronary segments, but the abnormalities may exist in the entire coronary and systemic arteries in patients with CSA.

Intravascular ultrasound (IVUS) imaging technique has enabled visualization of the intraluminal and intramural morphology of the coronary arteries (7). We previously showed that nitric oxide (NO) activity was decreased or deficient in the entire coronary arteries of patients with CSA (8). A decrease in NO has been shown to cause arterial intimal hyperplasia or thickening (9,10). We thus hypothesized that the intimal thickening or atherosclerotic changes might exist in the entire coronary arteries of patients with CSA even in patients with angiographically normal coronary arteries. To examine this hypothesis, we evaluated morphological abnormalities of coronary arteries in 26 patients with CSA and with angiographically normal coronary arteries using IVUS and compared the results with those in 31 control subjects.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Study subjects.   The present study included 26 consecutive patients with CSA and angiographically normal coronary arteries (17 men and 9 women; mean age 62 years; range 49 to 72 years) in whom an episode of spontaneous angina occurred at rest, associated with ischemic ST segment changes on 12-leads electrocardiogram (ECG) or ambulatory ECG. All patients with CSA had angiographically documented coronary spasm associated with ischemic ST-segment changes (ST-segment elevation in 15 patients, ST-segment depression in 11 patients) after intracoronary injection of ACh, as reported previously (3,5). This study also included 31 control subjects with atypical chest pain (14 men and 17 women; mean age 59 years; range 35 to 74 years) in whom age and gender was matched with those in the patients with CSA. These control subjects underwent diagnostic cardiac catheterization for evaluation of atypical chest pain and did not show coronary spasm after the intracoronary injection of ACh. Both groups of patients had no organic stenosis angiographically. All antianginal drugs except for sublingual nitroglycerin were withdrawn at least 3 days before the study. No study patient had taken nitroglycerin within 12 h of the study. No patient had previous myocardial infarction, congestive heart failure or other serious diseases. Characteristics of patients and control subjects are shown in Table 1. Written, informed consent was obtained from all patients before the study. The study was in agreement with the guidelines approved by the ethics committee at our institution.


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  		Table 1 Clinical Characteristics of Study Patients

 
Provocation test for coronary spasm.   Coronary angiography was performed by the standard Judkins technique with contrast material in the morning when the patients were fasting. The incremental doses of ACh (10, 50, 100 µg) were injected into the coronary artery to provoke coronary spasm as described previously (3,5). Coronary spasm was defined as total or subtotal occlusion of the epicardial coronary arteries associated with signs of myocardial ischemia such as chest pain and ischemic ST-segment changes.

Intravascular ultrasound imaging.   After intracoronary injection of 2 mg of isosorbide dinitrate, each segment was examined using a mechanical IVUS system (7). In both patients with CSA and control subjects, IVUS measurement was performed at the proximal, middle and distal segments of a coronary artery. The coronary artery, which showed the strongest constriction to ACh, was selected for the IVUS study among the three major coronary arteries in each individual. Coronary angiographies were repeatedly performed during the IVUS study to identify the exact location of the ultrasound catheter in relation to the coronary segments. The coronary angiograms were recorded in the same videotapes that included the ultrasound images. The segment for the IVUS measurement was selected as follows: proximal segment was 10 mm, middle segment was 30 mm and distal segment was 50 mm from the orifice of the each coronary artery. The size of Judkins catheter was used to calibrate the length of the coronary segment. The measurement was performed at three points (the center of each segment and points 5 mm proximal and distal to the center) in each segment and the IVUS parameters were averaged within each segment. The IVUS imaging system consisted of an imaging catheter (Sonicath; Boston Scientific Corp., Massachusetts) and a SONOS intravascular system imaging console (Hewlett-Packard). The imaging catheter had a 30-MHz single-piezoelectric crystal transducer mechanically rotating at 1,800 rpm within a 3.5-F monorail catheters sheath. A 7F guiding catheter (Vector; Medtoronic, Minneapolis, Minnesota) was used for insertion of the intravascular ultrasound catheter. After additional administration of heparin (2,000 U), a 0.014-in. angioplasty guide wire was advanced through the ultrasound catheter and fluoroscopically guided into the distal coronary artery. The ultrasound imaging catheter was then advanced over the guide wire into the coronary artery as distally as possible and was then carefully pulled back to continuously image the wall morphology. All images were recorded on super-VHS videotape for subsequent data analysis.

Intravascular ultrasound analysis.   Each videotape was analyzed off-line by two independent experienced IVUS analysts. With computer planimetry, the target sites were assessed quantitatively using the following measurements. The "total vessel area" represents the area within the border between the hypo echoic media and the echo reflective adventitia. The "lumen area" was planimetered along the lumen-intimal border. Intima + media (I + M) area was calculated as total vessel area minus lumen area and the percent intima + media area (%I + M area) was calculated as I + M area divided by total vessel area. The maximal I + M thickness was designated as the maximal diameter from the lumen-intimal border to the echo reflective adventitia border (Fig. 1). Analysis of intraobserver and interobserver variability for measurement of total vessel cross-sectional area showed high reproducibility (r = 0.999, p < 0.001; and r = 0.995, p < 0.001, respectively).



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  		Figure 1 Schematic representation of intravascular ultrasound analyses at coronary cross-sectional image.

 
Quantitative coronary angiography.   A quantitative coronary angiographic study was performed in the same manner as described in our previous reports (3,8). The coronary luminal diameter was measured quantitatively with the use of a computer-assisted coronary angiographic analysis system (Cardio 500; Kontron Instruments, Berlin, Germany) in the proximal and distal coronary artery segments where the IVUS study was performed. Coronary artery responses to ACh (10 µg) were defined as percent diameter changes from baseline values (3,8). Any coronary arteries or segments that were not suitable for measurement because they were hypoplastic, or because of interference by a superimposing branch or insufficient opacification with contrast medium, especially in segment distal to a spasm site, were excluded.

Statistical analysis.   Data are expressed as mean (±SD) unless otherwise indicated. For comparison of the IVUS parameters between patients with CSA and control subjects, two-way analysis of variance for repeated measures was used. When the group effect was significant, differences between spasm and control groups at specific segments were compared by Bonferroni’s test. Patients’ characteristics between the two groups were compared using unpaired Student t test or chi-square tests. Correlations between variables were tested with linear regression analysis. Multivariate analyses of the associations were assessed using standard linear regression techniques, with %I + M area (%) of the coronary arteries as the dependent variable (11). Of the independent variables, body mass index (kg/m2), total cholesterol (mg/dl) and triglycerides (mg/dl) were treated as continuous variables. Other independent variables were treated as categorical variables, which were coded as the following dummy variables: cigarette smoking (≥20 cigarettes/day for ≥10 years), 0 for nonsmokers and 1 for smokers; hypertension (blood pressure ≥140/90 mm Hg or taking an antihypertensive medication), 0 for normotension and 1 for hypertension; diabetes mellitus (according to the World Health Organization criteria or taking an antidiabetic medication) (12), 0 for absence and 1 for presence; and spasm, 0 for absence and 1 for presence. A value of p < 0.05 was considered significant.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Patients characteristics and provocation of coronary spasm.   There was no significant difference in the clinical characteristics except for smoking history between the patients with CSA and control subjects, as shown in Table 1. In patients with CSA, coronary spasm was demonstrated in 36 coronary arteries, including 15 left anterior descending coronary arteries (LAD), 5 left circumflex coronary arteries (LCx) and 16 right coronary arteries (RCA) by the intracoronary injection of ACh. Spasm occurred in one coronary artery in 13 patients, in two coronary arteries in 10 patients, and in three coronary arteries in 1 patient (i.e., multivessel spasm in 11 patients).

Comparison of IVUS measurements (table 2).  


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  		Table 2 Quantitative Data of IVUS

 
Intravascular ultrasound was performed in only one spasm coronary artery per each of 26 patients with CSA (9 left LAD, 3 LCx and 14 RCA). In control subjects, IVUS was performed at 31 coronary arteries (24 LAD, 4 LCx and 3 RCA). Percent intima + media area was significantly greater in all of proximal, middle and distal segments in spasm coronary arteries as compared with the respective segments in control coronary arteries. Maximal I + M thickness and I + M area were greater in all segments in spasm coronary arteries as compared with the respective segments in control coronary arteries. Total vessel area in spasm coronary arteries was also greater than that in control group (Fig. 2). Lumen area was comparable between patients with CSA and control subjects. Coronary artery spasm and coronary constriction did not occur during the IVUS study, assessed by coronary angiograms taken simultaneously during the IVUS study.



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  		Figure 2 Representative images of the left coronary angiogram and the intravascular ultrasound (IVUS) in a patient with coronary spastic angina. (Top right) Intracoronary injection of acetylcholine (100 µg) induced subtotal occlusion of the left anterior descending and left circumflex coronary artery. (Bottom left) After administration of isosorbide dinitrate, the coronary arteries were dilated and no fixed stenosis was noted. Intravascular ultrasound image exhibited a thickened I + M area and this lesion existed eccentrically (the position of the ultrasound transducer is noted by the black arrow on the angiogram after administration of isosorbide dinitrate).

 
Multiple regression analysis of %I + M area (table 3).  


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  		Table 3 Multiple Regression Analysis of %Intima + Media Area

 
Because the traditional risk factors are known to be associated with coronary atherosclerosis (13), the influence of these factors on the association of spasm with the intimal thickening was examined in multiple linear regression analyses. Coronary spasm and the traditional risk factors including hypertension, diabetes mellitus, smoking, serum levels of total cholesterol and triglyceride and body mass index were included as covariates in the multivariate analysis. In multiple-regression analysis, the presence of spasm and history of smoking were independently associated with the %I + M area, as shown in Table 3. The presence of spasm was the most powerful independent predictor of the increase in %I + M area. When the coronary arteries analyzed (LAD and RCA) were added with the covariates, spasm and smoking remained a significant and independent factor (spasm: regression coefficients = 13.63, standardized regression coefficients = 0.58, standard error = 2.61, p < 0.001; smoking: regression coefficients = 8.67, standardized regression coefficients = 0.37, standard error = 2.75, p < 0.01), but the coronary arteries did not have a significant association with the %I + M area (LAD: regression coefficients = 5.79, standardized regression coefficients = 0.25, standard error = 3.65, p = 0.12; RCA: regression coefficients = 1.56, standardized regression coefficients = 0.06, standard error = 4.02, p = 0.70).

Correlation of intimal thickening with vasomotor response to ACh.   It was further evaluated whether extent of intimal thickening may be related with hyperreactivity of coronary vasomotor response to ACh. The %I + M area was significantly and positively correlated with the degree of constrictive response to ACh in coronary arteries (Fig. 3).



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  		Figure 3 Correlation between percent I + M area versus percent changes from baseline in coronary lumen diameters in response to acetylcholine (10 µg).

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Diffuse intimal thickening.   The present study showed that the I + M area was thickened diffusely and entirely in a coronary artery in patients with CSA. Although the boundary of the intima and media cannot be distinguished accurately in atherosclerotic lesion by the IVUS technique, morphological change of media dose not occur except for very advanced atherosclerotic stages (14), and our histological study previously demonstrated that spasm coronary arteries had intimal hyperplasia but that they had no significant change of media (15). Accordingly, increase in I + M area and %I + M area might reflect an intimal thickening of coronary arteries in this study.

It was previously thought that coronary spasm was prone to occur at the sites of organic stenosis (16,17). A previous IVUS study also showed that intimal thickening was locally present at the spasm sites of coronary arteries in patients with CSA (18). However, hyperreactivity to various constrictors is not localized but is observed at the entire segments of coronary arteries, especially in angiographically normal coronary arteries in patients with CSA (3,19). We have shown that spasm frequently occurs in multiple coronary arteries in patients with CSA and that spasm is not confined to the sites of fixed coronary stenosis but occurs diffusely at angiographically normal segments (3,5,20). The present study further showed that extent of the ultrasound intimal thickening was positively correlated with the degree of constrictive response to ACh. Thus, intimal thickening and hyperconstrictive response exist concomitantly and entirely in a coronary artery with normal angiogram in patients with CSA. Taken together, coronary spasm is not a localized but a generalized disorder that involves the entire coronary arteries and is associated with intimal thickening.

Risk factors and intimal thickening.   It is also to be noted that atherosclerotic risk factors such as hypercholesterolemia and diabetes are not associated with intimal thickening in the present study. It is known that the traditional coronary risk factors are related to the extent of ultrasound atherosclerotic changes even in angiographically normal coronary arteries (21,22). However, the present study demonstrated that the extent of %I + M area was most strongly associated with spasm independently of other traditional risk factors in the patients with CSA and normal coronary angiograms. Thus, the presence of spasm may have causal relationship with intimal thickening in patients with CSA and normal coronary angiogram. Our and other histological studies previously showed that spasm coronary arteries had an intimal hyperplasia with few lipid-rich lesions, which was a distinct histological feature in spasm coronary arteries as compared with coronary arteries with atheromatous fixed stenosis (14,23). On the basis of the histological classification of human atherosclerotic lesions (14), this histoloical feature of spasm coronary arteries is likely to correspond to adaptive intimal thickening, which is elicited by low flow forces in the eccentric locations of coronary arteries. Hypercholesterolemia is a strong risk factor for atheromatous plaques enriched with foam cells (24). Also, smoking might be a risk factor for lipid-rich lesions in concert with hyperlipidemia, but smoking alone is thought to have less effect on the development of lipid-rich lesions (25). It is known that only smoking among traditional risk factors is strongly associated with patients with CSA (26–28). Thus, the intimate association of smoking but not hyperlipidemia with patients with CSA may be related to the intimal hyperplasia with few lipid-rich lesions in spasm coronary arteries.

Decrease in NO activity and intimal thickening.   The present study demonstrated that the total vessel area was greater in patients with CSA than control subjects, whereas the lumen area was comparable between both groups. This is compatible with the Glagov’s concept that coronary arteries enlarge by the increase in shear stress in relation to plaque development (29,30). Shear stress has an important role in the arterial remodeling and regulation of the arterial tone through various endothelium-derived factors such as NO released in response to shear stress (31,32). Nitric oxide, a known endogenous vasodilator, suppresses proliferation and migration of arterial smooth muscle cells (33,34). In fact, atherosclerotic lesions are prone to occur at coronary arterial bends and branch points where endothelium-derived NO may be decreased because of low and/or fluctuating shear stresses (35,36). Further, inhibitors of NO synthase or targeted disruption of endothelial NO synthase gene caused the arterial intimal thickening in experimental animals (9,10). We recently found that endothelial NO was deficient or decreased in spasm coronary arteries in patients with CSA (8,37). The decreased NO activity in spasm coronary arteries may be related to high frequency of smoking and mutations of endothelial NO synthase gene in these patients (26,27,38). The present study showed that intimal thickening had a close and positive relationship with the coronary constrictor response to acetylcholine, which was known to depend on endothelial NO activity, as shown in our and other previous reports (38,39). Thus, the decrease in endothelial NO activity may be one of the underlying mechanisms for the intimal thickening in spasm coronary arteries. Decrease in endothelial NO activity also results in the increase in endothelial endothelin production (40), which may also participate in the intimal thickening and the hyperconstrictive responses in spasm coronary arteries. And the endothelial injury caused by coronary spasm could, in turn, induce coronary spasm. This positive feedback mechanism may amplify this sequence of events, thereby leading to further progression of the intimal hyperplasia and the arterial remodeling.

Conclusions.   Intima is diffusely thickened in the spasm coronary arteries even in patients with normal angiograms, and this may possibly reflect the deficiency of NO activity that is intimately related with coronary spasm in these patients.


   Footnotes
 
This study was supported in part by a Research Grant from the Smoking Foundation, and a Research Grant for Cardiovascular Diseases (9A-3 and 10C-5) from the Ministry of Health and Welfare, Tokyo, Japan.


   References
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 Methods
 Results
 Discussion
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