International Journal of Cardiology 135 (2009) 202 – 206 www.elsevier.com/locate/ijcard
Association of plasma level of malondialdehyde-modified low-density lipoprotein with coronary plaque morphology in patients with coronary spastic angina: Implication of acute coronary events Shigemasa Tani a,b,⁎, Ken Nagao a,b , Takeo Anazawa a,b , Hirofumi Kawamata a,b , Shingo Furuya a,b , Takeshi Fuji a,b , Hiroshi Takahashi a,b , Kiyoshi Iida a,b , Michiaki Matsumoto a,b , Takamichi Kumabe a,b , Yuichi Sato a,b , Atsushi Hirayama b b
a Department of Cardiology, Nihon University Surugadai Hospital, Tokyo Japan Division of Cardiovascular Medicine, Department of Medicine, Nihon University School of Medicine, Tokyo Japan
Received 16 September 2007; received in revised form 8 February 2008; accepted 29 March 2008 Available online 9 July 2008
Abstract Background: Focal vasospasm is reportedly involved in a high incidence of acute coronary syndrome (ACS) as compared with diffuse vasospasm. No adequate studies have been conducted on the mechanism underlying the higher incidence of ACS involving focal vasospasm than of those involving diffuse vasospasm in patients with coronary spastic angina. Methods and results: Blood samples were collected from the aortic root (Ao) and the coronary sinus (CS) before provoking left coronary vasospasm using intracoronary administration of acetylcholine. After relief of vasospasm, volumetric analyses of vasospastic lesions were evaluated with 3-dimensional intravasucular ultrasound in 64 patients. The percent plaque volume was more prominent in focal (n = 31) than in diffuse vasospasm (n = 33) (40.9 ± 9.4 vs. 23.3 ± 9.2%, p b 0.0001). The Cs-Ao difference of malondialdehyde-modified low-density lipoprotein (MDA-LDL) level, as a marker of atherothrombosis, in focal vasospasm increased significantly as compared with diffuse vasospasm (6.9 ± 6.7 vs. 1.2 ± 5.7 U/L, p = 0.001). In a multiple-logistic regression analysis with the traditional risk factors, the Cs-Ao difference of MDA-LDL level was a variable differing independently between the 2 types of vasospasm. Conclusions: Higher MDA-LDL levels were observed in the coronary circulation in patients with focal vasospasm than in those with diffuse vasospasm. Under these conditions, the dramatically increased percent plaque volume in cases with focal vasoconstriction may play an important role in the development of acute coronary events. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Atherosclerosis; Coronary vasospasm; Intravascular ultrasound; Malondialdehyde-modified low-density lipoprotein
1. Introduction Coronary vasospasm is closely involved in the mechanism of onset of acute coronary syndrome [1]. Angiographically, coronary vasospasm assumes one of two morphological forms [2]. Focal vasospasm has been reported to be more likely to be ⁎ Corresponding author. Department of Cardiology, Nihon University Surugadai Hospital, 1-8-13 Kanda-Surugadai Chiyoda-ku, Tokyo 101-8309, Japan. Tel.: +81 3 3293 1711; fax: +81 3 3295 1859. E-mail address:
[email protected] (S. Tani). 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.03.071
associated with acute coronary events as compared with diffuse vasospasm [3,4]. In recent years, a method has been developed for measuring the antibody to malondialdehyde-modified low-density lipoprotein (MDA-LDL), which is a major epitope of oxidized LDL [5]. It has been reported that the plasma MDA-LDL level is useful not only as an indicator of oxidative stress, but also as a marker of progression of atherothrombosis [6,7]. The severity of atherosclerosis, as assessed by coronary angiography, has been reported to serve as a factor determining the prognosis of patients with coronary spastic angina (CSA) [8]. To date,
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however, the relationship between the morphological form of coronary vasospasm and the plasma MDA-LDL level has not been clarified. The present study was conducted to explore the reasons as to why focal vasospasm is more closely associated with the onset of acute coronary events as compared with diffuse vasospasm, by comparing the coronary plaque volume, plaque morphology and the plasma MDA-LDL levels between patients with focal vasospasm and diffuse vasospasm in patients with (CSA).
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catheter was introduced into the right ventricular apex through the right femoral vein and connected to a temporary pacemaker. The coronary vasospasm provocation test was performed with an intracoronary injection of acetylcholine chloride dissolved in 0.9% saline solution and administered over 20 s. The drug was injected in incremental doses of 50 and 100 μg into the left coronary artery, with an interval of at least 3 min between the injections. Coronary angiography was performed 2 min after the completion of each injection, or when ST segment changes or chest pain, or both, occurred.
2. Methods 2.3. Intravascular ultrasound procedures and analysis 2.1. Study group The subjects of the study were 64 patients who were admitted to our facility with the chief complaint of chest pain, but in whom coronary angiography revealed no significant organic stenosis (≤25% stenosis of the luminal diameter) of the coronary arteries as assessed by coronary angiography, and left coronary arterial vasospasm as assessed by intracoronary infusion of acetylcholine, seen between July 3, 2000, and December 31, 2004. The patients were divided into two groups according to the following angiographic criteria. Focal vasospasm was defined as discrete transient vessel narrowing localized to the proximal segment of a coronary artery, including the left anterior descending artery of ≥ 99%, associated with ST-T segment elevation or depression ≥ 0.1 mV on a 12-lead electrocardiogram (ECG). Diffuse vasospasm was diagnosed when transient vessel narrowing of ≥ 99%, as compared with that in the control coronary angiography, extending from the proximal to distal segment in all the 3 major coronary arteries was observed in association with ST-T segment elevation or depression ≥ 0.1 mV on a 12-lead ECG. The study was approved by the Ethics Committee of our institution. 2.2. Procedures for catheterization and the coronary vasospasm provocation test Coronary angiography was performed in the morning with the patients in the fasting state, using the Judkins technique with a 5F Judkins catheter and a contrast medium. All patients were given 50 U/kg of heparin. The 6F GCB6CSF3 (Goodman Co., Ltd., Nagoya, Japan) and 5F Judkins catheter were used for the blood samplings. The 6F GCB6CSF3 catheter was introduced through the right femoral vein and advanced into the coronary sinus (CS). The 5F Judkins catheter was placed in the aortic root (Ao). The blood samples for the MDA-LDL measurement were collected from the CS and Ao at the same speed. After this procedure, coronary angiography was performed in the right and left anterior oblique positions with adequate angulation to allow clear visualization of the left coronary artery. When the coronary angiogram showed no evidence of significant coronary stenosis, a tripolar electrode
After relief of vasospasm by isosorbide dinitrate administration, the intravascular ultrasound (IVUS) examinations were performed with a CVIS (Atlantis SR Plus 40 MHz; Boston Scientific, Maple Grove, Minnesota, USA). A 6F guiding catheter was used for the introduction of the IVUS catheter. A guidewire was then introduced as far distally as possible into the spasm-involved artery, and the IVUS catheter was then advanced over the guidewire into the coronary artery, again to the farthest extent possible The location of the transducer was checked fluoroscopically, and images obtained from within the coronary artery at the rate of 0.5 mm/s with a motorized pullback device were recorded on an S-VHS tape. The ‘online’ mode was selected and the inter-frame distance of IVUS was set at 0.1 mm. Images from the S-VHS videotape were then fed in. Subsequently, Using a Netra 3D IVUS system (ScImage, Los Altos, California, USA), the cross-sectional vessel, lumen, and plaque areas were measured. The plaque area was defined as the difference between the cross-sectional vessel area (the area lined by the tunica media and inner layers) and the cross-sectional lumen area (the area lined by the innermost layer of the tunica intima). These three areas were separately totaled to yield the vessel volume, lumen volume, and plaque volume, respectively. Then, the percent plaque volume was calculated as the plaque volume/vessel volume [9]. For the cases with diffuse vasospasm, the epicardial coronary artery in which spasm was provoked was divided into 3 segments. In each region, the vessel parameters were measured over a 10-mm segment covering 5 mm on either side of the center of the involved region. The percent plaque volume in the three regions were then averaged. For the cases with focal vasospasm also, the vessel parameters were measured over a 10-mm segment covering 5 mm on either side of the center of the site of focal vasospasm. 2.4. Measurements of laboratory profile All the laboratory values were measured after the patients had fasted overnight. The plasma MDA-LDL level was measured by enzyme-linked immunosorbent assay. Total cholesterol and triglyceride (TG) were measured enzymatically, and high-density lipoprotein (HDL) cholesterol and low-
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Table 1 Patient characteristics.
Sex, n (%) Men/women, n (%) Age, y Risk factors Hypertension, n (%) Diabetes mellitus, n (%) Current smoking, n (%) Body mass index (kg/m2) Serum lipid (mg/dl) Total cholesterol LDL cholesterol HDL cholesterol Triglyceride
Diffuse (n = 31)
Focal (n = 33)
P value
22 (71)/9 (29) 62 ± 9
26 (79)/7 (21) 59 ± 11
0.27 0.35
21 (70) 9 (26) 18 (64) 25 ± 4.2
18 (55) 8 (23) 25 (78) 24 ± 3.6
0.26 0.73 0.12 0.28
201 ± 35 119 ± 32 55 ± 13 127 ± 63
205 ± 27 120 ± 33 48 ± 14 150 ± 60
0.67 0.83 b0.05 0.45
LDL: low-density lipoprotein; HDL: high-density lipoprotein.
density lipoprotein (LDL) cholesterol were measured by homogeneous assays. 2.5. Statistical analysis All the values were expressed as mean±standard deviation and in percentages (cases/n). Comparison of continuous variables
between the groups was conducted by Student's t-test, and the categories variables were analyzed by the χ2 statistic. Because several reports have already been published concerning the morphological features of coronary plaques as assessed by IVUS in cases of diffuse vasospasm and focal vasospasm [10,11], a multiple-logistic regression analysis was performed to evaluate this variable as an independent variable, except the % plaque volume at the site of vasospasm differing between the patients with focal and diffuse vasospasm. A 2tailed p-value b0.05 was considered statistically significant. The analyses were performed using SPSS 11.0 (SPSS, Inc., Chicago, Illinois) for Windows. 3. Results 3.1. Patient characteristics Table 1 shows the clinical characteristics of the 2 groups. The plasma levels of HDL cholesterol were significantly lower in the focal vasospasm group than in the diffuse vasospasm group (p b 0.05). There were no significant differences in the other variables between the two groups. In the diffuse vasospasm group, 20 of the 31 patients had diffuse vasospasm affecting both the LAD and LCX. For these
Fig. 1. Angiographic and IVUS images in cases with diffuse and focal vasospasm. Left: Focal vasospasm seen in the proximal segment of the left anterior descending artery, causing complete obstruction. IVUS reveals a plaque at the site of complete obstruction (1, 2 and 3), while smaller plaques are visible in the periphery (4). Right: Diffuse vasospasm is noted in the proximal segment of the left anterior descending artery and throughout the extent of the diagonal branch. IVUS reveals slight initimal thickening throughout the coronary arteries (1, 2 and 3). Green color indicates atherosclerotic plaques or intimal thickening.
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20 cases, IVUS was performed on either the LAD (15 cases) or the LCX (5 cases). Of the remaining 11 patients from this group, 8 had diffuse vasospasm of the LAD and 3 had diffuse vasospasm of the LCX, and the IVUS was performed on the affected coronary artery in these 11 cases. In the focal vasospasm group, none of the patients had focal vasospasm affecting both the LAD and LCX, with only either of the two being affected by focal vasospasm (LAD in 20 cases and LCX in 13 cases). In the present study, there was no case with focal vasospasm affecting one branch and diffuse vasospasm affecting another. 3.2. Coronary plaque appearances and volumetric analyses of the lesions at the sites of vasospasm IVUS analysis revealed a greater volume of plaque in the area affected by focal vasospasm, even in cases without significant angiographic disease, while in cases of diffuse vasospasm, IVUS demonstrated a lower intimal thickness throughout the coronary arteries (Fig. 1). The mean percent plaque volume at the site of the vasospasm was significantly greater in the focal vasospasm group than in the diffuse vasospasm group (23.3 ± 9.2 vs. 40.9 ± 9.4%; p b 0.0001) (Fig. 2). 3.3. Comparison of the plasma levels of MDA-LDL between the diffuse and focal vasospasm groups As shown in Fig. 2, there was no significant difference in the mean plasma MDA-LDL level in the coronary sinus between the two groups (102.6 ± 29.0 vs. 107.5± 31.3 U/L, p =0.52). No significant difference in the mean MDA-LDL level in the aortic sinus was noted either between the two groups (101.3 ± 30.4 vs. 100.6 ± 29.5 U/L, p= 0.92). However, the mean coronary-aortic sinus difference in the MDA-LDL level, which represents the concentration in the coronary circulation, was significantly higher in the focal vasospasm group than in the diffuse vasospasm group (1.2 ± 5.7 vs. 6.9± 6.7 U/L, p= 0.001) (Fig. 2).
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The results of the multiple-logistic regression analysis showed that the Cs-Ao difference of the MDA-LDL level was independently associated with the occurrence of focal vasospasm in patients with CSA (Table 2). 4. Discussion In the present study, we demonstrated that amount of coronary atherosclerotic plaque volume at the site of vasospasm, which is strongly associated with a prognosis of CSA, was more prominent, and the plasma atherothrombogenic MDA-LDL level in the coronary circulation was significantly higher in the cases with focal vasospasm than in those with diffuse vasospasm. These results may support the view that focal vasospasm is likely to be associated with a higher risk of acute coronary events than diffuse vasospasm in patients with CSA. Atherosclerosis plays a significant fundamental role in the onset of coronary vasospasm. The common underlying factor in the mechanism of onset between diffuse and focal vasospasm, in that atherosclerosis serves as the underlying condition in both cases. However, strictly speaking, there are some differences in the mechanism of onset between these two forms of vasospasm; the onset of diffuse vasospasm is closely related to vascular endothelial dysfunction, genetic abnormalities, and autonomic imbalance, while atherosclerotic elements appear to be more closely involved in the pathogenesis of focal vasospasm in patients with CSA [12]. Thus, it has been pointed out that the pathogenesis of focal vasospasm may differ from that of diffuse vasospasm. The present study revealed that the plasma MDALDL level in the coronary circulation was higher in the group with focal vasospasm than in that with diffuse vasospasm. We have thus demonstrated that the atherothrombogenic effect, which stimulates the progression of occult atherosclerosis, is more closely involved in the onset of focal vasospasm than in the onset of diffuse vasospasm n patients with CSA. The higher plasma MDA-LDL level, which is a major epitope of oxidized LDL in the Cs than in Ao suggest that
Fig. 2. Comparison of the percent plaque volume and the plasma levels of MDA-LDL in the coronary sinus-aortic root differences between diffuse and focal vasospasm in patients with CSA.
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Table 2 Multiple-logistic regression analysis of a variable differing independently between diffuse and focal vasospasm in patients with CSA. Variables
χ2
Sex Age Hypertension Diabetes mellitus Current smoking LDL cholesterol HDL cholesterol Triglyceride Cs-Ao difference of MDA-LDL
0.01 0.00 0.20 0.00 0.02 0.00 0.36 0.00 0.05 0.00 0.08 0.00 3.08 − 0.12 0.01 0.00 6.40 0.24
Partial correlation OR coefficient 1.07 0.98 0.90 1.74 1.21 1.01 0.96 1.00 1.22
95% CI
a useful marker of occurrence of focal vasospasm which is more closely associated with the risk of acute coronary events than diffuse vasospasm n patients with CSA.
P value
0.18–6.43 0.94 0.92–1.05 0.65 0.22–3.63 0.88 0.29–10.51 0.55 0.22–6.59 0.83 0.98–1.02 0.77 0.91–1.01 0.08 0.99–1.01 0.94 1.04–1.42 b0.05
Cs: coronary sinus, Ao: aortic root, LDL: low-density lipoprotein; HDL: high-density lipoprotein MDA-LDL: malondialdhyde-modified low-density lipoprotein; OR: Odds ratio; CI: Confidence interval. Current smoker, 0 for non-smokers and 1 for smokers; hypertension (blood pressure ≥ 140/90 mmHg or taking antihypertensive medication), 0 for normotension and 1 for hypertension; diabetes mellitus (according to the World Health Organization criteria or taking antidiabetic medication), 0 for absence and 1 for presence.
MDA-LDL may be produced by coronary atherosclerotic plaques. In this connection, it has been reported that MDA-LDL, whose plasma levels have been reported to be correlated with the extent of atherosclerosis [13], is produced by reactive oxygen species within the coronary atherosclerotic plaques [14]. This report suggests that the plasma MDA-LDL may also originate from atherosclerotic plaques, and the results of the present study endorse these previous reports. We may therefore say that measurement of the Cs-Ao difference in the plasma MDA-LDL may be useful for estimating the type and prognosis of CSA. It has additionally been reported that oxidized LDL itself elevates the contractility of the coronary arteries [15] and stimulates the secretion of endothelin (a potent vasoconstrictor), and that coronary vasospasm increases the secretion of endothelin from the coronary vascular endothelial cells [16]. Furthermore, the plasma MDA-LDL has been shown to trigger plaque instability and thrombus formation [17]. Once intense focal vasospasm develops, the percent plaques volume increases dramatically and coronary vasospasm becomes persistent. If this condition is complicated by spasm-induced injury of the plaques [18], platelet aggregation may occur [19], and together with MDA-LDL, may induce the onset of acute coronary syndrome. 4.1. Study limitations This study had several limitations. First, to discuss the increased likelihood of thrombus formation in the presence of focal vasospasm, it is necessary to compare the parameters of the clotting and fibrinolysis system, platelet function, and the MDA-LDL level in the coronary circulation before and immediately after the occurrence of coronary vasospasm. 4.1.1. Conclusion In patients with CSA, the higher levels of the atherothrombogenic MDA-LDL in the coronary circulation may be
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