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Effect of statin therapy on coronary fibrous-cap thickness in patients with acute coronary syndrome: Assessment by optical coherence tomography study
Atherosclerosis 202 (2009) 491–497
Effect of statin therapy on coronary fibrous-cap thickness in patients with acute coronary syndrome: Assessment by optical coherence tomography study Shigeho Takarada, Toshio Imanishi, Takashi Kubo, Takashi Tanimoto, Hironori Kitabata, Nobuo Nakamura, Atsushi Tanaka, Masato Mizukoshi, Takashi Akasaka ∗ Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan Received 13 November 2007; received in revised form 30 April 2008; accepted 5 May 2008 Available online 15 May 2008
Abstract Background: The thickness of coronary fibrous caps is a major determinant of vulnerable plaques. Several clinical trials have suggested that statin therapy could stabilize vulnerable plaques. Recently, optical coherence tomography (OCT) has been proposed as an effective histology-resolution imaging modality for assessing such micro-structural changes. Methods: Forty AMI patients with hyperlipidemia were enrolled and underwent percutaneous coronary intervention (PCI). They were divided into two groups; statin treatment group (n = 23) or control group (n = 17). Serial OCT analyses were performed at baseline and 9-month follow-up for a non-PCI lipid-rich plaque lesion. Results: The LDL-cholesterol level in the statin group was significantly lower than that in the control group at follow-up. Although the fibrous-cap thickness was significantly increased in both the statin treatment group (151 ± 110 to 280 ± 120 m, p < 0.01) and the control group (153 ± 116 to 179 ± 124 m, p < 0.01) during follow-up period, the degree of increase was significantly greater in the statin treatment group than in the control group (188 ± 64% vs. 117 ± 39%, p < 0.01). Furthermore, when the patients in the statin treatment group were divided into two subgroups (fibrous-cap thickness
1. Introduction Recently, the development of catheter intervention has made notable progress including drug eluting stent, and antiplatelet therapy. However, the incidence of acute myocardial infarction and cardiac death are not significantly different before and after the development of drug eluting stent [1]. Therefore, the prevention of acute coronary syndrome (ACS) ∗ Corresponding author at: Department of Cardiovascular Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan. Tel.: +81 73 447 2300; fax: +81 73 446 0631. E-mail address: [email protected] (T. Akasaka).
0021-9150/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2008.05.014
is getting more important nowadays, because the prognosis of coronary artery disease would improve if we could predict the vulnerable plaques and prevent ACS. One of the effective approaches to prevent ACS might be the lipid lowering including statin therapy. Although the detailed mechanism of statin therapy is not fully understood, several reports have described their effects not only as a lipid lowering effect but also as a pleiotropic effect [2–5]. Several invasive imaging modalities have been developed in this decade. With regard to the characterization of coronary plaques, IVUS has an ability to differentiate vulnerable plaques such as positive remodeling, eccentric, low-echoic,
492
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and attenuated plaques, but it has a limitation to evaluate the plaque morphology in detail such as fibrous-cap thickness because of its poor resolution [6]. Recently, intravascular optical coherence tomography (OCT) has been proposed as a high-resolution imaging method for plaque characterization. OCT may allow us to evaluate micro-structural characterization of coronary plaques including the fibrous-cap thickness, rupture and erosion of them, which might be sometimes difficult to demonstrate by IVUS or coronary angioscopy [7]. Above all, OCT and corresponding histological images in postmortem study were correlated well for the measurement of the fibrous-cap thickness [8], which is thought to be a major factor in the assessment of plaque vulnerability as well as the amount of atherosclerotic plaque burden. In the present observational study, OCT data was retrospectively analyzed to determine whether lipidlowering therapy with statins could increase the fibrous-cap thickness of coronary plaques, which demonstrates one of the stabilization mechanisms of vulnerable plaques, in non-culprit sites in patients with acute myocardial infarction.
2. Methods 2.1. Study group From January 2006 through March 2007, 164 patients with ST-segment elevation AMI underwent emergency catheterization at our hospital. In this study, we retrospectively selected the patients who had hypercholesterolemia (total cholesterol > 220 mg/dl, and/or LDL cholesterol > 140 mg/dl) and had lipid-rich non-culprit plaque with measurable fibrous-cap thickness with OCT at the point of both first catheterization and 9-month follow-up. Exclusion criteria were presence of a culprit lesion in the left main coronary artery, cardiogenic shock, critical arrhythmia, recommended CABG, and administration of lipid-lowering drugs (statin, clofibrate, probucol or analog, nicotinic acid, or other prohibited drug) before enrollment. The study population was divided into two groups according to statin use for 9 months after percutaneous coronary intervention (PCI). The statin treatment group was defined as those who started statin treatment no later than 5 days following the primary PCI, and continued for at least 9 months. The control group was defined as those who had no statin treatment for more than 8 months during follow-up period, by one or more of the following reasons: preference of diet and exercise therapy, quit taking statin because of adverse effect, or withdrawal of statin administration. Both groups had not been administered any other lipid-lowering therapy during observation period. This protocol was approved by the Wakayama Medical University Ethics Committee, and all patients provided informed consent before participation.
2.2. Baseline catheterization and OCT image acquisition Oral aspirin (162 mg) and intravenous heparin (100 U/kg) were administered before PCI. Cardiac catheterization was performed via the femoral approach, using a 7F sheath and catheters. The culprit lesion was identified on the basis of a coronary angiogram as well as an electrocardiogram and an echocardiogram. After successful reperfusion with stent implantation, a 0.016-in. OCT catheter (ImageWireTM ; LightLab Imaging Inc., Westford, MA, USA) was advanced through a 3F occlusion balloon catheter to the distal site of the culprit branch. In order to remove blood from the field of view and allow clear visualization of the vessel wall, coronary artery was occluded within 1 min using a balloon catheter at the proximal site of the artery and Ringer’s solution was flushed (0.5 ml/s) through it. Serial OCT images were obtained using the automatic pullback function at a rate of 1.0 mm/s. The total time of the OCT data acquisition was approximately 30–50 s to obtain entire image of the target vessels. The target plaques for this study were lipid-rich plaques with recognizable fibrous cap, which were >10 mm far from the culprit site of AMI. When more than two plaques were recognized in one vessel, the proximal one plaque was selected for this study to maintain the safety of this procedure. After a 9-month follow-up period, coronary angiography and reassessment of the target branch with OCT were performed. 2.3. Follow-up catheterization and OCT image acquisition Nine months after initial study, the patients underwent follow-up cardiac catheterization and OCT examination. The operator placed the OCT catheter in the vessel originally interrogated and positioned it to the distal site to the culprit lesion, which was stented previously. An automatic pullback was repeated under conditions identical to the baseline study. 2.4. OCT image analysis OCT images were analyzed using proprietary off-line software provided by LightLab Imaging Inc. Lipid was semi-quantified as the largest arc (quadrants) of the target plaques on the cross-sectional OCT image according to previous reports [7,9]. Target plaques were initially defined as lipid-rich plaque, which were observed as a plaque with lipid content in two or more quadrants [10,11], and with a recognizable image of a fibrous cap. For each plaque, the cross-sectional image with the highest number of lipid quadrants was used for analysis. The fibrous-cap thickness was defined as the minimum distance from the coronary artery lumen to inner border of the necrotic core. The average of three measurements was taken for several non-culprit plaques. For each individual target plaque, the thinnest fibrous-cap thickness measurement obtained from three imaging locations was used for analysis. At the time of
S. Takarada et al. / Atherosclerosis 202 (2009) 491–497 Table 1 Baseline patient characteristics
Chicago, IL, USA). A value of p < 0.05 was considered to indicate statistical significance.
Statin treatment (n = 23)
Control (n = 17)
p-Value
Age (year) Men (%) BMI (kg/m2 )
62 ± 10 61 23 ± 4
62 ± 11 76 26 ± 5
0.64 0.47 0.17
Cardiovascular risk factors Prior CAD (%) Hypertension (%) Diabetes (%) Smoker (%)
13 61 30 43
18 71 24 35
0.69 0.52 0.63 0.60
48 70
53 71
0.75 0.94
52 22 0
65 24 0
0.43 0.89 1.000
Concomitant therapy Aspirin (%) ACE inhibitor or ARB (%) Beta blocker (%) Nitrates (%) Other lipid-lowering therapy (%)
493
Continuous variables expressed as mean ± S.D. and categorical variables expressed as percentage. Abbreviations: BMI = body mass index, CAD = coronary artery disease, ACE = angiotensin converting enzyme, ARB = angiotensin II receptor blocker, S.D. = standard deviation.
follow-up, the plaques were identified based on the distance from the landmarks such as major branches, calcification and stent edge. Interobserver and intraobserver variabilities were assessed by the evaluation of all images by two independent readers who were blinded to the clinical presentations and the time point of image acquisition and by the same reader at two different times to compute an average value, respectively. 2.5. Statistical analysis Continuous variables are expressed as mean ± S.D. and categorical variables as percentage. Differences between groups or periods were assessed with Fisher exact test for categorical variables, or Mann–Whitney rank-sum test for continuous data. Number of quadrants of lipid assessed by OCT which was non-normally distributed was assessed by Wilcoxon signed rank test. A univariable and multivariable logistic regression analysis was used to identify clinical predictors of well-thickened fibrous cap defined as the upper median of the percent change of fibrous-cap thickness. The odds ratios and 95% confidence intervals were calculated. The data were analyzed using SPSS (Release 10, SPSS Inc.,
3. Results A total of 47 patients could be measured fibrous-cap thickness with lipid-rich plaque from other than culprit lesions by use of OCT, and follow-up study was succeeded in 40 patients. Seven patients were excluded due to OCT image quality precluded analysis (n = 3), the equipment malfunctioned (n = 1), or refused follow-up study (n = 3). Twenty-three patients who received statin treatment were defined as a statin treatment group: atorvastatin was administered in 11 patients (48%), rosuvastatin in 5 (22%), simvastatin in 4 (17%), fluvastatin in 2 (9%), and pravastatin in 1 patient (4%). Seventeen patients had not been taken any kind of lipidlowering therapy (seven patients due to selected exercise and diet therapy, four patients discontinued statin administration within 30 days due to adverse side effect, and six patients withdrew from the therapy within 30 days). 3.1. Baseline characteristics The baseline characteristics of both the statin treatment group and the control group are described in Table 1. Although patients were not randomized to receive either statin treatment or not, there were no statistically significant differences in the baseline characteristics including patient age, gender, the incidence of diabetes, hypertension, previous MI, smoking, and the use of various medication except statin. 3.2. Fasting serum lipid levels Lipid levels at baseline and follow-up and the changes at follow-up are described in Table 2. There were no significant differences statistically in the baseline lipid parameters between these two groups. As expected, significant changes in total cholesterol (T-C) and LDL-C levels were observed in the statin treatment group (T-C 218 ± 16 to 166 ± 22 mg/dl, p < 0.001; LDL-C 144 ± 22 to 91 ± 12 mg/dl, p < 0.001) and not observed in control group (T-C 224 ± 48 to 207 ± 23 mg/dl, p = 0.088; LDL-C 152 ± 41
Table 2 Lipid data at baseline and follow-up Statin treatment (n = 23) Baseline Total-C (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) Triglycerides (mg/dl)
218 144 41 158
± ± ± ±
16 22 8 50
Control (n = 17)
Follow-up 166 91 45 142
± ± 12* ±6 ± 38 22*
C = cholesterol, LDL = low-density lipoprotein, HDL = high-density lipoprotein. * p < 0.01 vs. control.
p <0.001 <0.001 0.17 0.082
Baseline 224 152 43 144
± ± ± ±
48 41 6 46
Follow-up 207 133 45 140
± ± ± ±
23 19 6 42
p 0.088 0.091 0.39 0.15
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Fig. 1. Various coronary imagings in a patient with the statin treatment group (47-year-old male). Several four panels illustrate corresponding images with similar angle of coronary angiography (A and E) and corresponding cross-sectional images of IVUS (B and F), and OCT(C, D, G, H) at baseline and at 9-month follow-up. Fibrous-cap thickness at the same cross-sectional image was increased from 110 m (white arrows in D) to 320 m (white arrows in H) during 9-month follow-up period assessed by OCT.
to 133 ± 19 mg/dl, p = 0.091). In contrast, HDL-C and TG levels showed no significant differences between baseline and follow-up period in statin treatment group (HDL-C 41 ± 8 mg/dl vs. 45 ± 6 mg/dl, p = 0.17; TG 158 ± 50 mg/dl vs. 142 ± 38 mg/dl, p = 0.098) and in control group (HDL-C 43 ± 6 mg/dl vs. 45 ± 6 mg/dl, p = 0.39; TG 145 ± 46 mg/dl vs. 140 ± 42 mg/dl, p = 0.15). 3.3. OCT image analysis Fig. 1 demonstrated baseline and follow-up images of angiography, IVUS and OCT obtained from a representative patient in statin treatment group. In this case, quantitative coronary angiography and IVUS analysis showed no quantitative change of plaque burden between baseline and follow-up period. In contrast, a marked increase of the fibrous-cap thickness is observed in 9-month follow-up period (320 m) compared with baseline (110 m) after statin prescription for 9 months.
Table 3 shows the baseline and 9-month follow-up data of OCT analysis at the target plaques. The quadrant number of lipid rich plaques was decreased only two plaques in statin group and one plaque in control group. However, the fibrouscap thickness was significantly increased in both the statin treatment group (151 ± 110 to 280 ± 120 m, p < 0.001) and the control group (153 ± 116 to 179 ± 124 m, p < 0.01) during follow-up period. Interestingly, the rate of this increase of the fibrous-cap thickness was significantly greater in the statin treatment group than in the control group (188 ± 64 and 117 ± 39%, p < 0.01). Furthermore, the patients with both groups were divided into two subgroups based on the thickness of fibrous caps (fibrous-cap thickness
Table 3 OCT findings Statin treatment (n = 23) Baseline
Follow-up
Lipid plaque, number of quadrants 1 2 3 4
0 13 8 2
2 16 4 1
Lipid-rich plaque (>2 quadrants)
23
21
Fibrous-cap thickness (m)
151 + 110
% Change of thickness
188 ± 64
280 ± 120
Control (n = 17) p
Baseline
0.15 <0.001
Statin treatment vs. control
Follow-up
0 12 4 1
1 11 4 1
17
15
153 ± 116 117 ± 39
179 ± 124
p
0.31 <0.01 <0.01
S. Takarada et al. / Atherosclerosis 202 (2009) 491–497
495
Fig. 2. Absolute and percent change of fibrous-cap thickness of subjects with thickness < or ≥median. Absolute (A and C) and percent (B and D) change of fibrous-cap thickness with baseline thickness
control group between the thin and thick cap patients (total increase: 25 ± 8 m vs. 23 ± 8 m, p = 0.18, percent change: 117 ± 20% vs. 115 ± 21%, p = 0.10, respectively) (Fig. 2). 3.4. Predictors of well-thickened fibrous-cap The statin-use was the only significant predictor of a wellthickened fibrous-cap based on a univariable logistic regression analysis. Although the statin-use was examined with several confounding factors (age, sex, hypertension, diabetes mellitus) in multivariable logistic regression analysis, only statin-use (OR 5.73, 95% CI 1.055–31.172, p = 0.043) was significantly associated with a well-thickened fibrous-cap. 3.5. Reproducibility Independent experienced OCT investigators blinded to the patient groups performed measurements of fibrous-cap thickness. Intraobserver and interobserver differences for the measurements of coronary fibrous-cap thickness were low (11 ± 16 and 18 ± 32 m, respectively). The correlation coefficients were high for repeated measurements by the same observer (r = 0.96) and by two different observers (r = 0.90).
4. Discussion The current study demonstrated that lipid-lowering therapy using statins independently have a potential to increase in the fibrous-cap thickness of coronary plaques assessed by OCT analysis at 9 months after the onset of ACS.
It would be very important to evaluate the vulnerability of coronary plaque before it would advance into the cause of ACS. The pathological features of the most common form of vulnerable plaques include a large lipid pool inside a plaque, a thin fibrous cap, and macrophage accumulation within the cap, resulting in the expression of proteolytic enzymes that weaken the fibrous cap and ultimately promote plaque disruption [12,13]. One of the most effective medical therapies to prevent a coronary event at the moment is lipid-lowering therapy using statins. MIRACL study indicated that treatment with statin, initiated during the acute phase of ACS, reduces the risk of early, recurrent ischemic events. These results demonstrated the effect of aggressive LDL-lowering therapy to stabilize vulnerable plaques rapidly, and therefore statins have a good indication to treat coronary atherosclerosis even for secondary prevention of ACS [14]. Nowadays, OCT has been recognized as an ideal imaging modality for micro-structural evaluations because of its high resolution. Several reports confirmed it to demonstrate a good correlation between OCT and histological examinations of the thickness of the fibrous cap in the apolipoprotein E knockout mice [15], and human cadavers [6]. In the present study, first, we compared the change of lipid area as a number of quadrant of cross-sectional OCT images. However, we could not obtain the regression of plaque burden after 9 months follow-up period even in the statin treatment group. One of the reasons might be that the reduction of LDL-C levels in statin treatment group was insufficient to regression of plaque burden. And more, since the way we used to measure the amount of plaque volume by OCT is
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semi-quantitative method, combination method with IVUS might give us more precise information. Second, we considered fibrous-cap thickness might be important in the expression of atherosclerotic coronary plaque vulnerability as well as the amount of coronary plaque burden. We could obtain the exciting results that statin had an ability to increase fibrous-cap thickness, however, the mechanisms have not been fully understood. Ruptured human atherosclerotic plaques often have thin fibrous caps with little collagen and few SMCs [16]. Degradation of extracellular matrix, that is a main component of fibrous caps including collagen, may make fibrous caps to be thin and, as a result, stable plaques to be vulnerable. Furthermore, it has been also reported that atheromatous plaques of WHHL rabbits that had undergone cholesterol reduction with pravastatin contain more SMCs and collagen accumulation than those of placebo-treated animals [17]. Thus, inhibition of matrix metalloproteinases (MMPs) secretion by statin therapy might result in accumulation of collagen and several extracellular matrix components. And this accumulation of several components might account for the reason, which more vulnerable plaque with thinner fibrous-cap would have a potential to increase their thickness by statin treatment. In contrast, the reduction of LDL cholesterol itself might have a possibility to increase fibrous-cap thickness. LDL, especially oxidized LDL, which is known to promote apoptosis of SMCs in vitro [18,19]. Although, there was no independent correlation between the degree of LDL-C reduction and the change of fibrous-cap thickness in this study, lower ox-LDL level might inhibit SMCs apoptosis and help accumulation of SMCs, which is a main component of fibrous cap. 4.1. Study limitations First, this study was a non-randomized, retrospective study at a single center, with a small number of subjects. A randomized prospective study should be ideal to evaluate such micro-structural change, but it will be ethically difficult in the future to make a control group for AMI patients who have hypercholesterolemia. Second, the high-risk patients such as cardiogenic shock and fatal arrhythmia were excluded because these observations with OCT require the occlusion of the coronary flow with balloon and flush with Ringer’s solution to avoid red blood cell interference for visualization of the vessel wall for a while. Third, we may miss out the existence of the lipid-rich plaques which are especially placed in far distance from the lumen surface due to the poor penetration depth (2–3 mm) of OCT, as Manfrini et al. reported the sensitivity for atheroma and fibroatheroma of OCT were 45% in postmortem human coronary arterial segments [20]. However, in the present study, we compared the same lipid plaques between baseline and follow-up period. Manfrini et al. also reported the positive predictive value for atheroma and fibroatheroma was
not so low (77%) that we could rely on the result about the quantitative change of each coronary plaques.
5. Conclusions The lipid-lowering therapy by statin in patients with ACS has an ability to increase fibrous-cap thickness of coronary plaques. Furthermore, these effects are much more prominent in cases with thinner fibrous caps (indicating vulnerable plaques).
References [1] Kaiser C, Brunner-La Rocca HP, Buser PT, et al. BASKET investigators. Incremental cost-effectiveness of drug-eluting stents compared with a third-generation bare metal stent in a real-world setting: randomized Basel Stent Kosten Effektivitats Trial (BASKET). Lancet 2005;366:921–9. [2] Arntz HR, Agrawal R, Wunderlich W, et al. Beneficial effects of pravastatin (±colestyramine/niacin) initiated immediately after a coronary event (the randomized lipid-coronary artery disease [L-CAD] study). Am J Cardiol 2000;86:1293–8. [3] Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: MIRACLE study: a randomized controlled trial. JAMA 2001;285:1711–8. [4] Thompson PL. Clinical relevance of statins: instituting treatment early in acute coronary syndrome patients. Atheroscler Suppl 2001;2:15–9. [5] Newby LK, Kristinsson A, Bhapkar MV, et al. Early statin initiation and outcomes in patients with acute coronary syndromes. JAMA 2002;287:3087–95. [6] Mintz GS, Nissen SE, Anderson WD, et al. American college of cardiology clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS). A report of the American college of cardiology task force on clinical expert consensus documents. J Am Coll Cardiol 2001;37:1478–92. [7] Kubo T, Imanishi T, Takarada S, et al. Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. J Am Coll Cardiol 2007;50:933–9. [8] Kume T, Akasaka T, Kawamoto T, et al. Measurement of the thickness of the fibrous cap by optical coherence tomography. Am Heart J 2006;152(755):e1–4. [9] Jang IK, Tearney GJ, MacNeill B, et al. In vivo characterization of coronary atherosclerotic plaque by use of optical coherence tomography. Circulation 2005;111:1551–5. [10] Jang IK, Bouma BE, Kang DH, et al. Visualization of coronary atherosclerotic plaques in patients using optical coherence tomography: comparison with intravascular ultrasound. J Am Coll Cardiol 2002;39:604–9. [11] Yabushita H, Bouma BE, Houser SL, et al. Characterization of human atherosclerosis by optical coherence tomography. Circulation 2002;106:1640–5. [12] Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis: characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J 1983;50:127–34. [13] Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20:1262–75. [14] Schwartz GG, Olsson AG, Ezekowitz MD, et al. Myocardial ischemia reduction with aggressive cholesterol lowering (MIRACL) study investigators. Effects of atorvastatin on early recurrent ischemic events in
S. Takarada et al. / Atherosclerosis 202 (2009) 491–497 acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285:1711–8. [15] Cilingiroglu M, Oh JH, Sugunan B, et al. Detection of vulnerable plaque in a mirine model of atherosclerosis with optical coherence tomography. Catheter Cardiovasc Interv 2006;67:915–23. [16] Davies MJ, Richardson PD, Woolf N, Katz DR, Mann J. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J 1993;69:377–81. [17] Shiomi M, Ito T, Tsukada T, et al. Reduction of serum cholesterol levels alter lesional composition of atherosclerotic plaques: effect of pravastatin sodium on atherosclerosis in mature WHHL rabbits. Arterioscler Thromb Vasc Biol 1995;15:1938–44.
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[18] Guijarro C, Blanco-Colio LM, Ortego M, et al. 3-Hydroxy-3methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular sooth muscle cells in culture. Circ Res 1998;83:490–500. [19] Takarada S, Imanishi T, Hano T, Nishio I. Oxidized low-density lipoprotein sensitizes human vascular smooth muscle cells to FAS (CD95)-mediated apoptosis. Clin Exp Pharmacol Physiol 2003;30:289–94. [20] Manfrini O, Mont E, Ornella L, et al. Sources of error and interpretation of plaque morphology by optical coherence tomography. Am J Cardiol 2006;98:156–9.
Effect of statin therapy on coronary fibrous-cap thickness in patients with acute coronary syndrome: Assessment by optical coherence tomography study Shigeho Takarada, Toshio Imanishi, Takashi Kubo, Takashi Tanimoto, Hironori Kitabata, Nobuo Nakamura, Atsushi Tanaka, Masato Mizukoshi, Takashi Akasaka ∗ Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan Received 13 November 2007; received in revised form 30 April 2008; accepted 5 May 2008 Available online 15 May 2008
Abstract Background: The thickness of coronary fibrous caps is a major determinant of vulnerable plaques. Several clinical trials have suggested that statin therapy could stabilize vulnerable plaques. Recently, optical coherence tomography (OCT) has been proposed as an effective histology-resolution imaging modality for assessing such micro-structural changes. Methods: Forty AMI patients with hyperlipidemia were enrolled and underwent percutaneous coronary intervention (PCI). They were divided into two groups; statin treatment group (n = 23) or control group (n = 17). Serial OCT analyses were performed at baseline and 9-month follow-up for a non-PCI lipid-rich plaque lesion. Results: The LDL-cholesterol level in the statin group was significantly lower than that in the control group at follow-up. Although the fibrous-cap thickness was significantly increased in both the statin treatment group (151 ± 110 to 280 ± 120 m, p < 0.01) and the control group (153 ± 116 to 179 ± 124 m, p < 0.01) during follow-up period, the degree of increase was significantly greater in the statin treatment group than in the control group (188 ± 64% vs. 117 ± 39%, p < 0.01). Furthermore, when the patients in the statin treatment group were divided into two subgroups (fibrous-cap thickness
1. Introduction Recently, the development of catheter intervention has made notable progress including drug eluting stent, and antiplatelet therapy. However, the incidence of acute myocardial infarction and cardiac death are not significantly different before and after the development of drug eluting stent [1]. Therefore, the prevention of acute coronary syndrome (ACS) ∗ Corresponding author at: Department of Cardiovascular Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan. Tel.: +81 73 447 2300; fax: +81 73 446 0631. E-mail address: [email protected] (T. Akasaka).
0021-9150/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2008.05.014
is getting more important nowadays, because the prognosis of coronary artery disease would improve if we could predict the vulnerable plaques and prevent ACS. One of the effective approaches to prevent ACS might be the lipid lowering including statin therapy. Although the detailed mechanism of statin therapy is not fully understood, several reports have described their effects not only as a lipid lowering effect but also as a pleiotropic effect [2–5]. Several invasive imaging modalities have been developed in this decade. With regard to the characterization of coronary plaques, IVUS has an ability to differentiate vulnerable plaques such as positive remodeling, eccentric, low-echoic,
492
S. Takarada et al. / Atherosclerosis 202 (2009) 491–497
and attenuated plaques, but it has a limitation to evaluate the plaque morphology in detail such as fibrous-cap thickness because of its poor resolution [6]. Recently, intravascular optical coherence tomography (OCT) has been proposed as a high-resolution imaging method for plaque characterization. OCT may allow us to evaluate micro-structural characterization of coronary plaques including the fibrous-cap thickness, rupture and erosion of them, which might be sometimes difficult to demonstrate by IVUS or coronary angioscopy [7]. Above all, OCT and corresponding histological images in postmortem study were correlated well for the measurement of the fibrous-cap thickness [8], which is thought to be a major factor in the assessment of plaque vulnerability as well as the amount of atherosclerotic plaque burden. In the present observational study, OCT data was retrospectively analyzed to determine whether lipidlowering therapy with statins could increase the fibrous-cap thickness of coronary plaques, which demonstrates one of the stabilization mechanisms of vulnerable plaques, in non-culprit sites in patients with acute myocardial infarction.
2. Methods 2.1. Study group From January 2006 through March 2007, 164 patients with ST-segment elevation AMI underwent emergency catheterization at our hospital. In this study, we retrospectively selected the patients who had hypercholesterolemia (total cholesterol > 220 mg/dl, and/or LDL cholesterol > 140 mg/dl) and had lipid-rich non-culprit plaque with measurable fibrous-cap thickness with OCT at the point of both first catheterization and 9-month follow-up. Exclusion criteria were presence of a culprit lesion in the left main coronary artery, cardiogenic shock, critical arrhythmia, recommended CABG, and administration of lipid-lowering drugs (statin, clofibrate, probucol or analog, nicotinic acid, or other prohibited drug) before enrollment. The study population was divided into two groups according to statin use for 9 months after percutaneous coronary intervention (PCI). The statin treatment group was defined as those who started statin treatment no later than 5 days following the primary PCI, and continued for at least 9 months. The control group was defined as those who had no statin treatment for more than 8 months during follow-up period, by one or more of the following reasons: preference of diet and exercise therapy, quit taking statin because of adverse effect, or withdrawal of statin administration. Both groups had not been administered any other lipid-lowering therapy during observation period. This protocol was approved by the Wakayama Medical University Ethics Committee, and all patients provided informed consent before participation.
2.2. Baseline catheterization and OCT image acquisition Oral aspirin (162 mg) and intravenous heparin (100 U/kg) were administered before PCI. Cardiac catheterization was performed via the femoral approach, using a 7F sheath and catheters. The culprit lesion was identified on the basis of a coronary angiogram as well as an electrocardiogram and an echocardiogram. After successful reperfusion with stent implantation, a 0.016-in. OCT catheter (ImageWireTM ; LightLab Imaging Inc., Westford, MA, USA) was advanced through a 3F occlusion balloon catheter to the distal site of the culprit branch. In order to remove blood from the field of view and allow clear visualization of the vessel wall, coronary artery was occluded within 1 min using a balloon catheter at the proximal site of the artery and Ringer’s solution was flushed (0.5 ml/s) through it. Serial OCT images were obtained using the automatic pullback function at a rate of 1.0 mm/s. The total time of the OCT data acquisition was approximately 30–50 s to obtain entire image of the target vessels. The target plaques for this study were lipid-rich plaques with recognizable fibrous cap, which were >10 mm far from the culprit site of AMI. When more than two plaques were recognized in one vessel, the proximal one plaque was selected for this study to maintain the safety of this procedure. After a 9-month follow-up period, coronary angiography and reassessment of the target branch with OCT were performed. 2.3. Follow-up catheterization and OCT image acquisition Nine months after initial study, the patients underwent follow-up cardiac catheterization and OCT examination. The operator placed the OCT catheter in the vessel originally interrogated and positioned it to the distal site to the culprit lesion, which was stented previously. An automatic pullback was repeated under conditions identical to the baseline study. 2.4. OCT image analysis OCT images were analyzed using proprietary off-line software provided by LightLab Imaging Inc. Lipid was semi-quantified as the largest arc (quadrants) of the target plaques on the cross-sectional OCT image according to previous reports [7,9]. Target plaques were initially defined as lipid-rich plaque, which were observed as a plaque with lipid content in two or more quadrants [10,11], and with a recognizable image of a fibrous cap. For each plaque, the cross-sectional image with the highest number of lipid quadrants was used for analysis. The fibrous-cap thickness was defined as the minimum distance from the coronary artery lumen to inner border of the necrotic core. The average of three measurements was taken for several non-culprit plaques. For each individual target plaque, the thinnest fibrous-cap thickness measurement obtained from three imaging locations was used for analysis. At the time of
S. Takarada et al. / Atherosclerosis 202 (2009) 491–497 Table 1 Baseline patient characteristics
Chicago, IL, USA). A value of p < 0.05 was considered to indicate statistical significance.
Statin treatment (n = 23)
Control (n = 17)
p-Value
Age (year) Men (%) BMI (kg/m2 )
62 ± 10 61 23 ± 4
62 ± 11 76 26 ± 5
0.64 0.47 0.17
Cardiovascular risk factors Prior CAD (%) Hypertension (%) Diabetes (%) Smoker (%)
13 61 30 43
18 71 24 35
0.69 0.52 0.63 0.60
48 70
53 71
0.75 0.94
52 22 0
65 24 0
0.43 0.89 1.000
Concomitant therapy Aspirin (%) ACE inhibitor or ARB (%) Beta blocker (%) Nitrates (%) Other lipid-lowering therapy (%)
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Continuous variables expressed as mean ± S.D. and categorical variables expressed as percentage. Abbreviations: BMI = body mass index, CAD = coronary artery disease, ACE = angiotensin converting enzyme, ARB = angiotensin II receptor blocker, S.D. = standard deviation.
follow-up, the plaques were identified based on the distance from the landmarks such as major branches, calcification and stent edge. Interobserver and intraobserver variabilities were assessed by the evaluation of all images by two independent readers who were blinded to the clinical presentations and the time point of image acquisition and by the same reader at two different times to compute an average value, respectively. 2.5. Statistical analysis Continuous variables are expressed as mean ± S.D. and categorical variables as percentage. Differences between groups or periods were assessed with Fisher exact test for categorical variables, or Mann–Whitney rank-sum test for continuous data. Number of quadrants of lipid assessed by OCT which was non-normally distributed was assessed by Wilcoxon signed rank test. A univariable and multivariable logistic regression analysis was used to identify clinical predictors of well-thickened fibrous cap defined as the upper median of the percent change of fibrous-cap thickness. The odds ratios and 95% confidence intervals were calculated. The data were analyzed using SPSS (Release 10, SPSS Inc.,
3. Results A total of 47 patients could be measured fibrous-cap thickness with lipid-rich plaque from other than culprit lesions by use of OCT, and follow-up study was succeeded in 40 patients. Seven patients were excluded due to OCT image quality precluded analysis (n = 3), the equipment malfunctioned (n = 1), or refused follow-up study (n = 3). Twenty-three patients who received statin treatment were defined as a statin treatment group: atorvastatin was administered in 11 patients (48%), rosuvastatin in 5 (22%), simvastatin in 4 (17%), fluvastatin in 2 (9%), and pravastatin in 1 patient (4%). Seventeen patients had not been taken any kind of lipidlowering therapy (seven patients due to selected exercise and diet therapy, four patients discontinued statin administration within 30 days due to adverse side effect, and six patients withdrew from the therapy within 30 days). 3.1. Baseline characteristics The baseline characteristics of both the statin treatment group and the control group are described in Table 1. Although patients were not randomized to receive either statin treatment or not, there were no statistically significant differences in the baseline characteristics including patient age, gender, the incidence of diabetes, hypertension, previous MI, smoking, and the use of various medication except statin. 3.2. Fasting serum lipid levels Lipid levels at baseline and follow-up and the changes at follow-up are described in Table 2. There were no significant differences statistically in the baseline lipid parameters between these two groups. As expected, significant changes in total cholesterol (T-C) and LDL-C levels were observed in the statin treatment group (T-C 218 ± 16 to 166 ± 22 mg/dl, p < 0.001; LDL-C 144 ± 22 to 91 ± 12 mg/dl, p < 0.001) and not observed in control group (T-C 224 ± 48 to 207 ± 23 mg/dl, p = 0.088; LDL-C 152 ± 41
Table 2 Lipid data at baseline and follow-up Statin treatment (n = 23) Baseline Total-C (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) Triglycerides (mg/dl)
218 144 41 158
± ± ± ±
16 22 8 50
Control (n = 17)
Follow-up 166 91 45 142
± ± 12* ±6 ± 38 22*
C = cholesterol, LDL = low-density lipoprotein, HDL = high-density lipoprotein. * p < 0.01 vs. control.
p <0.001 <0.001 0.17 0.082
Baseline 224 152 43 144
± ± ± ±
48 41 6 46
Follow-up 207 133 45 140
± ± ± ±
23 19 6 42
p 0.088 0.091 0.39 0.15
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Fig. 1. Various coronary imagings in a patient with the statin treatment group (47-year-old male). Several four panels illustrate corresponding images with similar angle of coronary angiography (A and E) and corresponding cross-sectional images of IVUS (B and F), and OCT(C, D, G, H) at baseline and at 9-month follow-up. Fibrous-cap thickness at the same cross-sectional image was increased from 110 m (white arrows in D) to 320 m (white arrows in H) during 9-month follow-up period assessed by OCT.
to 133 ± 19 mg/dl, p = 0.091). In contrast, HDL-C and TG levels showed no significant differences between baseline and follow-up period in statin treatment group (HDL-C 41 ± 8 mg/dl vs. 45 ± 6 mg/dl, p = 0.17; TG 158 ± 50 mg/dl vs. 142 ± 38 mg/dl, p = 0.098) and in control group (HDL-C 43 ± 6 mg/dl vs. 45 ± 6 mg/dl, p = 0.39; TG 145 ± 46 mg/dl vs. 140 ± 42 mg/dl, p = 0.15). 3.3. OCT image analysis Fig. 1 demonstrated baseline and follow-up images of angiography, IVUS and OCT obtained from a representative patient in statin treatment group. In this case, quantitative coronary angiography and IVUS analysis showed no quantitative change of plaque burden between baseline and follow-up period. In contrast, a marked increase of the fibrous-cap thickness is observed in 9-month follow-up period (320 m) compared with baseline (110 m) after statin prescription for 9 months.
Table 3 shows the baseline and 9-month follow-up data of OCT analysis at the target plaques. The quadrant number of lipid rich plaques was decreased only two plaques in statin group and one plaque in control group. However, the fibrouscap thickness was significantly increased in both the statin treatment group (151 ± 110 to 280 ± 120 m, p < 0.001) and the control group (153 ± 116 to 179 ± 124 m, p < 0.01) during follow-up period. Interestingly, the rate of this increase of the fibrous-cap thickness was significantly greater in the statin treatment group than in the control group (188 ± 64 and 117 ± 39%, p < 0.01). Furthermore, the patients with both groups were divided into two subgroups based on the thickness of fibrous caps (fibrous-cap thickness
Table 3 OCT findings Statin treatment (n = 23) Baseline
Follow-up
Lipid plaque, number of quadrants 1 2 3 4
0 13 8 2
2 16 4 1
Lipid-rich plaque (>2 quadrants)
23
21
Fibrous-cap thickness (m)
151 + 110
% Change of thickness
188 ± 64
280 ± 120
Control (n = 17) p
Baseline
0.15 <0.001
Statin treatment vs. control
Follow-up
0 12 4 1
1 11 4 1
17
15
153 ± 116 117 ± 39
179 ± 124
p
0.31 <0.01 <0.01
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Fig. 2. Absolute and percent change of fibrous-cap thickness of subjects with thickness < or ≥median. Absolute (A and C) and percent (B and D) change of fibrous-cap thickness with baseline thickness
control group between the thin and thick cap patients (total increase: 25 ± 8 m vs. 23 ± 8 m, p = 0.18, percent change: 117 ± 20% vs. 115 ± 21%, p = 0.10, respectively) (Fig. 2). 3.4. Predictors of well-thickened fibrous-cap The statin-use was the only significant predictor of a wellthickened fibrous-cap based on a univariable logistic regression analysis. Although the statin-use was examined with several confounding factors (age, sex, hypertension, diabetes mellitus) in multivariable logistic regression analysis, only statin-use (OR 5.73, 95% CI 1.055–31.172, p = 0.043) was significantly associated with a well-thickened fibrous-cap. 3.5. Reproducibility Independent experienced OCT investigators blinded to the patient groups performed measurements of fibrous-cap thickness. Intraobserver and interobserver differences for the measurements of coronary fibrous-cap thickness were low (11 ± 16 and 18 ± 32 m, respectively). The correlation coefficients were high for repeated measurements by the same observer (r = 0.96) and by two different observers (r = 0.90).
4. Discussion The current study demonstrated that lipid-lowering therapy using statins independently have a potential to increase in the fibrous-cap thickness of coronary plaques assessed by OCT analysis at 9 months after the onset of ACS.
It would be very important to evaluate the vulnerability of coronary plaque before it would advance into the cause of ACS. The pathological features of the most common form of vulnerable plaques include a large lipid pool inside a plaque, a thin fibrous cap, and macrophage accumulation within the cap, resulting in the expression of proteolytic enzymes that weaken the fibrous cap and ultimately promote plaque disruption [12,13]. One of the most effective medical therapies to prevent a coronary event at the moment is lipid-lowering therapy using statins. MIRACL study indicated that treatment with statin, initiated during the acute phase of ACS, reduces the risk of early, recurrent ischemic events. These results demonstrated the effect of aggressive LDL-lowering therapy to stabilize vulnerable plaques rapidly, and therefore statins have a good indication to treat coronary atherosclerosis even for secondary prevention of ACS [14]. Nowadays, OCT has been recognized as an ideal imaging modality for micro-structural evaluations because of its high resolution. Several reports confirmed it to demonstrate a good correlation between OCT and histological examinations of the thickness of the fibrous cap in the apolipoprotein E knockout mice [15], and human cadavers [6]. In the present study, first, we compared the change of lipid area as a number of quadrant of cross-sectional OCT images. However, we could not obtain the regression of plaque burden after 9 months follow-up period even in the statin treatment group. One of the reasons might be that the reduction of LDL-C levels in statin treatment group was insufficient to regression of plaque burden. And more, since the way we used to measure the amount of plaque volume by OCT is
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semi-quantitative method, combination method with IVUS might give us more precise information. Second, we considered fibrous-cap thickness might be important in the expression of atherosclerotic coronary plaque vulnerability as well as the amount of coronary plaque burden. We could obtain the exciting results that statin had an ability to increase fibrous-cap thickness, however, the mechanisms have not been fully understood. Ruptured human atherosclerotic plaques often have thin fibrous caps with little collagen and few SMCs [16]. Degradation of extracellular matrix, that is a main component of fibrous caps including collagen, may make fibrous caps to be thin and, as a result, stable plaques to be vulnerable. Furthermore, it has been also reported that atheromatous plaques of WHHL rabbits that had undergone cholesterol reduction with pravastatin contain more SMCs and collagen accumulation than those of placebo-treated animals [17]. Thus, inhibition of matrix metalloproteinases (MMPs) secretion by statin therapy might result in accumulation of collagen and several extracellular matrix components. And this accumulation of several components might account for the reason, which more vulnerable plaque with thinner fibrous-cap would have a potential to increase their thickness by statin treatment. In contrast, the reduction of LDL cholesterol itself might have a possibility to increase fibrous-cap thickness. LDL, especially oxidized LDL, which is known to promote apoptosis of SMCs in vitro [18,19]. Although, there was no independent correlation between the degree of LDL-C reduction and the change of fibrous-cap thickness in this study, lower ox-LDL level might inhibit SMCs apoptosis and help accumulation of SMCs, which is a main component of fibrous cap. 4.1. Study limitations First, this study was a non-randomized, retrospective study at a single center, with a small number of subjects. A randomized prospective study should be ideal to evaluate such micro-structural change, but it will be ethically difficult in the future to make a control group for AMI patients who have hypercholesterolemia. Second, the high-risk patients such as cardiogenic shock and fatal arrhythmia were excluded because these observations with OCT require the occlusion of the coronary flow with balloon and flush with Ringer’s solution to avoid red blood cell interference for visualization of the vessel wall for a while. Third, we may miss out the existence of the lipid-rich plaques which are especially placed in far distance from the lumen surface due to the poor penetration depth (2–3 mm) of OCT, as Manfrini et al. reported the sensitivity for atheroma and fibroatheroma of OCT were 45% in postmortem human coronary arterial segments [20]. However, in the present study, we compared the same lipid plaques between baseline and follow-up period. Manfrini et al. also reported the positive predictive value for atheroma and fibroatheroma was
not so low (77%) that we could rely on the result about the quantitative change of each coronary plaques.
5. Conclusions The lipid-lowering therapy by statin in patients with ACS has an ability to increase fibrous-cap thickness of coronary plaques. Furthermore, these effects are much more prominent in cases with thinner fibrous caps (indicating vulnerable plaques).
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