Effect of Fluvastatin on Progression of Coronary Atherosclerotic Plaque Evaluated by Virtual Histology Intravascular Ultrasound
Kenya Nasu, MD*,*,
Etsuo Tsuchikane, MD, PhD*,
Osamu Katoh, MD*,
Nobuyoshi Tanaka, MD*,
Masashi Kimura, MD*,
Mariko Ehara, MD*,
Yoshihisa Kinoshita, MD*,
Tetsuo Matsubara, MD*,
Hitoshi Matsuo, MD*,
Keiko Asakura, MD*,
Yasushi Asakura, MD*,
Mitsuyasu Terashima, MD*,
Tadateru Takayama, MD ,
Junko Honye, MD,
Atsushi Hirayama, MD,
Satoshi Saito, MD,
Takahiko Suzuki, MD, PhD*
* Department of Cardiology, Toyohashi Heart Center, Toyohashi, Japan
Department of Cardiology, Nihon University Itabashi Hospital, Tokyo, Japan
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Abstract
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Objectives: The aim of this study was to evaluate the effect of treatment with statins on the progression of coronary atherosclerotic plaques of a nonculprit vessel by serial volumetric virtual histology (VH) intravascular ultrasound (IVUS).
Background: Recent clinical trials have demonstrated a reduction of atherosclerotic plaque, yet whether statin therapy affects the change in components of plaque remains unknown.
Methods: This study was a nonrandomized and nonblinded design. Eighty patients with stable angina pectoris were divided into either the fluvastatin group (n = 40) or the control group (n = 40) according to their total or low-density lipoprotein (LDL) cholesterol level. The volume of each plaque component (dense calcium, fibrous tissue, fibro-fatty, or necrotic core) was evaluated at baseline and at 12-month follow-up.
Results: The LDL cholesterol and high-sensitivity C-reactive protein (hsCRP) levels in the fluvastatin group were significantly decreased at time of follow-up. In VH IVUS findings, fibro-fatty volume was significantly decreased (baseline 80.1 ± 57.9 mm3 vs. follow-up 32.5 ± 27.7 mm3, p < 0.0001) and fibrous tissue volume was increased (baseline 146.5 ± 85.6 mm3 vs. follow-up 163.3 ± 94.5 mm3, p < 0.0001) in the fluvastatin group. In the control group, the volumes of all plaque components without fibrous tissue were significantly increased. Change in fibro-fatty volume has a significant correlation with a change in LDL cholesterol level (R = 0.703, p < 0.0001) and change in hsCRP level (R = 0.357, p = 0.006).
Conclusions: One-year lipid-lowering therapy by fluvastatin showed significant regression of plaque volume and alterations in atherosclerotic plaque composition with a significant reduction of fibro-fatty volume.
Key Words: atherosclerosis • imaging • lipids • lipoprotein • plaque
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Abbreviations and Acronyms
| | EEM = external elastic membrane | | hsCRP = high-sensitivity C-reactive protein | | IVUS = intravascular ultrasound | | LDL = low-density lipoprotein | | VH = Virtual Histology |
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The effect of lipid-lowering therapy with statins in reducing adverse cardiovascular events is well-recognized (1,2). Statins have a wide range of biologic effects, including reductions in the level of blood cholesterol and high-sensitivity C-reactive protein (hsCRP), for stabilization of atherosclerotic plaque (1–6). Although it is possible that statins might affect plaque stabilization by modifying plaque composition, there are few data regarding changes for each plaque component of the atherosclerotic plaque (7,8). Virtual histology (VH) (Volcano Corporation, Rancho Cordova, California) intravascular ultrasound (IVUS) uses spectral analysis of the radiofrequency ultrasound backscatter signals, which allows for identifying 4 different types of atherosclerotic plaque components: fibrous, fibro-fatty, dense calcium, and necrotic core (9). A direct comparison between in vivo VH IVUS and in vitro histopathology tissue sample obtained by directional coronary atherectomy was shown to have an 87% to 97% accuracy for each plaque component (10). The primary objective of this study is to evaluate the effect of fluvastatin on progression of coronary atherosclerotic plaque evaluated by VH IVUS.
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Methods
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Study population and study design.
This study was a prospective and multicenter study with nonrandomized and nonblinded design. The inclusion criteria consisted of patients older than 30 years of age with symptomatic stable angina pectoris. All patients had significant 1- or 2-vessel diseases and were good candidates for percutaneous coronary intervention. Angiographic inclusion criteria were: 1) target vessel for VH IVUS interrogation must not have undergone angioplasty or have more than 50% luminal narrowing throughout a target segment with a minimum length of 30 mm; 2) target vessel for VH IVUS interrogation had mild-to-moderate vessel tortuosity and calcification for safe and accurate examination; and 3) left ventricular ejection fraction >30%. Exclusion criteria were: 1) significant stenotic lesions in all coronary vessels; 2) unstable angina or myocardial infarction within the previous 4 weeks; 3) target vessel for VH IVUS interrogation had lesions with angiographically detected thrombus; 4) contraindications to IVUS examination; 5) other concomitant diseases or medical condition that could impact patient/procedural outcomes, such as history of bleeding diathesis, stroke, or transient ischemic neurological attacks within the past year or hypersensitivity to heparin, aspirin, ticlopidine, or X-ray contrast media; 6) secondary causes of hyperlipidemia or uncontrolled triglyceride level above 500 mg/dl; and 7) a positive pregnancy test. After diagnostic catheterization, patients who met eligibility criteria for this study were invited to participate in this study. No patients were receiving lipid-lowering therapy before the enrollment of this study. A control group was nonequivalent and designed for comparison with the fluvastatin group in this study. Patients were divided into 2 groups according to their total cholesterol or low-density lipoprotein (LDL) cholesterol level at baseline. Patients with total cholesterol level above 220 mg/dl or LDL cholesterol level above 140 mg/dl were treated by fluvastatin (60 mg/day). Usual care, such as a lipid-lowering diet, was administrated for patients with total cholesterol and LDL cholesterol levels <220 mg/dl and <140 mg/dl, respectively. Follow-up visits were scheduled every month. Major adverse cardiac events, including death attributed to cardiac causes and myocardial infarction or new angina related to the target vessel for VH IVUS interrogation or percutaneous coronary intervention, were reported. Angiographic and VH IVUS follow-up was scheduled for the target vessel after 1 year. Informed consent was obtained from patients and their relatives in all cases. The institutional ethics committee of the 2 centers approved the study.
Data acquisition and medication.
All patients were given aspirin (100 mg/day) and ticlopidine (200 mg/day) or clopidogrel (75 mg/day) for at least 1 week before the procedure. During the procedure, heparin was given as a bolus of 150 U/kg with additional boluses to 2,000 U/h. After successful percutaneous coronary intervention, IVUS imaging was performed for the target vessel for VH IVUS analysis after administration of 200 µg of nitroglycerin. For the IVUS procedure, a 20-MHz, 3.2-F, phased-array IVUS catheter (Eagle Eye, Volcano Corporation) was used. After placing the IVUS catheter at a point that was distant at least 30 mm from the coronary ostium, the catheter was pulled back to the coronary ostium with a motorized pull-back system at 0.5 cm/s. During pullback, gray-scale IVUS was recorded and raw radiofrequency data was captured at the top of the R-wave for reconstruction of the color-coded map by a VH IVUS data recorder (Volcano Corporation). The gray-scale IVUS movie and captured radiofrequency data were written on a recordable compact disc and recordable digital video disc, respectively.
Gray-scale and VH IVUS analyses.
Before IVUS analysis, baseline and follow-up IVUS images were reviewed side by side on a display, and the distal end of the target segment was determined by the presence of a reproducible index side branch. Manual contour detection of both the lumen and the media-adventitia interface was performed by an experienced analyst who was blinded to baseline clinical and angiographic lesion characteristics. Intra-observer analysis in random samples of 40 vessels was performed by the experienced analyst at least 2 weeks apart. Intra-observer differences in measurements of external elastic membrane (EEM) volume and lumen volume were 3.2 ± 2.0% and 3.7 ± 2.2%, respectively. The EEM volume and lumen volume were calculated, and the difference between the 2 values was defined as plaque plus media volume. Atherosclerotic coronary plaques between the lumen and media-adventitia contours were characterized automatically with the use of custom-built software (IVUSLab software, Volcano Corporation) that uses classification trees based on mathematical autoregressive spectral analysis of IVUS backscattered data, as described previously (11). Fibrous tissue was marked in green, fibro-fatty in yellow, dense calcium in white, and necrotic core in red on the VH IVUS image. The absolute value of each plaque component was also calculated automatically by the software.
Statistical analysis.
Continuous data are represented as mean ± SD. Categorical data were expressed as numbers or frequencies of occurrence. Comparison of continuous variables between baseline and follow-up in each group was performed by 2-tailed paired Student t test for normally distributed variables and by Aspin-Welch's t test for variables with heterogeneity of variance. The chi-square test or Fisher exact test for sparse data was used for comparing frequency of occurrence. Correlation changes in each plaque component volume with changes in LDL cholesterol and hsCRP were analyzed by liner regression analysis. The SPSS version 11.0 software (SPSS, Inc., Chicago, Illinois) was used for data analysis. A p value of <0.05 was considered to indicate statistical significance.
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Results
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Patient and analyzed vessel characteristics.
From September 2004 to December 2005, 85 patients met all inclusion and exclusion criteria, and informed consent was obtained. Of those patients, 5 were not included in this study due to artifacts or pull-back shorter than the pre-specified minimum length of 30 mm. During the study period, 1 patient in the control group was withdrawn due to the occurrence of lung cancer; however, no patient was withdrawn due to drug-related side effects such as rash, arthralgia, increase in creatinine, or deep venous thrombosis. Thus, both baseline and follow-up IVUS examinations were performed for 40 patients with 40 vessels in the fluvastatin group and 39 patients with 39 vessels in the control group. Baseline characteristics are summarized in Table 1. All patient and analyzed vessel characteristics did not vary between the 2 groups.
Laboratory outcomes.
Baseline and follow-up laboratory data are summarized in Table 2. At baseline, total cholesterol, LDL cholesterol, triglyceride, and hsCRP levels in the fluvastatin group were significantly higher than those of the control group. However, at 1-year follow-up, total cholesterol, triglyceride, LDL cholesterol, apolipoprotein B, and hsCRP levels of the fluvastatin group were significantly lower than those of the control group. Especially, LDL cholesterol and hsCRP levels were significantly decreased by 31.8% and 48.9% in the fluvastatin group during the follow-up period compared with increases of 1.5% (p < 0.0001) and 0.2%, respectively, in the control group (p < 0.0001).
Gray-scale IVUS measurements.
Table 3
shows baseline and 1-year follow-up results of volumetric gray-scale IVUS analyses. In the fluvastatin group, EEM and plaque plus media volumes were significantly decreased, but there was no change in lumen volume compared with baseline. In contrast, EEM, lumen, and plaque plus media volumes were not changed in the control group. Changes in EEM and plaque plus media volumes were also significantly smaller in the fluvastatin group compared with the control group.
VH IVUS measurements.
Volumetric VH IVUS analysis is summarized in Table 4. At baseline, fibro-fatty volume in the fluvastatin group was significantly higher than that in the control group. However, during the 1-year follow-up period, volumes of all plaque components without fibrous tissue in the control group were significantly increased. Conversely, the fibro-fatty volume was significantly decreased and the fibrous tissue volume was significantly increased in the fluvastatin group. However, necrotic core and dense calcium volumes remained unchanged during the follow-up period. Therefore, changes in volumes of all plaque components, excluding fibrous tissue in the fluvastatin group, were significantly smaller than those in the control group. Figure 1
shows the correlation change in volume of each plaque component with change in LDL cholesterol level. Change in fibro-fatty volume has a significant correlation with a change in LDL cholesterol level (R = 0.703, p < 0.0001); however, changes in volumes of the other plaque components are not correlated with a change in LDL cholesterol level (fibrous tissue: R = 0.233, p = 0.09; necrotic core: R = 0.199, p = 0.13; dense calcium: R = 0.056, p = 0.68). The correlation change in volume of each plaque component with change in hsCRP level is summarized in Figure 2. As with the correlation change in LDL cholesterol level, change in fibro-fatty volume was significantly correlated with change in hsCRP level (R = 0.357, p = 0.006); however, there were no correlations between changes in volumes of the other plaque components and change in hsCRP level (fibrous tissue: R = 0.032, p = 0.81; necrotic core: R = 0.198, p = 0.14; dense calcium: R = 0.107, p = 0.43). Figure 3
shows a representative vessel from each group. Baseline and 1-year follow-up gray-scale and VH IVUS images are presented side by side. In the fluvastatin group, volumetric analyses showed a marked increase of fibrous tissue volume (from 124.59 mm3 to 151.79 mm3) and reduction of fibro-fatty volumes (from 92.53 mm3 to 31.49 mm3) (Fig. 3A). However, in the control group, volumes of all plaque components without fibrous tissue increased during the follow-up period (Fig. 3B).
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Figure 1 Correlation Between Change in LDL Cholesterol Level and Change in Volume of Each Plaque Component
Change in fibro-fatty volume was significantly correlated with a change in low-density lipoprotein (LDL) cholesterol level as shown in B (p < 0.0001). There was no significant correlation between changes in volume of the other plaque components and change in LDL cholesterol level as shown in A, C, and D.
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Figure 2 Correlation Between Change in hsCRP Level and Change in Volume of Each Plaque Component
Change in fibro-fatty volume was significantly correlated with a change in high-sensitivity C-reactive protein (hsCRP) level as shown in B (p = 0.006). There was no significant correlation between changes in volume of the other plaque components and change in hsCRP level as shown in A, C, and D.
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Figure 3 Baseline and 1-Year Follow-Up Gray-Scale and Virtual Histology Intravascular Ultrasound Images Are Presented Side by Side
(A) A representative vessel from the fluvastatin group. Volumetric analyses showed the marked increase of fibrous tissue volume and reduction of fibro-fatty volumes. (B) A representative vessel from the control group. Volumes of all plaque components without fibrous tissue increased during the follow-up period.
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Major adverse cardiac events.
Major adverse cardiac events occurred in 4 fluvastatin and 11 control patients (Table 5).
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Discussion
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This is the first clinical study to assess the effect of statin for plaque components by serial volumetric VH IVUS study. The main finding of this study was that 1-year lipid-lowering therapy by fluvastatin showed a plaque regression by a significant reduction of fibro-fatty volume with a shift to a more fibrotic lesion morphology in hyperlipidemic patients. In addition, the degree of reduction in fibro-fatty volume was positively correlated with the changes in LDL cholesterol and hsCRP levels.
In this study, the reduction of EEM volume with a significant plaque reduction was shown in the fluvastatin group from gray-scale IVUS findings. However, the regression or progression of each plaque component was unknown from gray-scale IVUS findings. In native coronary lesions of nonhuman primates, histological studies have demonstrated lipid depletion and fibrosis during lipid-lowering therapy (12–14). A previous study using gray-scale IVUS tried to evaluate the change in plaque components during lipid-lowering therapy (15). In that study, a percent of hyperechogenic area, determined with a computer-aided gray-scale value analysis, was significantly increased, and the hypoechogenic area remained unchanged. However, identification of atherosclerotic plaque components by densitometric category of gray-scale IVUS is limited due to processing of the raw radiofrequency data (16–18). The VH IVUS uses spectral analysis of the radiofrequency ultrasound backscatter signals, which allows for identifying 4 different types of atherosclerotic plaque components: fibrous, fibro-fatty, dense calcium, and necrotic core. In the VH IVUS findings of this study, a significant reduction of fibro-fatty and increase of fibrous tissue by lipid-lowering therapy were observed. In contrast, fibro-fatty volume was significantly increased in the control group although total plaque plus media volume was not changed. In addition, change in fibro-fatty volume had a significant positive correlation with a change in LDL cholesterol level (R = 0.703, p < 0.0001). Fibro-fatty is defined as fibrous tissue with significant lipid interspersed in collagen in VH IVUS findings (9,10). The interspersed lipids in fibro-fatty tissue might be regressed from the atherosclerotic intima with reducing continued influx; hence, an accumulation of interstitial collagen in fibrous tissue might be significantly increased by lipid-lowering therapy (14). Thus, the fibro-fatty volume might possibly be a reversible step of atherosclerosis. However, the volume of necrotic core remained unchanged during follow-up period in the fluvastatin group, although that of the control group was significantly increased. In addition, the change in necrotic core volume had no correlation with the change in LDL-cholesterol level (R = 0.199, p = 0.13). In histopathological findings, necrotic cores have macrophage infiltrations, which are undergoing apoptotic cell death, and the matrix is no longer distinct. Thus, necrotic core might be an irreversible step of atherosclerosis (19). The results of the study indicate that statins might prevent the progression of atherosclerosis due to reduced fibro-fatty volume and retard the upward trend of necrotic core volume.
Additionally, statins have been recognized as having beneficial effects on vascular inflammation, lipid oxidation, and endothelial function, the so-called pleiotropic effects, as well as lipid-lowering functionality. A few previous studies showed that hsCRP, a marker of systemic inflammation, was synthesized locally in atherosclerotic plaque (20,21) and in higher amounts in unstable compared with stable plaque (22,23). In this study, change in fibro-fatty volume had a significant positive correlation with change in hsCRP level (R = 0.357, p = 0.006). These results were supported by a previous report that regression of local atherosclerosis was significantly associated with attenuating the endothelial inflammatory response and macrophage-to-foam cell transformation (24). However, although statin therapy reduced hsCRP level significantly, necrotic core volume—which might be an irreversible step of atherosclerosis—did not change, and there was no correlation change in necrotic core volume with change in hsCRP level (R = 0.198, p = 0.14) in this study. A previous study that evaluated stable and unstable coronary plaque by VH IVUS showed that high values of serum hsCRP level and necrotic core ratio were significantly associated with the degree of inflammation in the process of plaque instability (25). Thus, statin therapy can not reverse fibroatheroma to the previous stage of atherosclerosis. Even so, statin therapy could prevent plaque rupture by reduction of macrophage accumulations and matrix metalloproteinase activity (26). A previous study using optical coherence tomography showed that the incidence of plaque rupture was significantly decreased and the thickness of fibrous cap tended to increase with statin therapy (27). These might explain the mechanisms to prevent plaque rupture and stabilize fibroatheroma including a large necrotic core.
Study limitations.
First, this study population consisted of only 80 patients from 2 centers. A study of larger patient populations from various centers is warranted to confirm these data. Second, although averages of analyzed length in both groups were over 50 mm, those were only small segments of the entire coronary artery. Third, the present VH IVUS technology is unable to differentiate thrombus from other plaque components. The subjects of this study were stable angina pectoris patients, and lesions with angiographically detected thrombus were excluded; however, this algorithm relies on the placement of 2 borders—namely, the luminal border and the media-adventitia border—so that small thrombus within these 2 borders might lead to incorrect tissue characterization. Fourth, fluvastatin is not a strong statin, because follow-up LDL cholesterol level in the fluvastatin group (98.1 mg/dl) was higher than that in previous reports (3–5). However, fluvastatin might be delivered to the vessel wall in an amount sufficient for its therapeutic effect and have a direct action to stabilize atherosclerosis (28). Fifth, the presence of many drivers, including blood pressure, smoking, diabetes mellitus, or unknown genetic factors, might impact the results of this study. Finally, this study was nonrandomized. Those cases with either total cholesterol level more than 220 mg/dl or LDL cholesterol level more than 140 mg/dl were treated for hyperlipidemia, because of ethical considerations.
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Conclusions
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Statin therapies designed to reduce lipid profiles, and inflammation might change the plaque morphology and prevent progression of atherosclerosis. In addition, the change of plaque composition might be associated with clinical stabilization from the trend to fewer clinical events.
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Acknowledgments
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The authors thank Leigh Childs for assistance and his important contributions.
* Reprint requests and correspondence: Dr. Kenya Nasu, Department of Cardiology, Toyohashi Heart Center, 21-1, Gobudori, Oyama, Toyohashi, Aichi 441-8530, Japan (Email: nasu{at}heart-center.or.jp).
Manuscript received April 6, 2009;
accepted April 19, 2009.
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Abstract
Methods