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CLINICAL RESEARCH: CARDIAC IMAGING

Effect of lipid-lowering therapy with atorvastatin on atherosclerotic aortic plaques detected by noninvasive magnetic resonance imaging

Atsushi Yonemura, MD^*, Yukihiko Momiyama, MD^*,*, Zahi A. Fayad, PhD, Makoto Ayaori, MD^*, Reiko Ohmori, PhD^*, Kenji Higashi, MD^*, Teruyoshi Kihara, MS, Shojiro Sawada, MD^*, Noriyuki Iwamoto, MD^*, Masatsune Ogura, MD^*, Hiroaki Taniguchi, MD^*, Masatoshi Kusuhara, MD^*, Masayoshi Nagata, MD, Haruo Nakamura, MD^*, Seiichi Tamai, MD^* and Fumitaka Ohsuzu, MD, FACC^*

^* National Defense Medical College, Saitama, Japan
Iruma Heart Hospital, Saitama, Japan
Mount Sinai School of Medicine, New York, New York

Manuscript received August 3, 2004; revised manuscript received October 15, 2004, accepted November 3, 2004.

^* Reprint requests and correspondence: Dr. Yukihiko Momiyama, First Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan (Email: momiyama{at}me.ndmc.ac.jp).

	Abstract

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OBJECTIVES: We sought to elucidate the effects of 20-mg versus 5-mg atorvastatin on thoracic and abdominal aortic plaques.

BACKGROUND: Regression of thoracic aortic plaques by simvastatin was demonstrated using magnetic resonance imaging (MRI). However, the effects of different doses of statin have not been assessed.

METHODS: Using MRI, we investigated the effects of 20-mg versus 5-mg atorvastatin on thoracic and abdominal aortic plaques in 40 hypercholesterolemic patients who were randomized to receive either dose. Treatment effects were evaluated as changes in vessel wall thickness (VWT) and vessel wall area (VWA) of atherosclerotic lesions from baseline to 12 months of treatment.

RESULTS: The 20-mg dose induced a greater low-density lipoprotein (LDL) cholesterol reduction than did the 5-mg dose (–47% vs. –34%, p < 0.001). Although 20 mg and 5 mg reduced C-reactive protein (CRP) levels (–47% and –28%), the degree of CRP reduction did not differ between the two doses. The 20-mg dose reduced VWT and VWA of thoracic aortic plaques (–12% and –18%, p < 0.001), whereas 5 mg did not (+1% and +4%). Regarding abdominal aortic plaques, even 20 mg could not reduce VWT or VWA (–1% and +3%), but instead progression was observed with 5-mg treatment (+5% and +12%, p < 0.01). Notably, the degree of plaque regression in thoracic aorta correlated with LDL cholesterol (r = 0.64) and CRP (r = 0.49) reductions. Although changes in abdominal aortic plaques only weakly correlated with LDL cholesterol reduction (r = 0.34), they correlated with age (r = 0.41).

CONCLUSIONS: One-year 20-mg atorvastatin treatment induced regression of thoracic aortic plaques with marked LDL cholesterol reduction, whereas it resulted in only retardation of plaque progression in abdominal aorta. Thoracic and abdominal aortic plaques may have different susceptibilities to lipid lowering.

Abbreviations and Acronyms   hsCRP = high-sensitivity C-reactive protein   IMT = intima-media thickness   LA = lumen area   LDL = low-density lipoprotein   MRI = magnetic resonance imaging   PDW = proton density-weighted   T2W = T2-weighted   TVA = total vascular area   VWA = vessel wall area   VWT = vessel wall thickness

	Methods

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Study protocol.   Our study was a prospective, randomized, open-label trial to elucidate the effects of 20 mg/day versus 5 mg/day atorvastatin treatment on atherosclerotic plaques in the thoracic and abdominal aortas in asymptomatic hypercholesterolemic patients. Our study was approved by the ethics committee of our hospital. Written, informed consent was obtained from all patients. Patients with a history of atorvastatin treatment were excluded. If patients had been taking other statins, these drugs were discontinued for at least four weeks. After a four- to eight-week washout period, fasting blood samples were taken to assess lipid levels. If patients were found to have a serum LDL cholesterol level of >150 mg/dl, they were eligible for our study and underwent MRI of the aortas. Patients found to have thoracic and/or abdominal aortic plaques were randomized to receive either 20-mg or 5-mg atorvastatin daily. After 1, 2, 3, 6, and 12 months of atorvastatin treatment, blood samples were taken to assess lipid levels and safety parameters (creatinine kinase and liver enzymes). Lipid levels were measured by standard laboratory methods. Plasma high-sensitivity C-reactive protein (hsCRP) levels were measured using the BNII nephelometer (Dade Behring, Germany). Repeat MRI was scheduled at 12 months of treatment, because >6 months of treatment were required to observe plaque regression in the thoracic aorta (5). Throughout the study period, all patients were asked to maintain their dietary habits. If patients had been receiving antihypertensive drugs, they continued these drugs.

MRI of aortic wall.   MRI was performed on the Signa 1.5-T Cvi scanner (GE Medical Systems) using a commercially available phased-array body coil. The transverse proton density-weighted (PDW) and T2-weighted (T2W) images of the thoracic descending and abdominal aortas were obtained using an electrocardiographically gated, breath-hold, double-inversion-recovery, fast-spin-echo sequence, as previously reported (1,7). Imaging parameters were repetition time (TR) = 2 RR intervals, echo times (TE) = 10 ms (PDW) and 60 ms (T2W), 20-cm field of view, 4-mm slice thickness, 8-mm interslice gap, 256 x 256 acquisition matrix, and 32 echo-train. At baseline, nine slices of the thoracic aorta were obtained at 12-mm intervals above the lower corner of the ninth thoracic vertebrae, and nine slices of the abdominal aorta were obtained at 12-mm intervals above the upper corner of the fourth lumbar vertebrae, which each covered about 10-cm portions of the thoracic aorta below the arch, and of the abdominal aorta above the bifurcation of the common iliac artery (Fig. 1). Atherosclerotic plaque was defined as a clearly identified luminal protrusion with focal wall thickening.

View larger version (54K): [in this window] [in a new window]   Figure 1 The magnetic resonance imaging (MRI) slices of aortas and morphometric analysis. At baseline, nine slices of the thoracic aorta were obtained at 12-mm intervals above the lower corner of the ninth thoracic vertebrae (arrow), and nine slices of the abdominal aorta were obtained at 12-mm intervals above the upper corner of the fourth lumbar vertebrae (arrow). After 12 months of treatment, three contiguous slices for each plaque were obtained. The slice most closely matching the one at baseline was selected. The lumen area and total vascular area were calculated from the traced luminal and outer wall boundaries.

Morphometric analysis and plaque characterization.   Maximal and minimal vessel wall thickness (VWT), total vascular area (TVA), and lumen area (LA) in each slice were measured three times by manual planimetry using the National Institutes of Health Image software package (Scion Co.), and the averages were used for statistical analysis. The LA and TVA were calculated from the traced luminal and outer wall boundaries (Fig. 1). The vessel wall area (VWA) was calculated as TVA minus LA. All measurements were performed by Dr. Momiyama, who was blinded to the treatment assignment and the order of images. The accuracy and reproducibility of this method was previously reported (5,6,8,9). In our study, 10 patients were randomly selected for the evaluation of intraobserver variability.

Plaque characterization by MRI is based on the signal intensities of plaque on PDW, T1W, and T2W images (1,10,11). Lipid components are identified as hyperintense on PDW and T1W images and hypointense regions on T2W images. Fibrocellular components are identified as hyperintense regions on all three images. Calcium deposits are identified as hypointense regions on all the images. However, because of improved flow suppression and a higher signal-to-noise ratio of PDW images with the double-inversion-recovery, fast-spin-echo sequence, as compared with T1W images with the conventional spin-echo sequence (1), the T1W images were omitted to reduce examination time in our study. Total examination time was about 40 min.

Statistical analysis.   Differences between two groups were evaluated by the unpaired t test for continuous variables and by the chi-square test for categorical variables. Differences between baseline and after 12 months of treatment were evaluated by the paired t test for continuous variables. Correlations between changes in plaques and those in LDL cholesterol levels or other factors were evaluated by Pearson's correlation coefficient. A value of p < 0.05 was considered statistically significant. Results are presented as the mean value ± SD.

	Results

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Patient characteristics.   Of the 55 screened patients with hypercholesterolemia, 50 were found to have plaques in the thoracic and/or abdominal aortas by MRI. One-half of the patient group (n = 25) was randomized to receive either dose of atorvastatin. During the 12-month follow-up, six patients withdrew on their own accord, and four had adverse events (one cerebral infarction, one liver dysfunction, one eruption, and one general fatigue). As a result, 19 patients in the 20-mg dose group and 21 in the 5-mg dose group underwent repeat MRI after 12 months of treatment. Between the 20-mg and 5-mg dose groups, age, gender, risk factors, and lipid levels were not different (Table 1). A history of prior statin use was present in seven patients (37%) in the 20-mg dose group and 9 (43%) of the 5-mg dose group (p = NS).

MRI results.   A total of 50 thoracic and 75 abdominal aortic plaques were detected by MRI, and these atherosclerotic lesions were followed up. At baseline, there were no differences in VWT, VWA, and LA in these lesions between the 20-mg and 5-mg dose groups. After 12 months of treatment, 20-mg atorvastatin reduced maximal VWT (maxVWT) (–12%) and VWA (–18%) in thoracic aortic plaques (p < 0.001), whereas 5-mg atorvastatin did not (0% and +4%, p = NS) (Table 3). The 20-mg dose also increased LA in thoracic lesions (+5%). Differences in changes in maxVWT, VWA, and LA between the 20-mg and 5-mg dose groups were significant. However, there were no changes in minimal VWT in both groups. In contrast, even 20-mg atorvastatin could not reduce maxVWT and VWA in abdominal aortic plaques (–1% and +3%, p = NS), but instead a progression was observed in the 5-mg dose group (+5% and +12%, p < 0.01) (Table 4). The LA also decreased in the 5-mg dose group (–3%). Differences in these changes in abdominal aortic plaques between the 20-mg and 5-mg dose groups were significant. Examples of plaque regression or progression are shown in Figure 2.

View larger version (92K): [in this window] [in a new window]   Figure 2 Images at baseline and after 12 months of treatment. After 12 months, three contiguous slices (no interslice gap) for each plaque were obtained, and the slice most closely matching the one at baseline was selected. In selected slices, arrows indicate plaques. (A) Thoracic aortic plaque that showed regression (28% vessel wall area [VWA] reduction) with 38% low-density lipoprotein-cholesterol (LDL-C) reduction by 20-mg atorvastatin; (B) thoracic plaque that showed regression (–10%) with 34% LDL-C reduction by 5 mg; (C) thoracic plaque that showed progression (+15%) with 20% LDL-C reduction by 5 mg; and (D) abdominal aortic plaque that showed progression (+9%) despite 39% LDL-C reduction by 20 mg.

View larger version (22K): [in this window] [in a new window]   Figure 3 Correlations between the percent reduction in low-density lipoprotein-cholesterol (LDL-C) levels and the percent change in vessel wall area (VWA). The change in VWA in thoracic aortic plaques correlated well with the degree of LDL-C reduction (r = 0.64). A weak correlation was found in abdominal plaques (r = 0.34). Solid circles = 20-mg dose; open triangles = 5-mg dose.

View larger version (68K): [in this window] [in a new window]   Figure 4 Images of thoracic aortic plaque with a lipid-rich core. This plaque had a hypointense region within the plaque on the T2-weighted (T2W) image at baseline. After 12 months, it showed regression (–8%) with a marked low-density lipoprotein-cholesterol (LDL-C) reduction (–56%). Arrows = plaques. Arrowhead = a lipid-rich core. PDW = protein density-weighted; VWA = vessel wall area.

	Discussion

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Using MRI, simvastatin treatment was shown to reduce LDL cholesterol levels by 38% and the thoracic aortic plaque area by 11% at one year (5), as well as to reduce the thoracic aortic plaque area by 16% and increase the LA by 6% at two years (6). Our study also showed one-year statin treatment to regress thoracic aortic plaques. However, in our Japanese patients, we demonstrated 20-mg atorvastatin to induce a marked LDL cholesterol reduction (–47%), a large reduction in VWA (–18%), and an increase in lumen area (+5%) after one year. In Western countries, the Atorvastatin Versus Simvastatin on Atherosclerosis Progression (ASAP) trial compared the effect of intensive atorvastatin (80 mg) versus conventional simvastatin (40 mg) treatment on carotid intima-media thickness (IMT) by ultrasound (12). Atorvastatin caused a regression of carotid IMT with a marked LDL cholesterol reduction (–50%), whereas simvastatin did not. The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) trial also reported atorvastatin treatment to cause a regression of carotid IMT, but pravastatin did not (13). Recently, the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial compared the effect of atorvastatin (80 mg) versus pravastatin (40 mg) on coronary atheroma using intravascular ultrasound (14). Atorvastatin reduced the progression of coronary atheroma compared with pravastatin. In our study, we used 20 mg as the higher dose of atorvastatin, as it is the maximal approved dose in Japan. However, the degree of LDL cholesterol reduction by the 20-mg dose in our study was similar to that reported after 80-mg administration in the trials in Western countries (12–14). Moreover, we showed 20-mg atorvastatin to regress thoracic aortic plaques regardless of a history of other statin use. Therefore, intensive lipid lowering by atorvastatin is considered to be more effective for plaque regression in the thoracic aorta, as well as in the carotid and coronary arteries, as compared with conventional treatment.

Regarding correlations between plaque regression and LDL cholesterol reduction, the ASAP trial showed the change in carotid IMT to weakly correlate with the percent reduction in LDL cholesterol levels (r = 0.14) (12). The REVERSAL trial (14) also reported the change in coronary atheroma volume to correlate with the percent reduction in LDL cholesterol levels. Preliminary results (15) looking at the effects of 80 mg versus 20 mg simvastatin on thoracic aortic and carotid plaques using MRI showed no different effects on LDL cholesterol reduction or plaque regression between 80 mg and 20 mg. However, patients with a greater LDL cholesterol reduction showed a faster plaque regression. In our study, 20-mg atorvastatin induced a greater LDL cholesterol reduction than did the 5-mg dose (–47% vs. –34%). The 20-mg dose caused a regression of thoracic aortic plaques, whereas the 5-mg dose did not. Statin also reduces hsCRP levels (16,17). In our study, both 20-mg and 5-mg atorvastatin reduced hsCRP levels (–47% and –28%), but the degree of hsCRP reduction was not different. The degree of plaque regression in the thoracic aorta correlated with the percent reduction in hsCRP levels (r = 0.49), but it showed a better correlation with the percent reduction in LDL cholesterol levels (r = 0.64). Hence, the degree of LDL cholesterol reduction appears to be the most important factor for plaque regression in the thoracic aorta. Intensive LDL cholesterol lowering by at least 35% would induce a regression of thoracic aortic plaques (Fig. 3).

In contrast, even 20-mg atorvastatin could not cause a regression of abdominal aortic plaques. A significant progression was observed in the 5-mg dose treatment. The changes in abdominal aortic plaques weakly correlated with the degree of LDL cholesterol reduction. Figure 3 indicates that more intensive LDL cholesterol lowering by at least 50% may be needed for the regression of abdominal aortic plaques. These suggest that thoracic and abdominal aortic plaques appear to have different susceptibilities to lipid-lowering therapy. Among the plaques with >50% LDL cholesterol reduction, only four plaques showed >10% regression, but two had >10% progression (Fig. 3). The changes in abdominal aortic plaques also correlated with age, suggesting that older patients are more likely to have plaque progression. Hence, other factors, such as aging, may play an important role in plaque progression in the abdominal aorta.

The REGRESS trial (18) investigated the effect of 40-mg pravastatin on IMT of carotid and femoral arteries using ultrasound. The femoral artery showed a regression in IMT, but the carotid did not. Nolting et al. (19) also studied the effect of 80-mg simvastatin on IMT of carotid and femoral arteries and showed a greater effect in the femoral artery. However, no different effects of lipid-lowering therapy between the thoracic and abdominal aortas have been reported.

Although plaques are more common in the abdominal aorta than in the thoracic aorta (7,20), an autopsy study reported that patients with hypercholesterolemia had more severe plaques in the thoracic than in the abdominal aorta (20). Another study reported fatty streaks to be more common in the thoracic aorta, especially in areas with high shearing strain (21). Areas just distal to the ostia of intercostal arteries were commonly spared by fatty streaks. In rabbits fed by a cholesterol diet, the thoracic aorta had more atheromatous lesions with more cholesterol accumulation than the abdominal aorta (22). Plaque formation associated with hypercholesterolemia may thus be associated with high shearing strain in the thoracic aorta. In vivo, Tribouilloy et al. (23) reported an association between serum LDL cholesterol levels and thoracic aortic plaques by transesophageal echocardiography. In contrast, Giral et al. (24) found no association between LDL cholesterol levels and abdominal aortic plaques by ultrasonography. Using MRI, we previously reported LDL cholesterol levels to correlate with the plaque extent in the thoracic aorta but not in the abdominal aorta (7). On multivariate analysis, LDL cholesterol levels were a factor associated with only thoracic aortic plaques. Plaque formation in the thoracic aorta appears to be more closely associated with hypercholesterolemia than that in the abdominal aorta. Therefore, lipid-lowering therapy is more likely to be effective for plaque regression in the thoracic aorta. In the abdominal aorta, fibrous plaques were shown by autopsy studies to be more common than in the thoracic aorta and to increase with age (21,25). The abdominal aorta tapers geometrically and has higher blood pressures than the thoracic aorta. It is also stiffer with less elastin and more collagen (26). Vasa vasorum is common in the thoracic aorta but rare in the abdominal aorta, suggesting that oxygen and nourishment of the abdominal aorta comes mainly by diffusion from the aortic lumen (27). These may be the reason why the abdominal aorta has more plaques, especially fibrous plaques, than the thoracic aorta, and the abdominal aorta may be highly susceptible to plaque formation associated with risk factors, such as age and hypertension.

In the abdominal aorta, calcified plaques were also reported to be more common than in the thoracic aorta (21). In our study, calcification tended to be more common in abdominal aortic plaques (15%) than in thoracic aortic plaques (10%). The higher prevalence of calcified plaques, as well as fibrous plaques may be the reason why statin was less effective for plaque regression in the abdominal aorta. MRI can detect lipid-rich cores in atherosclerotic plaques in vivo (1,10). However, in our study, only one thoracic plaque was one with a lipid-rich core. Of the 40 patients, 16 (40%) had prior stain use. Because lipid-lowering therapy was reported to decrease lipid-rich cores in plaques (28) and because the in-plane resolution was 0.78 x 0.78 mm, small lipid-rich cores may not have been detected in our study.

Study limitations.   Our study was performed on a small number of Japanese patients. Like the REVERSAL trial (14) and unlike the PROVE-IT trial (29), we do not provide any clinical end point correlations. Moreover, the 20-mg dose was used as the high dose of atorvastatin, because it is the maximal approved dose in Japan. The 20-mg dose is less than the dose (80 mg) in trials in Western countries (12–14). Therefore, our results may not be applicable to other ethnics. However, the degree of LDL cholesterol reduction (–47%) by 20 mg in our study was similar to that reported after 80-mg administration in the REVERSAL trial (–46%) and the PROVE-IT trial (–51%). In our study, MRI was performed at baseline and after one year of treatment. To validate the effect of atorvastatin on aortic plaques, further follow-up is needed.

Conclusions.   Using MRI, we showed that one-year 20-mg atorvastatin treatment induced a significant regression of thoracic aortic plaques with a marked LDL cholesterol reduction, whereas it resulted in only a retardation of plaque progression in the abdominal aorta. The degree of plaque regression in the thoracic aorta correlated well with the degree of LDL cholesterol reduction. Although the change in abdominal aortic plaques weakly correlated with LDL cholesterol reduction, it also correlated with age. Plaques in the thoracic and abdominal aortas may thus have different susceptibilities to lipid lowering, and other factors, such as aging, may be more important for plaque progression in the abdominal than in the thoracic aorta.

	Footnotes

 
This study was supported by a grant from Pfizer Co.

	References

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