Lipid-lowering therapy and atherosclerotic aortic plaques

The assessment of atherosclerotic plaques has recently been performed noninvasively using magnetic resonance imaging (MRI).^1,2 In studies with rabbits, atherosclerotic plaques exhibited on MRI scans were shown to correlate with pathohistologic examination.³ Findings shown on MRI scans of the thoracic aorta also correlated with transesophageal echocardiographic results.¹ Recent studies evaluating the effects of lipid-lowering treatment with simvastatin (Zocor) on atherosclerotic lesions showed a decrease in thoracic aortic plaques on MRI.^4,5 Simvastatin reduced low-density lipoprotein (LDL) cholesterol levels by 38% and thoracic aortic plaque area by 11% at 1 year.⁴ Patients with a greater LDL cholesterol reduction showed a faster plaque regression.⁵ We compared the effects of 5 mg/day versus 20 mg/day of atorvastatin (Lipitor) on atherosclerotic plaques in the thoracic and abdominal aortas of patients with serum LDL cholesterol levels above 150 mg/dL, as shown on MRI scanning.

Methods

Study patients shown to have abdominal or thoracic plaques on aortic MRI were randomly assigned to receive 5 mg/day or 20 mg/day of atorvastatin. Because plaque regression in the thoracic aorta does not appear until 6 months following treatment,4 repeated MRI studies using the Signa 1.5T CVi scanner (GE Medical Systems) with a commercially available phased-array body coil were performed after 12 months of therapy.

As performed in other studies, using a black-blood sequence, we took transverse T2-weighted (T2W) and proton density-weighted (PDW) images of the abdominal and thoracic descending aortas.^1,6 The following were the imaging parameters used: echo times were 60 ms (T2W) and 10 ms (PDW), repetition time was 2 RR intervals, field of view was 20 cm, slice thickness was 4 mm, and interslice gap was 8 mm. Nine slices of abdominal aorta were obtained at 12-mm intervals above the bifurcation of the common iliac artery, and 9 slices of thoracic aorta were obtained at 12-mm intervals below the arch at the start of the study. A clearly identified luminal protrusion with focal wall thickening was considered to be an atherosclerotic plaque.

We tried to closely match the MRI images obtained after the 12 months of treatment to those taken at the start of the study. After treatment, 3 contiguous slices were taken for each plaque, and a number of anatomical landmarks were used, including mes­enteric arteries, pulmonary veins and arteries, lumbar and intercostal arteries, and vertebrae, to match the slice most similar to the baseline image. National Institutes of Health Image software (Scion Co.) was used to measure vessel wall area (VWA) and vessel wall thickness (VWT) with manual planimetry.

Results

Fifty of the 55 patients who were screened had abdominal or thoracic aorta atherosclerotic plaques. Half of the 50 patients were randomly as&shy;signed to receive either 5 mg or 20 mg of atorvastatin. The 5-mg-dose and 20-mg-dose groups were similar with regard to LDL cholesterol levels (200 ± 38 compared with 201 ± 46 mg/dL, respectively), gender, risk factors, and age (60 ± 6 compared with 59 ± 7 years, respectively). LDL cholesterol levels decreased by 34% in the 5-mg-dose group and by 47% in the 20-mg-dose group after 1 year of treatment (P < .001). The degree of LDL cholesterol reduction, however, was less in the 5-mg-dose group (P < .001). High-sensitivity C-reactive protein (hsCRP) was decreased by 28% in the 5-mg-dose group and by 47% in the 20-mg-dose group (P < .005), although the degree of reduction was the same for both groups.

Seventy-five abdominal aortic pla&shy;q&shy;ues and 50 thoracic aortic plaques were shown on MRI. The 5-mg-dose and 20-mg-dose groups were similar with regard to VWA and VWT at the start of the study. As shown in Figure 1, VWA and VWT in thoracic aortic plaques were not reduced in the 5-mg-dose group after 12 months of treatment (+4% and +1%, respectively), but they were reduced by 18% and 12%, respectively (P < .001), in the 20-mg-dose group. VWA and VWT were not reduced in abdominal aortic plaques, even in the 20-mg-dose group (+3% and -1%, respectively), and an increase was shown in the 5-mg-dose group (12% and 5%, respectively; P < .01). There was a correlation between the degree of hsCRP reduction and the percent change in VWA in thoracic aortic plaques (r = 0.49), as well as between the degree of LDL cholesterol reduction and the percent change in VWA (r = 0.64; Figure 2). There was no correlation between hsCRP reduction and the percent change in VWA in abdominal aortic plaques, and the correlation between the degree of LDL cholesterol reduction and the percent change in VWA in abdominal aortic plaques was weak (r = 0.34). There was a correlation, however, between age at baseline and the percent change in VWA in abdominal plaques (r = 0.41).

Discussion

Recently, intensive lipid-lowering therapy with atorvastatin has re&shy;ceived a great deal of attention. Using ultrasound scanning, the effect of conventional simvastatin treatment (40 mg/day) on carotid intima-media thickness (IMT) was compared with intensive atorvastatin treatment (80 mg/day) in the Atorvastatin Versus Sim&shy;vastatin on Atherosclerosis Pro&shy;gres&shy;sion (ASAP) study.⁷ Sim&shy;vastatin did not cause carotid IMT to decrease, whereas atorv&shy;astatin did, in addition to causing a significant reduction in LDL cholesterol (50%). Carotid IMT regression also resulted from atorva&shy;statin treatment in the Arterial Bi&shy;ology for the Investigation of the Treatment Effects of Reducing Cho&shy;lesterol (ARBITER) study, whereas no reduction was shown for pravastatin (Pravachol).⁸ Using intravascular ultra&shy;sound, the effects of 40 mg/day of pra&shy;vastatin on coronary atheroma was compared with 80 mg/day of atorvastatin in the Reversal of Athero&shy;sclerosis with Aggressive Lipid Lower&shy;ing (REVERSAL) study.⁹ Compared with pravastatin, atorvastatin reduced the progression of coronary atheroma. Our study showed that lipid-lowering therapy with 20 mg/day of atorvastatin induced a marked LDL cholesterol reduction and a plaque regression in the thoracic aorta. Because 20 mg/day of atorvastatin is the highest approved dose in Japan, we used it as the higher dose in our study. With the 20-mg dose, the decrease in the degree of LDL cholesterol (47%) was similar to the decrease achieved with 80 mg/day in Western studies.^7-9 Plaque regression in the thoracic aorta and in coronary and carotid arteries, therefore, is considered to be more effective with intensive atorvastatin lipid-lowering treatment than with conventional therapy. In addition, Japanese pa&shy;tients may be able to achieve many benefits with a lower dose of HMG-CoA reductase inhibitor than that used in Western countries.

With respect to LDL cholesterol levels and plaque regression, the change in coronary atheroma volume correlated with the percent reduction in LDL cholesterol levels in the REVERSAL trial.⁹ In the ASAP study, there was a weak correlation between the percent reduction in LDL cholesterol levels and the change in carotid IMT (r = 0.14).⁷ Our results showed that there was less of a reduction in LDL cholesterol with the 5-mg/day dose than with the 20-mg/day dose (34% compared with 47%, respectively). There was no regression of thoracic aortic plaques with the 5-mg dose; however, there was regression with the 20-mg dose. HsCRP levels were reduced with both doses of atorvastatin (28% in the 5-mg-dose group and 47% in the 20-mg-dose group). Although the percent reduction in hsCRP levels correlated with the degree of plaque regression in the thoracic aorta (r = 0.49), the percent reduction in LDL cholesterol levels showed a better correlation (r = 0.64). Thus, the most significant element for thoracic aorta plaque regression seems to be reduction of LDL cholesterol level. As shown in Figure 2, thoracic aorta plaque regression would be stim&shy;ulated by lowering LDL cholesterol levels by at least 35%.

Abdominal aortic plaques, however, were not reduced with the 20-mg dose of atorvastatin, and the 5-mg dose resulted in marked progression of the plaques. The correlation be&shy;tween LDL cholesterol level and abdominal aortic plaque reduction was weak. To achieve regression of abdominal aortic plaques, LDL cholesterol levels would need to be lowered by at least 50% (Figure 2). It appears that abdominal and thoracic aortic plaques respond differently to treatment with lipid-lowering drugs. It also appears that other elements may significantly affect abdominal aortic plaque progression. Age was shown to be a factor related to the changes in abdominal plaques in our study, indicating that the plaques may be more likely to progress in older patients.

Hypercholesterolemic patients were shown in an autopsy study to have more severe plaques in the thoracic aorta than in the abdominal aorta,¹⁰ although plaques occur more commonly in the abdominal than in the thoracic aorta.^6,10 More atheromatous lesions were shown to develop in the thoracic aorta than in the abdominal aorta in rabbits that were fed a high-cholesterol diet.¹¹ Using transesophageal echocardiography, a correlation between thoracic aortic plaques and serum LDL cholesterol levels was shown in 1 study.¹² Another study, which used ultrasound scanning, showed no association be&shy;tween abdominal aortic plaques and LDL cholesterol levels.¹³ In an earlier study, we showed that the extent of plaques correlated with LDL cholesterol level in the thoracic aorta but not in the abdominal aorta, using MRI.⁶

LDL cholesterol levels were shown on multivariate analysis to be a factor only for thoracic aortic plaques. In&shy;creased cholesterol levels appear to correlate more closely with plaque formation in the thoracic aorta than in the abdominal aorta. As a result, plaque regression in the thoracic aorta is more likely to be helped by treatment with lipid-lowering drugs. Autopsy studies have shown that fibrous plaques in&shy;crease with increasing age and are more likely to occur in the abdominal aorta than in the thoracic aorta.¹⁴ The ab&shy;dominal aorta has more collagen and less elastin than the thoracic aorta and is therefore stiffer.¹⁵ Blood pressures are also higher in the abdominal aorta, and the abdominal aorta tapers geometrically. This may possibly ex&shy;plain why more plaques, in particular, fibrous plaques, are present in the abdominal aorta and why such risk factors as age and hypertension make the abdominal aorta more susceptible to plaque formation.

Conclusion

The results of our study showed that a marked reduction in thoracic aortic plaques and in LDL cholesterol level occurred after 12 months of treatment with 20 mg/day of atorva-statin. The degree of reduction in LDL cholesterol level correlated with the degree of plaque regression in the thoracic aorta. In the abdominal aorta, however, there was a weak correlation between LDL cholesterol level and plaque regression, and plaque progression increased with age. These re&shy;sults suggest that lipid-lowering therapy affects plaques in the thoracic aorta differently from those in the abdominal aorta and that factors such as aging may affect the progression of plaque more in the abdominal aorta.