Although statin-induced regression in coronary atherosclerosis seems to be greater in patients with acute coronary syndrome than in those with stable coronary artery disease, no reports have examined this. The purpose of the present study was to compare the changes in coronary atherosclerosis in patients with stable versus unstable angina pectoris (AP). The effects of 8-month statin therapy on coronary atherosclerosis were evaluated using virtual histology intravascular ultrasound, and analyzable intravascular ultrasound data were obtained from 119 patients (83 patients with stable AP and 36 with unstable AP). A significant decrease in plaque volume was observed in patients with unstable AP (−2.2%, p = 0.02) but not in patients with stable AP. A significant increase in the necrotic-core component (0.30 mm 3 /mm, p = 0.009) was observed only in patients with unstable AP. Significant positive correlations were observed between the percentage of change in platelet-activating factor acetylhydrolase and the percentage of change in plaque volume (r = 0.346, p = 0.05) in patients with unstable AP. No significant correlations were observed in patients with stable AP. Multivariate regression analyses showed that a reduction in platelet-activating factor acetylhydrolase was associated with regression in coronary atherosclerosis, particularly of the fibrous component (β = 0.443, p = 0.003), in patients with unstable AP. In conclusion, regression of the coronary artery plaque volume was greater, although statin therapy did not halt the increases in plaque vulnerability, in patients with unstable AP compared to those with stable AP. A reduction in the serum platelet-activating factor acetylhydrolase level was associated with regression in coronary atherosclerosis, particularly the fibrous plaque volume, in patients with unstable AP.
Recent trials using intravascular ultrasound (IVUS) have shown that statins attenuate the progression or induce regression of coronary artery plaques. Although previous studies have suggested that statin-induced regression in coronary atherosclerosis seems to be greater in patients with acute coronary syndrome than in patients with stable coronary artery disease, no reports have examined this issue. Platelet-activating factor acetylhydrolase (PAF-AH), a member of the phospholipase A2 superfamily, hydrolyzes oxidized phospholipids to generate the proinflammatory and proatherogenic products lysophosphatidylcholine and oxidized fatty acids. These products play critical roles in endothelial cell dysfunction and smooth muscle cell apoptosis. Epidemiologic studies have shown that PAF-AH independently predicted the risk of coronary events. Furthermore, a recent IVUS study has demonstrated that a decrease in PAF-AH is associated with regression in coronary atherosclerosis in patients with acute coronary syndrome. However, no reports have compared the effects of serum PAF-AH on coronary atherosclerosis in patients with acute coronary syndrome versus those with stable coronary artery disease. Therefore, in the present study, we compared the statin-induced changes in coronary atherosclerosis and the correlations between those changes and serum PAF-AH in patients with stable angina pectoris (AP) versus those with unstable AP.
Methods
The present study is a subanalysis of the Treatment With Statin on Atheroma Regression Evaluated by Intravascular Ultrasound With Virtual Histology (TRUTH) study, a prospective, open-labeled, randomized, multicenter trial performed at 11 Japanese centers that used virtual histology-IVUS to evaluate the effects of 8 months of treatment with pitavastatin versus pravastatin on coronary artery plaque composition. Details of the study design have been previously reported. In brief, 164 patients with AP were randomized to either pitavastatin (4 mg/day, intensive lipid lowering) or pravastatin (20 mg/day, moderate lipid lowering) therapy after successful percutaneous coronary intervention (PCI) under virtual histology-IVUS guidance. None of the participants was taking a statin or another lipid-lowering drug at study enrollment. Follow-up IVUS examinations were performed after 8 months of statin therapy. The patients were included in the present study if they had measurable IVUS-detected lesions at enrollment and at the 8-month follow-up examination. A total of 119 patients (83 with stable AP [39 randomized to pitavastatin and 44 to pravastatin] and 36 with unstable AP [19 randomized to pitavastatin and 17 to pravastatin]) were included in the present subanalysis. We compared the serum lipid markers at baseline and at the 8-month follow-up examination, changes in these markers and the grayscale and virtual histology-IVUS parameters at baseline and the 8-month follow-up examination, and changes in these parameters between patients with stable AP and those with unstable AP.
The TRUTH trial was conducted in accordance with the Declaration of Helsinki and with the approval of the ethical committees of the 11 participating institutions. Each patient enrolled in the study provided written informed consent.
Details of the IVUS procedure and examination have been previously reported. In brief, after PCI of the culprit lesion, the IVUS examination was performed for angiographic lesions with <50% lumen narrowing on the distal and proximal sides of the culprit lesion in the PCI vessel. An IVUS catheter (Eagle Eye Gold, Volcano, San Diego, California) was used, and a motorized pullback device withdrew the transducer at 0.5 mm/s. During pullback, a grayscale IVUS was recorded, and raw radiofrequency data were captured at the top of the R wave using a commercially available IVUS console (IVG3, Volcano). After 8 months of statin therapy, the IVUS examination was repeated in the same coronary artery using the same type of IVUS catheter used at baseline.
All baseline and follow-up IVUS core laboratory analyses were performed by an independent and experienced investigator (M.T.) in a blinded manner. Before the IVUS analysis, the baseline and follow-up IVUS images were reviewed side by side on a display, and the distal and proximal ends of the target segment were identified on the basis of the presence of reproducible anatomic landmarks such as the side branch, vein, and stent edge. The target segment of interest had a ≥50% plaque burden according to the IVUS data. Plaques close to the PCI site (within 5 mm) were excluded. In patients who underwent multivessel PCI, the vessel with the greatest plaque volume was selected. Manual contour detection of the lumen and external elastic membrane (EEM) was performed for each frame. Quantitative IVUS grayscale analysis was performed according to the guidelines of the American College of Cardiology and European Society of Cardiology. All volumetric data were divided by the lesion length to obtain a volume index. The EEM volume index was calculated as Σ(EEM cross sectional area (CSA) )/lesion length. The lumen volume index was calculated as Σ(LUMEN CSA )/lesion length. The plaque volume index was calculated as Σ(EEM CSA − LUMEN CSA )/lesion length. Virtual histology-IVUS data analysis was determined by grayscale border contour calculation, and the relative and absolute amounts of the different coronary artery plaque components were measured using IVUS Lab, version 2.2 (Volcano).
Blood examinations to measure the lipid levels were performed at baseline and at the 8-month follow-up visit. The serum lipid, apolipoprotein, and high-sensitivity C-reactive protein levels were measured at a central clinical laboratory (SRL, Tokyo, Japan). The serum PAF-AH and high-density lipoprotein–PAF-AH levels were measured at another central clinical laboratory (BML, Tokyo, Japan).
Statistical analyses were performed using StatView, version 5.0 (SAS Institute, Cary, North Carolina). The results are expressed as the mean ± SD or median and range. Differences in continuous variables between the 2 groups were compared using an unpaired Student’s t test when the variables showed a normal distribution and the Mann-Whitney U test when the variables were not normally distributed. Differences in continuous variables within each group were compared using paired Student’s t tests when the variables showed a normal distribution and Wilcoxon’s signed rank sum tests when the variables were not normally distributed. Univariate regression analyses were performed to assess the correlations between percentage of changes in the EEM volume index or plaque volume index and the percentage of changes in several parameters. Statistically significant variables detected using univariate analysis were analyzed further in multivariate models. Statistical significance was set at p <0.05.
Results
The baseline characteristics of the subjects are listed in Table 1 . Of the 119 patients, 83 were included in the stable AP group and 36 included in the unstable AP group. No significant differences were present in the baseline characteristics between the 2 groups.
| Variable | Stable AP (n = 83) | Unstable AP (n = 36) | p Value |
|---|---|---|---|
| Age (yrs) | 67 ± 10 | 65 ± 11 | 0.3 |
| Men | 68 (82%) | 31 (86%) | 0.58 |
| Body mass index (kg/m 2 ) | 24.5 ± 3.4 | 24.3 ± 3.2 | 0.71 |
| Treatment allocation | 0.56 | ||
| Pitavastatin 4 mg/day | 39 (47%) | 19 (53%) | |
| Pravastatin 20 mg/day | 44 (53%) | 17 (47%) | |
| Diabetes mellitus | 35 (42%) | 15 (42%) | 0.96 |
| Hypertension | 55 (66%) | 20 (56%) | 0.27 |
| Smoker | 31 (37%) | 11 (31%) | 0.18 |
| Target coronary artery | 0.32 | ||
| Left anterior descending | 46 (55%) | 21 (58%) | |
| Left circumflex | 5 (6%) | 0 (0%) | |
| Right | 32 (39%) | 15 (42%) | |
| Medications | |||
| Aspirin | 81 (98%) | 36 (100%) | 0.35 |
| Thienopyridines | 82 (99%) | 36 (100%) | 0.51 |
| Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers | 42 (51%) | 19 (53%) | 0.83 |
| β Blockers | 11 (13%) | 2 (6%) | 0.22 |
| Calcium channel blockers | 47 (57%) | 13 (36%) | 0.04 |
| Follow-up duration (days) | 226 ± 37 | 229 ± 36 | 0.67 |
The risk factor controls at baseline and the 8-month follow-up examination are listed in Table 2 . The serum low-density lipoprotein cholesterol levels decreased significantly from 129 to 82 mg/dl in the stable AP group and from 138 to 91 mg/dl in the unstable AP group. A significant increase in the high-density lipoprotein cholesterol level was observed in the stable AP group, but this increase was not significant in the unstable AP group. A significant decrease in the high-sensitivity C-reactive protein level was observed in both groups, although the median high-sensitivity C-reactive protein levels at baseline and the 8-month follow-up visit were significantly greater in the unstable AP group than in the stable AP group. The serum PAF-AH and high-density lipoprotein–PAF-AH levels decreased significantly in both groups.
| Variable | Stable AP (n = 83) | Unstable AP (n = 36) | ||||
|---|---|---|---|---|---|---|
| Baseline | Follow-up | p Value | Baseline | Follow-up | p Value | |
| Total cholesterol (mg/dl) | 201 ± 34 | 157 ± 27 | <0.0001 | 215 ± 38 | 163 ± 31 | <0.0001 |
| % Change | −21 ± 13 | −24 ± 12 | ||||
| Low-density lipoprotein cholesterol (mg/dl) | 129 ± 31 | 82 ± 24 | <0.0001 | 138 ± 34 | 91 ± 26 | <0.0001 |
| % Change | −35 ± 16 | −33 ± 17 | ||||
| Triglycerides (mg/dl) | 129 ± 49 | 117 ± 68 | 0.08 | 136 ± 94 | 115 ± 52 | 0.14 |
| % Change | −6 ± 44 | −2 ± 41 | ||||
| High-density lipoprotein cholesterol (mg/dl) | 47 ± 11 | 52 ± 12 | <0.0001 | 46 ± 12 | 49 ± 14 | 0.21 |
| % Change | 13 ± 24 | 7 ± 24 | ||||
| Apolipoprotein A-I (mg/dl) | 119 ± 20 | 135 ± 24 | <0.0001 | 115 ± 19 | 124 ± 25 | 0.01 |
| % Change | 15 ± 19 | 8 ± 15 | ||||
| Apolipoprotein B (mg/dl) | 101 ± 23 | 72 ± 18 | <0.0001 | 110 ± 22 | 78 ± 17 | <0.0001 |
| % Change | −28 ± 15 | −28 ± 14 | ||||
| High-sensitivity C-reactive protein (ng/ml) | ||||||
| Median | 2,480 | 582 | 0.0005 | 7,680 ∗ | 729 † | 0.0003 |
| Range | 54–62,900 | 52–23,200 | 287–88,900 | 75–26,200 | ||
| % Change | ||||||
| Median | −71 | −81 | ||||
| Range | −100–275 | −100–636 | ||||
| Platelet-activating factor acetylhydrolase (μg/ml) | 1.58 ± 0.50 | 1.18 ± 0.39 | <0.0001 | 1.73 ± 0.60 | 1.25 ± 0.46 | <0.0001 |
| % Change | −23 ± 17 | −26 ± 18 | ||||
| High-density lipoprotein platelet-activating factor acetylhydrolase (ng/ml) | 215.2 ± 99.9 | 154.4 ± 66.9 | <0.0001 | 206.7 ± 97.2 | 146.8 ± 67.1 | <0.0001 |
| % Change | −22 ± 31 | −23 ± 35 | ||||
The parameters evaluated using grayscale IVUS are listed in Table 3 . No significant differences were seen in the EEM volume index, plaque volume index, or lumen volume index at baseline and at the 8-month follow-up examination between the 2 groups. The EEM volume index decreased significantly in both groups. A significant decrease in the plaque volume index was observed in the unstable AP group (−2.2%, p = 0.02) but not in the stable AP group. Significant positive correlations were observed between the percentage of change in PAF-AH and the percentage of change in EEM volume (r = 0.343, p = 0.05) or plaque volume (r = 0.346, p = 0.05) in the unstable AP group. However, no significant correlations were found between the percentage of change in PAF-AH and the percentage of change in the EEM volume or plaque volume in the stable AP group ( Figure 1 ). No other lipid or inflammatory markers correlated with the percentage of change in EEM volume or plaque volume in either group.
| Variable | Stable AP (n = 83) | Unstable AP (n = 36) | ||||
|---|---|---|---|---|---|---|
| Baseline | Follow-up | p Value | Baseline | Follow-up | p Value | |
| EEM volume index | ||||||
| Mean (mm 3 /mm) | 16.30 ± 5.47 | 16.08 ± 5.46 | 0.04 | 16.46 ± 4.97 | 16.13 ± 5.03 | 0.04 |
| % Change | −1.3 ± 5.6 | −2.0 ± 5.9 | ||||
| Plaque volume index | ||||||
| Mean (mm 3 /mm) | 8.80 ± 3.27 | 8.69 ± 3.20 | 0.28 | 9.28 ± 3.42 | 9.01 ± 3.28 | 0.02 |
| % Change | −0.9 ± 9.3 | −2.2 ± 8.8 | ||||
| Lumen volume index | ||||||
| Mean (mm 3 /mm) | 7.51 ± 2.73 | 7.39 ± 2.70 | 0.22 | 7.18 ± 2.29 | 7.12 ± 2.56 | 0.7 |
| % Change | −1.0 ± 11.3 | −1.0 ± 12.7 | ||||
| % Atheroma volume | ||||||
| Mean (%) | 54.0 ± 6.7 | 54.1 ± 6.7 | 0.89 | 55.9 ± 7.6 | 55.7 ± 7.6 | 0.78 |
| Nominal change (%) | 0.1 ± 4.1 | −0.2 ± 4.4 | ||||
| Average length (mm) | 24.2 ± 13.9 | 25.4 ± 17.2 | ||||
The parameters evaluated using virtual histology-IVUS are listed in Table 4 . No significant differences were seen between the 2 groups in any of the 4 plaque component volume indexes at baseline. A significant decrease in the fibrofatty plaque component and increase in the dense calcium plaque component were observed in both groups. A significant increase in the necrotic core plaque component (0.30 mm 3 /mm, p = 0.009) and decrease in the fibrous plaque component (−0.42 mm 3 /mm, p = 0.002) were observed only in the unstable AP group. Furthermore, a significant positive correlation was observed between the percentage of change in PAF-AH and the percentage of change in the fibrous plaque component (r = 0.559, p = 0.0009) in the unstable AP group. However, this correlation was not observed in the stable AP group ( Figure 2 ). The percentage of changes in the fibrofatty, dense calcium, and necrotic core components did not correlate with the PAF-AH levels in either group. Multivariate regression analyses showed that the percentage of change in PAF-AH levels (β = 0.443, p = 0.003), age (β = 0.396, p = 0.005), and the presence of hypertension (β = 0.280, p = 0.04) were significant predictors associated with the percentage of change in the fibrous plaque component in patients with unstable AP ( Table 5 ).
| Variable | Stable AP (n = 83) | Unstable AP (n = 36) | ||||
|---|---|---|---|---|---|---|
| Baseline | Follow-up | p Value | Baseline | Follow-up | p Value | |
| Necrotic core volume index | ||||||
| Absolute value | ||||||
| Mean (mm 3 /mm) | 0.76 ± 0.55 | 0.81 ± 0.57 | 0.33 | 0.70 ± 0.59 | 1.01 ± 0.61 | 0.009 |
| Mean change (mm 3 /mm) | 0.05 ± 0.49 | 0.30 ± 0.65 ∗ | ||||
| Relative value | ||||||
| Mean (%) | 14.8 ± 8.2 | 15.5 ± 6.5 | 0.47 | 12.0 ± 8.1 | 19.3 ± 8.7 ∗ | 0.0004 |
| Mean change (%) | 0.7 ± 8.6 | 7.2 ± 11.1 † | ||||
| Fibrofatty volume index | ||||||
| Absolute value | ||||||
| Mean (mm 3 /mm) | 1.01 ± 0.99 | 0.80 ± 0.71 | 0.01 | 1.22 ± 0.87 | 0.87 ± 0.81 | 0.01 |
| Mean change (mm 3 /mm) | −0.20 ± 0.64 | −0.35 ± 0.83 | ||||
| Relative value | ||||||
| Mean (%) | 17.2 ± 9.0 | 14.3 ± 7.7 | 0.006 | 21.1 ± 10.5 | 14.4 ± 8.8 | 0.005 |
| Mean change (%) | 2.9 ± 9.4 | 6.6 ± 13.4 | ||||
| Fibrous volume index | ||||||
| Absolute value | ||||||
| Mean (mm 3 /mm) | 3.22 ± 1.76 | 3.17 ± 1.61 | 0.62 | 3.47 ± 1.99 | 3.04 ± 1.78 | 0.002 |
| Mean change (mm 3 /mm) | −0.04 ± 0.81 | −0.42 ± 0.76 ∗ | ||||
| Relative value | ||||||
| Mean (%) | 59.6 ± 8.3 | 60.6 ± 7.6 | 0.3 | 60.2 ± 9.6 | 55.1 ± 9.0 † | 0.003 |
| Mean change (%) | 1.0 ± 8.7 | −5.1 ± 9.5 † | ||||
| Dense calcium volume index | ||||||
| Absolute value | ||||||
| Mean (mm 3 /mm) | 0.44 ± 0.43 | 0.52 ± 0.46 | 0.03 | 0.41 ± 0.39 | 0.62 ± 0.59 | <0.0001 |
| Mean change (mm 3 /mm) | 0.07 ± 0.31 | 0.21 ± 0.27 ∗ | ||||
| Relative value | ||||||
| Mean (%) | 8.3 ± 5.7 | 9.5 ± 5.5 | 0.04 | 6.7 ± 5.1 | 11.2 ± 7.8 | <0.0001 |
| Mean change (%) | 1.2 ± 5.3 | 4.6 ± 4.9 ‡ | ||||
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