Some investigations have looked into the ability of measurements of apolipoprotein B/apolipoprotein A-I (apoB/apoA-I) ratio to predict cardiovascular events. We hypothesized that a decrease in the apoB/apoA-1 ratio by statin therapy would act on suppression of coronary plaque progression. A 6-month prospective study was conducted of 64 patients with coronary artery disease treated with pravastatin. The plaque volume, assessed by volumetric intravascular ultrasonography, had decreased significantly by 12.6% (p <0.0001 vs baseline). Although a significant decrease of 6.4% and 14.6% was found in the serum level of apoB and the apoB/apoA-1 ratio (p = 0.0001 and p <0.0001, respectively, vs baseline), a significant increase of 14.0% of and 12.0% in the level of apoA-I and apoA-II (both p <0.0001 vs baseline). No significant changes were found in the level of apoC-II or apoE. A stepwise regression analysis revealed that the change in the apoB/apoA-1 ratio was an independent predictor of the change in coronary plaque volume (β coefficient 0.386; p = 0.0023). In conclusion, our results have indicated that the decrease in the apoB/apoA-I ratio is a simple predictor for coronary atherosclerotic regression: the lower the apoB/apoA-I ratio, the lower the risk of coronary atherosclerosis.
In several large-scale studies, the apolipoprotein B/apolipoprotein A-I (apoB/apoA-I) ratio has been shown to be strongly related to the risk of myocardial infarction, stroke, and other cardiovascular disease. The apoB/apoA-I ratio might integrate information about the potential for cardiovascular disease risk better than any other lipid or lipoprotein index. However, the relation between apoB/apoA-1 ratio and coronary atherosclerosis in statin-treated patients with coronary artery disease (CAD) has never been fully investigated. We hypothesized that decreasing the apoB/apoA-I ratio using statin therapy would act on suppressing coronary plaque progression. The purpose of the present study was to investigate the effects of statin on the serum levels of apolipoproteins and the apoB/apoA-I ratios and to clarify the relation between the apoB/apoA-I ratios and the inhibition of the progression of coronary atherosclerosis as determined by intravascular ultrasound (IVUS) imaging in patients with CAD.
Methods
The present study was a 6-month prospective observational study conducted at Nihon University Surugadai Hospital to investigate the association between change in the coronary atherosclerotic plaque volume and changes in the serum levels of apolipoprotein parameters (baseline to 6 months after treatment and the changes from baseline) in patients with CAD. Patients with stable CAD who had undergone percutaneous coronary intervention after serial volumetric analysis by IVUS imaging and who underwent IVUS imaging again 6 months later were enrolled in the present study. The primary efficacy parameter was regarded as the percentage of change in coronary plaque volume.
Immediately after the first IVUS examination, pravastatin therapy was initiated at a starting dose of 10 or 20 mg in patients with a serum low-density lipoprotein (LDL) cholesterol level <140 or ≥140 mg/dl, respectively. Subsequently, the patients’ LDL cholesterol levels were monitored, and the dose of pravastatin was adjusted to maintain a LDL cholesterol level of ≤100 mg/dl throughout the course of the study. All patients also received dietary and lifestyle-modification counseling.
Patients who underwent coronary angiography at our hospital from July 3, 2007 to December 31, 2008 were considered for enrollment in the present study. All the coronary angiography procedures were performed because of clinical indications, typically ischemic chest pain or an abnormal finding on a functional study, such as exercise testing or nuclear scintigraphy. Patients were enrolled in the present study if their angiographic results revealed at least one obstruction with an angiographic luminal diameter narrowing of ≥25% in any coronary vessel.
Patients were not enrolled in the present study if they met any of the following exclusion criteria: acute coronary syndrome, narrowing of the left main coronary artery (luminal diameter ≥50%), left ventricular ejection fraction <40%, hepatic or renal dysfunction (creatinine ≥1.5 mg/dl, and alanine aminotransferase and aspartate aminotransferase of ≥2 times normal), inflammatory disease, known malignant disease, or a history of lipid-lowering drug use. Any baseline level of LDL cholesterol was permitted; however, patients with uncontrolled triglyceride levels (<300 mg/dl) or poorly controlled diabetes (glycosylated hemoglobin levels <10%) were not enrolled.
A total of 84 patients were screened, and 64 patients were ultimately enrolled. All the enrolled patients had acceptable baseline IVUS results and were treated with pravastatin. Of the 84 patients, 10 were withdrawn from the study because of the development of adverse events (5 cases of myalgia and 5 cases of liver dysfunction), and 10 were withdrawn because the post-treatment IVUS results were not available. Thus, the final analysis included 64 patients. The ethics committee of our institution approved the study.
After percutaneous coronary intervention (PCI), the IVUS examinations were performed using a CVIS system (Atlantis SR Plus 40 MHz, Boston Scientific, Maple Grove, Minnesota). Before the IVUS examination, the arterial blood pressure was measured, and isosorbide dinitrate was administered directly into the coronary artery at a dose of 1 to 2 mg. A guidewire was then inserted as far as possible into the PCI-treated artery, and the IVUS catheter was inserted. The location of the transducer was checked fluoroscopically, and images taken inside the coronary artery at the rate of 0.5 mm/s with a motorized pullback device were recorded on an S-VHS tape.
The plaque area was defined as the difference between the cross-sectional vessel area (the area lined by the tunica media and inner layers) and the cross-sectional lumen area (the area lined by the innermost layer of the tunica intima). The “on-line” mode was selected and the interframe distance of the IVUS image was set at 0.1 mm. Images from the S-VHS videotape were then fed in. Subsequently, the baseline 3-dimensional images and the 3-dimensional images taken after 6 months were displayed in parallel on a computer screen, in the “off-line” mode, to determine the sites of measurement. Using a Netra 3-dimensional IVUS system (ScImage, Los Altos, California), the cross-sectional vessel, lumen, and plaque areas were measured. These 3 areas were separately totaled to yield the vessel volume, lumen volume, and plaque volume, respectively. The sites of IVUS measurement were selected in insignificantly narrowed side branches of the coronary artery. To minimize the influence of the PCI, only lesions ≥10 mm away from the PCI site were selected for the measurements.
The percentage of changes in the plaque volume after 6 months of pravastatin therapy was calculated using the following equation: Δ plaque volume = (plaque volume at 6 months − baseline plaque volume) / baseline plaque volume × 100. An independent investigator, unaware of the point of investigation, measured the vessel parameters. An analysis of the intraobserver and interobserver variability of the vessel parameters showed high reproducibility (r = 0.94 to 0.97 and r = 0.92 to 0.96, respectively).
Fasting blood samples were collected in the morning before the angiographic examinations. All the measurements of the laboratory chemical parameters were conducted at baseline were repeated after 6 months of treatment. The serum levels of total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured using standard methods. Serum apolipoprotein levels were determined by turbidimetric latex agglutination assays (Daiichi Pure Chemicals, Tokyo, Japan). The non-HDL cholesterol concentration was calculated as the total cholesterol minus the HDL cholesterol.
Data are expressed as the mean ± SD for continuous variables and as percentages for discrete variables. A paired t test was used to compare the changes in the variables measured from baseline to 6 months later. Because the data for the total vessel volume, lumen volume plaque volume, and serum triglycerides did not show a normal distribution, the data are expressed as medians (interquartile ranges). The Wilcoxon signed rank test was used to compare the differences in the vessel parameters between the baseline values and those at the examination 6 months later.
Univariate linear and multiple stepwise regression analyses with the change in plaque volume as the dependent variable was performed to determine the apolipoprotein parameters independently associated with coronary atherosclerosis. A p value of <0.05 was considered statistically significant. All statistical analyses were performed using the Statistical Package for Social Sciences for Windows, version 12.0.1, software (SPSS, Chicago, Illinois).
Results
No serious adverse reactions to pravastatin or other drugs were observed in any of the patients, and no coronary events occurred during the study period. The mean pravastatin dose was 12.5 ± 3.2 mg/day. The patient characteristics are listed in Table 1 .
| Characteristic | Value |
|---|---|
| Gender | |
| Male | 54 (84%) |
| Female | 10 (16%) |
| Age (years) | 63 ± 10 |
| Risk factors | |
| Hypertension | 44 (69%) |
| Diabetes mellitus | 17 (27%) |
| Smoking history | |
| Never | 12 (18%) |
| Current | 41 (64%) |
| Quit | 12 (18%) |
| Body mass index (kg/m 2 ) | 24 ± 3.1 |
| No. of narrowing coronary arteries | |
| 1 | 36 (57%) |
| 2 or 3 | 28 (43%) |
| Target plaque location | |
| Left anterior descending artery | 32 (50%) |
| Left circumflex coronary artery | 13 (20%) |
| Right coronary artery | 19 (30%) |
| Coronary artery intervention | |
| Balloon angioplasty | 13 (20%) |
| Stent | 51 (80%) |
| History | |
| Previous myocardial infarction | 2 (3%) |
| Stroke | 3 (5%) |
| Concomitant medications | |
| Aspirin | 64 (100%) |
| Angiotensin-converting enzyme inhibitors | 17 (27%) |
| Angiotensin II receptor blockers | 14 (22%) |
| Calcium channel blockers | 26 (41%) |
| β Blockers | 25 (39%) |
| Nitrates | 22 (35%) |
Before pravastatin treatment, the mean total cholesterol level was 204 ± 39 mg/dl, the mean LDL cholesterol level was 130 ± 38 mg/dl, the mean HDL cholesterol level was 47 ± 11 mg/dl, and the median triglyceride level was 125 mg/dl (range 90 to 194). After 6 months of pravastatin therapy, the corresponding levels had changed to 185 ± 29, 103 ± 26, 53 ± 13, and 118 (range 87 to 174) mg/dl. The reductions in the total cholesterol and LDL cholesterol levels after pravastatin therapy for 6 months were significant (both p <0.0001 vs baseline values), and the increase in the HDL cholesterol level was also significant (p <0.001 vs baseline value). The triglycerides level remained unchanged (p = 0.54 vs baseline value).
A significant increase in the serum apoA-I (p <0.0001) and apoA-II (p <0.0001) and a significant decrease in the serum apoB (p = 0.0001), and apoB/apoA-I (p <0.0001) after 6 months of treatment with pravastatin. No significant changes were found in the serum levels of apoC-II (p = 0.077) and apoE (p = 0.34; Table 2 ).
| Variable | Baseline | At 6 mo | Δ | p Value |
|---|---|---|---|---|
| Apolipoprotein A-I (mg/dl) | 122 ± 18 | 135 ± 20 | 14.0 ± 18.3 | <0.0001 |
| Apolipoprotein A-II (mg/dl) | 24.3 ± 4.30 | 26.7 ± 5.2 | 12.0 ± 19.1 | <0.0001 |
| Apolipoprotein B (mg/dl) | 96 ± 18 | 88 ± 15 | −6.4 ± 20.1 | 0.0001 |
| Apolipoprotein B/apolipoprotein A-I ratio | 0.81 ± 0.19 | 0.67 ± 0.15 | −14.6 ± 19.3 | <0.0001 |
| Apolipoprotein C-II (mg/dl) | 4.17 ± 1.70 | 3.85 ± 1.91 | −8.9 ± 36.0 | 0.077 |
| Apolipoprotein E (mg/dl) | 4.00 ± 1.04 | 3.99 ± 1.27 | 1.8 ± 27.4 | 0.999 |
The average lesion length was 10.5 ± 8.5 mm. The plaque volume was significantly reduced by 12.6 ± 20.2%, from 38.5 mm 3 (range 22.7 to 66.3) at baseline to 33.5 mm 3 (range 19.8 to 58.2) at the 6-month follow-up examination (p <0.0001). The lumen volume was significantly increased by 9.9 ± 22.3% from 43.6 mm 3 (range 27.3 to 68.8) at baseline to 50.2 mm 3 (range 31.9 to 73.32) at the 6-month follow-up examination (p = 0.005). The change in the total vessel volume from 88.5 mm 3 (range 53.9 to 134.6) at baseline to 89.7 mm 3 (range 56.6 to 118.0) at the 6-month follow-up examination was not statistically significant (p = 0.29; Figure 1 ).
To establish the independent value in predicting the inhibition of the development of coronary atherosclerosis, according to the determination of their significance in the univariate linear regression analysis with apolipoprotein parameters, 5 variables (6-month apoA-I, 6-month apoB/apoA-I, ΔapoA-I, ΔapoA-II, and ΔapoB/apoA-I) were entered into the multivariate model in a stepwise fashion. The results of the stepwise regression analysis showed that the ΔapoB/apoA-I ratio was an independent predictor of the change in the coronary plaque volume, suggesting that the reduction in ΔapoB/apoA-I was closely associated with regression of coronary atherosclerosis ( Tables 3 and 4 ). A correlation between the change in coronary plaque volume and the ΔapoB/apoA-I ratio is shown in Figure 2 .
| Variable | Baseline | At 6 mo | Δ | |||
|---|---|---|---|---|---|---|
| r | p Value | R | p Value | r | p Value | |
| Apolipoprotein A-I | 0.074 | 0.565 | −0.378 | 0.0016 | −0.365 | 0.0040 |
| Apolipoprotein A-II | 0.147 | 0.251 | −0.180 | 0.146 | −0.336 | 0.0087 |
| Apolipoprotein B | −0.135 | 0.293 | 0.013 | 0.919 | 0.141 | 0.284 |
| Apolipoprotein B/apolipoprotein A-I ratio | −0.153 | 0.230 | 0.246 | 0.046 | 0.386 | 0.0023 |
| Apolipoprotein C-II | 0.135 | 0.401 | 0.003 | 0.987 | −0.205 | 0.315 |
| Apolipoprotein E | 0.064 | 0.633 | 0.042 | 0.753 | −0.098 | 0.508 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
