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J Am Coll Cardiol, 1998; 32:1648-1656 © 1998 by the American College of Cardiology Foundation |
* Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Hospital, Stockholm, Sweden
Department of Emergency and Cardiovascular Medicine, Karolinska Hospital, Stockholm, Sweden
Department of Cardiology, Karolinska Hospital, Stockholm, Sweden
Department of Thoracic Radiology, Karolinska Hospital, Stockholm, Sweden
|| Division of Cardiology, Department of Medicine, Danderyd Hospital, Stockholm, Sweden
Manuscript received March 30, 1998; revised manuscript received July 1, 1998, accepted July 24, 1998.
Address for correspondence: Dr. Anders Hamsten, King Gustaf V Research Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden
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Abstract |
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Background. BECAIT, the first double-blind, placebo-controlled, randomized serial angiographic trial of a fibrate compound, showed that progression of focal coronary atherosclerosis in young survivors of myocardial infarction could be retarded by bezafibrate treatment.
Methods. A total of 92 dyslipoproteinemic men who had survived a first myocardial infarction before the age of 45 years were randomly assigned to treatment for 5 years with bezafibrate (200 mg three times daily) or placebo; 81 patients underwent baseline and at least one post-treatment coronary angiography.
Results. In addition to the decrease in very low density lipoprotein (VLDL) cholesterol (–53%) and triglyceride (–46%) and plasma apolipoprotein (apo) B (–9%) levels, bezafibrate treatment resulted in a significant increase in high density lipoprotein-3 (HDL3) cholesterol (+9%) level and a shift in the low density lipoprotein (LDL) subclass distribution toward larger particle species (peak particle diameter +0.32 nm). The on-trial HDL3 cholesterol and plasma apo B concentrations were found to be independent predictors of the changes in mean minimum lumen diameter (r = –0.23, p < 0.05), and percent (%) stenosis (r = 0.30, p < 0.01), respectively. Decreases in small dense LDL and/or VLDL lipid concentrations were unrelated to disease progression.
Conclusions. Our results suggest that the effect of bezafibrate on progression of focal coronary atherosclerosis could be at least partly attributed to a rise in HDL3 cholesterol and a decrease in the total number of apo B-containing lipoproteins.
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A significant proportion of patients with precocious CAD have hypertriglyceridemic lipoprotein phenotypes (9). Until recently, no controlled coronary angiographic trial had focused on the effects of intervention directed primarily toward lowering of triglyceride-rich lipoproteins. The Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) was the first double-blind, placebo-controlled, randomized serial angiographic trial of a fibrate compound (10). The BECAIT study showed that progression of focal coronary atherosclerosis in young survivors of myocardial infarction could be retarded by bezafibrate treatment and indicated that the treatment effect on the primary study end point (change in mean minimum lumen diameter [MLD]) was similar to the one obtained with statins in the Multicentre Anti-Atheroma Study (MAAS) (11) and the Regression Growth Evaluation Statin Study (REGRESS) (12). The angiographic effects observed in the bezafibrate-treated patients were accompanied by significant reductions in very low density lipoprotein (VLDL) cholesterol (–35%) and triglycerides (–31%) and an increase in HDL cholesterol (+9%), whereas LDL cholesterol concentrations did not change.
In the present report from BECAIT, treatment effects on lipids, lipoproteins, lipoprotein subfractions and apolipoproteins are presented in detail, and on-trial serum levels are related to the angiographic outcome measurements. It was hypothesized that the concentrations of triglyceride-rich lipoproteins and/or HDL, along with that of LDL cholesterol, would predict the progression of coronary lesions in the course of the study.
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Methods |
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Blood sampling was performed every 4 months for determinations of serum cholesterol, triglycerides and HDL cholesterol. Cholesterol and triglyceride concentrations in VLDL and LDL and serum apolipoprotein (apo) A-I, B and E levels were measured on samples taken once a year. The LDL particle size distribution was determined on serum samples that had been drawn at baseline and 2 and 5 years after randomization. Selective coronary angiography was repeated after 2 and 5 years.
Lipid, lipoprotein and apolipoprotein analyses. The major serum lipoproteins—that is, VLDL, LDL and HDL—were determined by a combination of preparative ultracentrifugation and precipitation of apo B-containing lipoproteins, followed by lipid analyses (14). Cholesterol (15) and triglycerides (16) were quantified after chloroform-methanol extraction (17) of whole serum, the VLDL fraction, the infranatant after ultracentrifugation (containing LDL and HDL), and the supernatant (HDL) after precipitation. The HDL3 was obtained as a bottom fraction in which cholesterol was determined after one preparative ultracentrifugal spin at a density of 1.125 kg/l (18). Total HDL was obtained as described above. Next, HDL2 cholesterol was then calculated as the difference between total HDL and HDL3 cholesterol. Serum lipoprotein (a) [Lp(a)] was measured by an enzyme immunoassay (Tint Elize Lp(a), Biopool). The assay utilizes affinity-purified polyclonal antibodies raised against purified Lp(a) (19). Serum apos A-I and B were determined by commercially available radioimmunoassays, and apo E by enzyme immunoassay (20).
LDL particle size distribution. Serum samples containing 1 µg of LDL cholesterol were applied to a 3% to 7.5% polyacrylamide gradient gel. They had been kept frozen at –70°C and were applied immediately after thawing at room temperature. All three samples from an individual patient (taken at baseline and 2 and 5 years after randomization) were applied to the same gel. Three standard reference proteins were also applied to each gel (21). Electrophoresis was run using Tris 90 mmol/liter, boric acid 80 mmol/liter and Na2EDTA 3 mmol/liter, pH 8.35, as running buffer (22). A double staining was performed. First a lipid staining was made with Sudan Black 0.5% and zinc acetate 2.4% for 2 h at 37°C, followed by destaining with 30% isopropanol; then, a protein staining was made with 0.04% Coomassie Brilliant Blue G-250 (Serva, Heidelberg, Germany) and 3.5% perchloric acid for 15 min, followed by destaining with 7% acetic acid. The gels were scanned twice (after the protein and lipid staining, respectively) by a laser densitometer (Ultroscan XL, Pharmacia-LKB) linked to a personal computer, and the area under the curve was calculated automatically with the use of the GelScan XL software package (Pharmacia-LKB). A linear regression was made for each gel between the location of the three reference proteins on the gel and their respective sizes. Based on the regression line and the linear profile of the gel, migration distance in the gel could be converted into LDL particle diameter size. Because the size of the gels did not change between the two stainings, the migration of reference proteins was used for determining LDL peak particle size and percent (%) small LDL from the densitometric scans of the lipid-stained gels. The LDL particles with a diameter less than 22.8 nm were defined as small LDL. The coefficients of variation for LDL peak particle size and for percentage small LDL were: intraassay 1.3% and 2.7%, interassay 2.3% and 6.6%, respectively.
Coronary angiography. Coronary angiographies were done by the percutaneous transfemoral technique and recorded on 35-mm cine film with the aid of cesium-iodode-activated image intensifiers, as described (10,23,24). The minimum lumen diameter (MLD, which reflects focal atherosclerosis) was measured at the site of the most severe atherosclerotic lesion in each segment that reduced the lumen diameter by at least 20%. Mean segment diameter (MSD) was calculated in all coronary segments irrespective of the presence of visually detectable atherosclerosis, as an indicator of diffuse as well as focal atherosclerosis. Percentage diameter stenosis (% stenosis) was calculated from the most narrow lesion in each segment with a diameter reduction of at least 20%.
Statistical analysis.
Continuous variables are presented as mean ± SD or median and interquartile range if not normally distributed; categorical variables are presented as numbers and percentages. The individual values of skewed variables were transformed to their natural logarithms before statistical tests. Per-patient means of MLD, MSD and % stenosis were calculated for baseline and repeat angiograms. The angiographic outcome variables were median change (
) between the baseline and the last follow-up angiogram for MLD and MSD, and between the last follow-up and the baseline angiogram for % stenosis. Only corresponding segments from the baseline and follow-up angiograms were used in the assessment of angiographic change. Student’s unpaired t test was used for comparing baseline characteristics between the two treatment groups. The responses of lipoprotein-related variables to the study drug over time in the bezafibrate and placebo groups were compared by two-way repeated measures analysis of variance (ANOVA). The disease progression data (MLD, MSD and % stenosis) were used either as continuous variables or divided according to tertiles. The association between baseline clinical characteristics and tertiles of angiographic outcome measurements was evaluated by ANOVA. The association between individual lipoprotein variables and disease progression was first assessed by calculation of univariate Pearson and partial correlation coefficients.
Treatment assignment and the baseline angiographic measurements alone or treatment assignment, baseline angiographic measurement, age, body mass index (BMI), smoking and alcohol consumption were controlled for when calculating partial correlation coefficients. Two multivariate models were then generated by multiple stepwise linear regression analysis to identify lipoprotein variables independently correlating with the angiographic outcome variables. In the first model, treatment assignment and the baseline angiographic measurement were first entered as forced variables, whereas the second model included treatment assignment, baseline angiographic measurement, age, BMI, smoking and alcohol consumption as forced variables. On-trial VLDL cholesterol, LDL cholesterol, HDL2 cholesterol, HDL3 cholesterol, LDL triglycerides, apo B, Lp(a), LDL peak particle size and % small LDL were included in the model as independent variables. Backward elimination of variables was used to establish the final model. All statistical tests were two-sided and p values of less than 0.05 were considered significant.
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Results |
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Treatment effects on lipids, lipoproteins and apolipoproteins. The treatment effect of bezafibrate on the serum levels of lipids and some lipoproteins and apolipoproteins has been published (10). Serum levels observed at baseline and at 1, 2, 3, 4 and 5 years after randomization are shown in Table 1. The baseline levels were generally similar in the two study groups, the exception being the slightly (p = 0.08) higher Lp(a) level in the placebo group. Over the 5-year follow-up, bezafibrate treatment resulted in significant decreases (mean difference between on-treatment mean and baseline serum concentrations) of serum cholesterol (–14%) and triglyceride (–32%) levels, whereas a smaller decrease of serum cholesterol (–5%) and an increase of serum triglycerides (+8%) were observed in the placebo group (p < 0.01 and p < 0.001 for group differences in serum cholesterol and serum triglycerides, respectively) (data not shown). The lowering of serum triglyceride levels in the bezafibrate group was accounted for by the significant lowering of triglycerides in the VLDL fraction (–46%), which was in contrast to the increase in VLDL triglycerides (+11%) in the placebo group (p < 0.001).
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LDL gradient gel electrophoresis.
Table 2 shows baseline, on-trial and values for LDL peak particle size and % small LDL in the two study groups. The LDL peak particle size and % small LDL were measured at baseline and at 2 and 5 years. On-trial values represent the means of the 2- and 5-year measurements; values are differences between on-treatment means and baseline values. Bezafibrate treatment resulted in significant changes in both LDL peak particle size (+0.32 nm vs. +0.02 nm in the placebo group, p = 0.0008) and % small LDL (–9.7% vs. –0.3% in the placebo group, p = 0.0002). Thus, LDL peak particle size increased, while % small LDL decreased by bezafibrate treatment in young male postinfarction patients. The treatment effects persisted unattenuated after 5 years (Fig. 1).
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MSD is excluded from the presentation, as this angiographic variable proved to be unrelated to all lipoprotein measurements. Table 3 shows baseline clinical characteristics according to tertiles of the angiographic outcome measurements. The low tertile group comprises patients who progressed least, the high tertile group those who progressed most. The BMI was related to change in % stenosis (% stenosis), that is, patients who progressed less had lower BMI, whereas those who progressed more had higher BMI. The BMI also showed a borderline association with change in MLD (MLD). Also, the baseline MLD was directly related to changes in both MLD and % stenosis. In contrast, baseline % stenosis was inversely related to changes in both MLD and % stenosis; that is, patients with higher values for baseline % stenosis progressed less, while those with lower % stenosis values progressed more.
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MLD and % stenosis. On-trial HDL3 cholesterol levels were inversely related to MLD (r = –0.23, p < 0.05), whereas total apo B level was directly related to % stenosis (r = 0.30, p < 0.01). The inverse HDL3 cholesterol relation to MLD remained significant after control for treatment assignment and the baseline angiographic measurement (r = –0.22, p < 0.05) as did the positive apo B correlation with % stenosis (r = 0.34, p < 0.01). In addition, control for treatment assignment and baseline angiographic status rendered the positive LDL cholesterol correlation with % stenosis statistically significant (r = 0.22, p < 0.05).
Although the inverse relationship between on-trial HDL3 cholesterol concentration and MLD weakened slightly when also BMI, smoking and alcohol consumption were included as covariates (r = –0.18, NS), the on-trial apo B and LDL cholesterol correlations with % stenosis were only marginally affected (r = 0.30, p < 0.01, and r = 0.21, NS, respectively). Of note, the LDL triglyceride content was also directly related to % stenosis (r = 0.26, p < 0.05) after control for the full range of clinical confounders.
Percentage change in serum lipid, lipoprotein and apo concentrations from baseline to mean on-trial levels did not correlate significantly with any of the angiographic outcome variables (partial correlation coefficients were computed with control for treatment assignment, baseline angiographic score, age, BMI, smoking and alcohol consumption).
Multiple stepwise regression analysis was used to study the independent relations of on-trial lipid, lipoprotein and apo measurements to the angiographic outcome measurements (Table 4). Treatment assignment and baseline angiographic score were entered as forced variables in the first model. On-trial HDL3 cholesterol level was found to be independently and inversely related to MLD in this model, accounting for 3% of the multiple R2. Inclusion of other lipoprotein variables did not significantly increase the value of R2. On-trial serum apo B level was independently related to % stenosis in the first model, accounting for 7% of the multiple R2. On-trial HDL3 cholesterol was not retained in the second multivariate model where, in addition to treatment assignment and the basic angiographic measurement, age, BMI, smoking and alcohol consumption were entered as forced variables. In contrast, serum apo B remained independently related to % stenosis also in the second multivariate model, accounting for 5% of the multiple R2. It is notable that baseline angiographic status was by far the strongest determinant of change in angiographic outcome variables.
The on-trial lipid, lipoprotein and apo relationships to changes in coronary lesions, summarized in Table 4, did not alter materially when we also controlled for the baseline lipoprotein measurements.
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Discussion |
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TopAbstractMethodsResultsDiscussionReferences |
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HDL effects. The BECAIT is the first controlled angiographic study demonstrating that treatment with a fibrate compound, bezafibrate, has beneficial effects on progression of focal coronary atherosclerosis (10). This effect could thus at least partly be attributed to a rise in HDL3 cholesterol concentration. Several serial angiographic studies have previously demonstrated an inverse relationship between increase in HDL, or its subfractions, and coronary artery disease progression, using different lipid-lowering treatment modalities. Increase of HDL2a and HDL2b subfractions (by cholestyramine treatment) was first found to be associated with slowing of progression or regression of CAD in the National Heart, Lung and Blood Institute (NHLBI) Type II Coronary Intervention Study (25). Subsequently, increase of HDL cholesterol levels has been linked to retarded progression of disease also in studies using colestipol and/or niacin (26,27), lovastatin (27) and pravastatin (28). It has been suggested that the HDL cholesterol-mediated effect of lipid-lowering treatment is mainly confined to smaller lesions causing <50% diameter stenosis (29). Such lesions dominated in the BECAIT cohort (78% of the lesions), and the bezafibrate effect on disease progression was restricted to mild-to-moderate lesions (30). The inverse association between on-trial HDL3 cholesterol level and disease progression could be explained by the active role of this lipoprotein species in reverse cholesterol transport.
LDL and its particle size distribution. As expected (31), bezafibrate treatment affected the LDL particle size distribution, reducing the small LDL particle subfraction and increasing the LDL peak particle size. The probable mechanism underlying the shift of LDL particles toward greater particle size is inhibition of lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities by bezafibrate (31) as well as a reduction in acceptor lipoproteins for the exchange of core lipid constituents. The decreased production of esterified cholesterol in HDL, and its decreased heteroexchange with triglyceride in larger and lighter LDL, would explain both the increase in LDL triglycerides and the concomitant increase in LDL peak particle size. The % dense LDL was unrelated to progression of both focal and diffuse coronary lesions. This is surprising as a small and dense LDL particle distribution pattern has been firmly linked to CAD (32). In contrast, the LDL triglyceride concentration, reflecting intermediate density lipoprotein (IDL) and larger and triglyceride-enriched LDL particles, was related to progression of distinct stenoses when confounders like smoking, alcohol consumption and BMI were taken into account. This is in agreement with studies that have linked IDL to CAD progression (6,33).
Despite its retarding effect on the further progression of focal coronary atherosclerosis, bezafibrate did not significantly influence the LDL cholesterol levels of the young postinfarction patients. Furthermore, on-trial LDL cholesterol levels were not related to change in mean MLD and only correlated weakly with change in % stenosis. However, it is notable that whole-serum apo B, primarily a marker of LDL particle number (34), was the strongest predictor of progression of distinct stenoses, as reflected by the % stenosis outcome measurement. This is in accord with most previous angiographic studies and suggests that the number of apo B-containing lipoproteins is an important determinant of the progression of focal atherosclerotic lesions and that the decrease in the total number of atherogenic apo B-containing particles seen in bezafibrate-treated patients in BECAIT contributed to the beneficial effect on the further progression of distinct stenoses.
Role of triglyceride-rich lipoproteins. Triglyceride-rich lipoproteins are indicated to be particularly important for the progression of coronary lesions causing (<50% diameter stenosis (5,8), the predominant lesion size in the young postinfarction patients participating in BECAIT (30). The main triglyceride-rich lipoproteins involved in this process are VLDL and their remnants, including IDL. The largest effect of bezafibrate treatment observed in BECAIT was the lowering of VLDL lipid concentrations. However, neither changes in VLDL lipids nor on-trial VLDL lipid levels correlated with the angiographic outcome measurements. This apparent discrepancy is likely to be accounted for by the fact that lipid concentrations in the total (density <1.006 kg/l) VLDL fraction mainly reflect the larger VLDL species, whereas primarily the small (Sf 20–60) VLDL remnants and IDL have been implicated in the progression of CAD (6,33).
Nonlipoprotein effects. Finally, the on-trial lipoprotein concentrations and the changes in individual lipoprotein fractions attributable to bezafibrate only explained part of the disease progression in BECAIT. The remaining part of the bezafibrate effect on CAD progression might have been due to nonlipoprotein mediated effects of the compound. For instance, bezafibrate has favorable effects on blood coagulation and fibrinolysis, which may be at least partly mediated by lowering of the plasma concentrations of triglyceride-rich lipoproteins (35). Of note, the plasma fibrinogen concentration, an established risk factor for CAD, fell substantially in the bezafibrate-treated group in BECAIT (treatment effect –12%) (10). However, the on-trial fibrinogen levels were not related to the angiographic outcome measurements (data not shown). Fibrates, which are gene regulators through activation of the peroxisome proliferator-activated receptor (36), may induce yet unknown protective mechanisms in the vascular wall. Limitations of this study, including the relatively small sample size and the fact that subfractions of triglyceride-rich lipoproteins were not determined directly, also restrict the interpretations of the current data. In particular, IDL was included in the LDL fraction.
Summary and implications. In conclusion, BECAIT is the first controlled angiographic study demonstrating that treatment with a fibrate compound, bezafibrate, has beneficial effects on the progression of focal coronary atherosclerosis. This effect could at least partly be attributed to a bezafibrate-induced rise in HDL3 cholesterol concentration, and a decrease in whole serum apo B, a marker of LDL particle number, which proved to be a strong predictor of progression of distinct stenoses. Furthermore, support was obtained for the notion that IDL is implicated in progression of CAD. Analysis of the lipoprotein relations to the angiographic outcome suggests that bezafibrate also exerts beneficial nonlipoprotein-mediated effects in patients with manifest CAD. In all, BECAIT provides further evidence that LDL and its cholesterol content are not the sole determinants of CAD progression and shows that bezafibrate treatment, mainly affecting triglyceride-rich lipoproteins and HDL, retards the further development of coronary lesions in patients with precocious CAD.
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Acknowledgments |
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