Minimum Obstruction Diameter Research Articles

Mannose binding lectin 2 haplotypes do not affect the progression of coronary atherosclerosis in men with proven coronary artery disease treated with pravastatin

ObjectiveMannose binding lectin (MBL) is one of the three initiators of complement activation. Polymorphisms of the MBL2 gene and its promoter, and especially haplotypes, determine MBL plasma levels. MBL deficiency has been associated with the development of atherosclerosis. We evaluated whether the rate of angiographic progression of coronary atherosclerosis during pravastatin treatment was associated with MBL2 haplotypes in REGRESS, a placebo-controlled 2 years intervention study. MethodsThree polymorphic sites in exon 1 (rs1800450, rs1800451 and rs5030737) of the MBL2 gene and 2 sites (rs7096206 and rs11003125) in the promoter region were genotyped in 398 subjects. Genotyping was performed using Applied Biosystems® TaqMan® Genotyping Assays. We divided the group in high, intermediate and low MBL2 secretor haplotypes. Quantitative coronary angiography was performed. Endpoints were mean segment diameter (MSD) and minimum obstruction diameter (MOD) established by quantitative coronary angiography. ResultsAt inclusion, 50.1, 31.7 and 17.6% of the patients in the REGRESS cohort carried the high, intermediate and low MBL2 secretor haplotypes, respectively. In 0.6% of the patients, the haplotype was not informative. There were no baseline differences between the MBL2 haplotypes for age, BMI, lipid levels, leukocyte counts, CRP, MSD and MOD. The intermediate MBL2 placebo group showed the greatest increase in MSD compared to the low MBL2 group (P=0.03). No difference was found for the change in MOD. No significant interaction between MBL2 haplotype groups and pravastatin therapy was observed. ConclusionIn men with proven coronary artery disease, MBL2 secretor haplotypes are not associated to the rate of progression of coronary sclerosis nor does pravastatin treatment influence progression based on MBL2 haplotypes.

Genetic variation in the rate-limiting enzyme in cholesterol catabolism (cholesterol 7α-hydroxylase) influences the progression of atherosclerosis and risk of new clinical events

CHD (coronary heart disease) is a complex disorder which is, in part, related to serum cholesterol levels. The rate-limiting enzyme in the catabolism of cholesterol into bile acids is CYP7A1 (cholesterol 7alpha-hydroxylase). The effect of the CYP7A1 A-278C promoter polymorphism on the progression of atherosclerosis, risk of a new clinical event and the influence of this variant on cholesterol-lowering therapy was investigated in 715 male patients with coronary atherosclerosis participating in REGRESS (Regression Growth Evaluation Statin Study). Genotype distributions were as follows: 283 with AA; 330 with AC and 102 with CC. There were no significant differences in baseline characteristics and serum lipids between genotypes. After 2 years, CC carriers had more progression of diffuse and focal atherosclerosis compared with AA carriers, as indicated by a larger decrease in MSD (mean segment diameter; 0.09 mm compared with 0.06 mm respectively; P=0.009) and MOD (minimum obstruction diameter; 0.09 mm compared with 0.05 mm respectively; P=0.024). Inclusion of risk factors for CHD in the model showed the same trend, although not significant for MOD (P=0.01 for MSD, and P=0.06 for MOD). In addition, CC carriers had an almost 2-fold higher risk of a new clinical event compared with AA carriers [RR (95% CI) 1.93 (1.11-3.36); P=0.02; where RR is relative risk and CI is confidence interval]. Inclusion of risk factors for CHD in the model showed the same trend, although not significant [RR (95% CI), 1.74 (0.96-3.12); P=0.06]. In conclusion, we present evidence that the CC variant of the A-278C polymorphism in the rate-limiting enzyme in the catabolism of cholesterol, CYP7A1, increases the progression of atherosclerosis and possibly the risk of a new clinical event.

A randomized, open-label, comparative study of simvastatin plus diet versus diet alone on angiographic retardation of coronary atherosclerosis in adult Japanese patients: Japanese utilization of simvastatin therapy (JUST) study

Background: Cholesterol-lowering therapy reduces the risk of cardiovascular events by slowing the progression or enhancing the regression of coronary atherosclerosis. Objective: This study assessed the effects of simvastatin 10 mg/d on progressive coronary atherosclerosis in Japanese patients with coronary artery disease and mild to moderate hypercholesterolemia. Methods: In a 2-year, open-label comparative study, patients with coronary atherosclerotic lesions (⩾50% diameter stenosis) and serum total cholesterol levels ⩾200 and ⩽280 mg/dL were randomly assigned to 2 groups: 1 group received simvastatin 10 mg/d taken orally with diet (S-D) and the other group was assigned to diet alone (D). Atherosclerotic progression in coronary segments was compared in the 2 groups using quantitative coronary angiography (QCA). QCA measurements were done under blinded conditions. The study's primary end point was the comparison of mean changes in each segment's minimum obstruction diameter (MOD) or mean segment diameter (MSD) between the S-D group and the D group. Results: A total of 299 patients were randomized, 146 to the S-D group and 153 to the D group. Mean (SD) age was 58.7 (8.0) years and mean (SD) total cholesterol level was 232.6 (21.6) mg/dL at baseline. After 2 years, serum low-density lipoprotein cholesterol levels decreased by 31.9% in the S-D group and by 2.0% in the D group. QCA showed significant stenotic progression in the D group, with reductions in MOD and MSD both by per-segment-based ( P < 0.001 and P = 0.004, respectively) and per-patient-based (both P = 0.004) analyses. Although simvastatin treatment suppressed atherosclerotic progression in both per-segment- and per-patient-based analyses, significant reductions were found only in MOD values with per-segment-based analyses ( P = 0.034). In a categorical approach, progression was found in significantly fewer segments in the S-D group compared with the D group (MOD, P = 0.014; MSD, P = 0.003), with odds ratios (S-D) group/D group) of 0.571 for MOD and 0.390 for MSD. Significantly fewer patients with angiographic progression were observed in the S-D group (23.3%) compared with the D group (39.4%) with respect to MSD ( P = 0.02). Conclusion: Two years of treatment with simvastatin 10 mg/d improved patients' lipid profile and retarded coronary atherosclerotic progression in Japanese patients with coronary artery disease and mild to moderate hypercholesterolemia.

Randomized, controlled trial of secondary prevention of coronary sclerosis in normocholesterolemic patients using pravastatin: final 5-year angiographic follow-up of the Prevention of Coronary Sclerosis (PCS) study

Background: The potential benefit of cholesterol-lowering therapy for normocholesterolemic patients with coronary artery disease (CAD) has not been clarified. The Prevention of Coronary Sclerosis (PCS) Study was designed to evaluate the effect of pravastatin on secondary prevention of progression of CAD in normocholesterolemic patients for a period of 5 years. Methods: A total of 329 patients with CAD were enrolled. Normocholesterolemic patients were defined by a serum total cholesterol (TC) level of 180–219 mg/dl. Patients in this group were randomized into pravastatin and dietary control groups. Patients whose serum TC level fell outside the normal range were divided into a high-cholesterol reference group (TC≥220 mg/dl) and a low-cholesterol reference group (TC<180 mg/dl). Patients in the pravastatin and high-cholesterol groups received pravastatin 10 mg/day. Coronary angiography was performed at baseline, 2 years, and 5 years and analyzed by quantitative coronary arteriography. Angiographic coronary progression was evaluated by minimum obstruction diameter (MOD) and mean segment diameter (MSD). Results: At 5 years, change in MOD was significantly (change, P=0.033; change/years, P=0.032) less in the pravastatin group (−0.04±0.17 mm) than in the dietary control group (−0.16±0.27 mm). Although a similar trend was observed in the MSD results, the differences were not significant. Conclusion: Long-term angiographic data show that cholesterol-lowering therapy by pravastatin prevents progression of coronary atherosclerosis in normocholesterolemic patients with CAD.

Randomized, controlled trial of secondary prevention of coronary sclerosis in normocholesterolemic patients using pravastatin: two-year follow-up of the prevention of coronary sclerosis study

Background: Reducing serum total cholesterol (TC) levels using 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in hypercholesterolemic patients has been shown to reduce the incidence of complications of coronary heart disease (CHD). However, few data are available on the potential benefit of reductions in serum cholesterol levels in normocholesterolemic patients with coronary atherosclerosis. Objective: The Prevention of Coronary Sclerosis Study is a single-center study designed to assess the effect of treatment with the HMG-CoA reductase inhibitor pravastatin on progression and regression of angiographically documented coronary atherosclerosis in normocholesterolemic patients with CHD. Methods: A total of 329 patients aged <70 years with CHD were enrolled and classified into 1 of 3 groups based on serum TC level: group 1, TC ≥220 mg/dL; group 2, TC 180–219 mg/dL; and group 3, TC <180 mg/dL. Patients in group 2 were randomized to 1 of 2 subgroups, 2a or 2b. Patients in groups 1 and 2a were given pravastatin 10 mg/d; patients in groups 2b and 3 did not receive cholesterol-lowering drugs. The subsequent coronary events of patients were followed for 2 years and reexamined by coronary angiography (CAG). Both baseline and follow-up CAGs were analyzed by quantitative coronary arteriography at a central laboratory. Results: Decreases in both mean segment diameter (MSD) and minimum obstruction diameter (MOD) in group 2a were significantly less than those in the control group 2b ( P = 0.015 and P = 0.023, respectively). The effects on MSD and MOD in group 2a and the low-cholesterol reference group 3 were similar. The incidence of clinical events was 8.9%, 3.7%, 12.1%, and 10.0% in groups 1, 2a, 2b, and 3, respectively, with no significant differences in rates between groups 2a and 2b. Conclusion: The results of this study suggest that cholesterol-lowering therapy with pravastatin may prevent progression of coronary atherosclerosis in normocholesterolemic patients with CHD.

Common genetic variation in ABCA1 is associated with altered lipoprotein levels and a modified risk for coronary artery disease.

Low plasma HDL cholesterol (HDL-C) is associated with an increased risk of coronary artery disease (CAD). We recently identified the ATP-binding cassette transporter 1 (ABCA1) as the major gene underlying the HDL deficiency associated with reduced cholesterol efflux. Mutations within the ABCA1 gene are associated with decreased HDL-C, increased triglycerides, and an increased risk of CAD. However, the extent to which common variation within this gene influences plasma lipid levels and CAD in the general population is unknown. We examined the phenotypic effects of single nucleotide polymorphisms in the coding region of ABCA1. The R219K variant has a carrier frequency of 46% in Europeans. Carriers have a reduced severity of CAD, decreased focal (minimum obstruction diameter 1.81+/-0.35 versus 1.73+/-0.35 mm in noncarriers, P:=0.001) and diffuse atherosclerosis (mean segment diameter 2.77+/-0.37 versus 2.70+/-0.37 mm, P:=0.005), and fewer coronary events (50% versus 59%, P:=0.02). Atherosclerosis progresses more slowly in carriers of R219K than in noncarriers. Carriers have decreased triglyceride levels (1.42+/-0.49 versus 1.84+/-0.77 mmol/L, P:=0.001) and a trend toward increased HDL-C (0.91+/-0.22 versus 0.88+/-0.20 mmol/L, P:=0.12). Other single nucleotide polymorphisms in the coding region had milder effects on plasma lipids and atherosclerosis. These data suggest that common variation in ABCA1 significantly influences plasma lipid levels and the severity of CAD.

The −323Ins10 Polymorphism for Factor VII Is Not Associated with Coronary Atherosclerosis in Symptomatic Men

Elevated factor VII coagulant activity (FVII:C) has been associated with an increased risk of ischaemic heart disease, particularly for fatal events. Results of studies on the association between FVII:C and atherosclerosis are not consistent. FVII:C levels are influenced by several environmental factors and by genetic factors. One of the genetic factors is the −323Ins10 polymorphism in the promoter region of the factor VII gene, which is strongly related to FVII:C, and thus may be associated with ischaemic heart disease. We studied the association of this polymorphism with the severity and progression of atherosclerosis. In 511 male patients of the Regression Growth Evaluation Statin Study, the genotype for the −323Ins10 polymorphism was determined. The minimum obstruction diameter and the mean segment diameter were determined at baseline and after a 2-year follow-up period, and new lesion formation was assessed as well. Cardiovascular events were recorded. No relationship was observed between the −323Ins10 polymorphism and angiographic measures of disease progression, nor on the risk of new cardiovascular events. The results suggest that there is no association between the −323Ins10 polymorphism for factor VII and the severity or progression of coronary atherosclerosis in male patients with symptomatic coronary artery disease.

Modulation of Lipoprotein(a) Atherogenicity by High Density Lipoprotein Cholesterol Levels in Middle-Aged Men With Symptomatic Coronary Artery Disease and Normal to Moderately Elevated Serum Cholesterol

Objectives. This study sought to examine whether lipoprotein(a) levels predict coronary artery lumen changes in patients with symptomatic coronary artery disease (CAD) and normal to moderate hypercholesterolemia.Background. Recent conflicting reports have confirmed or refuted the association of lipoprotein(a) with clinical events or angiographically verified disease progression.Methods. The association between serum lipoprotein(a) and changes in coronary artery lumen was studied in 704 men entered into the Regression Growth Evaluation Statin Study (REGRESS), a double-blind, placebo-controlled, quantitative angiographic study that assessed the effect of 2 years of pravastatin treatment. The primary end points were changes in average mean segment diameter (MSD) and average minimal obstruction diameter (MOD). Pavastatin- and placebo-treated patients were classified as having progressing, regressing or stable CAD, and median lipoprotein(a) concentrations were compared. Bivariate and multivariate regression analyses were performed in the overall patient group and in high risk subgroups.Results. Pravastatin treatment did not affect serum apolipoprotein(a) levels. Median in-trial (sampled at 24 months) apolipoprotein(a) levels for regressing, stable and progressing CAD were, respectively, 130, 162 and 251 U/liter in placebo-treated patients and 143, 224 and 306 U/liter in pravastatin-treated patients. Predictors of MSD and MOD changes were baseline MSD and MOD, in-trial apolipoprotein(a), in-trial high density lipoprotein (HDL) cholesterol and baseline use of long-acting nitrates. The multivariate models predicted 14% of MSD changes and 12% of MOD changes; apolipoprotein(a) predicted only 2.6% and 4.8%, respectively. However, in patients with in-trial HDL cholesterol levels <0.7 mmol/liter, apolipoprotein(a) predicted up to 37% of the arteriographic changes.Conclusions. Serum lipoprotein(a) levels predict coronary artery lumen changes in normal to moderately hypercholesterolemic white men with CAD; its atherogenicity is marked in the presence of concomitant hypoalphalipoproteinemia.

The influence of angiographic endpoints on the outcome of lipid intervention studies. A proposal for standardization. REGRESS study group.

The aims of this study were to evaluate the influence of different coronary angiographic endpoints on the outcome of lipid intervention studies and to formulate a proposal for angiographic endpoint standardization. In recent angiographic intervention studies a confusing diversity in angiographic endpoints has been used to determine the outcome. In addition, differences in study populations (eg, bypass patients included or not) could influence results. This makes comparisons between studies cumbersome and raises the question to what extent the results of various studies may be subject to the selection of angiographic endpoints. The investigators compared three frequently used endpoints (mean segment diameter, minimum obstruction diameter, and % stenosis) in a group of 505 patients who had just finished a trial designed to assess the effect of cholesterol lowering by pravastatin. To exclude a potential bias this analysis was carried out at the time that the study was still blinded. They found poor intercorrelation coefficients for mean segment diameter calculated in different ways, ranging from 0.55 to 0.95, dependent on inclusion or exclusion of segments influenced by coronary angioplasty or bypass grafting and on whether or not a value of 0 was assumed for occluded segments and segments distal to occlusions. The correlation between mean segment diameter and minimum obstruction diameter was 0.79; between minimum obstruction diamete and % stenosis, 0.85; and between mean segment diameter and % stenosis, only 0.64. Different endpoints sometimes correlate poorly. This may lead to differences in results of angiographic intervention trials. The authors propose standardization by (1) using both mean sement diameter and minimum obstruction diameter as endpoints and (2) excluding from the primary analysis segments influenced by mechanical interventions.

1028-122 The Beneficial Effects of Lipid Lowering Therapy by Pravastatin on Coronary Atherosclerosisis Diminished by 50% in Patients who Continue to Smoke

REGRESS (Regression Growth Evaluation Statin Study) is a placebo controlled multicenter study to assess the effect of 2 year treatment with Pravastatin (PRAV) on progression and regression of angiographically documented coronary atherosclerosis (CA) in patients with a serum cholesterol between 4–8 mmol/l (155–310 mg/dl). Baseline and follow-up analyses of the coronary arteriograms was performed by quantitative computer analysis. The primary endpoints of the study, change in Mean Segment Diameter and Minimum Obstruction Diameter (MOD) averaged per patient, showed significant retardation of mean progression of CA in the PRAV-group as compared to the placebo (PLAC)-group. To determine whether this beneficial effect is attenuated by the presence of risk factors like smoking, hypertension, and obesity, we analyzed our data in this regard. at baseline the median MOD was 1.83 mm for smokers (n = 190) and 1.89 mm for non-smokers (n = 451, P = 0.02). Median changes of the MOD in the PLAC- and PRAY-group for smokers and non-smokers are shown in the table below.Empty CellPLACPRAVEmpty Cellsmokers-0.07 mm-0.04 mmp = 0.32non-smokers-0.10 mm-0.03 mmP = 0.0003p = 0.08p = 0.29 The pravastatin effect for non-smokers was 0.07 mm less progression and for smokers 0.03 mm less progression of CA. Adjusting for baseline MOD differences between smokers and non-smokers did-not alter this result. No major differences of the pravastatin effect could be demonstrated for subgroups of patients with or without hypertension or obesity. the beneficial effect of lipid lowering therapy on coronary atherosclerosis is diminished by 50% in patients who continue to smoke.

769-1 The Influence of Pravastatin on Progression and Regression of Coronary Atherosclerosis in Men with Normal or Mildly Raised Serum Cholesterol. Results of the Regression Growth Evaluation Statin Study (REGRESS)

REGRESS is a double blind, placebo controlled multicenter study to assess the effect of 2 year treatment with pravastatin 40 mg once daily on pro- and regression of angiographically documented coronary artery disease in 885 patients with a serum cholesterol between 4–8 mmol/l (155 and 310 mg/dl). The REGRESS study comprises three blocks of patients: a percutaneous coronary angioplasty, a coronary artery bypass grafting and a medical management group. Analysis of baseline and follow-up coronary arteriograms was performed visually and by quantitative computer analysis (QCA). Primary endpoints were QCA assessments of 1. change in Mean Segment Diameter (MSD) averaged per patient and 2. change in Minimum Obstruction Diameter (MOD) averaged per patient. 778 patients (88%) of the patients had an evaluable final angiogram. Mean Segment Diameter decreased with 0.10 mm in the placebo group versus 0.06 mm in the pravastatin group (p = 0.019): the mean difference between treatment groups was 0.04 mm with 95% confidence interval (ci) of 0.01–0.07 mm. The median Minimum Obstruction Diameter decreased with 0.09 mm in the placebo group versus 0.03 mm in the pravastatin group (p = 0.001): the difference of the medians between the treatment groups was 0.06 mm with ci of 0.02–0.08 mm. At the end of the follow-up period 89% (ci 86–92%) of the pravastatin patients and 81% (ci 77–85%) of the placebo patients were without new cardiovascular events (p = 0.002). in symptomatic men with normal or moderately raised serum cholesterol, pravastatin slows progression of coronary atherosclerosis and reduces the number of cardiovascular events.

769-2 Progression and Regression of Coronary Atherosclerosis Occur within the Same Patient During Placebo Treatment and During Lipid-Lowering Therapy with Pravastatin

REGRESS (Regression Growth Evaluation Statin Study) is a placebo controlled multicenter study to asses the effect of 2-yr treatment with Pravastatin (PRAV) on progression and regression of angiographically documented coronary atherosclerosis (CA) in patients with a serum cholesterol between 4–8 mmol/l (155-310 mg/dl). Analyses of the coronary arteriograms were performed by quantitative computer analysis. The primary endpoints of the study, change in Mean Segment Diameter and Minimum Obstruction Diameter (MOD) averaged per patient, showed significant retardation of mean progression of CA in the PRAY-group as compared to the placebo (PLAC)-group. However, these mean changes per treatment group are hardly informative about individual CA-behavior. Therefore we determined for all 641 patients included in the primary MOD-analysis: 1. a mean progression score (MPS)-cumulative value of all &gt;0.4 mm progressing obstructions divided by the number of contributing obstructions-, and 2. a mean regression score (MRS)-cumulative value of all &gt;0.4 mm regressing obstructions divided by the number of contributing obstructions. Obstructions changing ≤0.4 mm were considered stable and do not contribute to the scores. Thus, each patient is characterized by a MPS and a MRS. An overview of the patient MPS and MRS is presented in the figure below. significant progression and regression of CA within the same patient occurred in 41 (13%) PRAY-patients and in 27 (9%) PLAC-patients. Thus, although pravastatin slows mean progression of CA, progression and regression of CA within the same patient still occurs in a considerable number of patients during lipid lowering therapy.

Long-acting coronary vasodilatory action of the molsidomine metabolite Sin 1: a quantitative angiographic study.

The vasodilatory action of molsidomine was studied by intracoronary injection of its active metabolite, Sin 1. In 10 patients repeat coronary angiography in multiple projections was performed before and 2 minutes after administration of 1 mg of Sin 1, and before and after a second injection 60 minutes later. Contours of obstructed and non-obstructed segments of the left coronary artery were quantitatively analysed with a computer-based angiography analysis system. Immediately after its administration, Sin 1 increased the mean diameters of 44 normal coronary segments by 12% (P less than 0.001). Significant vasodilation (8%) was still observed after 60 minutes. At that time, repeated administration of Sin 1 increased the vasodilation by an additional 14% with respect to the control situation. An increase in obstruction diameter was observed in 6 out of 8 obstructed segments. Mean increase in the minimal obstruction diameter was still 10% after 60 minutes.