Albert V.G. Bruschke

Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels : the Regression Growth Evaluation Statin Study (REGRESS)

BACKGROUND Intensive lowering of serum cholesterol may retard progression of coronary atherosclerosis in selected groups of patients. However, few data are available on the potential benefit of serum cholesterol reduction in the broad range of patients with coronary atherosclerosis and normal to moderately elevated serum cholesterol levels who undergo various forms of treatment. The Regression Growth Evaluation Statin Study (REGRESS) addresses this group of patients. METHODS AND RESULTS REGRESS is a double-blind, placebo-controlled multicenter study to assess the effects of 2 years of treatment with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin on progression and regression of coronary atherosclerosis in 885 male patients with a serum cholesterol level between 4 and 8 mmol/L (155 and 310 mg/dL) by quantitative coronary arteriography. Primary end points were (1) change in average mean segment diameter per patient and (2) change in average minimum obstruction diameter per patient. Clinical events were also analyzed. Of the 885 patients, 778 (88%) had an evaluable final angiogram. Mean segment diameter decreased 0.10 mm in the placebo group versus 0.06 mm in the pravastatin group (P = .019): The mean difference between treatment groups was 0.04 mm, with a 95% CI of 0.01 to 0.07 mm. The median minimum obstruction diameter decreased 0.09 mm in the placebo group versus 0.03 mm in the pravastatin group (P = .001): The difference of the medians between the treatment groups was 0.06 mm, with a CI of 0.02 to 0.08 mm. At the end of the follow-up period, 89% (CI, 86% to 92%) of the pravastatin patients and 81% (CI, 77% to 85%) of the placebo patients were without new cardiovascular events (P = .002). CONCLUSIONS In symptomatic men with significant coronary atherosclerosis and normal to moderately elevated serum cholesterol, less progression of coronary atherosclerosis and fewer new cardiovascular events were observed in the group of patients treated with pravastatin than in the placebo group.

The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group

BACKGROUND The high-density lipoprotein (HDL) cholesterol concentration is inversely related to the risk of coronary artery disease. The cholesteryl ester transfer protein (CETP) has a central role in the metabolism of this lipoprotein and may therefore alter the susceptibility to atherosclerosis. METHODS The DNA of 807 men with angiographically documented coronary atherosclerosis was analyzed for the presence of a polymorphism in the gene coding for CETP. The presence of this DNA variation was referred to as B1, and its absence as B2. All patients participated in a cholesterol-lowering trial designed to induce the regression of coronary atherosclerosis and were randomly assigned to treatment with either pravastatin or placebo for two years. RESULTS The B1 variant of the CETP gene was associated with both higher plasma CETP concentrations (mean [+/-SD], 2.29+/-0.62 microg per milliliter for the B1B1 genotype vs. 1.76+/-0.51 microg per milliliter for the B2B2 genotype) and lower HDL cholesterol concentrations (34+/-8 vs. 39+/-10 mg per deciliter). In addition, we observed a significant dose-dependent association between this marker and the progression of coronary atherosclerosis in the placebo group (decrease in mean luminal diameter: 0.14+/-0.21 mm for the B1B1 genotype, 0.10+/-0.20 mm for the B1B2 genotype, and 0.05+/-0.22 mm for the B2B2 genotype). This association was abolished by pravastatin. Pravastatin therapy slowed the progression of coronary atherosclerosis in B1B1 carriers but not in B2B2 carriers (representing 16 percent of the patients taking pravastatin). CONCLUSIONS There is a significant relation between variation at the CETP gene locus and the progression of coronary atherosclerosis that is independent of plasma HDL cholesterol levels and the activities of lipolytic plasma enzymes. This common DNA variant appears to predict whether men with coronary artery disease will benefit from treatment with pravastatin to delay the progression of coronary atherosclerosis.

Reduction in cardiovascular events during pravastatin therapy : Pooled analysis of clinical events of the pravastatin atherosclerosis intervention program

BACKGROUND It has been documented that the HMG coenzyme A reductase inhibitors, or statins, can decrease cardiovascular events and mortality in patients with clinical coronary disease and moderately to severely elevated lipid levels. Additional data are required to demonstrate a reduction of vascular events in coronary patients with less than severely elevated lipid levels and in subgroups of this population. METHODS AND RESULTS Clinical data from four atherosclerosis regression trials that evaluated pravastatin were pooled for a predetermined analysis of the effect of that agent on the risk of coronary events. All trials were double-masked, placebo-controlled designs that used pravastatin as monotherapy for 2 to 3 years. The 1981 participants in the trials had evidence of atherosclerosis and mildly to moderately elevated lipid levels. For fatal or nonfatal myocardial infarction, there was a 62% reduction in events attributable to pravastatin (P = .001). This effect was evident in younger and older patients, men and women, and patients with and without histories of hypertension and prior infarction. There was a 46% reduction in all-cause mortality (P = .17), which, although not statistically significant, is consistent with the results of other statin trials. There also was a 62% reduction in the risk of fatal or nonfatal stroke (P = .054). CONCLUSIONS These pooled results provide strong evidence that pravastatin reduces the risk of cardiovascular events in patients with atherosclerotic disease and mildly to moderately elevated lipid levels. The benefit for reducing myocardial infarction is evident in older and younger patients, men and women, and patients with and without histories of hypertension and prior infarction.

B-mode ultrasound assessment of pravastatin treatment effect on carotid and femoral artery walls and its correlations with coronary arteriographic findings: a report of the Regression Growth Evaluation Statin Study (REGRESS).

OBJECTIVES In this B-mode ultrasound study we assessed pravastatin treatment effects on carotid and femoral artery walls and investigated the correlations between the state and evolution of peripheral and coronary atherosclerosis. BACKGROUND The Regression Growth Evaluation Statin Study (REGRESS) was an 11-center, 2-year, double-blind, placebo-controlled, prospective study of 885 men with coronary artery disease (CAD) (total cholesterol 4 to 8 mmol/liter). The study primarily investigated pravastatin treatment effects on the coronary lumen. This report focuses on the 255 patients who participated in the REGRESS ultrasound study. METHODS Carotid and femoral artery walls were imaged at baseline and at 6, 12, 18 and 24 months. Pravastatin treatment effect was defined as the difference in progression of the combined intima-media thicknesses (IMT) between treatment groups. RESULTS Pravastatin treatment effects were highly significant (combined IMT: p = 0.0085; combined far wall IMT: p < 0.0001; common femoral artery far wall IMT: p = 0.004). Correlations between the IMTs of the arterial wall segments ranged from -0.17 to 0.81. Baseline correlations between IMT and percent coronary lumen stenoses ranged from 0.23 to 0.36. Baseline IMT correlated with the mean coronary segment diameter (r = -0.32, p = 0.001) and minimal coronary obstruction diameter (r = -0.27, p = 0.005). There were no individual correlations between IMT and coronary lumen variables (p > 0.30). CONCLUSIONS Pravastatin treatment effects on carotid and femoral artery walls were observed. B-mode ultrasound imaging studies of peripheral arterial walls could not describe the state and evolution of the coronary lumen in the individual patient, but proved to be a highly suitable tool for the assessment of antiatherosclerotic properties of agents.

Natural history of obstructive coronary artery disease: Ten-year study of 601 nonsurgical cases

The most important factors in the prognosis of coronary artery disease are the number of arteries severly obstructed, significant involvement of the left main coronary artery, and generalized impairment of left ventricular function or ventricular aneurysm. Other prognostic influences at least partially independent of these factors are the severity of functional impairment imposed by angina pectoris, electrocardiographic evidence of left ventricular hypertrophy or conduction defects, hypertension, and diabetes. Candidates for bypass operation have a better prognosis than noncandidates, but difference in left ventricular function is responsible. Refinement of prognostic precision will depend largely on future improvement in measurement of obstructive disease and left ventricular function serially and better knowledge of the cause or causes of coronary artery disease.

Reduction of Transient Myocardial Ischemia With Pravastatin in Addition to the Conventional Treatment in Patients With Angina Pectoris

BACKGROUND Lipid-lowering therapy reduces cardiac morbidity and mortality. Less is known about its potential anti-ischemic effect. METHODS AND RESULTS In a 2-year prospective randomized placebo-controlled study, the effect of pravastatin 40 mg on transient myocardial ischemia was assessed. Forty-eight-hour ambulatory ECGs with continuous ST-segment analysis were performed in 768 male patients with stable angina pectoris, documented coronary artery disease, and serum cholesterol between 4 and 8 mmol/L (155 and 310 mg/dL). During the trial, patients received routine antianginal treatment. In the patients randomized to pravastatin, transient myocardial ischemia was present at baseline in 28% and after treatment in 19%; in the placebo group, it was found in 20% and 23% of the patients, respectively (P = .021 for change in percentage between two treatment groups; odds ratio, 0.62; 95% CI, 0.41 to 0.93). Ischemic episodes decreased by 1.23 +/- 0.25 (SEM) episode with pravastatin and by 0.53 +/- 0.25 episode with placebo (P = .047). Under pravastatin, the duration of ischemia decreased from 80 +/- 12 minutes to 42 +/- 10 minutes (P = .017) and with placebo, from 60 +/- 13 minutes to 51 +/- 9 minutes (P = .56). The total ischemic burden decreased from 41 +/- 5 to 22 +/- 5 mm.min in the pravastatin group (P = .0058) and from 34 +/- 6 to 26 +/- 4 mm . min in the placebo group (P = .24). Adjusted for independent risk factors for the occurrence of ischemia, the effect of pravastatin on the reduction of risk for ischemia remained statistically significant (odds ratio, 0.45; 95% CI, 0.22 to 0.91; P = .026). CONCLUSIONS In men with documented coronary artery disease and optimal antianginal therapy, pravastatin reduces transient myocardial ischemia.

Detection and Quantification of Dysfunctional Myocardium by Magnetic Resonance Imaging A New Three-dimensional Method for Quantitative Wall-Thickening Analysis

BACKGROUND Regional left ventricular dysfunction is a major consequence of myocardial ischemia, and its extent determines long-term prognosis. Accurate and reproducible analysis of left ventricular dysfunction is therefore useful for risk stratification and patient management. METHODS AND RESULTS Short-axis cardiac cine magnetic resonance (MR) imaging was performed in 25 patients after anterior myocardial infarction at 21 +/- 2.1 days after the acute onset. The MR images were analyzed with the use of a dedicated analytical software package (MASS version 1.0), which includes a modified centerline method and a new three-dimensional analysis approach. A database of 48 healthy volunteers was constructed to objectively depict myocardial dysfunction in the patients; this database was compared with enzymatically determined infarct size. The mean (+/-SEM) quantity of dysfunctional myocardium and enzymatically calculated infarct size equaled 24.0 +/- 3.0 and 22.3 +/- 2.9 g, respectively (P = .69). Enzymatically determined infarct size correlated strongly with left ventricular dysfunction determined by cine MR imaging (y = 0.90x + .92. P < .0001). Segments related to the distribution of the left anterior descending coronary artery showed a significantly lower percentage wall thickening in patients than did corresponding segments of 48 normal subjects (46.0 +/- 8.22% versus 87.1 +/- mean SEM, respectively; P < .001). The mean (+/-SEM) end diastolic wall thickness of the infarcted segment did not differ from that of corresponding normal segments (7.4 +/- 0.33 versus 7.5 +/- 0.15 mm; P = .75). CONCLUSIONS We conclude that the use of three-dimensional quantitative analysis of cine MR images accurately quantities the extent of regional left ventricular dysfunction in the infarcted heart. This method of analysis may be useful in assessing the effect of interventional therapies.

−455G/A Polymorphism of the β-Fibrinogen Gene is Associated With the Progression of Coronary Atherosclerosis in Symptomatic Men: Proposed Role for an Acute-Phase Reaction Pattern of Fibrinogen

Increased plasma fibrinogen levels have been identified as a risk indicator for myocardial infarction, stroke, and thrombosis. Both environmental and genetic factors make an important contribution to plasma fibrinogen levels in humans. In the present study we evaluated, in patients with serum cholesterol levels between 4 and 8 mmol/L, the relation of plasma levels and polymorphisms of fibrinogen with coronary artery disease (CAD), cross-sectionally at baseline and after a 2-year follow-up period in which they received either a placebo or pravastatin. Higher plasma fibrinogen levels (3.9 g/L) were observed at baseline in patients with the -455AA genotype than in patients with the -455GA (3.2 g/L) and -455GG (3.1 g/L) genotypes of the -455G/A fibrinogen β gene polymorphism (P < .05). Plasma levels of fibrinogen were not related to the baseline angiographic variables (mean segment diameter [MSD] and minimum obstruction diameter [MOD]), nor to the quantitative changes in these angiographic variables. However, in the placebo group, patients with the - 455AA genotype had more progression of CAD, expressed by a significantly greater decrease of the MSD and MOD, after the 2-year follow-up period than patients with the other genotypes. The - 455G/A polymorphism was related to the progression of CAD, and pravastatin therapy seemed to offset this deleterious effect. We hypothesized that the - 455A allele may promote a stronger acute-phase response in fibrinogen and that the resulting higher fibrinogen levels may form the pathogenetic basis for the stronger progression of coronary atherosclerosis. Experiments to verify this hypothesis are being proposed and advocated, in view of the possibility of identifying a genetic marker that can recognize a subgroup of patients with an increased risk who may benefit from early treatment with lipid-lowering or anticoagulant drugs.

The Asp9 Asn Mutation in the Lipoprotein Lipase Gene Is Associated With Increased Progression of Coronary Atherosclerosis

BACKGROUND Many patients suffering from premature coronary artery disease report a family history for such events. A mutation in a particular gene, which confers susceptibility for atherosclerosis, will be found more frequently in individuals suffering from coronary atherosclerosis than in the general population. We have recently reported the identification of an Asp9 Asn substitution in the lipoprotein lipase (LPL) enzyme. We analyzed the impact of this mutation on the progression of coronary atherosclerosis and the effect of pravastatin in both carriers and noncarriers. METHODS AND RESULTS All patients were enrolled in the quantitative coronary angiographic clinical trial REGRESS, which studied the impact of pravastatin therapy on coronary atherosclerosis. The Asp9 Asn mutation was identified in 38 of 819 (4.8%) patients. Carriers of the mutation more often had a positive family history of cardiovascular disease and lower HDL cholesterol levels than noncarriers. In the placebo group, carriers showed more progression of coronary atherosclerosis than noncarriers: mean reduction of the minimum obstruction diameter of -0.25 mm versus -0.12 mm (P = .029) and increase of percentage diameter stenosis of 6.4% versus 1.4% (P = .004). Moreover, the adjusted relative risk for a clinical event for carriers was calculated at 2.16 (95% CI, 1.09 to 4.29; P = .027). Although the lipid-lowering effect of pravastatin was attenuated in carriers, it appeared that these patients showed a response similar to noncarriers in terms of less progression of atherosclerosis and event-free survival. CONCLUSIONS This study shows that heterozygosity for a mutation in the LPL gene, which causes only subtle changes in fasting plasma lipids, may promote the progression of coronary atherosclerosis and diminish clinical event-free survival.

Genetic Variant Showing a Positive Interaction With β-Blocking Agents With a Beneficial Influence on Lipoprotein Lipase Activity, HDL Cholesterol, and Triglyceride Levels in Coronary Artery Disease Patients The Ser447-Stop Substitution in the Lipoprotein Lipase Gene

Background Lipoprotein lipase (LPL) is the rate-limiting enzyme in the lipolysis of triglyceride-rich lipoproteins, and the gene coding for LPL is therefore a candidate gene in atherogenesis. We previously demonstrated that two amino acid substitutions in LPL, the Asn 291 -Ser and the Asp 9 -Asn, are associated with elevated triglycerides and lower HDL cholesterol and are present with greater frequency in coronary artery disease (CAD) patients than in normolipidemic control subjects. Conversely, a third frequent mutation in this gene, the Ser 447 -Stop, is reported by some investigators to underlie higher HDL cholesterol levels and would represent a beneficial genetic variant in lipoprotein metabolism. We therefore sought conclusive evidence for these allegations by investigating the effects of the LPL Ser 447 -Stop mutation on LPL and hepatic lipase (HL) activity, HDL cholesterol, and triglycerides in a large group of CAD patients (n=820) with normal to mildly elevated total and LDL cholesterol levels. Methods and Results Carriers of the Ser 447 -Stop allele (heterozygotes and homozygotes) had significantly higher postheparin LPL activity ( P =.034), normal postheparin HL activity ( P =.453), higher HDL cholesterol levels ( P =.013), and lower triglyceride levels ( P =.044) than noncarriers. The influence of the Ser 447 -Stop allele on LPL activity was pronounced in patients using β-blockers ( P =.042) and not significant in those not using them ( P =.881), suggesting a gene-environment interaction between the Ser 447 -Stop mutation and β-blockers. Conclusions We conclude that the LPL Ser 447 -Stop mutation has a significant positive effect on LPL activity and HDL cholesterol and triglyceride levels and that certain subgroups of CAD patients carrying the Ser 447 -Stop mutation will have less adverse metabolic effects when placed on β-blockers. The LPL Ser 447 -Stop mutation therefore should have a protective effect against the development of atherosclerosis and subsequent CAD.