Thomas G. Cole

The Effect of Pravastatin on Coronary Events after Myocardial Infarction in Patients with Average Cholesterol Levels

BACKGROUND In patients with high cholesterol levels, lowering the cholesterol level reduces the risk of coronary events, but the effect of lowering cholesterol levels in the majority of patients with coronary disease, who have average levels, is less clear. METHODS In a double-blind trial lasting five years we administered either 40 mg of pravastatin per day or placebo to 4159 patients (3583 men and 576 women) with myocardial infarction who had plasma total cholesterol levels below 240 mg per deciliter (mean, 209) and low-density lipoprotein (LDL) cholesterol levels of 115 to 174 mg per deciliter (mean, 139). The primary end point was a fatal coronary event or a nonfatal myocardial infarction. RESULTS The frequency of the primary end point was 10.2 percent in the pravastatin group and 13.2 percent in the placebo group, an absolute difference of 3 percentage points and a 24 percent reduction in risk (95 percent confidence interval, 9 to 36 percent; P = 0.003). Coronary bypass surgery was needed in 7.5 percent of the patients in the pravastatin group and 10 percent of those in the placebo group, a 26 percent reduction (P=0.005), and coronary angioplasty was needed in 8.3 percent of the pravastatin group and 10.5 percent of the placebo group, a 23 percent reduction (P=0.01). The frequency of stroke was reduced by 31 percent (P=0.03). There were no significant differences in overall mortality or mortality from noncardiovascular causes. Pravastatin lowered the rate of coronary events more among women than among men. The reduction in coronary events was also greater in patients with higher pretreatment levels of LDL cholesterol. CONCLUSIONS These results demonstrate that the benefit of cholesterol-lowering therapy extends to the majority of patients with coronary disease who have average cholesterol levels.

Cardiovascular Events and Their Reduction With Pravastatin in Diabetic and Glucose-Intolerant Myocardial Infarction Survivors With Average Cholesterol Levels Subgroup Analyses in the Cholesterol And Recurrent Events (CARE) Trial

BACKGROUND Although diabetes is a major risk factor for coronary heart disease (CHD), little information is available on the effects of lipid lowering in diabetic patients. We determined whether lipid-lowering treatment with pravastatin prevents recurrent cardiovascular events in diabetic patients with CHD and average cholesterol levels. METHODS AND RESULTS The Cholesterol And Recurrent Events (CARE) trial, a 5-year trial that compared the effect of pravastatin and placebo, included 586 patients (14.1%) with clinical diagnoses of diabetes. The participants with diabetes were older, more obese, and more hypertensive. The mean baseline lipid concentrations in the group with diabetes--136 mg/dL LDL cholesterol, 38 mg/dL HDL cholesterol, and 164 mg/dL triglycerides--were similar to those in the nondiabetic group. LDL cholesterol reduction by pravastatin was similar (27% and 28%) in the diabetic and nondiabetic groups, respectively. In the placebo group, the diabetic patients suffered more recurrent coronary events (CHD death, nonfatal myocardial infarction [MI], CABG, and PTCA) than did the nondiabetic patients (37% versus 25%). Pravastatin treatment reduced the absolute risk of coronary events for the diabetic and nondiabetic patients by 8.1% and 5.2% and the relative risk by 25% (P=0.05) and 23% (P<0.001), respectively. Pravastatin reduced the relative risk for revascularization procedures by 32% (P=0.04) in the diabetic patients. In the 3553 patients who were not diagnosed as diabetic, 342 had impaired fasting glucose at entry defined by the American Diabetes Association as 110 to 125 mg/dL. These nondiabetic patients with impaired fasting glucose had a higher rate of recurrent coronary events than those with normal fasting glucose (eg, 13% versus 10% for nonfatal MI). Recurrence rates tended to be lower in the pravastatin compared with placebo group (eg, -50%, P=0.05 for nonfatal MI). CONCLUSIONS Diabetic patients and nondiabetic patients with impaired fasting glucose are at high risk of recurrent coronary events that can be substantially reduced by pravastatin treatment.

VLDL, Apolipoproteins B, CIII, and E, and Risk of Recurrent Coronary Events in the Cholesterol and Recurrent Events (CARE) Trial

BackgroundPlasma triglyceride concentration has been an inconsistent independent risk factor for coronary heart disease, perhaps because of the metabolic heterogeneity among VLDL particles, the main carriers of triglycerides in plasma. Methods and ResultsWe conducted a prospective, nested case-control study in the Cholesterol and Recurrent Events (CARE) trial, a randomized placebo-controlled trial of pravastatin in 4159 patients with myocardial infarction and average LDL concentrations at baseline (115 to 174 mg/dL, mean 139 mg/dL). Baseline concentrations of VLDL–apolipoprotein (apo) B (the VLDL particle concentration), VLDL lipids, and apoCIII and apoE in VLDL+LDL and in HDL were compared in patients who had either a myocardial infarction or coronary death (cases, n=418) with those in patients who did not have a cardiovascular event (control subjects, n=370) in 5 years of follow-up. VLDL-cholesterol, VLDL-triglyceride, VLDL-apoB, apoCIII and apoE in VLDL+LDL and apoE in HDL were all interrelated, and each was a univariate predictor of subsequent coronary events. The significant independent predictors were VLDL-apoB (relative risk [RR] 3.2 for highest to lowest quintiles, P =0.04), apoCIII in VLDL+LDL (RR 2.3, P =0.04), and apoE in HDL (RR 1.8, P =0.02). Plasma triglycerides, a univariate predictor of coronary events (RR 1.6, P =0.03), was not related to coronary events (RR 1.3, P =0.6) when apoCIII in VLDL+LDL was included in the model, whereas apoCIII remained significant. Adjustment for LDL- and HDL-cholesterol did not affect these results. ConclusionsThe plasma concentrations of VLDL particles and apoCIII in VLDL and LDL are more specific measures of coronary heart disease risk than plasma triglycerides perhaps because their known metabolic properties link them more closely to atherosclerosis.

Effect of apolipoprotein E and A-IV phenotypes on the low density lipoprotein response to HMG CoA reductase inhibitor therapy

Our purpose was to assess the effect of apolipoprotein (apo) E and apo A-IV isoform variation on low density lipoprotein (LDL) cholesterol lowering response to the HMG CoA reductase inhibitor, pravastatin. Plasma samples were obtained from participants (apo E, n = 97; apo A-IV, n = 144) in the PLAC-I (Pravastatin Limitation of Atherosclerosis in Coronary Arteries Study-1). The mean LDL cholesterol reduction in these subjects who were randomized to pravastatin 40 mg/day was 28%. Subjects with the APOE*2 allele (n = 12) had significantly (P = 0.04) greater reductions at 36% than subjects homozygous for the APOE*3 allele (n = 66, 27%) or those with the APOE*4 allele (n = 19, 26%). No significant effect of apo A-IV phenotype on LDL cholesterol lowering in response to pravastatin was noted. A meta-analysis utilizing published data from 4 previously published studies as well as our own data with a total sample size of 625 subjects was carried out. This analysis indicates that the presence of the APOE*2 allele was associated with a significantly greater (P < 0.05) LDL-cholesterol lowering response at 37% than those subjects homozygous for the APOE*3 allele at 35%, while those with the APOE*4 allele had a significantly lower response (P < 0.05), at 33%. These data are consistent with the concept that apo E phenotype modulates the LDL cholesterol lowering response observed with the use of HMG CoA reductase inhibitors.

Oleic acid stimulation of apolipoprotein B secretion from HepG2 and Caco-2 cells occurs post-transcriptionally

HepG2 and Caco-2 cells were studied to compare the regulation of liver and intestinal apolipoprotein (apo) biosynthesis and secretion by fatty acids. Incubation with fatty acid consistently stimulated apoB production by both HepG2 and Caco-2 cells. Media concentrations of apoB, determined by radioimmunoassay, were approx. 3-fold greater for cells incubated for 24 h in serum-free medium containing oleic acid bound to albumin than for cells incubated with albumin alone. Oleic acid also resulted in a 2-3-fold accumulation of cellular triacylglycerol for HepG2 cells and Caco-2 cells. Cellular apoB and media and cellular apoA-I concentrations were not affected by oleic acid. Immunoblotting with a monoclonal antibody against human apoB confirmed a greater mass of apoB in media from HepG2 and Caco-2 cells incubated with oleic acid. Radiolabeled apoB-100 was also increased in media from HepG2 and Caco-2 cells incubated with [35S]methionine for 24 h in the presence of oleic acid, suggesting enhanced apoB synthesis. However, apoB mRNA concentrations were unchanged in response to oleic acid. Gel filtration of media by fast protein liquid chromatography (FPLC) revealed a redistribution of apoB from LDL-sized particles to VLDL or chylomicrons in media from Caco-2 cells incubated with oleic acid, whereas apoB remained in LDL for HepG2 cells. ApoA-I in media from HepG2 and Caco-2 cells eluted as free or lipid-poor apoA-I, and the apoA-I distribution was unaltered by incubation with oleic acid. These data demonstrate that HepG2 and Caco-2 cells maintained in supplemented serum-free medium respond to oleic acid by a similar post-transcriptional increase in apoB synthesis, but different packaging of apoB into triacylglycerol-rich lipoproteins.

Rationale and design of a secondary prevention trial of lowering normal plasma cholesterol levels after acute myocardial infarction : the cholesterol and recurrent events trial (CARE)

Recent clinical trials of primary and secondary prevention of cardiovascular disease have demonstrated that lowering plasma cholesterol decreases the incidence of coronary heart disease in patients with elevated plasma cholesterol. However, it is not known whether patients with established coronary artery disease and normal plasma cholesterol can be benefited. Several previous prevention trials reviewed in this report found that patients who had plasma cholesterol levels at baseline in the upper portion of the eligibility range (e.g., greater than 240 mg/dl) received greater benefit from hypolipidemic diet or drug therapy than patients who had lower plasma cholesterol levels at baseline. The recent availability of drugs that are more potent and less prone to cause adverse reactions than previous regimens permits this important question to be addressed. The Cholesterol and Recurrent Events trial is testing whether pravastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, will decrease the sum of fatal coronary heart disease and nonfatal myocardial infarction (MI) in patients who have recovered from a MI and who have normal total cholesterol levels. Fatal cardiovascular disease and total mortality are important secondary end points. The trial is enrolling 4,000 men and women from 80 centers throughout North America, age 21 to 75 years, who have survived MI for 3 to 20 months, who have plasma total cholesterol less than 240 mg/dl (6.2 mmol/liter) and low-density cholesterol of 115 to 174 mg/dl (3.0 to 4.5 mmol/liter), and who are representative of the general population of patients with MI. Patients are randomized to either active or inactive drug therapy. Active therapy consists of pravastatin, 40 mg/day, designed to achieve an average decrease in low-density lipoprotein cholesterol of approximately 30%, and an increase in high-density lipoprotein of 5%. The average duration of follow-up will be greater than or equal to 5 years. To protect against a lower than expected rate of recurrent events, the trial will be continued until a predetermined fixed number of coronary heart disease events occurs in the entire cohort so that the original sensitivity of the trial will be maintained.

Genetic heterogeneity of lipoproteins in inbred strains of mice: Analysis by gel-permeation chromatography☆

To assess genetic variation of murine lipoprotein profiles, plasma lipoproteins of 11 inbred strains, AKR/J, BALB/cByJ, C3H/HeJ, C57BL/6J, C57BL/6ByJ, C57L/J, DBA/1LacJ, 129/J, NZB/B1NJ, PL/J, and SWR/J, were analyzed by gel-permeation chromatography (fast peptide liquid chromatography) and nondenaturing gradient gel electrophoresis. Vena caval blood was drawn after 18 to 20 hours of fasting. Plasma triglyceride and cholesterol concentrations ranged from 12.9 mg/dL (C57BL/6ByJ) to 66.9 mg/dL (C3H/HeJ) and from 54.8 mg/dL (AKR/J) to 128.5 mg/dL (NZB/B1NJ), respectively. Mouse strain-related heterogeneities of very low-, low-, and high-density lipoprotein (VLDL, LDL, and HDL, respectively) concentrations were documented; VLDL-triglyceride concentrations ranged from 7.5 mg/dL to 38.8 mg/dL, LDL cholesterol from 12.0 mg/dL to 39.6 mg/dL, and HDL cholesterol from 41.3 mg/dL to 92.4 mg/dL. Hyper-VLDL-triglyceridemia was present in C3H/HeJ and SWR/J strains and hyper-LDL-cholesterolemia in NZB/B1NJ, C3H/HeJ, and DBA/1LacJ. VLDL cholesterol/VLDL triglyceride ratios also ranged widely among strains (0.13 to 0.43), with C57BL/6J, C57BL/6ByJ, and C57L/J, the strains particularly susceptible to diet-induced atherosclerosis, having the highest VLDL-lipid ratio. LDL and HDL size heterogeneities were also observed. LDL and HDL diameters ranged between 24.1 nm and 29.4 nm, and between 9.24 nm and 10.32 nm, respectively. Although LDL sizes showed no segregation, HDL sizes fell into two groups. C57L/J and C57BL/6J possessed low HDL-cholesterol concentrations and small-sized HDL. HDL sizes were positively correlated with HDL-cholesterol concentrations (r = .90, P less than .001) and LDL-cholesterol concentrations (r = .85, P less than .001), but LDL sizes did not correlate with lipoprotein concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Differences in the Aβ40/Aβ42 ratio associated with cerebrospinal fluid lipoproteins as a function of apolipoprotein E genotype

The ε4 allele of apolipoprotein E (ApoE) is a risk factor for Alzheimers disease (AD). ApoE, which is important for lipid metabolism, is also a major constituent of cerebrospinal fluid (CSF) lipoproteins (LPs). Although ApoE in the CSF is derived from the central nervous system, the relation between LP metabolism in plasma and CSF is not clear. Soluble amyloid‐β (Aβ) protein may normally be associated with CSF LPs. It is converted in AD to a fibrillar form in brain parenchyma. ApoE and CSF LPs may regulate this process. The purpose of this study was to characterize CSF LPs from healthy, cognitively normal, fasted, elderly individuals at different risk for AD based on ApoE genotype. Lipid composition of CSF LPs did not differ with ApoE genotype. Interestingly, plasma and CSF high‐density lipoprotein (HDL) cholesterol and apolipoprotein AI (ApoAI) levels were correlated. Importantly, as assessed by size‐exclusion chromatography, Aβ in CSF coeluted in fractions containing LPs and was influenced by ApoE genotype: E4‐positive subjects displayed significant elevations in Aβ40/Aβ42 ratios. These results suggest that plasma ApoAI/HDL levels can influence CSF ApoAI/HDL levels and that interactions between Aβ and central nervous system LPs may reflect changes in brain Aβ metabolism before the onset of clinical disease. Ann Neurol 2000;48:201–210

Cholesterol and recurrent events : a secondary prevention trial for normolipidemic patients

Although elevated plasma cholesterol levels represent a well-established and significant risk for developing atherosclerosis, there is a wide spectrum of cholesterol levels in patients with coronary artery disease (CAD). Most secondary prevention studies have generated convincing evidence that cholesterol reduction in patients with high cholesterol levels is associated with improved clinical outcome by reducing risk of further cardiovascular events. However, other risk factors may play a prominent role in the pathogenesis of coronary disease in the majority of patients with near-normal cholesterol values. The Cholesterol and Recurrent Events (CARE) study was designed to address whether the pharmacologic reduction of cholesterol levels with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, pravastatin, would reduce the sum of fatal coronary artery disease (CAD) and nonfatal myocardial infarction (MI) in patients who have survived an MI yet have a total cholesterol value < 240 mg/dl (< 6.2 mmol/liter). The other inclusion criteria for this study were age 21-75 years, low density lipoprotein (LDL) cholesterol levels of 115-174 mg/dl (3.0-4.5 mmol/liter), and fasting serum triglyceride levels < 350 mg/dl (< 4.0 mmol/liter). A total of 4,159 eligible consenting patients without other study exclusions were then randomly assigned to receive either pravastatin 40 mg daily or matching placebo in addition to their individualized conventional therapy. The trial was designed to have a median follow-up of 5 years. Study endpoints will be evaluated with respect to predefined subgroups according to baseline lipid values, age, gender, prior cardiovascular risk factors, and history.(ABSTRACT TRUNCATED AT 250 WORDS)

Association of Apolipoprotein B and Nuclear Magnetic Resonance Spectroscopy–Derived LDL Particle Number with Outcomes in 25 Clinical Studies: Assessment by the AACC Lipoprotein and Vascular Diseases Division Working Group on Best Practices

BACKGROUND The number of circulating LDL particles is a strong indicator of future cardiovascular disease (CVD) events, even superior to the concentration of LDL cholesterol. Atherogenic (primarily LDL) particle number is typically determined either directly by the serum concentration of apolipoprotein B (apo B) or indirectly by nuclear magnetic resonance (NMR) spectroscopy of serum to obtain NMR-derived LDL particle number (LDL-P). CONTENT To assess the comparability of apo B and LDL-P, we reviewed 25 clinical studies containing 85 outcomes for which both biomarkers were determined. In 21 of 25 (84.0%) studies, both apo B and LDL-P were significant for at least 1 outcome. Neither was significant for any outcome in only 1 study (4.0%). In 50 of 85 comparisons (58.8%), both apo B and LDL-P had statistically significant associations with the clinical outcome, whereas in 17 comparisons (20.0%) neither was significantly associated with the outcome. In 18 comparisons (21.1%) there was discordance between apo B and LDL-P. CONCLUSIONS In most studies, both apo B and LDL-P were comparable in association with clinical outcomes. The biomarkers were nearly equivalent in their ability to assess risk for CVD and both have consistently been shown to be stronger risk factors than LDL-C. We support the adoption of apo B and/or LDL-P as indicators of atherogenic particle numbers into CVD risk screening and treatment guidelines. Currently, in the opinion of this Working Group on Best Practices, apo B appears to be the preferable biomarker for guideline adoption because of its availability, scalability, standardization, and relatively low cost.