Leo J. Seman

Effects of Atorvastatin on Fasting and Postprandial Lipoprotein Subclasses in Coronary Heart Disease Patients Versus Control Subjects

The effects of atorvastatin at 20, 40, and 80 mg/day on plasma lipoprotein subclasses were examined in a randomized, placebo-controlled fashion over 24 weeks in 103 patients in the fasting state who had coronary heart disease (CHD) with low-density lipoprotein (LDL) cholesterol levels >130 mg/dl. The effects of placebo and atorvastatin 40 mg/day were examined in 88 subjects with CHD in the fasting state and 4 hours after a meal rich in saturated fat and cholesterol. These findings were compared with results in 88 age- and gender-matched control subjects. Treatment at the 20, 40, and 80 mg/day dose levels resulted in LDL cholesterol reductions of 38%, 46%, and 52% (all p <0.0001), triglyceride reductions of 22%, 26%, and 30% (all p <0.0001), and high-density lipoprotein (HDL) cholesterol increases of 6%, 5%, and 3%, respectively (all p <0.05 at the 20- and 40-mg doses). The lowest total cholesterol/HDL cholesterol ratio was observed with the 80 mg/day dose of atorvastatin (p <0.0001 vs placebo). Remnant-like particle (RLP) cholesterol decreased 33%, 34%, and 32%, respectively (all p <0.0001). Lipoprotein(a) [Lp(a)] cholesterol decreased 9%, 16%, and 21% (all p <0.0001), although Lp(a) mass increased 9%, 8%, and 10%, respectively (all p <0.01). In the fed state, atorvastatin 40 mg/day normalized direct LDL cholesterol (29% below controls), triglycerides (8% above controls), and RLP cholesterol (10% below controls), with similar reductions in the fasting state. At this same dose level, atorvastatin treatment resulted in 39%, 35%, and 59% decreases in fasting triglyceride in large, medium, and small very LDLs, as well as 45%, 33%, and 47% reductions in cholesterol in large, medium, and small LDL, respectively, as assessed by nuclear magnetic resonance (all significant, p <0.05), normalizing these particles versus controls (77 cases vs 77 controls). Moreover, cholesterol in large HDL was increased 37% (p <0.001) by this treatment. Our data indicate that atorvastatin treatment normalizes levels of all classes of triglyceride-rich lipoproteins and LDL in both the fasting and fed states in patients with CHD compared with control subjects.

Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study

The aim of this study was to assess the independent contributions of plasma levels of lipoprotein(a) (Lp(a)), Lp(a) cholesterol, and of apo(a) isoform size to prospective coronary heart disease (CHD) risk. Plasma Lp(a) and Lp(a) cholesterol levels, and apo(a) isoform size were measured at examination cycle 5 in subjects participating in the Framingham Offspring Study who were free of CHD. After a mean follow-up of 12.3 years, 98 men and 47 women developed new CHD events. In multivariate analysis, the hazard ratio of CHD was approximately two-fold greater in men in the upper tertile of plasma Lp(a) levels, relative to those in the bottom tertile (P < 0.002). The apo(a) isoform size contributed only modestly to the association between Lp(a) and CHD and was not an independent predictor of CHD. In multivariate analysis, Lp(a) cholesterol was not significantly associated with CHD risk in men. In women, no association between Lp(a) and CHD risk was observed. Elevated plasma Lp(a) levels are a significant and independent predictor of CHD risk in men. The assessment of apo(a) isoform size in this cohort does not add significant information about CHD risk. In addition, the cholesterol content in Lp(a) is not a significant predictor of CHD risk.

The effect of vitamin E, probucol, and lovastatin on oxidative status and aortic fatty lesions in hyperlipidemic-diabetic hamsters

Diabetes mellitus is associated with an increased risk of premature atherosclerosis, which may be due in part to an increased rate of low density lipoprotein (LDL) oxidation. Previous studies have shown that vitamin E, probucol, and lovastatin can reduce the oxidative susceptibility of LDL in normoglycemic animal models; however, few studies have investigated this in conjunction with aortic fatty streak lesion formation in diabetic hyperlipidemic models. Forty-eight Syrian hamsters were made diabetic by intraperitoneal injection of low dose streptozotocin. Diabetic animals (12 animals/groups) received a high saturated fat and cholesterol diet for 12.5 weeks. At 2.5 week of dietary treatments, the diet was supplemented with either: (1) 500 IU/day vitamin E (D+E); (2) 1% probucol w/w of the diet (D+P); (3) 25 mg/kg lovastatin (D+L); or (4) diabetic control (D). An age-matched group of hamsters (n=6) receiving the same diet but not made diabetic (ND) was used as control. At the end of the study, aortic arch foam cell-rich fatty streak lesion, plasma glucose, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides (TG), phospholipids, alpha-tocopherol, plasma lipid peroxide and the susceptibility of LDL to copper-catalyzed oxidation were determined. Diabetes increased plasma glucose, and when combined with an atherogenic diet resulted in a further increase of plasma lipids. Vitamin E, probucol, and lovastatin significantly reduced plasma TG in the diabetic hamsters fed the atherogenic diet. Vitamin E treatment increased TC, probucol reduced HDL-C without affecting TC; whereas lovastatin reduced TC and selectively decreased non-HDL-C, and significantly reduced fatty streak lesion formation in the aortic arch. While vitamin E and probucol were effective in reducing several indices of oxidative stress including plasma lipid peroxides, cholesterol oxidation products and in vitro LDL oxidation, they had no effect on fatty streak lesion formation. Our results indicate that the LDL in diabetic animals is more susceptible to oxidation than in non-diabetic hamsters and that not only vitamin E and probucol but also lovastatin provide antioxidant protection. It appears that in this combined model of diabetes and hypercholesterolemia, progression of fatty streak lesion formation is mainly associated with changes in TC and non-HDL-C as affected by lovastatin, and is less dependent on the extent of LDL oxidation, changes in plasma TG level and oxidative stress status.

Lipoprotein(a), homocysteine, and remnantlike particles: emerging risk factors.

Although lipoprotein(a) [Lp(a)] was first described more than 35 years ago, adequate prospective data have only recently supported Lp(a) as an independent risk factor for coronary heart disease (CHD). In vitro studies suggest that Lp(a) contributes to atherogenesis directly by cholesterol uptake and indirectly by the inhibition of fibrinolysis. In patients with CHD or a significant risk for CHD, Lp(a) should be measured and treated with either niacin or estrogen if the patient has Lp(a) cholesterol levels of more than 10 mg/dL or an Lp(a) mass of more than 30 mg/dL. In addition, homocysteine and remnantlike lipoprotein cholesterol are strongly supported by prospective or population-based prevalence data as independent risk factors for CHD. Homocysteine levels of more than 14 mumol/L should be treated with vitamin supplements of folate, B6, and B12. Remnantlike lipoprotein cholesterol is the product of a novel immunoassay that separates the partially hydrolyzed triglyceride-rich remnant particles. The association of these particles with CHD risk in women may explain the small independent CHD risk that triglycerides have in women in the Framingham Heart Study. A clear therapeutic intervention has not been documented but may include diet, fibric acid derivatives, or hydroxymethylglutamyl coenzyme A reductase inhibitors.

Lipoprotein(a) and coronary heart disease

Elevated plasma or serum lipoprotein(a) (Lp(a)) levels have been associated with premature coronary heart disease (CHD). Lp(a) levels can be assessed quantitatively by electrophoresis and quantitatively by immunoassays determining either total Lp(a) mass, apo(a) mass on Lp(a) protein mass, or by precipitation methods followed by measurement of Lp(a) cholesterol. We prefer the latter method because it can be standardized. Electrophoretic methods can detect total Lp(a) values > or = 30 mg/dl. These values correspond to Lp(a) cholesterol values > or = 10 mg/dl. Such values are above the 75th percentile and represent high risk values for CHD. Values above the 90th percentile for middle aged men and women in Framingham (n = 2678) are > or = 38 mg/dl for total Lp(a). About 16% of patients with premature CHD (n = 321) have such values and have familial Lp(a) excess. Lp(a) is atherogenic because it can be deposited in the arterial wall, and it also can interfere with fibrinolysis. Multiple apo(a) isoforms have been found and are due to a variable number of kringle 4 like repeats. Lower molecular weight apo(a) isoforms forms are associated with elevated Lp(a) values and are more frequent in CHD kindreds. Both Lp(a) levels and apo(a) isoforms are highly heritable in this Caucasian population. Lp(a) values can be decreased with niacin, and such therapy should be strongly considered in CHD patients with elevated Lp(a) levels (> or = 30 mg/dl) since niacin treatment has been shown to decrease CHD morbidity and mortality in unselected CHD patients.

Ascorbic acid supplementation does not lower plasma lipoprotein(a) concentrations

Elevated plasma concentrations of lipoprotein(a) (Lp[a]) are associated with premature coronary heart disease (CHD). Lp(a) is a lipoprotein particle consisting of low-density lipoprotein (LDL) with apolipoprotein (apo) (a) attached to the apo B-100 component of LDL. It has been hypothesized that ascorbic acid supplementation may reduce plasma levels of Lp(a). The purpose of this study was to determine whether ascorbic acid supplementation at a dose of 1 g/day would lower plasma concentrations of Lp(a) when studied in a randomized, placebo-controlled, blinded fashion. One hundred and one healthy men and women ranging in age from 20 to 69 years were studied for 8 months. Lp(a) values at baseline for the placebo group (n = 52) and the ascorbic acid supplemented group (n = 49) were 0.026 and 0.033 g/l, respectively. The 8-month concentrations were 0.027 g/l (placebo) and 0.038 g/l (supplemented group). None of these values were significantly different from each other. In addition, no difference in plasma Lp(a) concentration was seen between the placebo and supplemented groups when only subjects with an initial Lp(a) value of > or = 0.050 g/l were analyzed. Our data indicate that plasma Lp(a) concentrations are not significantly affected by ascorbic acid supplementation in healthy human subjects.

Lipid lowering and weight reduction by home-delivered dietary modification in coronary heart disease patients taking statins.

W diet therapy remains a standard treatment for hypercholesterolemia either alone or in combination with drug treatment,1–5 difficulties continue to exist with dietary compliance. In today’s fast food environment where fewer meals are prepared in the home, a dietary intervention program where meals and snacks are home-delivered may have beneficial effects in increasing diet adherence, while providing continuing nutrition education. This study examines if such a dietary program would result in additional serum lipid reductions beyond the reductions achieved by concurrent drug treatment for hypercholesterolemia in heart disease patients. • • • Forty-seven subjects with established heart disease were recruited from the greater Boston area to participate in a 10-week (8-week intervention, 2-week lead-in period) dietary and lifestyle modification study. Our results are based on 29 subjects (19 men and 10 postmenopausal women, mean age of 61 6 9 years, mean baseline body mass index [BMI] 32.4 6 5.4 kg/m). Six subjects were excluded from this analysis because they were not concurrently being treated with statins, 5 subjects withdrew, 5 subjects violated the protocol by making changes to current medications, and 2 subjects were excluded because of a lack of laboratory measurements. Informed consent, a brief medical history, and a list of current medications were collected at the first study visit. All subjects had been taking statins for at least 6 weeks on a stable dose before enrollment and were not taking vitamins for 4 weeks. Sixty-two percent of subjects were taking atorvastatin, 17% simvastatin, 14% pravastatin, and 7% lovastatin with mean doses (range) of 27 (10 to 60), 24 (20 to 40), 20 (20), and 30 (10 to 40) mg/day, respectively. At each of the 3 study visits (baseline, 4 weeks, and 8 weeks), anthropometric measurements (height, weight, waist circumference, hip circumference, waist-to-hip ratio, and BMI), blood pressure, fasting lipid profile (total cholesterol, low-density lipoprotein [LDL] cholesterol, triglycerides, and high-density lipoprotein [HDL] cholesterol), and 3-day food record were collected. Lipid profiles were processed by the Lipid Metabolism Lab of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University as previously described.5 LDL cholesterol was measured directly as previously described.6 Levels of serum vitamins, cysteine, and homocysteine were measured.7,8 All assays had coefficients of variation of ,5%. A registered dietitian analyzed food records using Nutritionist Five software, version 2.1, (First Data Bank, Inc. San Bruno, California). All other dietary interventions were facilitated by the LifeSpring Nutrition Inc., Richmond, California, registered dietitian. The LifeSpring-registered dietitian telephoned each subject to complete an in-depth interview, dietary assessment, and calculation of energy needs based on the Harris-Benedict equations to achieve weight loss (1 to 2 pounds/week) or maintenance (BMI goal of 23 kg/m). Weekly menu plans included a full week of breakfast, lunch, dinner, and snack recommendations and they were individualized to meet needs (diet restrictions, eating pattern, food allergies or intolerances, and food preferences). Weekly calls were made by the LifeSpring registered dietitian to discuss any questions, problems, to give encouragement, and to adjust calorie levels as needed to reach weight loss goals. Subjects were provided a LifeSpring program kit containing diet education materials From the New England Medical Center, Boston, Massachusetts; Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts; and LifeSpring Nutrition Inc., Richmond, California. E-mail: www.homenutrition.com. This report was supported by LifeSpring Nutrition Inc., Richmond, California; and Grant RO1 HL57477 From the National Institutes of Health, Bethesda, Maryland. Dr. Schaefer’s address is: Lipid Metabolism Laboratory, Tufts University, 711 Washington Street, Boston, Massachusetts 02111. E-mail: eschaefer@hnrc.tufts.edu. Manuscript received July 26, 2000; revised manuscript received and accepted November 6, 2000. TABLE 1 Mean Vitamin Content of Weekly LifeSpring Meal Plan