John R. Guyton

Association of levels of lipoprotein Lp(a), plasma lipids, and other lipoproteins with coronary artery disease documented by angiography.

In a study of 307 white patients who underwent coronary angiography, the relationship of coronary artery disease (CAD) to plasma levels of lipoprotein Lp(a) and other lipid-lipoprotein variables was examined. Lp(a) resembles low-density lipoprotein (LDL) in several ways, but can be distinguished and quantified by electroimmunoassay. CAD was rated as present or absent and was also represented by a quantitative lesion score derived from estimates of stenosis in four major coronary vessels. Coronary lesion scores significantly correlated with Lp(a), total cholesterol, triglycerides, LDL cholesterol, and high-density lipoprotein (HDL) cholesterol levels by univariate statistical analysis. By multivariate analysis levels of Lp(a) were associated significantly and independently with the presence of CAD (p less than .02), and tended to correlate with lesion scores (p = .06). Among subgroups Lp(a) level was associated with CAD in women of all ages and in men 55 years old or younger. An apparent threshold for coronary risk occurred at Lp(a) lipoprotein mass concentrations of 30 to 40 mg/dl, corresponding to Lp(a) cholesterol concentrations of approximately 10 to 13 mg/dl. Plasma Lp(a) in white patients appears to be a major coronary risk factor with an importance approaching that of the level of LDL or HDL cholesterol.

A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial.

Context Low-carbohydrate weight reduction diets are popular despite a dearth of data on long-term efficacy and adverse effects. Contribution Community-dwelling hyperlipidemic persons were randomly assigned to either a low-carbohydrate, ketogenic diet or a low-fat, low-cholesterol, reduced-calorie diet for 24 weeks. Compared to the low-fat group, patients in the low-carbohydrate group lost more weight, had a greater decrease in triglyceride levels, and had higher high-density lipoprotein cholesterol levels. Levels of low-density lipoprotein cholesterol remained stable in both groups. Side effects were more common in the low-cholesterol group but were generally mild. Cautions While the study suggests the efficacy and relative safety of the low-cholesterol diet, the high dropout rate, self-directed adherence to the diet, and relatively short observation period challenge the generalizability of the findings. The Editors As the prevalence of obesity has increased over the past 20 years (1), the difficulties faced by overweight patients and their health care practitioners have become apparent. Fewer than 25% of Americans who attempt to lose weight actually reduce caloric intake and increase exercise as currently recommended (2). Persons who successfully lose weight have difficulty maintaining their weight loss (3). Therefore, it is not surprising that consumers spend

A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.

33 billion yearly on weight loss products and services in search of effective therapies (2). Because many weight loss interventions are unproven and untested, practitioners often lack information with which to recommend a certain therapy or to monitor a patient once a therapy is chosen. One approach to weight loss that has gained recognition in the face of modest supportive scientific evidence is the low-carbohydrate diet. A popular version of this diet recommends extreme restriction of carbohydrate intake to less than 20 g/d initially (4). This level of carbohydrate restriction can induce serum and urinary ketones and weight loss (5, 6). However, until recently, available data on low-carbohydrate diets came from small studies of short duration, most of which were uncontrolled (5, 7-10). We examined body weight, body composition, serum lipid levels, and adverse effects over 24 weeks in hyperlipidemic persons who were randomly assigned to follow a low-carbohydrate, ketogenic diet or a low-fat, low-cholesterol, reduced-calorie diet commonly used to induce weight loss and decrease serum lipid levels. Methods Participants Generally healthy persons were recruited from the community. Inclusion criteria were age 18 to 65 years, body mass index of 30 to 60 kg/m2, desire to lose weight, elevated lipid levels (total cholesterol level > 5.17 mmol/L [>200 mg/dL], low-density lipoprotein [LDL] cholesterol level > 3.36 mmol/L [>130 mg/dL], or triglyceride level > 2.26 mmol/L [200 mg/dL]), and no serious medical condition. Exclusion criteria were use of any prescription medication in the previous 2 months (except for oral contraceptives, estrogen therapy, and stable thyroid medication), pregnancy or breastfeeding, use of any weight loss diet or diet pills in the previous 6 months, and baseline ketonuria. All participants provided written informed consent, and the institutional review board of Duke University Health System approved the study. Participants received no monetary incentive. Interventions By using a computer-generated simple randomization list, participants were allocated to receive the low-carbohydrate diet or low-fat diet. The intervention for both groups included group meetings, diet instruction, and an exercise recommendation. Group meetings took place at an outpatient research clinic twice monthly for 3 months, then monthly for 3 months. These meetings typically lasted 1 hour and consisted of diet instruction, supportive counseling, questionnaires, and biomedical measurements. During the study, participants selected their own menus and prepared or bought their own meals according to the guidelines presented to them. Participants were encouraged to exercise for 30 minutes at least 3 times weekly, but no formal exercise program or incentives were provided. Low-Carbohydrate Diet Using a popular diet book published by a lay press and additional handouts, trained research staff instructed participants to restrict intake of carbohydrates to less than 20 g/d (4). Participants were permitted unlimited amounts of animal foods (meat, fowl, fish, and shellfish), unlimited eggs, 4 oz of hard cheese, 2 cups of salad vegetables (such as lettuce, spinach, or celery), and 1 cup of low-carbohydrate vegetables (such as broccoli, cauliflower, or squash) daily. Participants were encouraged to drink 6 to 8 glasses of water daily. When participants were halfway to their goal body weight (determined at the week 10 visit with assistance from research personnel), they were advised to add approximately 5 g of carbohydrates to their daily intake each week until they reached a level at which body weight was maintained. To simulate the practice of the study sponsor, the low-carbohydrate diet group also received daily nutritional supplements (multivitamin, essential oils, diet formulation, and chromium picolinate; for a list of the composition of these supplements, see the Appendix) (6). Low-Fat Diet Using a commonly available booklet and additional handouts, a registered dietitian instructed participants in a diet consisting of less than 30% of daily energy intake from fat, less than 10% of daily energy intake from saturated fat, and less than 300 mg of cholesterol daily (11, 12). The recommended energy intake was 2.1 to 4.2 MJ (500 to 1000 kcal) less than the participants calculated energy intake for weight maintenance (body weight in pounds 10) (13). Primary Outcome Measure Body weight and body mass index were the primary outcome measures. At each visit, participants were weighed on the same calibrated scale while wearing lightweight clothing and no shoes. Body mass index was calculated as body weight in kilograms divided by height in meters squared. Secondary Outcome Measures Adherence Adherence to the diet was measured by self-report, food records, and, for the low-carbohydrate diet group, urinary ketone assessment. Diet Composition All participants completed a 24-hour recall of food intake at baseline and take-home food records (5 consecutive days, including a weekend) that were collected at each meeting during the study. Participants were instructed on how to document food intake and were given handouts with examples of how to complete the records. A sample of participants (13 in the low-carbohydrate diet group and 7 in the low-fat diet group) who completed the study was selected for food record analysis by the research staff on the basis of adequacy of detail in their records. A registered dietitian analyzed the food records by using a nutrition software program (Nutritionist Five, version 1.6 [First DataBank, Inc., San Bruno, California]). Ketonuria Restriction of dietary intake of carbohydrates to less than 40 g/d typically results in ketonuria that is detectable by dipstick analysis, which can be used to monitor adherence to the low-carbohydrate diet (14, 15). At each return visit, participants provided a fresh urine specimen for analysis. The following semi-quantitative scale was used to categorize ketone content: none, trace (up to 0.9 mmol/L [5 mg/dL]), small (0.9 to 6.9 mmol/L [5 to 40 mg/dL]), moderate (6.9 to 13.8 mmol/L [40 to 80 mg/dL]), large80 (13.8 to 27.5 mmol/L [80 to 160 mg/dL]), and large160 (>27.5 mmol/L [>160 mg/dL]). Body Composition Body composition was estimated by using bioelectric impedance (model TBF-300A [Tanita Corp., Arlington Heights, Illinois]) at approximately the same time of day (afternoon or evening) at each return visit. In a subset of 33 participants, the percentage of body fat as measured by bioelectric impedance had excellent correlation with the percentage as measured by dual-energy x-ray absorptiometry (r = 0.93 [95% CI, 0.87 to 0.97]). Vital Signs Blood pressure and pulse rate were measured in the nondominant arm by using an automated digital cuff (model HEM-725C [Omron Corp., Vernon Hills, Illinois]) after the participant had been sitting for 3 minutes. Two measurements were taken at each visit and averaged for the analysis. Serum Lipids and Lipoproteins Serum specimens for lipid measurement were obtained in the morning after at least 8 hours of fasting at the screening visit and at 8, 16, and 24 weeks. Other Metabolic Effects Serum tests for sodium, potassium, chloride, urea nitrogen, creatinine, calcium, phosphorus, total protein, albumin, uric acid, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, thyroid-stimulating hormone, iron, hemoglobin, leukocyte count, and platelet count were obtained at the screening visit and at 8, 16, and 24 weeks. The glomerular filtration rate was estimated by using an equation that included age; sex; race; and serum levels of albumin, creatinine, and urea nitrogen (Modification of Diet in Renal Disease Study equation) (16). Adverse Effects At all return visits, participants completed an open-ended questionnaire on side effects. At the 20- and 24-week visits, participants completed a checklist of the side effects that were most often mentioned during the study. Statistical Analysis Analyses were performed by using S-PLUS software, version 6.1 (Insightful Corp., Seattle, Washington), or SAS software, version 8.02 (SAS Institute, Inc., Cary, North Carolina). For categorical outcomes, groups were compared by using the chi-square test or Fisher exact test, as appropriate. For all primary and secondary continuous outcomes, linear mixed-effects models (PROC MIXED procedure in SAS software) that included fixed and random effects were used to determine expected mean values at each time point and to test hypotheses of group differences. In most body weight and b

Inhibition of rat arterial smooth muscle cell proliferation by heparin. In vivo studies with anticoagulant and nonanticoagulant heparin.

The compositions of lesion types that precede and that may initiate the development of advanced atherosclerotic lesions are described and the possible mechanisms of their development are reviewed. While advanced lesions involve disorganization of the intima and deformity of the artery, such changes are absent or minimal in their precursors. Advanced lesions are either overtly clinical or they predispose to the complications that cause ischemic episodes; precursors are silent and do not lead directly to complications. The precursors are arranged in a temporal sequence of three characteristic lesion types. Types I and II are generally the only lesion types found in children, although they may also occur in adults. Type I lesions represent the very initial changes and are recognized as an increase in the number of intimal macrophages and the appearance of macrophages filled with lipid droplets (foam cells). Type II lesions include the fatty streak lesion, the first grossly visible lesion, and are characterized by layers of macrophage foam cells and lipid droplets within intimal smooth muscle cells and minimal coarse-grained particles and heterogeneous droplets of extracellular lipid. Type III (intermediate) lesions are the morphological and chemical bridge between type II and advanced lesions. Type III lesions appear in some adaptive intimal thickenings (progression-prone locations) in young adults and are characterized by pools of extracellular lipid in addition to all the components of type II lesions.

Efficacy and safety of an extended-release niacin (Niaspan) : A long-term study

Heparin inhibits the proliferation of intimal smooth muscle cells which occurs after denudation of endothelium by air-drying injury in the rat carotid artery. We determined (1) whether the antiproliferative effect of heparin is secondary to effects on platelet adherence to subendothelium or endothelial regeneration and (2) whether the antiproliferative and anticoagulant activities of heparin are related. Morphometric observations by scanning electron microscopy showed that heparin did not alter platelet adherence 5 days after arterial injury and had little or no effect on endothelial regener- ation at 5 and 10 days. To study the relationship between the antiproliferative and anticoagulant effects, we fractionated heparin by affinity chromatography on antithrombin-Sepharose into purified anticoagulant and nonanticoagulant fractions. These heparin fractions were administered to rats in doses which were equivalent either in terms of anticoagulant activity or in terms of mass to the dosage of unfractionated heparin known to inhibit myointimal growth. Additionally, some rats received nonanticoagulant heparin at a dose which was greater in terms of mass than the highest dose of unfractionated heparin which could be administered without inducing fatal hemorrhage. Inhibition of myointimal growth, determined by morphometric analysis of total plaque volume 2 weeks after arterial injury, correlated with total mass of heparin administered but not with anticoagulant activity. Non- anticoagulant heparin given at high dose caused 77% inhibition of myointimal growth (P = 0.02 vs. controls). Heparin inhibition of arterial smooth muscle cell proliferation does not appear to be mediated either by effects on other cells at the level of the arterial wall or by antithrombin. This study should direct attention toward a potential growth regulatory role for arterial glycosaminoglycans. Circ Res 46: 625-634, 1980

Long-Term Safety and Efficacy of a Once- Daily Niacin/Lovastatin Formulation for Patients With Dyslipidemia*

Crystalline nicotinic acid (immediate-release niacin) is effective therapy for lipoprotein regulation and cardiovascular risk reduction. However, inconvenient regimens and unpleasant side effects decrease compliance. Sustained-release formulations designed to circumvent these difficulties increase hepatotoxicity. Niaspan, a new US Food and Drug Administration (FDA)-approved, once-daily, extended-release form, has been found effective and safe in short-term trials. The long-term efficacy and safety of Niaspan lipid monotherapy was studied in 517 patients (aged 21-75 years) for < or =96 weeks in dosages < or =3,000 mg/day. Primary efficacy endpoints were low-density lipoprotein (LDL) cholesterol and apolipoprotein B (apo B) changes from baseline; secondary efficacy endpoints were changes in total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, lipoprotein(a), and total cholesterol/HDL-cholesterol ratio; safety data included adverse events and laboratory values over the 2-year study period. LDL-cholesterol levels decreased significantly: 18% at week 48 and 20% at week 96; apo B reduction was similar (16% decrease at week 48 and 19% at week 96). Large elevations in HDL cholesterol (26%, week 48; 28%, week 96) allowed only modest decreases in total cholesterol (12% and 13%, respectively), whereas total cholesterol/HDL-cholesterol ratio decreased by almost one third. Triglyceride and lipoprotein(a) levels were decreased by 27% and 30%, respectively (week 48), and by 28% and 40%, respectively (week 96). All changes from baseline were significant (p <0.001). Niaspan was generally well tolerated, although flushing was common (75%); however, there was a progressive decrease in flushing with time from 3.3 episodes in the first month to < or = 1 episode by week 48. Aspirin was used by one third of patients before Niaspan dosing to minimize flushing episodes. Although serious adverse events occurred in about 10% of patients, none were considered probably or definitely related to Niaspan. Adverse events in general varied widely, but their true relation to the study drug is difficult to ascertain without a placebo (control) group. No deaths occurred. There were statistically significant changes in hepatic transaminases, alkaline phosphatase, direct bilirubin, phosphorus, glucose, amylase, and uric acid. However, these changes were mostly small and are not likely to be biologically or clinically significant (the decrease in phosphorus is a new finding in niacin therapy). No myopathy was observed. Thus, this long-term study confirms the earlier short-term findings that Niaspan is safe and effective as monotherapy in plasma lipoprotein regulation.

Quantitation and localization of apolipoproteins [a] and B in coronary artery bypass vein grafts resected at re-operation.

Combination therapy is increasingly recommended for patients with multiple lipid disorders, especially those at high risk for coronary events. We investigated the long-term safety and effectiveness of a new drug formulation containing once-daily extended-release niacin and lovastatin. A total of 814 men and women (mean age 59 years) with dyslipidemia were enrolled in a 52-week multicenter, open-label study. We used 4 escalating doses (niacin/lovastatin in milligrams): 500/10 for the first month, 1,000/20 for the second, 1,500/30 for the third, and 2,000/40 for the fourth month through week 52. Dose-dependent effects were observed for all major lipid parameters. At week 16, mean low-density lipoprotein (LDL) cholesterol and triglycerides were reduced by 47% and 41%, respectively; mean high-density lipoprotein (HDL) cholesterol was increased by 30% (all p <0.001). LDL/HDL cholesterol and total/HDL cholesterol ratios were also decreased by 58% and 48%, respectively. These effects persisted through week 52, except for the mean increase in HDL cholesterol, which had increased to 41% at 1 year. Lipoprotein (a) and C-reactive protein also decreased in a dose-related manner (by 25% and 24%, respectively, on 2,000/40 mg; p <0.01 vs baseline). Treatment was generally well tolerated. The most common adverse event was flushing, which caused 10% of patients to withdraw. Other adverse events included gastrointestinal upset, pruritus, rash, and headache. Drug-induced myopathy did not occur in any patient. The incidence of elevated liver enzymes to >3 times the upper limit of normal was 0.5%. Once-daily niacin/lovastatin exhibits substantial effects on multiple lipid risk factors and represents a significant new treatment option in the management of dyslipidemia.

Relationship of plasma lipoprotein Lp(a) levels to race and to apolipoprotein B.

Lp[a] is a lipoprotein whose plasma concentration is highly correlated with cardiovascular disease. Its protein moiety, apoLp[a], consists of two large polypeptides, apo[a] and apo B. The possible contribution of Lp[a] to atherosclerosis in saphenous vein aortocoronary bypass grafts was studied in a population of patients undergoing coronary re-bypass surgery. The vein graft tissue levels of apoLp[a] were compared with graft duration, gross and light microscopic pathology, as well as plasma levels of apoLp[a]. The localization pattern of apo[a] and apo B in vein graft tissue was determined. In addition, the plasma levels of cholesterol, triglycerides, apoproteins (apo) A-I, A-II, and E were measured. In a representative subpopulation of 17 patients with a mean age of 63 years from whom grafts with a mean duration of 112 months were resected, the mean total plasma cholesterol level was 221 mg/dl, the mean high density lipoprotein cholesterol level was 31 mg/dl, and the mean plasma triglyceride level was 228 mg/dl. In normal saphenous veins, the level of apoLp[a] was below measurable limits (less than 2 ng/mg), and the level of apo B was very low (3.3 ng/mg). In resected grafts, the mean tissue level of apoLp[a] was 32 ng/mg, and that of apo B was 70 ng/mg, demonstrating the net accumulation of these apoproteins in veins from the time of their grafting into the arterial bed. The apoLp[a]/apo B ratio was determined in 77 tissue segments from 59 grafts (28 patients) and was found to be 0.313. This tissue ratio was significantly higher (p = 0.02) than the plasma apoLp[a]/apo B ratio from these patients, which was 0.132. Immunostaining showed co-localization of apo[a] and apo B in the neointima of grafts. The most abundant pathologic features observed in resected grafts were proliferated intima (43/52), thrombus (28/52), and atherosclerotic core regions (21/52). The level of tissue apo B correlated well with the abundance of core regions (r = 0.501), whereas the level of tissue apoLp[a] did not correlate as well with this feature (r = 0.233). Although apo[a] and apo B are almost absent from normal saphenous vein, these apoproteins (and presumably the lipoproteins Lp[a] and low density lipoprotein) accumulate in bypass vein grafts. The data support the view that these lipoproteins play a significant role in vein graft atherosclerosis.

Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia☆

Lipoprotein Lp(a) is an atherogenic subfraction of plasma lipoproteins which has been studied predominantly in white populations. We quantified Lp(a) by electroimmunoassay in plasma from 105 black and 134 white healthy men and women. Results were correlated with clinical variables and plasma levels of lipids, other lipoproteins, and apolipoprotein (apo) B determined by radioimmunoassay. Black subjects had levels of Lp(a) that averaged twice those of whites (p < 0.001). Among blacks, Lp(a) levels showed a bell-shaped frequency distribution, while among whites the distribution was strongly skewed, with the highest frequencies at low levels. Contrary to previously published results, the apo B levels in our study correlated significantly, though weakly, with Lp(a) (r = 0.21, p = 0.001 among whites, and r = 0.15, p = 0.02 among blacks, Kendall rank correlation). The regression slopes and variances suggested that apo B in the Lp(a) lipoprotein could account for the correlation. Lp(a) levels did not correlate significantly with any other plasma lipoprotein or lipid levels. The implications of this study are as follows: Despite the high levels of Lp(a) among blacks in the Houston area, these blacks do not experience greatly increased atherosclerotic progression and mortality. Thus, the atherogenicity of Lp(a) in blacks must be decreased or counterbalanced by other factors. The correlation between Lp(a) and apo B should be taken into account when analyzing atherogenic risk, but this correlation is not strong enough to dispute the independence of Lp(a) and apo B as risk factors.

Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia∗ ☆

This multicenter trial evaluated the safety and efficacy of escalating doses of Niaspan (niacin extended-release tablets) and placebo (administered once-a-day at bedtime) in patients with primary hyperlipidemia on the percent change from baseline in levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein B. Extended-release niacin was initiated at a dose of 375 mg/day, raised to 500 mg/day, and further increased in 500-mg increments at 4-week intervals to a maximum of 3,000 mg/day. A total of 131 patients (n = 87, extended-release niacin; n = 44, placebo) were treated for 25 weeks with study medication after a 6-week diet lead-in/drug washout phase and 2-week baseline LDL cholesterol stability phase. Significant decreases from baseline in levels of LDL cholesterol and apolipoprotein B became apparent with the 500-mg/day dose and were consistent at all subsequent doses (p < or =0. 05), reaching 21% and 20%, respectively, at the 3,000-mg/day dose. Significant increases from baseline in levels of high-density lipoprotein cholesterol became apparent with the 500-mg/day dose and were consistent at all subsequent doses (p < or = 0.05), reaching 30% at the 3,000-mg dose. Significant decreases from baseline in triglycerides and lipoprotein(a) occurred at the 1,000-mg dose and were apparent at all subsequent doses (p < or =0.05), reaching 44% and 26%, respectively, at the 3,000-mg dose. The most common adverse events were flushing and gastrointestinal disturbance. Transaminase increases were relatively small, and the proportion of patients who developed liver function abnormalities on extended-release niacin was not significantly different from placebo. Thus, extended-release niacin was generally well tolerated and demonstrated a dose-related ability to alter favorably most elements of the lipid profile.