Requesting necropsies. Necropsy rate was increased to 21% in one hospital.
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Autopsy↗
Biomedical subjects
W S Harris
Publications and source records attributed to W S Harris.
Inhibition of cholesterol absorption with CP-148,623 lowers serum cholesterol in humans.
OBJECTIVE: To determine the effects of the reduction of intestinal cholesterol absorption with CP-148,623 on serum cholesterol levels in men with mild hyperlipidemia. METHODS: In an outpatient study in a university medical center, healthy male volunteers (n = 25) with borderline-high serum cholesterol levels participated in a double-blind, placebo-controlled parallel-group study. A 3-week dietary run-in period was followed by 2 weeks of treatment with either CP-148,623 (300 mg twice a day; n = 12) or placebo (n = 13). RESULTS: Fractional cholesterol absorption (by the dual-isotope, continuous-feeding technique), fecal neutral sterol excretion, and serum lipids were measured after the diet run-in and after the treatment periods. CP-148,623 caused a marked inhibition (by 38%) of fractional cholesterol absorption (50% +/- 2% [baseline] to 31% +/- 1%) and a 71% increase in fecal neutral sterol excretion (481 +/- 39 mg/day [baseline] to 804 +/- 55 mg/day), compared with negligible changes in the placebo group (p < 0.0001 for both). Mean percent reductions from baseline in serum low-density lipoprotein (LDL) cholesterol levels were 11.6% with CP-148,623 (119 +/- 17 mg/dl to 104 +/- 13 mg/dl) versus a nonsignificant 1.8% reduction with placebo (change with CP-148,623 versus placebo, p < 0.0002). CONCLUSIONS: In healthy male volunteers with mild hypercholesterolemia, treatment for 2 weeks with 600 mg/day CP-148,623 inhibited fractional cholesterol absorption by 35% to 40%, increased fecal neutral sterol excretion by 60% to 70%, and reduced serum LDL cholesterol by 10% to 12%.
Adult↗
Influence of fitness status on very-low-density lipoprotein subfractions and lipoprotein(a) in men and women.
The purpose of this study was to examine the influence of the physical activity level of men and women on the very-low-density lipoprotein (VLDL) subfractions and lipoprotein(a) [Lp(a)]. Fifty-four men (n = 30) and women (n = 24) aged 30 to 53 years were recruited based on their level of activity over the past 2 years, and formed three groups: sedentary (S), no routine activity; recreational exercise (R), routine moderate exercise three to five times per week; and trained (T), competition-based, high-volume aerobic training five to seven times per week. Each subject underwent a maximal oxygen consumption (VO2max) test and was measured for body composition (skinfolds) and waist to hip ratio (WHR). Following a prescribed 24-hour diet and abstinence from activity, a blood sample was obtained from each subject and the plasma was analyzed for cholesterol and triglycerides (TGs) in VLDL1, VLDL2, and VLDL3 subfractions. High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and Lp(a) also were analyzed. Total VLDL-C was higher in men than in women, but no gender differences were observed in VLDL subfractions. VLDL1-TG and VLDL2-TG were elevated in the S group compared with groups R and T, even though total VLDL-TG, LDL-C, and HDL-C values were not different among the groups. Values for Lp(a) were not significantly different between men and women or among the groups. The two exercising groups were not different on any lipoprotein variable or WHR. VLDL1-TG was inversely correlated with VO2max and HDL-C. These results suggest that life-style activity is associated with a favorable VLDL subfraction pattern and WHR, but not Lp(a). In addition, long-term recreational activity is associated with a lipoprotein profile and WHR similar to those obtained with higher-volume exercise training.
Adult↗
n-3 fatty acids and urinary excretion of nitric oxide metabolites in humans.
Fish oils rich in n-3 fatty acids have been shown to augment endothelium-dependent vasodilation in human peripheral and coronary arteries. This suggests that n-3 fatty acids may enhance arterial nitric oxide production. To explore this hypothesis we measured total urinary nitrate output in healthy volunteers supplemented with a fish oil concentrate (FOC; n = 15) or purified eicosapentaenoic acid (EPA; n = 14) in a placebo-controlled, parallel-group study. The FOC contained 41% EPA and 23% docosahexaenoic acid (DHA) ethyl esters, whereas EPA was 91% pure; the placebo contained olive oil ethyl esters. Doses were 5 g placebo, 5 g FOC, and 3 g EPA to keep the total n-3 fatty acid content equal in the latter two groups. The placebo period was 2 wk long and was followed by a 3-wk n-3 fatty acid phase. At the end of each period, 24-h urine collections and fasting blood samples were obtained. Serum and urinary nitrate concentrations were measured in a blinded fashion. The FOC produced a 43% increase in daily, creatinine-adjusted, nitrate excretion rates (P < 0.029). Because serum nitrate concentrations were not different, these findings suggest that FOC supplementation may stimulate systemic nitric oxide synthesis. The lack of effect with EPA supplementation suggests that this component of the FOC is not likely to be an active component. If confirmed, these observations suggest another mechanism whereby n-3 fatty acids may be antiatherogenic.
Adult↗
n-3 fatty acids and serum lipoproteins: animal studies.
This review examines the effects of n-3 fatty acids on serum lipid and lipoprotein concentrations in seven species of experimental animals. n-3 Fatty acids consistently lower serum triacylglycerol concentrations in humans but not in most animals. In addition, a common effect of n-3 fatty acids in animals is a marked reduction in high-density-lipoprotein-cholesterol concentrations, a response virtually never seen with fish-oil supplementation in humans. These differences between animals and humans arise not only from underlying species differences in lipoprotein metabolism but also from differences in experimental designs, the most notable of which is the tendency to feed animals much larger amounts of n-3 fatty acids than supplements provide for humans. Thus, great care must be taken not only to use appropriate animal models when studying lipoprotein metabolism but also to feed the animals comparable amounts of n-3 fatty acids. Failure to properly address these issues will make it difficult to uncover the biochemical basis for the hypolipidemic effect of fish oils in humans through use of experimental animals.
Animals↗
n-3 fatty acids and serum lipoproteins: human studies.
The effects of n-3 fatty acids from fish oils (eicosapentaenoic acid and docosahexaenoic acid) and plant oils (alpha-linolenic acid) on human serum lipids and lipoproteins are reviewed. Studies were included in this review if they were placebo-controlled, crossover, or parallel design studies providing < 7 g n-3 fatty acids/d and with treatment periods of > or = 2 wk duration. Only three studies were available for evaluation of the effects of alpha-linolenic acid on serum lipid concentrations. From these studies it appeared that alpha-linolenic acid (18:3n-3) was equivalent to n-6-rich oils vis-vis lipid and lipoprotein effects. Only when very large amounts of flaxseed oil were fed did the hallmark effect of marine n-3 fatty acids-reduced triacylglycerol concentrations-appear. Thus, in terms of effects on lipoprotein metabolism, the plant-derived n-3 fatty acid is not equivalent to the marine-based acids. More studies using the marine-based acids were examined and summarized. Both crossover (n = 36) and parallel (n = 29) design studies reached the same conclusions: total cholesterol is not materially affected by n-3 fatty acid consumption, low-density-lipoprotein cholesterol concentrations tend to rise by 5-10% and high-density-lipoprotein cholesterol by 1-3%, and serum triacylglycerol concentrations decrease by 25-30%. These effects of marine n-3 fatty acids are now well-established; what remains is to determine the mechanisms behind these effects and, more importantly, their health consequences.
Cholesterol↗
Influence of n-3 fatty acid supplementation on the endogenous activities of plasma lipases.
The aim of these studies was to explore the possibility that enhanced triacylglycerol clearance may contribute to the hypotriacylglycerolemic effect of n-3 fatty acids in humans. Healthy subjects (n = 20) and hypertriacylglycerolemic patients (n = 6) were given a placebo (olive oil, OO) or a fish-oil concentrate (FOC; 41% eicosapentaenoic acid and 23% docosahexaenoic acid) in two, independent, randomized, blind trials. For the healthy subjects, the FOC treatment period was 3 wk long and FOC intakes were 5 g/d. For the patients, treatment periods were 4 wk long and dosages were 5 g.70 kg body wt-1.d-1. Washout periods were 2-4 wk for both groups. Blood samples were drawn at the end of each phase and analyzed for plasma lipids, lipoproteins, and endogenous (nonheparin-stimulated) activities of lipoprotein lipase (LPL) and hepatic lipase (HL). In the healthy subjects the FOC decreased plasma triacylglycerol concentrations by 18% (P < 0.01), whereas in the patients concentrations were reduced by 35% (P < 0.05). Low-density-lipoprotein-cholesterol concentrations increased by 25% in the latter group (P = 0.06). FOC increased the endogenous activities of LPL and HL by 62% and 68%, respectively (P < 0.0001), in the healthy subjects, but only LPL in the patients (65%, P < 0.005). These data suggest that endogenous lipase activities may be altered by nutritional interventions, and further, that accelerated lipolysis could contribute, at least in part, to the observed effects of n-3 fatty acids on human lipoprotein metabolism.
Fatty Acids, Omega-3↗
Inhibiting cholesterol absorption with CP-88,818 (beta-tigogenin cellobioside; tiqueside): studies in normal and hyperlipidemic subjects.
CP-88,818 (beta-tigogenin cellobioside; tiqueside) is a synthetic saponin developed to treat hypercholesterolemia by inhibiting the absorption of biliary and dietary cholesterol. Two studies are reported here: one in patients to assess safety and efficacy, and one in normal volunteers to explore the mechanism of action. The former included 15 hypercholesterolemic outpatients [low-density lipoprotein cholesterol (LDL-C) > or = 160 mg/dl] treated with 1, 2, and 3 g of tiqueside daily (b.i.d.) in a crossover design for three 2-week treatment periods, each separated by a 3-week placebo period. The mechanistic study was conducted with 24 healthy male subjects who were randomized in a parallel group design to either placebo (n = 6) or tiqueside (2 or 4 g/day; n = 9 each) once daily for 3 weeks. All subjects in this study were fed a low-fat, low-cholesterol diet [National Cholesterol Education Program (NCEP) Step 1]. Fecal steroid excretion rates and plasma lipid levels were determined at baseline and after 3 weeks of treatment. Fractional cholesterol absorption was measured before and after treatment by the continuous feeding, dual-isotope method. Tiqueside produced a dose-dependent reduction in plasma LDL cholesterol levels in the hypercholesterolemic patients. In the mechanistic study, it decreased fractional cholesterol absorption rates and increased fecal neutral sterol excretion rates, changes associated with trends toward lower LDL cholesterol levels. Other lipoprotein levels were unaffected, as were fecal fat and bile acid excretion and fat-soluble vitamin absorption. Thus tiqueside dose-dependently inhibits cholesterol absorption in humans, resulting in a reduction in serum LDL cholesterol levels.
Adolescent↗
Exercise training, postprandial hypertriglyceridemia, and LDL subfraction distribution.
The purpose of this study was to examine differences in postprandial hypertriglyceridemia (PP-HTG) and low density lipoprotein (LDL) subfraction distribution among groups of men and women with different fitness levels. Fifty-four men and women (ages 30-53 yr) were recruited based on their previous two-year activity level: sedentary (S), recreational exercisers (R), and endurance trained (T). After a 24-h dietary preparation, blood was collected, and LDL subfractions were separated and analyzed for cholesterol (C) and apoprotein B100. Plasma triglyceride (TG) concentration was assessed before and at 2, 4, 6, and 8 h after fat meal. PP-HTG was significantly higher for the S group compared with the two activity groups. LDL3-C and LDL3-apoprotein B100 were significantly higher for the S group compared with the T group and for men compared with women. These findings suggest that both recreational and competitive aerobic training are associated with a lower TG response after a fatty meal. However, higher volume aerobic training may be necessary to reduce the number of dense LDL molecules and their cholesterol content.
Adult↗
N-3 fatty acids and chylomicron metabolism in the rat.
Dietary n-3 fatty acids (FAs) reduce postprandial triacylglycerol concentrations in humans by unknown mechanisms. Our goals were to reproduce this phenomenon in the rat, and then to determine the mechanism. In an oral fat tolerance study two groups of rats were fed diets containing 2.1% ethyl esters of n-3 FA or olive oil for 2 weeks. After gavaging with emulsified soybean oil, the postprandial chylomicron triacylglycerol levels in the n-3 FA group were reduced by 40% (P < 0.05). The hypothesis that n-3 FA feeding reduced chylomicron production/secretion from the gut was tested by blocking chylomicron removal with Triton WR1339 before gavaging the rats with the fat load. This completely eliminated the hypochylomicronemic effect suggesting that chylomicron input was not inhibited by n-3 FAs. Chylomicron clearance was studied by injecting chylomicrons containing radioactive retinyl esters and triacylglycerol into rats from both groups. Pre-feeding with n-3 FAs accelerated the removal of chylomicron triacylglycerol and retinyl esters from the plasma with significantly lower fractions of dose remaining at 2, 4, and 8 min post-injection for both tracers. These findings suggest than n-3 FAs reduce postprandial chylomicronemia in the rat by accelerating chylomicron lipid clearance.
Animals↗
Nicotinic acid--the underused ally in the fight against coronary disease.
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Clinical Trials as Topic↗
n-3 fatty acids and lipoproteins: comparison of results from human and animal studies.
The impact of n-3 fatty acids (FA) on blood lipoprotein levels has been examined in many studies over the last 15 yr in both animals and humans. Studies in humans first demonstrated the potent triglyceride-lowering effect of n-3 FA, and these were followed up with animal studies to unravel the mechanism of action. This paper reviews the reported effects of n-3 FA on blood lipoproteins in 72 placebo-controlled human trials, at least 2 wk in length and providing 7 or less g of n-3 FA/day. Trials in normolipidemic subjects (triglycerides < 2.0 mM; 177 mg/dL) were compared to those in hypertriglyceridemic patients (triglycerides > or = 2.0 mM). In the healthy subjects, mean triglyceride levels decreased by 25% (P < 0.0001), and total cholesterol (C) levels increased by 2% (P < 0.009) due to the combined increases in low density lipoprotein (LDL)-C (4%, P < 0.02) and high density lipoprotein (HDL)-C (3%, P < 0.008). In the patients, triglyceride levels decreased by 28% (P < 0.0001), LDL-C rose by 7% (P < 0.0001), but neither total C nor HDL-C changed significantly. Although the effect on triglyceride levels is also observed in rats and swine, it is rarely seen in mice, rabbits, monkeys, dogs, and hamsters. Whereas n-3 FA have only a minor impact on lipoprotein C levels in humans, they often markedly lower both total C and HDL-C levels in animals, especially monkeys. These differences are not widely appreciated and must be taken into account when studying the effects of n-3 FA on lipoprotein metabolism.
Animals↗
Eicosapentaenoic acid is primarily responsible for hypotriglyceridemic effect of fish oil in humans.
The aim of this study was to determine whether eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), or both, were responsible for the triglyceride (TG)-lowering effects of fish oil. EPA (91% pure) and DHA (83% pure), a fish oil concentrate (FOC; 41% EPA and 23% DHA) and an olive oil (OO) placebo (all ethyl esters) were tested. A total of 49 normolipidemic subjects participated. Each subject was given placebo for 2-3 wk and one of the n-3 supplements for 3 wk in randomized, blinded trials. The target n-3 fatty acid (FA) intake was 3 g/day in all studies. Blood samples were drawn twice at the end of each supplementation phase and analyzed for lipids, lipoproteins, and phospholipid FA composition. In all groups, the phospholipid FA composition changed to reflect the n-3 FA given. On DHA supplementation, EPA levels increased to a small but significant extent, suggesting that some retroconversion may have occurred. EPA supplementation did not raise DHA levels, however. FOC and EPA produced significant decreases in both TG and very low density lipoprotein (VLDL) cholesterol (C) levels (P < 0.01) and increases in low density lipoprotein (LDL) cholesterol levels (P < 0.05). DHA supplementation did not affect cholesterol, triglyceride, VLDL, LDL, or high density lipoprotein (HDL) levels, but it did cause a significant increase in the HDL2/HDL3 cholesterol ratio. We conclude that EPA appears to be primarily responsible for TG-lowering (and LDL-C raising) effects of fish oil.
Adult↗
Dietary fish oil and blood lipids.
Triglyceride lowering is the most consistent effect of fish oils, having been observed in Greenland Eskimos and subsequently in controlled clinical trials. Although total cholesterol levels are not altered, LDL levels may rise, especially in hypertriglyceridemic patients. The persistence of the hypotriglyceridemic effect has been documented in two recent trials following large numbers of patients from 6-9 months. These studies also provided evidence that the LDL raising effect may not persist. The safety of fish oils was also supported in these studies because problems with excessive bleeding and worsening glycemic control did not materialize. However, in one of these studies fish oils proved ineffective in slowing the rate of restenosis after coronary angioplasty.
Angioplasty, Balloon, Coronary↗
Lifestyle change for coronary artery disease. What to tell patients.
Heart-healthy living is a wise choice for anyone, but it assumes even greater importance in persons who have or are at risk for coronary artery disease. Such patients need to know which measures have proved most effective in the prevention and treatment of the disease. This article reviews the data regarding risk factor reduction and offers recommendations for effective lifestyle modifications.
Alcohol Drinking↗
Effects of pravastatin with niacin or magnesium on lipid levels and postprandial lipemia.
This study was designed to evaluate the therapeutic effectiveness of 3 different pharmacologic lipid-lowering regimens in the treatment of patients with clustered lipid risk factors. Sixty-five patients with low high-density lipoprotein (HDL) levels and hypertriglyceridemia were randomized to 1 of 3 treatment arms: pravastatin/niacin, pravastatin/magnesium, or pravastatin/placebo. After 18 weeks, patients in the pravastatin/niacin group had a -41% change in the total cholesterol/HDL ratio compared with -13% in the pravastatin/magnesium arm and -16% in the pravastatin/placebo group. The HDL2 and HDL3 subfractions, as well as the apolipoprotein A-I levels, were increased significantly only in the pravastatin/niacin arm. The levels of small dense low-density lipoprotein (LDL) cholesterol (LDL3) were decreased to a greater extent in the pravastatin/niacin arm (-43%) than in either the pravastatin/magnesium (-13%) or the pravastatin/placebo (-20%) arm. Only the pravastatin/niacin regimen significantly diminished postprandial lipemia (-32% change in the remnant particle triglyceride concentration and decreased very-low-density lipoprotein remnant levels). Thus, in this group of patients with clustered risk factors, the combination of pravastatin and niacin resulted in significant improvements in HDL and triglyceride levels, total cholesterol to HDL ratio, small dense LDL levels, and postprandial lipemia. Pravastatin alone or in combination with magnesium resulted in less significant changes that were largely limited to LDL cholesterol reduction.
Adult↗
Comparison of two scoring systems used to monitor diets in outpatient clinical trials.
BACKGROUND: Dietary stability and compliance are crucial to the proper interpretation of the results of clinical trials evaluating the efficacy of lipid-lowering drugs since dietary variations can obscure the true effects of the drugs being tested. Documentation of compliance to National Cholesterol Education Program (NCEP) dietary guidelines can be difficult to obtain, however, especially since many diets may meet one or two but not all the criteria for a Step 1 or 2 classification. The purpose of this study was to compare the ability of two diet scoring systems (the Food Record Rating [FRR] and the Ratio of Ingested Saturated fat and Cholesterol to Calories [RISCC]) to classify these ambiguous diets. METHODS: Three-day diet diaries (n = 622) were obtained from patients participating in a multicenter, clinical trial testing the lipid-lowering effects of a fiber supplement. The FRR score of each diary was calculated; the diary was then computer analyzed for nutrient composition, and the RISCC score was calculated. Based upon the NCEP dietary criteria for total fat, saturated fat, and cholesterol each diet was classified as either Step 1 or Step 2. Diets exceeding Step 1 criteria were classified as typical American (Step 0). Diets not meeting all 3 criteria for any given Step were considered 'NCEP unclassifiable'. Using the FRR and RISCC scores of only the NCEP-classifiable diets, the optimal RISCC and FRR cutoff points to distinguish between Step 0 and 1 diets and Step 1 and 2 diets were determined. RESULTS: Only 50% of the diets were NCEP-classifiable. Using these diets, a RISCC of 20 best distinguished a Step 0 from a Step 1 diet, and 13 segregated Step 1 from 2 diets. The FRR cutoff points were 14 and 8, respectively. Using these values, the RISCC was able correctly to classify 92-97% of the diets, whereas the FRR correctly classified only 73-80%. Variability of scores within each Step was twice as high for the FRR as for the RISCC. The FRR was more biased by total kilocalories than was the RISCC. CONCLUSION: We conclude that the RISCC scoring system was more accurate and precise than the FRR system for diet classification, and was a superior tool for classifying the ambiguous diets. Since the RISCC also requires (and therefore provides) quantitative nutrient data and the FRR does not, the former is a better dietary monitoring tool for clinical trials.
Diet Records↗
Comparison of effects of probucol versus vitamin E on ex vivo oxidation susceptibility of lipoproteins in hyperlipoproteinemia.
Oxidative modification of low-density lipoprotein (LDL) cholesterol appears to contribute to atherogenesis. Probucol reduces LDL cholesterol oxidation susceptibility, but the consistency, dose, and time course are not well described. Twelve hyperlipidemic patients were given probucol for 4 weeks at the usual dose for cholesterol reduction (1,000 mg/day), or one half (500 mg/day) or one quarter (250 mg/day) the usual dose. Lipoprotein oxidation susceptibility of apolipoprotein B-containing lipoproteins was assessed using a rapid test in which LDL cholesterol and very-low-density lipoprotein are precipitated with dextran sulfate and magnesium ions, redissolved, incubated with copper ions for 3 hours, and tested for thiobarbituric acid-reactive substances. Results are expressed as nmoles of malonyldialdehyde (MDA) generated per mg (nmol MDA/mg) non-high-density lipoprotein cholesterol. Lipoproteins from probucol-treated patients become resistant to oxidation with a predrug value of 85 +/- 19, and decreasing to 3 +/- 1 nmol MDA/mg after drug administration (p < 0.001). Both "half" and "full" doses were effective in lowering lipoprotein oxidation susceptibility by 95%. The "quarter" dose was less effective. Oxidation inhibition was maximized within 2 weeks, returning to baseline 4 to 6 weeks after discontinuing probucol. Four patients were subsequently crossed over to vitamin E (1,200 IU/day). Vitamin E had a milder, less predictable antioxidant effect, lowering lipoprotein oxidation susceptibility by a mean of 24%. In conclusion, probucol treatment effectively and predictably reduces plasma lipoprotein susceptibility to ex vivo, copper-induced oxidation. This clinically applicable test may provide quantitation of antioxidant effects of probucol or other antioxidants and thus facilitate dose adjustments and correlation with antiatherosclerotic effects.
Antioxidants↗