Adipose tissue mass and location affect circulating adiponectin levels.

AIMS/HYPOTHESIS: Plasma levels of adiponectin are inversely associated with body mass. We hypothesised that adipose tissue distribution and body composition influences adiponectin levels. METHODS: We assessed plasma adiponectin concentrations and dual-energy X-ray absorptiometry (DEXA) measurements of body composition among 2,820 participants from the Dallas Heart Study. RESULTS: Among both women and men, adiponectin levels were higher in whites than in either Hispanics or African-Americans (for women: median 9.99 µg/ml [25th,75th percentile 7.11, 13.77] vs 7.56 µg/ml [5.05, 9.98] vs 6.39 µg/ml [4.37, 9.41], respectively, p < 0.0001; for men: 6.43 µg/ml [4.66, 9.19] vs 5.55 µg/ml [3.64, 7.50] vs 5.03 µg/ml [3.39, 7.28], p < 0.0001). In univariate analysis, each individual component of body mass was inversely associated with adiponectin. After multivariate analysis, adiponectin levels were found to be positively associated with lower extremity fat, whether expressed in absolute mass (for women: ß = 0.055, p < 0.0001; for men: ß = 0.061, p < 0.0001), or as a relative proportion (for women: ß = 0.035, p < 0.0001; for men: ß = 0.034, p < 0.0001). This association was consistent across ethnicities. Conversely, adiponectin was negatively correlated with truncal fat, both in absolute (for women: ß = -0.039, p < 0.0001; for men: ß = -0.044, p < 0.0001) and relative terms (for women: ß = -0.027, p < 0.0001; for men ß = -0.033, p < 0.0001). At the extreme of body mass, higher degrees of lower extremity and truncal adiposity were associated with higher levels of adiponectin. CONCLUSIONS/INTERPRETATION: These data suggest that the location of adipose depots differentially influences circulating adiponectin concentrations-a finding observed across ethnicity and sex. Gross measures of body mass alone do not adequately account for adiponectin levels. This supports a role of adiponectin as a mediator of the positive effects of lower extremity adiposity on improvements in insulin sensitivity.

In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia.

The causes of primary moderate hypercholesterolemia are not understood, but some patients have reduced fractional clearance rates (FCRs) for low density lipoproteins (LDL). This could be due to either decreased activity of LDL receptors or to a defect in structure (or composition) of LDL that reduces its affinity for receptors. To distinguish between these causes, simultaneous turnover rates of autologous and normal homologous LDL were determined in 15 patients with primary moderate hypercholesterolemia. In 10, turnover rates of both types of LDL were indistinguishable, which indicated that autologous LDL was cleared as efficiently as normal homologous LDL. In five others, FCRs for autologous LDL were significantly lower than for homologous LDL. Two of the latter five were treated with mevinolin, and although FCRs for both types of LDL rose during treatment, differences in FCRs between the two types of LDL persisted. In these five patients, autologous LDL appeared to be a poor ligand for LDL receptors.

Comparison of visceral fat mass measurement by dual-X-ray absorptiometry and magnetic resonance imaging in a multiethnic cohort: the Dallas Heart Study.

BACKGROUND/OBJECTIVES: Visceral adipose tissue (VAT) mass, a risk factor for cardiometabolic complications of obesity, is usually measured by magnetic resonance imaging (MRI) but this method is not practical in a clinical setting. In contrast, measurement of VAT by dual-x-ray absorptiometry (DXA) appears to circumvent the limitations of MRI. In this study, we compared measurements of VAT mass by MRI and DXA in the large, multiethnic cohort of the Dallas Heart Study (DHS). SUBJECTS/METHODS: About 2689 DHS participants underwent paired measurement of VAT by MRI and DXA. Sex-stratified analyses were performed to evaluate the correlation and agreement between DXA and MRI. Model validation was performed using bootstrapping and inter-reader variability was assessed. RESULTS: Mean age of the cohort was 44 years, with 55% female, 48% Black and 75% overweight/obese participants. Regression analysis showed a linear relationship between DXA and MRI with R(2)=0.82 (95% confidence interval (CI) 0.81-0.84) for females and R(2)=0.86 (95% CI 0.85-0.88) for males. Mean difference between methods was 0.01 kg for females and 0.09 kg for males. Bland-Altman analysis showed that DXA tended to modestly underestimate VAT compared with MRI at lower VAT levels and overestimate it compared with MRI at higher VAT levels. Results were consistent in analyses stratified by race, body mass index status, waist girth and body fat. Inter-individual reader correlation among 50 randomly selected scans was excellent (inter-class correlation coefficient=0.997). CONCLUSIONS: VAT mass quantification by DXA was both accurate and valid among a large, multiethnic cohort within a wide range of body fatness. Further studies including repeat assessments over time will help determine its long-term applicability.

Effect of intensive diabetes treatment on low-density lipoprotein apolipoprotein B kinetics in type I diabetes.

The metabolism of low-density lipoprotein (LDL) was studied in six insulin-dependent (type I) diabetic patients during a 7-wk period of conventional and intensive therapy with insulin. Plasma glucose and HbA1c were normalized, demonstrating the effectiveness of our intensive treatment program. Plasma lipoprotein profiles and LDL apolipoprotein B kinetic parameters were estimated during conventional and then during intensive therapy for each patient. Intensive therapy resulted in a significant reduction of plasma and LDL cholesterol and an increase in high-density lipoprotein (HDL) cholesterol. The lower LDL levels resulted from a decreased production of lipoprotein rather than an increased fractional catabolic rate. These results are consistent with our previous observations of very-low-density lipoprotein (VLDL) metabolism during intensive therapy. VLDL production is significantly reduced; thus, a decreased production of LDL supports the contention that intensive therapy with insulin in normolipemic type I diabetic patients reduces the production of lipoproteins containing apolipoprotein B rather than increasing the clearance, and therapy also increases HDL cholesterol. Both of these effects may be beneficial in reducing the risk for coronary heart disease in type I diabetes.

Two different views of the relationship of hypertriglyceridemia to coronary heart disease. Implications for treatment.

Hypertriglyceridemia is commonly found in patients with coronary heart disease. The reason for this connection, however, is not well understood, and two different views have been put forth to explain the link. First, triglyceride-rich lipoproteins, particularly very-low-density lipoproteins, may be directly atherogenic. Or second, the metabolic consequences of hypertriglyceridemia may account for the triglyceride-coronary heart disease relationship. These consequences include an increase in postprandial lipoproteins, large very-low-density lipoprotein particles, small, dense low-density lipoprotein particles, low levels of high-density lipoprotein cholesterol, and possibly a procoagulant state. The appropriate treatment of hypertriglyceridemia depends on which of these views is nearer the truth. If triglyceride-rich lipoproteins are directly atherogenic, then the preferred therapy would be hepatic hydroxymethylglutaryl coenzyme A reductase inhibitors, which lower both very-low-density lipoprotein and low-density lipoprotein levels. On the other hand, if the link to atherogenesis is through the metabolic consequences of hypertriglyceridemia, the appropriate therapy would be to directly lower serum triglyceride levels, as with niacin or a fibric acid. Thus, discovery of the mechanism of the connection between triglycerides and coronary heart disease is crucial for developing a rational therapy.

Lipoprotein responses to treatment with lovastatin, gemfibrozil, and nicotinic acid in normolipidemic patients with hypoalphalipoproteinemia.

BACKGROUND: The lipoprotein responses to conventional lipid-modifying drugs have not been adequately evaluated in normolipidemic patients with hypoalphalipoproteinemia (low levels of high-density lipoproteins). The purpose of this study was to compare responses to lovastatin, gemfibrozil, and nicotinic acid in such patients. METHODS: The first phase of the study compared lipoprotein responses to lovastatin and gemfibrozil in 61 middle-aged men with low levels of high-density lipoproteins. In the second phase, 37 patients agreed to take nicotinic acid; 27 patients finished this phase at a dose of 4.5 g/d. Nicotinic acid results were compared with those with lovastatin and gemfibrozil in the same patients. RESULTS: In the first phase, both drugs effectively lowered triglyceride levels. Gemfibrozil therapy increased high-density lipoprotein cholesterol levels by 10% and lovastatin by 6%, but lovastatin was much more effective for reducing low-density lipoprotein levels. Nicotinic acid did not significantly lower low-density lipoprotein levels in the second phase, but it raised high-density lipoprotein levels by 30%. CONCLUSIONS: Gemfibrozil therapy produced the least favorable response of the three drugs. Lovastatin markedly lowered low-density lipoprotein levels but only modestly raised levels of high-density lipoprotein, whereas nicotinic acid had the opposite effect. Consequently, the latter two drugs similarly reduced low-density lipoprotein-high-density lipoprotein ratios, although these effects were obtained in different ways. Between these two drugs, lovastatin therapy was more likely to reduce low-density lipoprotein cholesterol levels to below 2.6 mmol/L (100 mg/dL), and in view of recent recommendations, it may be preferable to nicotinic acid for many normolipidemic patients with established coronary heart disease.

Management of primary mixed hyperlipidemia with lovastatin.

Many patients with high levels of serum total cholesterol have a concomitant elevation of serum triglyceride levels and thus have mixed hyperlipidemia. In this study, 13 patients with mixed hyperlipidemia were treated with the cholesterol-lowering drug lovastatin to determine its effectiveness. In 9 of these patients, lovastatin therapy used alone was compared with the drug combination of lovastatin and gemfibrozil. In the 13 patients, lovastatin therapy produced a 31% reduction in total cholesterol level and a 32% decrease in triglyceride levels compared with placebo. It lowered very-low-density plus intermediate-density lipoprotein cholesterol levels by 40%, low-density lipoprotein cholesterol levels by 36%, and total apolipoprotein B levels by 28%. Concentrations of high-density lipoprotein cholesterol and apolipoprotein A-I were unchanged, but total cholesterol (and low-density lipoprotein cholesterol)/high-density lipoprotein cholesterol ratios were markedly reduced. Compared with lovastatin alone, lovastatin plus gemfibrozil produced greater decreases in very-low-density plus intermediate-density lipoprotein cholesterol levels and an increase in high-density lipoprotein cholesterol levels, but, in view of the higher risk for severe myopathy with this combination, lovastatin used alone may be adequate therapy for many patients with mixed hyperlipidemia.

Lp(a) lipoprotein is an independent, discriminating risk factor for premature peripheral atherosclerosis among white men.

BACKGROUND: Elevated plasma levels of Lp(a) lipoprotein have been linked to the development of premature atherosclerosis in the coronary circulation (coronary artery disease [CAD]). Although Lp(a) lipoprotein has been implicated as a risk factor for premature atherosclerosis in other locations, the patient populations described were not carefully screened for the coexistence of premature CAD. The purpose of this prospective study was to determine whether carefully screened patients with premature peripheral vascular disease (PVD) have elevated plasma levels of Lp(a) lipoprotein and to test the relative strength of Lp(a) lipoprotein level as a risk factor for premature PVD. METHODS: We studied 55 consecutive white men with premature PVD (onset at 45 years of age or earlier) presenting to our vascular laboratory. Study subjects were substratified into 17 with PVD only and 38 with combined PVD and CAD (PVD + CAD). Two comparison groups included 26 age-matched white men with premature CAD recruited from the Cardiology Service after cardiac catheterization and 32 age-matched white male controls recruited from outpatient clinics. RESULTS: Mean plasma apolipoprotein B-100 levels were higher in the CAD group than in controls (P = .013). Mean plasma Lp(a) lipoprotein levels were higher among the 17 patients with PVD only than among controls (P = .008). The covariance-adjusted mean Lp(a) lipoprotein levels were higher among all 55 patients with PVD than among controls (P = .014). Logistic regression analysis demonstrated two variables to be significantly related to premature PVD: Lp(a) lipoprotein level greater than 30 mg/dL (odds ratio, 3.9; 95% confidence interval, 1.1 to 13.7) and apolipoprotein B level greater than 95 mg/dL (odds ratio, 3.2; 95% confidence interval, 1.0 to 10.0). CONCLUSIONS: Lp(a) lipoprotein level is an independent, discriminating risk factor for premature PVD among white men.

Effectiveness of low-dose crystalline nicotinic acid in men with low high-density lipoprotein cholesterol levels.

BACKGROUND: Hypoalphalipoproteinemia (low serum concentration of high-density lipoprotein cholesterol [HDL-C]) is a common pattern of dyslipidemia associated with coronary heart disease. High doses of nicotinic acid effectively raise HDL-C levels in this condition, but they are commonly accompanied by side effects. The efficacy of low doses of nicotinic acid that may produce fewer side effects has not been adequately studied. OBJECTIVE: To determine the effects of low-dose nicotinic acid on HDL-C levels in patients with hypoalphalipoproteinemia. METHODS: Forty-four men with low HDL-C levels (< 1.03 mmol/L [< 40 mg/dL]) entered the study. Twenty-four patients otherwise had normal lipid levels, and 20 were moderately hypertriglyceridemic (range of plasma triglyceride levels, 2.82 to 5.64 mmol/L 250 to 500 mg/dL). The trial consisted of 3 phases; each phase lasted 8 weeks. The first phase was diet only (30% fat diet); in the second phase, crystalline nicotinic acid was added at 1.5 g/d; and in the third phase, the dose was increased to 3 g/d. RESULTS: Of the 44 patients who entered the study, 37 completed the low-dose phase (1.5 g/d); the remaining patients were withdrawn because of side effects to nicotinic acid. Four other patients who completed the low-dose phase were excluded from the higher dose phase because of side effects that developed when they were receiving the low dose. Ten other patients withdrew during the high-dose phase because of side effects. In both groups, responses to nicotinic acid therapy tended to be dose-dependent. For both groups, the higher dose generally produced a greater reduction in apolipoprotein B-containing lipoproteins and a greater rise in HDL-C levels. However, for both groups, the low dose of nicotinic acid gave an average 20% increase in HDL-C levels. CONCLUSIONS: A low dose (1.5 g/d) of crystalline nicotinic acid causes an average 20% increase in HDL-C levels and significantly lowers triglyceride levels in both normolipidemic and hyperlipidemic patients with low HDL-C levels. Although the changes induced by this dose are less than those that can be achieved by a higher dose, the lower dose is better tolerated. Nicotinic acid may be useful in combined drug therapy for secondary prevention of coronary heart disease, and if higher doses cannot be tolerated, use of a lower dose should still be useful for producing a moderate rise in HDL-C levels in patients with hypoalphalipoproteinemia.

Coinheritance of two mild defects in low density lipoprotein receptor function produces severe hypercholesterolemia.

A family is described in which the probands, twin girls, had severe hypercholesterolemia suggestive of familial hypercholesterolemia (FH). The mother of the twins had normal plasma cholesterol levels, and the father had only moderate hypercholesterolemia. Moreover, low density lipoprotein (LDL) binding studies in cultured fibroblasts and isolated lymphocytes in the parents failed to reveal significantly reduced LDL receptor activity that is typical of FH heterozygotes. Turnover studies of LDL in the parents, however, revealed low fractional clearance rates (FCRs) for LDL. In cultured fibroblasts and isolated lymphocytes from the twin probands, binding of normal LDL was half normal or less. LDL turnover studies in the twins revealed a marked reduction in FCRs for LDL. When the twins were treated with lovastatin, however, FCRs for LDL increased significantly, suggesting enhancement of LDL receptor activity. This finding along with LDL binding studies in the cultured cells infer that the twins did not have homozygous FH. In addition, all family members tested negative for familial defective apolipoprotein-B-100, and LDL isolated from the mother and twins showed normal binding to normal fibroblasts. The overall data suggest that the severe hypercholesterolemia in the offspring was due to inheritance of mild to moderate defects of LDL receptor function from both parents. Although the latter defects could not be detected with certainty by in vitro tests in each parent, they were evident from LDL turnover tests. Coinheritance of these defects apparently produced severe hypercholesterolemia in the offspring.

Plasma cholesterol responsiveness to saturated fatty acids.

The variability in responsiveness to saturated fatty acids has not been studied systematically. For this reason data from three dietary studies carried out in our laboratory were pooled and used to evaluate how individuals vary in their responses in plasma concentrations of total cholesterol and low-density-lipoprotein cholesterol to the substitution of saturated fatty acids for unsaturated fatty acids. The data showed a marked variability in response. Some patients demonstrated a striking rise in cholesterol levels whereas others had more modest increases. This finding points to the need for further investigation on this issue.

Postheparin lipolytic activity and plasma lipoprotein response to omega-3 polyunsaturated fatty acids in patients with primary hypertriglyceridemia.

The hypotriglyceridemic action of omega-3 (n-3) fatty acids is attributed primarily to reduction in hepatic triglyceride synthesis and reduced secretion of very-low-density lipoproteins (VLDLs). However, increased catabolism of triglyceride-rich lipoproteins was reported and could be due to increased availability of peripheral lipoprotein lipase (LPL) or hepatic lipase (HL). In this study plasma lipoproteins and postheparin activities of LPL and HL were determined in 12 patients with primary hypertriglyceridemia before and during isocaloric substitution of omega-3 fatty acids (10 g/d) for 4 wk. Omega-3 polyunsaturates resulted in 53% and 61% reductions in plasma triglyceride and VLDL-cholesterol concentrations, respectively (P less than 0.0001). However, low-density-lipoprotein (LDL)-cholesterol concentrations increased by 26% (P less than 0.001). Activities of postheparin LPL and HL essentially remained the same. Thus, in patients with primary hypertriglyceridemia, reduction in plasma triglyceride concentrations and increase in LDL-cholesterol concentrations mediated by omega-3 polyunsaturates seem to occur without an increase in LPL or HL activities.

Estimation of turnover of low density lipoproteins by simplified methods.

This study was carried out to evaluate simplified methods for estimating parameters of kinetics of low density lipoproteins (LDL). Initially, LDL turnover studies were carried out in 78 patients, and fractional catabolic rates (FCRs) for LDL were determined from die-away curves of plasma radioactivity and from urine-to-plasma (U/P) ratios of radioactivity. When U/P ratios were calculated on a daily basis and throughout the study and averaged by a weighting procedure, the weighted U/P ratios were highly correlated with plasma decay FCRs (r = 0.92, P less than 0.001). One simplified method involved calculation of FCR for LDL from the U/P ratio on the seventh day after injection of radioactivity. Seventh-day U/P ratios also were correlated significantly with plasma decay FCRs (P less than 0.001), but the strength of correlation between the two was relatively weak (r = 0.52). Finally, another correlation was found to be significant. This was the plasma decay FCR vs. the fraction of injected dose disappearing from plasma during the first 24 h (r = 0.86). This comparison was extended to 140 turnover studies, and the correlation remained high (r = 0.90, P less than 0.0001). Thus, estimation of FCR for LDL from the fraction of dose disappearing at 24 h appears superior to that determined from the 7th-day U/P ratio.

Lovastatin therapy in familial dysbetalipoproteinemia: effects on kinetics of apolipoprotein B.

Familial dysbetalipoproteinemia is characterized by hyperlipidemia, increases in beta-migrating, very low density lipoproteins (beta-VLDL), and homozygosity for apolipoprotein E2 (apo E2). In this study, 3 patients with familial dysbetalipoproteinemia were treated with lovastatin, and kinetics for apolipoprotein B (apo B) were determined in control and drug treatment periods. Multicompartmental analyses of apo B kinetics in VLDL and in low density lipoproteins (LDL) were carried out. Lovastatin therapy generally lowered plasma concentrations of apo B and cholesterol in VLDL and LDL. The reductions in concentrations were due mainly to a decrease in transport (production) rates for these fractions. Indeed, the fractional clearance rate (FCR) for LDL-apo B was reduced during lovastatin therapy. The decreased transport rate for VLDL-apo B and LDL-apo B could have been due to an inhibition of the synthesis of lipoproteins containing apo B. An alternate explanation is that lovastatin promoted direct removal of a rapidly-catabolized fraction of VLDL-apo B that is a precursor for longer-lived lipoproteins in the circulation; this mechanism could decrease input rates of identifiable lipoprotein species and retard their clearance because of "saturation" of LDL receptors by more rapidly removed lipoproteins. Finally, both mechanisms, i.e., decreased production and increased clearance of lipoproteins, may have contributed to the fall in VLDL-apo B and LDL-apo B concentrations during lovastatin therapy.

Variability in cholesterol content and physical properties of lipoproteins containing apolipoprotein B-100.

The primary objective of this study was to determine the variability in cholesterol carrying capacity of low density lipoproteins (LDLs) and other apolipoprotein B (apo B)-containing lipoproteins in normolipidemic men. One hundred and fifty-nine normolipidemic men, ages 21 to 73 years, were enrolled. In addition to determining plasma lipids and lipoproteins, three primary measurements were made: ratios of cholesterol to apo B in LDL; the electrophoretic pattern of LDL, i.e. pattern A, AB, or B; and levels of cholesterol in all lipoproteins other than high density lipoproteins (nonHDL-cholesterol) along with total apo B. First, the data revealed that about 85% of the variability of LDL-cholesterol levels can be accounted for by LDL-apo B levels, whereas the remaining 15% can be explained by differences in LDL-cholesterol/apo B ratios. Second, LDL electrophoretic pattern A was the predominant pattern in young adult men, but in older men the pattern shifted increasingly to AB and B. And third, there was a high correlation between nonHDL-cholesterol levels and total apo B levels, which suggests that nonHDL-cholesterol can be used as a relatively accurate surrogate for total apo B levels in normolipidemic individuals.

Physiologic levels of ascorbate inhibit the oxidative modification of low density lipoprotein.

Oxidatively modified low density lipoprotein (LDL) could contribute to the atherosclerotic process by its cytotoxic effect, uptake by the scavenger receptor and influence on monocyte and macrophage motility. The aim of the present study was to examine the effect of physiologic levels of alpha-tocopherol and ascorbate on Cu2(+)-induced oxidative modification of LDL. Whereas alpha-tocopherol had an inhibitory effect on the oxidative modification of LDL only for 5 h, as evidenced by the electrophoretic mobility and lipid peroxide content, ascorbate inhibited the oxidative modification of LDL for both 5 and 24 h. By inhibiting the oxidative modification of LDL, ascorbate prevented the uptake and degradation of oxidatively modified LDL by the scavenger-receptor mechanism of cultured human monocyte derived macrophages. It thus appears that in this cell-free system (2.5 microM Cu2+), ascorbate is a more potent antioxidant than alpha-tocopherol. These findings indicate that ascorbate in physiologic concentrations should inhibit the oxidate modification of LDL in vivo.

Abnormal cholesterol distribution among lipoprotein fractions in normolipidemic patients with mild NIDDM.

This study was carried out to identify and define lipoprotein abnormalities in patients with noninsulin-dependent diabetes mellitus (NIDDM) who do not have clinical elevations of cholesterol or triglycerides. Thirty-four male patients with mild NIDDM and normolipidemia (plasma cholesterol < or = 240 mg/dl and triglycerides < or = 250 mg/dl) were compared with 35 healthy male normolipidemic subjects. The two groups had similar age and body mass index. Measurements in the two groups included concentrations and chemical composition of lipoproteins and sizing of low-density lipoprotein (LDL) particles. The patients with NIDDM, compared to control subjects, had two distinct lipoprotein abnormalities: first a significantly reduced level of high-density lipoprotein (HDL) cholesterol (mean +/- S.D., 35 +/- 8 mg/dl vs. 41 +/-10 mg/dl, respectively; P = 0.006), and second, a high cholesterol-to-apolipoprotein (apo) B ratio both in a very low density lipoprotein (VLDL) + intermediate density lipoprotein (IDL) fraction (mean +/- S.D.; 3.2 +/- 0.8 vs. 2.8 +/- 0.9, respectively; P = 0.02) and in LDL fraction (mean +/- S.D.; 1.61 +/- 0.11 vs. 1.52 +/- 0.13, respectively; P = 0.003). Increased cholesterol content in LDL was mainly due to free cholesterol. No differences were detected between the two groups in the frequency of LDL pattern A (major LDL peak > 255 A) and pattern B (major LDL peak < or = 255 A). However, a higher frequency of LDL pattern B was found in NIDDM patients with low plasma total triglyceride concentrations ( < 150 mg/dl) compared to the to the control subjects (45% vs. 7%, P = 0.02). Thus in normolipidemic patients with mild NIDDM, the major lipoprotein abnormalities were a low level of HDL cholesterol and compositional changes in LDL and VLDL + IDL fractions. Compositional abnormalities included enrichment of apo B-containing lipoproteins with cholesterol. These lipoprotein abnormalities could have atherogenic potential in patients with mild NIDDM and normolipidemia.

Influence of lovastatin on concentrations and composition of lipoprotein subfractions.

The effects of lovastatin therapy on concentrations and compositions of lipoproteins were examined in 14 patients with heterozygous familial hypercholesterolemia. The drug lowered plasma levels of cholesterol in total plasma, very low density + intermediate density lipoproteins (VLDL + IDL) and low density lipoproteins (LDL) by 25%, 41%, and 41%, respectively. Plasma total apo B was decreased by 35%. Three VLDL subfractions--VLDL-1, VLDL-2, and VLDL-3--of progressively higher density were examined. Lovastatin therapy reduced only the heaviest--VLDL-3. Concentrations of VLDL-1 and VLDL-2 were unchanged. Total VLDL-cholesterol/apo B was reduced significantly. Drug therapy also altered the composition of LDL as shown by decreasing the cholesterol/apo B. Finally, lovastatin significantly raised HDL-cholesterol concentrations. This study showed that lovastatin modifies the composition of the major apo B-containing lipoproteins as well as reducing their concentrations.

Rationale and management of hyperlipidemia of the nephrotic syndrome.

Hyperlipidemia is usually present in patients with the nephrotic syndrome. The most common lipid abnormality is hypercholesterolemia, although as the disorder progresses, hypertriglyceridemia may develop. Elevated plasma lipids have two potential vascular consequences, namely, atherosclerosis and progression of renal failure. Neither of these complications has been proven with certainty, but there is growing evidence to indicate that both may be long-term consequences of the nephrotic syndrome. Therefore, effective therapy of hyperlipidemia, particularly elevated cholesterol levels, is needed as a protection against these complications. Since nephrotic hypercholesterolemia frequently is severe, dietary therapy, although a valuable adjunct, will not normalize cholesterol levels in most nephrotic patients. Thus, if effective serum cholesterol lowering is to be achieved, drug therapy will be required. Bile acid-binding resins have been shown to lower cholesterol levels in nephrotic patients, but the decline in cholesterol concentrations is usually insufficient to produce a marked reduction in coronary risk. Nicotinic acid theoretically should be useful for treatment of nephrotic hyperlipidemia, but it has not been adequately tested. The new drugs that inhibit cholesterol synthesis, e.g., lovastatin, appear to be highly promising for treating elevations of both serum cholesterol and triglycerides in the nephrotic syndrome. However, testing of these drugs in this condition has been limited, and the possibility of significant side effects in an appreciable portion of patients has not been ruled out. Of particular concern is the development of severe myopathy that can produce myoglobinuria and acute renal failure. This side effect is relatively rare in patients without the nephrotic syndrome, but its prevalence in the latter condition has not been determined. The fibric acids will lower triglyceride levels in nephrotic patients, but they are not effective in lowering cholesterol levels; consequently, they probably have little role in the treatment of nephrotic hypercholesterolemia. Finally, the drug probucol will lower cholesterol levels in nephrotic patients, although not to desirable levels; still, probucol could prove useful in combination with other cholesterol-lowering drugs.

Fibric acids: effects on lipids and lipoprotein metabolism.

The major effect of the fibrates on triglycerides is to promote triglyceride-rich lipoprotein catabolism through increased lipoprotein lipase activity. Fibrates also enhance lipolysis of plasma triglycerides by a means different from that of caloric restriction. Their effect on very low-density lipoprotein metabolism also differs from that of nicotinic acid. The effect of fibrate therapy upon low-density lipoprotein-cholesterol concentrations depends upon the patients' overall lipoprotein status. The responsible mechanisms are not understood. In hypertriglyceridemic patients, fibrates often reverse abnormal changes in low-density lipoprotein composition; low-density lipoprotein heterogeneity is reduced and small dense low-density lipoproteins are eliminated, apparently secondary to reduced levels of triglyceride-rich lipoproteins. Kinetic studies indicate that fibrates do not enhance low-density lipoprotein formation rates, thus contradicting the idea that fibrate therapy causes increased low-density lipoprotein cholesterol levels via increased conversion of very low-density lipoprotein to low-density lipoprotein. Though enhanced low-density lipoprotein catabolism in hypertriglyceridemia could occur via several mechanisms, the responsible factors are largely reversed by fibrate therapy. In non-hypertriglyceridemic patients, fibrates may actually enhance the fractional clearance of low-density lipoprotein and thus reduce low-density lipoprotein levels. Fibrate therapy reverses the typical high-density lipoprotein pattern of hypertriglyceridemic patients, producing more high-density lipoprotein2a and less high-density lipoprotein2b. Such treatment also increases high-density lipoprotein cholesterol levels in patients without definite hypertriglyceridemia. Synthesis rates of apolipoproteins AI and AII may be affected by fibrates. The fibrates' major effects on sterol metabolism are interference with cholesterol and bile acid synthesis and increased cholesterol secretion into bile. Although bile saturation increases in most patients, in only a relatively small percentage do gallstones actually develop; super-saturated bile is not sufficient to induce gallstone formation in most patients. Available data strongly imply that fibrates mobilized cholesterol out of tissue pools, perhaps by altering tissue cell membranes to allow cholesterol release from the cell surfaces.