Low density lipoprotein particle diameter in young,nonobese, normolipidemic Japanese men

Background: prospective studies have demonstrated that a predominance of small, dense LDL particles (pattern B) precedes the clinical onset of coronary heart disease. Prevalence and characteristics of subjects with this LDL size abnormality were studied in young, nonobese, Japanese normolipidemic men. Methods and results: LDL peak particle diameter (PPD) was measured by continuous disc polyacrylamide gel electrophoresis in 223 nonobese normolipidemic men aged 18–20 years (mean±S.D. body mass index: 21.9±3.7 kg/m², total cholesterol: 180±29 mg/dl, triglyceride: 62±34 mg/dl, HDL cholesterol: 58±12 mg/dl). Men with small LDL (PPD <25.8 nm) were found in only 5.4% (n=12) whereas 197 men (88.3%) had a preponderance of large LDL (PPD 26.3 nm). As compared with men in a top tertile (PPD 27.5 nm) those in a low tertile (PPD <26.9 nm) had higher serum levels of LDL cholesterol (120±31 vs 104±24 mg/dl), triglyceride (72±39 vs 49±16 mg/dl) and apolipoprotein (apo) B (84±21 vs 68±14 mg/dl), and lower HDL cholesterol (54±10 vs 60±12 mg/dl). They also had greater body mass index (23.2±4.6 vs 20.9 3.1 kg/m²) and percent body fat (21.5±7.7 vs 17.5±4.9%). LDL-PPD was positively correlated with HDL cholesterol (R=0.20, P=0.002) and was negatively correlated with apoB (R=0.34, P<0.001), triglyceride (R=0.32, P<0.001), percent body fat (R=0.26, P<0.001), body mass index (R=0.24, P<0.001), fat mass (R=0.23, P=0.001), total cholesterol (R=0.20, P=0.002). In multiple regression analysis, apoB, triglyceride, HDL cholesterol, apoAI and percent body fat explained 18% of LDLPPD variability. Conclusion: even in young, nonobese, normolipidemic men, LDL size appears to be associated with triglyceride-rich lipoprotein metabolism and body fat.     

Distribution of lipids in 8,500 men with coronary artery disease

In the present study we measured fasting lipid profiles in over 8,500 community-living men with coronary artery disease (CAD) to determine the distribution of lipid abnormalities in this population: 81% were white and 16% black; mean age 62.9 ± 8 years; mean total cholesterol 214 ± 41 mg/dl; low-density lipoprotein (LDL) cholesterol 140 ± 37 mg/dl; high-density lipoprotein (HDL) cholesterol 39 ± 11 mg/dl; and triglycerides 190 ± 142 mg/dl. After adjusting for age, the only significant difference between blacks and whites was a higher HDL cholesterol in blacks (45 vs 38 mg/dl, p < 0.003). With use of cut points established by the National Cholesterol Education Program, 87% or subjects had high LDL cholesterol (≥100 mg/dl), 38% had low HDL cholesterol (<35 mg/dl), and 33% had high triglycerides (>200 mg/dl). We estimated that 42% of men with CAD would be definite candidates for cholesterol-lowering medication according to the National Cholesterol Education Program guidelines and that 41% of those in whom cholesterol-lowering medication would not be definitely indicated had low levels of HDL cholesterol. We conclude that (1) black men with CAD have substantially higher HDL cholesterol than white men, (2) almost 90% of male patients with CAD are candidates for dietary intervention and >40% may need medications to lower LDL cholesterol, and (3) 40% of patients without a definite indication for cholesterol-lowering medications have low levels of HDL cholesterol.     

Serum lipoprotein lipid concentration and composition in homozygous and heterozygous patients with cholesteryl ester transfer protein deficiency

Six homozygous, 10 heterozygous and 8 unaffected subjects in a CETP deficient family confirmed by CETP gene analysis were studied to characterize serum lipoproteins separated by ultracentrifugation, and to examine the relations between CETP levels and lipoprotein lipid concentration and composition. The serum CETP levels were measured by radioimmunoassay using ¹²⁵I-labeled monoclonal antibodies (TP2). The serum CETP levels in the homozygotes were undetectable and those in the heterozygotes were significantly lower than those in the unaffected subjects (1.5 ± 0.1 vs. 2.2 ± 0.5 μg/ml, P < 0.01). In the HDL fraction, esterified cholesterol (EC) levels in the homozygotes were significantly increased (P < 0.01), and those in the heterozygotes were slightly increased (n.s.), in comparison with those in the unaffected and the normolipidemic controls. The EC levels in the IDL fractions were lower in the homozygotes than in the normolipidemic controls. The EC/triglyceride (TG) molar ratios in IDL, the fraction obtained from the homo- and heterozygotes, were lower than those from the unaffected subjects (P < 0.01 and < 0.01, respectively), and the EC/TG ratios in the HDL fraction obtained from the homo- and heterozygotes were higher than those from the unaffected subjects (P < 0.01 and n.s., respectively). Linear regression analysis showed that positive correlates of the serum CETP levels in all subjects were: IDL-EC (r = 0.463), HDL-TG (r = 0.603) and VLDL- and IDL-EC/TG ratio (r = 0.698 and and 0.843). When the homozygotes were excluded from the analysis, the EC/TG ratios in VLDL IDL were still positively correlated with the serum CETP levels (r = 0.677 and 0.676). Inverse correlates of the serum CETP levels in all subjects were: HDL-EC (r = −0.783) and HDL-EC/TG ratio (r = −0.739). These results suggested that the decreased CETP concentration decreased IDL-cholesterol and increased HDL-cholesterol levels through reducing transport of EC from HDL to IDL, and produced an anti-atherogenic plasma lipoprotein pattern.     

Usefulness of the total cholesterol to high-density lipoprotein cholesterol ratio in predicting angiographic coronary artery disease in women

To investigate the relation between lipids and angiographic coronary artery disease (CAD) in women, fasting lipid profiles were obtained on 108 women undergoing coronary angiography (group I). CAD, defined as ≥25% luminal diameter narrowing in a major coronary artery, was present in 57 (53%). Neither serum total cholesterol nor triglyceride levels correlated with the presence of CAD. Mean total/high-density lipoprotein (HDL) cholesterol ratio was higher among women with than without CAD (5.5 ± 0.3 vs 4.2 ± 0.2, p < 0.0001). Multiple regression analyses identified a higher total/HDL cholesterol ratio as the variable most predictive of the presence (p < 0.001), extent (number of narrowed arteries) (p < 0.0001), and severity (% maximum stenosis) (p < 0.001) of CAD. Age and lack of estrogen use were also independently associated with the presence of CAD, age and lowdensity lipoprotein cholesterol level were additional indicators of extent, and age was the only other discriminator of severity of CAD.

In 56 women with total cholesterol <200 mg/dl (group II), mean total/HDL cholesterol ratio was higher in women with (n = 24) than without CAD (4.3 ± 0.2 vs 3.5 ± 0.2, P = 0.01). Higher total/HDL cholesterol ratio was the variable most predictive of the presence of CAD (p = 0.01), and the tone variable associated with severity (p < 0.001) after adjustment for other risk factors. Age was independently associated with presence and extent, and hypertension was also independently related to extent. Thus, among these women, total/HDL cholesterol ratio is the best predictor of the presence, severity and extent of CAD in general, and is the best predictor of presence, and severity in patients with total cholesterol <200 mg/dl.     

Association between hematological parameters and metabolic syndrome components in a Chinese population

Insulin resistance, an essential core contributing to the metabolic syndrome (MS), has been demonstrated in some studies to be associated with white blood cell (WBC) or red blood cell (RBC) counts. The present study was undertaken to assess systemically the relationship between WBC or RBC counts and various clinical features of MS in a large Chinese population at Taiwan. A total of 4938 subjects (2891 men and 2047 women with a mean age of 50.1±12.6 years), who had attended health examination at this hospital were enrolled. The Adult Treatment Panel III (ATP III) definition of MS components was adopted in this study with the exception of the definition of obesity. This was defined as body mass index (BMI) greater than 27 kg/m². Overall, 14% had high serum total triglyceride (TG), 8% had low high-density lipoprotein (HDL) cholesterol, and 18% were obese. WBC counts showed a statistically significant (P<.001) correlation with TG (r=.265), HDL(r=−.187), fasting glucose (r=.084), and BMI (r=.172) but not with blood pressure levels. In addition, RBC counts correlated significantly (P<.001) with TG (r=.250), HDL(r=−.269), fasting glucose (r=.098), and BMI (r=.228). WBC and RBC counts in subjects grouped according to the presence of 0, 1, 2, and ≥ 3 features of MS were 6268±1633, 6555±1782, 6995±1880, and 7185±1696 cells/mm³, and 4.63±0.56×10⁶, 4.73±0.54×10⁶, 4.84±0.60×10⁶, and 4.91±0.55×10⁶ cells/mm³, respectively (P for trend <.001). Subjects in the highest quartile of WBC or RBC counts demonstrated a three- or twofold increase, respectively, in the odds ratio for MS with 3 or more metabolic features compared to subjects in the lowest quartile of WBC or RBC counts. Increased WBC and RBC counts, albeit normal, were associated with a variety of MS features in a Taiwan Chinese population, suggesting that hematological parameters could potentially be used as indicators of this syndrome.     

High carbohydrate diets, triglyceride-rich lipoproteins, and coronary heart disease risk

In this study we compared the effects of variations in dietary fat and carbohydrate (CHO) content on concentrations of triglyceride-rich lipoproteins in 8, healthy, nondiabetic volunteers. The diets contained, as a percentage of total calories, either 60% CHO, 25% fat, and 15% protein, or 40% CHO, 45% fat, and 15% protein. They were consumed in random order for 2 weeks, with a 2-week washout period in between. Measurements were obtained at the end of each dietary period of plasma triglyceride, cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, remnant lipoprotein (RLP) cholesterol, and RLP triglyceride concentrations, both after an overnight fast and throughout an 8-hour period (8 A.M. to 4 P.M.) in response to breakfast and lunch. The 60% CHO diet resulted in higher (mean +/- SEM) fasting plasma triglycerides (206 +/- 50 vs 113 +/- 19 mg/dl, p = 0.03), RLP cholesterol (15 +/- 6 vs 6 +/- 1 mg/dl, p = 0.005), RLP triglyceride (56 +/- 25 vs 16 +/- 3 mg/dl, p = 0.003), and lower HDL cholesterol (39 +/- 3 vs 44 +/- 3 mg/dl, p = 0.003) concentrations, without any change in LDL cholesterol concentration. Furthermore, the changes in plasma triglyceride, RLP cholesterol, and RLP triglyceride persisted throughout the day in response to breakfast and lunch. These results indicate that the effects of lowfat diets on lipoprotein metabolism are not limited to higher fasting plasma triglyceride and lower HDL cholesterol concentrations, but also include a persistent elevation in RLPs. Given the atherogenic potential of these changes in lipoprotein metabolism, it seems appropriate to question the wisdom of recommending that all Americans should replace dietary saturated fat with CHO.     

Presence of very low density lipoprotein compositional abnormalities in Type 1 (insulin-dependent) diabetic patients; effects of blood glucose optimisation

Summary Plasma lipoprotein compositional abnormalities were investigated in eight normolipidaemic (plasma cholesterol <5.70 mmol/l; triglyceride <2.03 mmol/l) young male Type 1 (insulin-dependent) diabetic patients (before and after a short period of optimised blood glucose control) and in nine healthy control subjects, matched for sex, age and body mass index. Free and esterified cholesterol, triglyceride, phospholipids were assayed in all lipoprotein classes (VLDL, IDL, LDL) and in HDL subclasses (HDL2 and HDL3); apoB was measured only in very low density lipoproteins (VLDL). All VLDL constituents were increased in the diabetic group, the differences being more striking for apoB (6.0±1.1 mg/dl vs 2.0±0.1 mg/dl, p<0.02), free cholesterol (0.27±0.04 mmol/l vs 0.13±0.02 mmol/l, p<0.02) and esterified cholesterol (0.32±0.08 mmol/l vs 0.13±0.01 mmol/l, p<0.05). Also HDL subfractions showed differences between the two groups: all HDL2 constituents were increased, while in HDL3 only triglyceride was significantly increased (0.11±0.01 mmol/l vs 0.08±0.004 mmol/l, p<0.02). After two weeks of optimised blood glucose control all VLDL constituents were reduced and particularly: esterified cholesterol (–39%, p<0.02), free cholesterol (–37%, p<0.05), apoB (– 35%, p<0.05). Expressing each VLDL constituent as percent of the total lipoprotein mass, it was evident that the diabetic VLDL was rich in cholesterol both esterified (8.4±1.0% vs 5.4±0.5%, p<0.02) and free (8.5±0.7% vs 5.5±0.3%, p<0.001), apo B (5.1±0.6% vs 2.6±0.3%, p<0.001) and depleted in triglyceride (57.0±1.7% vs 64.1±1.7%, p<0.001). Two weeks of optimised blood glucose control were not able to correct the abnormal composition of VLDL. In conclusion, Type 1 (insulin-dependent) diabetic patients, although normolipidaemic, show an abnormal VLDL composition suggesting an increased prevalence of smaller and, possibly, more atherogenic VLDL particles. This abnormality is not corrected by a short period of blood glucose optimisation.     

Inhibition of lipoprotein lipase induced cholesterol ester accumulation in human hepatoma HepG2 cells

It has been suggested previously that lipoprotein lipase may act as a ligand to enhance binding and uptake of lipoprotein particles. In the present study we have examined the capacity of bovine milk lipoprotein lipase to induce intracellular accumulation of triglyceride and cholesterol ester by VLDL (S_f 60–400) isolated from Type IV hypertriglyceridemic subject (HTg-VLDL) in HepG2 cells, independent of its lipolytic activity. We have also attempted to elucidate the cellular receptor mechanisms responsible for these effects. HTg-VLDL-mediated increases in intracellular triglyceride and cholesterol ester were dependent on the presence of an active lipase. Bovine milk lipoprotein lipase (LPL) increases triglyceride mass by 301% ± 28% (P < 0.0005) and cholesterol ester mass by 176% ± 12% (P < 0.0005). These HTg-VLDL-mediated increases in intracellular triglyceride and cholesterol ester did not occur when heat-inactivated lipase was used. Rhizopus lipase could replace LPL and cause equivalent increases in intracellular triglyceride and cholesterol ester (472% ± 61% (P < 0.005) and 202% ± 25% (P < 0.025) respectively vs. control). HTg-VLDL treated with LPL and reisolated also caused equivalent increases (274% ± 18% (P < 0.01) and 177% ± 12% (P < 0.005) for triglyceride and cholesterol ester). LDL also caused increases in intracellular cholesterol ester (189% ± 20% (P < 0.005)), although three times more LDL cholesterol had to be added to achieve the same effect. These LDL-induced increases were effectively blocked by monoclonal antibodies directed against the B,E receptor binding domains of apo B (−97% ± 13% (P < 0.0005) with anti-apo B 5E11 and − 68% ± 13% (P < 0.05) for anti-apo B B1B3) or by anti-B,E receptor antibodies (− 77% ± 7% (P < 0.01) antibody C7). These same antibodies had little effect on the HTg-VLDL + LPL-induced increases in cholesterol ester (+21%, + 15% and − 22% for 5E11, B1B3 and C7, respectively). Monoclonal anti-apo E antibodies also had no effect on LDL-mediated increases in intracellular cholesterol ester, but had a small and significant effect on VLDL-mediated increases in cholesterol ester. However, heparin, which interferes with cell surface proteoglycan interaction, was very effective at blocking HTg-VLDL-mediated increases in cholesterol ester in the presence of LPL (− 86% ± 8% P < 0.0005). Heparin was also effective in the presence of Rhizopus lipase (−79%) or lipolyzed re-isolated HTg-VLDL (−95%). These results suggest that lipoprotein lipase may enhance the uptake process beyond its role in lipolytic remodelling but does not appear to be an absolute requirement. In contrast, heparin had no effect on LDL-mediated cholesterol ester accumulation. Lactoferrin, which inhibits interaction with the low density lipoprotein receptor-related protein (LRP), was also very effective at inhibiting HTg-VLDL increases in intracellular cholesterol ester (− 95% ± 6%, P < 0.01). However, there was no effect of either heparin or lactoferrin on HTg-VLDL-mediated triglyceride accumulation. Thus cell surface heparin sulphate may facilitate intracellular lipid acquisition by providing a stabilizing bridge with the lipoproteins and enhance uptake through receptor-mediated processes such as LRP.     

Long-term probucol treatment results in regression of xanthomas, but in progression of coronary atherosclerosis in a heterozygous patient with familial hypercholesterolemia

A 66-year-old male heterozygous familial hypercholesterolemia (FH) patient with significant coronary atherosclerosis has been treated by us with probucol (1000 mg daily) for eight years. This treatment has produced significant reductions in the cholesterol levels of his serum, low density lipoprotein (LDL), and high density lipoprotein (HDL) from 237 ± 20 mg/dl (mean ± S.D.) to 156 ± 15, from 175 ± 8 to 111 ± 16 mg/dl, and from 23 ± 4 to 19 ± 2 mg/dl, respectively. These reductions have been maintained for eight years. Serum triglyceride levels also decreased, from 220 ± 54 to 146 ± 36 mg/dl. During this period, marked regression of xanthomas on the eyelids and finger extensor tendons was observed, while thickness of the Achilles tendons was reduced from 21.0 mm to 13.0 mm. On the other hand, effort-induced anginal symptoms requiring additional antianginal medication have been noticed, and angiographically-demonstrated coronary atherosclerosis has progressed significantly during these eight years. These observations lead us to suggest that maintaining low levels of HDL cholesterol with probucol, even though resulting in satisfactory reduction of LDL cholesterol and marked regression of xanthomas, appears to be associated with the progression of atherosclerosis in the coronary arteries.     

The Pro12Ala polymorphism in PPARgamma2 gene affects lipid parameters in Greek primary school children: A case of gene-to-gender interaction

BACKGROUND: In the present study we sought to evaluate the impact of the PPAR-gamma2 Pro12Ala polymorphism on blood lipid levels of primary school children. METHODS: 81 male and 92 female schoolchildren were genotyped. Biochemical, anthropometric, and lifestyle variables were assessed. RESULTS: 14.1% females and 14.8% males were heterozygotes, while the rest of the subjects were homozygotes for the Pro allele. A significant interaction between the PPARgamma-2 gene and gender on blood lipid levels was detected. In particular, Pro/Pro females exhibited higher values of total cholesterol (194 +/- 32 vs 180 +/- 28 mg/dL, P = 0.06) and triglycerides (94 +/- 31 vs 77 +/- 11 mg/dL, P = 0.045) compared to Pro/Ala individuals. The gene-to-gender interaction term was highly significant (P < 0.001). On the other hand, Pro/Pro males showed higher values of HDL cholesterol (47 +/- 8 vs 43 +/- 9 mg/dL, P = 0.001), lower total cholesterol/HDL ratio (4.04 +/- 0.59 vs 4.45 +/- 0.61, P = 0.031), lower values of apoB (59.8 +/- 11.3 vs 66.8 +/- 6.6 mg/dL, P = 0.007) and lower values of apoB/apoA1 ratio (0.41 +/- 0.09 vs 0.48 +/- 0.08, P = 0.019) compared with Pro/Ala. Even after adjusting for body mass index (BMI), total energy intake, total fat intake and saturated fat intake, differences in total cholesterol/high-density lipoprotein (HDL) cholesterol and the apoB/apoA1 ratios remained significant. Regarding females, no differences were observed among genotypes concerning total cholesterol/HDL levels (P for gene-to-gender interaction = 0.001) and the apoB/apoA1 levels (P for gene-to-gender interaction = 0.029). CONCLUSION: We show for the first time a gene-to-gender interaction on total cholesterol/HDL and apoB/apoA1 ratios, in male schoolchildren genotyped for PPAR-gamma2 Pro12Ala.     

Effect of bezafibrate treatment on the altered lipoprotein profiles in hypertriglyceridemic subjects

The effects of bezafibrate treatment on lipoprotein metabolism were investigated in hypertriglyceridemic subjects. Bezafibrate, a fibric acid derivative, was administered at 200-400 mg/day to 8 patients with hyperlipoproteinemia (type IIb and IV) for 3-6 months. We evaluated the effects of bezafibrate on the plasma levels of total cholesterol(chol), triglyceride(TG), and apoB. In addition, the lipid and apoB contents were also analyzed in VLDL, IDL, LDL and HDL fractions before and after the treatment. It was revealed that plasma levels of chol, TG and apoB significantly decreased after the treatment, 236.3 vs 210.9,192.4 vs 90.2 (p< 0.01) and 129.8 vs 116.2 (p<0.05) mg/dl respectively. VLDL-chol, VLDL-TG and VLDL-apoB dropped from 26.5,127.6 and 11.1 mg/dl to 9.1, 49.5 and 6.7 mg/dl respectively after the treatment. Regarding qualitative alterations of VLDL, TG/apoB, chol/apoB and TG + chol/apoB ratios in VLDL were significantly reduced, indicating that the size of VLDL was diminished by the treatment. In addition, HDL-chol increased from 40.4 to 60.8 mg/dl after the treatment. Consequently LDL-chol/HDL-chol significantly decreased. In conclusion, bezafibrate administration decreased the TG, chol and apoB content in VLDL, suggesting a reduced number of VLDL. Significant rise of HDL-chol and decrease of LDL-chol/HDL-chol are additional beneficial effects following bezafibrate treatment.     

Apolipoprotein E-rich HDL in patients with homozygous familial hypercholesterolemia

Ordinarily, HDL1, a fraction of HDL enriched in apoE, is a minor fraction of plasma, but in human subjects and experimental animals eating diets high in fat and cholesterol and in patients with homozygous familial hypercholesterolemia (HFH) or CETP deficiency, HDL1 (or HDLc) concentrations in plasma are increased. However, little is known about the structures, compositions and metabolic sources of HDL1 in HFH patients. To obtain HDL1 for the study, we surveyed several fractions in the HDL density range for apoE by SDS-PAGE. The ratio of apoE to apoAI in the HDL (d = 1.063-1.21 g/ml) of 8 HFH patients was 0.14 +/- 0.03 compared to 0.03 +/- 0.005 in a control group of 8 normolipidemic subjects (P less than 0.001) suggesting that an apoE-rich fraction indeed was present in increased amounts. ApoE/apoAI ratios of lipoproteins of the density range 1.050-1.090 were even higher at 1.5 and 2.0 in 2 patients compared to 0.4 +/- 0.1 in controls, indicating that this density fraction may be particularly enriched with apoE-rich lipoproteins. By contrast, d = 1.020-1.050 g/ml and d greater than 1.090 fractions contained very little apoE. Therefore, we further characterized the d = 1.050-1.090 g/ml lipoproteins of HFH patients and controls. Fractionation of an d = 1.050-1.090 fraction by concanavalin-A chromatography (CONA) yielded an unbound apoE-rich fraction that contained apoE, apoAI and apoC but no apoB, and a bound LDL-like fraction that contained mostly apoB-100, as determined by SDS-PAGE and by solid phase immunoassays, containing monoclonal antibodies directed against apoB, apoE and apoAI. The apoE/apoAI ratio of the CONA unbound fraction of HFH patients was greater, and the fraction also contained more free cholesterol and phospholipids than the fraction of control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lipoprotein and apolipoprotein levels in angiographically defined coronary atherosclerosis

Recent studies suggest that apolipoproteins and subfractions of high-density lipoprotein (HDL) cholesterol may be better predictors of atherosclerotic coronary artery disease (CAD) than are plasma cholesterol and total HDL cholesterol. To examine this hypothesis, plasma cholesterol and triglyceride, cholesterol of low-density lipoprotein, HDL and its subfractions 2 and 3, apolipoproteln A-I, the apoplipoprotein B of low-density lipoprotein, the ratio of apolipoprotein E_II to E_III, and ratios of several of these variables were measured in a selected series of 126 patients (83 men and 43 women) who underwent coronary angiography for suspected CAD. Mean values of many of these variables differed significantly between the men with CAD and the men without significant CAD, when controlled for age, use of β blockers and diuretic drugs. Using multivariate logistic regression analysis, the only variable that made a significant independent contribution in predicting CAD in men was the ratio of HDL cholesterol to total plasma cholesterol (p <0.0001). The mean of this ratio was 0.17 ± 0.01 mg/dl in the men with CAD and 0.23 ± 0.02 mg/dl in the male controls. All men with ratios of less than 0.15 mg/dl had significant CAD, defined as 50% or greater luminal diameter narrowing of 1 or more of the major coronary arteries. No measurement was a significant univariate or multivariate predictor of CAD in the women, but the power to detect such predictors was reduced because of small group sizes. In conclusion, the ratio of HDL cholesterol to plasma cholesterol may be superior to many of the more recently described lipoprotein and apolipoprotein-derived predictors of CAD.     

Influence of beta 2 agonism and beta 1 and beta 2 antagonism on adverse effects and plasma lipoproteins: results of a multicenter comparison of dilevalol and metoprolol

Dilevalol combines vasodilation due to selective beta 2 agonism and nonselective beta antagonism. We studied 311 patients randomized to dilevalol and 138 to metoprolol in a multicenter trial. After a 4-week placebo washout, dilevalol was titrated from 200 to 1,600 mg once daily and metoprolol from 100 to 400 mg to a goal supine diastolic blood pressure less than 90 and greater than or equal to 10 mm Hg decrease from baseline. Responders were followed for 1 year. The average age of patients was 51 years; 72% were men and 54% were white. Both drugs reduced blood pressure effectively to a similar level. Fewer patients discontinued dilevalol than did those taking metoprolol (9 vs 16%; p less than 0.03). More metoprolol-treated patients withdrew because of depression (6 vs less than 1%; p = 0.03) and impotence (5 vs less than 1%; p = 0.03). Lipoprotein levels before and after treatment were measured in 99 patients treated for 53.5 weeks with dilevalol (mean dose 438 mg). Dilevalol increased high-density lipoprotein (HDL) cholesterol by 2.5 mg/dl to 47.2 (p = 0.05), reduced low-density lipoprotein (LDL) cholesterol by 2.5 mg/dl, increased HDL/LDL by 0.03, and decreased total cholesterol/HDL cholesterol by 0.18. Triglycerides increased by 21 mg/dl (p = 0.06). In patients with an initial HDL cholesterol less than 35 mg/dl, dilevalol increased it by 9 mg/dl. In patients treated with metoprolol, the only significant change (p = 0.02) was a 41.9-mg/dl increase in triglyceride levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of a low-fat diet on plasma lipoprotein levels

Lowering the intake of fat to decrease serum cholesterol levels has unknown effects on the proportion of cholesterol in low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Twenty normolipidemic nonvegetarians were given dietary instruction and supervision in a low-fat, semivegetarian diet for three months. Mean consumption of total fat, saturated fat, and cholesterol decreased, whereas intake of carbohydrate increased significantly on a low-fat diet. Plasma LDL levels decreased by 18% and HDL levels by 7% from prestudy baseline levels. The LDL/HDL ratio declined by 11%. Plasma triglyceride levels and body weight were unchanged. In individual subjects, the decrements in consumption of saturated fat and the increments in ingestion of polyunsaturated fat were each significantly correlated with decreases in LDL. One year after the subjects had returned to a self-selected diet, levels of dietary saturated fat and cholesterol and the plasma LDL/HDL ratio remained significantly below prestudy levels. This study and others suggest that a low-fat, high-carbohydrate diet favorably affects the plasma LDL/HDL proportion by decreasing LDL on a percentage basis 2 1/2 to three times more than it decreases HDL.     

Hyperbetalipoproteinemia with small low-density lipoprotein, a characteristic disorder of lipoprotein in essential hypertension

The purpose of the present study was to elucidate the characteristic lipoprotein disorder in essential hypertension. Twenty-six patients with essential hypertension (HT) but without diabetes mellitus or obesity and 24 healthy subjects (control) were recruited into this study. Lipoproteins of HT and controls were separated by ultracentrifugation to very-low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low-density liproprotein (LDL), and (HDL) fractions. Cholesterol and triglycerides were determined with enzyme assay, and apoB were determined by highly sensitive latex agglutination (Kyowa-hakko Co. LD). There was no difference in age (mean ± SE; HT, 63 ± 2 versus control, 60 ± 2 years) or body-mass index (22.7 ± 0.4 versus 21.7 ± 0.5 kg/m²) between HT and controls. Blood pressure in HT and controls was 158 ± 2/87 ± 12 mm Hg and 123 ± 3/72 ± 2 mm Hg, respectively. Cholesterol did not change significantly in plasma (192.1 ± 7.0 versus 176.4 ± 4.2 mg/dL), VLDL (15.2 ± 2.4 versus 11.8 ± 1.7 mg/dL), IDL (14.8 ± 2.4 versus 10.7 ± 1.6 mg/dL), LDL (93.7 ± 4.6 versus 83.1 ± 3.9 mg/dL), nor in HDL (51.9 ± 2.7 versus 58.1 ± 3.2 mg/dL). Triglycerides (TG) increased in plasma (120.0 ± 10.0 versus 87.5 ± 9.3 mg/dL, p < 0.05), although TG did not change in all subfractions. ApoB increased in plasma (105.5 ± 5.1 versus 85.6 ± 3.6 mg/dL, p < 0.01), IDL (9.0 ± 1.3 versus 5.4 ± 0.6 mg/dL, p < 0.05), and LDL (76.3 ± 4.3 versus 59.4 ± 3.7 mg/dL, p < 0.01) in HT compared with controls. The ratio of cholesterol to apoB in LDL decreased (1.27 ± 0.06 versus 1.48 ± 0.08, p < 0.05). In essential HT, number of apoB containing lipoproteins (IDL, LDL) increased. Low ratio of cholesterol to apoB was noted in LDL, indicating the presence of small, dense LDL. As cholesterol in LDL was normal, hyperbetalipoproteinemia is also a characteristic disorder of essential HT.     

Inverse relationship between blood levels of high density lipoprotein subfraction 2 and magnitude of postprandial lipemia.

Triglyceridemic response to a standard oral fat meal was determined in 28 healthy subjects and related to the levels of several lipids, lipoproteins, and apolipoproteins in the post-absorptive plasma. A fatty test meal was administered orally, and postprandial plasma triglyceride levels were determined. In the fasting blood samples, concentrations of apolipoproteins (apo) A-I, A-II, and B were determined by radioimmunoassay, and those of high density lipoprotein (HDL) subfractions HDL2 and HDL3, by zonal ultracentrifugation. The magnitude of triglyceridemic response showed a negative correlation with the plasma levels of HDL2 (r = -0.860, P less than 0.001), HDL-associated cholesterol (r = -0.605, P less than 0.001), and apoA-I (r = -0.459, P less than 0.02). No correlation was found between the triglyceridemic response and the levels of total cholesterol, HDL3, and apoA-II. Triglyceridemic response was correlated positively with fasting triglyceride concentrations (r = 0.450, P less than 0.02) and apoB levels (r = 0.396, P less than 0.03). In two subjects followed for 3 yr, when HDL2 levels rose or fell, the triglyceridemic response decreased or increased, respectively (r = -0.944; r = -0.863). Our data indicate that normolipidemic individuals with high HDL2 levels in the plasma are able to clear alimentary fat at a faster rate than normolipidemic subjects with low HDL2 levels. The pronounced difference in severity and duration of postprandial lipemia among subjects with varying HDL2 levels may help to explain the negative correlation between the risk of atherosclerosis and HDL cholesterol levels.     

Relation of the level of high-density lipoprotein subfractions to the presence and extent of coronary artery disease.

Plasma lipid profiles, including high-density lipoprotein (HDL) subfractions HDL2 and HDL3, were obtained in 115 men undergoing coronary angiography to assess the relation of lipid levels to coronary artery disease (CAD). CAD was present in 87 patients (76%) and absent in 28 (24%). The largest difference between the 2 groups were observed for HDL2 cholesterol, with a mean of 0.13 mmol/liter (5 mg/dl) in patients with CAD compared with 0.25 mmol/liter (10 mg/dl) in those without CAD (p less than 0.005). Smaller differences were found for HDL3 (1.02 mmol/liter [39 mg/dl] vs 1.19 mmol/liter [46 mg/dl]; p less than 0.005) and HDL (1.15 vs 1.42 mmol/liter [45 vs 55 mg/dl]; p less than 0.001) cholesterol, and apolipoprotein A-1 (1.37 vs 1.50 g/liter; p less than 0.01) and plasma triglycerides (1.79 vs 1.38 mmol/liter [159 vs 122 mg/dl]; p less than 0.05). No significant difference was found for plasma and low-density lipoprotein cholesterol, and apolipoprotein B levels. Simple regression analysis revealed that the most powerful independent variable associated with the extent of CAD was HDL2 cholesterol (Spearman rho = 0.311; p less than 0.001). Stepwise multiple regression analysis proved HDL2 cholesterol and age to be the strongest predictors of extent of CAD. The level of HDL2 cholesterol was reasonably well correlated with HDL cholesterol (r2 = 0.6; p less than 0.0001), but less so with plasma apolipoprotein A-1 (r2 = 0.4; p less than 0.0001). The data add to the growing body of information demonstrating an important association of HDL (and more specifically HDL2) with CAD in men.     

An open label crossover trial of effects of metronidazol on hyperlipidaemia

Metronidazole, a synthetic derivative of tile nitroimidazole class, is a known antibacterial and antiprotozoal agent. Following an anecdotal observation of hypolipidemic effect of metronidazole, a randomized open trial of 250 mg three times daily was conducted in 30 subjects. This open label crossover trial was performed in three stages—14 days each—as challenge, wash out and re-challenge on 30 subjects, including six male and 24 female in the age limits of 40 to 73 years (mean 58.7±10.6 years). Results of this trial revealed that metronidazole 750 mg daily in divided doses for 14 days decreased the average of total blood cholesterol in 30 cases by 46±27 mg/dl (14.6%, P=0.025) and LDL cholesterol by 39±28 mg/dl (22%, P=0.005). Decrease in total and LDL cholesterol and increase in HDL cholesterol by 3.8±4.1 mg/dl also accompanied fall of triglyceride level cases by 68±13 mg/dl. This study suggests that metronidazole or its derivatives may form a new class of lipid lowering compounds.