Increased apoC-III production is a characteristic feature of patients with hypertriglyceridemia

Apolipoprotein (apo) C-III plays an important role in regulating plasma triglyceride (TG) metabolism. In order to further investigate the plasma metabolism of apoC-III in hypertriglyceridemic subjects, we have studied the plasma kinetics of VLDL apoC-III, HDL apoC-III and total plasma apoC-III with a primed constant intravenous infusion of deuterated leucine in a group of male patients with mixed hyperlipidemia (type IIb hyperlipoproteinemia, HLP, n=6) and in a group with type III HLP (n=6). Compared to normolipidemic control subjects (n=5), patients with type IIb and type III HLP had significantly higher levels of plasma TG (0.89 +/- 0.15 mmol/l vs 2.56 +/- 0.40 mmol/l vs 8.76 +/- 1.39 mmol/l, respectively, P <0.01), plasma apoC-III (9.5 +/- 0.8 mg/dl vs 20.8 +/- 2.5 mg/dl vs 41.7 +/- 5.6 mg/dl, P <0.01) and VLDL apoC-III (3.6 +/- 0.8 mg/dl vs 14.6 +/- 2.2 mg/dl vs 35.4 +/- 5.1 mg/dl, P <0.01). VLDL apoC-III production rates were significantly elevated in type IIb and type III patients (1.35 +/- 0.23 mg kg(-1) day(-1) vs 3.53 +/- 0.43 mg kg(-1) day(-1) vs 5.60 +/- 0.78 mg kg(-1) day(-1), P <0.01), as were total plasma apoC-III production rates (1.80 +/- 0.22 mg kg(-1) day(-1) vs 4.16 +/- 0.44 mg kg(-1) day(-1) vs 7.26 +/- 0.74 mg kg(-1) day(-1), P <0.01). VLDL apoC-III but not total plasma apoC-III fractional catabolic rates were reduced in type IIb and type III patients. Together with our previous results showing an increase of apoC-III production in patients with type IV HLP, and in overweight subjects with reduced insulin sensitivity, our data suggest that increased apoC-III production is a characteristic feature of patients with hypertriglyceridemia.     

Lathosterol level in plasma is elevated in type III hyperlipoproteinemia, but not in non-type III subjects with apolipoprotein E2/2 phenotype, nor in type IIa or IIb hyperlipoproteinemia

We measured the serum lathosterol level, a reflection of the rate of whole body cholesterol synthesis, in 15 patients with manifest type III hyperlipoproteinemia (HLP), in 20 subjects with apolipoprotein (apo) E2/2 phenotype, but without type III HLP, in 21 patients with type IIA and 10 patients with type IIB HLP. A group of 100 subjects with apo E3/3 phenotype served as reference. Using ANCOVA, lathosterol was adjusted for serum cholesterol and triglyceride concentrations, since these parameters were found to independently correlate with lathosterol. The adjusted means (+/- SEM), in mumol/L, in these groups were 12.9 +/- 1.1, 8.2 +/- 1.1, 4.8 +/- 0.9, 9.8 +/- 1.4, and 7.8 +/- 0.4, respectively. Type III HLP patients had significantly higher lathosterol levels than all other groups except type IIB HLP. In addition, lathosterol was significantly lower in type IIA patients than in all other groups. The serum levels of plant sterols, used as a reflection of cholesterol absorption, did not differ among the various groups after adjustment for serum cholesterol. These findings suggest that an overproduction of cholesterol is one factor discriminating E2/2 homozygotes with type III HLP from those without the disease.     

Differential effects of oral estrone versus 17 beta-estradiol on lipoproteins in postmenopausal women

Toward the definition of optimal postmenopausal estrogen replacement we compared the effects of three graduated doses of two oral estrogens, estrone sulfate and 17 beta-estradiol, on the lipid profiles of two groups of six postmenopausal women. Because of metabolic interconversions equivalent serum concentrations of estrone and estradiol were produced with these regimens. However, differential effects were noted in lipoproteins. 17 beta-Estradiol caused an increase in total plasma cholesterol (from 5.71 +/- 0.36 to 5.99 +/- 0.57 mmol/L, baseline to high dose; P less than 0.02), high density lipoprotein (HDL) cholesterol (from 1.45 +/- 0.15 to 1.78 +/- 0.36 mmol/L; P less than 0.02), HDL2 cholesterol concentration (from 0.41 +/- 0.08 to 0.62 +/- 0.26 mmol/L; P less than 0.01), and triglyceride concentration (from 1.09 +/- 0.29 to 1.24 +/- 0.30 mmol/L; P less than 0.01) without affecting low density lipoprotein (LDL) cholesterol concentration. By contrast, estrone sulfate caused a decrease in total plasma cholesterol (from 6.51 +/- 0.85 to 5.87 +/- 0.41 mmol/L; P less than 0.05) and LDL cholesterol concentration (from 4.34 +/- 0.57 to 3.67 +/- 0.44 mmol/L; P less than 0.01) and an increase in HDL cholesterol (from 1.37 +/- 0.20 to 1.50 +/- 0.26 mmol/L; P less than 0.05) and HDL2 cholesterol concentration (from 0.34 +/- 0.18 to 0.49 +/- 0.18 mmol/L; P less than 0.01), but no change in total triglyceride concentration. We deduce that the differential effect of orally administered estrogens on lipoprotein metabolism in postmenopausal women may be attributed to a first pass effect on hepatic metabolism.     

Effects of estrogen replacement on plasma lipoproteins and apolipoproteins in postmenopausal, dyslipidemic women.

The effects of oral estrogen replacement (ethinyl estradiol 0.02 mg/d) on plasma triglyceride, total cholesterol, very-low-density lipoprotein (VLDL) cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and apolipoprotein (apo) A-I and B levels and LDL particle size were assessed in 20 postmenopausal women with a previous hysterectomy and various forms of dyslipidemia (LDL cholesterol > or = 4.14 mmol/L [160 mg/dL] and/or HDL cholesterol < or = 1.03 mmol/L [40 mg/dL]). All subjects were studied while on a standard cholesterol-lowering diet, and were sampled in the fasting state before beginning estrogen therapy and after a mean of 13 weeks of estrogen therapy. Lipids were measured by standardized enzymatic techniques, apos were measured by enzyme-linked immunoassays, and LDL particle size was measured by gradient gel electrophoresis. Mean values for plasma lipid parameters (mmol/L) at baseline and during estrogen replacement were as follows: triglyceride, 2.11 and 2.75 (30% increase); total cholesterol, 7.45 and 6.52 (13% decrease); VLDL cholesterol, 1.09 and 1.22 (12% increase); LDL cholesterol, 5.09 and 3.70 (27% decrease); and HDL cholesterol, 1.27 and 1.58 (24% increase). Mean values for apo A-I were 163 and 254 mg/dL (56% increase), and for apo B they were 170 and 148 mg/dL (13% decrease). The LDL particle score was 4.09 and 4.52 (11% smaller). Changes in all parameters were statistically significant (P = .05) except for VLDL cholesterol. These data indicate that estrogen replacement is effective in decreasing LDL cholesterol and apo B concentrations and increasing HDL cholesterol and apo A-I concentrations in dyslipidemic postmenopausal women, but it should not be used in patients with baseline fasting triglyceride levels higher than 2.82 mmol/L (250 mg/dL) unless it is accompanied by a progestin. Our data indicate that this form of estrogen replacement could lower the risk of coronary artery disease (CAD) by more than 50% in these women, based on favorable alterations in plasma lipoproteins.     

Conjugated equine estrogen improves glycemic control and blood lipoproteins in postmenopausal women with type 2 diabetes

The objective of this study was to determine the metabolic effects of estrogen replacement therapy in postmenopausal women with type 2 diabetes. Twenty-five postmenopausal, type 2 diabetic women completed a randomized, blinded, cross-over trial of conjugated equine estrogen, 0.625 mg/day, vs. placebo for 8 weeks, separated by a 4-week washout period. When compared with 8 weeks of placebo, estrogen reduced fasting serum glucose (7.2 +/- 0.3 vs. 8.4 +/- 0.4 mmol/L, P = 0.0003), glycated hemoglobin (8.7 +/- 0.4% vs. 9.3 +/- 0.4%, P = 0.04), total cholesterol (5.27 +/- 0.20 vs. 5.50 +/- 0.21 mmol/L, P = 0.04), low-density lipoprotein cholesterol (2.47 +/- 0.13 vs. 2.69 +/- 0.14 mmol/L, P = 0.02), serum apolipoprotein B (114 +/- 6 vs. 121 +/- 5 mg/dL, P = 0.03), and postprandial glucose area under the curve (by 12%, P = 0.015). Estrogen replacement therapy also increased high-density lipoprotein (HDL) cholesterol (1.27 +/- 0.08 vs. 1.1 +/- 0.07 mmol/L, P = 0.0002), high-density lipoprotein(2) cholesterol (0.41 +/- 0.04 vs. 0.30 +/- 0.03 mmol/L, P = 0.0001), and fasting triglyceride (2.17 +/- 0.21 vs. 1.94 +/- 0.16 mg/dL, P = 0.02) concentrations but not postprandial triglyceride area under the curve (P = not significant). We conclude that estrogen replacement therapy improves glycemic control, blood lipoproteins, and apolipoprotein B concentrations while modestly increasing triglyceride levels in postmenopausal, type 2 diabetic women.     

Endothelium-dependent relaxation by acetylcholine is impaired in hypertriglyceridemic humans with normal levels of plasma LDL cholesterol

OBJECTIVES: Patients with high triglyceride (of which very low density lipoproteins [VLDL] are the main carriers), but with normal low density lipoprotein (LDL) cholesterol levels, were examined for in vivo endothelium function status. BACKGROUND: Very low density lipoproteins inhibit endothelium-dependent, but not -independent, vasorelaxation in vitro. METHODS: Three groups were studied: 1) healthy volunteers (n = 10; triglyceride 1.24+/-0.14 mmol/liter, LDL cholesterol 2.99+/-0.24 mmol/liter); 2) hypertriglyceridemic (n = 11; triglyceride 6.97+/-1.19 mmol/liter, LDL cholesterol 2.17+/-0.2 mmol/liter, p < 0.05); and 3) hypercholesterolemic (n = 10; triglyceride 2.25+/-0.29 mmol/liter, LDL cholesterol 5.61+/-0.54 mmol/liter; p < 0.05) patients. Vasoactive responses to acetylcholine, sodium nitroprusside, noradrenaline, N(G)-monomethyl-L-arginine and postischemic hyperemia were determined using forearm venous occlusion plethysmography. RESULTS: Responses to acetylcholine (37 microg/min) were significantly dampened both in hypercholesterolemic (% increase in forearm blood flow: 268.2+/-62) and hypertriglyceridemic patients (232.6+/-45.2) when compared with controls (547.8+/-108.9; ANOVA p < 0.05). Responses to sodium nitroprusside (at 1.6 microg/min: controls vs. hypercholesterolemics vs. hypertriglyceridemic: 168.7+/- 25.1 vs. 140.6+/-38.9 vs. 178.5+/-54.5% increase), noradrenaline, N(G)-monomethyl-L-arginine and postischemic hyperemic responses were not different among the groups examined. CONCLUSIONS: Acetylcholine responses are impaired in patients with pathophysiologic levels of plasma triglycerides but normal plasma levels of LDL cholesterol. The impairment observed was comparable to that obtained in hypercholesterolemic patients. We conclude that impaired responses to acetylcholine normally associated with hypercholesterolemia also occur in hypertriglyceridemia. These findings identify a potential mechanism by which high plasma triglyceride levels may be atherogenic independent of LDL cholesterol levels.     

Inheritance of type-III hyperlipoproteinemia. Lipoprotein patterns in first-degree relatives.

The lipoprotein (LP) patterns were studied in the families of 19 index cases with type-III hyperlipoproteinemia (HLP). Seventy adult first-degree relatives (93% ascertainment) to the 19 probands were analyzed. The diagnosis of HLP type III among the first-degree relatives was based on three criteria, all of which had to be fulfilled to make the diagnosis: (1) presence of a slow-moving band in very-low-density LP (VLDL) on agarose gel electrophoresis migrating in beta or close to beta position; (2) A cholesterol/triglyceride ratio (mg/100 ml: mmoles/liter) in VLDL greater than 29.0; and (3) A "III-index" [cholesterol/triglycerides in VLDL x 10 divided by cholesterol/triglycerides in low-density LP (LDL)] greater than 1.30. When defined according to these criteria there was a marked over-representation of HLP type III among the relatives (27%). There was also an increased frequency of hypertriglyceridemia (28% against expected 15%), mainly because of a high prevalence of HLP type IV (24%). On agarose gel electrophoresis a "late pre-beta" band, probably indicative of an increased amount of intermediary LP particles, was frequently present (47%) among relatives not classified as HLP type III. Type-III patients with hypertriglyceridemia were characterized by a significantly higher body weight than those with normotriglyceridemic type III. However, there was no qualitative difference in the composition of the lipoproteins in normotriglyceridemic and hypertriglyceridemic type-III patients. A genetic analysis of the LP patterns within the families showed several examples of vertical transmission of HLP type III. There was no sex linkage. Six of thirteen analyzed parents showed LP patterns classified as HLP type III. Another two parents were most probably carriers of the gene. Of the siblings to the probands, 23% showed a type-III pattern and another four (7%) showed LP patterns very similar to type III, fulfilling two of three criteria for HLP type III. The data support the concept that HLP type III is inherited as an autosomal dominant gene. It was indicated that HLP type IV with a late pre-beta band in VLDL may represent another expression of the gene for HLP type III. It is suggested that HLP type III may be a pathogenetically heterogenous group of lipid disorders. A separation of type III into two subgroups with low or normal and high LDL cholesterol concentration, respectively, may facilitate the understanding of the inheritance of type III as well as of the pathogenesis behind this LP abnormality.     

Differences in apolipoproteins and low-density lipoprotein subfractions in postmenopausal women on and off estrogen therapy: results from the Framingham Offspring Study

The use of estrogens by postmenopausal women has been associated with reduced risk of coronary artery disease (CAD) in some studies, possibly due to favorable effects of estrogens on plasma lipoproteins. In order to examine such effects, we studied 180 postmenopausal women from the Framingham Offspring Study, selected by type of menopause (natural or oophorectopic) and estrogen use. We determined fasting plasma total cholesterol, triglyceride, very-low-density lipoprotein (VLDL) cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and apolipoprotein (apo) A-l and B concentrations, as well as LDL particle size (LDL 1 to LDL 6). Apo A-l levels were significantly (P less than .005) higher, and diastolic blood pressure and glucose levels were significantly (P less than .05) lower in postmenopausal women taking estrogen regardless of type of menopause. HDL cholesterol levels were also higher in women taking oral estrogens, but differences were significant only for the oophorectomized group (P less than .02). Total cholesterol, VLDL cholesterol, and LDL cholesterol levels were significantly lower (P less than .01) in women with natural menopause who were taking estrogens than in women with natural menopause not taking this medication. No significant differences between estrogen users and nonusers were found with regard to triglyceride levels or LDL particle score, in either the natural menopause or oophorectomy groups. These data indicate that estrogen use in postmenopausal women is associated with significantly elevated plasma apo A-l levels and decreased LDL cholesterol concentrations.     

Apolipoprotein-E2 and hyperlipoproteinemia in noninsulin-dependent diabetes mellitus

The association of apolipoprotein-E2 (apoE2) with hyperlipoproteinemia (HLP) was investigated in 23 noninsulin-dependent diabetes mellitus patients with apoE2 and 24 nondiabetic controls with apoE2. The frequency of HLP was significantly higher in diabetic subjects with apoE2 (73.9%) than in nondiabetic controls (37.5%). HLP in nondiabetic subjects with apoE2 included only type IV (n = 9), whereas HLP in diabetic subjects with apoE2 included type IIb (n = 1), type III (n = 7), and type IV (n = 9). Diabetic patients with apoE2 were characterized by increased levels of plasma triglyceride, total cholesterol (chol), very low density lipoprotein (VLDL)-chol, and apoE and an increased VLDL-chol/VLDL-triglyceride ratio, i.e. the accumulation of remnants. In addition, fasting plasma glucose and hemoglobin-A1 levels were significantly higher in hyperlipoproteinemic diabetic patients with apoE2 than in normolipidemic diabetic patients with apoE2. It is concluded that diabetes (poor metabolic control) predisposes apoE2 (epsilon 2)-carrying subjects to HLP (particularly type III) and that apoE2 may be one factor linking diabetes with HLP and cardiovascular disease.     

Appearance of multidisperse low density lipoprotein and altered lipoprotein composition in non-insulin-dependent diabetes with type IIa hyperlipoproteinemia

The purpose of the present study is to elucidate the characteristics of lipoprotein disorders in diabetes mellitus. By analytical ultracentrifugation, non-insulin-dependent diabetic patients (NIDDM) with type IIa hyperlipoproteinemia (HLP) showed significantly higher incidence of multidisperse low density lipoprotein (LDL) than non-diabetics with type IIa HLP. Furthermore, LDL multidispersity in diabetic subjects seemed to be directly related to neither triglyceride (TG) levels in very low density lipoprotein (VLDL) nor the degree of glycemic control. Diabetics with multidisperse LDL had a lipoprotein profile that was different from the subjects with paucidisperse LDL as follows: (1) enrichment in the cholesterol content of VLDL, (2) TG-rich LDL with small flotation coefficient, (3) low cholesterol levels in high density lipoprotein2 along with enrichment in TG, and (4) high plasma concentrations of apoprotein B. Although the underlying mechanism behind the prevalence of multidisperse LDL in NIDDM with type IIa HLP remains unknown, it seems important that lipoprotein disorders in diabetics with multidisperse LDL were potentially atherogenic.     

Two subpopulations of intermediate density lipoprotein and their relationship to plasma triglyceride and cholesterol levels

We observed the appearance of two intermediate density lipoprotein (IDL) subfractions on gradient gel electrophoresis of lipoproteins in the density range 1.006-1.030 g/ml and estimated their approximate concentrations in plasma in subjects with a wide range of lipid levels, from 0.55 to 28.0 mmol/l plasma triglyceride and 3.75-10.0 mmol/l cholesterol. The larger species, IDL-I (31.7 +/- 0.7 nm, mean +/- SD), showed little variation in size in normal and moderate hyperlipidaemic individuals. The estimated concentration of IDL-I was positively related to plasma triglyceride (r = 0.63, P = 0.0004) and low density lipoprotein (LDL) cholesterol (r = 0.68, P = 0.0003). These findings are consistent with the view that IDL-I is a metabolic intermediate between very low density lipoprotein (VLDL) and LDL. The smaller subfraction, IDL-II (25.7 +/- 2.4 nm) was virtually the only true species observed in subjects with plasma triglyceride < 1.0 mmol/l and its estimated concentration fell as plasma triglyceride increased (r = -0.58, P = 0.0002). IDL-II particle size changed in concert with LDL particle size (r = 0.61, P < 0.0001), suggesting that they were influenced by common metabolic factors. These observations provide further support for the hypothesis outlined by Musliner et al. [1] that IDL-I was part of the delipidation chain from VLDL to LDL, whereas IDL-II arose from a separate source, possibly directly released from the liver. Hence the two subpopulations of IDL differ in their relationship to plasma triglyceride and cholesterol levels.     

Does pravastatin increase chylomicron remnant catabolism in postmenopausal women with type 2 diabetes mellitus?

OBJECTIVE: We investigated the effects of pravastatin on chylomicron remnant catabolism measured with a 13C stable isotope breath test and plasma apolipoprotein (apo) B-48 and remnant-like particle (RLP)-cholesterol in postmenopausal women with type 2 diabetes mellitus. PATIENTS AND MEASUREMENTS: Nineteen postmenopausal women with type 2 diabetes were randomized to receive 40 mg/day pravastatin or no treatment for 6 weeks followed by a 2-week washout period, and crossed over for a further 6 weeks. Fractional catabolic rate (FCR) of a chylomicron remnant-like emulsion was determined from 13CO2 enrichment in the breath and plasma using isotope-ratio mass spectrometry and multicompartmental modelling. Plasma apo B-48 and RLP-cholesterol concentrations were also measured as static markers of chylomicron remnant metabolism. RESULTS: Pravastatin significantly reduced plasma concentrations of cholesterol (5.9 +/- 0.3 vs. 4.8 +/- 0.2 mmol/l; P < 0.001), low density lipoprotein (LDL)-cholesterol (3.5 +/- 0.2 vs. 2.6 +/- 0.2 mmol/l; P < 0.001), triglyceride (2.1 +/- 0.3 vs. 1.7 +/- 0.2 mmol/l; P = 0.017), non-high density lipoprotein (HDL)-cholesterol (4.4 +/- 0.3 vs. 3.3 +/- 0.2 mmol/l; P < 0.001), lathosterol/total cholesterol ratio (2.6 +/- 0.2 vs. 2.0 +/- 0.3, P = 0.035), apo B-100 (1.1 +/- 0.1 vs. 0.8 +/- 0.1 g/l; P = 0.001), apo B-48 (4.8 +/- 0.9 vs. 3.3 +/- 0.6 mg/l; P = 0.016), and RLP-cholesterol (31.4 +/- 8.2 vs. 18.6 +/- 4.6 mg/dl; P = 0.024). Pravastatin was also associated with an increase in sitosterol/total cholesterol ratio (2.8 +/- 0.3 vs. 3.1 +/- 0.3, P = 0.029). Chylomicron remnant-like emulsion catabolism was not, however, significantly altered by pravastatin estimated by either breath or plasma clearance measurements. CONCLUSIONS: In postmenopausal women, pravastatin decreases plasma concentrations of remnant lipoproteins by a mechanism that may relate chiefly to inhibition of remnant production, but this requires further evaluation.     

A young type III hyperlipoproteinemic patient associated with apolipoprotein E deficiency

A 13-year-old female patient had noticed tuberoeruptive xanthomas since 3 years of age. Her serum, VLDL, and IDL cholesterol levels were high (348, 158, and 60 mg/dL, respectively), while LDL and HDL cholesterol levels were 56 and 62 mg/dL, respectively. VLDL-cholesterol/serum triglyceride ratio was extremely high (0.86), suggesting type III hyperlipoproteinemia (HLP). Her apo E was undetectable by the single radial immunodiffusion studies and SDS-polyacrylamide gel electrophoresis. Her parents showed hypertriglyceridemia and her two siblings were normolipidemic, and their apo E levels were normal. Genomic DNA digested with BamHI or EcoRI did not show gross differences in the restriction fragment length between the apo-E-deficient patient and normal controls. Thus, apo E deficiency may be characterized by early appearance of clinical manifestations of type III HLP and higher VLDL-cholesterol/serum triglyceride ratio.     

Effect of hormone therapy, tibolone and raloxifene on circulating vascular endothelial growth factor in Greek postmenopausal women

OBJECTIVE: To evaluate the effect of continuous combined hormone therapy (HT), tibolone and raloxifene on circulating vascular endothelial growth factor (VEGF) in postmenopausal women. DESIGN: One-year prospective intervention study. METHODS: One hundred and forty-six postmenopausal women with a mean age of 51.8+/-4.1 (s.d.) years received 0.625 mg conjugated equine estrogen (CEE) plus 5 mg medroxyprogesterone acetate (MPA) (CEE/MPA, n=34), 2.5 mg tibolone (n=37), 60 mg raloxifene (n=40) or no active treatment (control group, n=35). Plasma VEGF was estimated at baseline and at 6 and 12 months. RESULTS: In both the CEE/MPA-treated and the tibolone-treated groups plasma VEGF increased significantly at month 6 and remained elevated at month 12 (CEE/MPA baseline: 268.1+/-187.8 pg/ml, month 6: 320.0+/-175.3 pg/ml, month 12: 321.1+/-181.8 pg/ml, P=0.01; tibolone baseline: 240.6+/-165.8 pg/ml, month 6: 271.4+/-172.7 pg/ml, month 12: 274.8+/-183.1 pg/ml, P=0.03). These changes were significantly different from the respective changes in the control group after adjusting for T-score in bone densitometry (CEE/MPA: P=0.02, tibolone: P=0.04). The effect of HT or tibolone on plasma VEGF was mainly evident in women with low baseline VEGF levels (<243.2 pg/ml, median for whole sample). On the contrary, VEGF levels in the raloxifene-treated or the control group did not change throughout the study. CONCLUSION: Both continuous combined HT and tibolone increased circulating VEGF in postmenopausal women, while raloxifene had no effect. Further research is needed to clarify the clinical relevance of these findings with respect to cardiovascular risk in postmenopausal women.     

Menopause is associated with reduced protection from postprandial lipemia

Deficiency of endogenous estrogens has been associated with a higher incidence of coronary heart disease (CHD) in women. We investigated whether natural menopause is associated with reduced protection from postprandial lipemia, which represents a risk indicator of CHD. Twenty-three postmenopausal women (mean age, 50+/-1 [SD] years; body mass index, 24.6+/-2.8 kg/m(2)) and 21 premenopausal women matched for age and body mass index (age, 49+/-1 years; body mass index, 24. 1+/-2.6 kg/m(2)) underwent an oral vitamin A fat-loading test. Vitamin A is a marker of the metabolism of chylomicrons and chylomicron remnants. All women were normolipidemic, were in good health, were nonsmokers, and used no medication. Postprandial lipids and vitamin A were measured at hourly intervals up to 12 hours. In postmenopausal women, plasma total cholesterol and LDL cholesterol concentrations were significantly higher. Fasting plasma triglyceride (TG) concentrations were 1.14+/-0.57 mmol/L in postmenopausal women and 0.88+/-0.33 mmol/L in premenopausal women (P=NS). In the postprandial phase, postmenopausal women had higher plasma TG (13.0+/-6.1 versus 9.5+/-3.3 mmol x L(-1) x h(-1); P=0.024) and vitamin A (54.1+/-22.9 versus 35.9+/-9.6 mg x L(-1) x h(-1); P=0. 001) responses. To correct for the possible confounding effect of fasting TG, 13 postmenopausal women were carefully matched with 19 premenopausal women. Although fasting TG levels were identical (0. 72+/-0.20 versus 0.73+/-0.21 mmol/L), differences in postprandial vitamin A (45.3+/-14.5 versus 33.0+/-7.7 mg x L(-1) x h(-1); P=0.006) and incremental TG (ie, after subtraction of baseline TG) (3.2+/-1.8 versus 2.3+/-1.0 mmol x L(-1) x h(-1); P=0.023) persisted between postmenopausal and premenopausal women. Natural menopause is associated with aggravated postprandial lipemia in women matched for age and body mass index. Higher postprandial lipemia potentially explains the relation of TGs and CHD mortality risk in postmenopausal women.     

Significant differential effects of lower doses of hormone therapy or tibolone on markers of cardiovascular disease in post-menopausal women: a randomized, double-blind, crossover study.

AIMS: We have previously reported that lower doses of hormone therapy (L-HT) and tibolone have different effects on markers of cardiovascular disease when compared with conventional doses of HT. The objective was to compare the effects of L-HT and tibolone on lipid profile, vasodilation, and factors associated with inflammation and haemostasis. METHODS AND RESULTS: Forty-one women received a combination of micronized progesterone 100 mg with conjugated equine estrogen 0.3 mg vs. tibolone 2.5 mg alone daily in random order during 2 months with 2 months washout period. When compared with L-HT, tibolone significantly reduced total cholesterol (P<0.001), triglyceride (P<0.001), HDL cholesterol (P<0.001) levels, and triglyceride/HDL cholesterol ratios (P=0.004) except total cholesterol/HDL cholesterol ratios. Tibolone improved flow-mediated response to hyperaemia from baseline values (P<0.001) by a similar magnitude to L-HT. L-HT and tibolone did not increase high-sensitivity C-reactive protein relative to baseline values. L-HT reduced antithrombin III from baseline values (P=0.037), compared with tibolone showing no changes. However, there was no difference between either. In contrast, tibolone increased pro-thrombin fragment 1+2 (F1+2) from baseline values (P=0.002), compared with L-HT showing no changes. Tibolone significantly reduced plasma plasminogen activator inhibitor type 1 (PAI-1) antigen levels from baseline values (P=0.004), compared with L-HT showing no changes. The effects of L-HT and tibolone on F1+2 and PAI-1 were significantly different (P=0.045 and P=0.008, respectively). CONCLUSION: Both tibolone and L-HT improved flow-mediated response by a similar magnitude and did not significantly increase high-sensitivity C-reactive protein. However, tibolone significantly reduced PAI-1, but increased F1+2 more than L-HT.     

A randomised placebo controlled trial of the effects of tibolone on blood pressure and lipids in hypertensive women

The effects of hormone replacement therapy in hypertensive women are controversial. This randomised placebo controlled trial assessed the effect of tibolone 2.5 mg on blood pressure and fasting plasma lipids in 29 hypertensive postmenopausal women over 6 months using a 2:1 randomisation to tibolone. The primary clinical end-point was mean office blood pressure. At 6 months systolic blood pressure declined by 5.30 +/- 2.87% vs 4.94 +/- 3.37% whilst diastolic blood pressure declined 5.38 +/- 2.65% vs 0.85 +/- 3.69% on tibolone and placebo respectively. These differences were not statistically significant. Triglycerides decreased by 33.3 +/- 6.1% vs 7.6 +/- 7.9% (P < 0.01) and high-density lipoprotein (HDL)-cholesterol by 21.7 +/- 3.8% vs 2.4 +/- 2.6% (P < 0.01) with tibolone as opposed to placebo. No significant differences were observed in total cholesterol, low-density lipoprotein (LDL)-cholesterol and lipoprotein (a). Fibrinogen levels were reduced by 13.6 +/- 6.8% on tibolone compared to a 19.3 +/- 15.4% rise (P < 0.05) on placebo. This study suggests that tibolone has no deleterious effect on blood pressure in women with hypertension but has contrasting effects on biochemical risk factors. Large-scale studies are required to determine the overall effect of tibolone on cardiovascular morbidity and mortality.     

Effects of nicotinic acid on serum cholesterol concentrations of high density lipoprotein subfractions HDL2 and HDL3 in hyperlipoproteinaemia

Nicotinic acid was given in a 4-g daily dose for 6 weeks to 41 weight-stable patients of mean age (+/- SD) 52 +/- 9 years, with type IIa, type IIb or type IV hyperlipoproteinaemia (HLP), in order to study its effects on serum cholesterol concentrations of high density lipoprotein (HDL) subfractions HDL2 and HDL3. The triglyceride and cholesterol levels of serum very low density (VLDL) and low density (LDL) lipoproteins decreased during treatment (P less than 0.001). Serum HDL and HDL2 cholesterol levels increased by 37% and 135%, respectively. These changes were positively correlated (r = 0.93; P less than 0.001). There was no significant change in mean serum HDL3 cholesterol concentration. A negative correlation existed between changes in HDL3 and HDL2 cholesterol levels (r = -0.54; P less than 0.001). Multiple stepwise linear regression analyses revealed that the initial HDL3 cholesterol predicted more than 30% of the increase in HDL2 cholesterol. Changes in the concentrations of HDL2 and HDL3 cholesterol after 6 weeks of drug treatment were not related to the type of HLP, neither were these effects of nicotinic acid correlated with changes in VLDL or LDL lipid levels. The concept has previously been proposed, on the basis of in vitro data, that HDL2 is formed from HDL3 particles in the blood. Our results suggest that, in man, this reaction is stimulated in vivo by prolonged nicotinic acid therapy.     

Menopause impacts the relation of plasma adiponectin levels with the metabolic syndrome

Abstract. Henneman P, Janssens ACJW, Carola Zillikens M, Frolich M, Frants RR, Oostra BA, van Duijn CM, van Dijk KW (Leiden University Medical Center, Leiden; Erasmus Medical Center, Rotterdam, The Netherlands). Menopause impacts the relation of plasma adiponectin levels with the metabolic syndrome. J Intern Med 2010; 267 : 402–409. Objective. Plasma adiponectin is negatively correlated with metabolic syndrome (MetS) components obesity and insulin sensitivity. Here, we set out to evaluate the effect of menopause on the association of plasma adiponectin with MetS. Design. Data on plasma adiponectin and MetS were available from 2256 individuals participating in the Erasmus Rucphen Family study. Odds ratios for MetS were calculated by logistic regression analysis using plasma adiponectin quartiles. The discriminative accuracy of plasma adiponectin for MetS was determined by calculating the area under the curve (AUC) of receiver operator. Analyses were performed in women and men, pre‐ and postmenopausal women and younger and older men. Results. Virtually all determinants of MetS differed significantly between groups. Low plasma adiponectin showed the highest risk for MetS in postmenopausal women (odds ratio = 18.6, 95% CI = 7.9–44.0). We observed a high discriminative accuracy of age and plasma adiponectin for MetS not only in postmenopausal women (AUC = 0.76) but also in other subgroups (AUC from 0.67 to 0.87). However, in all groups, the discriminative accuracy of age and body mass index (BMI) for MetS was similar to the discriminative accuracy of age and plasma adiponectin. Conclusions. Low plasma levels of adiponectin are associated with increased prevalence of MetS, especially in postmenopausal women. Age and BMI have similar discriminatory accuracies for presence of MetS when compared with age and plasma adiponectin. Thus, we conclude that the association of plasma adiponectin with MetS is significantly affected by menopause but challenge the additional value of adiponectin for the discriminatory accuracy for presence of MetS.     

A controlled study on the effects of n-3 fatty acids on lipid and glucose metabolism in non-insulin-dependent diabetic patients

Eight male non-insulin-dependent diabetic patients participated in a double-blind randomized cross-over study (2 weeks for each period) evaluating the effects of 10 g/day fish oil dietary supplementation on glucose and lipid metabolism. Fasting serum triglyceride concentrations were decreased by fish oil because of a reduction in VLDL (1.4 +/- 0.2 vs. 1.9 +/- 0.2 mmol/l, P less than 0.025). LDL cholesterol concentration was instead increased (3.4 +/- 0.3 vs. 2.8 +/- 0.3 mmol/l, P less than 0.025) and net changes in VLDL triglyceride and in LDL cholesterol were inversely correlated (r = -0.86, P less than 0.01). Plasma free fatty acids concentrations and turnover rate [( 3H]palmitate method) were similar after fish oil and placebo. Fish oil supplement did not induce significant changes in fasting blood glucose (8.1 +/- 1.1 vs. 8.5 +/- 1.2 mmol/l) and average daily blood glucose (BG) (9.4 +/- 3.2 vs. 9.3 +/- 3.5 mmol/l). Glucose stimulated plasma insulin response during a hyperglycemic clamp was not significantly influenced by fish oil both in the early phase and during steady state. Insulin sensitivity (M/I index) was also unchanged. In conclusion, this study shows that a dietary supplement of fish oil decreases plasma triglyceride levels in non-insulin-dependent diabetic patients, an increased conversion rate of VLDL to LDL playing a role in this change. With this dosage of fish oil no relevant variations in glycemic control, insulin secretion and insulin sensitivity occurred.