Beyond LDL-cholesterol: can further reductions in CAD risk be achieved by considering triglycerides?
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Cholesterol, LDL↗
Biomedical subjects
J Davignon
Publications and source records attributed to J Davignon.
Advances in drug treatment of dyslipidemia: focus on atorvastatin.
The focus of lipid-lowering therapy with drugs is prevention of complications of atherosclerosis. Landmark clinical trials have demonstrated that lowering low density lipoprotein cholesterol (LDL-C) may not only reduce coronary artery disease (CAD) risk but also may slow the progression and even induce regression of atherosclerosis in the coronary arteries. In addition, much attention has been given in recent years to the importance of triglyceride-rich lipoprotein (TRL) as a CAD risk factor, and the benefit of reducing plasma triglyceride levels and raising high density lipoprotein cholesterol (HDL-C) levels to prevent the recurrence of coronary events. Lipid-lowering drugs should be used within the framework of a systematic approach to treatment. Consideration must be given to the lipoprotein abnormality, the severity of disease, the role of combination therapy, and the spectrum of action of the drug and its pleiotropic effects (ie, effects beyond the expected action on lipoproteins). Five major agents have been used for the treatment of dyslipidemias. Three (resins, probucol and statins) target LDL-C, and two (fibrates and niacin) target primarily TRL and HDL-C. Fibrates and statins are the drugs of choice. Fibrates correct many abnormalities of lipoprotein metabolism in addition to having beneficial pleiotropic effects such as reducing fibrinogen and plasma viscosity. They inhibit the transcription of apolipoprotein (apo) CIII and enhance that of apoAI and lipoprotein lipase. Statins are safe and potent drugs for reducing LDL-C levels, and their efficacy in primary and secondary prevention of CAD has been amply demonstrated. They share a modes effect of raising HDL-C levels. Their pleiotropic effects, which include improvement of endothelial dysfunction, are numerous and may contribute to their spectacular beneficial effect of reducing CAD risk. They have effects that are complementary to those of fibrates, but the two drugs should be combined with caution because of the danger of myopathy. Atorvastatin is a major addition to this class of drugs because of its high efficacy and large spectrum of action. It lowers LDL-C levels effectively, not only in patients with severe forms of hypercholesterolemia but also in those with homozygous familial hypercholesterolemia. The effect of atorvastatin on LDL-C may be further enhanced by combining it with a resin. The ability of atorvastatin to lower triglyceride levels as well as LDL-C levels indicates that combined hyperlipidemia, a condition that, in the past, was best controlled with combination therapy, can now be treated with a single drug. It is also effective in patients with isolated hypertriglyceridemia and, although less potent than fenofibrate at reducing TRL and increasing HDL-C, it has a greater impact on the atherogenic risk ratios such as LDL-C:HDL-C. The profile of its pleiotropic effects is promising.
Anticholesteremic Agents↗
Angiotensin converting enzyme insertion/deletion polymorphism in French Canadian subjects with premature coronary artery disease.
The insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene has been postulated to be associated with CAD in some populations of European descent. As part of a study investigating metabolic and genetic factors in subjects with premature coronary artery disease (CAD), we examined the I/D polymorphism of the ACE gene in 134 subjects with premature CAD (105 men and 29 women, mean age 49 +/- 6 years) and 116 control subjects selected for health (71 men, 45 women; mean age 39 +/- 7 years). Both patients and controls were of French Canadian descent. As expected, significant differences were found between cases and controls with respect to age, plasma lipoprotein cholesterol, presence of smoking, diabetes and high blood pressure after correction for age. Multivariate analysis confirms the importance of age, HDL-C levels, smoking and apo B levels as determinants of CAD. Allele frequencies of the I and D polymorphism were 43.1% and 57.9% in controls, and 48.5% and 51.5% in CAD cases (chi 2 = 0.622, p = 0.430). No significant association between the I/D polymorphism and conventional cardiovascular risk factors, including plasma levels of lipids, lipoprotein cholesterol, diabetes or smoking, was found in cases or controls. Furthermore, the presence of the I/D polymorphism did not correlate with a history of hypertension or a family history of premature CAD in CAD patients. We conclude that, in our selected population, the I/D polymorphism of the ACE gene is not associated with CAD, conventional risk factors, or a family history of CAD. Although our sample size does not allow sufficient power to ascertain that the ACE I/D polymorphism is not associated with CAD, we do not recommend the routine measurement of the ACE polymorphism in our population to determine cardiovascular risk.
Adult↗
Association of apolipoprotein E with alpha2-macroglobulin in human plasma.
Apolipoprotein (apo) E plays a central role in the transport of lipids among different organs and cell types, whereas alpha2-macroglobulin (alpha2M) is responsible for the binding and inactivation of plasma proteases, as well as the transport of various cytokines, growth factors, and hormones. In the present study, evidence is presented for direct binding of apoE with alpha2M in human plasma, based on the observation that two-dimensional non-denaturing gradient gel electrophoretic separation of plasma resulted in co-migration of apoE with alpha2M in a complex intermediate in size (18.5 nm in diameter) between low (LDL) and high density lipoproteins (HDL). ApoE associated with alpha2M could be immunoprecipitated from plasma with anti-human alpha2M antiserum. Purified apoE, labeled with 125I, bound to native and methylamine-activated alpha2M (alpha2M-MA) in vitro in a time- and concentration-dependent manner. ApoE bound to alpha2M-MA with greater affinity than alpha2M. The binding of apoE to both alpha2M and alpha2M-MA did not depend on the presence of lipid. Ingestion of an oral fat load resulted in a reduction in the amount of apoE associated with alpha2M. Sphingomyelin vesicles and very low density lipoproteins (VLDL), but not phosphatidylcholine vesicles or HDL3, inhibited the in vitro binding of 125I-labeled apoE3 to alpha2M and alpha2M-MA. Binding of 125I-labeled apoE3 was also partially inhibited by an excess of platelet-derived growth factor and beta-amyloid protein, but not interferon-gamma. Subjects with an apoE 4/4 phenotype had less apoE associated with alpha2M in plasma than subjects with an apoE 3/3 or 2/2 phenotype, corresponding to reduced in vitro binding of apoE4 with alpha2M or alpha2M-MA. Although the functional significance of apoE binding to alpha2M remains to be determined, the present results demonstrate that: 1) apoE is non-covalently bound to alpha2M in human plasma, 2) alpha2M-MA has a greater capacity to bind apoE than alpha2M, 3) various proteins or lipoproteins known to bind apoE or alpha2M can potentially affect the interaction of apoE with alpha2M, and 4) association of apoE with alpha2M or alpha2M-MA is dependent on apoE phenotype.
Apolipoproteins E↗
Pseudo type III dyslipoproteinemia is associated with normal fibroblast lipoprotein receptor activity.
Pseudo type III (PT-III) dyslipoproteinemia is characterized by a plasma accumulation of triglyceride-rich lipoproteins (TRL) and their remnants. It mimics type III, but its etiology can not be ascribed to a genetic apo E defect. In order to determine whether PT-III is associated with a genetic lipoprotein receptor abnormality, we have measured (in cultured fibroblasts from affected and nonaffected individuals) the in vitro activity of three lipoprotein receptors which are implicated in the catabolism of TRL, namely the low-density lipoprotein receptor (LDL-R), the lipoprotein receptor-related protein (LRP) and the lipolysis-stimulated receptor (LSR). Specific cell association and degradation of 125I-LDL by LDL-R-upregulated PT-III fibroblasts was not significantly different from that of control cells (103 +/- 10% and 98 +/- 17% of controls; 20 microg/ml 125I-LDL). Specific cell association and degradation of rabbit 125I-beta-VLDL was also not significantly different. LRP activity was assessed by measuring the ability of PT-III and control cells to bind three different LRP ligands: activated alpha2-macroglobulin (alpha2M-MA), lactoferrin and apo E-enriched rabbit beta-VLDL. No significant differences were observed (24.0 +/- 2.1 vs. 23.4 +/- 5.7 fmol/mg for 5 nM of 125I-alpha2M-MA; 4.8 +/- 0.3 vs. 5.2 +/- 1.3 microg/mg for 20 microg/ml of 125I-lactoferrin; 319.4 +/- 51.2 vs. 309.5 +/- 23.2 ng/mg for 5 microg/ml of 125I-beta-VLDL, PT-III vs. control, respectively). LSR activity, as assessed by the cell association or degradation of 125I-LDL by fibroblasts in the presence of 0.5 mM oleate and human leptin, was also not different. No evidence was obtained for deficient cellular recognition of PT-III TRL (d < 1.006 g/ml) by normal human fibroblasts or mouse macrophages. These results suggest that PT-III dyslipoproteinemia is not due to an accumulation in plasma of poorly recognized TRL, nor due to a genetic defect in LDL-R, LRP or LSR.
Animals↗
Association of Lp(a) rather than integrally-bound apo(a) with triglyceride-rich lipoproteins of human subjects.
The majority of apolipoprotein (a) [apo(a)] in plasma is characteristically associated with Lipoprotein (a) [Lp(a)], having a buoyant density (1.05-1.08 g/ml) intermediate between low density lipoproteins (LDL) and high density lipoproteins (HDL). In the fed (postprandial) state or in the presence of fasting (endogenous) hypertriglyceridemia, a small proportion of plasma apo(a) is found in the density < 1.006 g/ml fraction of plasma, associated with larger and less dense triglyceride-rich lipoproteins (TRL). In order to further characterize the presence of apo(a) in ultracentrifugally-separated TRL (UTC-TRL), this lipoprotein fraction was isolated from plasma obtained in the fed state (three hours after an oral fat load) from healthy normolipidemic subjects (Lp(a): 38 +/- 8 mg/dl (mean +/- S.E.), n = 4) and also from plasma obtained after an overnight fast from hypertriglyceridemic patients (plasma TG: 8.16 +/- 2.00 mmol/l, Lp(a): 41 +/- 3 mg/dl, n = 18). Apo(a) in 3 h-postprandial UTC-TRL (5 +/- 2% of total plasma apo(a)) and in hypertriglyceridemic UTC-TRL (8 +/- 2% total apo(a)) was separable by electrophoresis and/or gel chromatography (FPLC) from the majority of UTC-TRL lipid. Apo(a) in UTC-TRL fractions had slow pre-beta electrophoretic mobility and was isolated in a lipoprotein size-range smaller than VLDL and larger than LDL, consistent with it being Lp(a). Recentrifugation of UTC-TRL resulted in the majority of apo(a) being recovered in the density > 1.006 g/ml fraction. Addition of proline to plasma samples before ultracentrifugation (final concentration: 0.1 M) substantially reduced the amount of Lp(a) in UTC-TRL. TRL separated from plasma by FPLC contained less apo(a) (2-5% of total plasma apo(a)), but this apo(a) was also readily dissociable from TRL lipid, had slow pre-beta electrophoretic mobility, and was associated with a lipoprotein with the size of Lp(a). Our data suggest that apo(a) in the TRL fraction of subjects with postprandial triglyceridemia or endogenous hypertriglyceridemia is not an integral component of plasma VLDL or chylomicrons, but represents the presence of non-covalently bound Lp(a).
Adult↗
Association of an exon 3 mutation (Trp66-->Gly) of the LDL receptor with variable expression of familial hypercholesterolemia in a French Canadian family.
The ligand-binding domain of low-density lipo-protein (LDL) is composed of seven 40-amino-acid repeats encoded by exons 2-6. Previous studies identified a missense mutation in codon 66 of exon 3, which resulted in the production of LDL receptor protein that is not processed to its mature form. In the current investigation, we documented the presence of two identical mutant LDL receptor alleles (Trp66-->Gly) in two familial hypercholesterolemia (FH) probands, II-1 and II-2, associated with markedly elevated plasma LDL cholesterol (17.22 +/- 0.78 and 11.95 +/- 0.24 mmol/liter, respectively). Functional assays of their fibroblast LDL receptor showed inefficient binding (39 and 50%), internalization (33 and 37%), and degradation (32 and 37%) compared with controls. The contribution of the apo B gene to variation in LDL levels was virtually eliminated given the normal ligand interaction with cell surface receptors and the absence of the mutation occurring in codon 3500 of the apo B gene. Similarly, the homozygous apo E3/E3 wildtype phenotype excluded any genetic contribution of apo E to the lipoprotein abnormalities. Furthermore, the LPL mutations commonly observed in French Canadians could not account for the observed lipid alterations. Several alterations in lipoprotein composition characterized VLDL, IDL, LDL, HDL2, and HDL3 fractions. Moreover, defective intestinal fat transport was observed in both probands (II-1 and II-2). Thus, the disturbance of lipoprotein concentration, composition, size, and metabolism may in part be related to the exon 3 mutation (Trp66-->Gly) of the LDL receptor gene. The biochemical phenotype was more severe in the father (I-1) than in the mother (I-2), and in the younger homozygous proband (II-1) than in the older (II-2). The greater severity was associated with a higher LDL cholesterol/HDL cholesterol ratio. Whether the differences between the two probands are due to polygenic factors or to a metabolic consequence of a major nonallelic trait is unknown. Nevertheless, the present biochemical findings stress the extent of the lipid abnormalities associated with homozygous FH and the importance of the phenotypic variability encountered even among subjects carrying the same mutation.
Apolipoproteins B↗
Lipid lowering in patients with coronary artery disease: low density lipoprotein cholesterol and beyond.
Now that the importance of LDL-C and its reduction are well established in the prevention of atherosclerotic vascular complications, we are moving to a new era in which physicians must pay more attention to factors beyond LDL-C lowering. More emphasis should be put on TRL and remnant lipoproteins as well as other contributors to the cardiovascular risk burden, such as thrombotic risk factors and impaired fibrinolysis. This should be carried out within the standard framework of a global approach to risk factor management in CAD patients.
Editorial↗
Geographic distribution of French-Canadian low-density lipoprotein receptor gene mutations in the Province of Quebec.
A total of 35 homozygous and 1320 heterozygous patients with familial hypercholesterolemia (FH) was screened for the presence of six low-density lipoprotein receptor (LDLR) gene mutations previously reported among French-Canadians. The geographic distribution of patients' birthplaces and the relative prevalence of these six mutations in the LDLR gene in the province of Quebec were compared. For this purpose, the 16 administrative regions of the province of Quebec were grouped into seven geographic regions. The relative frequency of the six mutations differed in the seven regions: the > 15 kb deletion (delta > 15 kb) had the highest relative frequency in the Bas St-Laurent/Gaspésie region, and the point mutation in exon 3 had the highest relative frequency in the Saguenay-Lac-St-Jean/Côte-Nord region. In the Montreal area, the delta > 15 kb and the mutation in exon 3 had prevalence rates of 71.2% and 13.0%, respectively, whereas the relative frequencies of the delta > 15 kb and the point mutation in exon 3 in the Quebec city region were 57.5 and 21.8%, respectively. Finally, in Saguenay-Lac-St-Jean/Côte-Nord, the relative frequency of the delta > 15 kb only reached 31.5% and the point mutation in exon 3, 59.2%. Thus, on the north shore of the St. Lawrence River, the prevalence of the delta > 15 kb decreases from west to north-east, whereas the relative frequency of the mutation in exon 3 appears to increase. These observations provide a better characterization of FH among French-Canadians of Quebec, a Canadian province with a high prevalence of this inherited disease.
Exons↗
Prevalence of double pre-beta lipoproteinemia in hyperlipidemic patients is influenced by gender, menopausal status, and ApoE phenotype.
Double pre-beta lipoproteinemia (DPBL) is a plasma lipoprotein phenotype characterized by the presence of two agarose gel electrophoretic populations of very low density lipoproteins (VLDLs, d < 1.006 g/mL), i.e., normal pre-beta-migrating VLDL and slow pre-beta VLDL. Slow pre-beta VLDL represents remnant lipoproteins derived from the hydrolysis of triglyceride (TG)-rich lipoproteins (TRLs), and thus DPBL is a characteristic of plasma remnant lipoprotein accumulation. To determine the prevalence of DPBL in our lipid clinic population, patients (n = 2501) were selected who (1) had an unambiguous VLDL electrophoretic phenotype and could be classified as having either DPBL (DPBL+), beta-migrating VLDL (beta-VLDL +), or an absence of both (DPBL/beta-VLDL-/-) and (2) had hypercholesterolemia (HC: plasma cholesterol > or = 6.2 mmol/L, n = 1017), hypertriglyceridemia (HTG: plasma TG > or = 2.3 mmol/L but < 15 mmol/L, n = 554) or combined hyperlipidemia (HC + HTG, n = 930). Patients with TG < 2.3 mmol/L and cholesterol < 5.2 mmol/L acted as control subjects (n = 343). Using a commercially available agarose gel electrophoresis system, we identified 220 hyperlipidemic patients (8.8%) with DPBL (versus < 1% of control). The prevalence of DPBL was higher in (1) male than in female patients (10.7% versus 6.7%), (2) postmenopausal than in premenopausal females (7.3% versus 4.1%), and (3) patients with HC + HTG than in those with HTG or HC alone (15.8% versus 8.3% versus 2.7%, respectively). Patients with an epsilon 2 allele had a higher prevalence of DPBL; i.e., 26.9% of apoE 3/2 and 26.2% of apoE 4/2 patients had DPBL compared with 6.5%, 6.8%, and 7.4% of apoE 3/3, 4/3, and 4/4 patients, respectively. DPBL patients consistently had increased levels of VLDL-C and (LDL + HDL)-TG and decreased levels of LDL-C, and their plasma lipid profiles were intermediate between those of beta-VLDL+ and DPBL/beta-VLDL -/- patients. These results demonstrate that male sex, postmenopausal status in women, and the presence of an apoE 3/2 or apoE 4/2 phenotype are associated with an increased incidence of DPBL in hyperlipidemic patients.
Adult↗
Efficacy and safety of a new hydroxymethylglutaryl-coenzyme A reductase inhibitor, atorvastatin, in patients with combined hyperlipidemia: comparison with fenofibrate.
This 24-week, randomized, open-label multicenter study evaluated the efficacy and safety of atorvastatin compared with fenofibrate in the treatment of patients with combined hyperlipidemia (CHL). Following a 6-week baseline period, 84 patients with CHL were randomly assigned to either atorvastatin treatment, 10 mg QD for 12 weeks increasing to 20 mg QD for 12 weeks, or fenofibrate treatment, 100 mg TID for 24 weeks. Changes from baseline in lipid parameters were evaluated at weeks 12 and 24. At both 10- and 20-mg doses, atorvastatin treatment resulted in significantly greater reductions in LDL cholesterol, apolipoprotein (apo) B, total cholesterol, LDL-apoB, and lipoprotein-B compared to 300-mg fenofibrate treatment (P < .05). While atorvastatin also resulted in clinically significant reductions in triglyceride, VLDL cholesterol, apoB in VLDL, triglyceride in VLDL, and apoC-III and significant increases in HDL cholesterol and apoA-I levels, fenofibrate was more effective than atorvastatin in altering all these parameters. However, by significantly affecting both the cholesterol-rich and triglyceride-rich particles, atorvastatin holds promise as a lipid-regulator able to adequately treat a broad range of patients that includes those with CHL.
Adult↗
Characterization of human plasma apolipoprotein E-containing lipoproteins in the high density lipoprotein size range: focus on pre-beta1-LpE, pre-beta2-LpE, and alpha-LpE.
We have used two-dimensional gel electrophoresis to separate and characterize human plasma apolipoprotein (apo) E-containing lipoproteins in the high density lipoprotein (HDL) size range. Lipoproteins were separated from whole plasma by electrophoresis (according to charge) in a 0.75% agarose gel, and then in the second dimension (according to size) in a 2-15% non-denaturing polyacrylamide gradient gel. ApoE-containing lipoproteins were detected by radiography after electrotransfer of lipoproteins to nitrocellulose membranes and incubation with 125I-labeled affinity-purified polyclonal apoE antibody. ApoE-containing lipoproteins in the HDL size range had a particle size ranging from 9 to 18.5 nm in diameter and could be characterized as having either gamma, pre-beta1-, pre-beta2- or alpha-electrophoretic mobility (designated gamma-LpE, pre-beta1-LpE, pre-beta2LpE, and alpha-LpE respectively). gamma-LpE and a substantial proportion of pre-beta1- and pre-beta2-LpE did not co-migrate with apoA-I, apoA-II, apoC-III, or apoB-100. Subsequent experiments focused on the pre-beta1-LpE, pre-beta2LpE, and alpha-LpE subfractions, which represented > 95% of apoE in HDL-sized lipoproteins. Storage of plasma at 4 degrees C or in vitro incubation of plasma at 37 degrees C caused a relative decrease in pre-beta1-LpE and increase in alpha-LpE. Normolipidemic patients with an apoE 2/2 phenotype tended to have increased levels of alpha-LpE, whereas apoE 4/4 subjects tended to have a greater proportion of HDL-apoE as pre-beta1-LpE. Decrease in plasma HDL apoE concentration after an oral fat load was associated with a reduction in the plasma concentration of all HDL-apoE subfractions. These results demonstrate that: 1) apoE-containing HDL are heterogeneous in size and charge; 2) pre-beta1-LpE is a relatively labile HDL subfraction; 3) HDL-apoE subfraction distribution is dependent on apoE phenotype; and 4) all apoE-containing HDL subfractions participate in the plasma transfer of apoE during the postprandial period.
Adult↗
Metabolic factors clustering, lipoprotein cholesterol, apolipoprotein B, lipoprotein (a) and apolipoprotein E phenotypes in premature coronary artery disease in French Canadians.
Plasma lipoprotein cholesterol abnormalities, diabetes, hypertension and smoking have all been identified as independent predictors of cardiovascular events. Clustering of multiple risk factors suggests a common metabolic link among high blood pressure, insulin resistance, plasma lipoprotein abnormalities and obesity. New guidelines for the management of dyslipidemias target patients with established coronary artery disease (CAD), and high risk patients with multiple risk factors and severe genetic lipoprotein disorders, such as familial hypercholesterolemia. To determine the prevalence of lipoprotein, apolipoprotein and metabolic disorders in premature CAD, 243 men and 61 women with premature CAD (occurring before age 60 years) and 203 age- and sex-matched controls (152 men, 61 women) were studied. After correcting for beta-blocker use (40% of men and 54% of women), hypertension and diabetes were seen more frequently in CAD patients than in controls. In men and women, cholesterol, triglycerides, low density lipoprotein (LDL) cholesterol, apolipoprotein B and lipoprotein (a) were significantly higher, and high density lipoprotein (HDL) cholesterol was lower, in CAD patients than in controls. By stratifying patients according to LDL cholesterol: HDL cholesterol ratio (5 or less, or greater than 5) and by triglyceride levels (less than 2.3 mmol/L, or 2.3 mmol/L or greater), significantly more men and women with CAD were found to have an elevated LDL cholesterol:HDL cholesterol ratio and elevated triglycerides (13.8% versus 1.9%, men and women combined, CAD versus controls, P < 0.0001). A metabolic factor index was devised, assigning a score of 1 each for presence of hypertension, lipoprotein abnormalities, diabetes or fasting blood glucose above 7.0 mmol/L, and a body mass index of 27 or greater. The prevalence of a metabolic factor index of 3 or more was 29.2% in CAD men versus 6.7% in controls (P < 0.0001) and 38.3% in CAD women versus 11.7% in controls (P < 0.01). Familial hypercholesterolemia was seen in fewer than 5% of patients with premature CAD and type III dyslipoproteinemia in one of 343 CAD patients. The distribution of apolipoprotein E phenotypes was the same in CAD patients and controls. Multivariate analysis revealed that in men, HDL cholesterol, lipoprotein (a) levels and smoking were the best predictors of risk. In men, plasma levels of LDL cholesterol, triglycerides or body mass index did not enter the model at the P < 0.05 level. In women, low HDL cholesterol, lipoprotein (a), the presence of diabetes, smoking and apolipoprotein B levels were all predictors of risk (P < 0.05). However, the clustering of risk factors may be the best predictor of risk. In this selected population, HDL and lipoprotein (a) are the best metabolic markers of premature CAD; metabolic factor clustering is common in patients with premature CAD.
Adult↗
Plasma lipoprotein distribution of apoC-III in normolipidemic and hypertriglyceridemic subjects: comparison of the apoC-III to apoE ratio in different lipoprotein fractions.
In order to assess the relationship between plasma accumulation of triglyceride-rich lipoproteins (TRL) and lipoprotein levels of apoC-III and apoE, we have measured apoC-III and apoE in lipoproteins separated according to size (by automated gel filtration chromatography) from plasma of normolipidemic subjects (plasma triglyceride (TG): 0.84 +/- 0.10 mmol/l; mean +/- SE, n = 8), and from type III (n = 8) and type IV (n = 8) hyperlipoproteinemic patients, matched for plasma TG (5.76 +/- 0.62 v 5.55 +/- 0.45 mmol/l, resp.). Total plasma apoC-III concentration was similar in type III and type IV patients (33.1 +/- 3.4 v 37.6 +/- 4.4 mg/dl, respectively), but was significantly increased compared to normolipidemic controls (10.0 +/- 1.0 mg/dl, P < 0.001). TRL apoC-III was lower and high density lipoprotein (HDL) apoC-III was significantly higher in type III versus type IV subjects (14.8 +/- 3.2 vs. 22.8 +/- 3.0 mg/dl, P < 0.05; 8.3 +/- 1.0 vs. 5.2 +/- 0.5 mg/dl, P < 0.05). Plasma concentration of apoC-III in lipoproteins that eluted between TRL and HDL (intermediate-sized lipoproteins, ISL) was similar in the two hypertriglyceridemic groups (10.1 +/- 1.3 vs. 9.7 +/- 1.6 mg/dl), but was significantly higher (P< 0.05) than controls (2.2 +/- 0.3 mg/dl). TRL, ISL, and HDL apoE concentrations were significantly higher in type III versus type IV subjects (P < 0.05). All lipoprotein fractions in type III patients were characterized by lower apoC-III to apoE ratios. In contrast, the TRL apoC-III to apoE ratio of type IV patients was similar and the ISL apoC-III to apoE ratio was significantly higher, compared to normolipidemic individuals. These results indicate that compared to normolipidemic individuals, remnant-like lipoproteins in the ISL fraction of type IV patients are enriched in apoC-III relative to apoE, whereas those of type III patients are enriched in apoE relative to apoC-III.
Adult↗
Apolipoprotein E genotype and gender influence response to tacrine therapy.
Our objective is to evaluate the effects of apolipoprotein E genotype (APOE) on clinical response to treatment with tacrine, in patients with Alzheimer's disease (AD). Only 25 to 50% of patients with AD, depending on dose and design, have been responders in previous tacrine trials. AD autopsy studies have suggested that APOE epsilon 4 is associated with decreased numbers of cholinergic markers in temporal cortex and the hippocampus. Our hypothesis was that cholinergic therapy might be less effective in epsilon 4 carriers. APOE phenotypes were determined from plasma samples previously saved from a large 30-week, randomized, double-blind placebo-controlled, parallel-group, multicenter trial of tacrine at dosages of 80, 120, or 160 mg/day. Outcome measures included Alzheimer's Disease Assessment Scale (ADAS) and its cognitive component (ADAS-Cog), Clinician's Interview-Based Impression (CIBI), Global Deterioration Scale (GDS), and the caregiver-rated Clinical Global Impression of Change (CGIC). Analyses were performed on the change in scores from baseline to last observation on 460 patients having APOE results available. There were 291 patients heterozygous or homozygous for APOE epsilon 4 and 169 patients with only APOE epsilon 2 or epsilon 3 alleles. Analysis of variance showed non-APOE epsilon 4 carriers (E2,3) on tacrine improved more versus placebo than patients with APOE epsilon 4 (E4) on tacrine versus placebo as measured by the ADAS (p = 0.04) and the ADAS-Cog (p = 0.05). A trend toward greater treatment effect in the E2,3 patients was seen with CIBI, GDS, and CGIC, but these differences did not achieve significance. APOE genotype may be a predictor for clinical response to tacrine in AD patients, APOE epsilon 4 associated with a lower probability of cognitive improvement. When the groups were further divided by gender, most of the effect of APOE on treatment response was seen in women. E2-3 women improved more than any other group, and E4 women the least. The interaction of gender and APOE genotype on treatment response as measured by ADAS-Cog was significant (p = 0.03). Future trials of cholinergic therapy in AD should include APOE genotyping.
Aged↗
Hyperhomocysteinemia induced by folic acid deficiency and methionine load--applications of a modified HPLC method.
The increasing possibility that homocysteine might be involved in atherosclerosis in non-homocysteinuric subjects has required the measurement of low concentrations of this aminothiol in biological samples. The procedure described here represents an improvement of different HPLC methods. We utilized an isocratic HPLC system with fluorescence detection of plasma total homocysteine derivatized after reaction with ammonium 7-fluoro-benzo-2-oxa-1,3-diazole-4-sulphonate. With the help of the rapidly eluting internal standard N-acetyl-cysteine, the method ensures very good recovery (approximately 100%), reproducibility and precision (within-assay: 2.31%; day-to-day: 2.8%) in the physiological concentration range. This procedure allowed us to validate various animal models of hyperhomocysteinemia such as dietary folic acid deficiency in rat and acute methionine loads in rat and hamster. Using this method, we also confirmed that men have higher plasma total homocysteine levels than women. Due to its simplicity and reliability, our procedure is suitable for routine analysis of total homocysteine and other aminothiols (cysteine, cysteinyl-glycine and glutathione) in biological samples, as required in clinical and research laboratories.
Adult↗
Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia.
OBJECTIVE: To assess the lipid-lowering effect of atorvastatin (a new 3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitor) on levels of serum triglycerides and other lipoprotein fractions in patients with primary hypertriglyceridemia, determine if atorvastatin causes a redistribution of triglycerides in various lipoprotein fractions, and assess its safety by reporting adverse events and clinical laboratory measurements. DESIGN: Randomized double-blind, placebo-controlled, parallel-group, multicenter trial. SETTING: Community- and university-based research centers. PATIENTS: A total of 56 patients (aged 26 to 74 years) with a mean baseline triglyceride level of 6.80 mmol/L (603.3 mg/dL) and a mean baseline low-density lipoprotein cholesterol (LDL-C) level of 3.07 mmol/L (118.7 mg/dL). INTERVENTIONS: Cholesterol-lowering diet (National Institutes of Health National Cholesterol Education Program Step I Diet) and either 5 mg, 20 mg, or 80 mg of atorvastatin, or placebo. MAIN OUTCOME MEASURES: Percent change from baseline in total triglycerides for three dose levels of atorvastatin compared with placebo. RESULTS: Mean reductions in total triglycerides between 5 mg, 20 mg, and 80 mg of atorvastatin and placebo after 4 weeks of treatment were -26.5%, -32.4%, -45.8%, and -8.9%, respectively. Mean reductions in LDL-C were -16.7%, -33.2%, -41.4%, and -1.4%, respectively, and very low-density lipoprotein cholesterol (VLDL-C) were -34.3%, -45.9%, -57.7%, and -5.5%, respectively. Similar mean changes in total apolipoprotein B (apo B) (-16.9%, -32.8%, -41.7%, and +1.0%), apo B in LDL (-14.8%, -29.8%, -42.0%, and -3.1%), and apo B in VLDL (-23.8%, -35.8%, -34.4%, and +11.7%) were observed. In addition, comparable mean changes in LDL triglycerides (-22.5%, -30.7%, -39.9%, and +3.9%) and VLDL triglycerides (-28.1%, -34.0%, -47.3%, and -10.8%) were seen. CONCLUSIONS: In atorvastatin treatment groups, total serum triglyceride levels decreased in a dose-dependent manner, reductions in the 20-mg and 80-mg groups were statistically significant (P < .05) compared with placebo. Atorvastatin did not cause a redistribution of triglycerides but consistently lowered triglycerides in all lipoprotein fractions. Atorvastatin was well tolerated.
Adult↗
Influence of genetic variability in the nondeletion LDL-receptor allele on phenotypic variation in French-Canadian familial hypercholesterolemia heterozygotes sharing a 'null' LDL-receptor gene defect.
We investigated the associations between low density lipoprotein (LDL)-receptor gene haplotypes and lipid and lipoprotein levels in French-Canadian individuals with familial hypercholesterolemia (FH). The 112 unrelated patients studied shared the same > 10 Kb deletion in the 5' region of the LDL-receptor gene, leading to a null allele. Support for the hypothesis that the deletion is carried on only one LDL-receptor restriction fragment length polymorphism (RFLP) haplotype in this sample has previously been demonstrated [1]. We studied associations of genetic variability in DNA polymorphisms of the nondeletion LDL-receptor allele with variation in plasma lipid levels in these patients heterozygous for the deletion. All analyses were done separately in males and females. The traits were adjusted for variation in the concomitants age, height and weight, and for variation in apolipoprotein (apo) E phenotype, and then the association between variability in haplotypes defined by two RFLP loci and variation in trait levels were tested. The results indicated that in this sample of French-Canadian > 10 Kb deletion FH heterozygotes, variability at the LDL-receptor gene contributes to quantitative variation in measures of lipid metabolism and that the effects are different in males and females. The results indicated that variability at the LDL-receptor gene defined by two RFLP loci contributes to quantitative variation in high density lipoprotein (HDL)-cholesterol and LDL-cholesterol concentrations in French-Canadian FH women heterozygous for the > 10 Kb deletion and not in men.
Alleles↗