Influence of triglyceride concentration on the relationship between lipoprotein cholesterol and apolipoprotein B and A-I levels.

A sample of 2,103 men aged 47 to 76 years from the Québec Cardiovascular Study cohort was examined to quantify the influence of plasma triglyceride (TG) levels on the relationship between plasma lipoprotein cholesterol and either apolipoprotein A-I (apo A-I) or apo B concentrations. Regression analyses between high-density lipoprotein cholesterol (HDL-C) and apo A-I through TG tertiles showed highly significant correlations (.62 < or = r < or = .75, P < .0001) in all TG tertiles between these 2 variables. The associations for plasma apo B versus low-density lipoprotein cholesterol (LDL-C) and non-HDL-C levels were also studied on the basis of TG concentrations, and correlation coefficients between either LDL-C or non-HDL-C and apo B were essentially similar among TG tertiles (.78 < or = r < or = .85 and .83 < or = r < or = .86 for LDL-C and non-HDL-C, respectively, P < .0001). Regression analyses also showed that lower HDL-C levels were found for any given apo A-I concentration among men in the 2 upper TG tertiles, whereas lower LDL-C concentrations were observed at any given apo B level among subjects in the upper TG tertile. We further investigated whether there were synergistic alterations in the HDL-C/apo A-I and LDL-C/apo B ratios as a function of increasing plasma TG. A significant association was noted between these 2 ratios (r = .37; P < .0001). Mean HDL-C/apo A-I and LDL-C/apo B ratios were then calculated across quintiles of plasma TG concentrations. Increased TG concentrations were first associated with a reduced HDL-C/apo A-I ratio, followed by a decreased LDL-C/apo B ratio. These results suggest that a relatively modest increase in TG may rapidly alter the relative cholesterol content of HDL particles. Finally, the cholesterol content of the non-HDL fraction appears to be influenced less by TG levels than HDL-C and LDL-C fractions. Thus, the plasma apo B-containing lipoprotein cholesterol level may provide a better index of number of atherogenic particles than the LDL-C concentration, particularly in the presence of hypertriglyceridemia (HTG).

Metabolic and antihypertensive effects of nebivolol and atenolol in normometabolic patients with mild-to-moderate hypertension.

This was a double-blind, randomized, two-center, active-controlled, prospective, parallel study designed to evaluate the effects of nebivolol at daily doses of 5 mg on lipid and carbohydrate metabolism and on blood pressure in comparison with atenolol at daily doses of 50 mg. Normometabolic subjects with mild-to-moderate essential hypertension were recruited for this study, which included a 4-week, single-blind placebo washout phase and a 12-week double-blind treatment phase. After 12 weeks of treatment, both drugs demonstrated a significant decrease from baseline in high-density lipoprotein (HDL) apolipoprotein A-I (HDL-apoA-I) (nebivolol, P <.02; atenolol, P <.05). A significant reduction in HDL cholesterol (HDL-C) from baseline was also observed with nebivolol (P <.05). There were no significant differences between the drugs for these parameters, and the ratio low-density lipoprotein cholesterol (LDL-C)-to-HDL-C did not change significantly after 12 weeks of active treatment with nebivolol or atenolol. There were no significant changes in total cholesterol, HDL (2) -C, HDL (3) -C, LDL-C, very-low-density lipoprotein cholesterol (VLDL-C), total triglycerides, HDL-triglycerides (TG), LDL-TG, VLDL-TG, total apoB, LDL-B, VLDL-B (including the ratio LDL-C-to-LDL-apoB), or Lp(a) during treatment with both drugs. No significant differences in plasma apoA-I and apoC-III as well as in apoA-I-, C-III-containing lipoprotein particles (including the apoC-III ratio) were observed between the drugs, neither before nor after each active treatment. There were no significant differences between the drugs or within each treatment group in plasma glucose, insulin, or C-peptide concentrations after a 2-hour oral glucose tolerance test. Mean clinic trough sitting systolic blood pressure (SBP)/diastolic blood pressure (DBP) significantly decreased from 150/98 mm Hg at baseline to 141/90 mm Hg at termination for nebivolol and from 160/99 mm Hg at baseline to 145/88 mm Hg at termination for atenolol. No significant between-treatment differences were observed for the mean clinic trough sitting SBP/DBP. Both drugs significantly increased the atrial natriuretic factor (ANF) N-terminal plasma levels, whereas no changes were observed in ANF C-terminal plasma concentrations. A significant decrease (P <. 05) in the plasma adrenocorticotropic hormone levels was observed after administration of both drugs. A significant decrease (P <.05) in plasma cortisol levels was observed only after atenolol treatment. The incidence of adverse events reported during nebivolol treatment was comparable to that observed during atenolol treatment. Heart rate was significantly reduced by both drugs. There were no significant changes in hematology, biochemistry, or urinalysis studies. Neither nebivolol nor atenolol adversely affected lipid or carbohydrate metabolism in normometabolic hypertensive patients. Both treatments demonstrated adequate and similar antihypertensive effects and were well tolerated.

Apolipoprotein E polymorphism and the relationships of physical fitness to plasma lipoprotein-lipid levels in men and women.

PURPOSE: A high level of cardiovascular fitness is generally associated with a plasma lipoprotein-lipid profile predictive of a low cardiovascular disease risk. We have investigated whether apolipoprotein (apo) E polymorphism could alter the relationships of physical fitness to plasma lipoprotein-lipid levels in a sample of healthy untrained subjects (64 premenopausal women and 65 men). METHODS: Subjects were grouped according to gender and apo E phenotype determined by isoelectric focusing electrophoresis. RESULTS: In both genders, VO2max expressed in mL x kg(-1) x min(-1) was negatively correlated with plasma triglyceride levels in apo E2 carriers and apo E3 homozygotes (-0.55< or =r< or =0.31; P<0.05), whereas these associations were not found in apo E4 groups. Plasma low-density lipoprotein (LDL)-C levels were negatively associated with VO2max (r = -0.39; P<0.05) only in women homozygotes for apo E3 whereas VO2max was positively correlated with plasma high-density lipoprotein (HDL)2-C levels only in men (r = 0.51; P<0.001) and women (r = 0.65; P<0.001) who were apo E3 homozygotes. A control for concomitant association with body fat mass and glucose intolerance performed by partial correlation analyses revealed that, with the exception of the plasma HDL2-C levels in the apo E3 homozygotes, most of the significant associations between VO2max (mL x kg(-1) x min(-1)) and plasma lipoprotein-lipid levels were mediated by concomitant variation in body fatness and glucose tolerance. CONCLUSIONS: These results suggest that the magnitude of the relationships between VO2max and plasma lipoprotein-lipid levels is influenced by the apo E polymorphism. Thus, apo E2 carriers may be particularly responsive to improved fitness, thereby preventing the development of hypertriglyceridemia and type III dyslipoproteinemia.

Fasting insulin and apolipoprotein B levels and low-density lipoprotein particle size as risk factors for ischemic heart disease.

CONTEXT: Epidemiological studies have established a relationship between cholesterol and low-density lipoprotein cholesterol (LDL-C) concentrations and the risk of ischemic heart disease (IHD), but up to half of patients with IHD may have cholesterol levels in the normal range. OBJECTIVE: To assess the ability to predict the risk of IHD using a cluster of nontraditional metabolic risk factors that includes elevated fasting insulin and apolipoprotein B levels as well as small, dense LDL particles. DESIGN: Nested case-control study. SETTING: Cases and controls were identified from the population-based cohort of the Quebec Cardiovascular Study, a prospective study conducted in men free of IHD in 1985 and followed up for 5 years. PARTICIPANTS: Incident IHD cases were matched with controls selected from among the sample of men who remained IHD free during follow-up. Matching variables were age, smoking habits, body mass index, and alcohol consumption. The sample included 85 complete pairs of nondiabetic IHD cases and controls. MAIN OUTCOME MEASURES: Ability of fasting insulin level, apolipoprotein B level, and LDL particle diameter to predict IHD events, defined as angina, coronary insufficiency, nonfatal myocardial infarction, and coronary death. RESULTS: The risk of IHD was significantly increased in men who had elevated fasting plasma insulin and apolipoprotein B levels and small, dense LDL particles, compared with men who had normal levels for 2 of these 3 risk factors (odds ratio [OR], 5.9; 95% confidence interval [CI], 2.3-15.4). Multivariate adjustment for LDL-C, triglycerides, and high-density lipoprotein cholesterol (HDL-C) did not attenuate the relationship between the cluster of nontraditional risk factors and IHD (OR, 5.2; 95% CI, 1.7-15.7). On the other hand, the risk of IHD in men having a combination of elevated LDL-C and triglyceride levels and reduced HDL-C levels was no longer significant (OR, 1.4; 95% CI, 0.5-3.5) after multivariate adjustment for fasting plasma insulin level, apolipoprotein B level, and LDL particle size. CONCLUSION: Results from this prospective study suggest that the measurement of fasting plasma insulin level, apolipoprotein B level, and LDL particle size may provide further information on the risk of IHD compared with the information provided by conventional lipid variables.

Association of specific LDL receptor gene mutations with differential plasma lipoprotein response to simvastatin in young French Canadians with heterozygous familial hypercholesterolemia.

In familial hypercholesterolemia (FH), the efficacy of the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase shows considerable interindividual variation, and several genetic and environmental factors can contribute to explaining this variability. A randomized, double-blind, placebo-controlled clinical trial with simvastatin, an HMG-CoA reductase inhibitor, was conducted in 63 children and adolescents with heterozygous FH. The patients were grouped according to known LDL receptor genotype. After 6 weeks of treatment with 20 mg/d simvastatin, the mean reduction in plasma LDL cholesterol in patients with the W66G mutation (n=14) was 31%, whereas in the deletion>15 kb (n=23) and the C646Y mutation groups (n=10), it was 38% and 42%, respectively (P<0.05). After treatment with simvastatin, HDL cholesterol levels were increased in all groups, and triglyceride concentrations were significantly reduced. Multiple regression analyses suggested that 42% of the variation of the LDL cholesterol response to simvastatin can be attributed to variation in the mutant LDL receptor locus, apolipoprotein E genotype, and body mass index, while 35% of the variation in HDL cholesterol response was explained by sex and baseline HDL cholesterol. These results show that simvastatin was an effective and well-tolerated therapy for FH in the pediatric population for all LDL receptor gene mutations. Moreover, the nature of LDL receptor gene mutations and other genetic and constitutional factors play a significant role in predicting the efficacy of simvastatin in the treatment of FH in children and adolescents.

Leptinemia is not a risk factor for ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study.

OBJECTIVE: To investigate the possibility that leptin levels may be predictive of the risk of ischemic heart disease (IHD) through the relationship of leptin to body fat. RESEARCH DESIGN AND METHODS: The Quebec Cardiovascular Study cohort consisted of 2,103 French-Canadian men without IHD in 1985 who were followed until 1990, by which time 114 had experienced an IHD event. These 114 men were then individually matched for age, BMI, cigarette smoking, and alcohol intake with 114 subjects who were free of IHD at follow-up. After exclusion of diabetic patients and those in whom leptin levels could not be measured, we were able to compare the initial metabolic profiles of 86 men in the IHD group and of 95 control subjects. RESULTS: Plasma leptin concentrations were positively correlated with BMI (r = 0.67, P < 0.0001) and with fasting insulin concentrations (r = 0.46, P < 0.0001) in the overall sample. These significant associations were also observed when men with IHD and the control subjects were examined separately (control subjects: r = 0.68 for BMI and r = 0.45 for insulin; IHD subjects: r = 0.65 for BMI and r = 0.50 for insulin). With the exception of plasma triglyceride (r = 0.25, P < 0.001), no significant association was found between leptin and plasma lipoprotein and lipid concentrations. Furthermore, plasma insulin remained significantly associated with leptin levels even after adjustment for BMI (r = 0.22, P < 0.005). There was no difference in baseline leptin levels among men who developed IHD versus men who remained IHD-free during the 5-year follow-up (5.56 +/- 3.12 vs. 5.36 +/- 2.90 ng/ml, respectively). Thus, although significantly correlated with the BMI and fasting insulin levels, plasma leptin concentration was not a significant predictor of the 5-year incidence of IHD. This lack of a relationship to IHD was noted when leptin levels were analyzed as tertiles and when leptin concentration was analyzed as a continuous variable. CONCLUSIONS: These prospective results suggest that leptinemia, despite being a strong correlate of obesity, does not appear to be an independent risk factor for the development of IHD in men.

Is lipoprotein(a) an independent risk factor for ischemic heart disease in men? The Quebec Cardiovascular Study.

OBJECTIVES: This study was undertaken to determine whether lipoprotein(a) [Lp(a)] is an independent risk factor for ischemic heart disease (IHD) and to establish the relation of Lp(a) to the other lipid fractions. BACKGROUND: Several, but not all, studies have shown that elevated Lp(a) concentrations may be associated with IHD; very few have been prospective. METHODS: A 5-year prospective follow-up study was conducted in 2,156 French Canadian men 47 to 76 years old, without clinical evidence of IHD. Lipid measurements obtained at baseline included total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, apoprotein B and Lp(a). During the follow-up period, there were 116 first IHD events (myocardial infarction, angina, death). Adjusted proportional hazards models were used to estimate the relative risk for the different variables. The cohort was also classified according to Lp(a) levels and other lipid risk factor tertiles to evaluate the relation of elevated Lp(a) levels to these risk factors. A cutoff value of 30 mg/dl was used for Lp(a). Risk ratios were calculated using the group with low Lp(a) levels and the first tertile of lipid measures as a reference. RESULTS: Lp(a) was not an independent risk factor for IHD but seemed to increase the deleterious effects of mildly elevated LDL cholesterol and elevated total cholesterol and apoprotein B levels and seemed to counteract the beneficial effects associated with elevated HDL cholesterol levels. CONCLUSIONS: In this cohort, Lp(a) was not an independent risk factor for IHD but appeared to increase the risk associated with other lipid risk factors.

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.

Effectiveness of atorvastatin for reducing low-density lipoprotein cholesterol to National Cholesterol Education Program treatment goals.

Atorvastatin is a highly efficacious hydroxymethylglutaryl-coenzyme A reductase inhibitor that has been shown to reduce low-density lipoprotein cholesterol by 40% to 60%. Monotherapy with atorvastatin (10 to 80 mg/day) is well-tolerated, convenient, and appears to be effective for achieving National Cholesterol Education Program treatment goals in most patients, regardless of risk status.

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.

Associations of HDL2 and HDL3 subfractions with ischemic heart disease in men. Prospective results from the Québec Cardiovascular Study.

Individuals with elevated plasma concentrations of HDL cholesterol are at lower risk for ischemic heart disease (IHD). Whether the cardioprotective effects of HDL can be attributed to one or both HDL subfractions (HDL2 and HDL3) remains, however, controversial. The relationship of HDL subfractions to the incidence of IHD was investigated in a sample of 1169 French-Canadian men younger than 60 years and living in the Quebec City suburbs. Between 1980 to 1981 and 1990, 83 of the 944 men with complete follow-up in 1990 (80.8%) had a first IHD. Men who developed IHD had lower HDL, HDL2, and HDL3 cholesterol concentrations at baseline than men who remained free from IHD. Adjusted relative risk (RR) of IHD was calculated among quartiles of HDL cholesterol and HDL subfractions with the use of Cox survival models. Men in the fourth quartile of HDL2 (RR = 0.21; 95% confidence interval [CI], 0.08 to 0.56) and HDL3 cholesterol distributions (RR = 0.37; 95% CI, 0.15 to 0.94) were at lower risk for IHD than men in the first quartile. Despite the fact that the respective contributions of HDL2 and HDL3 to IHD risk were of the same magnitude in a multivariate model that included both subfractions, the contribution of the HDL2 subfraction was statistically significant (standardized RR = 0.84; 95% CI, 0.74 to 0.95), whereas it did not reach significance for HDL3 (standardized RR = 0.87; 95% CI, 0.69 to 1.11). Neither the linear combination of HDL2 and HDL3 nor their ratio provided further information on the risk of IHD compared with HDL cholesterol alone or with the ratio of total to HDL cholesterol. From a statistical standpoint, the present data suggest that the HDL2 subfraction may be more closely related to the development of IHD than the HDL3 subfraction. However, the qualitative difference in the relative predictive value of each subfraction was trivial, since it only corresponded to a modest quantitative difference. Thus, the possibility that a significant proportion of the cardioprotective effect of elevated HDL cholesterol levels may be mediated by the HDL3 subfraction still cannot be excluded. Finally, from a clinical point of view and within the limits of resolution provided by these data, the measurement of HDL subfractions does not appear to provide any additional information on the risk of IHD than HDL cholesterol alone or the ratio of total to HDL cholesterol.

Comparison of the effect of two low-density lipoprotein receptor class mutations on coronary heart disease among French-Canadian patients heterozygous for familial hypercholesterolaemia.

The aim of this study was to compare the age at first elective coronary angiogram and the age at first revascularization (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) in 102 patients without familial hypercholesterolaemia (FH), who were matched for age and sex with 76 heterozygous FH patients carrying a defective allele at the low-density lipoprotein (LDL) receptor gene (LDL-R) and 26 heterozygous FH patients bearing a null mutation at the LDL-R. The prevalence of diabetes was significantly higher in the non-FH group than in the two FH groups (P < 0.05). Furthermore, mean body mass index (BMI) and waist circumference values were also higher in the non-FH group than in the two FH heterozygous groups (P < 0.005). However, FH patients who were null allele carriers had the highest plasma total and LDL-cholesterol levels and the highest cholesterol/HDL-cholesterol ratio, whereas the defective allele carriers group had intermediate levels between null allele carriers and non-FH patients. Comparison of the age at first coronary angiography revealed that the null allele carriers group were younger at first angiogram than the non-FH patients (P < 0.005). In addition, a trend was observed for a younger age at first angiogram in FH heterozygotes bearing a null allele than in carriers of a defective allele (P = 0.06). Moreover, null allele carriers were younger at first revascularization than defective allele carriers (P < 0.005) or non-FH patients (P < 0.005). Finally, the mean number of diseased vessels with > 50% stenosis was higher in null allele carriers than in non-FH patients and tended to be higher than among defective allele carriers (P < 0.01). Although no difference in plasma Lp(a) levels were noted between null allele carrier and non-FH patients, plasma Lp(a) concentrations were higher in the defective allele group than in the other two groups. In summary, the development of coronary artery disease as estimated by the age at first elective coronary angiography or at first revascularization is premature in FH patients carrying a null mutation compared with defective allele carriers or with non-FH patients. Moreover, the higher number of stenosed vessels among null allele carriers suggests that coronary artery disease was more severe in FH subjects with a null allele at the LDL-R locus.

The MspI polymorphism of the apolipoprotein A-II gene as a modulator of the dyslipidemic state found in visceral obesity.

The aim of the present study was to examine the effect of variation at the apolipoprotein (apo) A-II gene locus on lipoprotein levels in visceral obesity. A total of 145 sedentary men, free from metabolic disorders requiring pharmacotherapy, were classified into two groups on the basis of their apo A-II-MspI genotype determined by the polymerase chain reaction: 1) 43 M1 carriers or M1M2, including two M1M1 homozygotes and 41 M1M2 heterozygotes, and 2) 102 M2M2 homozygotes for the presence of a MspI restriction site. The two genotypic groups did not differ for body mass index (BMI, expressed in kg/m2), body fat mass, visceral adipose tissue (AT) accumulation, as well as for insulin, glucose and free fatty acids levels measured in the fasting state and in response to an oral glucose tolerance test. In addition, 65 and 63% of M1 carriers had plasma HDL2 cholesterol levels and a HDL2/HDL3 cholesterol ratio below the 50th percentile of their distributions compared with 45%(P < 0.05) and 46%(P = 0.06), respectively, in M2M2 homozygotes. When subjects were further divided on the basis of visceral AT accumulation (below and above a value of 130 cm2), M1 carriers with low levels of visceral AT were characterized by high plasma HDL cholesterol and HDL2 cholesterol concentrations as well as by a higher HDL2/HDL3 ratio, compared with M1 carriers with high levels of visceral AT (> 130 cm2), or with M2M2 homozygotes with either a high or a low accumulation of visceral AT. Furthermore, M1 carriers with high levels of visceral AT showed a trend for lower plasma HDL2 cholesterol levels and were characterized by a significantly lower HDL2/HDL3 cholesterol ratio compared with the other three groups. No difference in HDL and HDL2 cholesterol levels and in the HDL2/HDL3 cholesterol ratio was noted when M2 homozygotes with lower versus higher levels of visceral AT were compared. The contribution of hyperinsulinemia was also examined by dividing subjects on the basis of the 50th percentile of the integrated insulin response to an oral glucose challenge. Significantly lower plasma HDL2 cholesterol levels and a reduced HDL2/HDL3 cholesterol ratio were noted among M1 carriers with high plasma insulin responses compared with M1 carriers with low insulin responses. Among M2M2 homozygotes, no difference was noted in plasma HDL cholesterol and in HDL2 cholesterol concentrations between men with low versus high insulin responses to the oral glucose load. These results suggest that the apo A-II-MspI polymorphism could modulate plasma HDL cholesterol levels among visceral obese, insulin-resistant men.

Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Québec Cardiovascular Study.

BACKGROUND: Case-control studies have reported that patients with ischemic heart disease (IHD) have a higher proportion of small, dense LDL particles than do healthy control subjects. The extent to which the risk attributed to small LDL particles may be independent of concomitant variations in plasma lipoprotein-lipid concentrations remains to be clearly determined, however, particularly through prospective studies. METHODS AND RESULTS: Baseline characteristics were obtained in 2103 men initially free of IHD, among whom 114 developed IHD during a 5-year follow-up period. These 114 case patients were matched with healthy control subjects for age, body mass index, smoking habits, and alcohol intake. LDL peak particle diameter (PPD) was measured a posteriori in 103 case-control pairs by nondenaturing gradient gel electrophoresis of whole plasma. Conditional logistic regression analysis of the case-control status revealed that men in the first tertile of the control LDL-PPD distribution (LDL-PPD < or = 25.64 nm) had a 3.6-fold increase in the risk of IHD (95% CI, 1.5 to 8.8) compared with those in the third tertile (LDL-PPD > 26.05 nm). Statistical adjustment for concomitant variations in LDL cholesterol, triglycerides, HDL cholesterol, and apolipoprotein B concentrations had virtually no impact on the relationship between small LDL particles and the risk of IHD. CONCLUSIONS: These results represent the first prospective evidence suggesting that the presence of small, dense LDL particles may be associated with an increased risk of subsequently developing IHD in men. Results also suggest that the risk attributed to small LDL particles may be partly independent of the concomitant variation in plasma lipoprotein-lipid concentrations.

Associations between 12 year changes in body fatness and lipoprotein-lipid levels in men and women of the Québec Family Study.

OBJECTIVE: To investigate the associations between 12 year changes in body composition, subcutaneous fat distribution vs changes in plasma lipoprotein-lipid levels. DESIGN: 12 year prospective study. SUBJECTS: A sample of 95 women and 93 men of the Québec Family Study initially tested in 1980. MEASUREMENTS: Various body fatness variables as well as fasting plasma lipoprotein-lipid concentrations performed both in 1980 and 1992. RESULTS: In both 1980 and 1992, a high body fat mass and an elevated accumulation of subcutaneous trunk fat were associated with a significant deterioration in the plasma lipoprotein-lipid profile. Furthermore, correlation analysis performed on differences noted during the 12 years follow-up revealed significant associations between changes in body fat mass and in plasma cholesterol [r = 0.52, P < 0.0005] in women. In both men and women, an increased body fat mass was associated with an increased CHOL/HDL-cholesterol ratio [r = 0.37, P < 0.01 (men) and r = 0.54, P < 0.0005 (women)]. Correlations between changes in fat mass and plasma lipids were generally of higher magnitude in women than in men. Changes in subcutaneous trunk fat were associated with changes in plasma HDL-chol levels (r = -0.22, P < 0.05) in men whereas in women, changes in trunk adiposity were related to changes in both plasma CHOL (r = 0.25, P < 0.05) and TG (r = 0.32, P < 0.005) levels. CONCLUSION: These results support the notion that the increased adiposity observed among aging adult men and women is a significant component of the deterioration in the plasma lipoprotein-lipid profile noted over a 12 year follow-up period.

The apoB-100 gene EcoRI polymorphism influences the relationship between features of the insulin resistance syndrome and the hyper-apoB and dense LDL phenotype in men.

The aim of this study was to investigate whether the EcoRI polymorphism of the apolipoprotein B (apoB) gene influences the relationships between features of the insulin resistance syndrome and the dense LDL phenotype and apoB concentrations. A sample of 65 men was divided into two groups on the basis of the EcoRI genotype. Forty-four subjects were (+/+) homozygotes for the presence of the EcoRI restriction site that is associated with a glutamic acid at codon 4154. Twenty-one men were (+/-) heterozygotes for the absence of the restriction site resulting from a glutamic acid to a lysine substitution at codon 4154. In the (+/-) group, fasting plasma FFA levels were positively correlated with plasma apoB, LDL-apoB, and the LDL particle score that was calculated from the migration distances of LDL subspecies and their relative band intensities, reflecting the proportion of small dense LDL particles. However, these associations were not found among (+/+) subjects. The two genotypic groups were further divided into two subgroups on the basis of fasting FFA concentrations, and the LDL particle score and the LDL-apoB levels were compared. High FFA levels were associated with a higher proportion of small dense LDL particles, as reflected by a higher mean LDL particle score, irrespective of the genotype. However, the apoB-EcoRI polymorphism appeared to influence the association between high FFA levels and LDL-apoB concentrations because (+/-) heterozygotes with high FFA levels had higher LDL-apoB concentrations than (+/-) heterozygotes with low FFA levels. In addition, the integrated area under the curve of plasma insulin concentrations, measured in response to a 75-g oral glucose challenge, and the amount of visceral adipose tissue, measured by computed tomography, were positively associated with the LDL particle score only in (+/-) heterozygotes. When subjects were divided on the basis of insulin area (low vs. high) or visceral adipose tissue (low vs. high), (+/-) heterozygotes with high insulin area or with high levels of visceral adipose tissue had a higher mean LDL particle score than (+/-) heterozygotes with low insulin area or low visceral adipose tissue. However, among (+/+) homozygotes, low or high levels of insulin or visceral adipose tissue could not discriminate between men with large or small LDL particles. Therefore, (+/-) heterozygotes may be more susceptible to develop the dense LDL phenotype in presence of hyperinsulinemia and visceral obesity. Results of the present study suggest that the apoB-EcoRI polymorphism may exacerbate the alterations in the LDL particle (size and concentration) found among visceral obese-hyperinsulinemic men.

Importance of outside hospital mortality as a first acute ischemic heart event: the Quebec Cardiovascular Study.

Among 4371 men aged 35 to 64 in 1973 who were randomly selected, living in Quebec City suburbs, without clinical evidence of ischemic heart disease (IHD) at entry and followed for 16 years, 426 had a first acute IHD event; of these, 296 had a nonfatal myocardial infarction (MI), 50 a fatal MI (death within four weeks of the acute event) and 80 an early death, ie, they died before the diagnosis of MI was made. Among these 80 early deaths attributed to IHD in the absence of any other apparent cause, 55 men died within 1 h from the onset of symptoms or were found dead in their bed (group A) while 25 died more than 1 h after the onset of symptoms (group B). In this population, a first acute IHD event carried a 31% (130 of 426) case fatality within the first four weeks. Groups A and B accounted for 42% (55 of 130) and 19% (25 of 130) of the total acute ischemic mortality, respectively. As expected, fatal events increased with age, but the proportion of early deaths over the total IHD mortality was as frequent in younger men as in older men. Smoking, increased systolic and diastolic blood pressure and serum cholesterol were associated with increased nonfatal events. A similar association, except for serum cholesterol, was observed for all fatal events. No significant risk factor profile differentiated early from late fatal events. In conclusion, in this population, nearly a third of men with a first IHD event died, most of them outside the hospital. None of the main established risk factors differentiated men with a fatal MI from those with an early death.