Paul-J. Lupien

Hyperinsulinemia as an independent risk factor for ischemic heart disease.

BACKGROUND Prospective studies suggest that hyperinsulinemia may be an important risk factor for ischemic heart disease. However, it has not been determined whether plasma insulin levels are independently related to ischemic heart disease after adjustment for other risk factors, including plasma lipoprotein levels. METHODS In 1985 we collected blood samples from 2103 men from suburbs of Quebec City, Canada, who were 45 to 76 years of age and who did not have ischemic heart disease. A first ischemic event (angina pectoris, acute myocardial infarction or death from coronary heart disease) occurred in 114 men (case patients) between 1985 and 1990. Each case patient was matched for age, body-mass index, smoking habits, and alcohol consumption with a control selected from among the 1989 men who remained free of ischemic heart disease during follow-up. After excluding men with diabetes, we compared fasting plasma insulin and lipoprotein concentrations at base line in 91 case patients and 105 controls. RESULTS Fasting insulin concentrations at base line were 18 percent higher in the case patients than in the controls (P<0.001). Logistic-regression analysis showed that the insulin concentration remained associated with ischemic heart disease (odds ratio for ischemic heart disease with each increase of 1 SD in the insulin concentration, 1.7; 95 percent confidence interval, 1.3 to 2.4) after adjustment for systolic blood pressure, use of medications, and family history of ischemic heart disease. Further adjustment by multivariate analysis for plasma triglyceride, apolipoprotein B, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations did not significantly diminish the association between the insulin concentration and the risk of ischemic heart disease (odds ratio, 1.6; 95 percent confidence interval, 1.1 to 2.3). CONCLUSIONS High fasting insulin concentrations appear to be an independent predictor of ischemic heart disease in men.

Reduction of LDL Cholesterol by 25% to 60% in Patients With Primary Hypercholesterolemia by Atorvastatin, a New HMG-CoA Reductase Inhibitor

This 6-week, double-blind clinical trial evaluated lipid parameter responses to different dosages of atorvastatin in patients with primary hypercholesterolemia. Atorvastatin is a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor under development. After completing an 8-week placebo-baseline dietary phase, 81 patients were randomly assigned to receive either placebo or 2.5, 5, 10, 20, 40, or 80 mg atorvastatin once daily for 6 weeks. Plasma LDL cholesterol reductions from baseline were dose related, with 25% to 61% reduction from the minimum dose to the maximum dose of 80 mg atorvastatin once a day. Plasma total cholesterol and apo B reductions were also dose related. Previously, reductions in LDL cholesterol of the magnitude observed in this study have been seen only with combination drug therapy. In this study, atorvastatin was well tolerated by hyperlipidemic patients, had an acceptable safety profile, and provided greater reduction in cholesterol than other previously reported HMG-CoA reductase inhibitors.

Increase in plasma high-density lipoprotein concentration following complete androgen blockage in men with prostatic carcinoma

There is evidence that endogenous estrogens have a positive effect on plasma high density lipoprotein (HDL) concentration, whereas the relation between HDL and male sex hormones is unclear, since both positive and negative effects have been reported. This study examined the effects of LHRH agonist in combination with an antiandrogen on plasma lipids and lipoproteins in 17 elderly men with prostatic carcinoma. Subjects were examined prior to and after therapy at 4-week intervals up to 16 weeks. Prior to therapy, their lipid and lipoprotein profiles were not significantly different from a control group composed of individuals of similar age and living in the same community area. Following therapy plasma levels of testosterone and dihydrotestosterone were markedly decreased (above 90%) and their residual activity neutralized through effective use of an antiandrogen. Plasma estradiol decreased between 65% and 85% and the concentration of cortisol was unaffected. The very low density lipoprotein (VLDL) apo-B decreased and low density lipoprotein (LDL) apo-B increased; thus, no change was observed in the total plasma apo-B levels. Total plasma cholesterol increased by 6% (baseline v peak values, mg/dL, mean +/- SEM; 219 +/- 9 v 233 +/- 9, P less than 0.05) due to a significant rise in HDL cholesterol concentration (45.5 +/- 2.8 v 56.5 +/- 3.6, P less than 0.01). Both VLDL and LDL cholesterol levels remained unchanged. The mean elevation of 21% in HDL cholesterol was accompanied by a significant rise in HDL apo-A concentration (161 +/- 6 v 193 +/- 10, P less than 0.01), thus suggesting an increase in HDL mass and/or particle number.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence of dyslipidemic phenotypes in ischemic heart disease (prospective results from the Que´bec cardiovascular study)

In 1985, plasma cholesterol, triglyceride, high-density lipoprotein cholesterol, and plasma apoprotein (apo) B levels were measured in 2,103 men (aged 45 to 76 years) without ischemic heart disease from the Québec city suburbs. Occurrence of a first ischemic event (i.e., angina pectoris, acute myocardial infarction, or coronary-related death) was recorded in 114 men between 1985 and 1990. Men with and without ischemic heart disease were classified as normal or in various dyslipidemic groups according to an established algorithm. Of the 1,989 men who remained free of ischemic events, 50% had a normal lipid profile compared with 32% in men with ischemic heart disease. Although the prevalence of type IIb and IV dyslipidemias was similar in men with and without ischemic heart disease, type IIa (16% vs 10%), hyperapo B-hypertriglyceridemia (12% vs 6%), hyperapo B-normotriglyceridemia (11% vs 7%), and hypoalphalipoproteinemia (18% vs 13%) were more prevalent in men with than without ischemic heart disease. Adjusted odds ratios (ORs) were not increased in type IIb and IV phenotypes, whereas men with type IIa (OR 2.8), with the 2 hyperapo B phenotypes (hyperapo B-normotriglyceridemia, OR 2.7; hyperapo B-hypertriglyceridemia, OR 3.1) or with isolated hypoalphalipoproteinemia (OR 2.2), were at higher risk. The results of this prospective study confirm the importance of both elevated plasma cholesterol and decreased high-density lipoprotein cholesterol levels as risk factors for ischemic heart disease. They also emphasize the high prevalence of an elevated apo B dyslipidemic state in ischemic heart disease.

Mutations of low-density-lipoprotein-receptor gene, variation in plasma cholesterol, and expression of coronary heart disease in homozygous familial hypercholesterolaemia

Variation in plasma-cholesterol concentration and the expression of coronary heart disease in patients with homozygous familial hypercholesterolaemia (FH) is well documented, but the underlying reasons for variation are not clearly defined. Because FH is caused by mutations at the low-density-lipoprotein-gene locus, we compared plasma-cholesterol concentrations in 21 FH homozygotes with either the greater than 10 kb deletion (promoter region and exon 1) (11 subjects) or the exon 3 missense (trp66-->gly) mutation (10 subjects) of the low-density-lipoprotein gene. Subjects with the greater than 10 kb deletion had a higher mean plasma-cholesterol concentration than those with the exon 3 mutations (26.7 vs 16.1 mmol/L; p = 0.000006), and there was no overlap in individual plasma-cholesterol concentrations between subjects in the two groups. Although the frequency of coronary heart disease was similar in the two groups, age-of-onset was earlier in subjects with the greater than 10 kb deletion (p = 0.059). Also, coronary deaths were more frequent (p = 0.044) and occurred at an earlier age (p = 0.009) in subjects with the greater than 10 kb deletion. Our results provide evidence that there is less variation in plasma-cholesterol concentrations among FH homozygotes when they are subdivided into groups according to low-density-lipoprotein-receptor-gene defect. Furthermore, differences in plasma-cholesterol concentrations are reflected in the severity of coronary heart disease expression.

Homozygous familial hypercholesterolemia among French Canadians in Québec Province.

Nineteen patients with homozygous familial hypercholesterolemla (FH) living at the time of the 1981 Canada census are the subject of this report Their mean age at that time was 15, with a range of 1 to 26 years. All patients had extensive xanthomatosls but showed variable clinical manifestations of coronary heart disease (CHD); five (mean age, 21; range, 11 to 27 years) died from sudden death due to CHD. Plasma cholesterol levels varied more than twofold (557 to 1532 mg/dl). Variation In the concentrations of both plasma and low density llpoproteln cholesterol, as well as apolipoproteln B, were related neither to age at death from CHD nor to the clinical course of CHD. The mean high density llpoproteln cholesterol concentration (37 mg/dl) was lower than the mean value (49 mg/dl) in the control population (p<0.001). Both the clinical and biochemical features of this cohort are typical of homozygous FH. The prevalence of homozygotes among French Canadians in Quebec was ∼1:275 000, and the minimum estimated frequency of heterozygotes was 1 270. In northeastern Quebec, the frequency of homozygotes was ∼1:100 000, and the minimum estimated frequency of heterozygotes was 1 154. Only Afrikaaners In South Africa have correspondingly higher frequencies.

Triglycerides and HDL-cholesterol as risk factors for ischemic heart disease. Results from the Québec cardiovascular study

The relative importance of reduced plasma high density lipoprotein-cholesterol (HDL-C) levels and elevated plasma triglyceride (TG) concentrations as risk factors for ischemic heart disease (IHD) was examined in a sample of 2177 men from the Québec City suburbs. The sample included 202 men with known IHD. The relationship between HDL-C and TG levels, although significant (r = -0.49, P < 0.0001), was not linear, as most of the variation in HDL-C levels was observed within TG levels below 2.5 mmol/l. Reduced HDL-C (< 0.9 mmol/l) was a prevalent condition in men with IHD (50%) compared to those without IHD (30%). On the other hand 26% and 20% of men with and without IHD, respectively, had elevated TG levels (TG > 2.3 mmol/l). A 2-fold increase in prevalence odds ratio (OR) was observed in men with TG levels > 2.3 mmol/l (95% confidence intervals (CI) [1.2;3.3]). No residual association between elevated TG levels and IHD was found, however, after adjustment for HDL-C concentrations (OR 1.2, 95% CI 0.7;2.1). On the other hand, HDL-C remained a significant predictor of IHD after adjustment for other risk factors (OR 0.3, 95%, CI 0.2;0.6). Men with reduced HDL-C levels were also characterized by a cluster of risk factors such as obesity, diabetes mellitus and hypertension, which may contribute to increase the risk of IHD. Finally, the independent interpretation of cholesterol, TG or LDL-C levels may lead to an inadequate prediction of risk, as a large number of IHD patients showed a cluster of risk factors which included low HDL-C concentrations.

A new approach to the management of familial hypercholesterolaemia: Removal of plasma-cholesterol based on the principle of affinity chromatography.

Reduction of plasma-cholesterol by the removal of low-density lipoproteins (L.D.L.) in an extracorporeal system is described as a possible approach in the treatment of familial hypercholesterolaemia. L.D.L. were removed from the blood by their interaction with heparin linked to agarose beads in the presence of calcium ions. Plasma-L.D.L. was markedly decreased in two patients with heterozygous familial hypercholesterolaemia. The technique is specific for the removal of L.D.L., as the concentration of high-density lipoproteins was not affected. The treatment was well tolerated by all three subjects (i.e., two hypercholesterolaemic patients and a normal volunteer), and there were no undesirable effects. Several haematological parameters, clinical-chemistry tests, including serum enzymes, and immunoelectrophoresis of plasma proteins were all unaffected by the treatment.

Is body fat loss a determinant factor in the improvement of carbohydrate and lipid metabolism following aerobic exercise training in obese women

Thirty-one obese, premenopausal women aged 35.4 ± 5.1 (SD) years exercised for 90 minutes at approximately 55% of maximal aerobic power (Vo2max) four to five times a week for a period of 6 months. The training program induced a significant increase in Vo2max (P < .001) and significant improvements in carbohydrate and lipid metabolism, as reflected by decreased plasma insulin (INS) concentrations measured in the fasting state and after glucose (GLU) ingestion (INS area, P < .001), by reduced plasma cholesterol (C) and low-density lipoprotein cholesterol (LDL-C) levels (P < .001), and by increased ratios of high-density lipoprotein cholesterol (HDL-C)LDL-C and HDL2-CHDL3-C (P < .05 and P < .001, respectively). Changes in body fat mass were positively associated with changes in the INS area/GLU area ratio (r = .49, P < .05) and with changes in very-low-density lipoprotein triglycerides ([VLDL-TG] r = .49, P < .05). Furthermore, changes in the INS area were positively associated with changes in VLDL-TG (r = .51, P < .05). Although no significant mean change in body composition was observed, important individual variation was noted. Twenty women showed a reduction in body fat mass (mean reduction, 2.63 ± 2.2 kg), whereas 11 women showed an increase in adipose mass (mean increase, 2.79 ± 2.36 kg). Comparable increases in Vo2max were observed between the two groups. The group that showed a decrease in body fat mass with exercise also had significant improvements in carbohydrate and lipid metabolism. Indeed, fasting INS levels (P < .01), INS area/GLU area (P < .01), C (P < .01), and TG (P < .05) levels were all significantly decreased, whereas HDL2-C concentrations (P < .01) and the HDL2-CHDL3-C ratio (P < .001) were significantly increased following training. Women who showed an increase in body fat mass following the 6-month aerobic exercise training program showed a trend for an improved INS sensitivity (P < .06), as estimated by the decrease in fasting INS levels and in the INS area/GLU area ratio. No significant change in lipoprotein-lipid metabolism was noted, although there was a general trend for an improved lipoprotein-lipid profile. Comparisons of absolute and relative changes observed among the two subgroups showed that the improvements in carbohydrate and lipid metabolism in the fat loss group were not significantly different from the changes observed in the fat gainers. These results suggest that aerobic exercise training, per se, irrespective of the changes in total body fat, seems to have beneficial effects on carbohydrate and lipid metabolism that may potentially reduce the risk of coronary artery disease (CAD). However, a concomitant reduction in body fat mass probably amplifies the beneficial effects of aerobic exercise training on metabolism.

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, BM1, 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.