Apolipoprotein concentrations during treatment and recurrent coronary artery disease events.

The effect of untreated total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) as cardiovascular risk factors in both primary and secondary prevention has been extensively investigated. The predictive value of on-treatment lipid and apolipoprotein levels on subsequent cardiovascular events is as yet uncertain. Eight hundred forty-eight patients (675 men and 173 women) with angiographically proven coronary artery disease (CAD) who received effective statin therapy (>/=30% decrease of baseline TC) were studied. We analyzed the predictive value of on-treatment levels of TC, LDL-C, triglycerides (TG), apolipoprotein A-I (apoA-I) and apolipoprotein B (apoB) on subsequent myocardial infarction (MI) and all cause mortality. On-treatment LDL-C levels were 2.55+/-0.55 mmol/L and 2.58+/-0.62 mmol/L for men and women respectively. Age-adjusted Cox regression analysis showed that only on-treatment apoA-I was predictive for future CAD events in both men and women, whereas on-treatment HDL-C was exclusively predictive in women. On-treatment apoB levels were predictive for recurrent CAD events in the total population but not after separate analysis for men and women. On-treatment levels of TC, LDL-C, and TG did not predict subsequent events. Multivariate analysis showed that on-treatment apoA-I and apoB were the only significant predictors for future cardiovascular events. On-treatment levels of TC, LDL-C, and TG were no longer associated with increased risk of recurrent cardiovascular events in CAD patients treated to target levels, which justifies the current guidelines. However, on-treatment levels of apoB and in particular apoA-I (and HDL-C in women) were significantly predictive for MI and all-cause mortality and may therefore be more suitable for cardiovascular risk assessment in this population.

Effects of low-dose EPA-E on glycemic control, lipid profile, lipoprotein(a), platelet aggregation, viscosity, and platelet and vessel wall interaction in NIDDM.

OBJECTIVE: To assess the effects of low-dose eicosapentaenoic acid-ethyl-ester on diabetes regulation, lipid metabolism, blood rheology, and platelet reactivity. RESEARCH DESIGN AND METHODS: In a double-blind, randomized, placebo-controlled study, 24 NIDDM subjects received 1800 mg of EPA-E, 900 mg of EPA-E, or a placebo (1656 mg olive oil) daily for 8 wk. RESULTS: The EPA:arachidonic acid plasma ratio increased over an 8-wk period, then declined after a 4-wk wash-out period in the fish-oil groups in a dose-dependent way. Platelet-activating factor-induced platelet aggregation decreased from 75 +/- 7% at wk 0 to 35 +/- 21% at wk 8 in the 900-mg group (P = 0.016) and from 72 +/- 11 to 40 +/- 30% in the 1800-mg group (P = 0.039), but did not change in the placebo group. No effects on ADP- or collagen-induced aggregation could be attributed to EPA-E. In the 1800-mg group low-density-lipoprotein cholesterol increased significantly, without concomitant rise in apolipoprotein B. Triglycerides, glycemic control, lipoprotein (a), blood and plasma viscosity, erythrocyte deformability, and platelet adhesion to and aggregate formation on extracellular endothelial cell matrix were not significantly influenced. CONCLUSIONS: Purified EPA-E in doses of 900 and 1800 mg reduces Platelet-activating factor-induced platelet aggregation without negatively affecting glycemic control. Low-density-lipoprotein cholesterol was elevated in the 1800-mg group.

17 beta-Estradiol improves postprandial lipid metabolism in postmenopausal women.

We studied the effect of 2 mg micronized 17 beta-estradiol replacement therapy, administered orally during 6 weeks, on postprandial lipid and retinyl palmitate (RP) metabolism. In the human postprandial state, atherogenic chylomicron remnant particles are produced. RP is incorporated into the core of newly synthesized chylomicrons and can be used as a marker of chylomicrons and chylomicron remnants. Six normolipidemic (plasma cholesterol, 5.63 +/- 0.83 mmol/L; plasma triglycerides, 1.47 +/- 0.69 mmol/L) postmenopausal women (amenorrhea > 1 yr; aged 55.5 +/- 4.0 yr) received an oral fat load (50 g/m2 fat as cream, with 60,000 IU RP/m2) before and after 6 weeks of 17 beta-estradiol treatment. Plasma RP areas under the curve decreased significantly from 27.1 +/- 15.9 to 16.6 +/- 13.2 mg/h.L-1 (P = 0.01). Fasting cholesterol concentrations in intermediate density lipoproteins decreased significantly. Fasting and postprandial plasma triglyceride levels did not change. These findings indicated that 17 beta-estradiol improved the postprandial elimination of potentially atherogenic lipoprotein remnants.

Abnormal postprandial apolipoprotein B-48 and triglyceride responses in normolipidemic women with greater than 70% stenotic coronary artery disease: a case-control study.

Because remnants of triglyceride-rich lipoproteins (TRLP) are potentially atherogenic, the postprandial lipoprotein metabolism was studied in 12 normocholesterolemic, normotriglyceridemic women, aged 60 +/- 2 years, with angiographically proven coronary artery disease (CAD+; cholesterol 5.7 +/- 0.1 (S.E.) mmol/l, triglyceride 1.35 +/- 0.10 mmol/l) and in 12 individually matched controls, aged 59 +/- 2 years, without angiographical abnormalities (CAD-; cholesterol 5.1 +/- 0.2 mmol/l and triglyceride 1.16 +/- 0.13 mmol/l). Following an oral retinyl palmitate-fat load, the CAD+ women showed a significantly higher triglyceride response in the chylomicron, or Sf > 1000, fraction (P < 0.05 vs. controls). Total plasma apolipoprotein (apo) B and retinyl palmitate concentrations were similar in both groups. Fasting apo B-48 levels in the d < 1.006 g/ml fraction were significantly higher in CAD+ cases (0.25 +/- 0.03 integrated optical density (iod) units) than CAD- controls (0.15 +/- 0.03; P < 0.05). Furthermore, after the fat load, a greater absolute and incremental apo B-48 response in the intermediate density lipoprotein (IDL) fraction (d = 1.006-1.019 g/ml) was observed in CAD+ cases (incremental area under the curve (Delta-AUC)8: 0.40 +/- 0.12 h.iod) than CAD- controls (0.01 +/- 0.06 h.iod; P = 0.01). Post-heparin hepatic lipase (HL) activities were higher in the CAD+ group: 422 +/- 22 mU/l vs 288 +/- 20 mU/ml in the CAD- group (P < 0.001) while lipoprotein lipase (LPL) activities were identical. The results provide evidence that the metabolism of intestinal TRLP is significantly different in normolipidemic women with angiographically proven CAD compared with individually matched controls without coronary disease. Fasting apo B-48 levels in d< 1.006 g/ml fractions represent a potentially useful marker in women at risk for CAD.

Postprandial reduction in high-density lipoprotein cholesterol concentrations in postmenopausal women: improvement by 17beta-estradiol.

The aim of the study was to characterize postprandial high-density lipoprotein (HDL) cholesterol metabolism in postmenopausal women and to evaluate the effect of replacement therapy with 17beta-estradiol. Sixteen healthy normolipidemic (plasma cholesterol, 5.39 +/- 0.68 mmol/L; plasma triglycerides [TGds], 1.24 +/- 0.55 mmol/L) postmenopausal women received an oral vitamin A fat tolerance test (50 g fat with 60,000 IU vitamin A/m2 body surface area). Various blood samples were taken before the test, at hourly intervals up to 8 hours, and 24 hours after ingestion of the fat load for determination of HDL cholesterol, HDL TG, and HDL apolipoprotein (apo) A-I concentrations. TG and vitamin A concentrations were also measured. A subgroup of six women were treated with 2 mg micronized 17beta-estradiol orally each day for 6 weeks, after which the oral vitamin A fat tolerance test was repeated. A reduction in plasma HDL cholesterol concentrations was observed 3 to 8 hours after ingestion of the fat load, and the minimal postprandial HDL cholesterol concentration was, on average, 31.7% (P = .04) lower than the fasting HDL cholesterol concentration. HDL cholesterol had returned to the initial value 24 hours after the fat load. The decrease in postprandial HDL cholesterol concentrations was attenuated by treatment with 17beta-estradiol. The area under the curve (AUC) for the postprandial reduction in HDL cholesterol improved substantially by 66% during 17beta-estradiol (-2.4 +/- 2.6 mmol x h x L(-1) before 17beta-estradiol and - 1.1 +/- 1.2 mmol x h x L(-1)_ during 17beta-estradiol, P = .038). In conclusion, HDL cholesterol concentrations decreased by 32% in the postprandial state in normolipidemic postmenopausal women, indicating that HDL cholesterol must be measured in the fasting state. Replacement therapy with 17beta-estradiol reduced the postprandial decrease in HDL cholesterol by 66%. This effect of 17beta-estradiol can be beneficial in reducing the risk of coronary artery disease.

Effects of gemfibrozil or simvastatin on apolipoprotein-B-containing lipoproteins, apolipoprotein-CIII and lipoprotein(a) in familial combined hyperlipidaemia.

BACKGROUND: Familial combined hyperlipidaemia (FCH), characterized by elevated very-low-density lipoprotein (VLDL) and/or low-density lipoprotein (LDL), is associated with an increased prevalence of premature cardiovascular disease. Therefore, lipid-lowering is frequently indicated. METHODS: We evaluated in a parallel, double-blind randomized fashion the effect of gemfibrozil (1200 mg/day) (n = 40) or simvastatin (20 mg/day) (n = 41) on lipids, apolipoprotein-B (apo-B)-containing lipoproteins, apo-CIII and lipoprotein(a) [Lp(a)], in 81 well-defined FCH patients. RESULTS: While both drugs lowered plasma cholesterol and triglyceride levels, gemfibrozil lowered plasma triglycerides more effectively by reduction of triglycerides in VLDL and LDL, whereas simvastatin was more effective in its reduction of total plasma cholesterol by exclusively decreasing LDL cholesterol. High-density lipoprotein (HDL) increased to an equal extent on both therapies. Total serum apo-B levels were reduced with both drugs; however, gemfibrozil decreased apo-B only in VLDL + IDL, whereas simvastatin decreased apo-B in both VLDL + IDL and LDL. In keeping with a more effective reduction of VLDL particles, a more pronounced reduction of apo-CIII also was observed after gemfibrozil, which correlated with the reduction in plasma triglycerides. Baseline concentrations of Lp(a) showed a wide range in both treatment groups. Median Lp(a) levels increased after simvastatin, but were not affected by gemfibrozil. CONCLUSION: Both therapies exhibited their specific effects, although none of the drugs alone completely normalized the lipid profiles of these patients with FCH. Therefore, the choice of treatment should be based on the most elevated lipoprotein fraction, and in some cases a combination of the two drugs may be indicated.

Differential effect of female gender on coronary artery disease and peripheral artery disease.

BACKGROUND: Women are relatively protected against coronary artery disease (CAD). Whether female gender has a similar protective influence on the development of peripheral artery disease (PAD) has not been extensively investigated and was the main subject of our study. METHODS: We analysed 2707 consecutive patients (2008 men and 699 women) who underwent a first diagnostic coronary angiography for suspicion of CAD and 2367 consecutive patients (1426 men and 941 women) who underwent a first ankle arm index measurement because of suspicion of PAD. RESULTS: We found that a positive diagnosis for CAD and PAD was more common in men compared with women (80.7% vs 57.9%, p<0.0001 and 68.0% vs 60.7%, p<0.0001). Once CAD or PAD was established, severity of disease was similar for men and women, which pleads against a referral bias. Women had a reduced risk of CAD after adjustment for risk factors (odds ratio [OR] 0.32, 95% confidence interval [CI] 0.22-0.46, p<0.0001), but not of PAD (OR 0.82, 95% CI 0.66-1.03, p=NS). In patients with CAD and in those with PAD, women were older, more often had diabetes and hypertension, while men were more likely to be current smokers. Hypertension, smoking and diabetes were associated with CAD in both men and women. Current smoking was associated with PAD in men and women. Hypertension and diabetes were associated with PAD in women but not in men. CONCLUSION: After adjustment for risk factors, the female protection for CAD seems to less present for PAD.

Treatment with hormone replacement therapy lowers remnant lipoprotein particles in healthy postmenopausal women: results from a randomized trial.

BACKGROUND: Recent evidence indicates that remnant lipoprotein particles (RLPs) may play a role in atherosclerosis. Remnant lipoprotein particles have been suggested to be the most atherogenic particles among the triglyceride-rich lipoproteins. In particular, these triglyceride-rich particles were identified as an independent risk factor for cardiovascular diseases (CVD) in women. Postmenopausal hormone replacement therapy (HRT) beneficially affects lipid profile, although total triglyceride levels often increase. Evidence on the effects of HRT on RLPs is limited. We determined whether 3 months' treatment of postmenopausal women with Tibolone or conjugated oestrogens combined with medroxyprogesterone acetate (CEE + MPA) affects RLP-cholesterol (RLP-C). MATERIALS AND METHODS: One hundred and five healthy postmenopausal women were randomized to either 2.5 mg of Tibolone, 0.625 mg of CEE + 2.5 mg of MPA or placebo. At baseline and after 3 months the lipid profile was determined. For assessment of RLP-C we used an immunoseparation-based method. RESULTS: Treatment with CEE + MPA significantly reduced RLP-C (-0.03 mmol L-1, P-value = 0.01) and appeared to increase triglycerides (0.15 mmol L-1, P-value = 0.20) compared with placebo. Tibolone did not significantly change RLP-C (-0.01 mmol L-1, P-value = 0.35) and significantly decreased triglycerides (-0.35 mmol L-1, P-value = 0.004). CONCLUSIONS: Treatment of postmenopausal women with conjugated oestrogens and medroxyprogesterone acetate reduced RLP-C, without a reduction in total triglycerides, whereas Tibolone did affect triglyceride levels, but not RLP-C. These observations may be relevant for explaining the effect of HRT on cardiovascular risk in healthy postmenopausal women.

Apolipoprotein B and coronary artery disease in women: a cross-sectional study in women undergoing their first coronary angiography.

The association between plasma apolipoprotein (apo) B concentrations and angiographically determined coronary artery disease (CAD) was investigated in women in a cross-sectional study. Stenosis of >60% in 1 or more coronary arteries was classified as CAD+. CAD- was defined as a maximum stenosis of 10% in any coronary artery. Fasting plasma concentrations of apoB, apoA-I, cholesterol (chol), low density lipoprotein cholesterol (LDL-chol), high density lipoprotein cholesterol (HDL-chol), and triglycerides (TGs) were determined. Information on nonlipid risk factors was obtained from questionnaires. CAD+ women (n=160) were older than CAD- women (n=129), 64.0+/-7.8 vs 57.8+/-11.1 years, respectively. CAD+ compared with CAD- women had higher frequencies of diabetes (14.7% vs 5.8%, P=0.05), hypertension (53% vs 37%, P=0.018), and ever-smoking (48% vs 35%, P<0.001). CAD+ women had higher plasma concentrations of apoB (1.48+/-0.32 vs 1.25+/-0.34 g/L, P<0.001), chol (7.01+/-1.19 vs 6.38+/-1.22 mmol/L, P=0.001), LDL-chol (4.74+/-1.09 vs 4.13+/-1.13 mmol/L, P<0.001), and TGs (1.98+/-0.84 vs 1.71+/-0.93 mmol/L, P=0.007) and lower levels of HDL-chol (1.28+/-0.28 vs 1.37+/-1.38 mmol/L, P=0.028). After correction for nonlipid risk factors, apoB, chol, LDL-chol, HDL-chol, and TG were independently related to CAD. In the lowest quartiles of chol, LDL-chol, and TG, CAD+ women had higher apoB concentrations than CAD- women. In contrast, chol, LDL-chol, TG, or HDL-chol levels were not different in any quartile of apoB. ApoB showed the most significant relation with the number of stenotic vessels, and apoB was associated with CAD in the normolipidemic subgroup. In conclusion, apoB was superior to chol, LDL-chol, HDL-chol, TG, and apoA-I in discriminating between CAD+ and CAD-.