Coronary risk factors and metabolic disorders in first-degree relatives of normocholesterolaemic patients with premature atherosclerosis.

AIMS: Despite agreement on the need for screening for the presence of cardiovascular risk factors in first-degree family members of patients with premature coronary artery disease (CAD), this is not routinely carried out in relatives of normocholesterolaemic patients. We evaluated cardiovascular risk factors in family members of normocholesterolaemic patients with premature CAD. METHODS: Eligible index subjects were patients with premature CAD (<55 years in men and <65 years in women), who had undergone percutaneous transluminal coronary angioplasty. Patients with fasting total cholesterol levels >6.5 mmol/l were excluded. Sixteen index subjects were included with a mean age of 49±8 years and total cholesterol levels of 5.5±0.8 mmol/l. Sixty-four first-degree relatives from these 16 pedigrees were screened, namely 18 children, 42 siblings and four parents. National Cholesterol Education Program III guidelines were used to identify candidates for lipid-lowering treatment. Furthermore, the presence of four additional metabolic disorders was investigated: the metabolic syndrome, increased levels of lipoprotein(a) (Lp(a)), hyperhomocysteinaemia and postprandial hyperlipidaemia. RESULTS: Of 64 relatives free of CAD, 34 subjects (53%) fulfilled the criteria to receive therapeutic advice, 20 of whom (31% of the relatives) were candidates for drug therapy. Sixty-one relatives were available for a full assessment of metabolic disorders and in 37 relatives (61%) at least one metabolic abnormality was present. Twelve subjects had hyper-Lp(a), seven subjects had postprandial hyperlipidaemia and two had the metabolic syndrome. Furthermore, 16 subjects had a combination of at least two out of four metabolic disorders. CONCLUSION: Careful evaluation of coronary risk factors and metabolic variables in first-degree relatives of normocholesterolaemic CAD patients identifies a significant number of subjects at increased coronary risk in whom primary prevention measures should be initiated.

High blood pressure is inversely related with the presence and extent of coronary collaterals.

Patients with hypertension have an increased case fatality during acute myocardial infarction (MI). Coronary collateral (CC) circulation has been proposed to reduce the risk of death during acute ischaemia. We determined whether and to which degree high blood pressure (BP) affects the presence and extent of CC circulation. A cross-sectional study in 237 patients (84% males), admitted for elective coronary angioplasty between January 1998 and July 2002, was conducted. Collaterals were graded with Rentrop's classification (grade 0-3). CC presence was defined as Rentrop-grade > or =1. BP was measured twice with an inflatable cuff manometer in seated position. Pulse pressure was calculated by systolic blood pressure (SBP)-diastolic blood pressure (DBP). Mean arterial pressure was calculated by DBP+1/3 x (SBP-DBP). Systolic hypertension was defined by a reading > or =140 mmHg. We used logistic regression with adjustment for putative confounders. SBP (odds ratio (OR) 0.86 per 10 mmHg; 95% confidence interval (CI) 0.73-1.00), DBP (OR 0.67 per 10 mmHg; 95% CI 0.49-0.93), mean arterial pressure (OR 0.73 per 10 mmHg; 95% CI 0.56-0.94), systolic hypertension (OR 0.49; 95% CI 0.26-0.94), and antihypertensive treatment (OR 0.53; 95% CI 0.27-1.02), each were inversely associated with the presence of CCs. Also, among patients with CCs, there was a graded, significant inverse relation between levels of SBP, levels of pulse pressure, and collateral extent. There is an inverse relationship between BP and the presence and extent of CC circulation in patients with ischaemic heart disease.

Effects of increasing doses of simvastatin on fasting lipoprotein subfractions, and the effect of high-dose simvastatin on postprandial chylomicron remnant clearance in normotriglyceridemic patients with premature coronary sclerosis.

Postprandial hyperlipidemia has been linked to premature coronary artery disease (CAD) in fasting normotriglyceridemic patients. We investigated the effects of increasing doses of simvastatin up to 80 mg/day on fasting and postprandial lipoprotein metabolism in 18 normotriglyceridemic patients with premature CAD. Fasting lipoprotein subfractions and cholesteryl ester transfer protein (CETP) activity were determined after each 5-week dose titration (0, 20, 40 and 80 mg/day). At baseline and after treatment with simvastatin 80 mg/day, standardised Vitamin A oral fat loading tests (50 g/m2; 10 h) were carried out. Ten normolipidemic healthy control subjects matched for gender, age and BMI underwent tests without medication. Treatment with simvastatin resulted in dose-dependent reductions of fasting LDL-cholesterol, without changing cholesterol levels in the VLDL-1, VLDL-2 and IDL fractions. In addition, simvastatin decreased CETP activity dose-dependently, although HDL-cholesterol remained unchanged. Simvastatin 80 mg/day decreased fasting plasma triglycerides (TG) by 26% (P < 0.05), but did not decrease significantly TG levels in any of the subfractions. The TG/cholesterol ratio increased in all subfractions. The plasma TG response to the oral fat loading test, estimated as area under the curve (TG-AUC), improved by 30% (from 21.5 +/- 2.5 to 15.1 +/- 1.9 mmol h/L; P < 0.01). Treatment with simvastatin 80 mg/day improved chylomicron remnant clearance (RE-AUC) by 36% from 30.0 +/- 2.6 to 19.2 +/- 3.3 mg h/L (P < 0.01). After therapy, remnant clearance in patients was similar to controls (19.2 +/- 3.3 and 20.3 +/- 2.7 mg h/L, respectively), suggesting a normalization of this potentially atherogenic process. In conclusion, high-dose simvastatin has beneficial effects in normotriglyceridemic patients with premature CAD, due to improved chylomicron remnant clearance, besides effective lowering of LDL-cholesterol. In addition, the lipoprotein subfractions became more cholesterol-poor, as reflected by the increased TG/cholesterol ratio, which potentially makes them less atherogenic.

Activation of leukocytes by postprandial lipemia in healthy volunteers.

Activation of leukocytes is obligatory for inflammation and atherogenesis by adhering to the endothelium via specific ligands. Although in vitro studies have shown that triglycerides (TG) can activate leukocytes, it is unknown whether this occurs in vivo. Using flowcytometry, we studied the expression of leukocyte activation markers CD11A, CD11B, CD62L (all involved in endothelium adhesion) and CD66B (a neutrophil degranulation marker) during a 6 h fat challenge (50 g/m2) and a water test in 10 healthy males (52 +/- 3 years). After fat, neutrophil counts were increased between t=1 and t =6 h, with a maximum at t=3 h (+32% versus t=0, P <0.05), while they remained unchanged after water. Both tests showed gradual lymphocyte count increments. The expression of activation markers on lymphocytes was low and showed comparable responses after both tests. After fat, a significant increase up to a maximum at t=6 h was seen for CD11B on monocytes and on neutrophils for CD11B, CD62L and CD66B. Postprandial activation of monocytes and neutrophils was higher after fat than after water. The maximal postprandial TG increment was significantly related to the increase of CD11B on monocytes (Pearson's R=0.64, P <0.05). In conclusion, postprandially there is a TG-specific increase of neutrophil counts and increased activation of monocytes and neutrophils. These results are suggestive of a pro-inflammatory situation that may correspond with increased adhesive capacity of these cells contributing to the inflammatory component of atherosclerosis.

Normalization of daytime triglyceridemia by simvastatin in fasting normotriglyceridemic patients with premature coronary sclerosis.

Postprandial hyperlipidemia is associated with premature coronary sclerosis in fasting normolipidemic subjects. Self-determined daytime capillary triglyceride (cTG) profiles were compared between 26 fasting normotriglyceridemic patients with premature coronary artery disease (CAD) and 26 controls matched for gender, age and BMI. Daytime triglyceridemia was calculated as total area under the cTG-curve (cTG-AUC). Total and LDL cholesterol were not different between CAD patients (5.4+/-0.8 mmol/l and 3.6+/-0.7 mmol/l, respectively) and controls (5.0+/-0.9 mmol/l and 3.3+/-0.8 mmol/l, respectively). Patients with CAD were characterized by a 44% higher cTG-AUC than matched controls (P<0.01). Using logistic regression analysis, cTG-AUC was the strongest predictor of the presence of CAD (P<0.001). Adding apo AI to the model improved the predictive power from 71 to 77%. Sixteen patients were studied after increasing doses of simvastatin up to 80 mg/day. Although the target for LDL cholesterol was reached by simvastatin 20mg/day, significant effects on cTG-AUC were found only by higher doses of simvastatin. Simvastatin 40 mg/day decreased cTG-AUC by 28% (P<0.05 versus baseline), reaching comparable values as in controls, without further improvement with simvastatin 80 mg/day (26% reduction versus baseline; P<0.05). Daytime triglyceridemia is linked to premature coronary sclerosis in fasting normotriglyceridemic patients. A higher dose of simvastatin was needed to normalize daytime triglyceridemia than was required to "normalize" LDL cholesterol.

Gender differences in postprandial ketone bodies in normolipidemic subjects and in untreated patients with familial combined hyperlipidemia.

OBJECTIVE: An increased hepatic flow of free fatty acids (FFAs) is associated with impaired peripheral FFA trapping by malfunctioning of the complement component 3 (C3)/acylation-stimulating protein system and overproduction of VLDL in familial combined hyperlipidemia (FCHL). Postprandial ketone bodies reflect FFA oxidation in the liver, but the postprandial changes in male and female patients separately have not been determined yet. Gender differences in postprandial ketone bodies and C3 changes were investigated in normolipidemic patients and patients with untreated FCHL. METHODS AND RESULTS: Thirty-two normolipidemic patients (16 female and 16 male) and 19 patients with untreated normolipidemia (9 female and 10 male) underwent an oral fat-loading test. Total and incremental areas under the curves (AUC and dAUC, respectively) after the oral fat load were calculated. Triglyceride AUC was similar between genders in each group. Normolipidemic female subjects showed a higher levels of dAUC-hydroxybutyric acid than male subjects (1.37+/-0.49 and 0.98+/-0.43 mmol x h/L). In FCHL, a similar trend was observed in female (1.92+/-0.38) compared with male (1.55+/-0.87) subjects. In contrast to normolipidemia, FCHL did not show a postprandial increase in C3, although C3 was higher in FCHL. CONCLUSIONS: Women have higher postprandial ketone bodies than men, probably reflecting enhanced postprandial hepatic FFA oxidation. In FCHL, both genders have higher postprandial ketone bodies and therefore higher hepatic FFA delivery. The higher fasting and postprandial C3 levels in FCHL may reflect resistance of the C3/acylation-stimulating protein system to promote peripheral fatty acid trapping.