Fatty acids and breast cancer--is there a relationship?

In 1997 the current database for the relation of polyunsaturated fatty acids in the diet to breast cancer was extensively reviewed by expert committees of the American Institute for Cancer Research and the World Cancer Research Fund. They concluded: "Diets high in polyunsaturated or vegetable fats possibly have no relationship with the risk of breast cancer, independent of any contribution to total fat intake". On the other hand they stated that "Diets high in saturated fat possibly increase the risk of breast cancer" and "Diets high in monounsaturated fat per se possibly have no relationship with the risk of breast cancer, independent of that of total fat." The data in literature clearly confirm these interpretations. No new data exist which have changed the knowledge on the association between intake of fatty acids and breast cancer.

Hemorrheologic abnormalities in defined primary dyslipoproteinemias with both high and low atherosclerotic risks.

Dyslipoproteinemias are associated with hemorrheologic abnormalities (elevated fibrinogen concentration, higher viscosity of plasma and blood). Epidemiologic data suggest that not only elevated lipoprotein concentrations (eg, low-density lipoprotein [LDL] cholesterol), but also hemorrheologic abnormalities could causally be involved in the atherosclerotic process. To elucidate potential effects of hemorrheological disturbances, we investigated patients suffering from primary hyperlipoproteinemias with both low (familial hypertriglyceridemia, n = 25) and high (type III hyperlipoproteinemia, n = 21; familial hypercholesterolemia, n = 19; mixed hyperlipoproteinemia, n = 19) atherosclerotic risk, as well as healthy controls (n = 49) in a cross-sectional design. Dyslipoproteinemias were classified by lipoprotein measurements (using ultracentrifugation), family history, and apolipoprotein E phenotype. Hemorrheology was characterized by the measurement of fibrinogen concentration, viscosity of plasma and blood at different shear rates, and red cell aggregation (RCA) at stasis and low shear. Fibrinogen concentration was lower in controls (2.38 +/- 0.09 g/L) compared with familial hypercholesterolemia (3.19 +/- 0.19 g/L), to type III hyperlipoproteinemia (3.02 +/- 0.12 g/L), to familial hypertriglyceridemia (2.95 +/- 0.21 g/L) and to mixed hyperlipoproteinemia (3.01 +/- 0.12 g/L) (P < .05, respectively) without differences between dyslipoproteinemia groups. Plasma viscosity was higher in patients with type III hyperlipoproteinemia (1.42 +/- 0.03 mPas), with familial hypertriglyceridemia (1.47 +/- 0.04 mPas), and with mixed hyperlipoproteinemia (1.43 +/- 0.02 mPas) compared with controls (1.29 +/- 0.01 mPas) (P < .05, respectively). After including 6 lipoprotein parameters in a general linear model, plasma viscosity, blood viscosity, and RCA were higher in familial hypertriglyceridemia compared with healthy controls and familial hypercholesterolemia (P < .05, respectively). As most of the hemorrheologic abnormalities were still significant after adjusting for lipoprotein concentrations, they seem to be at least partly independent from direct lipoprotein effects. Hemorrheologic abnormalities in familial hypertriglyceridemia (low atherosclerotic risk) were at least as marked as in dyslipoproteinemias with high atherosclerotic risk, suggesting that it might be most important to determine lipoprotein concentrations and to define exactly the type of dyslipoproteinemia for estimating the individual cardiovascular risk in these patients.

The prevention education program (PEP). A prospective study of the efficacy of family-oriented life style modification in the reduction of cardiovascular risk and disease: design and baseline data.

We describe design and baseline data of the Prevention Education Program (PEP), a home-based and family-oriented intervention program, aimed to assess and improve cardiovascular risk factors in school children and their families during an intervention period of 10 years. Started in 1994 in the German town of Nuremberg, currently 37 elementary schools (22 control and 15 intervention schools) are enrolled including 1740 families (1740 first graders, 3046 parents, and 1521 siblings). Major cardiovascular risk factors as well as dietary behavior are evaluated yearly using structured interview, physical examination, laboratory analysis, and seven-day-dietary protocols. The intervention package is applied to all families from intervention schools using regular home visits, health curricula and group sessions. Primary outcome is any reduction in cardiovascular risk factors by dietary intervention and health education compared to the control group getting only written information on the individual risk profile. The presented baseline data showing a high prevalence of cardiovascular risk factors in adults and in their children underline the need for such an intervention program in Germany.

Three low density lipoprotein apheresis techniques in treatment of patients with familial hypercholesterolemia: a long-term evaluation.

Low density lipoprotein (LDL) apheresis is a treatment option for patients with severe hypercholesterolemia not adequately responding to drug treatment who have developed coronary heart disease. We regularly treated 18 patients with immunoadsorption, 8 with heparin induced extracorporeal LDL precipitation (HELP) and 8 with dextran sulfate adsorption for a mean of 4.6 +/- 2.6 years. The effects on LDL cholesterol, high density lipoprotein (HDL) cholesterol, and lipoprotein (a) were comparable among all 3 techniques. Twelve patients were treated for longer than 5 years and 18 patients for longer than 3 years. The evaluation of coronary angiograms (23 patients) revealed a definite regression of coronary lesions in 3 patients; in all other patients, there was a halt in progression. Three patients suffered a sudden cardiac death and 1 patient a nonfatal myocardial infarction due to the occlusion of a coronary bypass. In 9 of 11 patients, no atherosclerotic lesions developed in the coronary bypasses. No severe side effect of either procedure was observed. In conclusion, aggressive lipid lowering by LDL apheresis can stabilize coronary atherosclerosis in most patients.

Low-density lipoprotein (LDL) oxidizability before and after LDL apheresis.

Oxidation of low-density lipoprotein (LDL) plays a major role in the development of atherosclerosis. Hypercholesterolemia has been associated with enhanced in vitro oxidation of LDL, and lipid-lowering therapy reduces LDL oxidizability. In the present study, we investigated whether LDL apheresis performed with different techniques affects in vitro diene formation (lag phase) and modification of apolipoprotein B-100 (apoB). Baseline and posttreatment diene formation was correlated with the baseline pattern of plasma total fatty acids. We then performed a computer-simulation study to test the hypothesis that LDL apheresis-induced changes in LDL oxidizability are related to changes in the mass ratio between freshly produced and older LDL. In 19 patients aged 49+/-7 years with heterozygous familial hypercholesterolemia (FH) regularly treated with either immunoadsorption, heparin-induced LDL precipitation (HELP), or dextran sulfate (DS) adsorption, we determined lipoprotein levels, the lag phase, apoB modification, and the fatty acid pattern in plasma samples drawn at the onset and termination of one LDL apheresis. LDL apheresis significantly decreased total cholesterol, high-density lipoprotein (HDL) cholesterol, LDL cholesterol, and triglycerides by 50.4%, 14.9%, 62.6%, and 33.6%, respectively. The lag phase increased by a significant mean of 9.8%; the charge of apoB was not altered. The lag phase before treatment positively correlated with the baseline concentration of plasma total palmitic, myristic, and oleic acid. The increase in the lag phase during treatment correlated with a high pretreatment concentration of lauric, linoleic, and docosahexanoic acid. The simulation study indicates that a temporary imbalance between two LDL compartments, one representing freshly secreted LDL and the other representing older LDL, could explain the observed increase in the lag phase after LDL apheresis. In conclusion, in patients with heterozygous FH, LDL apheresis performed with different techniques decreases the susceptibility of LDL to oxidation. This decrease may be related to a temporary mass imbalance between freshly produced and older LDL particles. Furthermore, the baseline fatty acid pattern influences pretreatment and posttreatment susceptibility to oxidation.

Long-term effect of low-density lipoprotein apheresis on plasma lipoproteins and coronary heart disease in native vessels and coronary bypass in severe heterozygous familial hypercholesterolemia.

Low-density lipoprotein (LDL) apheresis is a potent treatment for patients with coronary heart disease and severe hereditary forms of LDL hypercholesterolemia not adequately responsive to drug treatment. Until now, the beneficial effect of aggressive reduction of LDL cholesterol by LDL apheresis on the course of coronary heart disease has been demonstrated in one 3-year study and several studies lasting 2 years. We now report on the clinical course, lipoprotein concentrations, coronary angiograms, and side effects in patients undergoing LDL apheresis for as long as 8.6 years. Thirty-four patients (21 men and 13 women) with coronary heart disease and heterozygous familial hypercholesterolemia (FH) not adequately responsive to lipid-lowering drugs received weekly (four patients biweekly) LDL apheresis for 4.6 +/- 2.6 years under diet and lipid-lowering drug therapy; after 0.5 to 3 years, simvastatin in the maximal tolerable dose was added. The baseline LDL cholesterol concentration was 6.9 +/- 1.6 mmol/L. Combined treatment in the steady state yielded a pretreatment and posttreatment LDL cholesterol concentration of 4.8 +/- 0.9 and 1.8 +/- 0.4 mmol/L, respectively. The calculated interval mean LDL cholesterol was 3.3 +/- 0.6 mmol/L. Evaluation of the coronary angiographies revealed a definite regression of coronary lesions in four patients (11.8%); in 19 patients, there was a cessation of progression. Two patients developed atheromatous lesions in bypass grafts (L.H., 60% stenosis; S.M., occlusion). Of 23 patients eligible for the scoring of anginal symptoms, five (21.7%) reported a reduction of the frequency and severity of angina pectoris. The mean coronary symptom score in 23 patients changed from 1.65 +/- 0.83 at baseline to 1.39 +/- 0.66 at the end of the study. During the whole observation period, we observed three sudden deaths, one nonfatal myocardial infarction, and five patients requiring hospital admission because of unstable angina pectoris, one of which was followed by a transluminal coronary angioplasty. Aggressive reduction of LDL cholesterol with combined LDL apheresis and drugs induced regression of coronary lesions in four of 34 patients and prevented progression in 29 patients for as long as 8.6 years. The effect on LDL and high-density lipoprotein (HDL) cholesterol and lipoprotein(a) [Lp(a)] was comparable with all three apheresis techniques. Therefore, no obvious difference between the three techniques was found regarding changes in coronary lesions.

Plasma total homocysteine levels in patients with early-onset coronary heart disease and a low cardiovascular risk profile.

Mild hyperhomocysteinemia has been associated with an increased risk to develop premature coronary heart disease. Recently, the homocysteine concentration has been positively correlated with several main cardiovascular risk factors. We addressed the issue as to whether patients with coronary heart disease and a low cardiovascular risk profile also have a higher prevalence of hyperhomocysteinemia than matched controls. Ninety-five patients (aged 50.5 +/- 6.6 years) and 34 controls (50.0 +/- 6.7 years) less than 60 years of age were selected from a sample of patients after coronary angiography. Subjects with hypertension, diabetes, and moderate or severe hyperlipidemia were excluded. We determined plasma aminothiols (total homocysteine, cysteine, and glutathione), lipoprotein fractions, fibrinogen, and uric acid, the body mass index (weight in kilograms divided by height in meters squared), and the waist to hip ratio. Furthermore, 37 healthy subjects aged 30.8 +/- 7.5 years underwent aminothiol determinations. Patients and controls were similar with regard to age and primary cardiovascular risk factors. Total homocysteine concentrations in the patient group (9.2 +/- 2.4 micromol/L) were significantly higher than in the healthy subjects (8.0 +/- 2.0 micromol/L). However, they did not differ from the levels in the age-matched controls (9.3 +/- 3.0 micromol/L). Neither total cysteine nor glutathione concentrations were significantly different between patients and controls. Male patients (n = 85) had higher mean very-low-density lipoprotein (VLDL) triglycerides (1.36 +/- 0.90 mmol/L) and lower high-density lipoprotein 3 (HDL3) cholesterol (0.75 +/- 0.21 mmol/L) than male controls (n = 28; 1.01 +/- 0.62 and 0.88 +/- 0.26 mmol/L, respectively). Female patients did not have any significant differences in lipoprotein concentrations versus the controls. Among further cardiovascular risk factors, we found a higher prevalence of central obesity in male patients. In conclusion, there was not a higher incidence of hyperhomocysteinemia among patients with premature coronary heart disease and a low cardiovascular risk profile. The higher prevalence of hyperhomocysteinemia found in other studies may be related to the primary risk factors seen in these populations, and may therefore be an indicator of the global cardiovascular risk.

[Homocysteine and coronary heart disease. Is slight or moderate homocysteinemia related to increased risk of coronary heart disease?]. / Homocystein und koronare Herzkrankheit. Geht eine gering- oder mässiggradige Homocysteinämie mit erhöhtem KHK-Risiko einher?

Homocystinuria, a rare inherited disturbance of amino acid metabolism is associated with severe atherosclerosis and thromboembolism already in childhood. The incidence of the homozygous disease of cystathionine beta synthase is estimated to be 1:200,000, that of the heterozygous form 1:300. There are, however, numerous other causes of a mild to moderate homocysteinemia, for example, a deficiency of the cofactors vitamin B6, B12 and folic acid. The question as to whether a mild to moderate elevation of homocysteine in the plasma is also associated with an increased risk of CAD has been investigated in a number of studies in recent years. In summary, however, the presently available data do not provide a basis of proof that a mild to moderate homocysteinemia is an independent risk factor for CAD. Our present knowledge suggests that only when the family history is clearly positive does it appear reasonable to undertake a diagnostic search for possible homocysteinemia.

Drug therapy of severe hypercholesterolemia.

Lowering of plasma cholesterol and particularly of LDL cholesterol has been shown to be an effective way of primary and secondary prophylaxis of coronary heart disease. A broad range of drugs is available (bile acid binding resins, HMG CoA reductase inhibitors, fibrates, nicotinic acid, probucol, beta-sitosterol) for therapy. The choice of the drug is based on the efficacy, possible side effects and proven effects on coronary heart disease.

Long term effect of LDL apheresis on coronary heart disease.

LDL-apheresis is a treatment option for patients with coronary heart disease and severe hypercholesterolemia not adequately responding to drug treatment. 34 patients (21 men, 13 women), aged 47 +/- 9 years, with coronary heart disease and heterozygous familial hypercholesterolemia not adequately responsive to lipid lowering drugs received weekly (4 patients biweekly) LDL apheresis for 3.5 +/- 2.5 years, after 0.5 - 3.0 years simvastatin in the maximally tolerable dose was added. Baseline LDL cholesterol concentration under diet and lipid lowering drugs in the patients receiving immunoadsorption, dextran sulfate adsorption and HELP apheresis was 265.4 +/- 54.9, 230.8 +/- 75.8 and 253.7 +/- 55.7 mg/dl, respectively. The calculated mean LDL cholesterol concentration of the last 5 treatments of the observation period was 123.7 +/- 22.8, 126.8 +/- 26.7 and 138.8 +/- 19.7 mg/dl, respectively. The evaluation of coronary angiographies revealed a definite regression of coronary lesions in 3 patients (8.8%), in all other patients there was a stop in progression. 3 patients died of cardiac complications during the observation period. We conclude that aggressive lipid lowering with combined LDL-apheresis and drugs can stabilize coronary atherosclerosis in most patients with refractory hypercholesterolemia.

Arachidonic acid of platelet phospholipids is decreased after extracorporeal removal of plasma low density lipoproteins in patients with familial hypercholesterolemia.

Platelet phospholipid composition was analyzed before and after extracorporeal removal of low density lipoproteins (LDL) by LDL apheresis in six patients with familial hypercholesterolemia. Elevated levels of total plasma cholesterol and the portion of plasma cholesterol carried by LDL were reduced by 56 and 66% after LDL apheresis. Platelet cholesterol contents remained unaffected. While the phosphatidylcholine (PC):sphingomyelin (SM) ratio in plasma lipoproteins was increased by 22% following apheresis, the same parameter was lowered by 14% in platelets. LDL apheresis induced decreases in the percentages of distinct molecular species containing arachidonic acid in platelet diacyl subgroups of PC, phosphatidylinositol (PI) and phosphatidylserine (PS) as well as in alkenylacyl (plasmalogen) phosphatidylethanolamine (PE). Directly after apheresis, the percentages of molecular species with arachidonic acid of diacyl PC, diacyl PI and alkenylacyl PE were reduced by 20, 23 and 8%, respectively. Two days after the procedure, total arachidonic acid of diacyl PC, diacyl PS and alkenylacyl PE was lowered by 11, 20 and 8%. Overall, the amount of phospholipid bound arachidonic acid was reduced by 16% after apheresis (from 79.1 to 66.4 nmol/10(8) platelets). The results are thus in agreement with previous data indicating decreased phospholipid bound arachidonic acid in red blood cells after apheresis (Engelman B. Bräutigam C, Kulschar R et al. Biochim Biophys Acta 1994:1196:154). Urinary 2,3-dinor thromboxane B2, an estimate of platelet thromboxane A2 (TXA2) production, tended to be decreased following the procedure. The percentage change in the TXA2 metabolite was positively related to the magnitude of change induced by apheresis in phospholipid bound arachidonic acid. In summary, the results suggest that in patients with hypercholesterolemia, the level of plasma LDL is an important determinant of the arachidonic acid content of several platelet phospholipids.

Effects of weekly LDL-apheresis on metabolic parameters of apolipoprotein B in heterozygous familial hypercholesterolemia.

Apheresis is a treatment option for patients with severe hypercholesterolemia and coronary artery disease. It is, however, unknown whether such therapy changes kinetic parameters of lipoprotein metabolism, such as apolipoprotein B (apoB) secretion rates, conversion rates, and fractional catabolic rates (FCR). We studied the long-term effect of regular apheresis therapy on metabolic parameters of apoB in five patients with heterozygous familial hypercholesterolemia (FH) using endogenous labeling with D3-leucine, mass spectrometry, and multicompartmental modeling. Patients were studied prior to (study 1) and after 3-6 months of weekly apheresis therapy (study 2). LDL-apoB concentration was 183 +/- 16 mg d-1 prior to apheresis therapy (study 1), 135 %/- 7 mg. dl-1 at the beginning of study 2, and 163 +/- 10 mg . dl-1 at the end of study 2. VLDL-apoB and IDL-apoB were not different between the two studies and did not change during study 2. Separate modeling of the two studies revealed very similar parameters in each patient. In a second step simultaneous modeling of both studies was performed taking the changing pool size as a non-steady-state condition into account. ApoB tracer data of both kinetic studies and the change in pool size could be described with one set of kinetic parameters (VLDL-apoB FCR 4.32 +/- 1.06 d-1, LDL-apoB FCR 0.17 +/- 0.05 d-1, apoB secretion rate 11.9 +/- 3.7 mg . kg-1 . d-1). These parameters are well within the range of those previously published for FH heterozygotes in steady state. We conclude that regular apheresis therapy did not alter kinetic parameters of apoB metabolism in these patients with heterozygous FH in the long term and that the decreased rate of delivery of neutral lipids or apoB to the liver does not regulate plasma apoB metabolism.

Short- and long-term effects on serum lipoproteins by three different techniques of apheresis.

Low-density lipoprotein (LDL) apheresis is applied in patients with coronary heart disease because of severe inherited forms of hypercholesterolemia, for which dietary and combined drug treatment cannot lower LDL cholesterol concentrations less than 130 mg/dl. The following article describes the changes in lipoprotein levels in a total of 19 patients undergoing weekly LDL apheresis. Immunoadsorption, operating with polyclonal antibodies against apolipoprotein B-100, was used in 6 patients. Five patients were put on heparin-induced extracorporeal LDL precipitation (HELP) therapy; 6 received dextran sulfate adsorption treatments. Under steady-state conditions a single treatment reduced LDL cholesterol by 149 + or - 3 mg/dl with immunoadsorption, 122 + or - 2 mg/dl with HELP, and 124 + or - 18 mg/dl with dextran sulfate adsorption. Lipoprotein (a) (Lp[a]) declined by 52 to 65%. Very low density lipoprotein (VLDL) cholesterol and VLDL triglycerides declined by 45 to 55% because of the activation of lipoprotein lipase and precipitation during the HELP procedure. In all procedures, there was a small reduction in the different high-density lipoprotein fractions, which had returned to normal after 24 h. The long-term HDL3 cholesterol levels increased significantly. During all procedures there was a decrease in the molar esterification rate of lecithin cholesterol acyltransferase activity. All changes in lipid fractions were paralleled by changes in the corresponding apolipoprotein levels. It is concluded that all three techniques described are powerful tools capable of lowering LDL cholesterol in severe hereditary forms of hypercholesterolemia. In HELP and dextran sulfate adsorption, the amount of plasma is limited by the elimination of other plasma constituents. Immunoadsorption may thus be preferred in very severe forms of hypercholesterolemia.