Paul J. Nestel

Soy Isoflavones Improve Systemic Arterial Compliance but Not Plasma Lipids in Menopausal and Perimenopausal Women

The possibility that the heightened cardiovascular risk associated with the menopause, which is said to be ameliorated by soybeans, can be reduced with soy isoflavones was tested in 21 women. Although several were perimenopausal, all have been included. A placebo-controlled crossover trial tested the effects of 80-mg daily isoflavones (45 mg genistein) over 5- to 10-week periods. Systemic arterial compliance (arterial elasticity), which declined with age in this group, improved 26% (P < .001) compared with placebo. Arterial pressure and plasma lipids were unaffected. The vasodilatory capacity of the microcirculation was measured in nine women; high acetylcholine-mediated dilation in the forearm vasculature was similar with active and placebo treatments. LDL oxidizability measured in vitro was unchanged. Thus, one important measure of arterial health, systemic arterial compliance, was significantly improved in perimenopausal and menopausal women taking soy isoflavones to about the same extent as is achieved with conventional hormone replacement therapy.

Association of LDL Cholesterol, Non–HDL Cholesterol, and Apolipoprotein B Levels With Risk of Cardiovascular Events Among Patients Treated With Statins: A Meta-analysis

CONTEXT The associations of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (apoB) levels with the risk of cardiovascular events among patients treated with statin therapy have not been reliably documented. OBJECTIVE To evaluate the relative strength of the associations of LDL-C, non-HDL-C, and apoB with cardiovascular risk among patients treated with statin therapy. DESIGN Meta-analysis of individual patient data from randomized controlled statin trials in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. DATA SOURCES Relevant trials were identified by a literature search updated through December 31, 2011. Investigators were contacted and individual patient data were requested and obtained for 62,154 patients enrolled in 8 trials published between 1994 and 2008. DATA EXTRACTION Hazard ratios (HRs) and corresponding 95% CIs for risk of major cardiovascular events adjusted for established risk factors by 1-SD increase in LDL-C, non-HDL-C, and apoB. RESULTS Among 38,153 patients allocated to statin therapy, 158 fatal myocardial infarctions, 1678 nonfatal myocardial infarctions, 615 fatal events from other coronary artery disease, 2806 hospitalizations for unstable angina, and 1029 fatal or nonfatal strokes occurred during follow-up. The adjusted HRs for major cardiovascular events per 1-SD increase were 1.13 (95% CI, 1.10-1.17) for LDL-C, 1.16 (95% CI, 1.12-1.19) for non-HDL-C, and 1.14 (95% CI, 1.11-1.18) for apoB. These HRs were significantly higher for non-HDL-C than LDL-C (P = .002) and apoB (P = .02). There was no significant difference between apoB and LDL-C (P = .21). CONCLUSION Among statin-treated patients, on-treatment levels of LDL-C, non-HDL-C, and apoB were each associated with risk of future major cardiovascular events, but the strength of this association was greater for non-HDL-C than for LDL-C and apoB.

The role of reducing intakes of saturated fat in the prevention of cardiovascular disease: where does the evidence stand in 2010?

Current dietary recommendations advise reducing the intake of saturated fatty acids (SFAs) to reduce coronary heart disease (CHD) risk, but recent findings question the role of SFAs. This expert panel reviewed the evidence and reached the following conclusions: the evidence from epidemiologic, clinical, and mechanistic studies is consistent in finding that the risk of CHD is reduced when SFAs are replaced with polyunsaturated fatty acids (PUFAs). In populations who consume a Western diet, the replacement of 1% of energy from SFAs with PUFAs lowers LDL cholesterol and is likely to produce a reduction in CHD incidence of ≥2-3%. No clear benefit of substituting carbohydrates for SFAs has been shown, although there might be a benefit if the carbohydrate is unrefined and has a low glycemic index. Insufficient evidence exists to judge the effect on CHD risk of replacing SFAs with MUFAs. No clear association between SFA intake relative to refined carbohydrates and the risk of insulin resistance and diabetes has been shown. The effect of diet on a single biomarker is insufficient evidence to assess CHD risk. The combination of multiple biomarkers and the use of clinical endpoints could help substantiate the effects on CHD. Furthermore, the effect of particular foods on CHD cannot be predicted solely by their content of total SFAs because individual SFAs may have different cardiovascular effects and major SFA food sources contain other constituents that could influence CHD risk. Research is needed to clarify the role of SFAs compared with specific forms of carbohydrates in CHD risk and to compare specific foods with appropriate alternatives.

The hyperlipidemia of pregnancy in normal and complicated pregnancies

Alterations in the concentrations of the cholesterol and triglyceride moieties of lipoproteins separated by ultracentrifugation and precipitation methods were studied at frequent intervals throughout pregnancy and the puerperium in a group of 43 women. The plasma cholesterol concentration rose on the average by about 50 per cent, the major increase occurring in the second trimester. The plasma triglyceride concentration rose threefold, reaching its peak during the third trimester. All major lipoproteins participated in these changes: in very-low-density lipoproteins, both lipids rose in proportion to the ratio in nonpregnant women, but in low-density and high-density lipoproteins, the ratio of triglyceride to cholesterol rose. The triglyceride enrighment in low-density lipoproteins reflected the inclusion of intermediate-density lipoproteins (d 1.006 to 1.019). The occurrence of hypertension or pre-eclampsia led to a further increase in lipids in very-low-density lipoproteins. Hypercholesterolemia was greatest in women with pre-existing hypercholesterolemia, and women in the third pregnancy showed higher plasma cholesterol concentrations than women in the first pregnancy. Both cholesterol and triglyceride concentrations decreased significantly within 24 hours of delivery and this was reflected in all lipoproteins. However, while triglyceride levels continued to decrease rapidly returning to nonpregnant levels during the puerperium, cholesterol in low-density lipoprotein remained elevated for at least six to seven weeks post partum.

The effects of changes in physical activity on major cardiovascular risk factors, hemodynamics, sympathetic function, and glucose utilization in man: a controlled study of four levels of activity.

The effects of four levels of activity on heart rate, blood pressure, cardiac index, total peripheral resistance index (TPRI), norepinephrine (NE) spillover rate, insulin sensitivity, and levels of lipids and some hormones were studied in 12 normal subjects. The randomized periods were (1) 4 weeks of below-sedentary activity, (2) 4 weeks of sedentary activity, (3) 4 weeks of 40 min of bicycling three times per week, and (4) 4 weeks of similar bicycling seven times per week. Exercise three times per week reduced resting blood pressure by 10/7 mm Hg (p less than .01) and it was reduced by 12/7 mm Hg after exercise seven times per week (both p less than .01). This was associated with reduction in TPRI, an increase in cardiac index, and cardiac slowing. At the highest level of activity, NE spillover rate, an index of sympathetic activity, fell to 35% of the sedentary value (p less than .001) in eight of 10 subjects. In two other subjects NE spillover rate rose, although blood pressure and TPRI were reduced. Metabolic changes included lowering of total cholesterol, but high-density lipoprotein level was unchanged. Insulin sensitivity rose by 27% after exercise three times per week, but declined to sedentary levels with seven times per week exercise. Maximum oxygen uptake increased linearly with activity. Exercise performed three times per week lowers blood pressure and should reduce cardiovascular risk. The same exercise seven times per week enhances physical performance with little further reduction in cardiovascular risk factors. Exercise is potentially a major nonpharmacologic method of lowering blood pressure.

The adaptive effects of dietary fish and safflower oil on lipid and lipoprotein metabolism in perfused rat liver

To elucidate the mechanisms underlying the plasma triacylglycerol-lowering effects of certain fish oils, livers from male rats fed either a standard commercial diet (controls) or diets supplemented with 15% (w/w) fish or safflower oils were perfused with undiluted rat blood. Rates of hepatic lipogenesis, measured by the incorporation of 3H2O into fatty acids, followed the order: control greater than safflower oil greater than fish oil. Secretion of newly synthesized fatty acids in very-low-density lipoproteins was also inhibited by the feeding of both oil-supplemented diets with the greater suppression being seen in livers from animals fed fish oil. The hepatic release of very-low-density lipoprotein triacylglycerol mass was also significantly depressed in animals fed the fish oil-supplemented diet but not in those fed safflower oil. Ketogenesis did not differ between livers from rats fed the control and safflower oil diets but was significantly raised in the fish oil group. Increased ketogenesis with fish oil was paralleled by a decrease in the sensitivity of carnitine palmitoyl transferase of isolated mitochondria to inhibition by malonyl-CoA. The inhibitory effect of malonyl-CoA in the safflower oil group was intermediate between that in the fish oil and control groups. Activities of glycerophosphate acyltransferase with either palmitoyl-CoA or oleyl-CoA were increased by feeding oil-supplemented diets. Activity with palmitoyl-CoA that was suppressible by N-ethylmaleimide was also considerably diminished in both groups. The results indicate that the lowering of plasma triacylglycerols by fish oil reflects: (a) diminished lipogenesis; (b) increased fatty acid oxidation possibly in peroxisomes; and (c) diminished secretion of triacylglycerols by the liver.

Fish oil and cardiovascular disease: lipids and arterial function

n-3 Fatty acids have been shown to modify several key risk factors for cardiovascular disease. However, it is not clear whether the apparent protection against cardiovascular disease is directly related to antiatherogenic functions of these fatty acids or is mediated through their modification of the risk factors through mechanisms not directly related to lipids. A major question concerns the importance of lipid modification, which is a potent outcome of fish-oil supplementation. On balance, lipid modification is likely to represent a significant antiatherogenic factor. The benefits include increased HDL(2)-cholesterol concentrations, reduced triacylglycerol-rich lipoprotein concentrations, reduced postprandial lipemia, and reduced remnant concentrations. In contrast, LDL-cholesterol concentrations have often been noted to rise and the potential of increased oxidizability of LDLs is potentially adverse with lipid modification, but this potential can be overcome with vitamin E supplementation. The characteristic lipid changes and the underlying mechanisms are reviewed. Additional benefits of fish oils include improved endothelial function and better arterial compliance (elasticity). Future trials will be needed to determine minimum effective dosages of eicosapentaenoic and docosahexaenoic acids over lengthy periods and to show cardiovascular disease reduction through intervention.

Catabolism of Very Low Density Lipoprotein B Apoprotein in Man

The turnover and the catabolic fate of the B apoprotein of very low density lipoprotein (VLDL-B) was studied in 15 normal and hyperlipidemic subjects using reinjected autologous VLDL labeled with radioiodine. The specific radioactivity-time curve of the B apoprotein in total VLDL (S(f)20-400) was multiexponential but conformed to a two-pool model during the first 48 h of catabolism. The flux was highest in several hypertriglyceridemic subjects. The mass of pool A exceeded the intravascular content of VLDL-B by 30% on average, indicating extravascular metabolism of VLDL. The two-pool model might reflect the input of several populations of particles or heterogeneity of catabolic processes or pools. The flux of B apoprotein was also measured in several subclasses of VLDL, in smaller intermediate density lipoproteins, and in low density lipoproteins (LDL). In three subjects the flux was similar in S(f) 60-400 and in S(f) 12-60 lipoproteins, suggesting that VLDL was catabolized at least to a particle in the density range S(f) 12-60. Subsequent catabolism appeared to proceed by two pathways: in normotriglyceridemic subjects, B apoprotein flux in the S(f) 20-400 and in S(f) 12-20 lipoproteins was similar, whereas in hypertriglyceridemic subjects flux through S(f) 12-20 accounted for only part of the VLDL-B flux. The flux of low density lipoprotein B apoprotein (LDL-B), which is believed to be derived from VLDL catabolism, was calculated from the area between the specific activity time curves of VLDL-B and LDL-B. In subjects with normal plasma triglyceride concentration, LDL-B flux was from 91% to 113% of that of VLDL-B; but in three hypertriglyceridemic subjects showing high rates of VLDL-B transport, LDL-B flux was only one-third that of VLDL-B. This suggests that when VLDL-B flux is high, VLDL is substantially catabolized by a route other than through LDL and possibly leaves the circulation as a particle in the S(f) 20-60 density range.

A reappraisal of the impact of dairy foods and milk fat on cardiovascular disease risk.

BackgroundThis review provides a reappraisal of the potential effects of dairy foods, including dairy fats, on cardiovascular disease (CVD)/coronary heart disease (CHD) risk. Commodities and foods containing saturated fats are of particular focus as current public dietary recommendations are directed toward reducing the intake of saturated fats as a means to improve the overall health of the population. A conference of scientists from different perspectives of dietary fat and health was convened in order to consider the scientific basis for these recommendations.AimsThis review and summary of the conference focus on four key areas related to the biology of dairy foods and fats and their potential impact on human health: (a) the effect of dairy foods on CVD in prospective cohort studies; (b) the impact of dairy fat on plasma lipid risk factors for CVD; (c) the effects of dairy fat on non-lipid risk factors for CVD; and (d) the role of dairy products as essential contributors of micronutrients in reference food patterns for the elderly.ConclusionsDespite the contribution of dairy products to the saturated fatty acid composition of the diet, and given the diversity of dairy foods of widely differing composition, there is no clear evidence that dairy food consumption is consistently associated with a higher risk of CVD. Thus, recommendations to reduce dairy food consumption irrespective of the nature of the dairy product should be made with caution.

Diurnal Variation in Glucose Tolerance and in Insulin Secretion in Man

The changes in blood glucose and plasma free fatty acid (FFA), insulin, and human growth hormone (HGH) concentrations in response to oral and intravenous glucose and intravenous insulin were measured at 7 a.m. and 7 p.m., on both occasions after a ten hour fast, in thirteen normal males and two juvenile diabetics. Basal concentration of plasma FFA was lower and that of plasma insulin higher in the morning than in the evening. Blood glucose and plasma HGH levels did not differ at these times. In the normal subjects, glucose tolerance was diminished and plasma insulin response was delayed in the evening. The delay was significantly less with intravenous glucose than with oral glucose. When compared with the usually accepted criteria for diagnosis of diabetes mellitus, the normal subjects responded in the evening as mild diabetics. Two juvenile-onset diabetics, who had virtually no increase in plasma insulin concentrations after ingestion or injection of glucose, showed no diurnal variation in glucose tolerance. No diurnal variation was seen in the blood glucose response to intravenously injected insulin or in the plasma clearance rate of insulin; these findings suggest that impairment in glucose tolerance in the evening is due to diminished early insulin response to glucose, rather than to abnormal handling of glucose or insulin. The effect of tolbutamide, phentolamine, and theophylline on the diurnal variation of glucose tolerance was studied. In four subjects, intravenous injection of tolbutamide induced a greater insulin response and a greater fall in the blood glucose concentration in the morning than in the evening. The disappearance rate of intravenously injected glucose and both early and delayed insulin responses to the glucose were enhanced to a much greater degree in the morning than in the evening by the simultaneous intravenous injection of tolbutamide. Intravenous infusion of phentolamine, an alpha-adrenergic blocking agent, in five subjects failed to influence responses to intravenous injection of glucose. Intravenous infusion of theophylline, which inhibits cyclic 3′5′-adenosine monophosphate phosphodiesterase activity, in five subjects potentiated the plasma insulin response to intravenous glucose in the evening but not in the morning; the substance did not influence the disappearance rate of glucose.