High density lipoproteins (HDLs) and atherosclerosis; the unanswered questions

The concentration of high density lipoprotein-cholesterol (HDL-C) has been found consistently to be a powerful negative predictor of premature coronary heart disease (CHD) in human prospective population studies. There is also circumstantial evidence from human intervention studies and direct evidence from animal intervention studies that HDLs protect against the development of atherosclerosis. HDLs have several documented functions, although the precise mechanism by which they prevent atherosclerosis remains uncertain. Nor is it known whether the cardioprotective properties of HDL are specific to one or more of the many HDL subpopulations that comprise the HDL fraction in human plasma. Several lifestyle and pharmacological interventions have the capacity to raise the level of HDL-C, although it is not known whether all are equally protective. Indeed, despite the large body of information identifying HDLs as potential therapeutic targets for the prevention of atherosclerosis, there remain many unanswered questions that must be addressed as a matter of urgency before embarking wholesale on HDL-C-raising therapies as strategies to prevent CHD. This review summarises what is known and highlights what we still need to know.

High density lipoprotein: guardian of the vascular system?

The role of low-density lipoprotein in the development of coronary heart disease (CHD) is well recognised. There is also growing evidence that high-density lipoprotein cholesterol (HDL-C) is a powerful inverse predictor for premature CHD and that maintaining a high HDL-C level may guard against atherosclerosis. Patients with low HDL-C levels often also have central obesity, insulin resistance and other features of the metabolic syndrome. This syndrome is both increasingly common and strongly implicated in the growing worldwide epidemic of type 2 diabetes. HDL-C may be increased by lifestyle changes, e.g. weight loss, physical activity and smoking cessation. Pharmacological agents such as fibrates, niacin and statins have also been shown significantly to elevate HDL-C. Although current guidelines are beginning to recognise the protective role of HDL-C level in preventing coronary events, HDL-C should be adopted soon as a target for intervention in its own right.

Dairy fat: perceptions and realities.

Milk provides many key nutrients but the saturated and trans fatty acids in milk fat are associated with perceived negative effects on human health, especially cardiovascular disease. Recent epidemiological studies and dietary intervention trials challenge this perception, however; available evidence does not support the concept that consumption of saturated fats or dairy products adversely affects the risk of coronary heart disease (although replacing some saturated fats with mono or polyunsaturated fats is likely to provide benefit). Furthermore, the trans fats found in dairy products are consumed in very low amounts and do not appear to have the negative health effects associated with the consumption of industrial sources of trans fat. Milk fat is an excellent source of oleic acid that originates mainly by endogenous synthesis from stearic acid, but increasing the milk fat content of unsaturated fatty acids requires dietary formulations that bypass rumen biohydrogenation. Recent research indicates that long-chain omega-3 fatty acids and conjugated linoleic acids have potential beneficial effects in health maintenance and the prevention of chronic diseases. Enhancing the milk fat content of these fatty acids offers exciting possibilities, but educating consumers about inaccurate and inappropriate generalisations about fat remains the primary challenge. Finally, individuals do not simply consume milk-fat-derived fatty acids on their own, but rather as components in dairy foods which are highly complex and may contain many beneficial ingredients. Overall, dairy products are critical in providing many of the essential nutrients in the human diet. Nevertheless, dairy products vary in their nutrient composition, including fat, and this needs to be considered in the context of dietary recommendations and our need to consume a balanced diet.

Multiprobabilistic prediction in early medical diagnoses

This paper describes the methodology of providing multiprobability predictions for proteomic mass spectrometry data. The methodology is based on a newly developed machine learning framework called Venn machines. Is allows to output a valid probability interval. The methodology is designed for mass spectrometry data. For demonstrative purposes, we applied this methodology to MALDI-TOF data sets in order to predict the diagnosis of heart disease and early diagnoses of ovarian cancer and breast cancer. The experiments showed that probability intervals are narrow, that is, the output of the multiprobability predictor is similar to a single probability distribution. In addition, probability intervals produced for heart disease and ovarian cancer data were more accurate than the output of corresponding probability predictor. When Venn machines were forced to make point predictions, the accuracy of such predictions is for the most data better than the accuracy of the underlying algorithm that outputs single probability distribution of a label. Application of this methodology to MALDI-TOF data sets empirically demonstrates the validity. The accuracy of the proposed method on ovarian cancer data rises from 66.7 % 11 months in advance of the moment of diagnosis to up to 90.2 % at the moment of diagnosis. The same approach has been applied to heart disease data without time dependency, although the achieved accuracy was not as high (up to 69.9 %). The methodology allowed us to confirm mass spectrometry peaks previously identified as carrying statistically significant information for discrimination between controls and cases.

p22phox C242T SNP inhibits inflammatory oxidative damage to endothelial cells and vessels

Background— T NADPH oxidase, by generating reactive oxygen species, is involved in the pathophysiology of many cardiovascular diseases and represents a therapeutic target for the development of novel drugs. A single-nucleotide polymorphism (SNP) C242T of the p22phox subunit of NADPH oxidase has been reported to be negatively associated with coronary heart disease (CHD) and may predict disease prevalence. However, the underlying mechanisms remain unknown. Methods and Results— Using computer molecular modelling we discovered that C242T SNP causes significant structural changes in the extracellular loop of p22phox and reduces its interaction stability with Nox2 subunit. Gene transfection of human pulmonary microvascular endothelial cells showed that C242T p22phox reduced significantly Nox2 expression but had no significant effect on basal endothelial O2.- production or the expression of Nox1 and Nox4. When cells were stimulated with TNFα (or high glucose), C242T p22phox inhibited significantly TNFα-induced Nox2 maturation, O2.- production, MAPK and NFκB activation and inflammation (all p<0.05). These C242T effects were further confirmed using p22phox shRNA engineered HeLa cells and Nox2-/- coronary microvascular endothelial cells. Clinical significance was investigated using saphenous vein segments from non CHD subjects after phlebectomies. TT (C242T) allele was common (prevalence of ~22%) and compared to CC, veins bearing TT allele had significantly lower levels of Nox2 expression and O2.- generation in response to high glucose challenge. Conclusions— C242T SNP causes p22phox structural changes that inhibit endothelial Nox2 activation and oxidative response to TNFα or high glucose stimulation. C242T SNP may represent a natural protective mechanism against inflammatory cardiovascular diseases.