Showing papers by "Gerald F. Watts published in 2010"

Lipoprotein(a) as a cardiovascular risk factor: current status

Abstract: AIMS: The aims of the study were, first, to critically evaluate lipoprotein(a) [Lp(a)] as a cardiovascular risk factor and, second, to advise on screening for elevated plasma Lp(a), on desirable levels, and on therapeutic strategies. METHODS AND RESULTS: The robust and specific association between elevated Lp(a) levels and increased cardiovascular disease (CVD)/coronary heart disease (CHD) risk, together with recent genetic findings, indicates that elevated Lp(a), like elevated LDL-cholesterol, is causally related to premature CVD/CHD. The association is continuous without a threshold or dependence on LDL- or non-HDL-cholesterol levels. Mechanistically, elevated Lp(a) levels may either induce a prothrombotic/anti-fibrinolytic effect as apolipoprotein(a) resembles both plasminogen and plasmin but has no fibrinolytic activity, or may accelerate atherosclerosis because, like LDL, the Lp(a) particle is cholesterol-rich, or both. We advise that Lp(a) be measured once, using an isoform-insensitive assay, in subjects at intermediate or high CVD/CHD risk with premature CVD, familial hypercholesterolaemia, a family history of premature CVD and/or elevated Lp(a), recurrent CVD despite statin treatment, ≥3% 10-year risk of fatal CVD according to European guidelines, and/or ≥10% 10-year risk of fatal + non-fatal CHD according to US guidelines. As a secondary priority after LDL-cholesterol reduction, we recommend a desirable level for Lp(a) <80th percentile (less than ∼50 mg/dL). Treatment should primarily be niacin 1-3 g/day, as a meta-analysis of randomized, controlled intervention trials demonstrates reduced CVD by niacin treatment. In extreme cases, LDL-apheresis is efficacious in removing Lp(a). CONCLUSION: We recommend screening for elevated Lp(a) in those at intermediate or high CVD/CHD risk, a desirable level <50 mg/dL as a function of global cardiovascular risk, and use of niacin for Lp(a) and CVD/CHD risk reduction.

Platelets Amplify Inflammation in Arthritis via Collagen-Dependent Microparticle Production

Abstract: In addition to their pivotal role in thrombosis and wound repair, platelets participate in inflammatory responses. We investigated the role of platelets in the autoimmune disease rheumatoid arthritis. We identified platelet microparticles—submicrometer vesicles elaborated by activated platelets—in joint fluid from patients with rheumatoid arthritis and other forms of inflammatory arthritis, but not in joint fluid from patients with osteoarthritis. Platelet microparticles were proinflammatory, eliciting cytokine responses from synovial fibroblasts via interleukin-1. Consistent with these findings, depletion of platelets attenuated murine inflammatory arthritis. Using both pharmacologic and genetic approaches, we identified the collagen receptor glycoprotein VI as a key trigger for platelet microparticle generation in arthritis pathophysiology. Thus, these findings demonstrate a previously unappreciated role for platelets and their activation-induced microparticles in inflammatory joint diseases.

Effect of Ezetimibe on Hepatic Fat, Inflammatory Markers, and Apolipoprotein B-100 Kinetics in Insulin-Resistant Obese Subjects on a Weight Loss Diet

Abstract: OBJECTIVE Nonalcoholic fatty liver disease is highly prevalent in obese and type 2 diabetic individuals and is strongly associated with dyslipidemia and inflammation. Weight loss and/or pharmacotherapy are commonly used to correct these abnormalities. RESEARCH DESIGN AND METHODS We performed a 16-week intervention trial of a hypocaloric, low-fat diet plus 10 mg/day ezetimibe ( n = 15) versus a hypocaloric, low-fat diet alone ( n = 10) on intrahepatic triglyceride (IHTG) content, plasma high sensitivity–C-reactive protein (hs-CRP), adipocytokines, and fetuin-A concentrations and apolipoprotein (apo)B-100 kinetics in obese subjects. ApoB-100 metabolism was assessed using stable isotope tracer kinetics and compartmental modeling; liver and abdominal fat contents were determined by magnetic resonance techniques. RESULTS Both weight loss and ezetimibe plus weight loss significantly (all P P CONCLUSIONS Addition of ezetimibe to a moderate weight loss diet in obese subjects can significantly improve hepatic steatosis, inflammation, and LDL–apoB-100 metabolism.

Synovial fibroblasts self-direct multicellular lining architecture and synthetic function in three-dimensional organ culture.

Abstract: Objective To define the intrinsic capacity of fibroblast-like synoviocytes (FLS) to establish a 3-dimensional (3-D) complex synovial lining architecture characterized by the multicellular organization of the compacted synovial lining and the elaboration of synovial fluid constituents. Methods FLS were cultured in spherical extracellular matrix (ECM) micromasses for 3 weeks. The FLS micromass architecture was assessed histologically and compared with that of dermal fibroblast controls. Lubricin synthesis was measured via immunodetection. Basement membrane matrix and reticular fiber stains were performed to examine ECM organization. Primary human and mouse monocytes were prepared and cocultured with FLS in micromass to investigate cocompaction in the lining architecture. Cytokine stimuli were applied to determine the capacity for inflammatory architecture rearrangement. Results FLS, but not dermal fibroblasts, spontaneously formed a compacted lining architecture over 3 weeks in the 3-D ECM micromass organ cultures. These lining cells produced lubricin. FLS rearranged their surrounding ECM into a complex architecture resembling the synovial lining and supported the survival and cocompaction of monocyte/macrophages in the neo–lining structure. Furthermore, when stimulated by cytokines, FLS lining structures displayed features of the hyperplastic rheumatoid arthritis synovial lining. Conclusion This 3-D micromass organ culture method demonstrates that many of the phenotypic characteristics of the normal and the hyperplastic synovial lining in vivo are intrinsic functions of FLS. Moreover, FLS promote survival and cocompaction of primary monocytes in a manner remarkably similar to that of synovial lining macrophages. These findings provide new insight into inherent functions of the FLS lineage and establish a powerful in vitro method for further investigation of this lineage.

Nonalcoholic fatty liver disease as the transducer of hepatic oversecretion of very-low-density lipoprotein-apolipoprotein B-100 in Obesity

Abstract: Objective— To examine the association between liver fat content and very low-density lipoprotein (VLDL)–apolipoprotein (apo) B-100 kinetics and the corresponding responses to weight loss in obese subjects. Methods and Results— VLDL–apoB-100 kinetics were assessed using stable isotope tracers, and the fat content of the liver and abdomen was determined by magnetic resonance techniques in 25 obese subjects. In univariate analysis, liver fat content was significantly ( P <0.05 in all) associated with body mass index ( r =0.65), visceral fat area ( r =0.45), triglycerides ( r =0.40), homeostasis model assessment score ( r =0.40), VLDL–apoB-100 concentrations ( r =0.44), and secretion rate ( r =0.45). However, liver fat content was not associated with plasma concentrations of retinol-binding protein 4, fetuin A, adiponectin, interleukin-6, and tumor necrosis factor-α. Of these 25 subjects, 9 diagnosed as having nonalcoholic fatty liver disease (which is highly prevalent in obese individuals and strongly associated with dyslipidemia) underwent a weight loss program. The low-fat diet achieved significant reduction in body weight, body mass index, liver fat, visceral and subcutaneous fat areas, homeostasis model assessment score, triglycerides, VLDL–apoB-100 concentrations, and VLDL–apoB-100 secretion rate. The percentage reduction of liver fat with weight loss was significantly associated with the corresponding decreases in VLDL–apoB-100 secretion ( r =0.67) and visceral fat ( r =0.84). Conclusion— In patients with obesity, hepatic steatosis increases VLDL–apoB-100 secretion. Weight loss can help reduce this abnormality.

Regulation of plasma LDL: the apoB paradigm.

Abstract: The objectives of this analysis are to re-examine the foundational studies of the in vivo metabolism of plasma LDL (low-density lipoprotein) particles in humans and, based on them, to reconstruct our understanding of the governance of the concentration of plasma LDL and the maintenance of cholesterol homoeostasis in the hepatocyte. We believe that regulation of cholesterol homoeostasis within the hepatocyte is demonstrably more complex than envisioned by the LDL receptor paradigm, the conventional model to explain the regulation of plasma LDL and the fluxes of cholesterol into the liver, a model which was generated in the fibroblast but has never been fully validated in the hepatocyte. We suggest that the LDL receptor paradigm should be reconfigured as the apoB (apolipoprotein B) paradigm, which states that the rate at which LDL particles are produced is at least an important determinant of their concentration in plasma as the rate at which they are cleared from plasma and that secretion of cholesterol within VLDL (very-low-density lipoprotein) particles is an important mechanism of maintaining cholesterol homoeostasis within the hepatocyte. These two paradigms are not mutually exclusive. The LDL receptor paradigm, however, includes only one critical aspect of the regulation of plasma LDL, namely the rate at which LDL particles are cleared through the LDL receptor pathway, but ignores another - the rate at which LDL particles are added to the plasma compartment. The apoB paradigm includes both and points to a different model of how the hepatocyte achieves cholesterol homoeostasis in a complex metabolic environment.

Activation state and intracellular trafficking contribute to the repertoire of endogenous glycosphingolipids presented by CD1d

Abstract: Myeloid antigen-presenting cells (APC) express CD1d molecules that present exogenous and endogenous lipid antigens that activate CD1d-restricted T cells, natural killer T (NKT) cells. NKT cell activation has been shown to mediate the potent downstream activation of other immune cells through cell–cell interactions and rapid, prolific cytokine production. Foreign antigens are not required for NKT cell activation. The endogenous lipids bound to CD1d are sufficient for activation of NKT cells in the setting of Toll-like receptor-induced cytokines. The most potent NKT cell antigens identified are glycosphingolipids (GSL). The GSL repertoire of endogenous ligands bound to CD1d molecules that are expressed in myeloid APC at steady state and in the setting of activation has not been delineated. This report identifies the range of GSL bound to soluble murine CD1d (mCD1d) molecules that sample the endoplasmic reticulum/secretory routes and cell surface-cleaved mCD1d that also samples the endocytic system. Specific GSL species are preferentially bound by mCD1d and do not solely reflect cellular GSL. GM1a and GD1a are prominent CD1d ligands for molecules following both the ER/secretory and lysosomal trafficking routes, whereas GM2 was eluted from soluble CD1d but not lysosomal trafficking CD1d. Further, after LPS activation, the quantities of soluble CD1d-bound GM3 and GM1a markedly increased. A unique α-galactose-terminating GSL was also found to be preferentially bound to mCD1d at steady state, and it increased with APC activation. Together, these studies identify the range of GSL presented by CD1d and how presentation varies based on CD1d intracellular trafficking and microbial activation.

Fenofibrate improves endothelial function in the brachial artery and forearm resistance arterioles of statin-treated Type 2 diabetic patients

Abstract: Dyslipidaemia contributes to endothelial dysfunction and CVD (cardiovascular disease) in Type 2 diabetes mellitus. While statin therapy reduces CVD in these patients, residual risk remains high. Fenofibrate corrects atherogenic dyslipidaemia, but it is unclear whether adding fenofibrate to statin therapy lowers CVD risk. We investigated whether fenofibrate improves endothelial dysfunction in statin-treated Type 2 diabetic patients. In a cross-over study, 15 statin-treated Type 2 diabetic patients, with LDL (low-density lipoprotein)-cholesterol <2.6 mmol/l and endothelial dysfunction [brachial artery FMD (flow-mediated dilatation) <6.0%] were randomized, double-blind, to fenofibrate 145 mg/day or matching placebo for 12 weeks, with 4 weeks washout between treatment periods. Brachial artery FMD and endothelium-independent NMD (nitrate-mediated dilatation) were measured by ultrasonography at the start and end of each treatment period. PIFBF (post-ischaemic forearm blood flow), a measure of microcirculatory endothelial function, and serum lipids, lipoproteins and apo (apolipoprotein) concentrations were also measured. Compared with placebo, fenofibrate increased FMD (mean absolute 2.1+/-0.6 compared with -0.3+/-0.6%, P=0.04), but did not alter NMD (P=0.75). Fenofibrate also increased maximal PIFBF {median 3.5 [IQR (interquartile range) 5.8] compared with 0.3 (2.1) ml/100 ml/min, P=0.001} and flow debt repayment [median 1.0 (IQR 3.5) compared with -1.5 (3.0) ml/100 ml, P=0.01]. Fenofibrate lowered serum cholesterol, triacylgycerols (triglycerides), LDL-cholesterol, apoB-100 and apoC-III (P < or = 0.03), but did not alter HDL (high-density lipoprotein)-cholesterol or apoA-I. Improvement in FMD was inversely associated with on-treatment LDL-cholesterol (r=-0.61, P=0.02) and apoB-100 (r=-0.54, P=0.04) concentrations. Fenofibrate improves endothelial dysfunction in statin-treated Type 2 diabetic patients. This may relate partly to enhanced reduction in LDL-cholesterol and apoB-100 concentrations.

Early recycling compartment trafficking of CD1a is essential for its intersection and presentation of lipid antigens

Abstract: A major step in understanding differences in the nature of Ag presentation was the realization that MHC class I samples peptides transported to the endoplasmic reticulum from the cytosol, whereas MHC class II samples peptides from lysosomes. In contrast to MHC class I and II molecules that present protein Ags, CD1 molecules present lipid Ags for recognition by specific T cells. Each of the five members of the CD1 family (CD1a-e) localizes to a distinct subcompartment of endosomes. Accordingly, it has been widely assumed that the distinct trafficking of CD1 isoforms must also have evolved to enable them to sample lipid Ags that traffic via different routes. Among the CD1 isoforms, CD1a is unusual because it does not have a tyrosine-based cytoplasmic sorting motif and uniquely localizes to the early endocytic recycling compartment. This led us to predict that CD1a might have evolved to focus on lipids that localize to early endocytic/recycling compartments. Strikingly, we found that the glycolipid Ag sulfatide also localized almost exclusively to early endocytic and recycling compartments. Consistent with colocalization of CD1a and sulfatide, wild-type CD1a molecules efficiently presented sulfatide to CD1a-restricted, sulfatide-specific T cells. In contrast, CD1a:CD1b tail chimeras, that retain the same Ag-binding capacity as CD1a but traffic based on the cytoplasmic tail of CD1b to lysosomes, failed to present sulfatide efficiently. Thus, the intracellular trafficking route of CD1a is essential for efficient presentation of lipid Ags that traffic through the early endocytic and recycling pathways.

Fenofibrate concomitantly decreases serum proprotein convertase subtilisin/kexin type 9 and very-low-density lipoprotein particle concentrations in statin-treated type 2 diabetic patients.

Abstract: Aim: Diabetic dyslipidaemia, characterized by hypertriglyceridaemia as a result of elevated serum very-low-density lipoprotein (VLDL) concentrations, contributes to the increased risk of cardiovascular disease (CVD) in type 2 diabetes (T2DM). Proprotein convertase subtilisin/kexin type 9 (PCSK9) may play a role in regulating VLDL metabolism. We investigated the effect of fenofibrate on serum PCSK9 and VLDL particle concentrations in T2DM patients already receiving statin therapy. Methods: In a double-blind randomized crossover study, 15 statin-treated T2DM patients (63 ± 8 years, body mass index (BMI) 29 ± 3 kg/m2) were treated with fenofibrate (145 mg/day) or matching placebo for 12 weeks. Serum PCSK9 concentrations were measured by immunoassay. VLDL particle concentration and size were determined by nuclear magnetic resonance spectroscopy. Results: Fenofibrate decreased serum triglycerides (−23%), VLDL-triglycerides (−51%), total cholesterol (−11%), LDL-cholesterol (−16%), apolipoprotein B-100 (−16%), apolipoprotein C-III (−20%) and PCSK9 (−13%) concentrations compared with placebo (p < 0.05). Fenofibrate also decreased serum concentrations of large (−45%), medium (−66%) and small VLDL (−67%) particles (p < 0.05), without altering VLDL particle size. Serum PCSK9 reduction correlated with decreases in total (r = 0.526, p = 0.044) and small (r = 0.629, p = 0.021) VLDL particle concentrations. Conclusions: Fenofibrate concomitantly decreased serum PCSK9 and VLDL particle concentrations in statin-treated T2DM patients. These findings support a mechanistic link between PCSK9 and VLDL metabolism, possibly through an effect of PSK9 on VLDL receptor degradation.

Omega-3 Fatty Acid Supplementation Decreases Liver Fat Content in Polycystic Ovary Syndrome: A Randomized Controlled Trial Employing Proton Magnetic Resonance Spectroscopy

Abstract: Both nonalcoholic fatty liver disease (NAFLD) and the polycystic ovary syndrome (PCOS) have a strong association with multiple cardiovascular risk factors. A number of studies have demonstrated a link between these 2 disorders. In patients with NAFLD, several interventions have reduced liver fat content through improved hepatic aminotransferases and liver histology as well as imaging markers of hepatic steatosis. There are no data, however, showing that such interventions provide a long-term prognostic advantage for hepatic or cardiovascular outcomes. Few studies have investigated these interventions in women with NAFLD and PCOS. In several small clinical studies, dietary supplementation with marine-derived omega-3 fatty acids improved biochemical and ultrasonographic features of NAFLD suggesting that omega-3 fatty acids may have beneficial effects in NAFLD. This double-blind, randomized, crossover study investigated whether dietary supplementation with omega-3 fatty acids in women with PCOS decreased liver fat content. The effects of this intervention on plasma lipids, blood pressure, and other cardiometabolic risk factors were also assessed. The participants were 25 women with PCOS at a mean age of 32.7 years and with a mean body mass index of 34.8 kg/m 2 . The study was conducted at a tertiary cardiovascular research center. All study subjects were randomized to either 4 g daily of omega-3 fatty acids or a control for 8 weeks. Liver fat content was determined using proton magnetic resonance spectroscopy. Fat content was determined in the whole liver and in subgroups of HLF (liver fat >5%, defined as hepatic steatosis) and NLF (liver fat ≤5%). Liver fat content was significantly reduced in women with PCOS by treatment with omega-3 fatty acids compared with the control (10.2 ± 1.1 vs. 8.4% ± 0.9%; P = 0.022). Treatment was also associated with significant decreases in systolic blood pressure (mean, 124.1 ± 12.1 vs. 122.3 ± 14.5 mm Hg; P = 0.018), diastolic blood pressure (mean, 73.2 ± 8.4 vs. 69.7 ± 8.3 mm Hg; P = 0.005), and triglycerides (geometric mean, 1.19; 95% confidence interval, 1.03-1.47 vs. 1.02; 95% confidence interval, 0.93-1.18) mmol/L; P = 0.002). Most of the decrease in liver fat content associated with dietary omega-3 fatty acids occurred among women with hepatic steatosis (placebo, 18.2 ± 11.1 vs. omega-3 fatty acids, 14.8% ± 9.3%, P = 0.03).

Niacin improves small artery vasodilatory function and compliance in statin-treated type 2 diabetic patients

Abstract: We investigated the effect of niacin (nicotinic acid prolonged release) on forearm vasodilatory function and arterial compliance in statin-treated type 2 diabetic patients with endothelial dysfunction. In a parallel group study, we randomised 15 subjects, with LDL-cholesterol ≤2.5 mmol/L, to niacin (dose titrated to 1500 mg/day over 8 weeks, then maintained for a further 12 weeks) or no additional treatment. Niacin increased maximal post-ischaemic forearm blood flow (mean ± SEM 6.4±2.4 vs. -2.3±1.2 ml/100 ml/min, p = 0.001) and small artery compliance (1.3±0.8 vs. -2.3±1.1 ml/mmHg, p = 0.01) compared with no additional treatment, but did not alter large artery compliance, blood pressure nor heart rate. Niacin decreased serum triglycerides by 47% (p = 0.04), with no change in LDL-cholesterol, HDL-cholesterol, apolipoprotein (Apo) B-100 nor ApoA-I (p > 0.05). Adding niacin to statin therapy improves small artery vasodilatory function and compliance in type 2 diabetes. This may relate to a decrease in serum triglycerides and/or a direct benefit of niacin on vascular biology.

A new model of care for familial hypercholesterolaemia from Western Australia: closing a major gap in preventive cardiology

Abstract: Familial hypercholesterolaemia (FH) is the most common monogenic cause of premature coronary artery disease. FH remains underdiagnosed and inadequately treated, with no national strategies for dealing with the problem. We report an executive summary of a comprehensive model of care for FH developed in Western Australia.

Family history: the neglected risk factor in disease prevention

Abstract: TO THE EDITOR: I agree with Emery and colleagues that family history can add much to downstream clinical interventions that provide tangible benefits to the presenting patient and his or her kin. The pedigree chart has some advantages over simple narrative recording of the same details, including the ability to instantly visualise relationships between individuals and the ease with which the chart can be updated and annotated. There is a familial aggregation (commonly an affected first-degree relative) in up to 25% of presenting cancer patients, while around 5% will harbour a highly penetrant genetic predisposition to cancer. In the cancer clinic, an acceptably detailed family cancer pedigree can typically be obtained in even less time than the 30 minutes suggested by Emery et al. Steps in drawing pedigrees have been outlined elsewhere and typically involve collecting information such as simple demographics, naming and symbolising different cancer types, and recording age of onset and age of death (if relevant) for the different individuals, starting with the presenting patient. The time required to construct a three-generation pedigree would typically be around 10 minutes, making it an attractive addition to routine history taking. If a cancer pattern emerges, the pedigree should be extended as far as possible. Of course, diagnosis verification (through death registries, etc) would be required before surveillance, prophylaxis and therapy decisions are addressed in the familial cancer setting. A convenient refresher for doctors who do not routinely draw pedigrees might be to first construct their own family tree, with reference to the symbols and relationship illustrators commonly used. It is likely that pedigrees in most clinics will be drawn by hand, at least initially, although there are software programs for pedigree creation available (eg, Family Tree Builder; ). Over the years, I have informally asked my specialist oncology trainees to routinely construct family pedigrees. I do not recall, among these highly clinically skilled doctors, one that was able to correctly draw a family pedigree until we had worked on it together. Given the benefits of family pedigree analysis across many disease categories, a little practice in pedigree drawing may be a useful exercise for many of us. Even without the requisite confirmation of disease status of the individuals represented, a simple pedigree chart, combined with quick reference to information on the potential clinical significance of any patterns it shows (eg, by consulting National Health and Medical Research Council guidelines), can help prioritise referrals to busy familial cancer clinics.

Genetic determinants of apolipoprotein B-100 kinetics

Abstract: Purpose of review We review stable isotope tracer studies of apolipoprotein B-100 (apoB) kinetics concerning genetic polymorphisms and mutations that affect human lipoprotein metabolism. Recent findings In obese men, the allelic combination of the apoB signal peptide, SP24, and cholesteryl ester transfer protein, CETP B1B1, is independently associated with lower VLDL apoB secretion. Microsomal triglyceride transfer protein -493G/T carriers have reduced IDL apoB and LDL apoB production as compared with controls. Mutations in cholesterol transporters (ATP-binding cassette transporter G8 and Niemann-Pick C1 Like 1) are associated with reduced VLDL apoB secretion and increased LDL apoB production and catabolism. The ATP-binding cassette transporter G8 400K variant is a significant, independent predictor of VLDL apoB secretion. Mutations in lipases (lipoprotein lipase and hepatic lipase) and transfer proteins (lecithin-cholesterol acyltransferase and cholesteryl ester transfer protein) alter their functional activity, which impact on VLDL and LDL kinetics. Summary Mutations in genes that regulate intrahepatic apoB assembly and lipid substrate availability to the liver impact on VLDL apoB secretion. Lipoprotein tracer studies can provide functional insight into the potential impact of genetic polymorphisms in regulating apoB metabolism in humans.

The effect of fenofibrate on HDL cholesterol and HDL particle concentration in postmenopausal women on tibolone therapy

Abstract: Summary Background Low high-density lipoprotein (HDL) cholesterol and particle concentration are risk factors for coronary heart disease in women. Tibolone lowers HDL cholesterol and HDL particle concentration, an effect that could be reversed by the peroxisome proliferator-activator receptor-α agonist fenofibrate. Objective To assess the effects of fenofibrate on plasma HDL particles in postmenopausal women taking tibolone therapy. Design and participants Randomized crossover study conducted in a women’s health clinic. Fourteen postmenopausal women taking tibolone 2·5 mg daily for menopausal symptoms were randomized to either fenofibrate 160 mg daily or no treatment for 8 weeks, followed by a 3- week wash-out for fenofibrate and then crossed over to alternate therapy for another 8 weeks. The main outcome measure was changes in plasma HDL cholesterol concentration, apoA-I and apoA-II, LpA-I and LpA-I-A-II. Results After 8 weeks of fenofibrate therapy, there was no change in HDL cholesterol, 1·13 ± 0·06 v 1·16 ± 0·06 mmol/l (P = 0·47) or apoA-I, 1·19 ± 0·05 v 1·20 ± 0·05 g/l (P = 0·23). LpA-I fell significantly 0·35 ± 0·03 v 0·29 ± 0·02 (P = 0·02) but there was a rise in apoA-II, 0·35 ± 0·01 v 0·39 ± 0·01 g/l (P = 0·01). There was a significant fall in total cholesterol, triglycerides, low-density lipoprotein cholesterol and apoB. Conclusion In women taking tibolone, fenofibrate increases plasma apoA-II concentration and effects a redistribution of HDL subfractions but does not correct tibolone-induced changes in HDL cholesterol or HDL particle concentration. The mechanism and significance of this require further investigation.

Nutrition and metabolism: new studies of the effects of diets and exercise on lipid and lipoprotein metabolism.

Abstract: This section provides a rapid update service, covering the whole field of lipidology, and lists papers entered into the publisher’s database between 1 October 2008 and 30 September 2009. Key articles are selected for comment by specialists and are highlighted in the following way: Papers considered to be of specialist interest Papers considered to be of outstanding interest A bibliographic listing follows each comment and selected papers are accompanied by an annotation in which the scope and context of the article are summarized briefly. Current Opinion in Lipidology 2010, 21:91–10

Therapeutic Regulation of High-Density Lipoprotein Transport in the Metabolic Syndrome

Abstract: Decreased plasma apoA-I and HDL-cholesterol concentrations are common abnormalities in insulin resistant subjects with obesity and type 2 diabetes mellitus that increase their risk of cardiovascular disease. HDL metabolism is a complex system: kinetic studies using stable isotope tracers and multicompartmental modelling have provided useful mechanistic insight into its regulation. Dysregulation of HDL metabolism in insulin resistance involves accelerated catabolism HDL particles, containing both apoA-I and apoA-II. In turn, this is largely consequent on hepatic oversecretion of VLDL and expansion in the plasma pool of triglyceride-rich lipoproteins; hepatic steatosis, elevated apoC-III and low adiponectin contribute to these changes. Weight loss and fish oils lower the fractional catabolism of HDL but “balancing feedback”, at least in the short-term, sees a fall in apoA-I production, with no net change in plasma HDL concentration. Rosuvastatin increases apoA-I and HDL-cholesterol concentrations by decreasing the catabolism of HDL-apoA-I. PPAR-α agonists increase apoA-I production and potentially enhance reverse cholesterol transport; this effect has also been described with niacin, but requires confirmation. The differential effects of rosuvastatin and fenofibrate on HDL metabolism provides a good rationale for their use as combination therapy. The clinical significance of lifestyle and pharmacologically induced changes in HDL metabolism must be recognized in the light of parallel improvements in apoB metabolism. New clinical methods are needed for investigating cellular and in vivo cholesterol transport.

On Reducing Cardiovascular Disease to a Rarity: Clinical Strategies and their Cost-Effectiveness

Abstract: P of atherosclerotic cardiovascular disease (CVD) by management of its major risk factors is remarkably effective. Yet it remains a dominant source of morbidity, mortality and healthcare expenditure. In the 1970s and 1980s, Australia was one of the first countries in which CVDmortality decreased; but the downward trend had all but ceased in younger Australians by 2000–2004 [1]. Recent economic analysis demonstrates that the direct cost of acute coronary syndromeevents continues to rise in A i a s