Common genetic variants do not predict recurrent events in coronary heart disease patients.

BACKGROUND: It is unclear whether genetic variants identified from single nucleotide polymorphisms (SNPs) strongly associated with coronary heart disease (CHD) in genome-wide association studies (GWAS), or a genetic risk score (GRS) derived from them, can help stratify risk of recurrent events in patients with CHD. METHODS: Study subjects were enrolled at the close-out of the LIPID randomised controlled trial of pravastatin vs placebo. Entry to the trial had required a history of acute coronary syndrome 3-36 months previously, and patients were in the trial for a mean of 36 months. Patients who consented to a blood sample were genotyped with a custom designed array chip with SNPs chosen from known CHD-associated loci identified in previous GWAS. We evaluated outcomes in these patients over the following 10 years. RESULTS: Over the 10-year follow-up of the cohort of 4932 patients, 1558 deaths, 898 cardiovascular deaths, 727 CHD deaths and 375 cancer deaths occurred. There were no significant associations between individual SNPs and outcomes before or after adjustment for confounding variables and for multiple testing. A previously validated 27 SNP GRS derived from SNPs with the strongest associations with CHD also did not show any independent association with recurrent major cardiovascular events. CONCLUSIONS: Genetic variants based on individual single nucleotide polymorphisms strongly associated with coronary heart disease in genome wide association studies or an abbreviated genetic risk score derived from them did not help risk profiling in this well-characterised cohort with 10-year follow-up. Other approaches will be needed to incorporate genetic profiling into clinically relevant stratification of long-term risk of recurrent events in CHD patients.

Familial hypercholesterolemia and elevated lipoprotein(a): double heritable risk and new therapeutic opportunities.

There is compelling evidence that the elevated plasma lipoprotein(a) [Lp(a)] levels increase the risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. Like low-density lipoprotein (LDL) particles, Lp(a) particles contain cholesterol and promote atherosclerosis. In addition, Lp(a) particles contain strongly proinflammatory oxidized phospholipids and a unique apoprotein, apo(a), which promotes the growth of an arterial thrombus. At least one in 250 individuals worldwide suffer from the heterozygous form of familial hypercholesterolemia (HeFH), a condition in which LDL-cholesterol (LDL-C) is significantly elevated since birth. FH-causing mutations in the LDL receptor gene demonstrate a clear gene-dosage effect on Lp(a) plasma concentrations and elevated Lp(a) levels are present in 30-50% of patients with HeFH. The cumulative burden of two genetically determined pro-atherogenic lipoproteins, LDL and Lp(a), is a potent driver of ASCVD in HeFH patients. Statins are the cornerstone of treatment of HeFH, but they do not lower the plasma concentrations of Lp(a). Emerging therapies effectively lower Lp(a) by as much as 90% using RNA-based approaches that target the transcriptional product of the LPA gene. We are now approaching the dawn of an era, in which permanent and significant lowering of the high cholesterol burden of HeFH patients can be achieved. If outcome trials of novel Lp(a)-lowering therapies prove to be safe and cost-effective, they will provide additional risk reduction needed to effectively treat HeFH and potentially lower the CVD risk in these high-risk patients even more than currently achieved with LDL-C lowering alone.

Implementing simple algorithms to improve glucose and lipid management in people with diabetes and acute coronary syndrome.

AIM: Diabetes mellitus is associated with increased risk of adverse outcomes following acute coronary syndrome. Translating evidence-based recommendations into practice is necessary to improve outcomes. We evaluated whether implementing algorithms to guide inpatient care improved glycaemic control, and increased use of sodium-glucose co-transporter 2 (SGLT2) inhibitors and lipid-lowering medication in a tertiary cardiac unit. METHOD: A 3-month audit (phase 1) was conducted to evaluate hyperglycaemia and dyslipidaemia management, and medication prescriptions. Consecutive people with diabetes admitted for acute coronary syndrome were prospectively identified. Target blood glucose level was defined as 5-10 mmol/l. A multidisciplinary committee designed and implemented decision-support algorithms plus education. A 3-month post-implementation audit (phase 2) was conducted. RESULTS: There were 104 people in phase 1 and 101 in phase 2, with similar characteristics [HbA1c 64 ± 20 mmol/mol vs. 61 ± 21 mmol/mol (8.0 ± 1.8% vs. 7.8 ± 1.9%]. Post implementation, the incidence of blood glucose levels > 10 mmol/l was lower [phase 1: 46.4% vs. phase 2: 31.8%, rate ratio (RR) = 0.77, 95% confidence intervals (CI) 0.60-0.98; P = 0.031], without a difference in blood glucose levels < 5mmol/l (phase 1: 4.9% vs. phase 2: 4.5%, RR = 1.20, 95% CI 0.70-2.08; P = 0.506). SGLT2 inhibitor prescriptions increased significantly (baseline to discharge: 12.5% to 15.4% vs. 7.9% to 24.8%; P = 0.007) but high-intensity statin prescriptions did not (baseline to discharge: 35.6% to 72.1% vs. 40.6% to 85.1%; P = 0.074). Prescription rates of non-statin lipid-lowering medications were not significantly increased. CONCLUSIONS: Implementing decision-support algorithms was associated with improved inpatient glycaemic control and increased use of cardioprotective therapies at discharge in people with diabetes and acute coronary syndrome.

A new dawn for managing dyslipidemias: The era of rna-based therapies.

The high occurrence of atherosclerotic cardiovascular disease (ASCVD) events is still a major public health issue. Although a major determinant of ASCVD event reduction is the absolute change of low-density lipoprotein-cholesterol (LDL-C), considerable residual risk remains and new therapeutic options are required, in particular, to address triglyceride-rich lipoproteins and lipoprotein(a) [Lp(a)]. In the era of Genome Wide Association Studies and Mendelian Randomization analyses aimed at increasing the understanding of the pathophysiology of ASCVD, RNA-based therapies may offer more effective treatment options. The advantage of oligonucleotide-based treatments is that drug candidates are targeted at highly specific regions of RNA that code for proteins that in turn regulate lipid and lipoprotein metabolism. For LDL-C lowering, the use of inclisiran - a silencing RNA that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis - has the advantage that a single s.c. injection lowers LDL-C for up to 6 months. In familial hypercholesterolemia, the use of the antisense oligonucleotide (ASO) mipomersen, targeting apolipoprotein (apoB) to reduce LDL-C, has been a valuable therapeutic approach, despite unquestionable safety concerns. The availability of specific ASOs lowering Lp(a) levels will allow rigorous testing of the Lp(a) hypothesis; by dramatically reducing plasma triglyceride levels, Volanesorsen (APOC3) and angiopoietin-like 3 (ANGPTL3)-LRx will further clarify the causality of triglyceride-rich lipoproteins in ASCVD. The rapid progress to date heralds a new dawn in therapeutic lipidology, but outcome, safety and cost-effectiveness studies are required to establish the role of these new agents in clinical practice.

A pragmatic comparative study of palliative care clinician's reports of the degree of shadowing visible on plain abdominal radiographs.

The assessment of constipation symptoms is based on history and physical examination. However, the experience is highly subjective perhaps explaining why palliative medicine doctors continue to use plain abdominal radiographs as part of routine assessment of constipation. Previous studies have demonstrated poor agreement between clinicians with this work in palliative care, limited further by disparity of clinicians' experience and training. The aim of this work was to explore whether there was less variation in the assessments of faecal shadowing made by more experienced clinicians compared to their less experienced colleagues. This pragmatic study was conducted across six palliative care services in Sydney (NSW, Australia). Doctors of varying clinical experience were asked to independently report their opinions of the amount of shadowing seen on 10 plain abdominal radiographs all taken from cancer patients who self-identified themselves as constipated. There were 46 doctors of varying clinical experience who participated including qualified specialists, doctors in specialist training and lastly, doctors in their second- and third post-graduate years. Poor agreement was seen between the faecal shadowing scores allocated by doctors of similar experience and training (Fleiss's kappa (FK): RMO 0.05; registrar 0.06; specialist 0.11). Further, when the levels of agreement between groups were considered, no statistically significant differences were observed. Although the doctors did not agree on the appearance of the film, the majority felt they were able to extrapolate patients' experiences from the radiograph's appearance. As it remains challenging in palliative care to objectively assess and diagnose constipation by history and imaging, uniform and objective assessment and diagnostic criteria are required. It is likely that any agreed criteria will include a combination of imaging and history. The results suggest the use of radiographs alone to diagnose and assess constipation in palliative care represents low value care.

A narrative overview of the current status of MRI of the hip and its relevance for osteoarthritis research - what we know, what has changed and where are we going?

OBJECTIVE: To review and discuss the role of magnetic resonance imaging (MRI) in the context of hip osteoarthritis (OA) research. DESIGN: The content of this narrative review, based on an extensive PubMed database research including English literature only, describes the advances in MRI of the hip joint and its potential usefulness in hip OA research, reviews the relevance of different MRI features in regard to symptomatic and structural progression in hip OA, and gives an outlook regarding future use of MRI in hip OA research endeavors. RESULTS: Recent technical advances have helped to overcome many of the past difficulties related to MRI assessment of hip OA. MRI-based morphologic scoring systems allow for detailed assessment of several hip joint tissues and, in combination with the recent advances in MRI, may increase reproducibility and sensitivity to change. Compositional MRI techniques may add to our understanding of disease onset and progression. Knowledge about imaging pitfalls and anatomical variants is crucial to avoid misinterpretation. In comparison to research on knee OA, the associations between MRI features and the incidence and progression of disease as well as with clinical symptoms have been little explored. Anatomic alterations of the hip joint as seen in femoro-acetabular impingement (FAI) seem to play a role in the onset and progression of structural damage. CONCLUSIONS: With the technical advances occurring in recent years, MRI may play a major role in investigating the natural history of hip OA and provide an improved method for assessment of the efficacy of new therapeutic approaches.

16S rRNA gene sequencing on a benchtop sequencer: accuracy for identification of clinically important bacteria.

AIMS: Test the choice of 16S rRNA gene amplicon and data analysis method on the accuracy of identification of clinically important bacteria utilizing a benchtop sequencer. METHODS AND RESULTS: Nine 16S rRNA amplicons were tested on an Ion Torrent PGM to identify 41 strains of clinical importance. The V1-V2 region identified 40 of 41 isolates to the species level. Three data analysis methods were tested, finding that the Ribosomal Database Project's SequenceMatch outperformed BLAST and the Ion Reporter Metagenomics analysis pipeline. Lastly, 16S rRNA gene sequencing mixtures of four species through a six log range of dilution showed species were identifiable even when present as 0·1% of the mixture. CONCLUSIONS: Sequencing the V1-V2 16S rRNA gene region, made possible by the increased read length Ion Torrent PGM sequencer's 400 base pair chemistry, may be a better choice over other commonly used regions for identifying clinically important bacteria. In addition, the SequenceMatch algorithm, freely available from the Ribosomal Database Project, is a good choice for matching filtered reads to organisms. Lastly, 16S rRNA gene sequencing's sensitivity to the presence of a bacterial species at 0·1% of a mixture suggests it has sufficient sensitivity for samples in which important bacteria may be rare. SIGNIFICANCE AND IMPACT OF THE STUDY: We have validated 16S rRNA gene sequencing on a benchtop sequencer including simple mixtures of organisms; however, our results highlight deficits for clinical application in place of current identification methods.

Metabolic syndrome in people with a psychotic illness: is cannabis protective?

BACKGROUND: Rates of the metabolic syndrome in people with psychotic illness are high. Emerging evidence suggests that cannabis use may have a positive impact on cardiometabolic risk factors in the general population, but little is known about its impact for people with psychotic illness. Our aim was to investigate whether the rate of the metabolic syndrome in people with psychotic illness was associated with frequency of cannabis use. METHOD: The 2010 Australian psychosis survey used a two-phase design to randomly select a nationally representative sample of 1825 adults with psychotic illness for interview and physical assessment. This study is based on 1813 participants who provided data on cannabis use. Multiple logistic regression was used to model the influence of frequency of cannabis use on the metabolic syndrome, adjusting for potential covariates including antipsychotic medication use, smoking, alcohol use and cognitive function. RESULTS: One-third (33.0%) of participants had used cannabis in the past year. The proportion of non-users, occasional users and frequent users with the metabolic syndrome was 63.0, 51.7 and 43.5%, respectively (p < 0.001). In unadjusted analyses, both occasional use and frequent cannabis use were associated with significantly lower odds of the metabolic syndrome. In the adjusted analyses, the association between the metabolic syndrome and frequent cannabis use remained significant [odds ratio = 0.56, 95% confidence interval (CI) 0.39-0.80], but not the association with occasional use (odds ratio = 0.75, 95% CI 0.49-1.13). CONCLUSIONS: While cannabis use may be detrimental for mental health, these data suggest that it may also have a cardiometabolic protective effect. Further investigation is required to understand the mechanism underlying this paradoxical finding.

Effect of niacin on triglyceride-rich lipoprotein apolipoprotein B-48 kinetics in statin-treated patients with type 2 diabetes.

AIM: To investigate the effects of extended-release (ER) niacin on apolipoprotein B-48 (apoB-48) kinetics in statin-treated patients with type 2 diabetes (T2DM). METHODS: A total of 12 men with T2DM were randomized to rosuvastatin or rosuvastatin plus ER niacin for 12 weeks and then crossed to the alternate therapy. Postprandial metabolic studies were performed at the end of each treatment period. D3-leucine tracer was administered as subjects consumed a high-fat liquid meal. ApoB-48 kinetics were determined using stable isotope tracer kinetics with fractional catabolic rates (FCRs) and secretion rates derived using a non-steady-state compartmental model. Area-under-the-curve (AUC) and incremental AUC (iAUC) for plasma triglyceride and apoB-48 were also calculated over the 10-h period after ingestion of the fat meal. RESULTS: In statin-treated patients with T2DM, apoB-48 concentration was lower with ER niacin (8.24 ± 1.98 vs 5.48 ± 1.14 mg/l, p = 0.03) compared with statin alone. Postprandial triglyceride and apoB-48 AUC were also significantly lower on ER niacin treatment (-15 and -26%, respectively; p < 0.05), without any change to triglyceride and apoB-48 iAUC. ApoB-48 secretion rate in the basal state (3.21 ± 0.34 vs 2.50 ± 0.31 mg/kg/day; p = 0.04) and number of apoB-48-containing particles secreted in response to the fat load (1.35 ± 0.19 vs 0.84 ± 0.12 mg/kg; p = 0.02) were lower on ER niacin. ApoB-48 FCR was not altered with ER niacin (8.78 ± 1.04 vs 9.17 ± 1.26 pools/day; p = 0.79). CONCLUSIONS: ER niacin reduces apoB-48 concentration by lowering fasting and postprandial apoB-48 secretion rate. This effect may be beneficial for lowering atherogenic postprandial lipoproteins and may provide cardiovascular disease risk benefit in patients with T2DM.

Correlates of physical activity in people living with psychotic illness.

OBJECTIVE: In the light of the high prevalence of physical comorbidities in people with psychotic illness, there is a need to explore modifiable risk factors that may contribute to this disease burden. The benefits of physical activity to both physical and mental health have been well established. We aimed to examine the prevalence and correlates of physical activity in a national sample of adults living with psychotic illness. METHODS: Physical activity was assessed in 1801 people using the International Physical Activity Questionnaire. Participants were dichotomised into low and moderate-high physical activity groups and associations between physical activity and a range of sociodemographic, clinical and physical comorbidity variables were examined using logistic regression. RESULTS: More than half the participants were categorised in the moderate-high physical activity group with nearly half of the sample engaged in physical activity every day. There were significant associations between low physical activity and older age, unemployment, educational non-participation, antipsychotic medication use, social dysfunction, self-reported loneliness and obesity. However, there was no significant association between physical activity and sex, psychosis type, illness duration, physical comorbidity or negative symptoms. CONCLUSION: The findings from this study may inform future interventions designed to increase physical activity in people with psychotic illness.

Effect of omega-3 fatty acid supplementation on arterial elasticity in patients with familial hypercholesterolaemia on statin therapy.

BACKGROUND AND AIMS: Increased arterial stiffness is closely linked with raised blood pressure that contributes substantially to enhanced risk of coronary heart disease in high risk individuals with familial hypercholesterolaemia (FH). Omega-3 fatty acid (ω3-FA) supplementation has been demonstrated to lower blood pressure in subjects with a high cardiovascular disease risk. Whether ω3-FA supplementation improves arterial stiffness in FH subjects, on background statin therapy, has yet to be investigated. METHOD AND RESULTS: We carried out an 8-week randomized, crossover intervention trial to test the effect of 4 g/d ω3-FA supplementation (46% eicosapentaenoic acid and 38% docosahexaenoic acid) on arterial elasticity in 20 adults with FH on optimal cholesterol-lowering therapy. Large and small artery elasticity were measured by pulse contour analysis of the radial artery. ω3-FA supplementation significantly (P < 0.05 in all) increased large artery elasticity (+9%) and reduced systolic blood pressure (-6%) and diastolic blood pressure (-6%), plasma triglycerides (-20%), apoB concentration (-8%). In contrast, ω3-FAs had no significant effect on small artery elasticity. The change in large artery elasticity was not significantly associated with changes in systolic blood pressure or plasma triglyceride concentration. CONCLUSIONS: ω3-FA supplementation improves large arterial elasticity and arterial blood pressure independent of statin therapy in adults with FH. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.com/NCT01577056.

The association between chronic hepatitis C infection and cardiovascular risk.

BACKGROUND: Vascular disease is a common cause of death in patients with chronic hepatitis C (CHC) infection; however, the association between CHC and atherosclerosis is unclear. AIMS: To determine whether patients with CHC have increased subclinical vascular disease and whether genotype or antiviral treatment modifies this risk. METHODS: Fifty CHC patients and 22 age-matched and sex-matched healthy controls underwent clinical and biochemical assessment for vascular risk factors. In addition, vascular risk was assessed by measuring arterial stiffness (aortic augmentation index and carotid-femoral pulse wave velocity (PWV)), endothelial dysfunction (brachial artery flow-mediated dilatation (FMD) and dilatation post-glycerol trinitrate administration) and carotid intima-media thickness (CIMT). Assessment was repeated in subset of CHC patients (n = 12) undergoing antiviral treatment 18 months after initiation of treatment. RESULTS: Baseline vascular risk factors and measures of arterial stiffness, endothelial dysfunction and CIMT were not different between cases and controls (P > 0.2 for all). Genotype 1 CHC patients had greater endothelial dysfunction with lower FMD (8.2 ± 3.5% vs 10.9 ± 5.2%, P = 0.03) and higher right CIMT (0.6 ± 0.1 mm vs 0.5 ± 0.07 mm, P = 0.04) compared with non-genotype 1. Patients who achieved sustained virological response (7/12) showed significant improvement in insulin resistance (homeostasis model of assessment of insulin resistance 2.3 ± 1.2 vs 1.8 ± 0.8, P = 0.02) and arterial stiffness (PWV 7.4 ± 1.1 m/s vs 6.5 ± 0.6 m/s, P = 0.04). CONCLUSIONS: Subclinical vascular disease is not greater in CHC subjects compared with controls. However, among CHC subjects, genotype 1 infection is associated with greater endothelial dysfunction and increased carotid-intima medial thickness compared with non-genotype 1 infection. Successful viral eradication may improve insulin resistance and arterial stiffness.

Effect of statin therapy on plasma proprotein convertase subtilisin kexin 9 (PCSK9) concentrations: a systematic review and meta-analysis of clinical trials.

AIMS: To evaluate the magnitude of the effect of statin therapy on plasma proprotein convertase subtilisin kexin 9 (PCSK9) levels through a systematic review and meta-analysis of clinical trials. METHODS: A random-effects model (using DerSimonian-Laird method) and the generic inverse variance method were used for quantitative data synthesis. Heterogeneity was quantitatively assessed using the I(2) index. Sensitivity analyses were conducted using the one-study remove approach. Random-effects meta-regression was performed using an unrestricted maximum likelihood method to evaluate the association between statin-induced elevation of plasma PCSK9 concentrations with duration of treatment and magnitude of LDL cholesterol reduction. RESULTS: A total of 15 clinical trials examining the effects of statin therapy on plasma PCSK9 levels were included. Meta-analysis of data from single-arm statin treatment arms [weighted mean difference (WMD) 40.72 ng/ml, 95% confidence interval (CI) 34.79, 46.65; p < 0.001] and randomized placebo-controlled trials (WMD 22.98 ng/ml, 95% CI 17.95, 28.01; p < 0.001) showed a significant increase in plasma PCSK9 concentrations after statin therapy, irrespective of the type of statin administered in either of the analyses (single-arm or randomized placebo-controlled trial). There was no significant elevation of plasma PCSK9 levels with statin/ezetimibe combination therapy compared with statin monotherapy (WMD 23.14 ng/ml, 95% CI -1.97, 48.25; p = 0.071); however, removal of one study in the meta-analysis yielded a significant result in the sensitivity analysis (WMD 31.41 ng/ml, 95% CI 7.86, 54.97; p = 0.009). CONCLUSIONS: This meta-analysis suggests that statin therapy causes a significant increase in plasma PCSK9 concentrations.

Fn14 receptor promotes invasive potential and metastatic capacity of non-small lung adenocarcinoma cells through the up-regulation of integrin α6.

UNLABELLED: Lung cancer is one of the leading cause of cancer-related death around the world with the majority of diagnoses being non-small cell lung cancer (NSCLC). Given the poor survival rate and efficacy of current therapy for NSCLC, there is a need to identify and develop new therapeutic targets for treatment. We have observed significantly up-regulated levels of Fn14 in clinical samples of lung cancer relative to normal adjacent tissue. However, the functional role of Fn14 in these tumors is not understood yet. We used RT-PCR to establish the Fn14 expression profile in various NSCLC cell lines. Using isogenic variants of H460 NSCLC cell line with low, intermediate and high Fn14 expression as a cellular model, we determined that increased levels of integrin α6 in cells over-expressing Fn14 is suggestive of an important role of α6ß1-fn14 interactions in motility of lung carcinoma and formation of metastases. Enhanced levels of Fn14 correlated with higher tumor cell migration and invasion in an MMP-1 dependent manner. Cells over-expressing Fn14 showed increased in vivo tumor formation with metastatic capacity to lymph nodes, lungs and liver. Thus, this research may be a step toward developing improved treatment strategies for NSCLC by improved detection and inhibition of metastases. KEYWORDS: Fn14, TNFRSF12A, non-small cell lung cancer, H460 cells, motility, tumor formation and metastasis, integrin α6.

Clinical guidelines on hyperlipidaemia: recent developments, future challenges and the need for an Australian review.

Large reductions in cardiovascular disease (CVD) mortality have been achieved over the last 50 years in developed countries. The health policies that have contributed so much to this success have largely been coordinated by means of expert guidelines for the management of the classic modifiable risk factors such as blood pressure, diabetes and blood lipids. National and international guidelines for lipid management have demonstrated a high degree of consistency between numerous sets of recommendations. It has been argued that some important components of the consensus that has been established over the past decade have been challenged by the latest guidelines of the American Heart Association - American College of Cardiologists (AHA-ACC). Clinicians can be reassured that continued reliance on extensive scientific evidence has reaffirmed the importance of lipid metabolism as a modifiable risk factor for atherosclerotic cardiovascular disease. On the other hand, the recent AHA-ACC guidelines suggest changes in the strategies by which metabolic risk factors may be modified. This small number of important changes should not be sensationalised because these differences usefully reflect the need for guidelines to evolve to accommodate different contexts and changing perspectives as well as emerging issues and new information for which clinical trial evidence is incomplete. This article will consider the recent policies and responses of national and supranational organisations on topics including components of CVD risk assessment, sources of CVD risk information and re-appraisal of lipid-lowering interventions. Timely review of Australian lipid management guidelines will require consideration of these issues because they are creating a new context within which new guidelines must evolve.

Association between skeletal muscle fat content and very-low-density lipoprotein-apolipoprotein B-100 transport in obesity: effect of weight loss.

AIMS: Ectopic deposition of fat in skeletal muscle is a feature of metabolic syndrome, but its specific association with very-low-density lipoprotein (VLDL)-apolipoprotein (apo) B-100 metabolism remains unclear. METHODS: We examined the association between skeletal muscle fat content and VLDL-apoB-100 kinetics in 25 obese subjects, and the responses of these variables to weight loss. The fat contents of liver, abdomen and skeletal muscle were determined by magnetic resonance imaging, and VLDL-apoB-100 kinetics were assessed using stable isotope tracers. RESULTS: In obese subjects who were insulin sensitive (homeostasis model assessment, HOMA, score ≤ 2.6, n = 12), skeletal muscle fat content was significantly associated with hepatic fat content (r = 0.636), energy intake (r = 0.694), plasma triglyceride (r = 0.644), apoB-100 (r = 0.529), glucose (r = 0.622), VLDL-apoB-100 concentrations (r = 0.860), VLDL-apoB-100 fractional catabolic rate (FCR; r = -0.581) and VLDL-apoB-100 secretion rate (r = 0.607). These associations were not found in obese subjects who were insulin resistant (HOMA score >2.6, n = 13). Of these 25 subjects, 10 obese subjects underwent a 16-week weight loss program. The low-fat diet achieved significant reduction (p < 0.05) in body weight, visceral and subcutaneous fat areas, liver and skeletal muscle fat, energy intake, triglyceride, insulin, HOMA score, VLDL-apoB100 concentrations and VLDL-apoB100 secretion rate. The percentage reduction of skeletal muscle fat with weight loss was significantly associated with the corresponding changes in VLDL-apoB100 concentration (r = 0.770, p = 0.009) and VLDL-apoB-100 secretion (r = 0.682, p = 0.030). CONCLUSIONS: Skeletal muscle fat content is associated with VLDL-apoB-100 transport. Weight loss lowers skeletal muscle fat and VLDL-apoB-100 secretion.

Atorvastatin plus omega-3 fatty acid ethyl ester decreases very-low-density lipoprotein triglyceride production in insulin resistant obese men.

AIM: To test the effect of atorvastatin (ATV) and ATV plus ω-3 FAEEs on VLDL-TG metabolism in obese, insulin resistant men. METHODS: We carried out a 6-week randomized, placebo-controlled study to examine the effect of ATV (40 mg/day) and ATV plus ω-3 FAEEs (4 g/day) on VLDL-TG metabolism in 36 insulin resistant obese men. VLDL-TG kinetics were determined using d5 -glycerol, gas chromatography-mass spectrometry and compartmental modelling. RESULTS: Compared with the placebo, ATV significantly decreased VLDL-TG concentration (-40%, p < 0.001) by increasing VLDL-TG fractional catabolic rate (FCR) (+47%, p < 0.01). ATV plus ω-3 FAEEs lowered VLDL-TG concentration to a greater degree compared with placebo (-46%, p < 0.001) or ATV monotherapy (-13%, p = 0.04). This was achieved by a reduction in VLDL-TG production rate (PR) compared with placebo (-32%, p = 0.008) or ATV (-20%, p = 0.03) as well as a reciprocal increase in VLDL-TG FCR (+42%, p < 0.05) compared with placebo. CONCLUSION: In insulin resistant, dyslipidaemic, obese men, ATV improves VLDL-TG metabolism by increasing VLDL-TG FCR. The addition of 4 g/day ω-3 FAEE to statin therapy provides further TG-lowering by lowering VLDL-TG PR.

Genotype-phenotype studies of VCP-associated inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia.

Valosin containing protein (VCP) disease associated with inclusion body myopathy, Paget disease of the bone and frontotemporal dementia is a progressive autosomal dominant disorder caused by mutations in Valosin containing protein gene. To establish genotype-phenotype correlations we analyzed clinical and biochemical markers from a database of 190 members in 27 families harboring 10 missense mutations. Individuals were grouped into three categories: symptomatic, presymptomatic carriers and noncarriers. The symptomatic families were further divided into ten groups based on their VCP mutations. There was marked intra and inter-familial variation; and significant genotype-phenotype correlations were difficult to establish because of small numbers. Nevertheless when comparing the two most common mutations, R155C mutation was found to be more severe, with an earlier onset of myopathy and Paget (p = 0.03). Survival analysis of all subjects revealed an average life span after diagnosis of myopathy and Paget of 18 and 19 years respectively, and after dementia only 6 years. R155C had a reduced survival compared to the R155H mutation (p = 0.03).We identified amyotrophic lateral sclerosis (ALS) was diagnosed in 13 individuals (8.9%) and Parkinson's disease in five individuals (3%); however, there was no genotypic correlation. This study represents the largest dataset of patients with VCP disease and expands our understanding of the natural history and provides genotype-phenotype correlations in this unique disease.

Postprandial hypertriglyceridemia and cardiovascular disease: current and future therapies.

Exaggerated postprandial hypertriglyceridemia is a risk factor for cardiovascular disease. This metabolic abnormality is principally due to overproduction and/or decreased catabolism of triglyceride-rich lipoproteins (TRLs) and is a consequence of pathogenic genetic variations and other coexistent medical conditions, particularly obesity and insulin resistance. Accumulation of TRL in the postprandial state promotes the formation of small, dense low-density lipoproteins, as well as oxidative stress, inflammation, and endothelial dysfunction, all of which compound the risk of cardiovascular disease. The cardiovascular benefits of lifestyle modification (weight loss and exercise) and conventional lipid-lowering therapies (statins, fibrates, niacin, ezetimibe, and n-3 fatty acid supplementation) could involve their favorable effects on TRL metabolism. New agents, such as dual peroxisome-proliferator-activated receptor α/δ agonists, diacylglycerol, inhibitors of diacylglycerol acyltransferase 1 and microsomal triglyceride transfer protein, antisense oligonucleotides for apolipoprotein B-100 and apolipoprotein C-III, and incretin-based therapies, may enhance the treatment of postprandial lipemia, but their efficacy needs to be tested in clinical end point trials. Further work is required to develop a simple clinical protocol for investigating postprandial lipemia, as well as internationally agreed management guidelines for this type of dyslipidemia.