Showing papers by "Gerald F. Watts published in 2009"

Omega-3 fatty acid supplementation decreases liver fat content in polycystic ovary syndrome: a randomized controlled trial employing proton magnetic resonance spectroscopy.

Abstract: Context: There is an association between nonalcoholic fatty liver disease (NAFLD) and the polycystic ovary syndrome (PCOS). Marine-derived omega-3 fatty acids have favorable effects on cardiovascular risk and could reduce liver fat in NAFLD. Objective: The primary aim of this study was to examine the effects of omega-3 fatty acids on liver fat in PCOS. The secondary aim was to assess their effects on traditional cardiovascular risk factors. Design and Setting: We conducted a randomized, crossover study at a tertiary cardiovascular research center. Subjects: Twenty-five women with PCOS (mean age, 32.7 yr; mean body mass index, 34.8 kg/m2) participated in the study. Intervention: We compared 4g/d of omega-3 fatty acids with placebo over 8 wk. Main Outcome Measures: The primary outcome measure was hepatic fat content quantified using proton magnetic resonance spectroscopy. Secondary outcome measures included fasting lipids and blood pressure. Results: Omega-3 fatty acids significantly decreased liver fat con...

Non-adherence to statin therapy: a major challenge for preventive cardiology.

Abstract: Background: Hypercholesterolemia is a major risk factor for atherosclerosis and cardiovascular disease, the leading cause of death worldwide. In the last twenty years, effective lipid-lowering therapies, particularly statins, have become widely available to prevent and reverse the progression of disease. However, there is a significant gap between expected and actual benefits; this may be attributed to poor adherence to statin therapy. Objective: To define the extent, causes (including psychological aspects), consequences and management of non-adherence to statins. Methods: Literature using PubMed and Medline up to and including 30 July 2009. Results: Adherence to statin therapy is suboptimal in both primary and secondary prevention of cardiovascular disease. Causes vary, and include patient factors (e.g., comorbidities, financial constraints, psychological issues), practitioner factors (e.g., poor knowledge of adherence, time constraints, poor communication skills and patient–doctor working alliance) and...

Coenzyme Q10 Improves Endothelial Dysfunction in Statin-Treated Type 2 Diabetic Patients

Abstract: OBJECTIVE The vascular benefits of statins might be attenuated by inhibition of coenzyme Q10 (CoQ10) synthesis. We investigated whether oral CoQ10 supplementation improves endothelial dysfunction in statin-treated type 2 diabetic patients. RESEARCH DESIGN AND METHODS In a double-blind crossover study, 23 statin-treated type 2 diabetic patients with LDL cholesterol <2.5mmol/l and endothelial dysfunction (brachial artery flow-mediated dilatation [FMD] <5.5%) were randomized to oral CoQ10 (200 mg/day) or placebo for 12 weeks. We measured brachial artery FMD and nitrate-mediated dilatation (NMD) by ultrasonography. Plasma F2-isoprostane and 24-h urinary 20-hydroxyeicosatetraenoic acid (HETE) levels were measured as systemic oxidative stress markers. RESULTS Compared with placebo, CoQ10 supplementation increased brachial artery FMD by 1.0 ± 0.5% ( P = 0.04), but did not alter NMD ( P = 0.66). CoQ10 supplementation also did not alter plasma F2-isoprostane ( P = 0.58) or urinary 20-HETE levels ( P = 0.28). CONCLUSIONS CoQ10 supplementation improved endothelial dysfunction in statin-treated type 2 diabetic patients, possibly by altering local vascular oxidative stress.

The effects of [omega]3 fatty acids and coenzyme Q10 on blood pressure and heart rate in chronic kidney disease: a randomized controlled trial.

Abstract: Results Eighty-five patients aged 56.5W1.4 years; BMI 27.3W0.5kg/m 2 ; supine blood pressure 125.0/72.3mmHg; and glomerular filtration rate 35.8W1.2ml/min/1.73m 2 , were randomized. Seventy-four completed the study. v3FA, but not CoQ, reduced 24-h ambulatory heart rate (P<0.0001) and blood pressure (P<0.0001). Main effects for v3FA on 24-h measurements were S3.3W0.7/ S2.9W0.5mmHg and S4.0W0.5bpm. Postintervention blood pressure showed significant interactions between treatments. v3FA reduced triglycerides 24% (P<0.001). There were no changes in glomerular filtration rate, urinary albumin or total protein excretion, cholesterol, HDLcholesterol (C), LDL-C, glucose, insulin, or high-sensitivity C-reactive protein. Conclusion This study has shown that v3FA reduce blood pressure, heart rate and triglycerides in patients with CKD. CoQ had no independent effect on blood pressure but increased heart rate. These results show that v3FA lower blood pressure and may reduce cardiovascular risk in nondiabetic patients with moderate-to-severe CKD. J Hypertens 27:1863‐1872 Q 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Plasma Proprotein Convertase Subtilisin/Kexin Type 9: A Marker of LDL Apolipoprotein B-100 Catabolism?

Abstract: Background: Experimental studies suggest that proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important regulator of LDL metabolism because of its ability to facilitate degradation of the LDL receptor. We investigated the association between plasma PCSK9 concentration and LDL apolipoprotein B-100 (apo B-100) metabolism in men with a wide range of body mass index values. Methods: We used GC-MS to study the kinetics of LDL apo B-100 after intravenous administration of deuterated leucine and analyzed the data by compartmental modeling. The plasma PCSK9 concentration was measured by ELISA. Results: Univariate regression analysis revealed the plasma PCSK9 concentration to be significantly and positively correlated with cholesterol ( r = 0.543; P = 0.011), LDL cholesterol ( r = 0.543; P = 0.011), apo B-100 ( r = 0.548; P = 0.010), and LDL apo B-100 concentrations ( r = 0.514; P = 0.023), and inversely correlated with the LDL apo B-100 fractional catabolic rate (FCR) ( r = −0.456; P = 0.038). The association between plasma PCSK9 concentration and the LDL apo B-100 FCR remained statistically significant after adjusting for age, obesity, plasma insulin, homeostasis model assessment score, and dietary energy; however, this association had borderline significance after adjusting for plasma lathosterol. Conclusions: In men, variation in plasma PCSK9 concentration influences the catabolism of LDL apo B-100. This finding appears to be independent of obesity, insulin resistance, energy intake, and age.

CD1a expression defines an interleukin-12 producing population of human dendritic cells.

Abstract: Human and murine dendritic cell (DC) subsets are often defined by phenotypic features that predict their functional characteristics. In humans and mice, DC have been shown to have the ability to polarize naive CD4 T cells to a T helper type 1 (Th1) or Th2 phenotype. However, human myeloid DC generated from monocytes (monocyte-derived DC) have often been regarded as a homogeneous population, both phenotypically and functionally. Monocytes give rise to subpopulations of DC in vitro that can be separated on the basis of their expression of CD1a, a well-described DC subset marker. Importantly, we show that the CD1a(+) DC subset produces significant quantities of interleukin-12p70 (IL-12p70) upon stimulation and, similar to the murine CD8 alpha(+) DC subset, can polarize naive CD4(+) T cells to a Th1 phenotype. In contrast, CD1a(-) DC, similar to murine CD8 alpha(-) DC, do not produce significant amounts of IL-12p70 upon stimulation or polarize T cells to a Th1 phenotype. Like monocyte-derived DC, CD1a(+) and CD1a(-) DC subsets obtained from CD34(+) haematopoietic progenitors under distinct culture conditions were found to have these same features, suggesting that CD1a expression is a marker for myeloid DC that are a major source of IL-12 and Th1 CD4(+) T cell polarization in man.

Very Low Density Lipoprotein Metabolism and Plasma Adiponectin as Predictors of High-Density Lipoprotein Apolipoprotein A-I Kinetics in Obese and Nonobese Men

Abstract: Context: Hypercatabolism of high-density lipoprotein (HDL) apolipoprotein (apo) A-I results in low plasma apoA-I concentration. The mechanisms regulating apoA-I catabolism may relate to alterations in very low density lipoprotein (VLDL) metabolism and plasma adiponectin and serum amyloid A protein (SAA) concentrations. Objective: We examined the associations between the fractional catabolic rate (FCR) of HDL-apoA-I and VLDL kinetics, plasma adiponectin, and SAA concentrations. Study Design: The kinetics of HDL-apoA-I and VLDL-apoB were measured in 50 obese and 37 nonobese men using stable isotopic techniques. Results: In the obese group, HDL-apoA-I FCR was positively correlated with insulin, homeostasis model of assessment for insulin resistance (HOMA-IR) score, triglycerides, VLDL-apoB, and VLDL-apoB production rate (PR). In the nonobese group, HDL-apoA-I FCR was positively correlated with triglycerides, apoC-III, VLDL-apoB, and VLDL-apoB PR and negatively correlated with plasma adiponectin. Plasma SAA w...

Dissociation of endothelial function and arterial stiffness in nonobese women with polycystic ovary syndrome (PCOS)

Abstract: Summary Objective Polycystic ovary syndrome (PCOS) is associated with cardiovascular risk but it is not clear if this is independent of obesity and insulin resistance. This study therefore investigates endothelial function and arterial stiffness in nonobese, noninsulin resistant women with PCOS. Design This is cross-sectional case–control study. Patients A total of 19 young women with PCOS, with body mass index (BMI) <30 kg/m2, and 19 healthy controls matched for age and BMI were included in the study. Measurements Endothelial function was assessed with flow mediated dilatation (FMD) of the brachial artery, while arterial stiffness was assessed with pulse wave velocity (PWV) and augmentation index (AI). Results There were no significant differences between PCOS and control subjects when assessing the following clinical and biochemical variables: blood pressure, homeostasis model assessment insulin-resistance index, lipids and oestradiol. Women with PCOS had higher free androgen index scores (5·14 ± 3·47 vs. 3·25 ± 1·42, P = 0·036). The PCOS subjects had significantly lower FMD of the brachial artery compared with the controls (6·5 ± 2·9%vs. 10·5 ± 4·0%, P < 0·01). There were no significant differences in markers of arterial stiffness (PWV 5·8 ± 1·1 vs. 6·0 ± 1·0, P = 0·58, AI 16·5 ± 10·2 vs. 20·3 ± 10·2, P = 0·25). Conclusions Women with polycystic ovary syndrome who are young, nonobese, and have no biochemical evidence of insulin resistance, have abnormal vascular function, but normal arterial stiffness, when compared with age and weight matched control subjects. Whether this leads to a greater risk of cardiovascular disease requires further investigation.

Severe HDL deficiency due to novel defects in the ABCA1 transporter.

Abstract: . Objectives. The objective was the identification and functional characterization of mutations in the ABCA1 gene in four patients with severe HDL deficiency. Subjects. Patients were referred to the clinic because of almost complete HDL deficiency. Methods. The ABCA1 gene was sequenced directly. The analysis of the ABCA1 protein, ABCA1 mRNA and ABCA1-mediated cholesterol efflux was performed in cultured fibroblasts. Intracellular localization of ABCA1 mutants was investigated in transfected HEK293 cells. Results. Two patients were homozygous for mutations in the coding region of the ABCA1 gene, resulting in an amino acid substitution (p.A1046D) and a truncated protein (p.I74YFsX76). The third patient was homozygous for a splice site mutation in intron 35 (c.4773 + 1g>a), resulting in an in-frame deletion of 25 amino acids (del p.D1567_K1591) in ABCA1. These patients had clinical manifestations of accumulation of cholesterol in the reticulo-endothelial system. The fourth patient, with preclinical atherosclerosis, was a compound heterozygote for two missense mutations (p.R587W/p.W1699C). ABCA1-mediated cholesterol efflux was abolished in fibroblasts from patients with p.A1046D and del p.D1567_K1591 mutants and in fibroblasts homozygous for p.R587W. A reduced ABCA1 protein content was observed in these cells, suggesting an increased intracellular degradation. The mutant p.W1699C was largely retained in the endoplasmic reticulum, when expressed in HEK293 cells. Conclusions. The homozygotes for mutations which abolish ABCA1 function showed overt signs of involvement of the reticulo-endothelial system. This was not the case in the compound heterozygote for missense mutations, suggesting that this patient retains some residual ABCA1 function that reduces cholesterol accumulation in the reticulo-endothelial system.

Regulatory Effects of Fenofibrate and Atorvastatin on Lipoprotein A-I and Lipoprotein A-I:A-II Kinetics in the Metabolic Syndrome

Abstract: Objectives- Subjects with the metabolic syndrome (MetS) have reduced HDL concentration and altered metabolism of HDL Lipoprotein (Lp) A-I and LpA-I:A-II particles. In MetS, fenofibrate and atorvastatin may have differential effects on HDL particle kinetics. Research Design and Methods- Eleven men with MetS were studied in a randomized double-blinded crossover trial of 5-week intervention periods with placebo, fenofibrate (200mg/day) and atorvastatin (40mg/day). LpA-I and LpA-I:A-II kinetics were examined using stable isotopic techniques and compartmental modelling. Results- Compared with placebo, fenofibrate significantly increased the production of both LpA-I:A-II (+30%, P<0.001) and apoA-II (+43%, P < 0.001), accounting for significant increases of their corresponding plasma concentrations (+10% and +23% respectively), but it did not alter LpA-I kinetics or concentration. Atorvastatin did not significantly alter HDL-cholesterol concentration or the kinetics of HDL particles. Conclusions- In MetS, fenofibrate, but not atorvastatin, influences HDL metabolism by increasing the transport of LpA-I:A-II particles.

Effect of weight loss on HDL-apoA-II kinetics in the metabolic syndrome.

Abstract: Reduced HDL (high-density lipoprotein) concentration in the MetS (metabolic syndrome) is associated with increased risk of cardiovascular disease and is related to defects in HDL-apoA-II (apolipoprotein A-II) kinetics. Dietary restriction is the most commonly used weight loss strategy. In the present study, we examined the effect of weight loss on HDL-apoA-II kinetics in men with the MetS at the start and end of a 16-week intervention trial of a hypocaloric low-fat diet (n=20) compared with a weight maintenance diet (n=15), using a stable isotope technique and compartmental modelling. The low-fat diet achieved a significant reduction (P<0.01) in BMI (body mass index), abdominal fat compartments and HOMA (homoeostasis model assessment) score compared with weight maintenance. Weight loss also significantly (P<0.05) decreased both the production rate (-23%) and FCR (fractional catabolic rate) (-12%) of HDL-apoA-II, accounting for a net decrease in apoA-II concentration (-9%). Reductions in the HDL-apoA-II production rate were significantly associated with changes in body weight (r=0.683, P<0.01), plasma triacylglycerols (triglycerides) (r=0.607, P<0.01) and, to a lesser extent, plasma insulin (r=0.440, P=0.059) and HOMA-IR (HOMA of insulin resistance) (r=0.425, P=0.069). Changes in the apoA-II FCR were also significantly associated with reductions in visceral adipose tissue mass (r=0.561, P=0.010). In conclusion, in obese men with the MetS, short-term weight loss with a low-fat low-caloric diet lowers plasma apoA-II concentrations by decreasing both the production and catabolism of HDL-apoA-II. The cardiometabolic significance of this effect on HDL metabolism remains to be investigated further.

NICE Guidance on Familial Hypercholesterolaemia: All Sugar and Spice?

Abstract: Familial hypercholesterolaemia (FH), due to dominant mutations of genes affecting the function of the LDL receptor, is the most common and serious form of inherited hyperlipidaemia [1]. It accelerates the onset of all forms of atherosclerotic cardiovascular disease by one to four decades. There is evidence that opportunistic and cascade screening can detect individuals at an early stage of FH [2]. This is important because lifestyle measures and cholesterol-lowering drugs, particularly statins [2], [3], [4], can substantially decrease the risk of coronary disease in affected people. It is estimated that only 20% of FH cases have been diagnosed in most western healthcare systems, and only approximately 7% are adequately treated [4]. If anything, Australia and New Zealand lag behind these statistics [5]. A recent audit of hospital patients with premature coronary disease in Western Australia emphasised the large gap in the detection and management of FH [6].

LDL apheresis for familial hypercholesterolemia: value, indications and demand

Abstract: Gerald F Watts† †Author for correspondence: Professor & Director, Lipid Disorders Clinic, Royal Perth Hospital, School of Medicine & Pharmacology, University of Western Australia, GPO Box X2213, Perth, WA 6857, Australia Tel.: +61 89224 0245 Fax: +61 89224 0246 gerald.watts@uwa.edu.au Sandra J Hamilton Specialist Nurse, Lipid & Disorders Clinic, Royal Perth Hospital, University of Western Australia LDL apheresis for familial hypercholesterolemia: value, indications and demand