Relationship between homocysteine and cardiorespiratory fitness is sex-dependent

Elevated plasma homocysteine is recognized as an independent risk factor for cardiovascular disease. Recently, there have been conflicting reports of the relationship between physical activity and homocysteine. A more objective measure of physical activity is cardiorespiratory fitness; however, its relationship with homocysteine has yet to be investigated. The aim of this study was to determine the relationship between cardiorespiratory fitness and plasma homocysteine. Cross-sectional associations between cardiorespiratory fitness (VO(2)max) and plasma homocysteine were examined in 49 men and 11 women. A submaximal bicycle test was used to determine VO(2)max and plasma homocysteine was measured using high performance liquid chromatography with fluorescence detection. Dietary analysis determined B vitamin intake. There was a significant inverse relationship between plasma homocysteine concentration and VO(2)max in women (r = -0.81, P = 0.003) but not in men (r = -0.09, P = 0.95). There were no significant relationships between plasma homocysteine and age, BMI, body fat, total cholesterol, and LDL cholesterol. In summary, elevated cardiorespiratory fitness is associated with decreased plasma homocysteine concentrations in women. (C) 2004 Elsevier Inc. All rights reserved.

Pioglitazone increases renal tubular cell albumin uptake but limits proinflammatory and fibrotic responses

Background. Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. which are known to be critical factors in lipid metabolism, have also been reported to reduce proteinuria. The mechanism and its relevance to progressive nephropathy have not been determined. The aims of this study were to assess the direct effects of a PPARgamma agonist on tubular cell albumin uptake, proinflammatory and profibrotic markers of renal pathology, using an opossum kidney model of proximal tubular cells. Methods. Cells were exposed to pioglitazone (10 mumol/L) in the presence and absence of low-density lipoprotein (LDL) 100 mug/mL +/- exposure to albumin 1 mg/mL. Results were expressed relative to control (5 mmol/L glucose) conditions. Results. Pioglitazone caused a dose-dependent increase in tubular cell albumin uptake (P < 0.0001). Despite the increase in albumin reabsorption, no concurrent increase in inflammatory or profibrotic markers were observed. Exposure to LDL increased monocyte chemoattractant protein-1 (MCP-1) (P < 0.05) and transforming growth factor-beta1 (TGF-beta1) (P < 0.05) production. which were reversed in the presence of pioglitazone. LDL induced increases in MCP-1 and TGF-β1 were independent of nuclear factor-κB (NF-κB) transcriptional activity. In contrast. tubular exposure to albumin increased tubular protein uptake, in parallel with an increase in MCP-1 (P = 0.05): TGF-β1 (P < 0.02) and NF-kappaB transcriptional activity (P < 0.05). which were unaffected by concurrent exposure to pioglitazone. Conclusion. These findings suggest that dyslipidemia potentiates renal pathology through mechanisms that may be modified PPARγ activation independent of NF-κB transcriptional activitv. In contrast, tubular exposure to protein induces renal damage through NF-κB-dependent mechanisms that are Unaffected by PPARγ activation.

Carotid artery intimal medial thickness, brachial artery flow-mediated vasodilation and cardiovascular risk factors in diabetic and non-diabetic indigenous Australians

Background: Indigenous Australians are at high risk for cardiovascular disease and type 2 diabetes. Carotid artery intimal medial thickness (CIMT) and brachial artery flow-mediated vasodilation (FMD) are ultrasound imaging based surrogate markers of cardiovascular risk. This study examines the relative contributions of traditional cardiovascular risk factors on CIMT and FMD in adult Indigenous Australians with and without type 2 diabetes mellitus. Method: One hundred and nineteen Indigenous Australians were recruited. Physical and biochemical markers of cardiovascular risk, together with CIMT and FMD were meausred for all subjects. Results: Fifty-three Indigenous Australians subjects (45%) had type 2 diabetes mellitus. There was a significantly greater mean CIMT in diabetic versus non-diabetic subjects (p = 0.049). In the non-diabetic group with non-parametric analyses, there were significant correlations between CIMT and: age (r = 0.64, p < 0.001), systolic blood pressure (r = 0.47, p < 0.001) and non-smokers (r = -0.30, p = 0.018). In the diabetic group, non-parametric analysis showed correlations between CIMT, age (r = 0.36, p = 0.009) and duration of diabetes (r = 0.30, p = 0.035) only. Adjusting forage, sex, smoking and history of cardiovascular disease, Hb(A1c) became the sole significant correlate of CIMT (r = 0.35,p = 0.01) in the diabetic group. In non-parametric analysis, age was the sole significant correlate of FMD (r = -0.31,p = 0.013), and only in non-diabetic subjects. Linear regression analysis showed significant associations between CIMT and age (t = 4.6,p < 0.001), systolic blood pressure (t = 2.6, p = 0.010) and Hb(A1c) (t = 2.6, p = 0.012), smoking (t = 2.1, p = 0.04) and fasting LDL-cholesterol (t = 2.1, p = 0.04). There were no significant associations between FMD and examined cardiovascular risk factors with linear regression analysis Conclusions: CIMT appears to be a useful surrogate marker of cardiovascular risk in this sample of Indigenous Australian subjects, correlating better than FMD with established cardiovascular risk factors. A lifestyle intervention programme may alleviate the burden of cardiovascular disease in Indigenous Australians by reducing central obesity, lowering blood pressure, correcting dyslipidaemia and improving glycaemic control. CIMT may prove to be a useful tool to assess efficacy of such an intervention programme. (c) 2004 Elsevier Ireland Ltd. All rights reserved.

Berberine - a novel approach to cholesterol lowering

Although low-density lipoprotein (LDL)-cholesterol lowering with the statins reduces the mortality and morbidity associated with coronary artery disease, considerable mortality and morbidity remains. Berberine upregulates the LDL receptor (LDLR) by a mechanism distinct from that of the statins, which involves stabilising the LDLR mRNA. In hamsters fed a high-fat and high-cholesterol diet for 2 weeks, the oral administration of berberine 100 mg/kg for 10 days reduced total serum cholesterol from &SIM; 4.8 to 2.7 mmol/l, and LDL-cholesterol from &SIM; 2.5 to 1.4 mmol/l. In subjects with hypercholesterolaemia, berberine hydrochloride (0.5 g b.i.d. for 3 months) reduced LDL-cholesterol (from 3.2 to 2.4 mmol/l) without any effect on high-density lipoprotein-cholesterol. Berberine also caused a reduction in triglyceride levels from 2.3 to 1.5 mmol/l. As berberine and statins both upregulate LDLR, their lipid-lowering profiles are similar. Thus, this mechanism is unlikely to make berberine an attractive alternative to statins for lipid lowering in most circumstances. However, the other effects of berberine (anti hypertensive, inotropic and class III antiarrhythmic properties) may make it a useful agent in the treatment of cardiovascular disease.

Inhibitors of cholesteryl ester transfer protein - a step forward in the treatment of coronary artery disease?

Although the LDL cholesterol-lowering statins have reduced the mortality and morbidity associated with coronary artery disease (CAD), considerable mortality and morbidity remains. Increasing HDL cholesterol levels is associated with reduced CAD mortality and morbidity. In healthy subjects with mild dyslipidemia, treatment with JTT-705 decreased cholesteryl ester transfer protein (CETP) activity, increased HDL cholesterol and decreased LDL cholesterol. Similarly, another CETP inhibitor, torcetrapib, has recently been shown to increase HDL cholesterol by 46%, decrease LDL cholesterol by 8% and have no effect on triglycerides in subjects with HDL cholesterol levels below 1.0 mmol/l. Increasing HDL cholesterol with inhibitors of CETP represents a new approach to dyslipidemia that requires further investigation, especially in patients with CAD.

Butyrylcholinesterase: Association with the metabolic syndrome and identification of 2 gene loci affecting activity

Background: Plasma cholinesterase activity is known to be correlated with plasma triglycerides, HDL- and LDL-cholesterol, and other features of the metabolic syndrome. A role in triglyceride metabolism has been proposed. Genetic variants that decrease activity have been studied extensively, but the factors contributing to overall variation in the population are poorly understood. We studied plasma cholinesterase activity in a sample of 2200 adult twins to assess covariation with cardiovascular risk factors and components of the metabolic syndrome, to determine the degree of genetic effects on enzyme activity, and to search for quantitative trait loci affecting activity. Methods and Results: Cholinesterase activity was lower in women than in men before the age of 50, but increased to activity values similar to those in males after that age. There were highly significant correlations with variables associated with the metabolic syndrome: plasma triglyceride, HDL- and LDL-cholesterol, apolipoprotein B and E, urate, and insulin concentrations; gamma-glutamyltransferase and aspartate and alanine aminotransferase activities; body mass index; and blood pressure. The heritability of plasma cholinesterase activity was 65%. Linkage analysis with data from the dizygotic twin pairs showed suggestive linkage on chromosome 3 at the location of the cholinesterase WHO gene and also on chromosome 5. Conclusions: Our results confirm and extend the connection between cholinesterase, cardiovascular risk factors, and metabolic syndrome. They establish a substantial heritability for plasma cholinesterase activity that might be attributable to variation near the structural gene and at an independent locus. (c) 2006 American Association for Clinical Chemistry.

Baseline serum lipids and renal function in chronic kidney disease patients entering the LORD trial

Objective: Previous studies investigating associations between serum lipids and renal disease have generally not taken into account dietary intake or physical activity - both known to influence circulating lipids. Furthermore, inclusion of patients on HMG-CoA reductase inhibitors may also have influenced findings due to the pleiotropic effect of this medication. Therefore, the aim of this study is to determine the relationships between serum lipids and renal function in a group of patients not taking lipid-lowering medication and taking into account dietary intake and physical activity. Methods: Data from 100 patients enrolled in the Lipid Lowering and Onset of Renal Disease (LORD) trial were used in this study. Patients were included with serum creatinine > 120 mu mol/l, and excluded if they were taking lipid-lowering medication. Unadjusted and adjusted relationships were determined between fasting serum lipid concentrations (total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol/HDL ratio) and measures of renal function (estimated glomerular filtration rate (eGFR), creatinine clearance and serum creatinine) and urinary protein excretion. Results: Significant (p < 0.05) negative unadjusted relationships were found between lipids (total cholesterol, LDL and HDL cholesterol) and serum creatinine. In support of these findings, logarithmically-transformed lipids (total cholesterol, LDL and HDL cholesterol) were significantly associated with eGFR and creatinine clearance although the effects were of a smaller magnitude. Adjustment for dietary saturated fat intake and physical activity did not substantially change these effects. Conclusion: These data do not support the premise that lipids are associated with renal dysfunction in patients with normocholesterolemia.

Ultra-endurance exercise and oxidative damage: Implications for cardiovascular health

At least 30 minutes of moderate-intensity physical activity accumulated on most, preferably all days is considered the minimum level necessary to reduce the risk of developing cardiovascular disease. Despite an unclear explanation, some epidemiological data paradoxically suggest that a very high volume of exercise is associated with a decrease in cardiovascular health. Although ultra-endurance exercise training has been shown to increase antioxidant defences (and therefore confer a protective effect against oxidative stress), an increase in oxidative stress may contribute to the development of atherosclerosis via oxidative modification of low-density lipoprotein (LDL). Research has also shown that ultra-endurance exercise is associated with acute cardiac dysfunction and injury, and these may also be related to an increase in free radical production. Longitudinal studies are needed to assess whether antioxidant defences are adequate to prevent LDL oxidation that may occur as a result of increased free radical production during very high volumes of exercise. In addition, this work will assist in understanding the accrued effect of repeated ultra-endurance exercise-induced myocardial damage.

Longitudinal Genetic Analysis of Plasma Lipids

The consensus from published studies is that plasma lipids are each influenced by genetic factors, and that this contributes to genetic variation in risk of cardiovascular disease. Heritability estimates for lipids and lipoproteins are in the range .48 to .87, when measured once per study participant. However, this ignores the confounding effects of biological variation measurement error and ageing, and a truer assessment of genetic effects on cardiovascular risk may be obtained from analysis of longitudinal twin or family data. We have analyzed information on plasma high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides, from 415 adult twins who provided blood on two to five occasions over 10 to 17 years. Multivariate modeling of genetic and environmental contributions to variation within and across occasions was used to assess the extent to which genetic and environmental factors have long-term effects on plasma lipids. Results indicated that more than one genetic factor influenced HDL and LDL components of cholesterol, and triglycerides over time in all studies. Nonshared environmental factors did not have significant long-term effects except for HDL. We conclude that when heritability of lipid risk factors is estimated on only one occasion, the existence of biological variation and measurement errors leads to underestimation of the importance of genetic factors as a cause of variation in long-term risk within the population. In addition our data suggest that different genes may affect the risk profile at different ages.