Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?

AIMS/HYPOTHESIS: Sphingolipid synthesis is typically initiated by the conjugation of L-serine and palmitoyl-CoA, a reaction catalysed by serine palmitoyltransferase (SPT). SPT can also metabolise other acyl-CoAs (C(12) to C(18)) and other amino acids such as L-alanine and glycine, giving rise to a spectrum of atypical sphingolipids. Here, we aimed to identify changes in plasma levels of these atypical sphingolipids to explore their potential as biomarkers in the metabolic syndrome and diabetes. METHODS: We compared the plasma profiles of ten sphingoid bases in healthy individuals with those of patients with the metabolic syndrome but not diabetes, and diabetic patients (n = 25 per group). The results were verified in a streptozotocin (STZ) rat model. Univariate and multivariate statistical analyses were used. RESULTS: Deoxysphingolipids (dSLs) were significantly elevated (p = 5 × 10⁻6) in patients with the metabolic syndrome (0.11 ± 0.04 µmol/l) compared with controls (0.06 ± 0.02 µmol/l) but did not differ between the metabolic syndrome and diabetes groups. Levels of C(16)-sphingosine-based sphingolipids were significantly lowered in diabetic patients but not in patients with the metabolic syndrome but without diabetes (p = 0.008). Significantly elevated dSL levels were also found in the plasma and liver of STZ rats. A principal component analysis revealed a similar or even closer association of dSLs with diabetes and the metabolic syndrome in comparison with the established biomarkers. CONCLUSIONS/INTERPRETATION: We showed that dSLs are significantly elevated in patients with type 2 diabetes mellitus and non-diabetic metabolic syndrome compared with healthy controls. They may, therefore, be useful novel biomarkers to improve risk prediction and therapy monitoring in these patients.

Hypoxia induces apelin expression in human adipocytes.

Adipokines play a central role in the development of diseases associated with insulin resistance and obesity. Hypoxia in adipose tissue leads to a dysregulation of the expression of adipokines. The effect of hypoxia on the more recently identified adipokine apelin in human adipocytes is unclear. Therefore, we aimed at investigating the role of hypoxia on the expression of the adipokine apelin. Differentiated human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were cultured under hypoxic conditions for varying time periods. A modular incubator chamber was used to create a hypoxic tissue culture environment (defined as 1% O(2), 94% N, and 5% CO(2)). In addition, hypoxic conditions were mimicked by using CoCl(2). The effect of hypoxia on the expression of the investigated adipokines was measured by real-time PCR and the secretion of apelin was quantified by ELISA. Induction of hypoxia significantly induced mRNA expression of leptin and apelin in differentiated SGBS adipocytes compared with the normoxic control condition. Expression of adiponectin was significantly decreased by hypoxia. In addition, the amount of secreted apelin protein in response to hypoxia was elevated compared to untreated cells. Furthermore, we could demonstrate that the observed hypoxia-induced induction of apelin mRNA expression is in the first phase dependent on HIF-1α. In our study, we could demonstrate for the first time that apelin expression and secretion by human adipocytes are strongly induced under hypoxic conditions and that the early response on hypoxia with apelin induction is dependent on HIF-1α.

Low bone mineral density is not associated with angiographically determined coronary atherosclerosis in men.

UNLABELLED: This study for the first time investigates the association of bone mineral density (BMD) with angiographically determined coronary atherosclerosis in men. Our data show that the prevalence of low BMD is very high in men undergoing coronary angiography. However, neither osteopenia nor osteoporosis is associated with an increased prevalence of angiographically determined coronary atherosclerosis. INTRODUCTION: The association of low BMD with angiographically determined coronary atherosclerosis in men is unknown. METHODS: We enrolled 623 consecutive men undergoing coronary angiography for the evaluation of established or suspected coronary artery disease (CAD). BMD was assessed by dual X-ray absorptiometry. CAD was diagnosed in the presence of any coronary artery lumen narrowing at angiography; coronary stenoses with lumen narrowing > or =50% were considered significant. RESULTS: From the total study cohort (mean age of 64 +/- 11 years), 207 patients (33.2%) had osteopenia and 65 (10.4%) had osteoporosis; at angiography, CAD was diagnosed in 558 patients (89.6%) and 403 (64.7%) had significant coronary stenoses. In multivariate logistic regression analysis neither osteopenia nor osteoporosis was associated with an increased prevalence of CAD (adjusted odds ratios (ORs) = 0.71 [95% confidence interval 0.40-1.23]; p = 0.222 and 1.03 [0.38-2.80]; p = 0.955, respectively) or with significant coronary stenoses (OR 0.74 [0.52-1.07], p = 0.112 and 0.72 [0.41-1.26]; p = 0.251, respectively). Also, as a continuous variable, BMD was not associated with angiographically diagnosed CAD. CONCLUSIONS: The prevalence of low BMD is very high in men undergoing coronary angiography. However, low BMD is not associated with angiographically determined coronary atherosclerosis in men.

[High-dose statin therapy for high-risk patients]. / Hochdosierte Statintherapie für kardiovaskuläre Risikopatienten.

Lowering LDL cholesterol (LDL-C) with statins decreases cardiovascular risk; therefore LDL-C is the primary target in lipid therapy. The amount of risk reduction is the greater, the lower the LDL-C values achieved by statin therapy are. Current guidelines therefore require an LDL-C as low as < 70 mg/dl in patients who are at a very high risk of cardiovascular events. This stringent treatment goal depending on the baseline LDL-C values typically can only be obtained with higher doses of potent statins. Randomised trials demonstrate the efficacy of high-dose therapy with atorvastatin 80 mg/day with regard to the prevention of cardiovascular events in patients after acute coronary syndromes (PROVE-IT TIMI 22 trial), in patients with stable coronary artery disease (TNT trial), and in patients after stroke or TIA (SPARCL trial). Moreover, potent statin treatment reduces the progression of coronary atherosclerosis (REVERSAL and ASTEROID trials). Furthermore, large meta-analyses of the efficacy of high-dose statin therapy confirm its safety; in particular, muscle-related adverse events are not more frequent than with standard statin doses. It is recommended that evidence-based statin doses be used in clinical practice; the dosages used in clinical trials should be given rather than titrating patients to LDL-C targets by increasing statin doses in a stepwise manner. Whether the strong LDL-C lowering combination of simvastatin plus ezetimibe will reduce cardiovascular events over and above simvastatin monotherapy is currently being tested in the ongoing IMPROVE-IT trial. Importantly, despite the large body of evidence in favour of high-dose statin therapy for patients at high cardiovascular risk, high-dose statin therapy is still underused and LDL-C goals are still not met in the majority of these patients.

Metabolic and anti-inflammatory benefits of eccentric endurance exercise - a pilot study.

BACKGROUND: Eccentric endurance exercise (e.g. hiking downwards) is less strenuous than concentric exercise (e.g. hiking upwards) but its potential to reduce cardiovascular risk is unknown. MATERIALS AND METHODS: We randomly allocated 45 healthy sedentary individuals (16 men and 29 women, mean age 48 years) to one of two groups, one beginning with two months of hiking upwards, the other with two months of hiking downwards the same route, with a crossover for a further two months. For the opposite way, a cable car was used where compliance was recorded electronically. The difference in altitude was 540 metres; the distance was covered three to five times a week. Fasting and postprandial metabolic profiles were obtained at baseline and after the two month periods of eccentric and concentric exercise, respectively. RESULTS: Forty-two of the 45 participants completed the study; the compliance rate was therefore 93%. Compared with baseline, eccentric exercise lowered total cholesterol (by 4.1%; P = 0.026), low-density lipoprotein (LDL) cholesterol (by 8.4%, P = 0.001), Apolipoprotein B/Apolipoprotein A1 ratio (by 10.9%, P < 0.001), homeostasis model assessment of insulin resistance scores (by 26.2%, P = 0.017) and C-reactive protein (by 30.0%; P = 0.007); the magnitude of these changes was comparable to that of concentric exercise. Eccentric exercise improved glucose tolerance (by 6.2%, P = 0.023), whereas concentric exercise improved triglyceride tolerance (by 14.9%, P = 0.022). CONCLUSIONS: Eccentric endurance exercise is a promising new exercise modality with favourable metabolic and anti-inflammatory effects and is well applicable to sedentary individuals.

Relationship between various measures of bone mineral density and vertebral fractures in cardiac transplant recipients.

BACKGROUND: The incidence rates of osteoporosis and fractures are increased after cardiac transplantation. METHODS: We performed a cross-sectional analysis of cardiac transplant recipients in a late post-transplantation period (4.4 [2.5] years after cardiac transplantation, n = 27). We measured bone mineral density (BMD) by DXA at the hip and lumbar spine and by quantitative ultrasound (QUS) at the calcaneus. Vertebral fracture (vfx) prevalence was analysed by anterior-posterior and lateral radiographs of the thoracic and lumbar spine. RESULTS: Overall, vfx were present in 13 of 27 patients (48.2%, n = 51 vfx). Vfx were observed in 1 out of 5 patients with normal DXA results, 7 out of 14 osteopenic and 5 out of 8 osteoporotic cardiac transplant recipients. BMD at the femoral neck and more prominently at Ward's triangle were significantly lower in vfx patients compared to patients without vfx, with adjusted mean values (95% CI) of 0.804 [0.750-0.859] vs. 0.915 [0.860-0.969] g/cm2 and 0.573 [0.501-0.646] vs. 0.766 [0.697-0.836] g/cm2, respectively. CONCLUSIONS: These findings suggest an association between DXA measurements of the hip with vertebral fractures in a late post-transplantation period and thus extend knowledge from previous reports on cardiac transplant recipients studied earlier after CTX. In particular, our data pinpoint a potentially interesting role for BMD at Ward's triangle.

Synergistic effects of the apolipoprotein E epsilon3/epsilon2/epsilon4, the cholesteryl ester transfer protein TaqIB, and the apolipoprotein C3 -482 C>T polymorphisms on their association with coronary artery disease.

The single nucleotide polymorphisms (SNPs) apolipoprotein E (APOE) epsilon3/epsilon2/epsilon4, cholesteryl ester transfer protein (CETP) TaqIB, and apolipoprotein C3 (APOC3) -482 C>T have been associated with an atherogenic lipid profile and, in some studies, with increased cardiovascular risk. However, no data exist on their combined impact on atherosclerotic disease. We therefore aimed at investigating the combined impact of these SNPs on the presence of angiographically determined coronary artery disease (CAD). Genotyping was performed in 557 consecutive Caucasian patients undergoing coronary angiography for the evaluation of CAD. From the individual SNPs, only the APOE epsilon3epsilon4/epsilon4epsilon4 genotype was significantly associated with an increased risk of significant coronary stenoses with lumen narrowing >or=50% (odds ratio (OR)=1.77 [1.16-2.71]; p=0.008). However, the risk of CAD strongly increased when more than one of the analysed genetic variants was present: ORs were 2.74 [1.29-5.83]; p=0.009 for patients with both the APOE epsilon3epsilon4/epsilon4epsilon4 and the CETP B1B1 genotype, 1.97 [1.06-3.66]; p=0.031 for patients with both the APOE epsilon3epsilon4/epsilon4epsilon4 genotype and the APOC3 -482T allele, 2.12 [1.31-3.44]; p=0.002 for patients with both the CETP B1B1 genotype and the APOC3 -482T allele, and 3.99 [1.57-13.79]; p=0.029 for patients with all three variants. Multivariate analyses confirmed these results. We conclude that there are strong synergistic effects of the APOE epsilon3/epsilon2/epsilon4, the CETP TaqIB, and the APOC3 -482 C>T polymorphisms on their association with CAD.

The metabolic syndrome and risk of cardiovascular disease and diabetes: experiences with the new diagnostic criteria from the International Diabetes Federation.

Since the publication of the International Diabetes Federation (IDF) consensus definition of the metabolic syndrome (MetS) in 2005, numerous studies have compared the new IDF MetS category with previous MetS definitions in its association with the prevalence of cardiovascular disease, and in its ability to predict vascular events and incident diabetes. The present review shows that the amount of cardiovascular risk conferred by the respective MetS definitions varies between populations; in most populations it is lower with the IDF MetS than with alternative MetS definitions. For incident diabetes, the number of existing studies appears too limited to draw definite conclusions. Like earlier definitions of the MetS, the IDF MetS is based on distinctive cutoff points for MetS stigmata, neglecting the fact that the risk factors are continuous and not categorical variables.

Leptin, leptin soluble receptor and coronary atherosclerosis.

BACKGROUND: The adipose tissue-related hormone leptin plays an important role in the regulation of body weight. The associations of leptin and leptin soluble receptor (sOb-R) with coronary artery disease (CAD) are not clear. DESIGN: We measured leptin and sOb-R in 543 consecutive patients (379 men, 164 women) referred for coronary angiography for the evaluation of CAD. Coronary artery stenoses with lumen narrowing > or = 50% were considered significant. RESULTS: Serum leptin correlated significantly with body mass index (r(s) = 0.443), with insulin resistance as assessed by the homeostasis model for the assessment of insulin resistance (r(s) = 0.339), with serum triglycerides (r(s) = 0.181), with systolic as well as diastolic blood pressure (r(s) = 0.170 and r(s) = 0.133, respectively) and, inversely, with sOb-R (r(s) = -0.346; P < 0.01 for all correlations). Coronary angiography revealed significant coronary artery stenoses in 331 (61%) of our patients. Serum leptin was significantly lower in patients with significant coronary artery stenoses than in patients without such lesions (8.5 +/- 7.8 vs. 13.2 +/- 12.2 ng mL(-1); P < 0.001). Multivariate logistic regression analysis proved serum leptin inversely and independently associated with the presence of significant coronary artery stenoses (standardized adjusted odds ratio 0.746, 95% confidence interval 0.566-0.983, P = 0.038). In contrast to serum concentrations of leptin, serum concentrations of sOb-R did not significantly differ between patients with significant stenoses and those without such lesions (22.4 +/- 8.3 vs. 23.1 +/- 12.1 ng mL(-1); P = 0.655). CONCLUSIONS: Serum leptin but not sOb-R is significantly lower in patients with angiographically determined CAD. Despite its association with cardiovascular risk factors, leptin should not be simply regarded as a promoter of atherosclerosis.

Lipoprotein(a), type 2 diabetes and vascular risk in coronary patients.

BACKGROUND: Lipoprotein(a) [Lp(a)] is an important cardiovascular risk factor in the general population. However, prospective data on the vascular risk conferred by Lp(a) in patients with diabetes mellitus are scarce and controversial. It is not known whether the diabetic state affects the association of Lp(a) with vascular events among coronary patients. DESIGN: We measured Lp(a) in 587 consecutive patients undergoing coronary angiography for the evaluation of coronary artery disease. The incidence of vascular events was recorded over 4 years. RESULTS: At baseline, Lp(a) was significantly lower in patients with type 2 diabetes (T2DM) (n = 136) than in nondiabetic individuals (11 (0.8-30) mg dL(-1) vs. 16 (0.8-51) mg dL(-1); P = 0.025). Prospectively, Lp(a) was a strong and independent predictor of vascular events in nondiabetic patients (standardized adjusted hazard ratio (HR) = 1.461 (1.121-1.904); P = 0.005), but not in patients with T2DM [HR = 0.812 (0.539-1.223); P = 0.320]. An interaction term diabetes x Lp(a) was significant (P = 0.008), indicating that Lp(a) was a significantly stronger predictor of vascular events in nondiabetic patients than in patients with T2DM. CONCLUSIONS: Lp(a) in diabetic coronary patients is low and not associated with the incidence of vascular events. Although measurement of Lp(a) provides useful information in nondiabetic coronary patients, it is of little value in coronary patients with T2DM.

Impact of total and central obesity on vascular mortality in patients undergoing coronary angiography.

OBJECTIVE: To prospectively investigate the impact of total and central obesity on vascular mortality in patients undergoing coronary angiography. DESIGN: Prospective cohort study; mean follow-up 2.2 y. SUBJECTS: Men (n=513) and women (n=243) undergoing coronary angiography for the evaluation of coronary artery disease. MEASUREMENTS: Body mass index (BMI) was used as a measure of total obesity; waist-to-hip ratio (WHR) and waist circumference (WCf) as measures of central obesity. The primary study end point was vascular mortality; secondary study end points were total mortality, major coronary events, and cumulative vascular events. RESULTS: For both genders, BMI, WHR, and WCf correlated significantly with fasting plasma glucose, with HOMA insulin resistance, with triglycerides, and inversely with HDL cholesterol (P<0.001 for all correlations). In Cox regression analysis adjusting for age, gender, smoking, and total cholesterol, BMI was not associated with any study end point. In contrast, WHR (standardized adjusted odds ratios (OR) 2.01, 95% CI 1.02-3.93 for men and 2.63, 95% CI 1.38-5.00 for women), and WCf (OR=2.31, 95% CI 1.16-4.60 for men and 8.71, 95% CI 1.78-42.68 for women) proved independently predictive of vascular mortality. Additional adjustment for diabetes and hypertension did not substantially alter these results. Also, the predictive value of WHR and Wcf was retained after adjustment for drug treatment and the presence of significant coronary artery disease at baseline. Further, WHR and WCf were associated with total mortality, major coronary events, and cumulative vascular end points. CONCLUSION: Both total and central obesity are associated with insulin resistance and with an atherogenic lipoprotein profile. However, only central obesity is significantly and independently predictive of the 2-y vascular mortality in coronary patients.