Visfatin: a putative biomarker for metabolic syndrome is not influenced by pioglitazone or simvastatin treatment in nondiabetic patients at cardiovascular risk -- results from the PIOSTAT study.

OBJECTIVE: The aim of the study was to analyze the effect of pioglitazone (PIO) and simvastatin (SIMVA) on adiponectin and visfatin concentrations in nondiabetic patients with metabolic syndrome and increased risk for cardiovascular complications in a prospective randomized clinical trial. RESEARCH DESIGN AND METHODS: One-hundred twenty-five nondiabetic patients with increased cardiovascular risk [78 females, 47 males, age (mean+/-STD:58.6+/-7.8years, BMI:30.8+/-4.2(kg/m2] were included after randomization to PIO+lacebo, SIMVA+placebo, or PIO+SIMVA treatment for 3 months. At baseline and endpoint, measurements of HbA1c, glucose, insulin, LDL cholesterol, adiponectin and visfatin were performed. Insulin resistance was assessed by means of the HOMAIR-score. RESULTS: Improvement in the HOMAIR-score was observed with PIO and the combination, but not with SIMVA alone, which was accompanied by an increase in adiponectin with PIO treatment groups, but a decrease with SIMVA alone (baseline/endpoint: PIO: 14.0+/-8.2 mg/l/ 27.6+/- 14.5 mg/l, p<0.05; PIO+SIMVA: 11.7+/-10.0 mg/l/26.7+/-15.7 mg/l, p<0.05; SIMVA: 15.5+/-12.7 mg/l/ 11.6+/-7.0 mg/l, p<0.05). No change could be observed in the visfatin concentrations (PIO: 47.6+/-14.5 ng/ml/48.0+/-11.6 ng/ml, PIO+SIMVA: 45.1+/-10.9 ng/ml/47.9+/-10.1 ng/ml, SIMVA: 49.2+/- 13.4 ng/ml/52.1+/-16.7 ng/ml, n. s. in all cases). CONCLUSIONS: Insulin resistance and/or cardiovascular risk indicators were not associated with visfatin levels. Regulation of visfatin secretion occurs through biochemical pathways independent from those influenced by pioglitazone or simvastatin.     

Effects of pioglitazone and metformin on beta-cell function in nondiabetic subjects at high risk for type 2 diabetes

Thiazolidinediones (TZDs) and metformin decreased the incidence of diabetes in subjects at risk for developing diabetes and improved peripheral or hepatic insulin sensitivity, respectively. Whether they also directly improved beta-cell function is not clear. In vitro studies showed improved beta-cell function in response to TZDs and metformin; however, the effects of TZDs or metformin on beta-cell function in humans are still uncertain. We hypothesized that both TZDs and metformin directly affect beta-cell function. We evaluated beta-cell function and insulin sensitivity (S(I)) in subjects with impaired glucose tolerance or a history of gestational diabetes using oral and intravenous glucose tolerance tests in addition to the glucose-potentiated arginine stimulation test. In contrast to metformin, pioglitazone improved S(I), glucose tolerance, and insulin-independent glucose disposal [glucose effectiveness (S(G))]. Neither pioglitazone nor metformin significantly improved beta-cell compensation for insulin resistance [disposition index (DI)], but the change in DI significantly correlated with baseline S(I). Insulin secretion in response to arginine at maximally potentiating glucose levels (AIR(max)) tended to increase after metformin and to decrease after pioglitazone; however, when adjusted for S(I), the changes were not significant. Our results demonstrate that, in nondiabetic subjects at risk for diabetes, pioglitazone, but not metformin, significantly improved glucose tolerance by improving S(I) and S(G). We did not find any evidence that either pioglitazone or metformin improved beta-cell function. Improved beta-cell compensation was observed primarily in the subgroup of subjects that had the lowest S(I) at baseline.     

Novel biomarkers with potential for cardiovascular risk reclassification

Precise estimation of the absolute risk for CVD events is necessary when making treatment recommendations for patients. A number of multivariate risk models have been developed for estimation of cardiovascular risk in asymptomatic individuals based upon assessment of multiple variables. Due to the inherent limitation of risk models, several novel risk markers including serum biomarkers have been studied in an attempt to improve the cardiovascular risk prediction above and beyond the established risk factors. In this review, we discuss the role of underappreciated biomarkers such as red cell distribution width (RDW), cystatin C (cysC), and homocysteine (Hcy) as well as imaging biomarkers in cardiovascular risk reclassification, and highlight their utility as additional source of information in patients with intermediate risk.     

Effects of high phenolic olive oil on cardiovascular risk factors: A systematic review and meta-analysis

BackgroundCardiovascular diseases are the world's leading cause of death. Prevention by nutrition is an easy and effective approach especially by advising foods with nutraceutic properties like high phenolic olive oil (HPOO).AimThe aim of this review was to systematically access and meta-analyse the effects of HPOO on risk factors of the cardiovascular system and thusly to evaluate its use as a nutraceutical in prevention.Data synthesisMedline/PubMed, EMBase, the Cochrane Library, CAMbase and CAM-QUEST were searched through July 2013. Randomized controlled trials (RCTs) comparing high vs. low (resp. non) phenolic olive oils in either healthy participants or patients with cardiovascular diseases were included. For study appraisal the Cochrane Collaboration's risk of bias tool was used. Main outcomes were blood pressure, serum lipoproteins and oxidation markers. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated and analysed by the generic inverse variance methods using a random effects model. Eight cross over RCTs comparing ingestion (21–90 d) of high vs. low (resp. non) phenolic olive oils with a total of 355 subjects were included.ResultsThere were medium effects for lowering systolic blood pressure (n = 69; SMD −0.52; CI −0.77/−0.27; p < 0.01) and small effects for lowering oxLDL (n = 300; SMD −0.25; CI [−0.50/0.00]; p = 0.05). No effects were found for diastolic blood pressure (n = 69; SMD −0.20; CI −1.01/0.62; p = 0.64); malondialdehyde (n = 71; SMD −0.02; CI [−0.20/0.15]; p = 0.79), total cholesterol (n = 400; SMD −0.05; CI [−0.16/0.05]; p = 0.33); HDL (n = 400; SMD −0.03; CI [−0.14/0.08]; p = 0.62); LDL (n = 400; SMD −0.03; CI [−0.15/0.09]; p = 0.61); and triglycerides (n = 360; SMD 0.02; CI [−0.22/0.25]; p = 0.90).LimitationsThe small number of studies/participants limits this review.ConclusionsHPOO provides small beneficial effects on systolic blood pressure and serum oxidative status (oxLDL). HPOO should be considered as a nutraceutical in cardiovascular prevention.     

The effects of simvastatin treatment on plasma lipid-related biomarkers in men with dyslipidaemia

Background: Lipidomic biomarkers will facilitate the development of novel anti-atherosclerotic therapies.

Objective: To evaluate the responses of circulating biomarkers to simvastatin treatment.

Methods: A randomized, cross-over study in men with mixed dyslipidaemia was used to compare effects of simvastatin 40?mg/day with placebo.

Results: Plasma concentrations of nine fatty acids (FA; of 33 evaluated) were reduced significantly by simvastatin. No changes in the rates of FA synthesis or in hepatic lipase or lipoprotein lipase activities were apparent. Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels increased.

Conclusion: We identified lipidomic biomarkers of simvastatin treatment effect that are consistent with statin inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase.

Trial registration: ClinicalTrials.gov identifier: NCT00935259.     

The relationship between subclinical atherosclerosis and electrocardiographic abnormalities as biomarkers of cardiovascular risk

Electrocardiographic findings indicating myocardial disease, such as left ventricular hypertrophy or ST-T wave abnormalities, or the presence of coronary artery calcium, indicating atherosclerotic coronary artery disease, are both biomarkers of future cardiovascular (CV) risk. Although the risk factors for myocardial and coronary artery disease are similar, their concomitant expression has implications for CV disease screening and prevention programmes. The relationship between the resting 12-lead ECG and subclinical atherosclerosis measured as coronary artery calcium (CAC) with electron beam tomography was examined in 937 healthy participants (aged 40-50 years) enrolled in a CV risk screening study. Electrocardiograms and CAC were interpreted in blinded fashion, using standard criteria. An abnormal ECG was coded in 268 (28.6%) participants, most commonly left ventricular hypertrophy (3.1%), delayed precordial R wave transition (5.7%), T-wave abnormalities (10.0%) and intraventricular conduction delay (10.4%). Although abnormal ECG findings were associated with CV risk variables, the prevalence of any CAC was similar in subjects with any ECG finding (43 of 268, 16.0%) compared with those with normal ECGs (125 of 669, 18.7%, p=NS). In a logistic model controlling for CV risk factors including systolic blood pressure, low-density lipoprotein cholesterol (LDL-C), body mass index (BMI), glycosylated haemoglobin, race, age and gender, significant associations with CAC were found for LDL-C, race and BMI. There was no significant relationship between CAC and ECG abnormalities (odds ratio 0.80, 95% confidence interval 0.54-1.20). In conclusion, electrocardiographic abnormalities and subclinical calcified atherosclerosis were not significantly associated with each other in this middle-aged screening population. This suggests these two biomarkers may be complementary towards broader detection of latent CV risk.     

Randomised controlled trial of health promotion in general practice for patients at high cardiovascular risk.

OBJECTIVE--To assess the value of health education for patients with angina in reducing risk factors for cardiovascular disease and lessening the effect of angina on everyday activities. DESIGN--Randomised controlled trial of personal health education given every four months. SETTING--18 general practices in the greater Belfast area. SUBJECTS--688 patients aged less than 75 years and known to have had angina for at least six months; 342 randomised to receive education and 346 to no education. MAIN OUTCOME MEASURES--Restriction of everyday activities, dietary habit, smoking habit, frequency of physical exercise; blood pressure, body mass index, and serum total cholesterol concentration at entry to trial and after two years. RESULTS--317 in the intervention group and 300 in the control group completed the trial. At the two year review more of the intervention group (140, 44%) reported taking daily physical exercise than the control group (70, 24%). The intervention group also reported eating a healthier diet than the control group and less restriction by angina in any everyday activity. No significant differences were found between the groups in smoking habit, systolic or diastolic blood pressure, cholesterol concentration, or body mass index. CONCLUSION--Despite having no significant effect on objective cardiovascular risk factors, personal health education of patients with angina seems to increase exercise and improve dietary habits and is effective in lessening the restriction of everyday activities.     

The utility of inflammation and platelet biomarkers in patients with acute coronary syndromes

Introduction

Thrombotic and inflammatory mechanisms are involved in the pathophysiology of acute coronary syndrome (ACS). The aim of the study was the evaluation of inflammation (white blood cells count/WBC, C-reactive protein/CRP, interleukin-6/IL-6) and platelet (platelet count/PLT, mean platelet volume/MPV, large platelet/LPLT, beta-thromboglobulin/β-TG) biomarkers in the groups of ACS patients depending on the severity of signs and symptoms and compared to controls without coronary artery disease.

Correlation between two markers of inflammation, serum C-reactive protein and interleukin 6, and indices of oxidative stress in patients with high risk of cardiovascular disease.

As evidence of the involvement of inflammation and oxidative damage in pathogenesis of age-related chronic diseases is growing, epidemiologists need to develop measures of both conditions to study their relationships in human populations. One way of searching for appropriate biomarkers is to examine correlations between different inflammatory markers and oxidative indices. We examined cross-sectional correlations between two inflammatory markers, serum C-reactive protein (CRP) and interleukin (IL)-6, and three oxidative indices, plasma levels of alpha-tocopherol and beta-carotene, and urinary levels of 2,3-dinor-5,6-dihydro-15-F2t-isoprostane (F2-IsoP), in 60 individuals at high risk of cardiovascular disease. Correlations between the biomarkers were examined graphically and using the Pearson correlation coefficient. No correlation was found between plasma levels of alpha-tocopherol and either of the inflammatory markers. Plasma beta-carotene inversely correlated with IL-6 (r = -0.46, p=0.0002) and CRP (r = -0.41, p = 0.001). Although urinary F2-IsoP did not correlate with IL-6, this biomarker positively correlated with CRP (r = 0.31, p = 0.002). As only urinary F2-IsoP levels have been validated against known oxidative assaults, their positive association with CRP levels is interpreted as evidence of an interconnection between low-level inflammation and oxidative status. Urinary levels of F2-IsoP and serum levels of CRP represent appropriate biomarkers for future studies of inflammation and oxidative status in humans.     

Endotoxin-induced cardiovascular dysfunction in mice: effect of simvastatin

Lung infections are associated with acute lung injury (ALI), systemic inflammation, and vascular events. Clinical studies suggest that statins improve health outcomes of patients with pneumonia and ALI. The mechanisms by which this occurs are unknown. The aim of this study was to determine whether statins attenuate systemic inflammation and cardiovascular dysfunction related to ALI in mice. Simvastatin (SS; 20 mg/kg) or vehicle solution was instilled intraperitoneally into mice 24 h before and again just prior to intratracheal LPS instillation (1 μg/g). These mice were then anesthetized with 2.0% isoflurane and underwent a short surgical procedure to instill LPS. Four hours later, IL-6 levels in bronchoalveolar lavage fluid and in arterial and venous serum were measured. Cardiac function was evaluated using 2-D echocardiography, and endothelial function was determined using wire myography on aortic sections. LPS induced a significant increase in serum IL-6 levels. SS reduced venous (P = 0.040) but not arterial concentrations of IL-6 (P = 0.112). SS improved the maximal vasodilatory response of the aorta to ACh (P = 0.004) but not to sodium nitroprusside (P = 1.000). SS also improved cardiac output (P = 0.023). Vasodilatory response to ACh was impaired when aorta from untreated mice was incubated with ex vivo IL-6 (P = 0.004), whereas in the aorta from mice pretreated with SS, the vasodilatory response did not change with IL-6 incubation (P = 0.387). SS significantly improved LPS-induced cardiovascular dysfunction possibly by reducing systemic expression of IL-6 and its downstream signaling pathways. These findings may explain how statins improve health outcomes in patients with ALI.     

Impact of cardiovascular risk factors on oxidative stress and DNA damage in a high risk Mediterranean population

Abstract

The impact of classic cardiovascular risk factors on oxidative stress status in a high-risk cardiovascular Mediterranean population of 527 subjects was estimated. Oxidative stress markers (malondialdehyde, 8-oxo-7′8′-dihydro-2′-deoxyguanosine, oxidized/reduced glutathione ratio) together with the activity of antioxidant enzyme triad (superoxide dismutase, catalase, glutathione peroxidase) were analysed in circulating mononuclear blood cells. Malondialdehyde, oxidized glutathione and the ratio of oxidized to reduced glutathione were significantly higher while catalase and glutathione peroxidase activities were significantly lower in high cardiovascular risk participants than in controls. Statistically significant differences were obtained after additional multivariate control for sex, age, obesity, diabetes, lipids and medications. Among the main cardiovascular risk factors, hypertension was the strongest determinant of oxidative stress in high risk subjects studied at a primary prevention stage.     

Associations of religious and existential variables with psychosocial factors and biomarkers of cardiovascular risk in bereavement

Bereavement increases in prevalence as people age and is associated with multiple psychological and health risks, including cardiovascular risk. Religious and existential variables may play an important role in the health impacts of bereavement. Theorized pathways linking religious and existential variables with health have suggested these associations are due to intermediary psychosocial variables, but have not been tested in bereavement. This research empirically tested these pathways in a bereaved population. In N = 73 adults within 1 year of bereavement (mean age = 64.36), this study examined associations between (1) religious and existential characteristics (religious and spiritual struggles, intrinsic religiosity, and existential quest) and intermediary psychosocial variables (depression, loneliness, and difficulties in emotion regulation), and between (2) intermediary psychosocial variables and bereavement-relevant health outcomes (self-reported health, change in health since last year, grief severity, and cardiovascular biomarkers). Cardiovascular biomarkers (heart rate, heart rate variability, and blood pressure) were collected before, during, and after a laboratory grief recall emotion elicitation. Anticipated associations between self-reported religious and existential characteristics and intermediary variables, and between intermediary variables and self-reported bereavement-relevant outcomes, were consistently observed. However, associations between intermediary variables and cardiovascular biomarkers were largely unobserved. This study examined the role of religious and existential variables in whole-person health after bereavement and is among the first to include biomarkers of cardiovascular risk. Results suggest that although religious and existential variables are associated with important bereavement-related outcomes, these associations may be “skin-deep,” and extensions to cardiovascular functioning should be re-examined.     

Estrogen, medroxyprogesterone acetate, endothelial function, and biomarkers of cardiovascular risk in young women

Medroxyprogesterone acetate (MPA) is widely known for its use in combination hormone therapy for postmenopausal women. However, MPA is also commonly used in young women for contraception and treatment of a number of gynecological conditions. Despite its widespread use, the cardiovascular effects of MPA in young women are unclear. Therefore, the purpose of this study was to determine the acute effects of MPA when used in combination with estradiol on markers of cardiovascular risk in young women. We suppressed endogenous estrogens and progesterone in 10 premenopausal women using a gonadotropin-releasing hormone antagonist (GnRHa) for 10 days. On day 4 of GnRHa subjects received 0.1 mg of estradiol (GnRHa+E(2)), and on day 7 5 mg of MPA was added (GnRHa+E(2)+MPA). Endothelium-dependent vasodilation and endothelium-independent vasodilation of the brachial artery, lipids, homocysteine, high-sensitivity C-reactive protein, and endothelin-1 were assessed during treatment with GnRHa, GnRHa+E(2), and GnRHa+E(2)+MPA. Four additional subjects were tested to validate the efficacy of the GnRHa model and confirm the findings. Endothelium-dependent vasodilation was greater during GnRHa+E(2) than during GnRHa or GnRHa+E(2)+MPA (P = 0.006). Endothelin-1 was lower during GnRHa+E(2) than GnRHa alone (P = 0.039). Endothelin-1 increased with the addition of MPA and was not significantly different from GnRHa alone. There were no differences in the other markers of cardiovascular risk between hormone treatment days. These data suggest that acute MPA administration negates the beneficial effects of estradiol on endothelium-dependent vasodilation in young women. In addition, these data suggest that estradiol decreases endothelin-1 concentrations and the addition of MPA may counteract the effect of estradiol on endothelin-1.     

Predictive value of metabolomic biomarkers for cardiovascular disease risk: a systematic review and meta-analysis

Abstract

Background: Metabolomic analysis aids in the identification of novel biomarkers by revealing the metabolic dysregulations underlying cardiovascular disease (CVD) aetiology. The aim of this study was to evaluate which metabolic biomarkers could add value for the prognosis of CVD events using meta-analysis.

Methods: The PRISMA guideline was followed for the systematic review. For the meta-analysis, biomarkers were included if they were tested in multivariate prediction models for fatal CVD outcomes. We grouped the metabolites in biological classes for subgroup analysis. We evaluated the prediction performance of models which reported discrimination and/or reclassification statistics.

Results: For the systematic review, there were 22 studies which met the inclusion/exclusion criteria. For the meta-analysis, there were 41 metabolites grouped into 8 classes from 19 studies (45,420 subjects, 5954 events). A total of 39 of the 41 metabolites were significant with a combined effect size of 1.14 (1.07–1.20). For the predictive performance assessment, there were 21 studies, 54,337 subjects, 6415 events. The average change in c-statistic after adding the biomarkers to a clinical model was 0.0417 (SE 0.008).

Conclusions: This study provides evidence that metabolomic biomarkers, mainly lipid species, have the potential to provide additional prognostic value. Current data are promising, although approaches and results are heterogeneous.     

Minimal versus umbilical waist circumference measures as indicators of cardiovascular disease risk

Objective: Measures of central obesity are strongly correlated with cardiovascular disease (CVD) risk. Although waist circumference (WC) is a commonly used measure of central obesity, there is no standard measurement location. We examined two WC locations to determine which was more highly correlated with CVD risk factors and metabolic syndrome (MS). Research Methods and Procedures: WC measures were taken on 266 sedentary, overweight men and women 45 to 60 years old. Intravenous glucose tolerance tests, fasting plasma lipid analysis, and computed tomography scans were conducted. Correlational analyses followed by the Test for Equal Correlations determined whether one WC measure better correlated with the cardiovascular risk factors. Results: In women, minimal waist had higher correlation coefficients than umbilical waist for all eight variables presented. High‐density lipoprotein‐cholesterol, low‐density lipoprotein particle size, and MS score were significantly correlated with minimal waist, but not umbilical waist. For high‐density lipoprotein size and insulin sensitivity, minimal waist was a better correlate, although the difference between waist measures only approached statistical significance (p < 0.06). In men, minimal waist had a higher correlation coefficient than umbilical waist for insulin sensitivity, fasting insulin, and visceral adipose tissue. Additionally, minimal waist was significantly correlated with MS in men and umbilical waist was not. For both genders, minimal waist was more highly correlated with visceral adipose tissue than umbilical waist. Discussion: For every metabolic variable presented, minimal WC was more highly correlated with CVD risk than was umbilical WC in women. The data for women indicate that WC location is important when determining CVD risk. In men, minimal waist was better, although the data were less compelling.     

Biglycan and atherosclerosis: Lessons from high cardiovascular risk conditions

Atherosclerosis (ATH) is a chronic, dynamic, evolutive process involving morphological and structural subversion of artery walls, leading to the formation of atherosclerotic plaques. ATH generally initiates during the childhood, occurring as a result of a number of changes in the intima tunica and in the media of arteries. A key event occurring during the pathobiology of ATH is the accumulation of lipoproteins in the sub-intimal spaces mediated by extracellular matrix (ECM) molecules, especially by the chondroitin sulfate/dermatan sulfate (CS/DS) –containing proteoglycans (CS/DSPGs). Among them, the proteoglycan biglycan (BGN) is critically involved in the onset and progression of ATH and evidences show that BGN represents the missing link between the pro-atherogenic status induced by both traditional and non-traditional cardiovascular risk factors and the development and progression of vascular damage. In the light of these findings, the role of BGN in dyslipidemia, hypertension, cigarette smoking, diabetes, chronic kidney disease and inflammatory status is briefly analyzed and discussed in order to shed new light on the underlying mechanisms governing the association between BGN and ATH.