Markers Of Vascular Stress Research Articles

A composite immune and vascular stress marker in patients newly diagnosed with bipolar disorder and their unaffected first-degree relatives

AimsSubstantial evidence emphasizes immune dysregulation in patients with bipolar disorder (BD). However, whether immune dysregulation is present already in the early illness stages of BD or even precedes development of BD is largely unknown. In this study we compared immune and vascular stress markers in patients newly diagnosed with BD, their unaffected first-degree relatives (UR) and healthy control individuals (HC) and investigated the ability a composite immune and vascular stress marker to discriminate between the three groups of participants. MethodsIn a unique sample including 373 patients newly diagnosed with BD, 95 UR and 190 HC, we compared 47 immune and vascular stress markers at the baseline visit in the ongoing longitudinal Bipolar Illness Onset study. For comparison of individual immune and vascular stress markers between groups, we applied linear mixed models, whereas the composite immune and vascular stress marker was investigated using the SuperLearner ensemble-method. ResultsCompared with HC, patients newly diagnosed with BD had higher levels of the anti-inflammatory interleukin-1 receptor antagonist (IL-1RA) and IL-10, and of the pro-inflammatory IL-6, eotaxin, monocyte chemoattractant protein-1 (MCP-1), MCP-4, Macrophage Derived Chemokine (MDC), and Thymus and Activation-Regulated Chemokine (TARC) in analyses adjusted for sex and age ranging from 26 % higher levels of IL-6 (1.26, 95 %CI: [1.12–1.43], p < 0.001, adjusted p = 0.009) and IL-10 (1.26, 95 %CI: [1.09–1.46], p = 0.002, adjusted p = 0.049), respectively, to 9 % higher eotaxin levels (1.09, 95 %CI: [1.04–1.15], p = 0.001, adjusted p = 0.024). Of these, MDC levels were 12 % higher in BD compared with UR (1.12, 95 %CI: [1.02–1.22], p = 0.001, adjusted p = 0.024). For all other markers, UR showed no difference from patients with BD or HC.Based on a data-driven model, a composite marker including all 47 immune and vascular stress markers, sex, age, BMI, smoking status, and alcohol intake, discriminated patients with BD from HC with a with an area under the receiver operating curve (AUC) of 0.76 (95 % CI: 0.75–0.77) ConclusionsHigher levels of pro-inflammatory and anti-inflammatory immune markers are present in patients newly diagnosed with BD but not in UR compared with HC, supporting immune dysregulation playing a role in the pathophysiology of BD.

Impaired bone matrix glycoprotein pattern is associated with increased cardio-metabolic risk profile in patients with type 2 diabetes mellitus

Osteopontin (OPN), osteoprotegerin (OPG) and osteocalcin (OC) are matrix glycoproteins which mediate bone mineralization; moreover, their effects on glucose/insulin homeostasis have recently been demonstrated. Higher circulating OPN and OPG levels have been associated with the presence of insulin resistance, atherosclerosis and coronary heart disease. No data are available on contextual changes of these markers in type 2 diabetes mellitus (T2DM). Therefore, aims of this study were to evaluate serum OPN, OPG and OC levels in T2DM patients and their clinical correlates. We recruited 83 consecutive T2DM patients referring to our diabetes outpatient clinics at Sapienza, University of Rome, and 71 non-diabetic sex and age-comparable subjects as a control group. Study population underwent metabolic characterization and carotid ultrasound for intima-media thickness measurement. Plasma OPN, OPG and OC were measured by MILLIPLEX Multiplex Assays Luminex. T2DM patients had significantly higher circulating OPN and OPG levels than controls (14.3 ± 13.6 vs 10.6 ± 13.7ng/ml p < 0.001, 0.70 ± 0.60 vs 0.54 ± 4.1ng/ml, p = 0.02) while OC levels were similar in the two cohorts (6.35 ± 5.8 vs 7.80 ± 7.0ng/ml, p = n.s). OPN and OPG positively correlated with greater systolic blood pressure (SBP) values, HOMA-IR and HOMA-β, and with the presence of dyslipidemia and carotid atherosclerosis. The association between greater OPN and OPG levels and SBP was independent from possible confounders (both p = 0.01). Circulating OPN and OPG levels are increased in T2DM patients and identify a particularly unfavourable metabolic profile, mostly expressed by higher SBP. Bone peptides may represent novel markers of vascular stress and accelerated atherosclerosis in diabetes, constituting a possible tool for cardiovascular risk stratification in diabetes.

Vascular disease risk in type 2 diabetes: high sugars, fluctuating sugars, both?

Optimal glucose control is important for the prevention of the microvascular complications in type 1 and type 2 diabetes (T2D). Although hyperglycemia is associated with oxidative stress, studies in adults have demonstrated that increased blood glucose variability can magnify this effect and may be as important or potentially, even more important, than the degree of blood glucose control in increasing the risk of microvascular and macrovascular disease. As the TODAY study demonstrated, youth with T2D have earlier appearance and more rapid progression of complications than do adults with T2D; it is important to determine if adolescents have the same effect of glycemic variability on oxidative stress as do adults. In this issue of The Journal, Dasari et al evaluated the mean amplitude of glycemic excursion (MAGE) using continuous glucose monitoring in normal weight (n = 12), normoglycemic obese (n = 10), and adolescents with T2D (n = 12). The authors quantified MAGE and counted the number of glucose excursions, calculating the mean and standard deviation for each set of glucose values. All subjects wore a continuous glucose monitor and step activity monitor for 5 days. Markers of oxidative stress were correlated with MAGE, with oxidized low density lipoprotein, an inflammatory marker of atherosclerotic risk, having the highest correlation. Traditional cardiovascular risk factors moderately to strongly associated with MAGE were body mass index, body fat, high density lipoprotein-cholesterol, low density lipoprotein-cholesterol, C-reactive protein, and nonesterified fatty acids. The vascular inflammatory biomarkers, E-selectin and intercellular adhesion molecule 1, also correlated with MAGE. This study demonstrates the significance of glycemic variability in inducing oxidative stress in youth with T2D. Although diabetologists typically have patients measure blood glucose values before meals, at bedtime, and occasionally at 2:00 a.m., glycemic variability is not assessed routinely. Pre- and postprandial blood glucose concentrations are usually measured only when adjusting insulin doses in an effort to improve glycemic control. Because this study indicates that glycemic variability is at least as important as blood glucose concentrations as a risk for endothelial dysfunction, clinicians should consider asking patients to monitor both pre- and postprandial blood glucose levels routinely and to adjust bolus insulin doses to attempt to minimize pre- and postprandial glucose excursions. Article page 47▶ Glycemic Variability Is Associated with Markers of Vascular Stress in AdolescentsThe Journal of PediatricsVol. 172PreviewWe used continuous glucose monitoring to test the hypothesis that mean amplitude of glycemic excursions (MAGE) is associated with circulating markers of oxidative and vascular stress in adolescents with habitually low physical activity classified as healthy weight, healthy obese, or obese with type 2 diabetes mellitus (T2DM). Full-Text PDF

Glycemic Variability Is Associated with Markers of Vascular Stress in Adolescents

We used continuous glucose monitoring to test the hypothesis that mean amplitude of glycemic excursions (MAGE) is associated with circulating markers of oxidative and vascular stress in adolescents with habitually low physical activity classified as healthy weight, healthy obese, or obese with type 2 diabetes mellitus (T2DM). A group of 13- to 21-year-olds (healthy weight=12, healthy obese=10, T2DM=12) wore a continuous glucose monitor and step activity monitor for 5days. Physical activity was similar among groups (6551±401 steps/d), but aerobic fitness (peak rate of oxygen consumption) was lower (P<.05) in T2DM (15.6±1.8mL/kg/min) than either healthy weight (26.2±2.2) or healthy obese (24.4±2.5). MAGE (mg/dL) was higher (P<.01) in T2DM (82±10) vs healthy obese (33±3) and healthy weight (30±3). Average glucose followed a similar pattern as MAGE. Oxidized low density lipoprotein was higher (P<.05) in T2DM (70.3±5.0 U/L) and healthy obese (58.1±3.8) than healthy weight (48.4±2) and positively correlated with MAGE (r=0.77). Other stress markers that were both elevated in T2DM and correlated with MAGE included E-selectin (r=0.50), intercellular adhesion molecule 1 (r=0.35), and C-reactive protein (r=0.52); soluble receptor for advanced glycosylation end product was lower in T2DM and inversely correlated with MAGE (r=-0.38). MAGE is highest in obese youth with T2DM. The associations between MAGE and oxidative stress markers support the proposed contribution of glycemic variability to risk for future cardiovascular disease.

Abstract 133: Prognostic Utility of the GDF-15/FSTL-1 Axis for Adverse Cardiac and Limb Events in Patients With Peripheral Artery Disease

Background: Peripheral artery disease (PAD) confers greater vulnerability to cardiovascular events. Inflammatory activation and tissue ischemia induce expression of a vasoprotective cytokine network including GDF15 and FSTL1. We sought to evaluate the clinical utility of novel vascular stress biomarkers for risk stratification in PAD. Methods and Results: We followed 245 PAD patients prospectively over two years for adverse cardiac events (n=40, myocardial infarction, unstable angina, coronary revascularization, transient ischemic event, stroke, congestive heart failure, cardiac death) and adverse limb events (n=52, worsening claudication, peripheral revascularization, critical limb ischemia, amputation, graft or stent failure). At baseline, we measured serum GDF15 and FSTL-1 and disease severity by the ankle-brachial index (ABI). In survival analyses, higher GDF15 was associated with both adverse cardiac and limb events (P&lt;0.0001, P&lt;0.01). FSTL-1 was associated with adverse limb (P=0.03) but not cardiac events. In multivariable models adjusting for relevant covariates including ABI, higher GDF15 remained associated with higher risk of limb events (HR 1.83, 95% CI 1.10, 3.06, P=0.02) and cardiac events (HR 1.92, 95% CI 1.09, 3.32, P=0.02). There was a trend for an association of higher FSTL1 with limb events (HR 2.34, 95% CI 0.93, 5.75, P=0.07). Addition of GDF15 to clinical variables led to an increase in the c statistic (P&lt;0.05) and net reclassification improvement (P&lt;0.01) for both cardiac and limb events. Conclusions: Our findings show that vascular stress markers involving the GDF15-FSTL1 axis provide additional prognostic value over clinical factors and disease severity for predicting adverse cardiac and limb events in patients with PAD.

Walnuts Reduce Aortic ET-1 mRNA Levels in Hamsters Fed a High-Fat, Atherogenic Diet

Walnut consumption is associated with reduced coronary vascular disease (CVD) risk; however, the mechanisms responsible remain incompletely understood. Recent clinical studies suggested that these mechanisms involve non-plasma lipid-related effects on endothelial function. Male Golden Syrian hamsters (12 groups, n=10-15) were fed for 26 wk atherosclerotic, high-fat, hyperlipidemic diets with increasing concentrations of whole walnuts (61-150 g/kg diet), or alpha-tocopherol (alpha-T, 8.1-81 mg/kg diet) and single diets with either walnut oil (32 g/kg diet) or pure gamma-tocopherol (gamma-T; 81 mg/kg diet) added. Aortic endothelin 1 (ET-1), an important endothelial regulator, was assayed as mRNA. Aortic cholesterol ester (CE) concentration along with other vascular stress markers (Cu/Zn and Mn superoxide dismutase, biliverdin reductase) and plasma lipid concentrations were determined. Hyperlipidemia (plasma LDL cholesterol approximately 6 times normal) occurred in all groups. Aortic CE concentration, a measure of atherosclerotic plaque, was highest in the lowest alpha-T only group and declined significantly with increasing alpha-T. The aortic CE of all walnut groups was decreased significantly relative to the lowest alpha-T only group but showed no dose response. The diets did not produce changes in the other vascular stress markers, whereas aortic ET-1 mRNA levels declined dramatically with increasing dietary walnuts (to a 75% reduction in the highest walnut content group compared with the lowest alpha-T group) but were unaltered in the alpha-T groups or gamma-T group. The study results are consistent with those of human walnut feeding studies and suggest that the mechanisms underlying those results are mediated in part by ET-1-dependent mechanisms. The contrasting results between the alpha-tocopherol or gamma-tocopherol diets and the walnut diets also make it unlikely that the non-plasma lipid-related CVD effects of walnuts are due to their alpha-tocopherol or gamma-tocopherol content. Finally, the results indicate that the walnut fat compartment is a likely location for the components responsible for the reduced aortic CE concentration.