Cardiovascular Disease In Subjects Research Articles

Serum Gamma-Glutamyl Transferase Activity as a Potential Novel Cardiovascular Biomarker in COPD.

Gamma-glutamyl transferase (gamma-GT) is an enzyme present in the cell membranes, which is used as a new biomarker in prediction of inflammation, myocardial infarction, stroke, and cardiac death. The objective of this study was to investigate the relationship between serum levels of gamma-GT and cardiovascular disease in subjects with COPD and the correlation between serum gamma-GT level and degree of the limitation of air flow in COPD. A total of 70 subjects (46.1%) with Global Initiative for Chronic Obstructive Lung Disease (GOLD) A-B and normal function of the liver and biliary tract (mean age [IQR] 59 [51.75-70] y; 77.1% men) and 82 subjects (53.9%) with GOLD C-D (mean age [IQR] 59 [56-66] y; 79.3% men) participated. Serum levels of gamma-GT and C-reactive protein were measured and compared between the 2 groups. The serum level of gamma-GT was found to be significantly (P < .001) higher in the GOLD stage C and D group than in the GOLD stage A and B group. Mean values of C-reactive protein, aspartate aminotransferase, and alanine aminotransferase did not differ significantly between the 2 groups. The prevalence of cardiovascular disease was statistically significantly higher in subjects in the GOLD stage C and D group than in the GOLD stage A and B group (P < .001). The serum level of gamma-GT was higher in subjects with COPD with coexisting cardiovascular disease than in those without cardiovascular disease (64 units/L [interquartile range 57-72.5] vs 17.5 units/L [interquartile range 10-25]). Our results demonstrate that serum levels of gamma-GT may be helpful in grading the severity of COPD as the marker of oxidative stress, and there is a strong correlation between high serum levels of gamma-GT and cardiovascular events in subjects with COPD.

Association of Cardiovascular Disease and Sleep Apnea at Different Altitudes.

Otero, Liliana, Patricia Hidalgo, Rafael González, and Carlos A. Morillo. Association of cardiovascular disease and sleep apnea at different altitudes. High Alt Med Biol. 17:336-341, 2016.-We evaluated the prevalence of sleep apnea (SA) in patients with cardiovascular disease (CVD) at different altitudes. A total of 398 subjects with coronary artery disease (CAD), 144 subjects with atrial fibrillation (AF), and 292 controls (without CVD) were recruited in three cities at sea level, moderate altitude, and high altitude. All participants underwent polysomnography. Multinomial logistic regression, X2, and Hosmer and Lemeshow tests were used to determine interactions among CVD, SA, and altitude. Men and women with CVD at high altitude had a higher risk for SA than men and women living at lower altitudes. The highest risk of SA was observed in men with AF and men with CAD living at high altitude. Obstructive SA (OSA) prevalence was significantly increased in CVD subjects living at high altitude (OR: 5.52; p < 0.0001). Central SA (CSA) was more frequent in subjects with CVD than control group (OR: 2.44; p < 0.021). OSA was the most frequent type of SA in subjects with CVD and overweight subjects, and in control individuals with obesity or being overweight. Significant differences in the prevalence of SA associated with altitude and gender were noted in subjects with CAD and AF.

Low Endogenous Secretory Receptor for Advanced Glycation End-Products Levels Are Associated With Inflammation and Carotid Atherosclerosis in Prediabetes.

Prediabetes is associated with atherosclerotic vascular damage. We investigated the correlation of endogenous secretory receptor for advanced glycation end-products (esRAGE), total soluble RAGE (sRAGE) and markers of inflammation, with early cardiovascular disease in subjects with prediabetes. We particularly focused on individuals with prediabetes identified only by glycated hemoglobin A1c (HbA1c) (5.7–6.4%) who had normal fasting glucose and were normotolerant after oral glucose tolerance test. This was a cross-sectional study. The study was conducted in the Department of Clinical and Molecular Medicine, University of Catania, Italy. sRAGE, esRAGE, carboxymethyl-lysine, S100A12, HbA1c, fasting glycemia, oral glucose tolerance test, pulse wave velocity, and intima-media thickness were evaluated in subjects with prediabetes. Three hundred eighty subjects without previous history of diabetes were stratified into three groups: controls (n = 99), prediabetes (n = 220), and new-onset type 2 diabetes (n = 61). Subjects with prediabetes exhibited the following: lower esRAGE (0.29 ± 0.18 vs 0.45 ± 0.26 ng/mL; P < .05) and higher S100A12 levels than controls. RT-PCR analysis in mononuclear cells revealed that the mRNA expression level of the esRAGE splice variant progressively decreased in patients with prediabetes and type 2 diabetes with respect to controls. No difference was observed in sRAGE and carboxymethyl-lysine plasma levels between the groups. After multiple regression analyses, only age, HbA1c, and hs-CRP were independently associated with esRAGE levels. Age, HbA1c, and esRAGE were the major determinants of intima-media thickness, whereas S100A12 and systolic blood pressure were the major determinants of pulse wave velocity. When we analyzed the subjects with HbA1c prediabetes (normal fasting glucose/normotolerant and HbA1c 5.7–6.4%), esRAGE and inflammatory markers plasma levels still remained significantly different in respect to controls. Subjects with HbA1c prediabetes exhibited significantly reduced esRAGE levels and increased levels of markers of inflammation. These alterations are associated with early markers of cardiovascular disease.

Low circulating vitamin D levels are associated with increased arterial stiffness in prediabetic subjects identified according to HbA1c

Background and aimsWe investigated serum -hydroxyvitamin D levels [25(OH)D] and their correlation with early markers of cardiovascular disease in subjects with pre-diabetes. We particularly focused on individuals identified only by glycated hemoglobin A1c (HbA1c 5.7–6.4%) according to the American Diabetes Association criteria but who were normotolerant (NT) after oral glucose tolerance test (OGTT) and had normal fasting glucose (NFG). Methods25(OH)D levels, HbA1c, OGTT, arterial stiffness and intima-media thickness (IMT) were evaluated in 286 subjects without history of diabetes. Subjects were stratified into four groups: controls with HbA1c <5.7%, NFG and NT; prediabetic patients with pre-diabetes according to only HbA1c (HbA1c 5.7–6.4% and NFG/NT); subjects with impaired fasting glucose and impaired glucose tolerance (IFG/IGT); new onset type 2 diabetes (HbA1c ≥ 6.5%). ResultsSubjects with NFG/NT and HbA1c 5.7–6.4% (n = 83) showed lower 25(OH)D levels compared with controls (n = 80) (21.7 [15.8–31.1] vs 23.1 [17.1–29.7] ng/mL, P = 0.009); these values were similar to those of the IFG/IGT group and were higher but not significantly different from subjects with new onset type 2 diabetes. After multiple regression analyses, only HbA1c and BMI were independently associated with 25(OH)D levels. Age, HbA1c and 25(OH)D were the major determinants of Augmentation Index. No independent association between 25(OH)D and IMT was found. ConclusionsSubjects with pre-diabetes (HbA1c 5.7–6.4% and NFG/NT) had significantly reduced 25(OH)D levels compared with controls. Reduction of 25(OH)D levels is inversely associated with arterial stiffness independently of classical risk factors and inflammatory markers. Based on these data, subjects with NFG and NT are not a homogeneous population of patients, and they present different cardiovascular and glycometabolic risks. Our data suggest considering HbA1c as a reliable marker of cardiovascular and metabolic risk independent of fasting and post-load glycemia.

Elevated Plasma Levels of MMP-12 Are Associated With Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects With Type 2 Diabetes

Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus. Plasma levels of MMP-1, -3, -7, -10, and -12 were analyzed by the Proximity Extension Assay technology in 1500 subjects participating in the SUMMIT (surrogate markers for micro- and macrovascular hard end points for innovative diabetes tools) study, 384 incident coronary cases, and 409 matched controls in the Malmö Diet and Cancer study and in 205 carotid endarterectomy patients. Plasma MMP-7 and -12 were higher in subjects with type 2 diabetes mellitus, increased with age and impaired renal function, and was independently associated with prevalent cardiovascular disease, atherosclerotic burden (as assessed by carotid intima-media thickness and ankle-brachial pressure index), arterial stiffness, and plaque inflammation. Baseline MMP-7 and -12 levels were increased in Malmö Diet and Cancer subjects who had a coronary event during follow-up. The plasma level of MMP-7 and -12 are elevated in type 2 diabetes mellitus, associated with more severe atherosclerosis and an increased incidence of coronary events. These observations provide clinical support to previous experimental studies, demonstrating a role for these MMPs in plaque development, and suggest that they are potential biomarkers of atherosclerosis burden and cardiovascular disease risk.

Abstract 118: Phospholipid Transfer Protein, High Density Lipoprotein Particle Concentration and Cardiovascular Disease Risk

High density lipoprotein (HDL) plays a key role in reverse cholesterol transport from arteries and protects against development of atherosclerosis by removing cholesterol from lipid loaded macrophages in atherosclerotic lesions. Low levels of HDL-cholesterol (HDL-C) strongly associate with increased risk of cardiovascular disease (CVD) in clinical and epidemiological studies. However, recent trials with drugs that elevate HDL-C failed to reduce CVD events. In contrast recent studies strongly suggested that HDL sterol efflux capacity-its ability to remove cholesterol from macrophages-predict incident cardiovascular disease risk. Moreover, CVD risk strongly associates with low levels of HDL particle concentration (HDL-P). However, the relations between HDL efflux capacity, HDL particle concentration and HDL composition are not well understood. Using proteomics analysis, we have previously identified over 50 proteins on HDL. Here we investigated the relationship of HDL composition, and HDL-P in two independent populations of people with and without CVD (Study 1, n=40, and Study 2, n=65). Using quantitative targeted multiplex MS/MS analysis quantifying majority (40) of HDL associated proteins, we found that phospholipid transfer protein (PLTP) and clusterin (CLU or ApoJ) strongly correlated in HDL (r = 0.9, P &lt; 0.001) indicating that the two proteins likely coexist in a single population of HDL particles. Furthermore, abundance of these two proteins correlated strongly with the concentration of large HDL particles (PLTP r = 0.58; CLU r = 0.61, both P &lt; 0.001) and negatively with the concentration of small HDL particles (both PLTP and CLU r = -0.49, P &lt; 0.001) as determined by calibrated ion mobility analysis. Moreover, both PLTP and CLU were significantly decreased in CVD subjects, and both predicted CVD status after adjustment for age and sex (PLTP, OR 0.53, 95% CI, 0.28-0.94, P = 0.02). Collectively, this data supports the hypothesis that PLTP and CLU play important roles in determining HDL-P and that these are interrelated factors determining HDL’s anti-atherogenic properties.

Abstract 473: Development of High-throughput ABCA1, ABCG1 and SR-BI Mediated HDL Efflux Assays

Studies have shown an inverse association between HDL-efflux capacity and cardiovascular disease (CVD). The efflux of cholesterol from cells to HDL can occur by several mechanisms, including unmediated aqueous diffusion and ABCA1, ABCG1 and SR-BI specifically mediated process. We developed a high throughput assay to measure pathway specific HDL efflux capacity using BHK cells expressing inducible ABCA1, ABCG1, or SR-BI in 96-well plate format. We found that ABCA1-mediated cholesterol efflux in BHK cells correlated significantly with that of J774 macrophages when apoA-I, HDL or 2% apoB-depleted serum were used as acceptors (R 2 =0.98 to 0.99, p&lt;0.0001). Compared with J774 macrophages, ABCA1-mediated efflux using BHK cells is more sensitive, consistent and has better reproducibility (Intro-assay CV=3.0%, R 2 =0.99; Inter assay CV=3.2%, R 2 =0.98). The consistence and reproducibility for ABCG1 and SR-BI mediated cholesterol efflux were also excellent as judged by intro-assay and inter-assay CV and R 2 . When pathway specific assay was employed in a high-throughput format to measure HDL efflux capacity among subjects with or without CVD, we found that ABCA1-mediated cholesterol efflux was significantly lower in CVD subjects when compared with that of control (p&lt;0.01), while ABCG1 or SR-BI mediated cholesterol efflux was not significantly different among the two groups. ABCG1-mediated cholesterol efflux was significantly associated with HDL-C (R 2= 0.65, p&lt;0.01), but ABCA1 or SR-BI mediated cholesterol efflux was not correlated with HDL-C. Those studies demonstrate that BHK cells with inducible ABCA1, ABCG1, or SR-BI expression provide a sensitive, reproducible high throughput efflux assay that can be used to screen large number of serums in mechanistic studies or drug discovery program.

Abstract 637: Hyperhomocysteinemia-mediated sCD40L induction and CD16 + CD40 + Monocyte Differentiation in Chronic Kidney Disease

Chronic kidney disease (CKD) with uremia is associated with high mortality of cardiovascular disease (CVD) and Hyperhomocysteinemia (HHcy) is highly prevalent in uremic CKD patients. Elevated inflammatory monocyte (MC) is a cellular hallmark of chronic inflammation and CVD. Here we investigated mechanism in uremia-associated HHcy on MC differentiation in CKD-associated CVD. Data base mining revealed that CD40 is induced in MC from CKD subjects and associated with CVD, inflammatory disease and MC activation. Blood samples were obtained from 28 vascular disease patients with or without CKD. By flow cytometric analysis using CD14+ as a MC marker, we observed inflammatory CD16+ MC is increased in CVD, whereas CD40+ MC and CD16+CD40+ MC are increased in CKD-associated CVD. CD40+ MC expresses T cell activation markers CD86, HLA-DR, adhesion receptor CD62L, and chemokine receptor Ccr2. Plasma CD40L levels are increased in CVD, positively correlated with CD16+ MC. Interestingly, plasma Hcy levels are increased in CKD-associated CVD, positively correlated with cellular Hcy, plasma creatinine, CD16+CD40+ MC, and negatively correlated with S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH), an indicator of methylation. In addition, MC and T cell inflammatory cytokines TNFα, IL-6, and IFN[[Unable to Display Character: &amp;#612;]] are induced in CKD-associated CVD subjects. Next, we examined mechanism of CD16+CD40+ MC differentiation using cultured human peripheral blood mononuclear cells (hPBMC). CKD serum, Hcy, and CD40L induced CD16+CD40+ MC differentiation, which were prevented by folic acid and CD40L antibody. IFN[[Unable to Display Character: &amp;#1003;]], TNFα, and IL-6 synergistically induced CD16+CD40+ MC differentiation, which was blocked by neutralizing antibodies to TNFα and IL-6. Hcy inhibited DNA methyltransferase 1 activity in isolated human blood MC. Finally, by gene analysis and pyrosequencing, we identified that the core promoter of CD40 gene is located at sole CpG island and hypomethylated at p65 consensus element in WBC from CKD-associated CVD subjects with low SAM/SAH ratio. In conclusion, we identified CD16+CD40+ MC as a novel inflammatory MC subset which is increased in uremic HHcy-associated CVD. CD16+CD40+ MC differentiation may be due to CD40 promoter DNA hypomethylation.

Cardiac troponin I levels in an elderly population from the community — The implications of sex

ObjectivesThe importance of sex on cardiac troponin levels is increasingly recognized. We investigated whether the entities associated with troponin leakage and the prognostic consequences thereof would differ between elderly men and women from the community. Design and methodsCardiac troponin I (cTnI) levels were measured using a high-sensitivity assay (Abbott Laboratories) in 70-year old men (n=502) and women (n=502) from the PIVUS study. All study participants were followed up for 10years regarding all-cause mortality and incident cardiovascular (CV) disease. ResultsMedian cTnI levels were 4.1 and 3.0ng/L in men and women, respectively (p<0.001). By multiple linear regression, the relative contribution of lower left-ventricular ejection fraction and ischemic ECG changes to cTnI levels was greater in men compared to women. For other clinical and echocardiographic variables, similar associations were found. cTnI independently predicted all-cause mortality in men (n=93 [18.5%]; hazard ratio [HR] 1.38 [1.12–1.70]) and women (n=62 [12.4%]; HR 1.59 [1.11–2.28]) but not incident CV disease in subjects being CV healthy at baseline (n=163/857). The interaction terms of sex on the associations of cTnI with both outcomes were non-significant. Sex-specific cut-offs did not improve prognostication. Variations in the pattern of entities associated with cTnI leakage had no impact on event rates. ConclusionsWe found some differences in the entities associated with higher cTnI levels in elderly community-dwelling men and women. However, this did not translate into differences in the associations of cTnI with adverse outcome.

Measures of atherosclerotic burden are associated with clinically manifest cardiovascular disease in type 2 diabetes: a European cross-sectional study.

There is a need to develop and validate surrogate markers of cardiovascular disease (CVD) in subjects with diabetes. The macrovascular changes associated with diabetes include aggravated atherosclerosis, increased arterial stiffness and endothelial dysfunction. The aim of this study was to determine which of these factors is most strongly associated with clinically manifest cardiovascular events. Vascular changes were measured in a cohort of 458 subjects with type 2 diabetes (T2D) and CVD (myocardial infarction, stroke or lower extremity arterial disease), 527 subjects with T2D but without clinically manifest CVD and 515 subjects without T2D and with or without CVD. Carotid intima-media thickness (IMT) and ankle-brachial pressure index were independently associated with the presence of CVD in subjects with T2D, whereas pulse wave velocity and endothelial function provided limited independent additive information. Measurement of IMT in the carotid bulb provided better discrimination of the presence of CVD in subjects with T2D than measurement of IMT in the common carotid artery. The factors most significantly associated with increased carotid IMT in T2D were age, disease duration, systolic blood pressure, impaired renal function and increased arterial stiffness, whereas there were no or weak independent associations with metabolic factors and endothelial dysfunction. Measures of atherosclerotic burden are associated with clinically manifest CVD in subjects with T2D. In addition, vascular changes that are not directly related to known metabolic risk factors are important in the development of both atherosclerosis and CVD in T2D. A better understanding of the mechanisms involved is crucial for enabling better identification of CVD risk in T2D.

Measurement of arterial stiffness in subjects with and without renal disease: Are changes in the vessel wall earlier and more sensitive markers of cardiovascular disease than intima media thickness and pulse pressure?

There is increased cardiovascular (CV) mortality in subjects with chronic kidney disease (CKD). Arterial stiffness in these subjects is increased when compared to a healthy population. Markers of arterial stiffness and intima media thickness (IMT) are predictors of CV mortality. The aim of this study was to investigate whether there is any difference in markers of arterial stiffness and IMT between subjects with normal renal function and those with mild renal disease. The arterial distension waveform, IMT, diameter, and brachial blood pressure were measured to calculate Young's modulus (E) and elastic modulus (Ep) in the common carotid arteries of subjects with normal kidney function (estimated glomerular filtration rate [eGFR] >90) and those mild CKD (stage 2, eGFR 89–60). Data were available for 15 patients with normal kidney function and 29 patients with mild CKD. The subjects with mild CKD were older, but other co-variables were not significantly different. Both arterial wall stiffness parameters (E and Ep), but not IMT were significantly higher in the mild CKD group. Logistic regression demonstrated that only the arterial wall stiffness parameters (Ep and E) were independently associated with mild renal disease compared with normal, in a model adjusting for sex, age and diabetes and history of cardiovascular disease (CVD). E and Ep may be early markers of CVD in subjects with mild CKD that may manifest change before other more recognized markers such as IMT and pulse pressure.

The Frequencies of Ten Platelet Polymorphisms Associated with Atherosclerotic Cardiovascular Disease in Patients with Venous Thromboembolism: A Population-Based Case-Control Study

Background: At present, atherosclerotic CardioVascular Disease (CVD) and the Vein ThromboEmbolism (VTE) are considered to have many common risk factors. The aim of our study was to determine the frequencies of ten platelet gene polymorphisms that were associated with atherosclerotic CVD in subjects (n=2369) with VTE in comparison with their frequencies in a control group (n=1460) of healthy persons. Methods: The polymorphisms of platelet receptors P2Y12 (rs2046934, rs6785930), GPIa (rs1126643), GP IIIa (rs5918), GP VI (rs1613662) and PAR-1(rs168753) and the variations in the genes coding for cyclooxygenase 1 (COX- 1; rs10306114) and platelet endothelial aggregation receptor 1 (PEAR1; (rs41299597, rs11264579, rs2768759) were determined. Results: The examinations did not show any significant differences between the polymorphism frequencies in subjects with VTE in comparison to the results obtained in control group of healthy persons. Only in the subgroup of VTE patients (n 732) with a family history of myocardial infarct and/or stroke were weakly significant increases in the “risk” genotype frequencies in GP Ia (rs1126643) and in PEAR1 (rs 11264579) (both p=0.04) observed, but no significant differences were noted in the allele frequencies. Conclusions: We suggest that the observed platelet gene polymorphisms play no significant role as independent hereditary risk factors in the pathogenesis of VTE.

Reference ranges for TSH and thyroid hormones

Though TSH remains the most commonly used endocrine test in clinical practice, the issue of an appropriate TSH, and to a lesser extent, free T4 and free T3 reference ranges is still under debate. First of all the distribution of TSH reference range is not normal, with median values (also depending on population iodine intake) usually between 1-1.5 mU/L [1-3]. On the other hand, upper TSH reference limit is (assay-dependent) usually around 4.2-4.5 mU/L. There is also an argument that significant number of patients (up to 30%) with TSH above 3.0 mU/L have an occult autoimmune thyroid disease [4]. On the other hand the upper normal TSH reference range in elderly subjects (i.e. 70 plus years) may extend up to around 6.0 mU/L, with relative small changes in free hormones. This phenomenon also applies to elderly patients, where autoimmune thyroid disease had been ruled out [1,2]. Furthermore, there is little evidence of any adverse effects of autoimmune thyroid disease in the elderly in the absence of an overt hypothyroidism. Indeed, Wang et al [5] surprisingly demonstrated decreased frailty in elderly subjects with raised titres of thyroid autoantibodies. It is also well known that in the setting of subclinical hypothyroidism, concentrations of free T4 start to decline below 10 pmol/L only with TSH above 6-7 mU/L in elderly subjects, though a decline in free T4 is more pronounced in the young (particularly in those aged 20-29 years), where free T4 starts to decline for TSH concentrations above 4.5 mU/l [6]. Another issue pertains to the risk of cardiovascular disease in subjects with subclinical hypothyroidism. There are data from post-menopausal women enrolled into the Women Health Initiative study, where an increase in the risk of myocardial infarction was demonstrated only for TSH concentrations above 7.0 mU/L [7]. A separate issue, extensively discussed elsewhere [8], pertains to alterations of TSH and free thyroid hormones during pregnancy. In particular there is decrease in TSH in the first trimester followed by a gradual return to pre-pregnancy values. In contrast, there is an increase in free T4 in the first trimester, while in the third trimester free T4 concentrations are usually at the lower end of the standard (i.e. pre-pregnancy) reference range, or even just below the lower reference limit. Hence, there is an urgent need (postulated in the Endocrine Society Guidelines [8]) to create separate reference ranges for TSH and free thyroid hormones during pregnancy, possible with reference to each trimester. There are also recent data from China [9], where the authors demonstrated that the above-mentioned first trimester-related alterations in TSH and free T4, become only really visible after about 5th-6th week of gestation. The authors of this study suggest that standard reference ranges for TSH and free T4 can be applied up to this point of gestation.

Total and differential white blood cell counts, high-sensitivity C-reactive protein, and cardiovascular risk in non-affective psychoses.

Schizophrenia is associated with increased cardiovascular disease morbidity and mortality. Schizophrenia is also associated with immune and inflammatory abnormalities, including aberrant blood levels of lymphocytes, cytokines and high-sensitivity C-reactive protein (hsCRP). The purpose of this study is to investigate the relationship between total and differential white blood cell (WBC) counts, hsCRP, and indices of cardiovascular disease risk in patients with schizophrenia and related non-affective psychoses. 108 inpatients and outpatients age 18-70 with non-affective psychoses and 44 controls participated in this cross-sectional study. Subjects had a fasting blood draw between 8 and 9am for glucose, lipids, total and differential WBC counts, and hsCRP. Vital signs and medical history were obtained. Patients with non-affective psychosis had significantly higher hsCRP levels than controls (p=0.04). In linear regression analyses, lymphocyte and monocyte counts were a significant predictor of the total-to-HDL cholesterol ratio in subjects with non-affective psychosis (p⩽0.02 for each). In binary logistic regression analyses, total WBC count was a significant predictor of an elevated 10-year estimated risk of myocardial infarction and cardiovascular disease in subjects with non-affective psychosis (p⩽0.03 for each). Associations between total and differential WBC counts and cardiovascular disease risk indices were stronger in males than females with non-affective psychosis. Our findings provide further evidence that measurement of total and differential WBC counts may be germane to the clinical care of patients with schizophrenia and related disorders, and support an association between inflammation and cardiovascular disease risk in these patients.

Additive effects of postchallenge hyperglycemia and low-density lipoprotein particles on the risk of arterial stiffness in healthy adults.

BackgroundTo determine the effects of post-challenge hyperglycemia potentiate low-density lipoprotein cholesterol (LDL) particles on the risk of arterial stiffness in non-diabetic adults.MethodsDuring 2009–2011, 592 adults without clinical diabetes (fasting glucose <7.0 mmol/L) or known coronary heart disease or stroke were recruited. All subjects underwent standard 75-g oral glucose tolerance test (OGTT) after overnight fasting. The glucose area under curve (GluAUC) after OGTT was defined as the postchallenge glucose load. Levels of LDL-C and small dense LDL-C (sdLDL-C) were measured. Arterial stiffness in terms of brachial–ankle pulse wave velocity (baPWV) was also measured.ResultsThe baPWV in tertile distributions were significantly associated with all conventional cardiovascular risk factors, LDL-C, and sdLDL-C. Multivariate logistic regression analyses revealed that LDL-C (or sdLDL-C) combined with one of the seven glycemic indices (glucose levels at 0, 30, 60, 90, and 120 min; GluAUC; HbA1C) was associated with arterial stiffness after covariates being adjusted. Further interaction analyses showed only concurrent higher levels of both glycemic indices and atherogenic LDL-C or sdLDL-C have significant risk for arterial stiffness.ConclusionsAdditive effects of both postchallenge hyperglycemia and LDL subclass particles potentiate the risk of arterial stiffness. The adverse joint effects of hyperlipidemia and postchallenge hyperglycemia on subclinical cardiovascular function provide important information in primary prevention of cardiovascular disease in subjects without clinical diabetes.

Abstract 13272: High Density Lipoprotein Subclasses Predict Non-Cardiovascular Disease, Non-Cancer Chronic Inflammatory-Related Death and Hospitalization More Strongly than Cardiovascular Disease Events in the Multi-Ethnic Study of Atherosclerosis

In vitro studies have demonstrated that high density lipoprotein particles (HDL-P) antagonize inflammatory processes. We studied the predictive value of HDL-P and inflammatory markers for incident cardiovascular disease (CVD) and non-CVD, non-cancer, chronic inflammatory-related events. Methods: In the Multi-Ethnic Study of Atherosclerosis, we studied 6475 men and women free of overt CVD, baseline age 45-84 years, who had fasting venous samples for lipid profile, lipoprotein particles, and inflammatory markers Interleukin-6 (IL-6), hs-CRP and D-dimer at baseline. Median follow-up was 10.1 years. Poisson regression models predicted non-CVD, non-cancer, chronic inflammatory-related events (death and hospitalization), based on diagnostic codes, n=1054) and CVD events due to coronary heart disease, myocardial infarction, coronary artery disease requiring revascularization, stroke, peripheral arterial disease, congestive heart failure and CVD or unwitnessed death (adjudicated, n=756). Adjustment was for age, race, gender, clinic, heart rate, smoking, body mass index, blood pressure, blood pressure and lipid lowering medication, diabetes mellitus, plus all lipid, lipoprotein particle and inflammatory variables. Results: Non-CVD, non-cancer, chronic inflammatory-related events were inversely associated with the sum of small+medium HDL-P independent of covariates (relative risk (RR) per standard deviation (95% confidence limits), RR: 0.85 (0.79-0.91, P &lt; 0.0001). Non-CVD, non-cancer, chronic inflammatory-related events were positively associated with IL-6, RR:1.19 (1.11-1.27, P &lt; 0.0001) and D-dimer, RR: 1.10 (1.05-1.16, P &lt; 0.0001). CVD was associated with small+medium HDL-P, RR: 0.90 (0.82-0.99, P &lt; 0.03) and IL-6, RR:1.15 (1.06-1.25 P &lt; 0.0001). hsCRP was unrelated to either outcome after adjustment for other inflammatory markers. Conclusion: The long-term inverse association of small+medium HDL-P with non-CVD, non-cancer, chronic inflammatory-related death and hospitalization was stronger than with fatal and non-fatal CVD in subjects initially free of overt CVD. These findings provide clinical evidence that small+medium HDL-P have anti-inflammatory properties and may rethink the importance of HDL-P beyond CVD.

Efficacy of a unique omega-3 formulation on the correction of nutritional deficiency and its effects on cardiovascular disease risk factors in a randomized controlled VASCAZEN(®) REVEAL Trial.

Low blood levels of long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) have been reported to be associated with increased risk for cardiovascular disease (CVD) deaths. Systematic studies measuring LC n-3 PUFA blood levels (pre and post-treatment) in defined subjects, and monitoring the correction of nutritional deficiency with a pure LC n-3 PUFA formulation in sufficient doses, while monitoring CVD risk factors are lacking. We tested the efficacy of a novel LC n-3 PUFA Medical Food formulation (VASCAZEN®, > 90 % pure with a 6:1 eicosapentaenoic acid-(EPA):docosahexaenoic acid-(DHA) ratio; 6:1-OM3), to correct such deficiency and determine the concomitant effects on lipid profiles. Of 655 subjects screened, 89 % were LC n-3 PUFA deficient (Omega-Score, (OS) = blood EPA + DHA + Docosapentaenoic acid < 6.1 %). From these, a study was conducted on 110 ambulatory cardiovascular subjects. Placebo: corn oil. Primary endpoint: change in OS. Secondary endpoint: changes in blood lipid profiles. At 8 weeks of treatment with 6:1-OM3 (4 g/day), placebo-adjusted median OS levels (n = 56) significantly improved (132 %, P < 0.0001) with a decrease in AA (arachidonic acid): EPA ratio (82 %, P < 0.0001). In hypertriglyceridemic subjects (TG 2.26–5.65 mmol/L), HDL-C improved (9 %, P = 0.0069), TG-reduced (48 %, P < 0.0001), and VLDL-C reduced (30 %, P = 0.0023), without significantly affecting LDL-C levels. This study confirms that LC n-3 PUFA deficiency is prevalent in the US population, and its correction with 6:1-OM3 in CVD subjects improves lipid profiles. The purity, EPA:DHA ratio and dose are determinant factors for optimal efficacy of a formulation in reducing CVD risk factors.

Evidence for an exclusive association of matrix metalloproteinase-9 with dysfunctional high-density lipoprotein: A novel finding

ObjectiveHigh-density lipoprotein is a heterogeneous class of lipoprotein with diverse antiatherogenic functions. However, these antiatherogenic properties of HDL can be compromised in atherosclerotic conditions. We have recently identified dysfunctionality in HDL even among healthy subjects, during systemic inflammation. This study was carried out with the objective of examining whether dysfunctional HDL is associated with pro-inflammatory proteins other than the acute phase proteins as reported earlier. MethodsSerum HDL was isolated by three different methods-density gradient ultracentrifugation, PEG precipitation and electroelution. The antioxidant property of HDL was assessed as change in oxidation of LDL based on Dichloro-dihydro-fluorescein diacetate assay. HDL was subjected to gelatin zymography and western blot for assessment of MMP 9 activity. ResultsDysfunctional HDL did not prevent the auto-oxidation of LDL. On the contrary the oxidation was enhanced. The zymogram data indicated enhanced MMP-9 activity selectively in dysfunctional HDL, irrespective of HDL isolation methods. This was confirmed by western blot of HDL probed with antibody specific to MMP 9. We also observed that dysfunctional HDL induced inflammatory response in monocyte/macrophages as evidenced by enhanced TNF-α and decreased IL-10 production. Further, invitro incubation of functional HDL with MMP-9 provided direct evidence for the association of MMP-9 with HDL and the role of MMP-9 in HDL dysfunction. ConclusionA remarkable finding in the present study is the previously unrecognized association of MMP-9 with dysfunctional HDL and its proinflammatory property, indicating a novel molecular connection that can enhance the risk of cardiovascular disease in subjects with dysfunctional HDL.

Is a flavonoid-rich diet with steamer cooking safe during calcineurin inhibitors therapy?

Dietary therapy is recommended for decreasing the symptoms of the metabolic syndrome and the risk of type 2 diabetes and cardiovascular diseases in subjects on calcineurin inhibitors. However, food-drug interactions may occur particularly with patients on such immunosuppressive therapy. This article comments on the benefit/risk assessment of a flavonoid-rich diet and steam-cooking of such food during calcineurin inhibitors therapy. Patients are commonly advised against consuming citrus fruits and juices, grape juice and green tea. High vegetable intake may however increase the risk of food-diet interactions by inhibiting drug metabolic enzymes and transporters. Vegetable glucosinolates are potential interactants and may lead to adverse effects of drugs with narrow therapeutic indices and in the presence of genetic polymorphism. Examples of food components with potential drug interactants include all members of the Brassicaceae family. The potential additive and synergistic effects of flavonoids with other molecules in interfering with drug bioavailability need to be taken into account. The risk is highest with drugs with a narrow therapeutic index and in subjects with genetic polymorphisms of proteins involved in the disposition of those drugs.

Plasma Antimicrobial Peptide LL-37 Level Is Inversely Associated with HDL Cholesterol Level in Patients with Type 2 Diabetes Mellitus.

Introduction. Relation between atherosclerosis and innate immunity has attracted attention. As the antimicrobial peptide, LL-37, could have an important role in atherosclerosis, we supposed that there could be a meaningful association of plasma LL-37 level with risk factors for cardiovascular disease in subjects with type 2 diabetes mellitus. Materials and Methods. We evaluated plasma LL-37 level and other clinical markers in Japanese subjects with type 2 diabetes mellitus (n = 133, 115 men and 18 women; age 64.7 ± 11.5 years; HbA1c 8.1 ± 1.6%). Plasma level of LL-37 was measured by ELISA. Results. Mean plasma LL-37 level was 71.2 ± 22.3 ng/mL. Plasma LL-37 level showed significant correlations with HDL cholesterol (r = −0.450, P < 0.01), triglyceride (r = 0.445, P < 0.01), and high sensitive C-reactive protein (r = 0.316, P < 0.01) but no significant correlation with age, body mass index, HbA1c, estimated glomerular filtration rate, 25-hydroxyvitamin D, or vitamin D binding protein. Multiple linear regression analysis showed significant correlations of plasma LL-37 level with HDL cholesterol (β = −0.411, P < 0.01) and high sensitive C-reactive protein (β = 0.193, P < 0.05). Conclusion. Plasma LL-37 level was positively correlated with inflammatory markers and negatively correlated with HDL cholesterol in patients with type 2 diabetes mellitus.