Metabolites predict cardiovascular disease events in persons living with HIV: a pilot case-control study.

Introduction: Persons living with HIV (PLWH) are at higher risk for cardiovascular disease (CVD) events than uninfected persons. Current risk-stratification methods to define PLWH at highest risk for CVD events are lacking.

Methods: Using tandem flow injection mass spectrometry, we quantified plasma levels of 60 metabolites in 24 matched pairs of PLWH [1:1 with and without known coronary artery disease (CAD)].

High-Density Lipoprotein Particle Subfractions in Heart Failure With Preserved or Reduced Ejection Fraction.

Background: Circulating high-density lipoprotein particle (HDL-P) subfractions impact atherogenesis, inflammation, and endothelial function, all of which are implicated in the pathobiology of heart failure (HF).

Objectives: The authors sought to identify key differences in plasma HDL-P subfractions between patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) to determine their prognostic utility.

Methods: Patients with HFrEF (n = 782), HFpEF (n = 1,004), and no HF (n = 4,742) were identified in the CATHGEN (Catheterization Genetics) biorepository of sequential patients undergoing cardiac catheterization.

Improvement in insulin resistance after gastric bypass surgery is correlated with a decline in plasma 2-hydroxybutyric acid.

Background: Gastric bypass surgery for weight reduction often corrects dysglycemia in diabetic patients, but a full understanding of the underlying biochemical pathways continues to be investigated.

Objectives: To explore the effects of weight loss by surgical and dietary interventions on plasma metabolites using both targeted and discovery-oriented metabolomics platforms.

Setting: An academic medical center in the United States.

Brain-derived neurotrophic factor rs6265 (Val66Met) polymorphism is associated with disease severity and incidence of cardiovascular events in a patient cohort.

Background: The rs6265 (Val66Met) single-nucleotide polymorphism in the BDNF gene has been related to a number of endophenotypes that have in turn been shown to confer risk for atherosclerotic cardiovascular disease (CVD). To date, however, very few studies have examined the association of the Val66Met single-nucleotide polymorphism with CVD clinical outcomes.

Methods: In a cohort of 5,510 Caucasian patients enrolled in the CATHeterization GENetics (CATHGEN) study at Duke University Hospital between 2001 and 2011, we determined the severity of coronary artery disease (CAD) and CVD event incidence through up to 11.

Atherogenic Lipoprotein Determinants of Cardiovascular Disease and Residual Risk Among Individuals With Low Low-Density Lipoprotein Cholesterol.

Background: Levels of LDL (low-density lipoprotein) cholesterol in the population are declining, and increasing attention is being focused on residual lipid-related pathways of atherosclerotic cardiovascular disease risk beyond LDL cholesterol. Among individuals with low (<130 mg/dL) LDL cholesterol, we undertook detailed profiling of circulating atherogenic lipoproteins in relation to incident cardiovascular disease in 2 populations.

Methods And Results: We performed proton nuclear magnetic resonance spectroscopy to quantify concentrations of LDL and VLDL (very low-density lipoprotein) particle subclasses in 11 984 JUPITER trial participants (NCT00239681).

Plasma acylcarnitines are associated with pulmonary hypertension.

Quantifying metabolic derangements in pulmonary hypertension (PH) by plasma metabolomics could identify biomarkers useful for diagnosis and treatment. The objective of this paper is to test the hypotheses that circulating metabolites are differentially expressed in PH patients compared with controls and among different hemodynamic subtypes of PH associated with left heart disease. We studied patients enrolled in the CATHGEN biorepository with PH (right heart catheterization mPAP ≥ 25 mmHg; n = 280).

Apolipoprotein L1 Genetic Variants Are Associated with Chronic Kidney Disease but Not with Cardiovascular Disease in a Population Referred for Cardiac Catheterization.

Background: While the association between genetic variants and chronic kidney disease (CKD) has been established, their association with cardiovascular disease (CVD) is unclear. This study sought to understand CKD and cardiovascular risk conferred by variants in a secondary cardiovascular prevention population.

Methods: Two risk variants in were genotyped in African-Americans ( = 1,641) enrolled in the CATHGEN biorepository, comprised of patients referred for cardiac catheterization at Duke University Hospital, Durham, NC, USA (2001-2010).

A Novel Protein Glycan-Derived Inflammation Biomarker Independently Predicts Cardiovascular Disease and Modifies the Association of HDL Subclasses with Mortality.

Background: Evidence suggests that systemic inflammation may adversely impact HDL function. In this study we sought to evaluate the independent and incremental predictive performance of GlycA-a novel serum inflammatory biomarker that is an aggregate measure of enzymatically glycosylated acute phase proteins-and HDL subclasses on adverse events in a retrospective observational study of a secondary prevention population and to understand a priori defined potential interactions between GlycA and HDL subclasses.

Methods: GlycA and HDL subclasses were measured using proton nuclear magnetic resonance spectroscopy in 7617 individuals in the CATHGEN (CATHeterization GENetics) cardiac catheterization biorepository.

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure.

Background: Metabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF).

High-density lipoprotein subclass measurements improve mortality risk prediction, discrimination and reclassification in a cardiac catheterization cohort.

Background And Aims: Recent failures of HDL cholesterol (HDL-C)-raising therapies to prevent cardiovascular disease (CVD) events have tempered the interest in the role of HDL-C in clinical risk assessment. Emerging data suggest that the atheroprotective properties of HDL depend on specific HDL particle characteristics not reflected by HDL-C. The purpose of this study was to determine the association of HDL particle concentration (HDL-P) and HDL subclasses with mortality in a high-risk cardiovascular population and to examine the clinical utility of these parameters in mortality risk discrimination and reclassification models.

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.

Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis.

ADAM12: a genetic modifier of preclinical peripheral arterial disease.

In prior studies from multiple groups, outcomes following experimental peripheral arterial disease (PAD) differed considerably across inbred mouse strains. Similarly, in humans with PAD, disease outcomes differ, even when there are similarities in risk factors, disease anatomy, arteriosclerotic burden, and hemodynamic measures. Previously, we identified a locus on mouse chromosome 7, limb salvage-associated quantitative trait locus 1 (LSq-1), which was sufficient to modify outcomes following experimental PAD.

Genetic variants associated with vein graft stenosis after coronary artery bypass grafting.

Background: Vein graft stenosis after coronary artery bypass grafting (CABG) is common. Identifying genes associated with vein graft stenosis after CABG could reveal novel mechanisms of disease and discriminate patients at risk for graft failure. We hypothesized that genome-wide association would identify these genes.

Effects of left ventricular assist device support on biomarkers of cardiovascular stress, fibrosis, fluid homeostasis, inflammation, and renal injury.

Objectives: The purpose of this study was to examine changes in a broad panel of biomarkers following left ventricular assist device (LVAD) support in advanced heart failure (HF).

Background: LVAD therapy mechanically unloads the failing heart and may result in reversal of certain aspects of the end-stage HF phenotype. Changes in markers of myocardial stress, fibrosis, inflammation, fluid homeostasis, and renal injury in this setting are unknown.

Validation of the association between a branched chain amino acid metabolite profile and extremes of coronary artery disease in patients referred for cardiac catheterization.

Objective: To validate independent associations between branched-chain amino acids (BCAA) and other metabolites with coronary artery disease (CAD).

Methods: We conducted mass-spectrometry-based profiling of 63 metabolites in fasting plasma from 1983 sequential patients undergoing cardiac catheterization. Significant CAD was defined as CADindex ≥ 32 (at least one vessel with ≥ 95% stenosis; N = 995) and no CAD as CADindex ≤ 23 and no previous cardiac events (N = 610).

A functional polymorphism in the 5HTR2C gene associated with stress responses also predicts incident cardiovascular events.

Previously we have shown that a functional nonsynonymous single nucleotide polymorphism (rs6318) of the 5HTR2C gene located on the X-chromosome is associated with hypothalamic-pituitary-adrenal axis response to a stress recall task, and with endophenotypes associated with cardiovascular disease (CVD). These findings suggest that individuals carrying the rs6318 Ser23 C allele will be at higher risk for CVD compared to Cys23 G allele carriers. The present study examined allelic variation in rs6318 as a predictor of coronary artery disease (CAD) severity and a composite endpoint of all-cause mortality or myocardial infarction (MI) among Caucasian participants consecutively recruited through the cardiac catheterization laboratory at Duke University Hospital (Durham, NC) as part of the CATHGEN biorepository.

Matrix metalloproteinase-9 genetic polymorphisms and the risk for advanced pelvic organ prolapse.

Objective: Matrix metalloproteinase-9 (MMP9) is a protease associated with degradation of collagen and elastin. Because increased MMP9 activity in vaginal tissue has been associated with pelvic organ prolapse (POP), we sought to comprehensively estimate MMP9 genetic variants and the risk for advanced prolapse.

Methods: This is a candidate gene association study of women with stage III-IV prolapse (case group, n=239) and women with stage 0-1 prolapse (control group, n=197).

Risk factors for 1-year mortality after thoracic endovascular aortic repair.

Objective: Thoracic endovascular aortic repair, although physiologically well tolerated, may fail to confer significant survival benefit in some high-risk patients. In an effort to identify patients most likely to benefit from intervention, the present study sought to determine the risk factors for 1-year mortality after thoracic endovascular aortic repair.

Methods: A retrospective review was performed on prospectively collected data from all patients undergoing thoracic endovascular aortic repair from 2002 to 2010 at a single institution.

Comprehensive analysis of LAMC1 genetic variants in advanced pelvic organ prolapse.

Objective: We sought to comprehensively evaluate the association of laminin gamma-1 (LAMC1) and advance pelvic organ prolapse.

Study Design: We conducted a candidate gene association of patients (n = 239) with stages III-IV prolapse and controls (n = 197) with stages 0-I prolapse. We used a linkage disequilibrium (LD)-tagged approach to identify single-nucleotide polymorphisms (SNPs) in LAMC1 and focused on non-Hispanic white women to minimize population stratification.

Metabolic profiles predict adverse events after coronary artery bypass grafting.

Objective: Clinical models incompletely predict the outcomes after coronary artery bypass grafting. Novel molecular technologies can identify biomarkers to improve risk stratification. We examined whether metabolic profiles can predict adverse events in patients undergoing coronary artery bypass grafting.

Effect of heparin administration on metabolomic profiles in samples obtained during cardiac catheterization.

Background: Metabolic profiling holds promise for early detection of coronary artery disease and assessing risk for ischemic events. Heparin is frequently administered (1) to treat acute coronary syndromes; and (2) during routine cardiac catheterization procedures. Because it stimulates lipolysis, heparin is a potential confounder of metabolic profiling in these populations.

Fentanyl does not reduce the incidence of laryngospasm in children anesthetized with sevoflurane.

Background: The modifying effects of fentanyl on protective airway reflexes have not been characterized in children. The aim of this study was to assess the impact of increasing doses of fentanyl on laryngeal reflex responses in children anesthetized with sevoflurane. The authors hypothesized that the incidence of laryngospasm evoked by laryngeal stimulation is reduced with increasing doses of fentanyl.

Right ventricular hypertrophy with early dysfunction: A proteomics study in a neonatal model.

Objective: Right ventricular hypertrophy and subsequent dysfunction is common in patients with congenital heart defects, but the molecular mechanisms underlying change from adaptive hypertrophy to dysfunction remain elusive. We used the novel technique of proteomics to characterize protein changes in right ventricular myocardium in a neonatal model of right ventricular hypertrophy and early dysfunction.

Methods: Twelve neonatal piglets were equally randomized to pulmonary artery banding (PAB group), or sham operation (thoracotomy without banding).

Complement factor 1 inhibitor improves cardiopulmonary function in neonatal cardiopulmonary bypass.

Background: The inflammatory insult associated with cardiopulmonary bypass (CPB) continues to result in morbidity for neonates undergoing complex repair of congenital cardiac defects. Complement and contact activation are important mediating processes involved in this injury. Complement factor 1 esterase inhibitor (C1-inh), a natural inhibitor of complement, kallikrein, and coagulation pathways, may be decreased in children undergoing cardiac operations requiring CPB.