Transcriptional, epigenetic and metabolic signatures in cardiometabolic syndrome defined by extreme phenotypes.

Background: This work is aimed at improving the understanding of cardiometabolic syndrome pathophysiology and its relationship with thrombosis by generating a multi-omic disease signature.

Methods/results: We combined classic plasma biochemistry and plasma biomarkers with the transcriptional and epigenetic characterisation of cell types involved in thrombosis, obtained from two extreme phenotype groups (morbidly obese and lipodystrophy) and lean individuals to identify the molecular mechanisms at play, highlighting patterns of abnormal activation in innate immune phagocytic cells. Our analyses showed that extreme phenotype groups could be distinguished from lean individuals, and from each other, across all data layers.

Plasma proteomic approach in patients with heart failure: insights into pathogenesis of disease progression and potential novel treatment targets.

Aims: To provide insights into pathogenesis of disease progression and potential novel treatment targets for patients with heart failure by investigation of the plasma proteome using network analysis.

Methods And Results: The plasma proteome of 50 patients with heart failure who died or were rehospitalised were compared with 50 patients with heart failure, matched for age and sex, who did not have an event. Peptides were analysed on two-dimensional liquid chromatography coupled to tandem mass spectrometry (2D LC ESI-MS/MS) in high definition mode (HDMSE).

Proenkephalin and prognosis in heart failure with preserved ejection fraction: a GREAT network study.

Background: Proenkephalin (PENK), a stable endogenous opioid biomarker related to renal function, has prognostic utility in acute and chronic heart failure. We investigated the prognostic utility of PENK in heart failure with preserved ejection fraction (HFpEF), and its relationship to renal function, Body Mass Index (BMI), and imaging measures of diastolic dysfunction.

Methods: In this multicentre study, PENK was measured in 522 HFpEF patients (ejection fraction > 50%, 253 male, mean age 76.

Using matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling in order to predict clinical outcomes of patients with heart failure.

Background: Current risk prediction models in heart failure (HF) including clinical characteristics and biomarkers only have moderate predictive value. The aim of this study was to use matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling to determine if a combination of peptides identified with MALDI-MS will better predict clinical outcomes of patients with HF.

Methods: A cohort of 100 patients with HF were recruited in the biomarker discovery phase (50 patients who died or had a HF hospital admission vs.

Proteomic diversity of high-density lipoprotein explains its association with clinical outcome in patients with heart failure.

Aims: Previously, low high-density lipoprotein (HDL) cholesterol was found to be one of the strongest predictors of mortality and/or heart failure (HF) hospitalisation in patients with HF. We therefore performed in-depth investigation of the multifunctional HDL proteome to reveal underlying pathophysiological mechanisms explaining the association between HDL and clinical outcome.

Methods And Results: We selected a cohort of 90 HF patients with 1:1 cardiovascular death/survivor ratio from BIOSTAT-CHF.

Proenkephalin, Renal Dysfunction, and Prognosis in Patients With Acute Heart Failure: A GREAT Network Study.

Background: Proenkephalin A (PENK) and its receptors are widely distributed. Enkephalins are cardiodepressive and difficult to measure directly. PENK is a stable surrogate analyte of labile enkephalins that is correlated inversely with renal function.

Prognostic value of human mature adrenomedullin in patients with acute myocardial infarction.

Adrenomedullin (ADM) correlates with adverse cardiovascular outcomes in patients with acute myocardial infarction (AMI) and in patients with heart failure. Measurement of human mature ADM (mADM) has been difficult, and recent studies have used its surrogate - the mid-regional pro-ADM (MRproADM). Our objective was to determine whether mADM measured by a novel sandwich immunoassay, using the anti-C-terminal and an anti-mid-regional monoclonal antibody, was prognostic of 30-day, 90-day, 1-year, and 2-year major adverse cardiovascular events (MACEs) in 1111 consecutive patients who have suffered an AMI.

Growth hormone for risk stratification and effects of therapy in acute myocardial infarction.

Context: Excess growth hormone (GH) is associated with early mortality.

Objectives: We assessed the association of GH with prognosis after acute myocardial infarction (AMI), and the effects of secondary prevention therapies.

Methods: GH was measured using a high-sensitivity assay in 953 AMI patients (687 males, mean age 66.

Identification of novel biomarkers in plasma for prediction of treatment response in patients with heart failure.

Background: Heart failure is a complex clinical syndrome that occurs at the end stage of heart disease. Despite advances in therapy for heart failure, improvement of clinical outcomes remains a challenge for physicians. The identification of treatment response early in the course of disease would be useful to improve management of these patients.

Pro-substance p for evaluation of risk in acute myocardial infarction.

Background: Pro-substance P (ProSP) is a stable surrogate marker for labile substance P, which has pro-inflammatory effects, increases platelet aggregation and clot strength, and reduces fibrinolysis.

Objectives: This study assessed whether ProSP was associated with poor prognosis after acute myocardial infarction (AMI) to identify novel pathophysiological mechanisms.

Methods: ProSP was measured in 1,148 AMI patients (825 men, mean age 66.

Plasma cortisol and prognosis of patients with acute myocardial infarction.

Aims: Cortisol is associated with increased cardiovascular morbidity and mortality in patients with chronic heart failure and in the general population. The negative predictive effect of cortisol on survival in non-diabetic patients who have suffered an acute myocardial infarction (AMI) has been shown. We aimed to determine the prognostic significance of cortisol in a general group of AMI patients, as this is not well known.

Protein Kinase C Epsilon Contributes to NADPH Oxidase Activation in a Pre-Eclampsia Lymphoblast Cell Model.

Pre-eclampsia is a pregnancy-specific disorder characterised by hypertension and proteinuria, which in severe cases results in multi-system disturbances. The maternal syndrome is associated with a pro-inflammatory state, consisting of leukocyte activation, which is thought to contribute to the widespread endothelial dysfunction. We previously showed increased activation of NADPH oxidase in pre-eclampsia, in both neutrophils and B-lymphoblast cell lines (B-LCLs).

Proenkephalin and prognosis after acute myocardial infarction.

Objectives: The goal of this research was to assess the prognostic value of proenkephalin (PENK) levels in acute myocardial infarction (AMI) by using N-terminal pro-B-type natriuretic peptide and Global Registry of Acute Coronary Events (GRACE) scores as comparators and to identify levels that might be valuable in clinical decision making.

Background: PENK is a stable analyte of labile enkephalins. Few biomarkers predict recurrent AMI.

Pre-discharge risk stratification in unselected STEMI: is there a role for ST2 or its natural ligand IL-33 when compared with contemporary risk markers?

Background: Soluble ST2 is a marker of cellular stress and injury whose natural ligand is interleukin-33. We investigate, for the first time, the relationship of IL-33 and ST2 with death at 30-days, 1-year and beyond in unselected STEMI patients. We assess the incremental value they offer over GRACE score and NT-proBNP.

Aldosterone predicts major adverse cardiovascular events in patients with acute myocardial infarction.

Objective: Aldosterone is associated with increased mortality in chronic heart failure patients and correlates with adverse outcomes after an acute myocardial infarction (AMI) in smaller cohorts. We evaluated the prognostic significance of plasma aldosterone in a large cohort of post-AMI patients in relation to major adverse cardiovascular events (MACE).

Design: A prospective cohort study.

Interleukin 33 and ST2 in non-ST-elevation myocardial infarction: comparison with Global Registry of Acute Coronary Events Risk Scoring and NT-proBNP.

Background: Soluble ST2 is a marker of biomechanical strain for which the natural ligand is interleukin 33 (IL-33). They have not been studied together in non-ST-elevation myocardial infarction (NSTEMI). We investigated their relationship with death, heart failure (HF) readmission, and reinfarction combined (termed major adverse cardiac events [MACE]) and, separately, in unselected patients using Global Registry of Acute Coronary Events Risk Scoring (GRACE-RS) and n terminal pro B type natriuretic peptide (NT-proBNP) as benchmark comparators.

Prognostic value of mid-regional pro-adrenomedullin levels taken on admission and discharge in non-ST-elevation myocardial infarction: the LAMP (Leicester Acute Myocardial Infarction Peptide) II study.

Objectives: The purpose of this study was to assess the prognostic value of admission and discharge mid-regional pro-adrenomedullin (sAM) levels in non-ST-elevation myocardial infarction (MI) and identify values to aid clinical decision making. N-terminal pro-B-type natriuretic peptide and GRACE (Global Registry of Acute Coronary Events) score were used as comparators.

Background: sAM is a stable precursor of adrenomedullin.

Activation of a novel natriuretic endocrine system in humans with heart failure.

Proguanylin and prouroguanylin are the inactive precursors of guanylin and uroguanylin, natriuretic peptides involved in the regulation of sodium balance. Urinary uroguanylin levels have been found previously to be elevated in patients with HF (heart failure). The aim of the present study was to investigate whether plasma proguanylin and prouroguanylin levels are increased in patients with HF and to evaluate their relationship with cardiac and renal function.

Matrix metalloproteinase-2 predicts mortality in patients with acute coronary syndrome.

The aim of the present study was to investigate the predictive value of MMP (matrix metalloproteinase)-2, MMP-3 and MMP-9 levels in patients with acute coronary syndrome for death, readmission with HF (heart failure) or recurrent MI (myocardial infarction) and to compare them with established markers, NT-proBNP (N-terminal pro-B-type natriuretic peptide) and the GRACE (Global Registry of Acute Coronary Events) score. A single blood test was taken 4 days after admission in 1024 consecutive patients with acute MI with end points observed over 519 (134-1059) days [value is median (range)]. MMP-2 and MMP-3 were increased in patients who died (n=111) compared with survivors (P<0.

Improving the diagnostic accuracy of N-terminal B-type natriuretic peptide in human systolic heart failure by plasma profiling using mass spectrometry.

We have combined the measurement of N-terminal pro-B type natriuretic peptide (NTproBNP) with plasma peptide profiling to evaluate the effect on sensitivity and specificity of systolic heart failure (SHF) diagnosis. Plasma NTproBNP levels were measured from 100 SHF patients and 100 age/gender matched controls and plasma protein profiles obtained using MALDI-MS. Sixty-seven m/z peaks were significantly different between SHF and normals, and following logistic regression analysis with NTproBNP values, 6 peaks retained independent predictive value.

C-terminal provasopressin (copeptin) as a novel and prognostic marker in acute myocardial infarction: Leicester Acute Myocardial Infarction Peptide (LAMP) study.

Background: The role of the vasopressin system after acute myocardial infarction is unclear. Copeptin, the C-terminal part of the vasopressin prohormone, is secreted stoichiometrically with vasopressin. We compared the prognostic value of copeptin and an established marker, N-terminal pro-B-type natriuretic peptide (NTproBNP), after acute myocardial infarction.

Oxygen-regulated protein 150 and prognosis following myocardial infarction.

ORP150 (oxygen-regulated protein 150) is a chaperonin expressed in tissues undergoing hypoxic or endoplasmic reticulum stress. In the present study, we investigated plasma levels of ORP150 in patients with AMI (acute myocardial infarction) and its relationship with prognosis, together with a known risk marker N-BNP (N-terminal pro-B-type natriuretic peptide). Plasma from 396 consecutive patients with AMI was obtained for measurement of ORP150 and N-BNP.

Measurement of calcium and movement in heart cells.

Preparations of calcium-tolerant cardiac myocytes for studies on intracellular calcium ([Ca(2+)](i)) signaling and contraction have been difficult owing to the susceptibility of these cells to the enzymatic digestion process. This often leads to the cells acquiring a bricklike contracted shape with a granular cytoplasm and membrane blebbing. A successful preparation results in single myocytes that do not show spontaneous contractions and that remain relaxed in Ca(2+)-containing buffers, indicating that the sarcolemmal membrane was not damaged during enzymatic digestion and led to membrane depolarization.

Advanced glycation end products stimulate an enhanced neutrophil respiratory burst mediated through the activation of cytosolic phospholipase A2 and generation of arachidonic Acid.

Background: Advanced glycation end products (AGEs) enhance NADPH oxidase, and hence respiratory burst activity, of stimulated neutrophils. They are thus potentially vasculopathic, especially in diabetes, uremia, and aging, in which AGEs classically accumulate. We investigated the underlying mechanisms.