Plasma soluble fms-like tyrosine kinase-1, placental growth factor, and vascular endothelial growth factor system gene variants as predictors of survival in heart failure.

Aims: Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), components of the vascular endothelial growth factor (VEGF) system, play key roles in angiogenesis. Reports of elevated plasma levels of sFlt-1 and PlGF in coronary heart disease and heart failure (HF) led us to investigate their utility, and VEGF system gene single nucleotide polymorphisms (SNPs), as prognostic biomarkers in HF.

Methods And Results: ELISA assays for sFlt-1, PlGF and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were performed on baseline plasma samples from the PEOPLE cohort (n = 890), a study of outcomes among patients after an episode of acute decompensated HF.

Convalescent Growth Differentiation Factor-15 and Long-Term Outcomes after an Acute Coronary Syndrome.

Background: Growth differentiation factor-15 (GDF-15) has been shown to be associated with adverse clinical outcomes in patients after an acute coronary syndrome when measured soon after an event. Although dynamic in the acute phase after myocardial injury, GDF-15 has been shown to remain stable during convalescence. In this study, we aimed to assess the value of GDF-15 as a long-term prognostic marker for clinical outcomes when measured in the convalescent phase following an acute coronary syndrome.

Regional Handling and Prognostic Performance of Circulating Insulin-Like Growth Factor Binding Protein-7 in Heart Failure.

Background: Regional handling and the prognostic performance of insulin-like growth factor binding protein (IGFBP)-7, in contrast or in combination with other candidate biomarkers, in chronic heart failure (CHF) remain uncertain.

Objectives: The authors investigated the regional handling of plasma IGFBP-7 and its association with long-term outcomes in CHF in comparison with selected circulating biomarkers.

Methods: Plasma concentrations of IGFBP-7, N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin-T, growth differentiation factor-15, and high-sensitivity C-reactive protein were measured prospectively in a cohort with CHF (n = 863).

Vascular endothelial growth factor-A promoter polymorphisms, circulating VEGF-A and survival in acute coronary syndromes.

Background: Development of a competent collateral circulation in established coronary artery disease is cardio-protective. The vascular endothelial growth factor (VEGF) system plays a key role in this process. We investigated the prognostic performance of circulating VEGF-A and three genetic variants in the VEGFA gene in a clinical coronary cohort.

Mid-regional pro-adrenomedullin outperforms N-terminal pro-B-type natriuretic peptide for the diagnosis of acute heart failure in the presence of atrial fibrillation.

Aims: The performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in diagnosing acute decompensated heart failure (ADHF) among patients presenting with breathlessness is markedly impaired in the presence of atrial fibrillation (AF). We evaluated the diagnostic performance of mid-regional pro-adrenomedullin (MR-proADM) and cardiac troponin T as possible alternative markers for discrimination of ADHF in this setting.

Methods And Results: Breathless patients (n = 1107) were prospectively and contemporaneously recruited in emergency departments in Singapore and New Zealand.

Plasma levels of soluble VEGF receptor isoforms, circulating pterins and VEGF system SNPs as prognostic biomarkers in patients with acute coronary syndromes.

Background: Development of collateral circulation in coronary artery disease is cardio-protective. A key process in forming new blood vessels is attraction to occluded arteries of monocytes with their subsequent activation as macrophages. In patients from a prospectively recruited post-acute coronary syndromes cohort we investigated the prognostic performance of three products of activated macrophages, soluble vascular endothelial growth factor (VEGF) receptors (sFlt-1 and sKDR) and pterins, alongside genetic variants in VEGF receptor genes, VEGFR-1 and VEGFR-2.

The heart regulates the endocrine response to heart failure: cardiac contribution to circulating neprilysin.

Aims: Heart failure (HF) is accompanied by major neuroendocrine changes including the activation of the natriuretic peptide (NP) pathway. Using the unique model of patients undergoing implantation of the CARMAT total artificial heart and investigating regional differences in soluble neprilysin (sNEP) in patients with reduced or preserved systolic function, we studied the regulation of the NP pathway in HF.

Methods And Results: Venous blood samples from two patients undergoing replacement of the failing ventricles with a total artificial heart were collected before implantation and weekly thereafter until post-operative week 6.

Release kinetics of high-sensitivity cardiac troponins I and T and troponin T upstream open reading frame peptide (TnTuORF) in clinically induced acute myocardial infarction.

Context: Troponin T upstream open reading frame peptide (TnTuORF) may be useful as a novel biomarker in acute cardiac syndromes.

Objective: The study examined the early release kinetics of TnTuORF.

Materials And Methods: We analyzed the time course of the release of cardiac troponins I and T and TnTuORF in patients (n = 31) with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy (TASH).

Superior performance of N-terminal pro brain natriuretic peptide for diagnosis of acute decompensated heart failure in an Asian compared with a Western setting.

Aims: This study was conducted to test the diagnostic performance of NT-proBNP for discrimination of acute decompensated heart failure (ADHF) among breathless patients presenting in an Asian compared with a Western centre.

Methods And Results: Patients with breathlessness were prospectively and contemporaneously recruited in Emergency Departments in Singapore and New Zealand (NZ). The diagnosis of ADHF was adjudicated by two clinician specialists.

B-type natriuretic peptide signal peptide (BNPsp) in patients presenting with chest pain.

Objectives: We assessed the ability of B-type natriuretic peptide signal peptide (BNPsp) to assist with the identification of patients with myocardial infarction (MI) and unstable angina pectoris (UAP).

Design And Methods: We studied 505 patients who presented to hospital within 4h of onset of chest pain suspicious of ACS. Blood samples were drawn at 0, 1, 2 and 24h from presentation and assayed for BNPsp, NT-proBNP, TnI and high sensitivity TnT.

CNP Signal Peptide in Patients with Cardiovascular Disease.

We have previously reported that signal peptide fragments of C-type natriuretic peptide (CNP) are present in the human circulation. Here, we provide the first preliminary assessment of the potential utility of CNP signal peptide (CNPsp) measurement in acute cardiovascular disease. Utilizing our specific and sensitive immunoassay, we assessed the potential of CNPsp measurement to assist in the identification of acute coronary syndromes in 494 patients presenting consecutively with chest pain.

Reference Values and Release Kinetics of B-Type Natriuretic Peptide Signal Peptide in Patients with Acute Myocardial Infarction.

Background: The signal peptide for human B-type natriuretic peptide preprohormone (BNPsp), which is released from cardiomyocytes, is increased in plasma of patients with acute myocardial infarction (AMI); however, its exact release kinetics have not been defined.

Methods: We measured BNPsp and high-sensitivity cardiac troponin T (hs-cTnT) in a reference group of individuals without structural heart disease (n = 285) and determined the release kinetics of these biomarkers in patients (n = 29) with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy (TASH), a procedure allowing exact timing of onset of iatrogenic AMI. Blood samples were collected before TASH and at numerous preselected time points after TASH.

Signal peptides: new markers in cardiovascular disease?

Proteins and peptides are well-documented as useful marker adjuncts to cardiovascular clinical decision-making. Most markers measured derive from a defined, stable proprotein region of their respective gene. However, a neglected portion of preproproteins known as the signal peptide (SP) is also present in the circulation and may also present as a measurable marker.

C-type natriuretic peptide (CNP) signal peptide fragments are present in the human circulation.

Background: Signal peptides may be novel biomarkers in cardiovascular diseases.

Methods: We developed a novel immunoassay to the signal peptide of preproCNP (CNPsp) and used this to document circulating venous concentrations of CNPsp in normal healthy volunteers (n=109), regional plasma CNPsp concentrations in patients undergoing clinically indicated catheterisation (n=24) and temporal CNPsp concentrations in patients with ST-elevation myocardial infarction (STEMI) <4h after symptom onset (n=8). The structure/sequence of circulating CNPsp was confirmed by tandem mass spectrometry (MS/MS).

First identification of circulating prepro-A-type natriuretic peptide (preproANP) signal peptide fragments in humans: initial assessment as cardiovascular biomarkers.

Background: New biomarkers are needed to assist clinical decision making in cardiovascular disease. We have recently shown that signal peptides may represent a novel biomarker target in cardiovascular diseases.

Methods: We developed a novel immunoassay for the signal peptide of preproANP (ANPsp) and used it to document cardiac tissue levels of ANPsp in explant human hearts (n = 9), circulating venous concentrations of ANPsp in healthy volunteers (n = 65), temporal ANPsp concentrations in patients with ST-elevation myocardial infarction (STEMI) <4 h after chest pain onset (n = 23), and regional plasma ANPsp concentrations in patients undergoing clinically indicated catheterization (n = 10).

B-type natriuretic peptide signal peptide circulates in human blood: evaluation as a potential biomarker of cardiac ischemia.

Background: The diagnosis of cardiac necrosis such as myocardial infarction can be difficult and relies on the use of circulating protein markers like troponin. However, there is a clear need to identify circulating, specific biomarkers that can detect cardiac ischemia without necrosis.

Methods And Results: Using specific immunoassay and tandem mass spectrometry, we show that a fragment derived from the signal peptide of B-type natriuretic peptide (BNPsp) not only is detectable in cytosolic extracts of explant human heart tissue but also is secreted from the heart into the circulation of healthy individuals.

Metformin increases plasma ghrelin in Type 2 diabetes.

What Is Already Known About This Subject: * Metformin, unlike the other major antihyperglycaemic drugs, is not associated with weight gain. * Ghrelin is an appetite-stimulating hormone whose concentrations vary in relation to food, obesity and diabetes control. * Reports are conflicting about how metformin affects ghrelin concentrations, and this study was aimed at resolving this issue in patients with Type 2 diabetes.

Cardiac chymase converts rat proAngiotensin-12 (PA12) to angiotensin II: effects of PA12 upon cardiac haemodynamics.

Aims: The aim of this study was to observe the direct physiological and biochemical cardiac effects in response to a newly identified putative component of the renin-angiotensin system, proangiotensin-12 (PA12); and investigate whether PA12 can serve as a substrate for Angiotensin II (AngII) generation.

Methods And Results: The direct cardiac actions of PA12 and its role as a substrate for chymase-dependent AngII generation were investigated in Sprague-Dawley rats using an isolated heart model of cardiac ischaemia-reperfusion injury. PA12 potently constricted coronary arteries with no significant effect on left-ventricular contractility.

Biochemistry of ghrelin precursor peptides.

Since its discovery in 1999, the stomach-derived hormone ghrelin has been studied intensively. Proghrelin is 94 amino acids long in mammals and this undergoes proteolytic processing to produce ghrelin [residues 1-28 of proghrelin(1-94)] and the C-terminal peptide C-ghrelin, which likely contains the entire 66 amino acids of the prohormone C-terminus. The accumulating data identifies ghrelin as having important roles in growth hormone (GH) release, appetite, metabolism, energy balance, cardiovascular function, reproduction, and bone growth.

Direct cardiac actions of erythropoietin (EPO): effects on cardiac contractility, BNP secretion and ischaemia/reperfusion injury.

EPO (erythropoietin) has recently been shown to have protective actions upon the myocardium; however, the direct effects of EPO upon cardiac contractile and secretory functions are unknown and the signalling mechanisms are not well defined. In the present study, we provide the first evidence of direct cardiac contractile actions of EPO. In isolated perfused Sprague-Dawley rat hearts, a 30 min infusion of EPO significantly increased contractility in a dose-dependent fashion (maximal change 18+/-2% with 1 unit/ml EPO; P<0.