Characterization of late-outgrowth EPCs.

<p>Morphology and phenotype of late-outgrowth EPC derived from human peripheral blood mononuclear cells. Colonies of late-outgrowth EPCs with a cobblestone-like morphology (A). Representative flow cytometry analysis of late-outgrowth EPCs (red) compared to early EPCs (purple) for the expression of CD31, KDR, CD146 and CD14 (B). Immunofluorescent staining of late-outgrowth EPCs for CD34, Ve-cad (vascular endothelial cadherin) and vWF (von Willebrand factor) (C), immunofluorescence staining of late-outgrowth EPC for DiI-LDL (red), lectin (green) and merge (bar = 50 µm) (D). eNOS and GAPDH gene expression in late EPCs (E) (bp = base pairs; eNOS = endothelial nitric oxide synthase; GAPDH = Glyceraldehyde 3-phosphate dehydrogenase).</p

Clinical characteristics of the study population.

<p>Data expressed as mean±SD or N. Laboratory and diagnostic assays were from fasted blood samples.</p><p>HbA_1c = glycated hemoglobin;</p><p>HDL = high-denisty lipoprotein;</p><p>LDL = low-density lipoprotein;</p><p>GOT = glutamic-oxaloacetic transaminase;</p><p>GPT = glutamic-pyruvic transaminase;</p><p>BMI = body mass index;</p><p>SBP = systolic blood pressure;</p><p>DBP = diastolic blood pressure.</p><p>Cigarette smoking refers to current cigarette smoker.</p

Pioglitazone effect on EPC pro-inflammatory molecule expression.

<p>Effect of pioglitazone on PPARγ, adhesion molecule and TNFα expression in EPCs. PPARγ gene expression in early and late-outgrowth EPC exposed to pioglitazone (10 µM) and pioglitazone + GW9662 (1 µM) (A) Effect of pioglitazone in modulating ICAM-1 and VCAM-1 expression by early and late-outgrowth EPCs (cytofluorimetric analyses). Results are reported as delta % of MFI (mean fluorescence intensity) with vehicle condition (B). Effects of pioglitazone on TNFα gene (C) and protein (D) expression in early and late-outgrowth EPC. (*p<0.05 vs vehicle; **p<0.01 vs vehicle). Real time PCR data are expressed as −ΔΔCt and represent the relative gene expression of EPC cultured in the presence of pioglitazone 10 µM (with or without GW9662 1 µM) in relation to vehicle, normalized for the endogenous control GAPDH. Protein expression is measured with ELISA assay from culture supernatants. Results from five independent experiments performed in duplicate are shown (*p<0.05 vs vehicle) (Pio = pioglitazone).</p

Effect of pioglitazone on EPC function.

<p>Effect of pioglitazone (10 µM), pioglitazone + GW9662 (1 µM) and vehicle culture conditions on early and late-outgrowth EPC tube formation capacity expressed as total tube length (A) and as number of closed circles formed by tube-like structures (B); representation of early and late-outgrowth EPC tube formation assay showing the network formed by EPCs plus HUVEC on Matrigel (EPCs are red stained with Dil) in the presence of pioglitazone and vehicle (C); (*p<0.05 vs vehicle) (Pio = pioglitazone).</p

Effect of pioglitazone on EPC viability.

<p>The effects of pioglitazone (10 µM), pioglitazone (10 µM) + GW9662 (1 µM) and 0.2% DMSO vehicle culture conditions were examined on early (A) and late-outgrowth EPC viability alone and in the presence of H₂O₂ (500 µM, 24 h) (B); (*p<0.05 vs vehicle; **p<0.01 vs vehicle; §p<0.01 vs vehicle+H₂O₂).</p

Implications of serial measurements of natriuretic peptides in heart failure: insights from BIOSTAT-CHF

Natriuretic peptides [NP, including B-typenatriuretic peptide (BNP) and amino-terminalprohormone of BNP (NT-proBNP)] arethe gold-standard biomarkers in heart failure (HF) management,1 with NP levels atpresentation/admission routinely used fordiagnostic and prognostic purposes. NPlevels at discharge/follow-up also showassociation with outcomes, and NP levelsfollowing HF treatment add further value totailoring risk. However, the usefulness of NPserial measurements beyond conventionalHF treatment in clinical practice still remainsa matter of controversy. A cohort withcurrent HF guideline-based treatment wouldprovide an ideal setting to revisit usefulnessof NP serial measurements in risk stratification of HF patients, including the role ofrecently identified BNP molecular forms.The European multi-national BIOlogy Studyto TAilored Treatment in Chronic HeartFailure (BIOSTAT-CHF) provides an opportunity for the aforementioned analysis, beinga European cohort in which serial sampling ofNPs was done before and after titration of HFmedications according to current Europeanguidelines in a multi-centre, observational,real-world setting.</div

Additional file 1 of Intravenous ferric carboxymaltose for iron repletion following acute heart failure in patients with and without diabetes: a subgroup analysis of the randomized AFFIRM-AHF trial

Additional file 1: Table S1. First-time initiation of therapy within new diabetes medication class* during the AFFIRM-AHF trial. Fig S1. Outcomes in the placebo arms of patients with and without diabetes. Fig S2. Outcomes with FCM vs placebo in patients with and without diabetes (COVID-19 sensitivity analysis). Fig S3. Iron parameters with FCM vs placebo in patients with and without

Biomarker signature and pathophysiological pathways in chronic heart failure patients with metabolic syndrome.

AimThe comorbidities that collectively define metabolic syndrome are common in patients with heart failure. However, the role of metabolic syndrome in the pathophysiology of heart failure is not well understood. We therefore investigated the clinical and biomarker correlates of metabolic syndrome in patients with heart failure.MethodsIn 1103 patients with heart failure, we compared the biomarker expression using a panel of 363 biomarkers among patients with (n = 468[42%]) and without (n = 635[58%]) metabolic syndrome. Subsequently, a pathway overrepresentation analysis was performed to identify key biological pathways. Findings were validated in an independent cohort of 1433 patients with heart failure of whom 615 (43%) had metabolic syndrome. Metabolic syndrome was defined as the presence of ≥ three of five criteria, including central obesity, elevated serum triglycerides, reduced high-density lipoprotein cholesterol, insulin resistance and hypertension.ResultsThe most significantly elevated biomarkers in patients with metabolic syndrome were leptin (log2 fold change 0.92,P = 5.85 × 10-21 ), fatty acid-binding protein 4 (log2 fold change 0.61,P = 1.21 × 10-11 ), interleukin-1 receptor antagonist (log2 fold change 0.47,P = 1.95 × 10-13 ), tumour necrosis factor receptor superfamily member 11a (log2 fold change 0.35,P = 4.16 × 10-9 ), and RET proto-oncogene (log2 fold change 0.31,P = 4.87 × 10-9 ). Network analysis identified 10 pathways in the index cohort and 6 in the validation cohort, all related to inflammation. The primary overlapping pathway in both the index and validation cohort was up-regulation of the natural killer cell-mediated cytotoxicity pathway.ConclusionMetabolic syndrome is highly prevalent in heart failure and is associated with biomarkers and pathways relating to obesity, lipid metabolism and immune responses underlying chronic inflammation. This article is protected by copyright. All rights reserved

Distinct pathophysiological pathways in women and men with heart failure

Aims: Clinical differences between women and men have been described in heart failure (HF). However, less is known about the underlying pathophysiological mechanisms. In this study, we compared multiple circulating biomarkers to gain better insights into differential HF pathophysiology between women and men. Methods and results: In 537 women and 1485 men with HF, we compared differential expression of a panel of 363 biomarkers. Then, we performed a pathway over-representation analysis to identify differential biological pathways in women and men. Findings were validated in an independent HF cohort (575 women, 1123 men). In both cohorts, women were older and had higher left ventricular ejection fraction (LVEF). In the index and validation cohorts respectively, we found 14/363 and 12/363 biomarkers that were relatively up-regulated in women, while 21/363 and 14/363 were up-regulated in men. In both cohorts, the strongest up-regulated biomarkers in women were leptin and fatty acid binding protein-4, compared to matrix metalloproteinase-3 in men. Similar findings were replicated in a subset of patients from both cohorts matched by age and LVEF. Pathway over-representation analysis revealed increased activity of pathways associated with lipid metabolism in women, and neuro-inflammatory response in men (all p < 0.0001). Conclusion: In two independent cohorts of HF patients, biomarkers associated with lipid metabolic pathways were observed in women, while biomarkers associated with neuro-inflammatory response were more active in men. Differences in inflammatory and metabolic pathways may contribute to sex differences in clinical phenotype observed in HF, and provide useful insights towards development of tailored HF therapies

Heart failure with normal LVEF in BIOSTAT-CHF

Aims: Several studies have shown that heart failure (HF) drug treatment seems to benefit patients with preserved ejection fraction (HFpEF) and a left ventricular ejection fraction (LVEF) up to 55–60% but not with higher LVEF. Certain HF drugs are now indicated in patients with HFpEF and a LVEF below normal. However, not much is known about patients with a normal LVEF. Therefore, we investigated the prevalence, clinical characteristics and outcome of patients with HF and a normal LVEF.  Methods and results: Normal LVEF was defined according to the Recommendations for Cardiac Chamber Quantification from the American Society of Echocardiography as a LVEF ≥62% for men and ≥ 64% for women. Preserved ejection fraction was defined as a LVEF ≥50% and reduced ejection fraction as a LVEF Conclusion: Only 3.6% of patients with HF had a sex-adjusted normal LVEF. Despite the sex-adjusted cut-offs they were more frequently female with less ischemic heart disease, higher cardiac output and better clinical outcomes.</p