mocetinostat and Heart-Failure

Chronic kidney disease (CKD) is associated with high cardiovascular risk and mortality. Myeloperoxidase (MPO) has been linked to adverse events in patients with mild-moderate CKD. We sought to investigate whether MPO levels are associated with adverse outcomes in patients with CKD. We studied participants with mild to moderate CKD in the prospective chronic renal insufficiency cohort (CRIC). We followed patients for incident heart failure (HF), death, and composite outcome (myocardial infarction, incident peripheral arterial disease, cerebrovascular accident and death). A total of 3872 patients were included (2702 without CVD, 1170 with CVD). After multiple adjustments, doubling of MPO in patients with prior CAD was associated with risk of HF (HR 1.15 [1.01-1.30], P = 0.032) and mortality (HR 1.16 [1.05-1.30], P = 0.005), and composite outcome of MI, PAD, CVA and death (HR 1.12 [1.01-1.25], P = 0.031). In this cohort of patients with mild to moderate CKD and CAD, MPO levels are independently associated with incident HF, all-cause mortality, and a composite outcome.

Topics: Coronary Artery Disease; Heart Failure; Humans; Peroxidase; Prospective Studies; Renal Insufficiency, Chronic; Risk Factors; Stroke

Myocardial inflammation following acute ischemic injury has been linked to poor cardiac remodeling and heart failure. Many studies have linked myeloperoxidase (MPO), a neutrophil and inflammatory marker, to cardiac inflammation in the setting of acute coronary syndrome (ACS). However, the prognostic role of MPO for adverse clinical outcomes in ACS patients has not been well established.. MEDLINE and Cochrane databases were searched for studies from 1975 to March 2018 that investigated the prognostic value of serum MPO in ACS patients. Studies which have dichotomized patients into a high MPO group and a low MPO group reported clinical outcomes accordingly and followed up patients for at least 30 days to be eligible for enrollment. Data were analyzed using random-effects model. Sensitivity analyses were conducted for quality control.. Our meta-analysis included 13 studies with 9090 subjects and a median follow-up of 11.4 months. High MPO level significantly predicted mortality (odds ratio (OR) 2.03; 95% confidence interval (CI): 1.40-2.94;. Our meta-analysis suggests that high MPO levels are associated with the risk of mortality and that MPO can be incorporated in risk stratification models that guide therapy of high-risk ACS patients.

Topics: Acute Coronary Syndrome; Arrhythmias, Cardiac; Biomarkers; C-Reactive Protein; Female; Heart Failure; Humans; Inflammation; Male; Myocardial Infarction; Odds Ratio; Peroxidase; Predictive Value of Tests; Prognosis; Recurrence; Regression Analysis; Risk Assessment; Sensitivity and Specificity; Sex Factors; Signal Transduction; Smoking; Treatment Outcome

Myeloperoxidase (MPO), a heme protein released by leukocytes, is one of the most widely studied during the last decades molecule that plays a crucial role in inflammation and oxidative stress in the cellular level. It has become increasingly recognized that MPO performs a very important role as part of the innate immune system through the formation of microbicidal reactive oxidants, whilst it affects the arterial endothelium with a number of mechanisms that include modification of net cellular cholesterol flux and impairment of Nitric Oxide (NO)-induced vascular relaxation. In that way, MPO is implicated into both the formation and propagation of atheromatosis and there is substantial evidence that it also promotes ischemia through destabilization of the vulnerable plaque. Numerous studies have added information on the notion that MPO and its oxidant products are part of the inflammatory cascade initiated by endothelial injury and they are significantly overproduced at the site of arterial inflammation. Subsequent studies achieved quantification of this observation showing significant elevations of the systemic levels of MPO in a wide spectrum of cardiovascular disease scenarios with acute coronary syndromes and heart failure being the most studied. This review highlights key-aspects of MPO's pathophysiological properties and summarizes the role of MPO as a diagnostic and prognostic tool for a number of cardiovascular pathologies.

Topics: Animals; Biomarkers; Cardiovascular Diseases; Endothelium, Vascular; Halogens; Heart Failure; Humans; Hydrogen Peroxide; Hypertension; Inflammation; Metabolic Syndrome; Oxidative Stress; Peroxidase; Predictive Value of Tests; Prognosis

Myeloperoxidase (MPO) is an enzyme found in myeloid cells, particularly in neutrophils, and to a lesser extent in monocytes and tissue macrophages. MPO plays an important role in the host defense against bacteria and viruses. Since MPO is also an important enzyme in the inflammatory process, and inflammation is a key component in the development and progression of atherosclerotic and other forms of cardiovascular disease, there is ongoing interest in the use of MPO as a biomarker in different fields of cardiology. We aimed to review the current state of literature regarding the role of MPO in cardiovascular disease, especially highlighting the practical implications of the fast growing data from clinical studies.

Topics: Cardiology; Cardiovascular Diseases; Coronary Artery Disease; Disease Progression; Heart Failure; Humans; Inflammation; Lipoproteins, LDL; Macrophages; Monocytes; Neutrophils; Peroxidase

In this review, we present recent insights on chronic heart failure (CHF) and the potential role of tumor necrosis factor (TNF)-alpha, interleukins, myeloperoxidase (MPO), and nitrosative stress in the progression of this disease process. Reactive oxygen species (ROS) are produced as a consequence of aerobic metabolism. Under physiologic conditions, their unfavourable effect in causing oxidative damage is counteracted by antioxidants. An imbalance in favour of oxidants leads to oxidative stress, and contributes to myocyte apoptosis, direct negative inotropic effects, and reduced bioavailability of nitric oxide (NO). Together, these effects lead to impaired vasodilatation of the coronary, pulmonary and peripheral vascular beds. In patients with moderate to severe forms of CHF, TNF-alpha leads to the formation of nitrotyrosine and consumption of nitric oxide by virtue of activation of myeloperoxidase. Further studies are required to better elucidate the complex interaction of oxidative stress, endothelial dysfunction and inflammatory activation in CHF. Such insights would likely lead to development of better strategies for the assessment of the disease severity by monitoring of new bio-humoral indices and better treatment approaches.

Topics: Biomarkers; Chronic Disease; Endothelium, Vascular; Heart Failure; Humans; Natriuretic Peptide, Brain; Nitrosation; Oxidative Stress; Peroxidase

Endothelial cells are key modulators of diverse physiological processes, and their impaired function is a cause of numerous cardiovascular diseases. Under physiologic condition, the reactive oxygen and nitrogen mediators in endothelia lead to the signal propagation of the initial stimulus, by forming molecules with a longer half-life like hydrogen peroxide. Hydrogen peroxide is the focus of growing attention in endothelial biology, and consequently the enzymes involved in its generation and clearance are viewed as novel mediators of great importance. In particular, among peroxidases, myeloperoxidase is recognized as a key enzyme, capable of impairing intracellular NO reservoirs as well as producing oxidized amino acids such as 3-chlorotyrosine or 3-nitrotyrosine. This process switches the functional pathways from normal signalling to a condition characterized by oxidative and/or nitrosative stress. Understanding the molecular mechanisms involved in these stress responses in endothelium will lead to better therapeutic strategies for oxidative stress-driven cardiovascular diseases.

Topics: Chronic Disease; Endothelium, Vascular; Heart Failure; Humans; Oxidative Stress; Peroxidase; Reactive Oxygen Species

Oxidative stress is the relative excess of reactive oxygen species (ROS) versus endogenous defense mechanisms. Abundant evidence has demonstrated the role of ROS, along with reactive nitrogen species (RNS), in the pathophysiology of cardiovascular disease, including heart failure. Many biomarkers of oxidative stress have been studied as surrogates of oxidative damage. Recently, markers of impaired nitric oxide signaling have also been identified. Many biomarkers have been associated with prognosis and mortality, and some may even be modified by therapy. However, the clinical utility is limited by less than optimal standardization techniques and the lack of sufficient large-sized, multimarker prospective trials.

Topics: Biomarkers; Heart Failure; Hemoglobins; Humans; Lipoproteins, LDL; Oxidative Stress; Peroxidase; Uric Acid

Topics: Biomarkers; C-Reactive Protein; Cytokines; Fatty Acid-Binding Proteins; Heart Failure; Humans; Inflammation; Myosin Light Chains; Natriuretic Peptide, Brain; Norepinephrine; Nurse's Role; Nursing Assessment; Peroxidase; Prognosis; Risk Assessment; Sensitivity and Specificity; Troponin

Systemic microvascular dysfunction and inflammation are postulated to play a pathophysiologic role in heart failure with preserved ejection fraction (HFpEF).. This study aimed to identify biomarker profiles associated with clinical outcomes in HFpEF and investigate how inhibition of the neutrophil-derived reactive oxygen species-producing enzyme, myeloperoxidase, affects these biomarkers.. Using supervised principal component analyses, the investigators assessed the associations between baseline plasma proteomic Olink biomarkers and clinical outcomes in 3 independent observational HFpEF cohorts (n = 86, n = 216, and n = 242). These profiles were then compared with the biomarker profiles discriminating patients treated with active drug vs placebo in SATELLITE (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure), a double-blind randomized 3-month trial evaluating safety and tolerability of the myeloperoxidase inhibitor AZD4831 in HFpEF (n = 41). Pathophysiological pathways were inferred from the biomarker profiles by interrogation of the Ingenuity Knowledge Database.. TNF-R1, TRAIL-R2, GDF15, U-PAR, and ADM were the top individual biomarkers associated with heart failure hospitalization or death, and FABP4, HGF, RARRES2, CSTB, and FGF23 were associated with lower functional capacity and poorer quality of life. AZD4831 downregulated many markers (most significantly CDCP1, PRELP, CX3CL1, LIFR, VSIG2). There was remarkable consistency among pathways associated with clinical outcomes in the observational HFpEF cohorts, the top canonical pathways being associated with tumor microenvironments, wound healing signaling, and cardiac hypertrophy signaling. These pathways were predicted to be downregulated in AZD4831 relative to placebo-treated patients.. Biomarker pathways that were most strongly associated with clinical outcomes were also the ones reduced by AZD4831. These results support the further investigation of myeloperoxidase inhibition in HFpEF.

Topics: Antigens, Neoplasm; Biomarkers; Cell Adhesion Molecules; Heart Failure; Humans; Peroxidase; Proteomics; Quality of Life; Stroke Volume

Mitiperstat (formerly AZD4831) is a novel selective myeloperoxidase inhibitor. Currently, no effective therapies target comorbidity-induced systemic inflammation, which may be a key mechanism underlying heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). Circulating neutrophils secrete myeloperoxidase, causing oxidative stress, microvascular endothelial dysfunction, interstitial fibrosis, cardiomyocyte remodelling and diastolic dysfunction. Mitiperstat may therefore improve function of the heart and other organs, and ameliorate heart failure symptoms and exercise intolerance. ENDEAVOR is a combined, seamless phase 2b-3 study of the efficacy and safety of mitiperstat in patients with HFpEF/HFmrEF.. In phase 2b, approximately 660 patients with heart failure and ejection fraction >40% are being randomized 1:1:1 to mitiperstat 2.5 mg, 5 mg or placebo for 48 weeks. Eligible patients have baseline 6-min walk distance (6MWD) of 30-400 m with a <50 m difference between screening and randomization and Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) ≤90 points at screening and randomization. The dual primary endpoints are change from baseline to week 16 in 6MWD and KCCQ-TSS. The sample size provides 85% power to detect placebo-adjusted improvements of 21 m in 6MWD and 6.0 points in KCCQ-TSS at overall two-sided alpha of 0.05. Safety is monitored throughout treatment, with a focus on maculopapular rash. In phase 3 of ENDEAVOR, approximately 820 patients will be randomized 1:1 to mitiperstat or placebo.. ENDEAVOR is the first phase 2b-3 study to evaluate whether myeloperoxidase inhibition can improve symptoms and exercise capacity in patients with HFpEF/HFmrEF.

Topics: Comorbidity; Exercise Tolerance; Heart Diseases; Heart Failure; Humans; Peroxidase; Stroke Volume

We evaluated safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics of AZD4831, a novel oral myeloperoxidase (MPO) inhibitor, in a randomized, single-blind, placebo-controlled study, following once-daily multiple ascending dosing to steady-state in healthy subjects. Target engagement was measured as specific MPO activity in plasma following ex vivo zymosan stimulation of whole blood. Except for generalized maculopapular rash in 4 of 13 subjects receiving the 2 highest doses, 15 and 45 mg AZD4831, no clinically relevant safety and tolerability findings were observed. AZD4831 was rapidly absorbed and plasma concentrations declined slowly with an elimination half-life of ~ 60 hours. A dose/concentration-effect relationship between MPO inhibition vs. AZD4831 exposure was established with > 50% MPO inhibition in plasma at concentrations in the low nanomolar range. Steady-state levels were achieved within 10 days. Taken together, the PK profile, the sustained dose/concentration-dependent MPO inhibition, and available clinical data support further clinical development of AZD4831 in patients with heart failure with preserved ejection fraction.

Topics: Administration, Oral; Adult; Dose-Response Relationship, Drug; Double-Blind Method; Healthy Volunteers; Heart Failure; Humans; Male; Middle Aged; Peroxidase; Pyrimidines; Pyrroles; Single-Blind Method; Stroke Volume; Ventricular Function, Left; Young Adult

The role of neutrophil extracellular traps (NETs) in acute heart failure is unknown. We recently showed that interleukin 8, a putative NETs stimulator, was associated with myocardial recovery in acute heart failure complicating ST-elevation myocardial infarction (STEMI). In this exploratory post-hoc study, we aimed to investigate the role of NETs components in relation to myocardial function and interleukin 8 in STEMI patients with symptomatic acute heart failure.. In 61 STEMI patients developing acute heart failure within 48 hours of successful revascularization, wall motion score index (WMSI), global longitudinal strain (GLS) and left ventricular ejection fraction (LVEF) were assessed by echocardiography at baseline and on day 5. Blood drawn at baseline and days 1, 2 and 5 was used to quantify double-stranded DNA (dsDNA), myeloperoxidase-DNA complexes (MPO-DNA) and citrullinated histone 3 (CitH3). The area under the curve (AUC) of each NETs marker and interleukin 8 was approximated for the first 5 days.. dsDNAAUC and MPO-DNAAUC correlated significantly with change in WMSI from baseline to day 5 (rs = 0.28 for both, p≤0.05), whereas NETs AUCs did not correlate with changes in GLS and LVEF. dsDNAAUC was significantly correlated with interleukin 8AUC (r = 0.40, p = 0.003). However, mixed model regression could not identify a significant effect of the NETs components on myocardial function parameters.. In this cohort with acute heart failure complicating STEMI, NETs components were partly correlated with myocardial function and interleukin 8 levels, yet no causal relationship between NETs components and myocardial recovery could be established.. ClinicalTrials.gov, identifier: NCT00324766.

Topics: Adult; Aged; Aged, 80 and over; DNA; Echocardiography; Extracellular Traps; Female; Heart Failure; Histones; Humans; Interleukin-8; Male; Middle Aged; Myocardium; Peroxidase; Recovery of Function; ST Elevation Myocardial Infarction

Endothelial progenitor cells (EPCs) contribute to the maintenance of endothelial integrity and function. We investigated the effects of rosuvastatin and allopurinol on the number of EPCs in patients with heart failure and aimed to provide insight into the molecular inflammatory and oxidative mechanisms that could be responsible for the alterations in EPC levels after treatment.. Sixty patients with systolic heart failure were randomized to receive rosuvastatin 10mg/d, allopurinol 300mg/d or placebo and followed up for 1 month. The number of CD34(+)/KDR(+) and CD34(+)/CD133(+)/KDR(+) EPCs in blood was evaluated by flow cytometry. Endothelial function was assessed by brachial artery flow-mediated dilation. Levels of markers of inflammation and oxidative stress were also determined.. Circulating EPCs were significantly increased after rosuvastatin treatment (from 230 (170-380) and 10 (8-24) to 390 (230-520) and 19 (8-33) cells/10(6) lymphomonocytes, respectively, p=0.004 and p=0.008), whereas they remained unchanged in the other groups. The increase in EPC levels was not associated with the changes in the levels of the measured inflammatory and oxidative markers.. Short-term treatment with rosuvastatin, but not allopurinol, significantly increases the number of circulating EPCs in patients with heart failure providing further insights into its role in these individuals. The impact of rosuvastatin on EPCs is not mediated by changes in inflammatory and oxidative status.

Topics: AC133 Antigen; Aged; Allopurinol; Antigens, CD; Antigens, CD34; Endothelial Cells; Enzyme Inhibitors; Female; Fluorobenzenes; Glycoproteins; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Middle Aged; Oxidative Stress; Peptides; Peroxidase; Pyrimidines; Rosuvastatin Calcium; Stem Cells; Sulfonamides; Vascular Endothelial Growth Factor Receptor-2; Xanthine Oxidase

Studies indicate that myeloperoxidase (MPO) is associated with disease progression and severity in heart failure (HF), while it may provide a mechanistic link between inflammation and adverse cardiac remodeling. The mechanisms that regulate MPO are unclear, while it is unknown whether specific treatments such as HMG-CoA reductase inhibitors and xanthine oxidase inhibitors may modify MPO. Therefore in the present study we examined the effects of rosuvastatin and allopurinol on MPO levels in patients HF.. Sixty clinically stable patients with systolic HF were randomized to receive rosuvastatin 10mg/day, allopurinol 300mg/day or placebo and followed up for 1 month. Plasma levels of MPO and serum levels of soluble CD40 ligand, interleukin-6, and oxidized LDL were determined using ELISA. All measurements were made before and after 1-month treatment.. Rosuvastatin significantly reduced plasma levels of MPO (p=0.003), which remained unchanged in the other groups. Furthermore, the change of MPO levels in the rosuvastatin-treated group was significantly different compared with the other groups (p<0.05). Rosuvastatin administration also led to a significant decrease in oxidized LDL (p=0.009), while the other inflammatory markers remained unchanged in all groups. In the total population, a significant correlation was observed between the baseline levels of MPO and hsCRP (r=0.275, p=0.027), fibrinogen (r=0.278, p=0.025), and sCD40L (r=0.288, p=0.021).. Short-term treatment with rosuvastatin regulates inflammatory process in patients with heart failure by significantly reducing plasma levels of MPO. This finding reveals a novel pleiotropic effect of statins in patients with heart failure, and provides further insights into the pathophysiological mechanisms of MPO in heart failure.

Topics: Aged; Allopurinol; Biomarkers; Cholesterol; Cholesterol, LDL; Chronic Disease; Female; Fluorobenzenes; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Peroxidase; Pyrimidines; Rosuvastatin Calcium; Sulfonamides; Triglycerides

Myeloperoxidase levels were shown to reflect endothelial dysfunction, inflammation, atherosclerosis and oxidative stress.. To examine the role of circulating myeloperoxidase, a leukocyte-derived enzyme, as a predictor of mortality in patients with congestive heart failure.. Baseline serum MPO levels were measured in 285 consecutive CHF patients and 35 healthy volunteers. N-terminal pro-brain natriuretic peptide and high sensitivity C-reactive protein concentrations were also measured. The primary outcome endpoint was overall mortality.. MPO levels were significantly elevated in patients with CHF compared to healthy volunteers (P = 0.01). During a mean follow-up of 40.9 +/- 11.3 months there were 106 deaths. On a univariate Cox regression analysis MPO levels were of marginal value (P = 0.07) whereas NT-proBNP was of considerable value (P < 0.0001) in predicting all-cause mortality. By dividing our cohort according to NT-proBNP levels into high, intermediate and low risk groups a clear difference in mortality was shown. By further dividing the patient cohort according to MPO levels above or below the median (122.5 ng/ml), mortality prediction improved in the patients with intermediate NT-proBNP values.. MPO levels are elevated in CHF and correlate with disease severity. MPO has an additive predictive value on mortality in patients with intermediate NT-proBNP levels.

Topics: Aged; C-Reactive Protein; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Oxidative Stress; Peptide Fragments; Peroxidase; Predictive Value of Tests; Proportional Hazards Models; Severity of Illness Index; Surveys and Questionnaires

The causality between myeloperoxidase (MPO) and cardiovascular disease still remains unclear. We performed a two-sample Mendelian randomization (MR) study to estimate the potential causal effect of MPO on the risks of ischemic stroke, ischemic stroke subtypes, heart failure (HF), and atrial fibrillation (AF).. Seventeen independent single-nucleotide polymorphisms associated with MPO levels were identified as instrumental variables from a European-descent genome-wide association study. Summary-level data on ischemic stroke originated from the Multiancestry Genome-wide Association Study of Stroke Consortium with 440 328 European individuals. We used the inverse-variance weighted method to assess the potential causality of plasma MPO with ischemic stroke and its subtypes in the main analysis. Genetically determined higher plasma MPO concentration was significantly associated with increased risks of ischemic stroke (odds ratio [OR] per standard deviation [SD] increase, 1.05; 95% confidence interval [CI], 1.02-1.09; P = 0.002) and cardioembolic stroke (CES) (OR per SD increase, 1.10; 95% CI, 1.03-1.18; P = 0.005), but was not associated with risks of large artery stroke or small vessel stroke. In the secondary analysis, MPO was associated with a high risk of HF (OR per SD increase, 1.05; 95% CI, 1.02-1.07; P = 0.001) and AF (OR per SD increase, 1.04; 95% CI, 1.01-1.07; P = 0.004). MR-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses further confirmed these findings.. High plasma MPO levels were potentially associated with increased risks of ischemic stroke, CES, HF, and AF, suggesting that MPO plays an important role in the development of cardiovascular disease.

Topics: Atrial Fibrillation; Genome-Wide Association Study; Heart Failure; Humans; Ischemic Stroke; Mendelian Randomization Analysis; Peroxidase; Polymorphism, Single Nucleotide; Stroke

Heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) are distinct clinical entities, yet there is scant evidence for associations of proteomic signatures with future development of HFpEF versus HFrEF.. We evaluated the association of 71 protein biomarkers with incident HFpEF versus HFrEF (left ventricular ejection fraction ≥ versus <50%) among Framingham Heart Study participants using multivariable Cox models.. Among 7038 participants (mean age 49 years; 54% women), 5 biomarkers were associated with increased risk of incident HFpEF (false discovery rate q<0.05): NT-proBNP (N-terminal pro-B-type natriuretic peptide; hazard ratio [HR], 2.13; 95% CI, 1.52-2.99;. We identified 5 protein biomarkers of new-onset HFpEF representing pathways of inflammation, cardiac stress, and vascular stiffness, which partly overlapped with HFrEF. We found 14 biomarkers associated with new-onset HFrEF, with some distinct associations including myeloperoxidase, resistin, and paraoxanase-1. Taken together, these findings provide insights into similarities and differences in the development of HF subtypes.. URL: https://clinicaltrials.gov/ct2/show/NCT00005121; Unique identifier: NCT0005121.

Topics: Biomarkers; C-Reactive Protein; Female; Growth Differentiation Factors; Heart Failure; Humans; Male; Middle Aged; Peroxidase; Prognosis; Proteomics; Resistin; Stroke Volume; Ventricular Function, Left

Topics: Heart Failure; Humans; Inflammation; Peroxidase; Stroke Volume; Ventricular Function, Left

Topics: Animals; Heart Failure; Humans; Iodide Peroxidase; Peroxidase; Pyrimidines; Pyrroles; Stroke Volume

This study aimed to determine if changes in myeloperoxidase (MPO) levels correlate with response to cardiac resynchronization therapy (CRT) and the potential role of MPO as a predictor of response to CRT.. CRT is a well-established treatment option in chronic heart failure (CHF) with 50-80% of patients benefiting. Inflammation and oxidative stress play a key role in CHF pathophysiology. Previous studies have demonstrated increased levels of MPO in CHF patients, but the correlation with CRT response remains incompletely understood.. Fifty-three patients underwent CRT implantation. During follow-up, patients were divided into two groups, responders and non-responders to CRT, based on improved physical capacity and NYHA classification. Levels of MPO and NT-pro-brain-natriuretic-peptide (NT-proBNP) were determined prior to implantation, 30 and 90 days after. Physical capacity, including a 6-min walking-test, NYHA class, and LVEF were evaluated at baseline and during follow-up.. Thirty-four patients (64%) responded to CRT, showing improved physical capacity and LVEF. All responders revealed a significant decrease of MPO levels (503.8 ng/ml vs. 188.4 ng/ml; p < 0.001). Non-responding patients did not show any significant changes in clinical parameters or MPO levels (119.6 ng/ml vs. 134.3 ng/ml; p = 0.672) during follow-up. At baseline, physical capacity and NYHA class, as well as MPO levels differed significantly between both groups (p < 0.001). A ROC analysis identified an MPO cut-off value for response to CRT of 242 ng/ml with a sensitivity of 93.5% and specificity of 71.4%. There was a strong correlation between MPO and improvement of LVEF (Spearman's rho: - 0.453; p = 0.005) and physical capacity (Spearman's rho: - 0.335; p = 0.042).. Response to CRT and course of MPO levels correlate significantly. MPO levels differ between responders and non-responders prior to CRT, which may indicate an additional value of MPO as a predictor for CRT response. Further randomized studies are required to confirm our data in larger patient cohorts.

Topics: Aged; Biomarkers; Cardiac Resynchronization Therapy; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Peroxidase; Predictive Value of Tests

Brain natriuretic peptide is an established, surrogate follow-up marker, strongly correlated with heart failure severity. Several other biomarkers and tests are useful for assessing the prognosis of patients with HF, such as oxidized low-density lipoprotein antibodies and C-reactive protein. Some inflammatory cells, including monocytes, lymphocytes, and neutrophils, are involved in coronary heart disease and may be useful for prognosis also. This study assessed the potential usefulness of various laboratory biomarkers in predicting long-term outcomes and hospitalization among a cohort of outpatients with chronic, advanced HF.This retrospective, 18-year follow-up study included all patients admitted to the Heart Failure Outpatient Unit in our tertiary care medical center from 2000 through 2001 due to chronic HF. Excluded were patients with malignant disease, severe stroke, active inflammatory disease, or infection. At the first visit, blood was sampled for routine analysis and biomarkers NT-proBNP, C-reactive protein, myeloperoxidase, heat shock protein, and antibodies to oxidized low density lipoprotein. left ventricular ejection fraction and New York Heart Association class class were also established. Patients were followed every 3 months. Study endpoints were mortality or first hospitalization.Among 305 study patients, HF duration ranged from 2 months to 18 years. Mean follow-up was 9.1 ± 6 years. Mean time to first hospitalization was 60 ± 58.1 months, median = 38 (range 0-179). Mortality rate was 41%. Regression analysis showed New York Heart Association class, lymphocyte count and alkaline phosphatase were independent predictors of survival, with hazard ratios of 1.0, 0.973, and 1.006, respectively (P < .05).N-terminal pro-B-type natriuretic peptide, alkaline phosphatase, and lymphocyte count are important prognostic predictors for very long-term follow-up among patients with chronic HF.

Topics: Age Factors; Aged; Aged, 80 and over; Biomarkers; Blood Pressure; Body Weight; C-Reactive Protein; Chronic Disease; Comorbidity; Female; Follow-Up Studies; Heart Failure; Heart Rate; Heat-Shock Proteins; Hematologic Tests; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Peroxidase; Retrospective Studies; Sex Factors; Ventricular Function, Left

The study is aimed at investigating the changes in expressions of heat shock protein 27 (HSP27), HSP70, and soluble glycoprotein (SGP) in heart failure (HF) rats complicated with pulmonary edema and exploring their potential correlations with cardiopulmonary functions. The rat model of HF was established, and the rats were divided into HF model group (model group,

Topics: Airway Resistance; Animals; Blood Urea Nitrogen; Compliance; Creatine Kinase; Creatinine; Gene Expression Regulation; Glycoproteins; Heart Failure; HSP27 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Matrix Metalloproteinase 9; Oxygen; Partial Pressure; Peroxidase; Pulmonary Edema; Rats, Sprague-Dawley; Solubility; Tumor Necrosis Factor-alpha

In heart failure (HF) with preserved ejection fraction (HFpEF), microvascular inflammation is proposed as an underlying mechanism. Myeloperoxidase (MPO) is associated with vascular dysfunction and prognosis in congestive HF.. In HFpEF, MPO-dependent oxidative stress reflected by uric acid and calprotectin is increased, and SDMA is associated with diastolic dysfunction and uric acid with outcome. This suggests microvascular neutrophil involvement mirroring endothelial dysfunction, a central component of the HFpEF syndrome and a potential treatment target.

Topics: Aged; Biomarkers; Female; Heart Failure; Humans; Inflammation; Male; Middle Aged; Peroxidase; Stroke Volume

Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury. In this study, we evaluate the role of lipopolysaccharide (LPS) and various inflammatory markers in the developing acute kidney injury (AKI) in acute heart failure (AHF) patients.. We enrolled 31 AHF patients and 20 CRS type 1 (the cause of AKI was presumed to be related to cardiac dysfunction) and 17 healthy volunteers without AHF, AKI or CKD, as control group (CTR). We assessed levels of LPS, proinflammatory cytokines (TNF-α, IL-6, IL-18), and oxidative stress marker (myeloperoxidase, MPO).. We observed a significant increase in LPS, TNF-α, IL-6, IL-18 and MPO levels in CRS type 1 and AHF group compared to CTR. LPS levels resulted significantly higher in CRS type 1 patients compared with AHF (118.2 pg/mL, IQR 77.8-217.6 versus 13.5 pg/mL, IQR 12.0-17.0, p = 0.008). We found a cytokines and oxidative stress dysregulation in CRS type 1 patients compared with AHF. Furthermore, we observed a strong positive significant correlation between LPS levels and IL-6 (Spearman's rho = 0.79, p < 0.001), and IL-18 (Spearman's rho = 0.77, p < 0.001) and MPO (Spearman's rho = 0.80, p < 0.001), all confirm by simple linear regression analysis.. CRS type 1 patients presented an increased level of LPS, pro-inflammatory cytokines, and MPO. Furthermore, there is a direct correlation between LPS and pro-inflammatory cytokines and stress oxidative marker. LPS may play a role in the pathophysiology of CRS type 1 inducing inflammation, oxidative stress and finally kidney damage.

Topics: Acute Disease; Acute Kidney Injury; Aged; Aged, 80 and over; Biomarkers; Cardio-Renal Syndrome; Female; Heart Failure; Humans; Inflammation; Interleukin-18; Interleukin-6; Lipopolysaccharides; Male; Oxidative Stress; Peroxidase; Prospective Studies; Tumor Necrosis Factor-alpha

The aim of current study was to investigate the level of Myeloperoxidase (MPO) in chronic heart failure patients with different severity and find the correlation with cardiac structural and functional markers and disease outcome. Initially eighty-six patients with different stages of CHF and ten healthy persons were included in our study. Excluded criteria were myocardial infarction or other concomitant acute diseases, renal failure (creatinine >250 µmol/L) in past 3 months. All patients underwent ECG, echocardiographic evaluation, anthropometric and other clinical examination, as well as plasma samples were collected for further analysis. MPO level (ng/ml) was measured by ELISA method, hs-CRP (mg/L) was measured by turbidimetric immunoassay and Leukocyte level (109/L) - by flow cytometry. Echocardiographic studies were performed using standard methods by parasternal and apical view. Statistical analyses were performed using IBM SPSS Statistics 16.0. After 6 month follow up we investigate our research primary outcome (mortality). The data were collected by telephone follow up from patients or members of family. Collection of information had been became possible in 79% of total cases (68 patients), from which 10 patients died: 8 cases were cardiovascular mortality, 1 case - suicide and 1 case from cancer. We found that MPO levels in the patients with CHF (mean value 9.3±7) are different from control group (mean value 4.19±2). MPO correlates with HF severity. MPO significantly were elevated in mortality group p<0,007 , as the level of hs-CRP p˂ 0.001. Changes of RV (right ventricule) sizes from normal ranges also were associated to worse outcome ( p<0.005). Depending on our data certain level of MPO (˃7.1 ng/ml) in studied patients and increased RVDD have independent importance for identification of patients with worse outcome.

Topics: Biomarkers; Echocardiography; Heart Failure; Humans; Myocardial Infarction; Peroxidase; Prognosis

A sensitive amperometric immunosensor has been prepared by immobilization of capture antibodies onto gold nanoparticles (AuNPs) grafted on a screen-printed carbon electrode (SPCE) through aryl diazonium salt chemistry using 4-aminothiophenol (AuNPs-S-Phe-SPCE). The immunosensor was designed for the accurate determination of clinically relevant levels of B-type natriuretic peptide (BNP) in human serum samples. The nanostructured electrochemical platform resulted in an ordered layer of AuNPs onto SPCEs which combined the advantages of high conductivity and improved stability of immobilized biomolecules. The resulting disposable immunosensor used a sandwich type immunoassay involving a peroxidase-labeled detector antibody. The amperometric transduction was carried out at -0.20V (vs the Ag pseudo-reference electrode) upon the addition of hydroquinone (HQ) as electron transfer mediator and H

Topics: Aniline Compounds; Antibodies; Biomarkers; Biosensing Techniques; Carbon; Diazonium Compounds; Electrochemical Techniques; Electrodes; Gold; Heart Failure; Humans; Hydrogen Peroxide; Hydroquinones; Immunoassay; Immunoconjugates; Metal Nanoparticles; Nanostructures; Natriuretic Peptide, Brain; Peroxidase; Sulfhydryl Compounds

Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Inflammation and oxidative stress seem to play a pivotal role in its pathophysiology. In this in vivo study, we examined the putative role of inflammation and humoral markers in the pathogenesis of the CRS type 1.. We enrolled 53 patients with acute heart failure (AHF); 17 of them developed AKI (CRS type 1). The cause of AKI was presumed to be related to cardiac dysfunction after having excluded other causes. We assessed the plasma levels of proinflammatory cytokines (TNF-α, IL-6, IL-18, sICAM, RANTES, GMCSF), oxidative stress marker (myeloperoxidase, MPO), brain natriuretic peptide (BNP), and neutrophil gelatinase-associated lipocalin (NGAL) in AHF and CRS type 1 patients.. We observed a significant increase in IL-6, IL-18, and MPO levels in CRS type 1 group compared to AHF (p < 0.001). We found higher NGAL at admission in the CRS type 1 group compared to the AHF group (p = 0.008) and a positive correlation between NGAL and IL-6 (Spearman's rho = 0.45, p = 0.003) and between IL-6 and BNP (Spearman's rho = 0.43, p = 0.004). We observed lower hemoglobin levels in CRS type 1 patients compared to AHF patients (p < 0.05) and inverse correlation between hemoglobin and cytokines (IL-6: Spearman's rho = -0.38, p = 0.005; IL-18: Spearman's rho = -0.32, p = 0.02).. Patients affected by CRS type 1 present increased levels of proinflammatory cytokines and oxidative stress markers, increased levels of tissue damage markers, and lower hemoglobin levels. All these factors may be implicated in the pathophysiology of CRS type 1 syndrome.

Topics: Acute Disease; Aged; Aged, 80 and over; Biomarkers; Cardio-Renal Syndrome; Cytokines; Heart Failure; Hemoglobins; Humans; Intercellular Signaling Peptides and Proteins; Lipocalin-2; Natriuretic Peptide, Brain; Oxidative Stress; Peroxidase; Receptors, Interleukin-6

Myeloperoxidase (MPO) is a heme-containing peroxidase found in azurophilic granules of neutrophils and monocytes. Epidemiological studies have reported greater plasma MPO concentration to be associated with increased incidence of several cardiovascular diseases (CVD), but the association of intracellular monocyte MPO (mMPO) with CVD is unclear. The prospective population-based Atherosclerosis Risk in Communities (ARIC) cohort study measured mMPO using flow cytometry in 1,465 participants. The association of mMPO with incident cardiovascular disease (CVD, comprising incident coronary heart disease (CHD), heart failure, stroke, peripheral artery disease, and cardiovascular mortality) was examined over a median 9.6 years of follow-up (n = 290 CVD events). There was no statistically significant association between mMPO and all incident CVD events in either age, sex, and race-adjusted proportional hazards models (HR (95% CI) across tertiles of mMPO: 1, 1.09 (0.76, 1.57), and 0.78 (0.52, 1.15), P-trend = 0.21) or adjusted for other major CVD risk factors (HR (95% CI): 1, 1.17 (0.81, 1.69), and 0.87 (0.58, 1.29), P-trend = 0.50). There also was no association between mMPO tertiles and incident CHD, heart failure, or all-cause mortality, examined separately. In conclusion, intracellular monocyte myeloperoxidase was not associated with incident cardiovascular disease in this prospective population-based study.

Topics: Aged; Atherosclerosis; Coronary Disease; Female; Flow Cytometry; Heart Failure; Humans; Male; Middle Aged; Monocytes; Peroxidase; Risk Factors

In addition to their role in the central nervous system (CNS), N-methyl-d-aspartate (NMDA) receptors activation contributes to myocardial pathogenesis. This study sought to determine the potential cardioprotective effects of pre-treatment with memantine, an NMDA receptor antagonist, in heart failure (HF). A subcutaneous injection of isoproterenol (5 mg/kg/day) for 14 days was used for the induction of heart failure in rats. Memantine was injected intraperitoneally (ip) at doses of 5 and 20 mg/kg one week before isoproterenol injection for 21 days (n = 8 each group). Then, hemodynamic, electrocardiogram and histopathological changes as well as lipid peroxidation, myeloperoxidase (MPO) and adenosine monophosphate-activated protein kinase (AMPK) activity were evaluated. Histopathological analysis showed a marked attenuation of myocyte necrosis and fibrosis in memantine 20 mg/kg pre-treated group (p < 0.001) in comparison to HF group. Pre-treatment with memantine 20 mg/kg significantly reduced myocardial edematous, MPO activity and malondialdehyde (MDA) levels in comparison to HF group (p < 0.05, p < 0.05 and p < 0.001 respectively). Memantine had no significant effect on hemodynamic parameters and AMPK activity but improved the electrocardiogram (ECG) pattern. Our results for the first time showed cardioprotective effects of memantine in HF through reduction in cardiac remodeling, lipid peroxidation and neutrophil infiltration. In addition these effects are through an AMPK-independent pathways.

Topics: Adenylate Kinase; Animals; Cardiotonic Agents; Electrocardiography; Heart Failure; Hemodynamics; Lipid Peroxidation; Male; Memantine; Myocardium; Neutrophil Infiltration; Neutrophils; Organ Size; Peroxidase; Phosphorylation; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Ventricular Remodeling

Myeloperoxidase (MPO) is a leukocyte-derived enzyme involved in the process of heart failure and is found to have good diagnostic and prognostic values in humans with chronic heart failure. This study evaluated the relationship between serum MPO levels and the severity of heart failure (HF) due to chronic mitral valvular insufficiency (CMVI) in dogs. Eighty-two client-owned dogs consisting of 69 dogs with different stages of HF due to CMVI and 13 age-matched healthy dogs were enrolled in this study. Serum MPO concentrations in the healthy and CMVI groups were determined by enzyme-linked immunosorbent assay (ELISA) using a canine-specific monoclonal anti-MPO antibody. Serum MPO concentrations were 273.3 ± 179.6 ng/L in the controls, 140.8 ± 114.1 ng/L in the International Small Animal Cardiac Health Council (ISACHC) I group, 109.0 ± 85.2 ng/L in the ISACHC II group, and 106.0 ± 42.3 ng/L in the ISACHC III group. Close negative correlation to serum MPO concentration was found in the severity of heart failure (ISACHC stage). Although this study found a modest relationship between serum MPO levels and the severity of HF due to CMVI in dogs, it also suggested that serum MPO levels decreased as the severity of HF increased.. La myéloperoxydase (MPO) est une enzyme dérivée des leucocytes impliquée dans le processus d’une défaillance cardiaque et est reconnue pour avoir une bonne valeur pour le diagnostic et le pronostic chez les humains souffrant d’insuffisance cardiaque chronique. La présente étude a évalué la relation entre les niveaux sériques de MPO et la sévérité de défaillance cardiaque (DC) due à une insuffisance chronique de la valvule mitrale (ICVM) chez des chiens. Quatre-vingt-deux chiens propriété de clients, dont 69 avec différents stades de DC due à une ICVM et 13 chiens en santé jumelés pour l’âge, ont été inclus dans cette étude. Les concentrations sériques de MPO chez les chiens en santé et les groupes de chiens avec ICVM ont été déterminées par épreuve immuno-enzymatique (ELISA) en utilisant un anticorps monoclonal anti-MPO spécifique à l’espèce canine. Les concentrations sériques de MPO étaient de 273,3 ± 179,6 ng/L chez les témoins, de 140,8 ± 114,1 ng/L dans le groupe I du Conseil International de la Santé Cardiaque des Animaux de Compagnie (CISCAS), de 109,0 ± 85,2 ng/L dans le groupe II du CISCAS, et de 106,0 ± 42,3 ng/L dans le groupe III du CISCAS. Une tendance vers une corrélation négative avec la concentration sérique de MPO a été trouvée dans la sévérité de la défaillance cardiaque (stade selon le CISCAS). Bien que dans cette étude une relation modeste entre le niveau sérique de MPO et la sévérité de DC due à une ICVM chez les chiens fut trouvée, il est aussi suggéré que les niveaux sériques de MPO diminuaient à mesure que la sévérité de la DC augmentait.(Traduit par Docteur Serge Messier).

Topics: Animals; Biomarkers; Case-Control Studies; Dog Diseases; Dogs; Heart Failure; Mitral Valve Insufficiency; Peroxidase

Several biomarkers have individually been shown to be useful for risk stratification in patients with acute myocardial infarction (MI). The optimal multimarker strategy remains undefined.. Biomarkers representing different pathobiological axes were studied, including myocardial stress/structural changes (NT-pro B-type natriuretic peptide [NT-proBNP], midregional proatrial natriuretic peptide [MR-proANP], suppression of tumorigenicity 2 [ST2], galectin-3, midregional proadrenomedullin [MR-proADM], and copeptin), myonecrosis (troponin T), and inflammation (myeloperoxidase [MPO], high sensitivity C-reactive protein [hsCRP], pregnancy-associated plasma protein A [PAPP-A], and growth-differentiation factor-15 [GDF-15]), in up to 1258 patients from Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28), a randomized trial of clopidogrel in ST-elevation MI (STEMI). Patients were followed for 30 days. Biomarker analyses were adjusted for traditional clinical variables. Forward step-wise selection was used to assess a multimarker strategy. After adjustment for clinical variables and using a dichotomous cutpoint, 7 biomarkers were each significantly associated with a higher odds of cardiovascular death or heart failure (HF) through 30 days, including NT-proBNP (adjusted odds ratio [ORadj], 2.54; 95% CI, 1.47-4.37), MR-proANP (2.18; 1.27-3.76), ST2 (2.88; 1.72-4.81), troponin T (4.13; 1.85-9.20), MPO (2.75; 1.20-6.27), hsCRP (1.96, 1.17-3.30), and PAPP-A (3.04; 1.17-7.88). In a multimarker model, 3 biomarkers emerged as significant and complementary predictors of cardiovascular death or HF: ST2 (ORadj, 2.87; 1.61-5.12), troponin T (2.34; 1.09-5.01 and 4.13, 1.85-9.20, respectively for intermediate and high levels), and MPO (2.49; 1.04-5.96). When added to the TIMI STEMI Risk Score alone, the multimarker risk score significantly improved the C-statistic (area under the curve, 0.75 [95% CI, 0.69-0.81] to 0.82 [0.78-0.87]; P=0.001), net reclassification index (0.93; P<0.001), and integrated discrimination index (0.09; P<0.001).. In patients with STEMI, a multimarker strategy that combines biomarkers across pathobiological axes of myocardial stress, myocyte necrosis, and inflammation provides incremental prognostic information for prediction of cardiovascular death or HF.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Blood Proteins; C-Reactive Protein; Cardiovascular Diseases; Female; Galectin 3; Galectins; Glycopeptides; Growth Differentiation Factor 15; Heart Failure; Humans; Interleukin-1 Receptor-Like 1 Protein; Male; Middle Aged; Natriuretic Peptide, Brain; Odds Ratio; Peptide Fragments; Peroxidase; Pregnancy-Associated Plasma Protein-A; Prognosis; Protein Precursors; Risk Assessment; ST Elevation Myocardial Infarction; Troponin T

Our aim was to investigate the possible relationship between myeloperoxidase (MPO) and myocardial damage markers such as heart-type fatty acid-binding protein (H-FABP) and troponin T (TnT) in patients with chronic heart failure (HF).. Forty-two consecutive patients (age range: 27-80 years) with chronic HF were enrolled in the study. Serum H-FABP, TnT and MPO levels were measured. Routine biochemical and clinical parameters were recorded. Echocardiographic examinations were performed on all patients. A linear regression analysis was performed to determine the correlates of serum H-FABP.. The MPO, H-FABP and TnT levels were 255 ± 227, 60.6 ± 48.5 and 0.07 ± 0.15 ng/ml, respectively. In multiple linear regression analysis, age (β = -0.36, p = 0.006), creatinine level (β = 0.3, p = 0.024) and serum MPO level (β = 0.41, p = 0.009) were significant determinants of H-FABP levels. Bivariate predictors were not significantly associated with TnT levels in linear regression analyses.. The MPO was significantly associated with serum H-FABP levels but not with TnT.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Blood Urea Nitrogen; Chronic Disease; Echocardiography; Fatty Acid-Binding Proteins; Female; Heart Failure; Humans; Linear Models; Male; Middle Aged; Outpatients; Peroxidase; Troponin T; Turkey

Cardiorenal Syndrome Type 1 (Type 1) is a specific condition which is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Even though its pathophysiology is complex and not still completely understood, oxidative stress seems to play a pivotal role. In this study, we examined the putative role of oxidative stress in the pathogenesis of CRS Type 1. Twenty-three patients with acute heart failure (AHF) were included in the study. Subsequently, 11 patients who developed AKI due to AHF were classified as CRS Type 1. Quantitative determinations for IL-6, myeloperoxidase (MPO), nitric oxide (NO), copper/zinc superoxide dismutase (Cu/ZnSOD), and endogenous peroxidase activity (EPA) were performed. CRS Type 1 patients displayed significant augmentation in circulating ROS and RNS, as well as expression of IL-6. Quantitative analysis of all oxidative stress markers showed significantly lower oxidative stress levels in controls and AHF compared to CRS Type 1 patients (P < 0.05). This pilot study demonstrates the significantly heightened presence of dual oxidative stress pathway induction in CRS Type 1 compared to AHF patients. Our findings indicate that oxidative stress is a potential therapeutic target, as it promotes inflammation by ROS/RNS-linked pathogenesis.

Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Cardio-Renal Syndrome; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Heart Failure; Humans; Interleukin-6; Male; Nitric Oxide; Oxidative Stress; Peroxidase; Peroxidases; Pilot Projects; Reactive Nitrogen Species; Reactive Oxygen Species; Superoxide Dismutase; Up-Regulation

Treatment of decompensated heart failure often includes administration of levosimendan. Myeloperoxidase (MPO) is released during polymorphonuclear neutrophil (PMN) degranulation, and mediates dysregulation of vascular tone in heart failure. We evaluated the effects of levosimendan-treatment on MPO in patients with acute decompensation of chronic heart failure over a one week course. Plasma MPO levels were significantly decreased after levosimendan treatment (from 252.1 ± 31.1 pmol/l at baseline to 215.02 ± 27.96 pmol/l at 6 h, p < 0.05). Ex vivo incubation of whole blood with levosimendan decreased MPO release after PMN-stimulation (8.2 ± 1.4-fold increase at baseline vs. 6.0 ± 1.1-fold increase with levosimendan). MPO levels also significantly correlated with diastolic blood pressure over the time course. In a multivariate linear model, the main contributor to systolic, diastolic and mean blood pressure was level of PMN elastase. MPO contributed only in heparin-treated patients, suggesting a more significant role for endothelial-bound MPO than for circulating MPO or elastase with respect to blood pressure regulation. We here provide the first evidence that levosimendan treatment inhibits MPO release by PMNs in decompensated heart failure patients. This mechanism may regulate endothelial function and vascular tone in heart failure patients.

Topics: Anti-Inflammatory Agents; Biomarkers; Blood Pressure; Cardiotonic Agents; Cell Degranulation; Female; Heart Failure; Humans; Hydrazones; Inflammation; Leukocytes; Male; Middle Aged; Neutrophils; Nitric Oxide; Peroxidase; Pyridazines; Severity of Illness Index; Simendan; Time Factors

Recent studies have linked histone deacetylases (HDAC) to remodeling of the heart and cardiac fibrosis in heart failure. However, the molecular mechanisms linking chromatin remodeling events with observed anti-fibrotic effects are unknown. Here, we investigated the molecular players involved in anti-fibrotic effects of HDAC inhibition in congestive heart failure (CHF) myocardium and cardiac fibroblasts in vivo.. MI was created by coronary artery occlusion. Class I HDACs were inhibited in three-week post MI rats by intraperitoneal injection of Mocetinostat (20 mg/kg/day) for duration of three weeks. Cardiac function and heart tissue were analyzed at six week post-MI. CD90+ cardiac fibroblasts were isolated from ventricles through enzymatic digestion of heart. In vivo treatment of CHF animals with Mocetinostat reduced CHF-dependent up-regulation of HDAC1 and HDAC2 in CHF myocardium, improved cardiac function and decreased scar size and total collagen amount. Moreover, expression of pro-fibrotic markers, collagen-1, fibronectin and Connective Tissue Growth Factor (CTGF) were reduced in the left ventricle (LV) of Mocetinostat-treated CHF hearts. Cardiac fibroblasts isolated from Mocetinostat-treated CHF ventricles showed a decrease in expression of collagen I and III, fibronectin and Timp1. In addition, Mocetinostat attenuated CHF-induced elevation of IL-6 levels in CHF myocardium and cardiac fibroblasts. In parallel, levels of pSTAT3 were reduced via Mocetinostat in CHF myocardium.. Anti-fibrotic effects of Mocetinostat in CHF are associated with the IL-6/STAT3 signaling pathway. In addition, our study demonstrates in vivo regulation of cardiac fibroblasts via HDAC inhibition.

Topics: Animals; Benzamides; Cicatrix; Collagen; Connective Tissue Growth Factor; Disease Models, Animal; Fibroblasts; Fibronectins; Fibrosis; Gene Expression; Heart Failure; Histone Deacetylase Inhibitors; Histone Deacetylases; Interleukin-6; Myocardial Ischemia; Pyrimidines; Rats; Signal Transduction; STAT3 Transcription Factor; Ventricular Function

Cardiac c-Kit+ cells have a modest cardiogenic potential that could limit their efficacy in heart disease treatment. The present study was designed to augment the cardiogenic potential of cardiac c-Kit+ cells through class I histone deacetylase (HDAC) inhibition and evaluate their therapeutic potency in the chronic heart failure (CHF) animal model. Myocardial infarction (MI) was created by coronary artery occlusion in rats. c-Kit+ cells were treated with mocetinostat (MOCE), a specific class I HDAC inhibitor. At 3 weeks after MI, CHF animals were retrogradely infused with untreated (control) or MOCE-treated c-Kit+ cells (MOCE/c-Kit+ cells) and evaluated at 3 weeks after cell infusion. We found that class I HDAC inhibition in c-Kit+ cells elevated the level of acetylated histone H3 (AcH3) and increased AcH3 levels in the promoter regions of pluripotent and cardiac-specific genes. Epigenetic changes were accompanied by increased expression of cardiac-specific markers. Transplantation of CHF rats with either control or MOCE/c-Kit+ cells resulted in an improvement in cardiac function, retardation of CHF remodeling made evident by increased vascularization and scar size, and cardiomyocyte hypertrophy reduction. Compared with CHF infused with control cells, infusion of MOCE/c-Kit+ cells resulted in a further reduction in left ventricle end-diastolic pressure and total collagen and an increase in interleukin-6 expression. The low engraftment of infused cells suggests that paracrine effects might account for the beneficial effects of c-Kit+ cells in CHF. In conclusion, selective inhibition of class I HDACs induced expression of cardiac markers in c-Kit+ cells and partially augmented the efficacy of these cells for CHF repair.. The study has shown that selective class 1 histone deacetylase inhibition is sufficient to redirect c-Kit+ cells toward a cardiac fate. Epigenetically modified c-Kit+ cells improved contractile function and retarded remodeling of the congestive heart failure heart. This study provides new insights into the efficacy of cardiac c-Kit+ cells in the ischemic heart failure model.

Topics: Acetylation; Animals; Benzamides; Biomarkers; Cell Differentiation; Cells, Cultured; Collagen; Disease Models, Animal; Epigenesis, Genetic; Heart Failure; Histone Deacetylase Inhibitors; Histones; Interleukin-6; Male; Myocardial Infarction; Myocytes, Cardiac; Pluripotent Stem Cells; Proto-Oncogene Proteins c-kit; Pyrimidines; Rats; Rats, Sprague-Dawley; Recovery of Function; Tissue Culture Techniques; Ventricular Function, Left; Ventricular Remodeling

Heart failure (HF) is accompanied by the development of an imbalance between oxygen- and nitric oxide-derived free radical production leading to protein nitration. Both chlorinating and peroxidase cycle of Myeloperoxidase (MPO) contribute to oxidative and nitrosative stress and are involved in tyrosine nitration of protein. Ceruloplasmin (Cp) has antioxidant function through its ferroxidase I (FeOxI) activity and has recently been proposed as a physiological defense mechanism against MPO inappropriate actions.. We investigated the relationship between plasma MPO-related chlorinating activity, Cp and FeOxI, and nitrosative stress, inflammatory, neurohormonal, and nutritional biomarkers in HF patients.. In chronic HF patients (n = 81, 76 ± 9 years, NYHA Class II (26); Class III (29); Class IV (26)) and age-matched controls (n = 17, 75 ± 11 years, CTR), plasma MPO chlorinating activity, Cp, FeOxI, nitrated protein, free Malondialdehyde, BNP, norepinephrine, hsCRP, albumin, and prealbumin were measured. Plasma MPO chlorinating activity, Cp, BNP, norepinephrine, and hsCRP were increased in HF versus CTR. FeOxI, albumin, and prealbumin were decreased in HF. MPO-related chlorinating activity was positively related to Cp (r = 0.363, P < 0.001), nitrated protein, hsCRP, and BNP and inversely to albumin.. Plasma MPO chlorinated activity is increased in elderly chronic HF patients and positively associated with Cp, inflammatory, neurohormonal, and nitrosative parameters suggesting a role in HF progression.

Topics: Aged; Aged, 80 and over; Albumins; Biomarkers; C-Reactive Protein; Ceruloplasmin; Chronic Disease; Cross-Sectional Studies; Female; Halogenation; Heart Failure; Humans; Inflammation; Male; Natriuretic Peptide, Brain; Peroxidase

Peroxidases serve diverse biological functions including well-characterized activities in host defence and hormone biosynthesis. More recently, peroxidasin (PXDN) was found to be involved in collagen IV cross-linking in the extracellular matrix (ECM). The aim of this study was to characterize the expression and function of peroxidasin-like protein (PXDNL), a previously unknown peroxidase homologue.. We cloned the PXDNL cDNA from the human heart and identified its expression pattern by northern blot, in situ hybridization, and immunohistochemistry. PXDNL is expressed exclusively in the heart and it has evolved to lose its peroxidase activity. The protein is produced by cardiomyocytes and localizes to cell-cell junctions. We also demonstrate that PXDNL can form a complex with PXDN and antagonizes its peroxidase activity. Furthermore, we show an increased expression of PXDNL in the failing myocardium.. PXDNL is a unique component of the heart with a recently evolved inactivation of peroxidase function. The elevation of PXDNL levels in the failing heart may contribute to ECM dysregulation due to its antagonism of PXDN function.

Topics: Animals; Cells, Cultured; Extracellular Matrix; Extracellular Matrix Proteins; Gene Expression Regulation; Heart; Heart Failure; Humans; In Situ Hybridization; Oxidation-Reduction; Peroxidase; Peroxidasin; RNA, Messenger

Lipoxins (LXs) are proresolving and anti-inflammatory eicosanoids whose role in chronic heart failure (CHF) pathogenesis has never been investigated. This study evaluated levels of LXs in CHF patients, its relationship with disease severity and correlation with established CHF biomarkers. The effect of low-dose aspirin [acetylsalicylic acid (ASA)] on the levels of LXs was also studied.. Lipoxin A4 (LXA4 ), 15-epi-lipoxin A4 (15-epi-LXA4 ) and myeloperoxidase (MPO) concentration and activity were evaluated by immunoenzymatic and spectrophotometric assays in 34 CHF patients [New York Heart Association (NYHA) functional class I to IV]. B-type natriuretic peptide (BNP), troponin, myoglobin, C-reactive protein (CRP) and uric acid (UA) were also analyzed.. Patients were stratified into mild-to-moderate CHF (NYHA, classes I and II) and severe CHF (NYHA classes III and IV). Severe patients had lower plasma LXA4 (0·262 ± 0·034 vs. 0·362 ± 0·039 ng/mL, P < 0·05) and decreased urinary 15-epi-LXA4 levels (2·28 ± 0·44 vs. 4·88 ± 1·03 μg/day, P < 0·05) besides exhibiting increased plasma BNP (1464 ± 442 vs. 555 ± 162 pg/mL, P < 0·05) and MPO activity (45·15 ± 11·56 vs. 15·90 ± 2·80 μmol/min/mg protein, P < 0·05). Plasma LXA4 was inversely correlated with BNP, troponin, myoglobin, CRP, UA and MPO activity. ASA treatment was associated with higher urinary excretion of 15-epi-LXA4 (7·70 ± 1·48 vs. 2·06 ± 0·30 μg/day, P < 0·05) in mild-to-moderate CHF patients and lower BNP levels in both groups.. Higher severity of CHF is associated with reduced levels of LXs. Plasma LXA4 appears to be a valuable marker for risk stratification in CHF. Furthermore, the ASA-related increase in urinary 15-epi-LXA4 suggests enhanced renal synthesis of this eicosanoid and may represent a disregarded benefit of ASA.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Biomarkers; Cardiovascular Diseases; Chronic Disease; Female; Glomerular Filtration Rate; Heart Failure; Humans; Inflammation; Leukocyte Count; Lipoxins; Male; Peroxidase; Risk Factors

Myeloperoxidase (MPO) is a heme enzyme abundantly expressed in polymorphonuclear neutrophils. MPO is enzymatically capable of catalyzing the generation of reactive oxygen species (ROS) and the consumption of nitric oxide (NO). Thus MPO has both potent microbicidal and, upon binding to the vessel wall, pro-inflammatory properties. Interestingly, MPO - a highly cationic protein - has been shown to bind to both endothelial cells and leukocyte membranes. Given the anionic surface charge of red blood cells, we investigated binding of MPO to erythrocytes. Red blood cells (RBCs) derived from patients with elevated MPO plasma levels showed significantly higher amounts of MPO by flow cytometry and ELISA than healthy controls. Heparin-induced MPO-release from patient-derived RBCs was significantly increased compared to controls. Ex vivo experiments revealed dose and time dependency for MPO-RBC binding, and immunofluorescence staining as well as confocal microscopy localized MPO-RBC interaction to the erythrocyte plasma membrane. NO-consumption by RBC-membrane fragments (erythrocyte "ghosts") increased with incrementally greater concentrations of MPO during incubation, indicating preserved catalytic MPO activity. In vivo infusion of MPO-loaded RBCs into C57BL/6J mice increased local MPO tissue concentrations in liver, spleen, lung, and heart tissue as well as within the cardiac vasculature. Further, NO-dependent relaxation of aortic rings was altered by RBC bound-MPO and systemic vascular resistance significantly increased after infusion of MPO-loaded RBCs into mice. In summary, we find that MPO binds to RBC membranes in vitro and in vivo, is transported by RBCs to remote sites in mice, and affects endothelial function as well as systemic vascular resistance. RBCs may avidly bind circulating MPO, and act as carriers of this leukocyte-derived enzyme.

Topics: Acute Coronary Syndrome; Animals; Aorta; Biological Transport; Cells, Cultured; Endothelium, Vascular; Erythrocytes; Heart; Heart Failure; Heparin; Humans; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Organ Culture Techniques; Peroxidase; Protein Binding; Tissue Culture Techniques; Vascular Resistance

Topics: Anemia; Disease Progression; Fibrin Fibrinogen Degradation Products; Heart Failure; Hemodynamics; Humans; Interleukin-6; Oxidative Stress; Peroxidase; Prothrombin Time; Thrombin

Myeloperoxidase (MPO) plays a central role in the innate immune system by generating leukocyte-derived oxidants to combat invading pathogens. These reactive intermediates have been increasingly recognized to be potentially deleterious, causing oxidative injury in inflammatory disease states such as cardiovascular disease. Recent evidence now suggests that circulating MPO can act as a clinical prognostic indicator for patients with cardiovascular disease.

Topics: Biomarkers; Case-Control Studies; Coronary Artery Disease; Free Radicals; Gene Expression; Heart Failure; Humans; Immunity, Innate; Peroxidase; Plaque, Atherosclerotic; Prognosis; Reactive Nitrogen Species; Reactive Oxygen Species; Survival Analysis; Tyrosine

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antirheumatic Agents; Chronic Disease; Cyclophosphamide; Dermatitis, Atopic; Eosinophilia; Female; Glomerulonephritis; Glucocorticoids; Heart Failure; Hemorrhage; Humans; Lung Diseases; Methylprednisolone; Peroxidase; Prednisone; Tomography, X-Ray Computed

The predictive value of myeloperoxidase (MPO) in ST-segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PCI) has not been established. The aim of the present study was to investigate MPO as a predictor of in-hospital mortality in STEMI patients treated by primary PCI.. Study population consisted of 189 STEMI patients having undergone primary PCI. Plasma MPO level was measured 24 hours after symptom onset using chemiluminescent microparticle immunoassay (Abbott Diagnostics, Germany). The Receiver Operating Characteristic analysis was performed to identify the most useful MPO cut-off level for the prediction of in-hospital mortality. The patients were divided into two groups according to the cut-off MPO level: high MPO group (> or = 840 pmol/L, n = 65) and low MPO group (< 840 pmol/L, n = 124).. The high MPO group had significantly more frequent anterior wall infarctions (p < 0.001) and Killip class > 1 on admission (p = 0.013) as well as lower left ventricular ejection fraction (LVEF) (p = 0.011) and higher B-type natriuretic peptide (BNP) (p = 0.029) than the low MPO group. The incidence of in-hospital mortality was 5.8% and was significantly higher in the high MPO group (13.8%) than in the low MPO group (1.6%) (p = 0.001). Multiple logistic regression analysis identified the plasma MPO level as an independent predictor of in-hospital mortality (OR 3.88, 95% CI 1.13 - 13.34, p = 0.031).. Plasma MPO level independently predicts in-hospital mortality in STEMI patients treated by primary PCI.

Topics: Angioplasty, Balloon, Coronary; Arrhythmias, Cardiac; Biomarkers; Echocardiography; Electrocardiography; Female; Heart Failure; Hospital Mortality; Humans; Male; Middle Aged; Myocardial Infarction; Peroxidase; Predictive Value of Tests; ROC Curve; Serbia; Survival Rate

To analyze the prognostic value of myeloperoxidase (MPO) in relation to in-hospital mortality and to identify the optimum time point for sampling in patients with the first anterior ST-segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (pPCI).. A total of 100 consecutive patients with the first anterior STEMI undergoing pPCI were included. Blood samples were collected at baseline, 4, 8, 12, 18, 24, 48 and 168 hours (h) after pPCI.. MPO concentrations have showed a biphasic pattern over time; the highest MPO levels were at4h and 24h after pPCI. In-hospital mortality was 6%. MPO at 24h significantly correlated with troponin I as well as heart failure. After multivariate adjustment, MPO at 24h was an independent predictor of the in-hospital mortality (OR 3.34, 95% CI 1.13-9.86, P=0.029).. In patients with the first anterior STEMI treated by pPCI, MPO at 24h after procedure was an independent predictor of the in-hospital mortality.

Topics: Aged; Angioplasty; Angioplasty, Balloon, Coronary; Aspirin; Biomarkers; Blood Chemical Analysis; Clopidogrel; Coronary Angiography; Female; Heart Failure; Hospital Mortality; Humans; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Peroxidase; Predictive Value of Tests; Prospective Studies; ROC Curve; Ticlopidine; Time Factors; Troponin I

This study was carried out to investigate the prognostic utility of biomarkers in advanced stage heart failure (HF) patients requiring ICU admission for pulmonary artery catheter (PAC) guided therapy.. Thirty patients admitted to an ICU for PAC guided HF therapy were enrolled; concentrations of soluble ST2 (sST2), highly sensitive troponin I, an experimental ultrasensitive troponin I, amino-terminal pro-B type natriuretic peptide, cystatin C, and myeloperoxidase were measured over the first 48 hours. Outcomes included response of filling pressures and hemodynamics to tailored therapy and 90-day event-free survival (death, left ventricular assist device implantation, transplant).. Of the biomarkers evaluated, only sST2 concentrations were higher in those who failed to achieve goals for central venous pressure ((CVP), 225.3 versus 104.6 ng/mL; P = 0.003) and pulmonary capillary wedge pressure ((PCWP), 181.7 versus 88.2 ng/mL; P = 0.05). Only sST2 concentrations were associated with adverse events (186.7 versus 92.2 ng/mL; P = 0.01). In age-adjusted Cox proportional hazards analysis, an elevated sST2 during the first 48 hours following ICU admission independently predicted 90-day outcomes (Hazard Ratio = 5.53; P = 0.03) superior to the Simplified Acute Physiology Score for this application; in Kaplan-Meier analysis the risk associated with elevated sST2 concentrations was present early and sustained through the duration of follow-up (log rank P = 0.01).. In patients undergoing HF therapy guided by invasive monitoring, sST2 concentrations were associated with impending failure to reduce filling pressures and predicted impending events. Elevated sST2 values early in the ICU course theoretically could assist therapeutic decision-making in advanced stage HF patients.. ClinicalTrials.gov Identifier: NCT00595738.

Topics: Aged; Biomarkers; Cardiac Catheterization; Cystatin C; Female; Heart Failure; Hemodynamics; Humans; Intensive Care Units; Interleukin-1 Receptor-Like 1 Protein; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Peroxidase; Prognosis; Pulmonary Artery; Receptors, Cell Surface; Troponin I

We investigated the prognostic importance of plasma myeloperoxidase levels in patients with ST-elevation myocardial infarction (STEMI) at long-term follow-up, and we analyzed the correlations between plasma myeloperoxidase levels and other biochemical values. We evaluated 73 consecutive patients (56 men; mean age, 56 ± 11 yr) diagnosed with acute STEMI and 46 age- and sex-matched healthy control participants. Patients were divided into 2 groups according to the median myeloperoxidase level (Group 1: plasma myeloperoxidase ≤ 68 ng/mL; and Group 2: plasma myeloperoxidase > 68 ng/mL). Patients were monitored for the occurrence of major adverse cardiovascular events (MACE), which were defined as cardiac death; reinfarction; new hospital admission for angina; heart failure; and revascularization procedures. The mean follow-up period was 25 ± 16 months. Plasma myeloperoxidase levels were higher in STEMI patients than in control participants (82 ± 34 vs 20 ± 12 ng/mL; P = 0.001). Composite MACE occurred in 12 patients with high myeloperoxidase levels (33%) and in 4 patients with low myeloperoxidase levels (11%) (P = 0.02). The incidences of nonfatal recurrent myocardial infarction and verified cardiac death were higher in the high-myeloperoxidase group. In multivariate analysis, high plasma myeloperoxidase levels were independent predictors of MACE (odds ratio = 3.843; <95% confidence interval, 1.625-6.563; P = 0.003). High plasma myeloperoxidase levels identify patients with a worse prognosis after acute STEMI at 2-year follow-up. Evaluation of plasma myeloperoxidase levels might be useful in determining patients at high risk of death and MACE who can benefit from further aggressive treatment and closer follow-up.

Topics: Adult; Aged; Aged, 80 and over; Angina Pectoris; Biomarkers; Case-Control Studies; Chi-Square Distribution; Female; Heart Failure; Humans; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Myocardial Revascularization; Odds Ratio; Patient Readmission; Peroxidase; Prognosis; Proportional Hazards Models; Prospective Studies; Recurrence; Risk Assessment; Risk Factors; Time Factors; Turkey; Up-Regulation; Young Adult

A multimarker approach may be useful for risk stratification in AMI (acute myocardial infarction) patients, particularly utilizing pathways that are pathophysiologically distinct. Our aim was to assess the prognostic value of PR3 (proteinase 3) in patients post-AMI. We compared the prognostic value of PR3, an inflammatory marker, with an established marker NT-proBNP (N-terminal pro-B-type natriuretic peptide) post-AMI. We recruited 900 consecutive post-AMI patients (700 men; age, 64.6±12.4 years) in a prospective study with follow-up over 347 (0-764) days. Plasma PR3 was significantly higher in patients who died [666.2 (226.8-4035.5) ng/ml; P<0.001] or were readmitted with heart failure [598 (231.6-1803.9) ng/ml, P<0.004] compared with event-free survivors [486.9 (29.3-3118.2) ng/ml]. Using Cox modelling, log10 PR3 [HR (hazard ratio), 3.80] and log10 NT-proBNP (HR, 2.51) were significant independent predictors of death or heart failure. When patients were stratified by plasma NT-proBNP (median, 1023 pmol/l), PR3 gave additional predictive value for death or heart failure, in both the patients in whom NT-proBNP level was above the median (log rank for trend, 12.54; P<0.0004) and those with NT-proBNP level below the median (log rank for trend, 3.83; P<0.05). Neither marker predicted recurrent AMI. In conclusion, this is the first report showing a potential role for the serine protease PR3 in determining mortality and incidence of heart failure following AMI, independent of established conventional risk factors. PR3 may represent a clinically useful marker of prognosis after an AMI as part of a multimarker strategy.

Topics: Aged; alpha 1-Antitrypsin; Biomarkers; Clinical Enzyme Tests; Epidemiologic Methods; Female; Heart Failure; Humans; Inflammation Mediators; Male; Middle Aged; Myeloblastin; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Peroxidase; Prognosis

Atherosclerosis is a chronic inflammatory process, and myeloperoxidase (MPO) seems to contribute directly to the pathogenesis of acute coronary syndrome (ACS).. To compare MPO levels among the patients with stable and unstable ischemic heart disease and to evaluate their independent prognostic value for cardiovascular events.. MPO and C-reactive protein (CRP) were assessed in two cohorts of coronary artery disease patients, including 178 patients with stable angina and 130 patients with ACS evaluated at the emergency department.. MPO and CRP levels were significantly higher among patients with ACS [MPO 93 (54-127) vs. 9.9 pmol/l (5-21) and high sensitivity-CRP 11 (3-27) vs. 2.6 mg/l (1-5)]. Among patients with stable angina, high sensitivity-CRP levels greater than 3 mg/l were associated with a three-fold risk of further cardiovascular events during a mean follow-up period of 13+/-4 months, although there was no significant association between MPO levels and outcomes. Among patients with ACS, baseline MPO level was an independent predictor of major adverse cardiac events during hospitalization, odds ratio of 3.8 (95% confidence interval: 1.2-12) for the combined endpoint (death, recurrent angina, heart failure, and arrhythmia). CRP levels were associated with hospital mortality in patients with ACS, but were not independently related to cardiovascular events.. Elevated MPO levels among the ACS patients suggest that this marker may participate in plaque vulnerability and instability process, whereas higher CRP levels were predictive of cardiac events only among the stable angina patients. These findings suggest distinct role of the inflammatory markers studied in the pathophysiology of coronary artery disease.

Topics: Acute Coronary Syndrome; Aged; Angina Pectoris; Angina, Unstable; Arrhythmias, Cardiac; Biomarkers; C-Reactive Protein; Chi-Square Distribution; Coronary Artery Disease; Female; Heart Failure; Humans; Inflammation Mediators; Kaplan-Meier Estimate; Male; Middle Aged; Odds Ratio; Peroxidase; Prognosis; Proportional Hazards Models; Prospective Studies; Recurrence; Risk Assessment; Risk Factors; Time Factors; Up-Regulation

Topics: Acute Disease; Heart Failure; Humans; Peroxidase

Myeloperoxidase (MPO) is a biomarker of inflammation and oxidative stress produced by neutrophils, monocytes, and endothelial cells. Concentrations of MPO predict mortality in patients with chronic heart failure. This study sought to investigate the diagnostic accuracy and prognostic value of MPO in patients with acute heart failure (AHF).. We prospectively enrolled 667 patients presenting to the emergency department with dyspnea and observed them for 1 year. MPO and B-type natriuretic peptide (BNP) were measured at presentation. Two independent cardiologists adjudicated final discharge diagnoses.. MPO concentrations were similar in patients with AHF (n = 377, median 139 pmol/L) and patients with noncardiac causes of dyspnea (n = 290, median 150 pmol/L, P = 0.26). The diagnostic accuracy of MPO for AHF was limited [area under the ROC curve (AUC) 0.53] and inferior to that of BNP (AUC 0.95, P < 0.001). In patients with AHF, MPO concentrations above the lowest tertile (MPO >99 pmol/L) were associated with significantly increased 1-year mortality (hazard ratio 1.58, P = 0.02). The combination of MPO (< or = 99 vs >99 pmol/L) and BNP (median of < or = 847 vs >847 ng/L) improved the prediction of 1-year mortality (hazard ratio 2.80 for both variables increased vs both low, P < 0.001). After adjustment for cardiovascular risk factors in multivariable Cox proportional hazard analysis, increases in MPO contributed significantly toward the prediction of 1-year mortality (hazard ratio 1.51, P = 0.045).. MPO is an independent predictor of 1-year mortality in AHF, is additive to BNP, and could be helpful in identifying patients with a favorable prognosis despite increased BNP concentrations.

Topics: Acute Disease; Aged; Aged, 80 and over; Dyspnea; Female; Heart Failure; Humans; Male; Middle Aged; Peroxidase; Prognosis; Prospective Studies

Inflammatory activation plays an important role in the pathogenesis and progression of left ventricular (LV) heart failure. In right ventricular (RV) heart failure, little is known about the role of inflammatory activation. We aimed to study the role of inflammatory activation in RV heart failure by serial monitoring during disease progression.. Right ventricular heart failure was induced in male Wistar rats by intraperitoneal injection of monocrotaline (MCT). Two groups were studied: MCT-treated rats (MCT-rats), and age-matched controls (CON-rats). Serial echocardiography and in vivo 67-Gallium ((67)Ga) scintigraphy were performed. Local inflammation in the RV was assessed by (i) ex vivo semi-quantitative (67)Ga autoradiography, (ii) immunohistochemistry of myeloperoxidase (MPO), a marker of neutrophil activity, and (iii) mRNA assays of tumour necrosis factor-alpha (TNF-alpha). In MCT-rats, (67)Ga scintigraphy showed increased myocardial uptake which started during the early stages of RV disease. (67)Ga autoradiography revealed that this increased (67)Ga uptake occurred in the RV and inter-ventricular septum, but not in the LV. The stage-dependent increases of in vivo (67)Ga RV myocardial uptake were paralleled by increases in mRNA gene expression for TNF-alpha in RV, and increased MPO staining in RV.. Development and progression of RV heart failure is associated with an early increase in RV inflammation. (67)Ga scintigraphy may be used for the serial assessment of inflammation and monitoring of disease progression in RV heart failure.

Topics: Animals; Autoradiography; Disease Models, Animal; Disease Progression; Gallium Radioisotopes; Gene Expression Profiling; Heart Failure; Hypertrophy, Right Ventricular; Immunochemistry; Inflammation; Male; Monocrotaline; Myocardium; Neutrophil Activation; Peroxidase; Radionuclide Imaging; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Right

Plasma myeloperoxidase (MPO), an inflammatory biomarker, is associated with increased mortality in patients with acute coronary syndrome or chronic left ventricular systolic dysfunction. We sought to assess the diagnostic accuracy of MPO for acute decompensated heart failure (ADHF) and its prognostic value for patients with acute dyspnea.. In a prospective, observational study conducted in 5 US centers, 412 patients [mean (SD) age, 58 (14) years; 39% women] presenting with dyspnea to the emergency department were enrolled and followed for 1 year. Clinical, serum/plasma biomarker [MPO, B-type natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP)], and transthoracic echocardiographic data were obtained.. We observed no differences in MPO concentration (P = 0.07) between patients with ADHF [n = 147; median, 553 pmol/L; interquartile range (IQR), 415-738 pmol/L] and those without ADHF (n = 265; median, 576 pmol/L; IQR, 413-884 pmol/L). The diagnostic accuracy for ADHF was excellent for BNP [area under the ROC curve (AUC), 0.90; P < 0.001] and NT-proBNP (AUC, 0.90; P < 0.001) but poor for MPO (AUC, 0.46; P = 0.18). MPO appeared uncorrelated with echocardiographic measures of cardiac structure or function. The observed 1-year mortality rate was 12%. MPO concentration also appeared unrelated to mortality [hazard ratio, 1.25 (above vs below the median); 95% CI, 0.71-2.18], whereas BNP (P = 0.001) and NT-proBNP (P < 0.001) were significant predictors of mortality. MPO concentration provided no prognostic information in addition to that of BNP or NT-proBNP concentration.. Unlike natriuretic peptides, MPO concentration was not predictive of ADHF diagnosis or 1-year mortality in a heterogeneous sample of emergency department patients with acute dyspnea.

Topics: Acute Disease; Aged; Autoanalysis; Biomarkers; Cohort Studies; Dyspnea; Female; Follow-Up Studies; Heart Failure; Humans; Immunoassay; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Peroxidase; Predictive Value of Tests; Prognosis; Prospective Studies; Reproducibility of Results; Sensitivity and Specificity; Survival Analysis

Topics: Acute Disease; Biomarkers; Chronic Disease; Heart Failure; Humans; Immunoassay; Peroxidase; Sensitivity and Specificity

Increased oxidative stress has been implicated in the pathogenesis of a number of cardiovascular diseases. Recent findings suggest that myeloperoxidase (MPO) may play a key role in the initiation and maintenance of chronic heart failure (CHF) by contributing to the depletion of the intracellular reservoir of nitric oxide (NO). NO consumption through MPO activity may lead to protein chlorination or nitration, leading to tissue damage. Primary cultures of human endocardial endothelial cells (EEC) obtained at heart transplantation of patients with CHF and human umbilical vein endothelial cells (HUVEC) were subjected to oxidative stress by incubation with hydrogen peroxide at non lethal (60 microM) dose for different exposure times (3 and 6 h). Treated and control cells were tested by immunohistochemistry and RT-PCR for MPO and 3-chlorotyrosine expression. Both endothelial cell types expressed myeloperoxidase following oxidative stress, with higher levels in EEC. Moreover, 3-chlorotyrosine accumulation in treated cells alone indicated the presence of MPO-derived hypochlorous acid. Immunohistochemistry on sections from post-infarcted heart confirmed in vivo the endothelial positivity to MPO, 3-chlorotyrosine and, to a minor extent, nitrotyrosine. Immunohistochemical observations were confirmed by detection of MPO mRNA in both stimulated EEC and HUVEC cells. This study demonstrates for the first time that EEC can express MPO after oxidative stress, both in vitro and in vivo, followed by accumulation of 3-chlorotyrosine, an end product of oxidative stress. Deregulation of endothelial functions may contribute to the development of a number of cardiovascular diseases, including CHF. The results also highlight the notion that endothelium is not only a target but also a key player in oxidative-driven cardiovascular stress.

Topics: Cells, Cultured; Chronic Disease; Endothelial Cells; Gene Expression; Heart Failure; Humans; Hydrogen Peroxide; Immunohistochemistry; Myocardium; Oxidants; Oxidative Stress; Peroxidase; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tyrosine; Umbilical Veins

The presence of a reciprocal link between inflammation and oxidative/nitrosative stress has been postulated in chronic heart failure (CHF). We aimed to determine signs of nitrosative stress in serum/plasma of CHF patients. ELISA tests were used for quantification of serum/plasma levels of Nitrotyrosine (NT), H(2)O(2), total NO, nitrite (NO(2)(-)), myeloperoxidase (MPO), Tumor Necrosis Factor-alpha (TNFalpha) and pro-Brain Natriuretic Peptide (proBNP) in 66 CHF patients (9 in NYHA I, 34 NYHA II, 23 NYHA III) and in 14 age-matched healthy subjects. NT levels were higher in NYHA III CHF patients compared to NYHA II (p<0.05), NYHA I (p<0.03) and controls (p<0.02), whereas NO(2)(-) and total NO were higher in NYHA III compared to I (p<0.05 and p<0.04, respectively) and controls (p<0.004 and 0.002) and in NYHA II compared to controls (p<0.04 and p<0.009). NT levels correlated significantly with MPO (r=0.37, p<0.003), TNFalpha (r=0.32, p<0.01) and proBNP (r=0.32, p<0.01). These data demonstrate an increased NT plasma level in patients with moderate/severe CHF which is associated to increased levels of markers of systemic inflammation.

Topics: Aged; Biomarkers; Chronic Disease; Cohort Studies; Female; Heart Failure; Humans; Inflammation Mediators; Male; Middle Aged; Peroxidase; Tyrosine

Increased systemic myeloperoxidase (MPO) has been associated with both the presence and severity of heart failure (HF). This study tested the hypothesis that increased systemic MPO in apparently healthy elderly subjects may predict increased risk of developing HF. Systemic MPO was measured in all available samples from the 1992 to 1993 visit of the Cardiovascular Health Study (CHS). After excluding subjects without available blood samples or with a history of prevalent HF, myocardial infarction (MI), or stroke, 3,733 subjects were included. A total of 569 subjects developed incident HF during 7.2 +/- 2.3 years of follow-up. Patients in the highest MPO quartile (>432 pmol/L) showed higher risk of developing incident HF after adjusting for MI, age, gender, systolic blood pressure, smoking, low-density lipoprotein cholesterol, diabetes mellitus, and any subclinical cardiovascular disease (hazard ratio 1.34, 95% confidence interval 1.06 to 1.72, p = 0.013). However, the relation was more apparent after censoring subjects with incident MI before incident HF, even when adjusted for C-reactive protein and cystatin C (hazard ratio 1.46, 95% confidence interval 1.08 to 1.97, p = 0.02). Interestingly, stratified analyses showed that the relation between increased MPO and HF risk was stronger in subjects without traditional cardiovascular risk factors (

Topics: Age Factors; Aged; Aged, 80 and over; Biomarkers; Disease Progression; Female; Geriatric Assessment; Heart Failure; Humans; Longitudinal Studies; Male; Peroxidase; Predictive Value of Tests; Probability; Prognosis; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Sex Factors

Inflammation plays a critical role in acute myocardial infarction (MI). One such inflammatory marker is myeloperoxidase (MPO). Its role as a predictor of death or MI in patients with ST segment elevation myocardial infarction (STEMI) is unclear.. To investigate the role of MPO as a predictor of death or MI in patients with STEMI and to compare it with N-terminal pro-B-type natriuretic peptide (NT-BNP).. 384 post STEMI patients were studied. Patients were followed up for the combined end point of death or readmission with non-fatal MI.. There were 40 deaths and 37 readmissions with MI. Median MPO was raised in patients experiencing death or MI than in survivors (median (range), 50.6 (15.3-124.1) ng/ml vs 33.5 (6.6-400.2) ng/ml, p = 0.001). Using a Cox proportional hazards model, log median MPO (HR 6.91, 95% CI 1.79 to 26.73, p = 0.005) and log median NT-BNP (HR 4.21, 95% CI 1.53 to 11.58, p = 0.005) independently predicted death or non-fatal MI. MPO had predictive power in both below and above median NT-BNP levels (log rank 5.60, p = 0.020 and log rank 5.12, p = 0.024, respectively). The receiver-operating curve for median NT-BNP yielded an area under the curve (AUC) of 0.72 (95% CI 0.65 to 0.79, p<0.001); for median MPO, the AUC was 0.62 (95% CI 0.55 to 0.69, p = 0.001). The logistic model combining the two markers yielded an AUC of 0.76 (95% CI 0.69 to 0.82, p<0.001).. MPO and NT-BNP may be useful tools for risk stratification of all acute coronary syndromes, including patients with STEMI at higher risk.

Topics: Aged; Biomarkers; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Peroxidase; Prognosis; Regression Analysis; Risk Factors; Survival Analysis

The purpose of this study was to explore the relationship between myeloperoxidase (MPO) and cardiac structure, performance, and prognosis.. Myeloperoxidase is an inflammatory marker that is elevated in patients with heart failure (HF) and cardiac dysfunction, with mechanistic links to plaque vulnerability and left ventricular (LV) remodeling.. We evaluated plasma MPO levels (CardioMPO, PrognostiX, Inc., Cleveland, Ohio) in 140 patients with chronic systolic HF (LV ejection fraction <35%) and examined the plasma MPO levels' relationships with echocardiographic indexes of systolic and diastolic performance, as well as long-term clinical outcomes (death, cardiac transplantation, or HF hospitalization).. Within the overall cohort, increasing plasma MPO levels were associated with increasing likelihood of more advanced HF (restrictive diastolic stage, right ventricular systolic dysfunction > or =3+, and tricuspid regurgitation area > or =1.8 cm2). Plasma MPO levels were predictive of long-term clinical outcomes (risk ratio [95% confidence interval] = 3.35 [1.52 to 8.86]), even after adjustment for age, LV ejection fraction, plasma B-type natriuretic peptide (BNP), creatinine clearance, or diastolic stage. In receiver-operator characteristic curve analyses, addition of MPO to BNP testing augmented the predictive accuracy of future adverse clinical events (area under the curve 0.66 for BNP only [chi-square test = 12.9, p = 0.0003], and 0.70 for BNP plus MPO [chi-square test = 15.87, p = 0.0004]).. In chronic systolic HF, elevated plasma MPO levels are associated with an increased likelihood of more advanced HF. Moreover, elevated plasma MPO levels within a HF subject seem to be predictive of increased adverse clinical outcomes.

Topics: Aged; Arabidopsis Proteins; Chronic Disease; Creatinine; Cyclophilins; Female; Heart Failure; Humans; Leukocyte Count; Male; Middle Aged; Neutrophils; Peroxidase; Prognosis; Proportional Hazards Models; Stroke Volume; Ultrasonography; Ventricular Dysfunction, Left; Ventricular Dysfunction, Right

Topics: Biomarkers; C-Reactive Protein; Heart Failure; Humans; Natriuretic Peptide, Brain; Peptide Fragments; Peroxidase; Sensitivity and Specificity; Ventricular Dysfunction, Left

N-terminal pro-B-type natriuretic peptide (N-BNP) is elevated in left ventricular systolic dysfunction (LVSD) and may be cost-effective for screening in the community but is relatively nonspecific. We sought to improve specificity using inflammatory markers such as C-reactive protein (CRP) and myeloperoxidase (MPO), which have been implicated in cardiovascular disease.. A total of 1360 subjects (45-80 years) were invited in this prospective screening study for undiagnosed LVSD (defined as wall motion score >1.8 [ejection fraction < or = 40%]), and 1331 had analyzable echocardiographic scans and plasma specimens. Peptides were measured using immunoluminometric assays.. Twenty-eight patients with LVSD had elevated plasma N-BNP, CRP, and MPO levels compared with healthy subjects (P < .0005). Receiver operating characteristic curve areas for N-BNP, CRP, and MPO were 0.839, 0.824, and 0.909, respectively. All tests had high negative predictive values (>99%). Specificity was maximized to 88.4% in a logistic model with all 3 markers (all independent predictors, accounting for 44.8% of the variance). This reduced the number of cases to scan to detect 1 case of LVSD from 29.7 (using N-BNP alone) to 6.6. Using plasma MPO (at 33.9 ng/mL) or urinary N-BNP (at 10.7 fmol/mL) as initial screening tests, combinations of plasma N-BNP, MPO, and CRP can achieve specificities up to a maximum of 94.3%. Costs were minimized by using urinary N-BNP as the initial screening test, followed by plasma biomarkers.. Plasma CRP and MPO increased the specificity of N-BNP in LVSD screening. Screening is optimized by urinary N-BNP as an initial test, followed by plasma CRP, N-BNP, and MPO.

Topics: Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Female; Heart Failure; Humans; Male; Mass Screening; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Peroxidase; Prospective Studies; ROC Curve; Sensitivity and Specificity; Ventricular Dysfunction, Left

Increased oxidative stress and endothelial dysfunction are commonly observed in patients with chronic heart failure (HF). The relation between myeloperoxidase (MPO), an inflammatory marker with mechanistic links to plaque vulnerability and abnormal ventricular remodeling, and degrees of severity in chronic HF has not been reported. Plasma MPO levels were measured in 105 normal controls (no history of HF or left ventricular dysfunction) and 102 patients with chronic systolic HF (left ventricular ejection fraction <50%), and the relations among plasma MPO levels, plasma B-type natriuretic peptide levels, and the left ventricular ejection fraction were examined. Plasma MPO levels in patients with chronic systolic HF were significantly elevated compared with those of healthy controls (1,158 +/- 2,965 vs 204 +/- 139 pM, p <0.0001). Plasma MPO levels increased in parallel with increasing New York Heart Association class (p <0.0001) and were correlated with plasma B-type natriuretic peptide levels (Spearman's r = 0.39, p <0.0001). Levels of MPO were strongly associated with the prevalence of HF (unadjusted odds ratio 30.3, 95% confidence interval 11.1 to 94.5) and remained significant when adjusted for age and B-type natriuretic peptide (odds ratio 27.7, 95% confidence interval 3.6 to 371.1). In conclusion, in a cohort of patients with chronic HF, plasma MPO levels were elevated compared with those of normal controls and were associated with worsening functional class.

Topics: Adult; Aged; Biomarkers; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peroxidase; Sensitivity and Specificity; Stroke Volume

Chronic heart failure (CHF) is associated with adaptive structural changes at the alveolocapillary barrier that may be associated with altered protein permeability. Bidirectional protein movement across the barrier was studied in anesthetized rats with infarct-induced CHF by following (125)I-labeled albumin ((125)I-albumin) flux into the alveoli and the leakage of surfactant protein (SP)-B from the alveoli into the circulation. Three groups were studied: controls [0% left ventricular (LV) infarction], moderate infarct (25-45% LV infarction), and large infarct (>46% LV infarction). Wet and dry lung weights increased in the large infarct group (both P < 0.001), consistent with increased lung water and solid lung tissue. (125)I-albumin flux increased across the endothelial (P < 0.001) and epithelial (P < 0.01) components of the alveolocapillary barrier in the large infarct group. Plasma SP-B increased 23% with moderate infarcts (P < 0.05) and 97% with large infarcts (P < 0.001), independent of alveolar levels. Lavage fluid immune cells (P < 0.01) and myeloperoxidase activity (P < 0.05) increased in the large infarct group, consistent with inflammation. Bidirectional protein movement across the alveolocapillary barrier is increased in CHF, and alveolar inflammation may contribute to this pathophysiological defect.

Topics: Animals; Blood-Air Barrier; Bronchoalveolar Lavage Fluid; Capillaries; Erythrocytes; Extravascular Lung Water; Heart Failure; Hemodynamics; In Vitro Techniques; Inflammation; Lung; Male; Myocardial Infarction; Peroxidase; Proteins; Pulmonary Alveoli; Pulmonary Surfactants; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Respiratory Mechanics; Serum Albumin, Radio-Iodinated; Ventricular Dysfunction, Left