losartan-potassium and Heart-Failure

In patients with heart failure, sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to decrease hepcidin and ferritin and increase transferrin receptor protein, changes that are typically indicative of worsening absolute iron deficiency, as would be seen with poor dietary intake or gastrointestinal bleeding, neither of which is provoked by SGLT2 inhibitors. Therefore, 2 alternative conceptual frameworks may explain the observed pattern of changes in iron homeostasis proteins. According to the "cytosolic iron depletion hypothesis," the effect of SGLT2 inhibitors to decrease hepcidin and ferritin and increase transferrin receptor is related to a decline in cytosolic Fe

Topics: Erythropoietin; Ferritins; Heart Failure; Hepcidins; Humans; Inflammation; Iron; Iron Deficiencies; Receptors, Transferrin; Sodium-Glucose Transporter 2 Inhibitors; Transferrin

Heart failure (HF) remains a leading cause of morbidity, hospitalization, and mortality worldwide. Advancement of mechanical circulatory support technology has led to the use of continuous-flow left ventricular assist devices (LVADs), reducing hospitalizations, and improving quality of life and outcomes in advanced HF. Recent studies have highlighted how metabolic and endocrine dysfunction may be a consequence of, or associated with, HF, and may represent a novel (still neglected) therapeutic target in the treatment of HF. On the other hand, it is not clear whether LVAD support, may impact the outcome by also improving organ perfusion as well as improving the neuro-hormonal state of the patients, reducing the endocrine dysfunction. Moreover, endocrine function is likely a major determinant of human homeostasis, and is a key issue in the recovery from critical illness. Care of the endocrine function may contribute to improving cardiac contractility, immune function, as well as infection control, and rehabilitation during and after a LVAD placement. In this review, data on endocrine challenges in patients carrying an LVAD are gathered to highlight pathophysiological states relevant to this setting of patients, and to summarize the current therapeutic suggestions in the treatment of thyroid dysfunction, and vitamin D, erythropoietin and testosterone administration.

Topics: Cardiac Rehabilitation; Endocrine System Diseases; Erythropoietin; Heart Failure; Heart-Assist Devices; Humans; Testosterone; Thyroid Diseases; Vitamin D

Heart Failure (HF) is recognized as an important public health concern worldwide, especially in developed countries, due to its high rate of morbidity and mortality. Although new pharmacological and non-pharmacological agents have improved the clinical sequelae of HF in patients, its mortality remains high, especially among the elderly. Erythropoietin (EPO), a glycoprotein, besides its traditional role in promoting erythropoiesis and production of erythroid progenitors, its beneficial role in reducing infarct area and improving heart function through EPO-induced antiapoptotic and antioxidant effects have been increasingly recognized. This review gathers the evidence to date about the effectiveness of EPO in HF patients. In addition to the growing evidence of EPO in the treatment of HF in the animal studies for improving cardiac function and infarct size, more clinical studies are needed to assess the role of EPO treatment in the management of HF.

Topics: Animals; Antioxidants; Chronic Disease; Erythropoietin; Heart Failure; Humans

Despite multiple factors correlating with the high prevalence of anaemia in heart failure, the prevailing mechanisms have yet to be established. The purpose of this study is to systematically review the literature and determine whether low circulating haemoglobin is primarily underlain by erythropoietin resistance or defective production in heart failure.. We conducted a systematic search of MEDLINE since its inception until May 2017 for articles reporting erythropoietin and haemoglobin concentrations in heart failure patients not treated with erythropoietin-stimulating agents. The primary outcome was the mean difference in observed/predicted (O/P) erythropoietin ratio between heart failure patients and normal reference values. Meta-regression analyses assessed the influence of potential moderating factors.. Forty-one studies were included after systematic review, comprising a total of 3137 stable heart failure patients with mean age and left ventricular ejection fraction ranging from 52 years to 80 years and 21% to 59%. The O/P erythropoietin ratio was below reference values in 24 of 25 studies in anaemic heart failure patients ( n = 1094, range = 0.49-1.05), whereas only one out of 16 studies in non-anaemic heart failure patients presented a low O/P erythropoietin ratio ( n = 2043, range = 0.91-1.97). In studies comparing anaemic versus non-anaemic heart failure patients ( n = 1531), the mean O/P erythropoietin ratio was consistently reduced in anaemic heart failure patients (mean difference = -0.68, 95% confidence interval = -0.78, -0.57; p < 0.001). In meta-regression, the O/P erythropoietin ratio was negatively associated with age, female sex, left ventricular ejection fraction, inflammation and disease severity.. Anaemia in heart failure is overwhelmingly characterized by impaired erythropoietin production, which is exacerbated with age, female sex, left ventricular ejection fraction, inflammation and disease severity.

Topics: Age Factors; Aged; Aged, 80 and over; Anemia; Biomarkers; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Male; Middle Aged; Prognosis; Risk Factors; Severity of Illness Index; Sex Factors; Stroke Volume; Ventricular Function, Left

Topics: Adenosine Triphosphate; Cell Hypoxia; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diabetic Nephropathies; Disease Progression; Diuresis; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Glucose; Heart; Heart Failure; Hematocrit; Hemoglobins; Humans; Kidney; Kidney Tubules, Proximal; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors; Sodium-Potassium-Exchanging ATPase; Sympathetic Nervous System

An estimated 5.1 million Americans have chronic heart failure and this is expected to increase 25% by 2030. Heart failure is a clinical syndrome that evolves from either functional or structural changes to the ventricles that lead to filling or ejection abnormalities. Thus far, pharmacotherapy has been show to be beneficial in patients only with reduced ejection fraction; however, new therapies have been developed in hopes of reducing the burden of heart failure. In this review, we will discuss current pharmacotherapies recommended in American College of Cardiology/American Heart Association guidelines, the evidence behind these recommendations as well as new and emerging therapies that have been developed.

Topics: Adrenergic beta-Antagonists; American Heart Association; Amides; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Antihypertensive Agents; Atrial Natriuretic Factor; Benzazepines; Biphenyl Compounds; Calcium Channel Blockers; Cardiology; Cardiotonic Agents; Cardiovascular Agents; Digoxin; Diuretics; Drug Combinations; Erythropoietin; Evidence-Based Medicine; Fumarates; Heart Failure; Hematinics; Humans; Hydralazine; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Iron; Isosorbide Dinitrate; Ivabradine; Mineralocorticoid Receptor Antagonists; Peptide Fragments; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Societies, Medical; Stroke Volume; Tetrazoles; United States; Valsartan; Vasodilator Agents

Topics: Adaptation, Physiological; Altitude Sickness; Calcium; Chronic Disease; Endothelium, Vascular; Erythropoietin; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Muscle, Smooth; Pulmonary Edema; Vascular Diseases; Vascular Remodeling; Vasoconstriction

Anemia is present in about 40% of heart failure (HF) patients. Iron deficiency (ID) is present in about 60% of the patients with anemia (about 24% of all HF patients) and in about 40% of patients without anemia (about 24% of all HF patients). Thus ID is present in about half the patients with HF. The ID in HF is associated with reduced iron stores in the bone marrow and the heart. ID is an independent risk factor for severity and worsening of the HF. Correction of ID with intravenous (IV) iron usually corrects both the anemia and the ID. Currently used IV iron preparations are very safe and effective in treating the ID in HF whereas little information is available on the effectiveness of oral iron. In HF IV iron correction of ID is associated with improvement in functional status, exercise capacity, quality of life and, in some studies, improvement in rate of hospitalization for HF, cardiac structure and function, and renal function. Large long-term adequately-controlled intervention studies are needed to clarify the effect of IV iron in HF. Several heart associations suggest that ID should be routinely sought for in all HF patients and corrected if present. In this paper we present our approach to diagnosis and treatment of iron deficiency in heart failure.

Topics: Anemia, Iron-Deficiency; Erythropoietin; Heart Failure; Humans

Anemia is a frequent comorbidity of heart failure and is associated with poor outcomes. Anemia in heart failure is considered to develop due to a complex interaction of iron deficiency, kidney disease, and cytokine production, although micronutrient insufficiency and blood loss may contribute. Currently, treatment of anemia of heart failure lacks clear targets and specific therapy is not defined. Intravenous iron use has been shown to benefit anemic as well as nonanemic patients with heart failure. Treatment with erythropoietin-stimulating agents has been considered alone or in combination with iron, but robust evidence to dictate clear guidelines is not currently available. Available and emerging new agents in the treatment of anemia of heart failure will need to be tested in randomized, controlled studies.

Topics: Age Factors; Aged; Anemia; Anemia, Iron-Deficiency; Chronic Disease; Erythropoietin; Female; Heart Failure; Hematinics; Humans; Incidence; Inflammation Mediators; Iron; Male; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Renin-Angiotensin System; Sex Factors

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Heart Failure; Hematinics; Humans; Iron

Discovered as the primary regulator of erythropoiesis, erythropoietin (EPO) is involved in a broad variety of processes that play a major role in cardiovascular diseases. In particular, the antiapoptotic and pro-angiogenic properties of EPO have prompted a growing interest in the use of EPO for the treatment of myocardial infarction and heart failure. In a variety of myocardial ischemic injury animal models, EPO administration has been shown to acutely reduce infarct size, thereby preserving ventricular function. In addition, cardiac long-term effects of EPO, such as prevention of ventricular remodeling and heart failure, have been described. In recent years, several trials have tested the effects of recombinant human erythropoietin (rhEPO) administration in patients with myocardial infarction and chronic heart failure, in the attempt to translate the cardioprotection found in experimental models to human patients. In view of the generally controversial findings, in this updated review we provide an overview of the results of the most recent trials that investigated the role of erythropoiesis-stimulating agents (ESAs), including rhEPO and its analogue darbepoetin, in the treatment of acute myocardial infarction and heart failure. The problems related to safety and tolerability of ESA therapy are also discussed. Our analysis of the available literature demonstrates that the results of clinical studies in patients with cardiac disease are not uniform and the conclusions are contradictory. Further larger prospective studies are required to test clinical efficacy and safety of EPO.

Topics: Animals; Disease Models, Animal; Erythropoietin; Heart Failure; Humans; Myocardial Infarction; Randomized Controlled Trials as Topic; Recombinant Proteins

Erythropoietin (EPO) stimulates erythropoiesis through its specific receptor (EPO-R). Preclinical work has assigned a role for the EPO/EPO-R system in the heart and blood vessels. The potential use of erythropoiesis-stimulating agents (ESAs) for nonhematopoietic indications is a focus of current research. This article considers proven actions of EPO in the cardiovascular system, with emphasis on the human responses.. By use of specific anti-EPO-R antibody no EPO-R protein was detected by Western blotting in normal non-erythroid tissues. Clinical trials failed to demonstrate clear beneficial effects of high-dosed ESAs in patients with coronary syndrome or myocardial infarct. While ESA therapy may lead to an elevation in arterial blood pressure in previously anemic patients, several studies have reported no effects on vessels/blood pressure with ESAs. EPO has been reported to stimulate angiogenesis. EPO-R mRNA is detectable in human vascular endothelium. However, in most vitro studies very high concentrations of EPO were applied and well-designed studies have failed to show direct effects of ESAs on endothelial cells. Whether EPO promotes the mobilization of myeloid progenitor cells into the blood stream still needs to be studied in more detail, as this effect may prove useful for augmenting the neovascularization of ischemic tissues. With respect to the administration of ESAs to tumor patients, a deeper insight into the role of EPO for tumor angiogenesis is desirable.. The enthusiastic reports of the nonhematopoietic cytoprotective potential of EPO and its derivatives in the cardiovascular system have not yet been confirmed in placebo-controlled clinical trials.

Topics: Animals; Endothelium, Vascular; Erythropoietin; Heart Failure; Humans; Myocardial Infarction; Neovascularization, Pathologic; Neovascularization, Physiologic; Receptors, Erythropoietin

Trials studying iron repletion in patients with chronic heart failure (CHF) and iron deficiency are underpowered to find consistent hard endpoint (mortality and hospitalization) reductions. We conducted a meta-analysis of controlled trials to examine the effects of iron repletion on these parameters.. Pubmed, CENTRAL, EMBASE and NIH Clinical Trials databases were searched for controlled trials utilizing intravenous iron, with or without erythropoietin, in patients with CHF with NYHA class ≥ II, iron deficiency, and left ventricular dysfunction. Data regarding hospitalizations, mortality, adverse events, NYHA class, and ejection fraction were extracted, analyzed for heterogeneity, and pooled using the DerSimonian and Laird random effects model. We identified 5 controlled trials (n = 631 patients). Patients treated with intravenous iron had significant reductions in hospitalizations (OR 0.26, 95% CI 0.08-0.80), adverse events (OR 0.35, 95% CI 0.21-0.60), NYHA class (mean improvement 1.2 classes, 95% CI 0.69-1.78, and LVEF (mean improvement 5.0%, 95% CI 0.13-9.80) but no relationship was found on mortality (OR 0.66, 95% CI 0.30-1.44).. Treatment of iron deficiency in patients with CHF reduces the risk of hospitalizations without increased adverse events, suggesting its role as a potential therapeutic target in this group of patients.

Topics: Administration, Intravenous; Anemia, Iron-Deficiency; Erythropoietin; Heart Failure; Humans; Iron; Treatment Outcome

Even though anemia is a significant comorbidity regularly observed in patients with chronic heart failure (HF), only in recent years systematic therapeutic research has been started. This article aims to review the aspects of anemia in chronic HF that are relevant for making treatment decisions, beginning with the definition of anemia and its incidence and prevalence of anemia in patients with chronic HF. Considering the etiology and prognostic impact of anemia in chronic HF, several treatment options will be considered. The latter are the application of erythropoiesis-stimulating agents (erythropoietin or darbepoetin alfa) or in the application of intravenous iron (e.g., iron carboxymaltose). According to the results seen in the FAIR-HF trial, iron supplementation should be particularly considered to improve symptoms and quality of life. Intravenous iron application may result in higher compliance and much faster treatment response than oral iron. The RED-HF study will show whether use of darbepoetin alfa in anemic patients with chronic HF will reduce the combined endpoint of death for any reason or hospitalization for heart failure.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Iron; Prognosis

Recently, it has been suggested that erythropoietin may be useful in the treatment of cardiovascular disease, particularly heart failure. This may be by improving microvascular blood supply and ventricular function through prevention of apoptosis and angiogenesis. Promising results were seen in animals but the few, limited clinical trials have shown modest benefits. Additionally, concerns exist regarding potential serious adverse effects of erythropoietin. Our current understanding of the non-haematopoietic mechanisms of erythropoietin is presented here, with a review of trials to date, and a discussion of the questions that remain over the use of this drug in heart failure.

Topics: Anemia; Animals; Erythropoietin; Heart Failure; Humans; Signal Transduction

Anemia is a common comorbidity in heart failure (HF), and is associated with increased morbidity and mortality. However, it remains unclear whether anemia is merely a marker of poor prognosis or whether anemia itself confers risk. The pathogenesis of anemia in HF is multifactorial. Iron deficiency also confers risk in HF, either with or without associated anemia, and treatment of iron deficiency improves the functional status of patients with HF. An ongoing large clinical trial studying the use of darbepoetin-alfa in patients with anemia and systolic HF is expected to provide information that should improve our understanding of anemia in HF.

Topics: Anemia; Comorbidity; Erythropoietin; Heart Failure; Hematinics; Humans; Iron; Iron Deficiencies; Prognosis; Randomized Controlled Trials as Topic

In experimental models of acute myocardial infarction (AMI), erythropoietin (EPO) reduces infarct size and improves left ventricular (LV) function. However, in the clinical setting, the effect of EPO in AMI was unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) of EPO to explore the safety and therapeutic effects of EPO in patients with AMI.. We identified reports of RCTs comparing EPO to placebo for AMI in adult humans in PubMed, Cochrane Central Register of Controlled Trials, and EMBASE. Outcomes included all-cause mortality, major cardiovascular events, cardiac function by LV ejection fraction and infarct size.. We included 13 articles of RCTs with data for 1,564 patients. Erythropoietin therapy did not improve LV ejection fraction (weighted mean difference [WMD] 0.33, 95% CI -1.90 to 1.24, P = .68) and had no effect on infarct size, as measured by cardiac magnetic resonance imaging (WMD -0.12, -2.16 to 1.91, P = .90) or serum peak value of creatine kinase-MB (WMD -2.01, -25.70 to 21.68, P = .87). Erythropoietin treatment did not decrease the risk of total adverse cardiac events (relative risk [RR] 1.02, 0.65-1.61, P = .92). Erythropoietin treatment also failed to decrease the risk of heart failure (RR, 0.69, 0.27-1.72, P = .42) and all-cause mortality (RR 0.55, 0.22-1.33, P = .18). Moreover, EPO had no effect on the risk of stent thrombosis (RR, 0.69, 0.29-1.64, P = .40).. Erythropoietin in patients with AMI seems to have no clinical benefit for heart function or reducing infarct size, cardiovascular events, and all-cause mortality. Erythropoietin may not be a choice for patients with AMI.

Topics: Adult; Aged; Cardiovascular Agents; Drug Administration Schedule; Erythropoietin; Female; Heart Failure; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Myocardial Infarction; Randomized Controlled Trials as Topic; Risk; Stroke Volume; Survival Rate; Thrombosis; Treatment Failure; Ventricular Function, Left

Cardiorenal anemia syndrome (CRAS) refers to the simultaneous presence of anemia, heart failure (HF), and chronic kidney disease (CKD) that forms a pathologic triad with an observe impact on morbidity and mortality. Certain researches were made regarding the usage of erythropoietin (EPO) in patients with the above mentioned disorders. This leads to the improvement of left ventricular function, quality of life and physical tolerance with decreased risk of hospitalization. Despite successful anemia treatment with EPO in dialysis patients with CKD, HF and cardiorenal syndrome type 2, it should be important to reveal the target Hb level and role of EPO in this category of patients. According to European guidelines in 85% of hemodialysis patients targeted Hb level should be no more than 11g/dl, moreover, the treatment of anemia can be organized before dialysis and it will certainly increase the quality of life in this type of patients.

Topics: Anemia; Cardio-Renal Syndrome; Erythropoietin; Heart Failure; Hospitalization; Humans; Kidney Failure, Chronic; Quality of Life; Renal Dialysis; Treatment Outcome; Ventricular Function, Left

Anemia is common in Congestive Heart Failure (CHF) and is associated with an increased mortality, morbidity and progressive renal failure. The most common causes of the anemia in CHF are (1) the associated Chronic Kidney Disease (CKD), which causes depression of erythropoietin (EPO) production in the kidney, and (2) excessive cytokine production in CHF, which can cause both depression of erythropoietin production in the kidney and depression of erythropoietin response in the bone marrow. The cytokines can also induce iron deficiency by increasing hepcidin production from the liver, which both reduces gastrointestinal iron absorption and reduces iron release from iron stores located in the macrophages and hepatocytes. It appears that iron deficiency is very common in CHF and is rarely recognized or treated. The iron deficiency can cause a thrombocytosis that might contribute to cardiovascular complications in both CHF and CKD and is reversible with iron treatment. Thus, attempts to control this anemia in CHF will have to take into consideration both the use of both Erythropoiesis Stimulating Agents (ESA) such as EPO and oral and, probably more importantly, intravenous (IV) iron. Many studies of anemia in CHF with ESA and oral or IV iron and even with IV iron without ESA have shown a positive effect on hospitalization, New York Heart Association functional class, cardiac and renal function, quality of life, exercise capacity and reduced Beta Natriuretic Peptide and have not demonstrated an increase in cardiovascular damage related to the therapy. However, adequately powered long-term placebo-controlled studies of ESA and of IV iron in CHF are still needed and are currently being carried out.

Topics: Anemia; Bone Marrow; Cardiovascular System; Clinical Trials as Topic; Erythropoietin; Heart Failure; Hematinics; Humans; Infusions, Intravenous; Iron; Iron Deficiencies; Kidney; Outcome Assessment, Health Care; Renal Insufficiency, Chronic; Syndrome; Trace Elements

EPO (erythropoietin) has long been identified as a primary regulator of erythropoiesis. Subsequently, EPO has been recognized as playing a role in a broad variety of processes in cardiovascular pathophysiology. In particular, the tight interactions of EPO with the nitric oxide pathway, apoptosis, ischaemia, cell proliferation and platelet activation appear of great interest. Although enhanced EPO synthesis is viewed as an appropriate compensatory mechanism in the cardio-renal syndrome, which features CHF (congestive heart failure) and CRF (chronic renal failure), maladaptative excessive EPO synthesis in the advanced stages of these diseases appears to be predictive of higher mortality. Clinical trials based on the use of EPO in both heart and renal failure have so far produced contradictory results, whereas treatment targeted to restore low Hb levels appears rational and is supported by regulatory authorities. New areas for therapeutic use of EPO, such as acute coronary syndromes, are under investigation, and they are discussed in the present review together with other clinical applications in cardiovascular diseases. The revisited concept of a potential use of endogenous EPO levels as a predictor of CHF severity, as well as in the monitoring of responses to treatment, deserves appropriate investigation, as this may identify EPO as a useful biomarker in the clinical management of cardiovascular diseases.

Topics: Biomarkers; Cardiovascular Diseases; Erythropoietin; Heart Failure; Humans; Myocardial Infarction; Prognosis; Signal Transduction

Anemia is a common comorbidity in heart failure (HF) patients. Its occurrence and severity are associated with worse prognosis. Although the etiology of anemia is multifactorial, inappropriate erythropoietin (EPO) production and/or bone-marrow resistance to EPO appear crucial in majority of anemic HF patients. Consequently, treatment based on this pathophysiological background may prove to be most effective and beneficial. In a number of smaller clinical studies, administration of erythropoiesis-stimulating agents (ESAs) to anemic HF patients improved a number of surrogate endpoints, including left ventricular function, exercise capacity, renal function, and different quality of life parameters. However, two larger, phase II studies, did not fully confirm these promising results. Furthermore, many concerns have been raised on the safety of ESAs after the recent publication of studies correcting anemia in patients with chronic kidney disease (CKD). On the other hand, chronic HF population varies significantly from CKD patients, with different comorbidities, renal function, and etiology of anemia. Moreover, ESAs have been shown to possess robust nonhematopoietic effects in the heart, namely inhibition of apoptosis and stimulation of neovascularization. Therefore, large-scale trials with ESAs are required to examine the effect and safety of anemia treatment in HF patients.

Topics: Anemia; Erythropoietin; Heart Failure; Hematinics; Humans; Randomized Controlled Trials as Topic; Renal Insufficiency

Chronic heart failure is a substantial public health problem. Anemia is an important comorbidity frequently observed in patients with the disease and, in heart failure, anemia has only recently started to attract systematic epidemiological and therapeutical research endeavor. This article describes the many aspects of anemia in chronic heart failure, starting with the ongoing discussion of how to define anemia, which has important consequences for the estimation of its prevalence and incidence. Further, we discuss prognostic implications of anemia in patients with chronic or acute heart failure, the etiology of anemia in heart failure and treatment possibilities. Such therapeutic avenues embrace intravenous iron preparations and subcutaneous administration of erythropoietin and its derivatives, all of which have been extensively studied over the last several years. Finally, this article describes the potential costs incurred by treating anemic patients with heart failure.

Topics: Anemia; Comorbidity; Darbepoetin alfa; Erythropoietin; Ferric Compounds; Heart Failure; Hematinics; Humans; Injections, Intravenous; Iron Compounds; Maltose; Prognosis; Risk Assessment; Risk Factors; United States

Anemia is a disease that is often associated with heart failure (HF) and renal insufficiency (RI). This unfavorable triad of conditions has been called Cardio-Renal-Anemia Syndrome (CRS). The association of HF, RI, and anemia is poorly reported in multicenter clinical trials, so the pathophysiologic mechanisms and treatment options need to be better defined. When CRS patients develop anemia, a "perfect storm" often occurs: HF and RI cause anemia which will worsen the first two conditions. Anemia appears to be the result of complex interactions between cardiac performance, bone marrow homeostasis, renal dysfunction, and various drug side effects. However, neurohormonal and inflammatory activities play a key role in the beginning and progression of the disease. As a consequence, endogenous erythropoietin activity dysfunction with inadequate production and tissue resistance occurs. Despite the advances of therapy in the neurohormonal activation blockade, mortality and hospitalization in HF still remain unacceptably high, suggesting that specific comorbidity treatments could have a significant positive prognostic impact. Anemia should be recognized as one of the novel targets in HF treatment.

Topics: Anemia; Bone Marrow; Cardiovascular System; Clinical Trials as Topic; Disease Progression; Drug Therapy, Combination; Erythropoietin; Heart Failure; Hemoglobins; Humans; Iron; Patient Selection; Prognosis; Renal Insufficiency; Risk Factors; Severity of Illness Index; Syndrome; Water-Electrolyte Balance

Anemia in heart failure is both common and associated with worse symptoms and increased mortality. Several small randomized controlled trials (RCTs) have assessed erythropoiesis-stimulating agents (ESAs), but definitive evaluation and clinical guidance are required. We sought to systematically review the effects of ESAs in chronic heart failure.. An extensive search strategy identified 11 RCTs with 794 participants comparing any ESA with control over 2 to 12 months of follow-up. Published and additionally requested data were incorporated into a Cochrane systematic review (CD007613).. Nine studies were placebo controlled, and 5, double blinded. Erythropoiesis-stimulating agent treatment significantly improved exercise duration by 96.8 seconds (95% CI 5.2-188.4, P = .04) and 6-minute walk distance by 69.3 m (95% CI 17.0-121.7, P = .009) compared with control. Benefit was also noted for peak oxygen consumption (+2.29 mL/kg per minute, P = .007), New York Heart Association class (-0.73, P < .001), ejection fraction (+5.8%, P < .001), B-type natriuretic peptide (-226.99 pg/mL, P < .001), and quality-of-life indicators with a mean increase in hemoglobin level of 2 g/dL. There was a significantly lower rate of heart failure-related hospitalizations with ESA therapy (odds ratio 0.56, 95% CI 0.37-0.84, P = .005). No associated increase in adverse events or mortality (odds ratio 0.58, 95% CI 0.34-0.99, P = .047) was observed, although the number of events was limited.. Meta-analysis of small RCTs suggests that ESA treatment can improve exercise tolerance, reduce symptoms, and have benefits on clinical outcomes in anemic patients with heart failure. Confirmation requires larger, well-designed studies with careful attention to dose, attained hemoglobin level, and long-term outcomes.

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Randomized Controlled Trials as Topic; Treatment Outcome

Anemia is a common comorbidity in patients with acute and chronic heart failure (HF) with preserved and reduced systolic function. It is recognized as a new therapeutic goal in HF since the reduction in hemoglobin levels is considered a significant independent predictive factor of mortality and hospitalization. At present, it is difficult to determine the real magnitude of the problem in terms of actual incidence and prevalence as no consistent definition of anemia associated with HF does exist, and a variety of hemoglobin thresholds have been used in clinical trials and epidemiological studies. The etiology of anemia is multifactorial with the main causes including renal failure, gastrointestinal bleeding and nutritional deficiency. Nevertheless, such criteria are not present in some patients, who show a peculiar type of anemia that may be classified as anemia of chronic diseases, likely due to the chronic inflammatory process of HF. No guidelines for the treatment of anemia in HF patients are available. Most of the previous studies in the literature are limited by small sample sizes. The very few randomized multicenter studies that evaluated the effects of erythropoiesis-stimulating agents associated with intravenous iron therapy did not provide the expected results. Indeed, despite an increase in hemoglobin levels, they did not show any improvement of NYHA functional class, nor of left ventricular ejection fraction. In addition, reasonable hemoglobin levels as a goal of therapy have not been established yet, in particular in relation to the side effects and the cardiovascular risk observed after the administration of erythropoiesis-stimulating agents in oncologic patients. Further studies are warranted to define the magnitude of the problem and establish appropriate therapeutic strategies. It is likely that more reliable data will be derived from an ongoing randomized, double-blind, multicenter study, the RED-HF (Reduction Event with Darbepoetin alfa in Heart Failure), which aims at evaluating morbidity and mortality in a cohort of 2600 HF patients with anemia treated with darbepoetin alfa.

Topics: Anemia; Cardiovascular Agents; Cytokines; Darbepoetin alfa; Defibrillators, Implantable; Double-Blind Method; Erythropoiesis; Erythropoietin; Heart Failure; Hematinics; Hematocrit; Hemoglobins; Humans; Iron; Malnutrition; Models, Biological; Multicenter Studies as Topic; Practice Guidelines as Topic; Prognosis; Randomized Controlled Trials as Topic; Research Design; Stroke Volume

Cell-based therapy is emerging as an exciting potential therapeutic approach for cardiac regeneration following myocardial infarction (MI). As heart failure (HF) prevalence increases over time, development of new interventions designed to aid cardiac recovery from injury are crucial and should be considered more broadly. In this regard, substantial efforts to enhance the efficacy and safety of cell therapy are continuously growing along several fronts, including modifications to improve the reprogramming efficiency of inducible pluripotent stem cells (iPS), genetic engineering of adult stem cells, and administration of growth factors or small molecules to activate regenerative pathways in the injured heart. These interventions are emerging as potential therapeutic alternatives and/or adjuncts based on their potential to promote stem cell homing, proliferation, differentiation, and/or survival. Given the promise of therapeutic interventions to enhance the regenerative capacity of multipotent stem cells as well as specifically guide endogenous or exogenous stem cells into a cardiac lineage, their application in cardiac regenerative medicine should be the focus of future clinical research. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."

Topics: Animals; Clinical Trials as Topic; Erythropoietin; Genetic Engineering; Genetic Therapy; Granulocyte Colony-Stimulating Factor; Heart; Heart Failure; Humans; Regeneration; Stem Cell Transplantation; Stem Cells

Despite the advances in the cardiovascular field, cardiovascular diseases remain an important health problem with a high mortality rate. Novel therapeutic attempts that target myocardial ischemia and heart failure offer attractive adjuncts and/or alternatives to commonly employed regimens. The development of novel laboratory technologies over the last decade has led to substantial progress in bringing new therapies to the bedside.. Current experimental and clinical trials in the use of erythropoietin (EPO) in cardiovascular diseases are reviewed.. This review will widen knowledge of the therapeutic potential of EPO's non-erythropoietic beneficial effects in a clinical cardiovascular setting.. Results from preclinical trials regarding the non-erythropoietic effects of erythropoietin are really encouraging. Further clinical studies are warranted to define the beneficial role of EPO in the clinical setting of coronary artery disease, heart failure and peripheral artery disease.

Topics: Animals; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Clinical Trials as Topic; Erythropoietin; Heart Failure; Humans; Myocardial Infarction; Receptors, Erythropoietin; Recombinant Proteins

Anaemia is common in congestive heart failure (CHF) and is associated with increased mortality, morbidity and progressive renal failure. The common causes of the anaemia are the associated renal failure and excessive cytokine production, both of which can cause depression of the erythropoietin (EPO) production in the kidney and depression of EPO response in bone marrow. The cytokines can also induce iron deficiency by increasing hepcidin production from the liver, which both reduces gastrointestinal iron absorption and reduces iron release from iron stores located in the macrophages and hepatocytes. Attempts to control this anaemia will have to consider the use of both erythropoiesis stimulating agents (ESA) as well as oral and, probably more importantly, intravenous (IV) iron. Studies of anaemia in CHF with ESA and oral or IV iron and even with IV iron alone have shown a positive effect on hospitalisation, fatigue and shortness of breath, cardiac and renal function, quality-of-life, exercise capacity and reduced beta natriuretic peptide and have not demonstrated an increase in cardiovascular damage related to therapy. Although some studies and meta-analyses have revealed improvement in these parameters others have not. Adequately powered long-term placebo-controlled studies of ESA and of IV iron in CHF are needed and are currently being carried out.

Topics: Anemia; Anemia, Iron-Deficiency; Cytokines; Darbepoetin alfa; Electric Countershock; Erythropoietin; Heart Failure; Hematinics; Humans; Iron; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors

Renal dysfunction and neurohormonal and proinflammatory cytokine activation appear to contribute to anemia of chronic disease in most patients, resulting in inappropriate erythropoietin production and defective iron utilization. Under normal conditions, reduced tissue oxygenation caused by chronic anemia results in non-hemodynamic and hemodynamic compensatory responses to enhance oxygen carrying capacity. Erythropoiesis is the predominant non-hemodynamic response to hypoxia, but because erythropoiesis is defective in heart failure, hemodynamic mechanisms may predominate in chronic severe anemia. Hemodynamic responses are complex and involve a vasodilation-mediated high-output state with neurohormonal activation. The high output state initially helps to increase oxygen transport. However, the hemodynamic and neurohormonal alterations could potentially have deleterious long-term consequences and may contribute to anemia's role as an independent risk factor for adverse outcomes.

Topics: Anemia, Iron-Deficiency; Cytokines; Disease Progression; Erythropoietin; Heart Failure; Hemodynamics; Humans; Kidney Failure, Chronic; Prognosis; Renin-Angiotensin System; Risk Factors

Anemia is highly prevalent in patients with chronic heart failure (CHF) and is associated with poor clinical outcome. Increased prevalence of anemia in CHF has been linked to advanced age, female gender, renal function impairment, severity of symptoms, and clinical settings. Overall, the anemia of CHF shares many common features with the anemia of chronic disease. Both impaired iron metabolism and inflammatory stress appear to be the key mediators of the anemia of CHF.

Topics: Age Factors; Anemia, Iron-Deficiency; Disease Progression; Erythropoietin; Female; Heart Failure; Humans; Inflammation; Iron, Dietary; Kidney Failure, Chronic; Male; Prevalence; Prognosis; Renin-Angiotensin System; Risk Factors; Sex Factors; Stress, Physiological; United States

Chronic untreated anemia or iron deficiency (ID) can result in an increased cardiac output, chronic sympathetic activation, left ventricular hypertrophy, and left ventricular dilation, leading to symptomatic chronic heart failure (CHF). Only in the past decade has there been an increase in interest in anemia and ID occurring in the course of CHF. The pharmacologic support in erythropoietin signaling or the correction in iron metabolism may activate molecular pathways that can protect the heart and prevent myocardial remodeling, and hence become a novel therapeutic approach in patients with CHF. Most of the data come from experimental models. Further studies, in particular performed in clinical settings, are warranted.

Topics: Anemia, Iron-Deficiency; Erythropoietin; Heart Failure; Hemodynamics; Humans; Hypertrophy, Left Ventricular; Myocardium; Risk Factors

Anemia resulting from iron and erythropoietin deficiencies is a common complication of advanced chronic kidney disease (CKD). This article covers major advances in our understanding of anemia in patients with CKD, including newly discovered regulatory molecules, such as hepcidin, to innovative intravenous iron therapies. The use of erythropoiesis-stimulating agents (ESA) in the treatment of anemia has undergone seismic shift in the past 3 years as a result of adverse outcomes associated with targeting higher hemoglobin levels with these agents. Potential mechanisms for adverse outcomes, such as higher mortality, are discussed. Despite the disappointing experience with ESAs, there is a tremendous interest in other novel agents to treat anemia in CKD. Lastly, while awaiting updated guidelines, the authors outline their recommendations on how to best manage patients who are anemic and have CKD.

Topics: Anemia, Iron-Deficiency; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Cardiovascular Diseases; Erythropoietin; Ferrosoferric Oxide; Heart Failure; Hematinics; Hepcidins; Humans; Indicators and Reagents; Iron, Dietary; Kidney Failure, Chronic

Over the past decade, a growing body of literature has led to a greater understanding of the relationship between anemia and the outcomes in patients with heart failure. This article reviews the current literature on the association between anemia and a broad range of clinical outcomes, including mortality, hospitalization, health status, and cost.

Topics: Anemia, Iron-Deficiency; Disease Progression; Erythropoietin; Health Status; Heart Failure; Hemoglobins; Hospitalization; Humans; Prevalence; Risk Factors; Treatment Outcome; United States

Anemia is a complex issue in patients with heart failure (HF). In past years, clinicians accepted anemia as a given or an "accessory" diagnosis in HF patients. This attitude has changed since understanding of the causes and morbidity of anemia in HF has improved and with the introduction of targeted treatments. Increasing health care costs have stimulated vigorous debate about the cost-effectiveness of such treatments. It behooves clinicians to understand the effectiveness of specific treatments, risks and benefits, and costs. This review addresses the impact of anemia's prevalence, etiology, associated outcomes, and treatments on the economic burden of HF patients.

Topics: Anemia, Iron-Deficiency; Comorbidity; Cost-Benefit Analysis; Erythropoietin; Health Care Costs; Heart Failure; Humans; Prevalence; Quality of Life; Risk Assessment; Treatment Outcome; United States

Anemia in patients with heart failure (HF) may be caused by several factors, including hemodilution, iron or erythropoietin deficiency, and chronic kidney disease. Published pilot studies of erythropoiesis-stimulating agents (ESAs) and intravenous iron therapy in anemic heart failure patients demonstrate improvement in surrogate markers of functional capacity and quality of life, and reasonable safety profile during short-term use. However, the long-term safety of ESA in treatment of anemia in patients with HF remains a concern due to documented harmful side effects of ESA in anemic patients with advanced chronic kidney disease and cancer. Ongoing prospective clinical outcomes studies of ESA and intravenous iron therapies will provide important data that may pave the way for new avenues in the treatment of anemia in the future.

Topics: Anemia, Iron-Deficiency; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Biomarkers; Erythropoietin; Heart Failure; Hematinics; Hemodilution; Hepcidins; Humans; Iron; Quality of Life; Risk Factors; Time Factors; Treatment Outcome

Anaemia is a relatively frequent co-morbidity of chronic heart as well as chronic renal failure. In both conditions, it represents a strong and independent predictor of increased morbidity and mortality. Aetiology of this anaemia is multi-factorial. A number of various factors play a role in its development, e.g. inadequate erythropoietin production in the kidneys, bone marrow inhibition, iron deficiency as well as haemodilution associated with fluid retention. Treatment strategies aim at two directions. One is the stimulation of erythropoiesis with recombinant human erythropoietin or its analogues such as darbepoetin alpha. The other involves iron substitution, administered preferably intravenously for improved efficacy and tolerability. Clinical studies evaluating treatment of anaemia in chronic heart failure with erythropoiesis-stimulating agents conducted so far were ofa small scale, were not controlled with placebo and usually assessed proxy parameters. Their results suggested that effective treatment of anaemia in patients with chronic heart failure improves exertion tolerance, clinical status (NYHA class) as well as the quality of life and reduces the need for blood transfusions. Recently completed TREAT study was the first large morbidity and mortality study evaluating treatment of anaemia with an erythropoietin analogue compared to placebo. On a sample of more than 4000 patients with diabetes mellitus, chronic renal failure and significant anaemia, this study has shown that effective treatment of anaemia with darbepoetin alpha did not affect at all the incidence of cardiovascular and renal events; on the other hand, it had lead to a nearly two-fold increase in the incidence of cerebrovascular events. Some doubts about the safety of treatment with erythropoiesis-stimulating agents have occurred in the past based on the studies of anaemia treatment in patients with cancer and renal diseases. An answer to the question whether the treatment of anaemia associated with chronic heart failure affects positively the patient prognosis will be provided following the completion of the currently running morbidity and mortality RED-HF study.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Iron

Topics: Anemia; Biomarkers; Erythropoietin; Heart Failure; Humans; Population Surveillance; Predictive Value of Tests; Survival Rate

Hepcidin is a key regulator controlling iron intestinal absorption and distribution through the body. The article by van der Putten et al. examined the association between hepcidin-25 and erythropoietin responsiveness and inflammation in erythropoietin-naive, iron-replete patients with chronic heart failure and chronic kidney disease. A cross-sectional observation revealed that serum hepcidin-25 was elevated almost twofold when compared with levels in healthy subjects. Hepcidin-25 was inversely correlated with hemoglobin (r(2) = 0.18; p < 0.02), and positively with ferritin (r(2) = 0.51; p < 0.01) and transferrin saturation (r(2) = 0.14; p < 0.03), while it did not correlate with levels of IL-6 and highly sensitive C-reactive protein. They found that 2-week erythropoietin therapy (50 IU/kg/week) significantly decreased hepcidin-25 levels. The magnitude of the decrease in hepcidin-25 levels correlated with the increase in reticulocytes (r(2) = 0.23; p < 0.03) and soluble transferrin receptor (r(2) = 0.23; p = 0.03), but not with inflammatory markers. A decline in hepcidin-25 correlated with the increment of hemoglobin after 6 months (r(2) = 0.49; p < 0.01). The findings convincingly suggest that hepcidin-25 may be useful in predicting erythropoietin responsiveness in stable chronic heart failure patients. However, further studies will be needed to establish clinically available methods to reliably measure hepcidin-25 level.

Topics: Anemia; Antimicrobial Cationic Peptides; Biomarkers; C-Reactive Protein; Cystatin C; Erythropoietin; Glomerular Filtration Rate; Heart Failure; Hepcidins; Humans; Iron; Kidney Failure, Chronic; Mass Screening; Recombinant Proteins; Statistics as Topic; Treatment Outcome

It has recently been recognized that many patients with congestive heart failure (CHF) are anemic. The anemia is very often associated with chronic kidney disease (CKD). The more severe the anemia the more severe the CHF, with higher mortality, morbidity, and hospitalization rate. The only way to prove that the anemia is itself a causative factor in the progression of both the CKD and the CHF is to correct it. In this paper we review the results of published papers and some preliminary reports about correction of this anemia in CHF. These studies frequently showed that erythropoietic stimulating agents (ESA) with oral or IV iron often resulted in improvement in left ventricular systolic and diastolic function, dilation, and hypertrophy, stabilization or improvement in renal function, reduced hospitalizations, diuretic dose, mitral regurgitation, pulmonary artery pressure, plasma volume, heart rate, serum brain natriuretic peptide levels, and the inflammatory markers C reactive protein and Interleukin 6, and an improvement in New York Heart Association class, exercise capacity, oxygen utilization during exercise, sleep apnea, caloric intake, depression, and quality of life. The activity of endothelial progenitor cells was also increased. Iron deficiency may also play an important role in the anemia, because significant improvement of cardiac, renal, and functional status in these anemic CKD-CHF has been seen after treatment with IV iron alone. Clearly more work is needed to clarify the relationship between anemia, CKD and CHF.

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Iron; Renal Insufficiency, Chronic

Anaemia is common in patients with chronic heart failure (HF), and erythropoiesis stimulating proteins (ESPs) are frequently used for its treatment. However, recent studies in patients with malignancies and renal failure have raised concerns about the safety of these agents.. To determine whether treatment of anaemic patients with chronic HF with ESPs is associated with an effect on morbidity and mortality.. A systematic literature search in Medline, the Cochrane Controlled Trials Register Database and ClinicalTrials.gov through July 2008 was performed.. Randomised clinical trials comparing the effect of ESP treatment with placebo or usual care in anaemic patients with HF were included.. Seven randomised controlled trials were identified that enrolled 650 patients, of whom 363 were treated with ESPs and 287 with placebo. ESP treatment had a significantly lower risk of HF hospitalisation (risk ratio (RR) = 0.59; 95% CI 0.41 to 0.86; p = 0.006).There was no significant difference in the mortality risk between the two groups (RR = 0.69; 95% CI 0.39 to 1.23; p = 0.21). No significant differences were observed in the occurrence of hypertension or venous thrombosis.. In chronic HF, treatment with ESPs is not associated with a higher mortality rate or more adverse events, whereas a beneficial effect on HF hospitalisation is seen. These outcomes are in contrast with studies in cancer and kidney disease, and support a large phase III morbidity and mortality trial of anaemia correction in patients with chronic HF.

Topics: Anemia; Chronic Disease; Erythropoietin; Heart Failure; Hematinics; Humans; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors

Topics: Anemia; Comorbidity; Darbepoetin alfa; Erythropoietin; Ferric Compounds; Germany; Heart Failure; Hematinics; Humans; Injections, Intravenous; Prevalence; Prognosis

Anemia has been recognized as a very common and serious comorbidity in heart failure, with a prevalence ranging from 10 to 79%, depending on diagnostic definition, disease severity and patient characteristics. A clear association of anemia with worse prognosis has been confirmed in multiple heart failure trials. This finding has recently triggered intense scrutiny in order to identify the underlying pathophysiology and the best treatment options. Etiology is multifactorial, with iron deficiency and cytokine activation (anemia of chronic disease) playing the most important roles. Treatment is aimed at not only restoring hemoglobin values back to normal, but also at improving the patient's symptoms, functional capacity and hopefully the outcome. Iron supplementation and erythropoietin-stimulating agents have been used for this purpose, either alone or in combination. In this review, the recent advances in elucidating the mechanisms leading to anemia in the setting of heart failure are presented and the evidence supporting the use of different treatment approaches are discussed.

Topics: Anemia; Anemia, Iron-Deficiency; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Comorbidity; Cytokines; Erythropoietin; Heart Failure; Hemodilution; Humans; Kidney Diseases; Prevalence; Prognosis

Besides stimulating erythropoiesis, erythropoietin (EPO) exerts powerful proangiogenic and antiapoptotic effects. These erythropoiesis-independent effects are potentially useful as a supplement for the treatment of chronic heart failure (CHF). EPO may improve microvascular capacity of ischemic myocardial tissue and could thereby (partially) restore myocardial function. In addition, EPO could protect cardiomyocytes from hypoxic damage and prevent them from apoptosis. However, the clinical value of these erythropoiesis-independent effects for the treatment of CHF remains to be elucidated. Small-sized trials evaluating the effects of EPO treatment on surrogate endpoints in patients with CHF showed positive effects in general; however, their mutual results are not always unambiguous. Moreover, increasing hematocrit levels with EPO has been associated with increased blood viscosity and an inherent risk of thromboembolic events. A currently running multicenter phase III trial is designed to provide clarity concerning the effects of EPO on outcome and safety in patients with CHF. Focusing primarily on outcome, however, does not provide insight into the mode of action and isolated benefits of the erythropoiesis-independent effects of EPO. Further exploration of these effects is a key issue to gain knowledge of the full potential of EPO for the treatment of CHF.

Topics: Anemia; Animals; Apoptosis; Chronic Disease; Erythropoietin; Heart Failure; Humans; Myocardial Reperfusion

Anaemia is common in patients with heart failure and is associated with poorer prognosis. The aetiology of anaemia in heart failure is diverse and includes renal failure, iron and vitamin deficiency, the use of medication, and insensitivity of the bone marrow to erythropoietin. Recently, small-scale clinical trials investigating the effect of erythropoietin on anaemia showed an improvement in the surrogate cardiovascular endpoints exercise tolerance, haemodynamics and number of hospitalisations. Erythropoietin also has non-haematopoietic (pleiotropic) effects, such as inhibition of apoptosis and neovascularisation. In preclinical studies, erythropoietin had a beneficial effect on heart function following acute myocardial infarction and in heart failure. Currently, these pleiotropic effects are being studied in patients with acute myocardial infarction.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Heart Failure; Humans; Myocardial Infarction; Myocardial Revascularization; Prognosis

The pathophysiological condition, in which combined cardiac and renal dysfunction amplifies a progression in the failure of the individual organ, has been denoted as severe cardiorenal syndrome (SCRS). An interactive network of cardiorenal connectors, i.e., the renin-angiotensin system (RAS), nitric oxide (NO) and reactive oxygen species (ROS) balance, the sympathetic nervous system (SNS), and inflammation, has been proposed as the cornerstones of the pathophysiology of SCRS. Because erythropoietin (Epo) production declinesin chronic renal failure (CRF) and Epo sensitivity might decrease by the cardiorenalconnectors in patients with the SCRS, it is not surprising thatanaemia is a commonly occurring state coinciding with CRF and chronic heart failure (CHF). Epo treatment in patients with SCRS acts via haematopoietic effects, but also may intervenes in the vicious circle of cardiorenal connectors with subsequent deteriorating effects on cardiac, renal, and vascular function. It appears that regular Epo treatment in anaemic patients with diminished renal function improves cardiac performance, delays the progression of kidney disease, and may be of clinical benefit even to patients suffering from CHF with relatively mild anaemia. Despite growing evidence about Epo having positive effects on both renal and cardiac function, little is known about the underlying mechanisms of action.

Topics: Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Syndrome

The triad of chronic kidney disease, heart failure and anemia is well described and frequently encountered in clinical practice. While individually these disease states are associated with significant morbidity and mortality, the presence of the triad portends an even worse prognosis. Anemia is prevalent among cohorts of patients with chronic kidney disease and heart failure, indicating that its presence may serve as a central unifying hypothesis to explain poor outcomes in these populations. Observational and interventional trials of erythropoietin-stimulating agents, however, have had variable results on cardiovascular end points. Data are now emerging that suggest that treating erythropoietin deficiency in and of itself may be as or more important than the absolute levels of hemoglobin attained. Future research in this arena must focus on the optimal dose of erythropoietin administered to hemoglobin level achieved that will result in improved cardiovascular outcomes for patients with heart failure and kidney disease.

Topics: Anemia; Comorbidity; Erythropoiesis; Erythropoietin; Female; Forecasting; Heart Failure; Humans; Kidney Failure, Chronic; Male; Prognosis; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Assessment; Severity of Illness Index; Survival Analysis; Syndrome

Anemia is a common comorbidity in patients with heart failure and is associated with worse long-term outcomes. Although the cause of anemia in heart failure is unclear, the weight of evidence suggests that renal dysfunction, along with neurohormonal and proinflammatory cytokine activation in heart failure, favors the development of anemia of chronic disease, with defective iron utilization, inappropriate erythropoietin production, and depressed bone marrow function. Similarly, the mechanisms by which anemia worsens heart failure outcomes are unknown but may be related to increased myocardial workload. If anemia is a mediator and not just a marker of poor outcomes, correcting anemia could become an important and novel therapeutic target to improve long-term outcomes in such patients. Indeed, several small-sized studies have shown the beneficial effects of empirically treating anemia in heart failure patients with recombinant erythropoietin and intravenous iron. However, the ideal threshold at which therapy should be initiated and the extent of correction considered safe and desirable in the individual patient with heart failure need to be known. These issues become more important because of increasing safety concerns that recombinant erythropoietin therapy for treating anemia may be associated with adverse cardiovascular outcomes in patients with chronic kidney disease and may worsen cancer in patients receiving chemotherapy to treat various types of cancer. Therefore, further prospectively designed studies are required to address some of these questions. Fortunately, 2 large mortality morbidity trials, TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) in patients with chronic kidney disease and RED-HF (Reduction of Events with Darbepoetin alfa in Heart Failure) in heart failure patients, are in progress and are likely to provide definitive answers.

Topics: Anemia; Biomarkers; Bone Marrow; Erythropoietin; Female; Heart Failure; Humans; Inflammation; Iron Compounds; Kidney Failure, Chronic; Male; Receptors, Erythropoietin; Risk Factors

Many patients with Congestive Heart Failure (CHF) are anaemic. This anaemia is associated with more severe CHF and a higher incidence of mortality, hospitalisation and morbidity. The only way to prove that the anaemia is causing this worsening of CHF is to correct it. We review here some of the published papers about correction of anaemia. Many studies show a positive effect of Erythropoietin (EPO) or its' derivatives when administered in combination with oral or IV iron, with improvements in left and right ventricular systolic and diastolic function, dilation and hypertrophy and renal function. In addition, a reduction in hospitalisations, diuretic dose, pulmonary artery pressure, plasma volume, heart rate, serum Brain Natriuretic Peptide levels, the inflammatory marker Interleukin 6, soluble Fas ligand--a mediator of apoptosis, and improvements in New York Heart Association class, exercise capacity, oxygen utilization, caloric intake, Quality of Life and the activity of Endothelial Progenitor Cells, have been observed. Iron deficiency may also play an important role in this anaemia, since improvements in CHF have also been reported following treatment with IV iron alone. However, until the ongoing large placebo-controlled studies of the EPO derivative darbepoetin or IV iron are completed, we will not know whether these treatments really influence CHF outcome.

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Heart Failure; Humans; Iron; Practice Guidelines as Topic

Erythropoietin is a hormone produced by the kidney, which regulates proliferation, differentiation and maturation of red cells. Recombinant human EPO (rH-EPO) is well known to correct anaemia in patients with chronic renal failure in terminal stage. However, recent studies showed the existence of several not haematopoietic effects of erythropoietin. EPO receptors have been found to be expressed in several tissues, included the cardiovascular system. An increase in cardiac systolic function has been observed in patients with chronic heart failure treated with EPO. Other beneficial effects appear to be related to the pro-angiogenic properties on endothelial cells and could be useful for treatment of ischemic heart disease. These findings suggest that EPO could provide potential therapeutic benefits in the management of cardiovascular diseases beyond anaemia correction. This review focuses its attention on the pleiotropic effects of EPO and its future promising applications in cardiovascular pathology.

Topics: Anemia; Apoptosis; Cardiovascular Diseases; Endothelium, Vascular; Erythropoietin; Heart Failure; Humans; Myocardial Ischemia; Receptors, Erythropoietin; Recombinant Proteins

Topics: Anemia; Erythropoietin; Global Health; Heart Failure; Hematinics; Humans; Prevalence; Prognosis; Recombinant Proteins

Although many studies have found a high prevalence of anaemia in patients with congestive heart failure (CHF), few have carefully examined the relationship between the CHF and the prevalence of anaemia and chronic renal insufficiency (CRI). Patients with advanced renal failure, significant anaemia, diffuse atherosclerosis, respiratory disease and more elderly patients have been systematically excluded from the great majority of the randomised clinical trials.. Both anaemia and renal insufficiency are very common associated diseases associated with increased mortality, morbidity and rate of hospitalisation in CHF patients. Impaired renal function is associated with adverse outcomes because it represents a marker of coexistent disease and more diffuse atherosclerosis. In patients with CHF, progressive renal dysfunction leads to a decrease in erythropoietin (EPO) levels with reduced erythrocyte production from bone marrow. This may explain the common association between CHF, anaemia and CRI in clinical practice. The normalisation of haemoglobin concentration by EPO in patients with CHF and CRI results in improved exercise capacity by increasing oxygen delivery and improving cardiac function.. In this review, we describe the mechanisms linking anaemic status, CRI and CHF, the prognostic relevance of each disease, treatment implications, and potential benefit of EPO administration.

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Iron; Kidney Failure, Chronic; Prognosis; Syndrome

Anemia is common in patients who have both heart failure and chronic kidney disease, and there is an association between anemia and progression of both diseases. The main causes of anemia are deficient production of erythropoietin (EPO), iron deficiency, and chronic disease with endogenous EPO resistance. EPO has been successfully used for over a decade to treat anemia in patients with chronic kidney disease. Less obvious are the safety and efficacy of EPO treatment in patients with both heart failure and renal disease. Up to 10% of patients receiving EPO are hyporesponsive to therapy and require large doses of the agent. Several mechanisms could explain resistance to endogenous and exogenous EPO. Proinflammatory cytokines antagonize the action of EPO by exerting an inhibitory effect on erythroid progenitor cells and by disrupting iron metabolism (a process in which hepcidin has a central role). EPO resistance might also be caused by inflammation, which has a negative effect on EPO receptors. Furthermore, neocytolysis could have a role. As resistance to exogenous EPO is associated with an increased risk of death, it is important to understand how cardiorenal failure affects EPO production and function.

Topics: Anemia; Drug Resistance; Erythropoietin; Heart Failure; Humans; Renal Insufficiency

Anemia is increasingly recognized as a common, important and treatable condition in patients with congestive heart failure. Despite increasing knowledge of anemia, as well as its co-association with chronic renal disease, advanced New York Heart Association class and worse prognosis, there are very few evidence-based recommendations for treatment. The use of supplemental iron, especially intravenous forms, for the treatment of iron-deficiency anemia in heart failure patients is associated with improved symptoms, cardiac size and function, and possibly improved outcomes. However, many patients with heart failure suffer from anemia due to other causes, including renal failure (so-called cardiorenal syndrome), erythropoietin resistance, possible ACE inhibitor use and extracellular fluid expansion. The association between anemia and adequate iron stores has led to interest in the use of erythrocyte-stimulating agents, such as erythropoietin and darbepoetin. While early data are promising, recent evidence in non-heart failure trials has led to caution in their use and given way to anticipation of results of ongoing definitive randomized trials of this therapy, such as the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) and Reduction of Events with Darbepoetin-alpha in Heart Failure (RED-HF) studies.

Topics: Anemia; Cardiology; Darbepoetin alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Ventricular Dysfunction, Left

Anemia is common in patients with chronic heart failure, and is related to increased morbidity and mortality. The etiology of anemia in heart failure is complex and still not fully resolved. The review will describe current advances in the understanding of the pathophysiology of anemia and the potential therapeutic effects of recombinant human erythropoietin.. Recent attempts to resolve the preponderant etiology of anemia in chronic heart failure have further defined its multifactorial nature. Impaired renal perfusion and function resulting in blunted erythropoietin production as well as impaired erythropoiesis in the bone marrow account for a vulnerable erythropoietic system. Moreover, fluid retention causes hemodilutional anemia. Correction of anemia with recombinant human erythropoietin seems feasible and is currently being evaluated in a phase 3 clinical trial. In addition, recombinant human erythropoietin improves cardiac function in chronic heart failure through the recruitment of endothelial progenitor cells and exerts cytoprotective effects during acute myocardial infarction. Although recombinant human erythropoietin shows great promise, we should not neglect other treatable causes of anemia.. Although the etiology of anemia in chronic heart failure is clearly multifactorial, correction of anemia with recombinant human erythropoietin seems promising. In addition to correction of anemia, recombinant human erythropoietin might exert important protective and regenerative effects on the myocardium.

Topics: Anemia; Chronic Disease; Erythropoietin; Heart Failure; Humans; Recombinant Proteins

An association between anaemia, poor functional status and, compared to non-anaemic patients, worse clinical status and a higher risk of hospitalisation and death has been consistently reported in chronic heart failure (CHF), although cause an effect has not been proven. While it is attractive to think that correction of a co-morbidity that exacerbates already diminished delivery of oxygen to the tissues in heart failure is likely to beneficial, the possible haemodynamic effects of increasing haemoglobin, for example vasoconstriction, might not be. Consequently, the balance of benefit and risk of anaemia correction in CHF is uncertain, may vary according to the severity of anaemia (and other factors) and needs to be properly evaluated. To date, most studies of anaemia correction in CHF have used erythropoiesis stimulating agents (ESAs). The trials with erythropoietin have been of small size, uncontrolled or unblended/single blind, raising concerns again about interpretation of subjective outcomes. In addition, the analyses of these trials have been suboptimal. Two double-blind, placebo-controlled, darbepoetin studies have been published in full. Neither showed an improvement in functional capacity or consistent effect on patient reported symptoms/quality of life. Darbepoetin is, however, currently being tested in a large-scale, phase III morbidity and mortality trial, the Reduction of Events with Darbepoetin alfa in Heart Failure (RED-HF) which should contribute important information of the safety and efficacy of ESAs in this syndrome. Other approaches, notably parenteral iron supplementation, are also being evaluated and other agents for anaemia correction are under development.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Iron; Iron Deficiencies

Erythropoietin is a haematopoietic hormone with extensive non-haematopoietic effects. The discovery of an erythropoietin receptor outside the haematopoietic system has fuelled the research into the beneficial effects of erythropoietin for various conditions, predominantly in cardiovascular disease. Experimental evidence has revealed the cytoprotective and angiogenic properties of erythropoietin and it seems that the erythropoietin-erythropoietin receptor system provides a powerful backbone against acute and chronic myocardial ischemia, each gaining from the different properties of erythropoietin. Clinical trials in which erythropoietin was titrated to achieve certain haematocrit levels have generated equivocal results. It has been suggested that a (too) high haematocrit is undesirable in cardiovascular disease. We have shown that intermittent (low-dose) erythropoietin administration, that does not increase haematocrit substantially, suffices to activate the beneficial downstream pathways of erythropoietin. We postulate that intermittent administration or a lower than conventional dose of erythropoietin, not only aimed at increasing haemoglobin at high levels, will provide powerful cellular protection and will improve cardiac outcome, without the side effects of erythropoietin associated with increased haematocrit.

Topics: Animals; Cardiovascular Physiological Phenomena; Chronic Disease; Erythropoietin; Heart Diseases; Heart Failure; Humans; Receptors, Erythropoietin; Recombinant Proteins

Recombinant human erythropoietin has been used for more than 20 years for the treatment of renal anaemia, with epoetin-alfa and -beta representing the common traditional preparations. By the modification of the molecule's carbohydrate moiety or structure a longer duration of erythropoietin receptor stimulation was achieved. The administration of these new molecules (darbepoetin, C.E.R.A.) once or twice a month is also sufficient to achieve serum haemoglobin target levels, making the treatment safer and more comfortable both for the patients and the personnel. These recently developed synthetic erythropoietin receptor stimulating molecules, along with recombinant human erythropoietin, are together called "Erythropoiesis Stimulating Agents". In haemodialysed patients the intravenous route is preferred, but the subcutaneous administration can substantially reduce dose requirements. In praedialysed, transplanted or peritoneally dialysed patients, erythropoiesis stimulating agents should preferably be given subcutaneously both for economic and practical reasons. There are ongoing clinical trials with erythropoiesis stimulating molecules that can be administered by inhalation or per os. Current evidence suggests that the serum haemoglobin level should preferably not exceed 12 g/dl with the use of erythropoiesis stimulating agents. No cardiovascular protective effect of higher serum haemoglobin levels was demonstrated in two large clinical trials. Further well-designed studies are necessary to set evidence-based haemoglobin targets for erythropoiesis stimulating treatment. Arguments for a more widespread use of agents with extended duration include medical, financial and patient satisfaction reasons. The release of new erythropoiesis stimulating agents may further simplify the treatment of renal anaemia.

Topics: Administration, Cutaneous; Administration, Inhalation; Administration, Oral; Anemia; Darbepoetin alfa; Epoetin Alfa; Erythropoiesis; Erythropoietin; Heart Failure; Hematinics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Infusions, Intravenous; Kidney Failure, Chronic; Receptors, Erythropoietin; Recombinant Proteins; Renal Dialysis

Congestive heart failure (CHF) is a common clinical problem, especially affecting the elderly. Current strategies of neurohormonal blockade with medications like angiotensin converting enzyme inhibitors have improved morbidity and mortality, but further improvement in outcomes requires new strategies. Both anemia and chronic renal disease commonly accompany congestive heart failure; their close relationship, in which one disease exacerbates the other, has been termed the cardio-renal-anemia syndrome. Correction of anemia in CHF patients using recombinant erythropoietin is feasible; small studies suggest that anemic congestive heart failure patients may have improved morbidity with this therapy. Recent animal and human studies of erythropoietin have shown that its benefit may be derived from both hematological and newly discovered non-hematological properties. Anemia might soon be considered a modifiable risk factor for optimal CHF management.

Topics: Anemia; Erythropoietin; Heart Failure; Humans

Topics: Anemia; Animals; Cardiotonic Agents; Clinical Trials as Topic; Dogs; Drug Administration Schedule; Erythropoietin; Heart Failure; Humans; Mice; Myocardial Infarction; Myocardial Ischemia; Rats; Recombinant Proteins; Signal Transduction

Anemia is commonly observed in patients with heart failure, and portends worsening functional capacity and poorer long-term prognosis. Nevertheless, uncertainty remains regarding the underlying pathophysiology and natural history of anemia in the setting of chronic heart failure. The optimal therapeutic targets and treatment options for this "anemia of heart failure" are also uncertain. Careful evaluation of potential underlying reversible causes, particularly renal insufficiency and iron or nutritional deficiencies, may lead to potential treatment options. Recent concerns have focused on the appropriate hemoglobin target and the efficacies of erythropoiesis-stimulating agents (ESAs), such as erythropoietin and darbepoetin alfa, in reducing long-term clinical events. Much work is needed to clarify the safety and efficacy of this drug class. Nevertheless, early unblinded studies and phase II results using ESAs in patients with heart failure have found overall significant improvements in exercise capacity and quality of life, and it is hoped that ongoing pivotal outcome trials and investigations into iron supplementation will clarify their appropriate use.

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Heart Failure; Hemoglobins; Humans; Prognosis

Stage 3 chronic kidney disease (CKD), which is characterized by a glomerular filtration rate of 30 to 60 mL/min/1.73 m2 (reference range, 90-200 mL/min/1.73m2 for a 20-year-old, with a decrease of 4 mL/min per decade), affects approximately 8 million people in the United States. Anemia is common in patients with stage 3 CKD and, if not corrected, contributes to a poor quality of life. Erythropoiesis-stimulating agents (ESAs), introduced almost 2 decades ago, have replaced transfusions as first-line therapy for anemia. This review summarizes the current understanding of the role of ESAs in the primary care of patients with anemia of CKD and discusses pharmacological and pharmacoeconomic issues raised by recent data. Relevant studies in the English language were identified by searching the MEDLINE database (1987-2006). Two ESAs are currently available in the United States, epoetin alfa and darbepoetin alfa. More frequent dosing with epoetin alfa is recommended by the labeled administration guidelines because it has a shorter half-life than darbepoetin alfa. Clinical experience also supports extended dosing intervals for both these ESAs. Use of ESAs in the management of anemia of CKD is associated with improved quality of life, increased survival, and decreased progression of renal failure. Some evidence suggests that ESAs have a cardioprotective effect. However, correction of anemia to hemoglobin levels greater than 12 g/dL (to convert to g/L, multiply by 10) appears to increase the risk of adverse cardiac outcomes and progression of kidney disease in some patients. The prescription of ESAs in the primary care setting requires an understanding of the accepted use of these agents, the associated pharmacoeconomic challenges, and the potential risks. This review considers the need to balance effective ESA dosing intervals against the potential risks of treatment.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Disease Progression; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Ferric Compounds; Ferritins; Heart Failure; Hematinics; Humans; Kidney Diseases; Physician's Role; Primary Health Care; Quality of Life; Recombinant Proteins

Erythropoietin (EPO), a renal cytokine, regulates proliferation, differentiation and maturation of erythroid cells. Recombinant human erythropoietin (rH-EPO) is well known to correct anemia in patients with chronic renal failure undergoing dialysis. Recent studies have reported several non-hematopoietical effects of EPO. Erythropoietin receptors have been discovered in a variety of tissues, including the cardiovascular system. Recently published data including recent patent documented an enhancement of cardiac function in patients with heart failure receiving EPO treatment. Furthermore, experiments carried out in animal models of ischemia/reperfusion (IR) injury have shown a significant reduction in infarct size following EPO treatment. Other beneficial effects of EPO are related to its pro-angiogenic action on endothelial cells, which might be of potential value in patients with ischemic heart disease. Taken together, these findings suggest that EPO may be clinically useful as an adjunct in the treatment of different cardiovascular conditions, besides the simple correction of anemia. This review will focus on the pleiotropic effects of EPO in the cardiovascular system and its promising novel applications.

Topics: Animals; Apoptosis; Erythropoietin; Heart Failure; Humans; Myocardial Infarction; Myocardial Ischemia; Neovascularization, Physiologic; Receptors, Erythropoietin; Recombinant Proteins

Topics: Anemia; Animals; Disease Models, Animal; Erythropoiesis; Erythropoietin; Female; Heart Failure; Humans; Male; Multicenter Studies as Topic; Myocardial Ischemia; Neovascularization, Physiologic; Oxygen Consumption; Prognosis; Randomized Controlled Trials as Topic; Rats; Recombinant Proteins; Risk Assessment; Stroke Volume; Survival Analysis; Treatment Outcome

Many patients with congestive heart failure (CHF) fail to respond to maximal CHF therapy and progress to end stage CHF with many hospitalizations, poor quality of life (QoL), progressive chronic kidney disease (CKD) which can lead to end stage kidney disease (ESKD), or die of cardiovascular complications within a short time. One factor that has generally been ignored in many of these people is the fact that they are often anemic. The anemia in CHF is due mainly to the frequently-associated CKD but also to the inhibitory effects of cytokines on erythropoietin production and on bone marrow activity, as well as to their interference with iron absorption from the gut and their inhibiting effect on the release of iron from iron stores. Anemia itself may further worsen cardiac and renal function and make the patients resistant to standard CHF therapy. Indeed anemia in CHF has been associated with increased severity of CHF, increased hospitalization, worse cardiac function and functional class, the need for higher doses of diuretics, progressive worsening of renal function and reduced QoL. In both controlled and uncontrolled studies of CHF, the correction of the anemia with erythropoietin (EPO) and oral or intravenous (IV) iron has been associated with improvement in many cardiac and renal parameters and an increased QoL. EPO itself may also play a direct role in improving the heart unrelated to the improvement of the anemia--by reducing apoptosis of cardiac and endothelial cells, increasing the number of endothelial progenitor cells, and improving endothelial cell function and neovascularization of the heart. Anemia may also play a role in the worsening of acute myocardial infarction and chronic coronary heart disease (CHD) and in the cardiovascular complications of renal transplantation. Anemia, CHF and CKD interact as a vicious circle so as to cause or worsen each other- the so-called cardio renal anemia syndrome. Only adequate treatment of all three conditions can prevent the CHF and CKD from progressing.

Topics: Anemia; Cardiology; Chronic Disease; Erythropoietin; Heart Failure; Humans; Interdisciplinary Communication; Iron; Kidney Diseases; Nephrology; Syndrome

We have recently proposed severe cardiorenal syndrome (SCRS), in which cardiac and renal failure mutually amplify progressive failure of both organs. This frequent pathophysiological condition has an extremely poor prognosis. Interactions between inflammation, the renin-angiotensin system, the balance between the nitric oxide and reactive oxygen species and the sympathetic nervous system form the cardiorenal connectors and are cornerstones in the pathophysiology of SCRS. An absolute deficit of erythropoietin (Epo) and decreased sensitivity to Epo in this syndrome both contribute to the development of anemia, which is more pronounced than renal anemia in the absence of heart failure. Besides expression on erythroid progenitor cells, Epo receptors are present in the heart, kidney, and vascular system, in which activation results in antiapoptosis, proliferation, and possibly antioxidation and anti-inflammation. Interestingly, Epo can improve cardiac and renal function. We have therefore reviewed the literature with respect to Epo and the cardiorenal connectors. Indeed, there are indications that Epo can diminish inflammation, reduce renin-angiotensin system activity, and shift the nitric oxide and reactive oxygen species balance toward nitric oxide. Information about Epo and the sympathetic nervous system is scarce. This analysis underscores the relevance of a further understanding of clinical and cellular mechanisms underlying protective effects of Epo, because this will support better treatment of SCRS.

Topics: Animals; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Oxidative Stress

Anemia, defined as a hemoglobin level of less than 12 g/dL, often is seen in congestive heart failure (CHF). It is associated with an increased mortality and morbidity and increased hospitalizations. Compared with nonanemic patients the presence of anemia also is associated with worse cardiac clinical status, more severe systolic and diastolic dysfunction, a higher beta natriuretic peptide level, increased extracellular and plasma volume, a more rapid deterioration of renal function, a lower quality of life, and increased medical costs. The only way to determine if anemia is merely a marker for more severe CHF or actually is contributing to the worsening of the CHF is to correct the anemia and see if this favorably influences the CHF. In several controlled and uncontrolled studies, correction of the anemia with subcutaneous erythropoietin (EPO) or darbepoetin in conjunction with oral and intravenous iron has been associated with an improvement in clinical status, number of hospitalizations, cardiac and renal function, and quality of life. However, larger, randomized, double-blind, controlled studies still are needed to verify these initial observations. The effect of EPO may be related partly to its nonhematologic functions including neovascularization; prevention of apoptosis of endothelial, myocardial, cerebral, and renal cells; increase in endothelial progenitor cells; and anti-inflammatory and antioxidant effects. Anemia also may play a role in increasing cardiovascular morbidity in chronic kidney insufficiency, diabetes, renal transplantation, asymptomatic left ventricular dysfunction, left ventricular hypertrophy, acute coronary syndromes including myocardial infarction and chronic coronary heart disease, and in cardiac surgery. Again, controlled studies of correction of anemia are needed to assess its importance in these conditions. The anemia in CHF mainly is caused by a combination of renal failure and CHF-induced increased cytokine production, and these can both lead to reduced production of EPO, resistance of the bone marrow to EPO stimulation, and to cytokine-induced iron-deficiency anemia caused by reduced intestinal absorption of iron and reduced release of iron from iron stores. The use of angiotensin-converting enzyme inhibitor and angiotensin receptor blockers also may inhibit the bone marrow response to EPO. Hemodilution caused by CHF also may cause a low hemoglobin level. Renal failure, cardiac failure, and anemia therefore all interact

Topics: Anemia; Animals; Attitude; Cardiology; Erythropoietin; Heart Diseases; Heart Failure; Hemoglobins; Humans; Internal Medicine; Iron; Kidney Failure, Chronic; Natriuretic Peptide, Brain; Nephrology; Recombinant Proteins

Topics: Anemia; Darbepoetin alfa; Diabetes Mellitus; Epoetin Alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins; Treatment Outcome

Improving anemia in patients with chronic renal failure (CRF) and congestive heart failure (CHF) also improves left ventricular hypertrophy (LVH). No previous meta-analyses have been conducted to further examine this association, including the association between LVH and mortality in these patients.. Literature searches on MEDLINE, EMBASE, and OVID were performed using Cochrane Library protocols. Two hundred sixteen abstracts were reviewed preliminarily for inclusion in the meta-analysis of epoetin alfa, anemia and 5 pre-selected parameters of LVH. One hundred seventy-nine abstracts were reviewed for LVH and mortality. The predominant hematologic and left ventricular function changes observed during epoetin alfa treatment in patients with CHF and CRF are (1) increases in hemoglobin (Hb) and hematocrit (Hct); (2) decreases in left ventricular mass (LVM) and LVM index; (3) increase in ejection fraction (EF); and (4) decreases in left ventricular end-diastolic and end-systolic volume. Three independent factors-target Hb, duration of disease, and duration of follow-up-each had a statistically significant association with Hb, Hct, and EF, respectively. A separate meta-analysis using 3 risk models showed LVH is strongly and positively associated with both cardiovascular and all-cause mortality, with two- to three-fold increases in risk.. LVH is common in patients with CRF and CHF. Current findings indicate epoetin alfa therapy results in anemia amelioration, as evidenced by higher Hb and Hct levels, and reduction of key LVH parameters. LVM regression is associated with lower incidence of cardiovascular-related morbidity and mortality, therefore epoetin alfa therapy may provide a survival benefit.

Topics: Adult; Anemia; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Hematinics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Regression Analysis; Ventricular Function, Left

The number of diabetic patients with renal disease increased significantly in the last years worldwide. Anemia is an important and frequent component of diabetic nephropathy that may begin early in the course of the chronic renal disease of diabetics, and is more severe in diabetic patients with renal disease than in non - diabetic renal patients controlled for the same level of renal function. The reason for the anemia is decreased erythropoietin level caused by diminished production and, in a lesser degree, by increased excretion of erythropoietin in the urine. There is a close connection between diabetic nephropathy, anemia and cardiovascular complications. On the basis of small studies correction of anemia may decrease the progression of diabetic nephropathy and cardiovascular complications. However, the result of ongoing large randomised controlled studies are required to get "evidence-based" data to prove that correction of anemia has beneficial effects on microvascular and macrovascular diabetic complications, particularly cardiac disease, and on progression of diabetic nephropathy.

Topics: Anemia, Hypochromic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Epoetin Alfa; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Time Factors

Heart failure represents a major public health problem in the industrialized countries and despite of optimal medical treatment its mortality remains high. The history of its management reflects growth and changes in our understanding of its pathophysiology. In the past, pharmacological treatment of heart failure was aimed only at relieving edema and improving hemodynamics. Today, however, a major aim of treatment is to antagonize the sympathetic nervous system and renin-angiotensin-aldosterone system, to avert harmful effects of neurohormonal activation on the myocardium and peripheral vessels. Currently, the major pharmacological treatments for heart failure are diuretics, ACE inhibitors, beta-blockers and (in NYHA classes III-IV) aldosterone antagonists. Some patients may also require specific treatment with additional drugs (e.g. anti-arrhythmia agents, anticoagulants, or vasodilators) or procedures such as coronary revascularization, or implantable devices such as pacemakers and implantable cardioverter defibrillators, or resynchronization devices. Patients with end-stage heart failure may require cardiac transplantation or ventricular assist devices. This review is summarized the recent practical drug therapy of heart failure and the results of the newer clinical trial.

Topics: Adrenergic beta-Antagonists; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Defibrillators, Implantable; Digitalis Glycosides; Diuretics; Endothelin Receptor Antagonists; Erythropoietin; Heart Failure; Heart-Assist Devices; Humans; Hungary; Immunologic Factors; Mineralocorticoid Receptor Antagonists; Pacemaker, Artificial; Peptide Hydrolases; Primary Prevention; Risk Factors; Severity of Illness Index; Vasopressins

While advances in treatment strategies and pharmacotherapy have produced a dramatic reduction in the mortality of patients with heart failure during the past 15 years, there is still a major challenge to improve patient well being, reduce hospitalizations and reduce mortality further. The prevalence of heart failure is not decreasing, and heart failure is currently a cause for hospitalization in >25% of admissions to internal medicine and cardiology departments. It has recently become apparent that anaemia is present in 20-30% of patients with heart failure, and the severity of anaemia has important implications regarding outcome and prognosis. Anaemia may be due to a number of causes, including iron and vitamin deficiency, insidious blood loss, haemodilution, renal impairment and bone marrow depression with resistance to erythropoietin. In the presence of a damaged heart and often coronary artery disease, anaemia may worsen contractile ability and systolic function, while the necessary volume load and ventricular hypertrophy which accompany anaemia contribute to diastolic dysfunction. Preliminary data show that appropriate treatment of anaemia, based on correction of the underlying cause, with, in most patients, the addition of exogenous erythropoietin and iron therapy, improves ventricular function and clinical status. Treatment of anaemia has opened a new frontier in the management of heart failure. We await the results of ongoing clinical trials for more detailed information regarding appropriate haemoglobin targets, choice of medication and dosing and the degree of improvement that may be expected when the issue of anaemia is properly addressed.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Erythropoietin; Heart Failure; Humans; Iron; Middle Aged; Prevalence; Ventricular Dysfunction, Left

Heart failure (HF) is a common disease associated with poor prognosis. Anaemia is commonly associated with HF due to bone marrow depression, reduced availability of iron and haemodilution, and is sometimes aggravated by too frequent blood testing. Low haemoglobin is very detrimental to the haemodynamic state of the patient with decreased cardiac output as it further diminishes the oxygen supply to the tissues. When anaemia is associated with HF. and renal failure, the patient enters a vicious cycle called cardio renal anaemia syndrome. The prognosis of patients with HF is worse as the haemoglobin is lower and even mild anaemia is associated with <1 year survival. Aggressive correction of the anaemia by subcutaneous injections of erythropoeitin and intravenous iron has been shown to improve the functional capacity and quality of life of patients with cardio renal anaemia syndrome and to reduce the need for hospitalization. However, intravenous iron can be detrimental because of increased formation of free radicals, oxidative stress and risk of infection. The level of haemoglobin needed to be achieved is not clear, but it seems indicated to maintain it above 12 g%.

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Iron; Prognosis; Renal Insufficiency

Erythropoietin, a hormone known to be a stimulator of erythropoiesis, is widely used in the treatment of anemia in patients with chronic renal failure. The latest experiments proved that it can also bring beneficial effects in patients with cardiovascular disease. It prevents cardiomyocyte apoptosis during myocardial infarction and can relieve disease symptoms in patients with congestive heart failure and anemia. Further experiments and clinical trials are necessary to investigate the pathophysiological mechanisms and clinical effects of this treatment.

Topics: Cardiotonic Agents; Cytokines; Erythropoietin; Heart Failure; Humans; Myocardial Infarction

Erythropoietin is a hypoxia-induced hormone that is a major regulator of normal erythropoiesis. Over the last decade, the production of recombinant human erythropoietin has revolutionized the treatment of anemia associated with chronic renal failure, and has led to a greater understanding of anemia pathophysiology and to the elucidation of the interactions of erythropoietin, iron, and erythropoiesis. Anemia has been shown to be independently associated with increased mortality and disease progression. Potential survival benefits associated with correction of anemia have expanded considerably the indications of erythropoietin use in various patient populations and are leading to consideration of earlier, more aggressive treatment of mild to moderate anemia. The results of such treatment are promising in a variety of new clinical settings, including anemia associated with congestive heart failure. Furthermore, the erythropoietin receptor is widely distributed in the cardiovascular system, including endothelial cells, smooth muscle cells and cardiomyocytes and preclinical studies have established erythropoietin to be a pleiotropic cytokine with anti-apoptotic activity and tissue-protective actions in the cardiovascular system, beyond correction of hemoglobin levels. Despite some potential adverse effects, such as hypertension, and the occurrence of erythropoietin resistance, early studies in heart failure patients with anemia suggest that erythropoietin therapy is safe and effective in reducing left ventricular hypertrophy, enhancing exercise performance and increasing ejection fraction. Anemia is found in about one-third of all cases of congestive heart failure (CHF). The most likely common cause is chronic renal insufficiency, which is present in about half of all CHF cases. However, anemia can occur in CHF without renal insufficiency and is likely to be due to excessive cytokine production. The anemia itself can worsen cardiac function, both because it causes cardiac stress through tachycardia and increased stroke volume, and because it can cause a reduced renal blood flow and fluid retention, adding further stress to the heart. Long-standing anemia of any cause can cause left ventricular hypertrophy, which can lead to cardiac cell death through apoptosis and worsen CHF. Therefore, a vicious circle, cardio-renal anemia syndrome, is set up wherein CHF causes anemia, and the anemia causes more CHF and both damage the kidneys worsening the anemia and the CHF

Topics: Amino Acid Sequence; Cardiovascular Diseases; Erythropoietin; Heart Failure; Humans; Molecular Sequence Data; Recombinant Proteins

Congestive heart failure (CHF) and chronic kidney disease (CKD) often progress to end stage even with optimum medical therapy. One factor that is common to both conditions is anemia, which is present in about a third of CHF patients. CHF can cause or worsen both anemia and CKD, and CKD can cause or worsen both anemia and CHF. Thus, a vicious circle exists between these three conditions, with each causing or worsening the other. We have called this condition the cardio-renal-anemia syndrome. Anemia in CHF is associated with increased mortality and hospitalization, reduced cardiac function and evidence of more severe CHF and CKD than in nonanemic patients. Intervention studies in anemic CHF patients have shown that optimum medical treatment of CHF and the correction of the associated anemia with subcutaneous erythropoietin and oral iron or intravenous iron sucrose can improve cardiac function, patients' functional status, renal function and quality of life, and reduce the frequency of hospitalization and the dose of diuretics required.

Topics: Anemia; Disease Progression; Drug Therapy, Combination; Erythropoietin; Heart Failure; Humans; Iron; Kidney Failure, Chronic; Treatment Outcome

Heart failure affects 5 million persons in the United States, with 400,000 new cases occurring every year. Paradoxically, although advances in coronary angioplasty and effective drugs have increased survival post infarction, the myocardial damage and subsequent neurohormonal activation-induced remodeling causes significant morbidity years later in the form of heart failure. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) together with beta blockers modify the neurohormonal activation associated with heart failure and are key treatments for improving cardiac function and survival. Anemia is a significant risk factor predicting morbidity and mortality in heart failure. This article describes the various etiologies of anemia in heart failure. Of particular importance is the fact that recent stem cell studies have shown that the drugs acting on the renin-angiotensin system inhibit erythropoiesis in vivo and may cause anemia in patients with both normal renal function and end-stage renal disease (ESRD). The role of angiotensin-II as an erythropoietic growth factor and ACE in facilitating erythropoiesis is described in this article. Anemia has been shown to be a modifiable risk factor and its treatment correlates with improvement in clinical outcomes. Thus, anemia, its etiology (especially the contribution of ACEIs and ARBs), physiologic and prognostic impact, and treatment in the setting of heart failure are critical areas for investigation.

Topics: Anemia; Animals; Clinical Trials as Topic; Cytokines; Erythropoietin; Heart Failure; Humans; Renin-Angiotensin System; Risk Factors

Anaemia is common in patients with congestive heart failure (CHF). Its prevalence increases with disease severity as a consequence of renal insufficiency, cytokine production, blood loss, iron deficiency, malnutrition and/or plasma volume overload. Anaemia can contribute to worsening of CHF. There is a nonlinear relationship (U-shaped curve) between haemoglobin and survival. Prevalence of anaemia among elderly people with acute myocardial infarction is high and is associated with more frequent in-hospital events, including death. Anaemia is also associated with higher in-hospital mortality rate after coronary bypass surgery and with all-cause and cardiac mortality after percutaneous coronary interventions. Patients with anaemia and cardiovascular disease have a higher mortality rate after cardiac/noncardiac surgery as compared to those with anaemia but without cardiovascular disease or those with cardiovascular disease but without anaemia. However, not all authors confirmed these findings. Therefore, multicentre trials to clarify this issue are urgently needed. Pleiotropic effects of recombinant human erythropoietin include reduction of myocardial and cerebral infarct size without an increase in haematocrit, neovascularization as well as mobilization of endothelial progenitor cells.

Topics: Aged; Anemia; Coronary Circulation; Erythropoietin; Heart; Heart Failure; Humans; Myocardial Infarction; Myocardial Revascularization; Recombinant Proteins

Anaemia is a frequent complication of diabetic nephropathy. It has only recently been recognised that in diabetic patients anaemia is seen not only in preterminal renal failure, but also frequently in patients with only minor derangement of renal function. At any level of glomerular filtration rate (GFR) anaemia is more frequent and severe in diabetic compared to nondiabetic patients. A major cause of anaemia is an inappropriate response of erythropoietin to anaemia. Additional factors are iron deficiency and iatrogenic factors, e.g. ACE inhibitor treatment. When serum creatinine is still normal, the erythropoietin concentration is predictive of more rapid loss of glomerular function. When serum creatinine is elevated, the haemoglobin values are predictive of the rate of progression. It is currently under investigation whether reversal of anaemia attenuates the rate of progression. Because most of the late complications of diabetes (retinopathy, neuropathy, heart disease, peripheral arterial disease) involve ischaemic tissue damage, it would be intuitively plausible that treatment with human recombinant erythropoietin should be beneficial, but definite evidence for this hypothesis is currently not available.

Topics: Anemia; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Erythrocytes, Abnormal; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Myocardial Ischemia; Peripheral Vascular Diseases

Anaemia is common in severe cardiac failure due to systolic dysfunction. The mechanisms are varied. Anaemia is a negative prognostic factor. Treatment with erythropoietin seems to improve the quality of life, functional status, effort tolerance and systolic function of these patients. Large scale clinical trials are on-going.

Topics: Anemia; Erythropoietin; Heart Diseases; Heart Failure; Humans; Recombinant Proteins

The incidence of both congestive heart failure (CHF) and end-stage renal disease both are increasing. Anemia is common in both conditions and is associated with a marked increase in mortality and morbidity in both CHF and chronic kidney insufficiency (CKI). Each of these 3 conditions can cause or worsen the other 2. In other words, a vicious circle frequently is present in which CHF can cause or worsen both anemia and CKI, in which CKI can cause or worsen both anemia and CHF, and in which anemia can cause or worsen both CHF and CKI. We have called this vicious circle the cardio renal anemia syndrome. Optimal treatment of CHF with all the recommended CHF medications at their recommended doses will, in our experience, frequently fail to improve the CHF and CKI if anemia is present and is not corrected. On the other hand, correction of the anemia with subcutaneous erythropoietin and intravenous iron has caused a great improvement in the CHF including a marked improvement in patient and cardiac function and a marked reduction in the need for hospitalization and for high-dose diuretics. It also frequently has caused renal function to improve or at least stabilize. In addition, patients' quality of life and exercise capacity also have improved with the correction of the anemia. In CKI patients, anemia also may play an important role in increasing the risk for death, coronary heart disease, stroke, and progression to end-stage renal disease. Erythropoietin may have a direct positive effect on the heart and brain unrelated to correction of the anemia by reducing cell apoptosis and by increasing neovascularization, both of which could prevent tissue damage. This could have profound therapeutic implications not only in CHF but in the future treatment of myocardial infarction, coronary heart disease, strokes, and renal failure.

Topics: Age Factors; Aged; Anemia, Iron-Deficiency; Animals; Cohort Studies; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Follow-Up Studies; Heart Failure; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Middle Aged; Recombinant Proteins; Renal Dialysis; Risk Assessment; Severity of Illness Index; Survival Rate; Treatment Outcome

Chronic heart failure (CHF) is a leading cause of hospitalization and is associated with a poor prognosis, although in the past decade substantial progress has been made in understanding the pathophysiology and therapy of CHF with reduced left ventricular (LV) ejection fraction. Use of angiotensin-converting-enzyme inhibitors and angiotensin-receptor antagonists either individually or in combination, certain beta-receptor blockers, and judicious use of aldosterone antagonists, has reduced hospital admission rates and mortality from CHF with reduced LV ejection fraction. More clinical trials are needed, however, particularly in patients with CHF and preserved LV ejection fraction. In patients who remain symptomatic despite medical therapy, and who have long QRS intervals (>0.12 s) and markedly reduced LV ejection fraction, the value of cardiac resynchronization therapy with a biventricular pacemaker has now been demonstrated. Yet, morbidity and mortality remain high, indicating a major need for further improvement. Novel therapies include medical management with statins, vasopressin antagonists, erythropoietin, oxypurinol and levosimendan, which improve vascular and myocardial function and reduce fluid overload, in addition to surgical approaches, which reduce LV remodeling. These routes might not, however, suffice in patients with CHF and LV dysfunction. Prevention of apoptosis and particularly regeneration of cardiac muscle would represent a shift of the current paradigm. Stem-cell-based therapies are rapidly evolving, and while basic science is needed to optimize these strategies, medium-sized clinical studies could help to verify the beneficial effects on LV function. In this review, we discuss current treatment methods and new strategies to improve treatment of CHF.

Topics: Angiotensin II Type 1 Receptor Blockers; Apoptosis; Cardiac Glycosides; Erythropoietin; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mineralocorticoid Receptor Antagonists; Oxidative Stress; Pacemaker, Artificial; Spironolactone; Stroke Volume; Tetrazoles; Valine; Valsartan; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Many patients with chronic heart failure also have anemia, an association that has been increasingly recognized in recent years. Whether treating anemia will improve outcomes in patients with heart failure has yet to be determined, however. The decision to use an agent to treat anemia in heart failure should be made on a case-by-case basis.

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Recombinant Proteins; Survival Rate; Treatment Outcome

The importance of anemia in chronic kidney disease (CKD) has become increasingly well recognized over recent years, as have the benefits of treating anemic CKD patients with recombinant human erythropoietin (rHuEPO, epoetin). As well as reducing the need for blood transfusions and the complications associated with renal failure in CKD patients, rHuEPO treatment decreases patient morbidity and mortality, particularly as a result of cardiovascular disease. The strong correlation between anemia, renal failure and cardiac failure is one that has received much attention recently, with each factor recognized to cause the other to worsen in a 'vicious cycle'. Recent studies have concentrated on the possible benefits of anemia treatment in patients with CHF. Currently available data suggest improvements in CHF symptoms, left ventricular ejection fraction (LVEF) and a reduction of hospitalizations associated with anemia correction through epoetin treatment. Available data from CKD patients suggest that anemia management should begin as early as possible, although the optimal target level for individual patients is as yet unclear. In addition to the currently available evidence, additional large, randomized, controlled studies are required to further define the morbidity/mortality benefits of epoetin treatment in CHF patients with anemia.

Topics: Anemia; Chronic Disease; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Prognosis

Recombinant human erythropoietin (rHuEPO) is a hormone essential for normal erythropoiesis. The rHuEPO receptor is distributed in the cardiovascular system predominantly in endothelial cells and cardiomyocytes. RHuEPO has potentially beneficial effects on cardiovascular system, including anti-apoptic, mitogenic and angiogenic activity. On the other hand rHuEPO improves anemia observed in some patients with heart failure. Direct cardiac activity of rHuEPO and indirect influence on anemia suggest that rHuEPO therapy is safe and useful in chronic heart failure patients and other cardiovascular settings.

Topics: Cardiology; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Heart Failure; Humans; Recombinant Proteins; Signal Transduction

Recombinant human erythropoietin (epoetin alfa) has been used in clinical settings for more than a decade. Its indications have expanded considerably from its original use as hormone therapy in the treatment of anemia in adults with chronic kidney disease. Since the introduction of epoetin alfa, a greater understanding of anemia pathophysiology and the interactions of erythropoietin, iron, and erythropoiesis has been elucidated. Anemia is now independently associated with increased mortality and disease progression. Potential survival benefits associated with correction of anemia in various patient populations are leading to consideration of earlier, more aggressive treatment of mild to moderate anemia with epoetin alfa. Moreover, this agent's therapeutic use may extend beyond currently accepted roles. Epoetin alfa is undergoing evaluation with promising results in a variety of new clinical settings, including anemia associated with congestive heart failure, ribavirin-interferon alfa treatment of hepatitis C virus infection, and critical illness. Preclinical studies also have established erythropoietin and its recombinant equivalent to be a pleiotropic cytokine with antiapoptotic activity and neuroprotective actions in the central nervous system. The therapeutic potential of epoetin alfa appears yet to be fully realized.

Topics: Anemia; Clinical Trials as Topic; Cytokines; Epoetin Alfa; Erythropoiesis; Erythropoietin; Heart Failure; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; United States

Death from malaria occurs from the complications of the infection: cerebral manifestations leading to coma and a severe and refractory anemia leading to hypoxia and cardiac decompensation. Several mechanisms have been identified to play a role in the pathogenesis of malarial anemia, such as erythrocyte lysis and phagocytosis, and sequestration of parasitized red blood cells, but recent data indicate that these mechanisms (singly or in combination) do not adequately explain the severity of this anemia. By contrast, hematologic studies have shown that bone marrow suppression and ineffective erythropoiesis contribute importantly to the severe anemia of malaria infection. The host mechanisms responsible for suppression of erythropoiesis may involve an excessive or sustained innate immune response or a pathologic skewing of the T-cell differentiation response with the attendant production of certain proinflammatory cytokines. Experimental data also indicate that severe malarial anemia is associated with the immunologic expression of a circulating inhibitor of erythropoiesis that functionally antagonizes the action of erythropoietin. We review the clinical and experimental basis for these concepts and discuss ongoing experimental and genetic studies aimed at unraveling the molecular basis of this malaria-induced bone marrow suppression.

Topics: Adult; Anemia; Animals; Aotus trivirgatus; Bone Marrow; Child; Child, Preschool; Cytokines; Erythropoiesis; Erythropoietin; Genetic Predisposition to Disease; Heart Failure; Humans; Hypoxia; Infant; Inflammation Mediators; Malaria; Malaria Vaccines; T-Lymphocyte Subsets

Anemia can be the cause of heart failure, but also its consequence. The pathogenesis of anemia in chronic heart failure (CHF) has yet to be fully elucidated, but is likely to be complex. Epidemiologic studies suggest that kidney dysfunction (by reducing the erythropoietic response to anemia), inflammation (by inducing erythropoietin resistance), decreased body mass index, old age, female gender, and poor clinical status may be important factors in the development of anemia in CHF. Intestinal malabsorption, chronic aspirin use, and proteinuria predisposes to iron deficiency. Proinflammatory cytokines are likely to play a significant role in anemia in CHF by generating the "anemia of chronic illness" that is a hallmark of inflammatory conditions. Few studies have investigated the mechanisms of anemia in CHF. There is a need for such studies.

Topics: Anemia; Chronic Disease; Erythropoietin; Female; Heart Failure; Humans; Male; Risk Factors

Anemia occurs frequently in chronic heart failure (CHF) patients and is associated with increased morbidity and mortality risk. Clinical trials with recombinant human erythropoietin in patients with chronic kidney disease and concomitant structural heart disease have demonstrated beneficial effects on ventricular remodeling but variable effects on clinical outcome. Preliminary clinical trials in patients with CHF demonstrate that erythropoietin therapy is well-tolerated and associated with short-term clinical benefits. The optimum target hemoglobin, erythropoietin dosing regimen, and role of iron supplementation in patients with CHF are not known. Darbepoetin alfa is a glycosylated derivative of erythropoietin with a prolonged half-life that may allow less frequent dosing in CHF populations. Additional studies are needed to determine the safety and efficacy of long-term erythropoietic therapy in CHF patients.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Heart Failure; Humans; Morbidity; Randomized Controlled Trials as Topic; Renal Insufficiency; Treatment Outcome

Topics: Anemia; Autoimmune Diseases; Cell Hypoxia; Disease-Free Survival; Double-Blind Method; Erythropoietin; Heart Failure; Humans; Kidney; Kidney Diseases; Lymphoma, Non-Hodgkin; Multiple Myeloma; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins

Heart failure is defined as the inability of the heart to pump blood at an amount sufficient to meet the metabolic needs of the body. In heart failure, the inability to meet the body's metabolic needs is based on hemodynamic derangement and suboptimal oxygen-carrying capacity of the blood itself. Current pharmacologic therapy attempts to improve survival and reduce symptomatology by optimizing hemodynamics to increase oxygen delivery, but does not address oxygen-carrying capacity. Unfortunately, there is a high prevalence of anemia in patients with heart failure, which compromises oxygen-carrying capacity, is an independent predictor of mortality, and may be caused in part by pharmacologic agents that confer morbidity and mortality benefits in this population. Recombinant human erythropoietin supplementation improves the functional capacity of the failing myocardium, reverses and antagonizes the detrimental remodeling induced by autoimmune activity, and may reduce mortality and morbidity among patients receiving maximal pharmacologic therapy for heart failure. However, limited clinical data prohibit widespread recommendations for its use in patients with heart failure.

Topics: Anemia; Blood Viscosity; Erythropoietin; Heart Failure; Humans; Survival Analysis

Topics: Acute Kidney Injury; Animals; Biomarkers; Contrast Media; Endothelin Receptor Antagonists; Endothelin-1; Endotoxemia; Erythropoietin; Fibrosis; Glycopeptides; Heart Failure; Humans; Hypotension; Kidney Failure, Chronic; Peptides, Cyclic; Peritoneal Dialysis; Peritoneum; Prognosis; Recombinant Proteins; Renal Dialysis

Anemia has recently been recognized as an important comorbid condition and potentially novel therapeutic target in patients with heart failure (HF). Anemia is common in HF patients, with a prevalence ranging from 4% to 55% depending on the population studied. Multiple potential mechanisms of interaction exist between anemia and the clinical syndrome of HF, including hemodilution, inflammatory activation, renal insufficiency, and malnutrition. A growing body of literature from observational databases and clinical trials suggests that anemia is an independent risk factor for adverse outcomes in patients with HF. Although preliminary data suggest that treatment of anemia may result in significant symptomatic improvement in HF, aggressive treatment of anemia may also be associated with increased risk of hypertension or thrombosis. Multiple ongoing studies will provide definitive data on the balance of risks and benefits of anemia treatment in chronic HF.

Topics: Anemia; Comorbidity; Erythropoietin; Heart; Heart Failure; Hematocrit; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Risk Factors

To review the use of erythropoietin for anemia in heart failure (HF).. Peer-reviewed articles in MEDLINE (1966-June 2004) were identified and citations from available articles were reviewed using the search terms anemia, erythropoietin, and heart failure.. Anemia worsens HF prognosis. Clinical studies in patients with New York Heart Association Class III/IV HF who had hemoglobin <12 mg/dL and were refractory to maximal medical management showed that erythropoietin improves symptoms. Larger scale studies with mortality endpoints are required to confirm the benefits.. In selected patients with severe, chronic HF, erythropoietin may be considered for functional improvement. However, routine use of this treatment strategy is not recommended until more data are available.

Topics: Anemia; Erythropoietin; Heart Failure; Hematinics; Humans; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Aged; Anemia; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic

Over the past few years, anemia has emerged as a powerful independent predictor of adverse outcomes in chronic heart failure (CHF). It affects up to 50% of patients with CHF, depending on the definition of anemia used and on the population studied. Even small reductions in hemoglobin are associated with worse outcome. However, the causes of anemia in CHF remain unclear, although impairment of renal function and inflammatory cytokines are proposed mechanisms. Both may act through impairment of the synthesis or action of erythropoietin. Preliminary studies have demonstrated improvement in symptoms, exercise tolerance, quality of life, and reductions in hospitalizations when patients with severe CHF were treated with erythropoietin. The benefits and the potential risks of such therapies will be further addressed in upcoming larger randomized trials. The recent interest in anemia reflects a new perspective in heart failure therapy, focusing on non-cardiovascular comorbidities.

Topics: Aged; Anemia; Anemia, Iron-Deficiency; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cytokines; Erythropoietin; Female; Heart Failure; Hemodilution; Humans; Kidney Failure, Chronic; Male; Prevalence; Prognosis; Risk Factors

Anemia is seen in chronic kidney insufficiency (CKI), dialysis patients, congestive heart failure (CHF), and renal transplantation. Anemia can lead to progressive cardiac damage as well as progressive renal damage. It is not generally appreciated that CHF itself may be a very common contributor to both the production of anemia as well as to the progression of the renal failure. Correction of the anemia with erythropoietin and, as necessary, intravenous iron, may prevent the deterioration of both the heart and the kidneys. We suggest that there is a triangular relationship, a vicious circle, between CHF, CKI and anemia where each of these three can both cause and be caused by the other. We call this syndrome the cardio-renal anemia (CRA) syndrome. All physicians, especially cardiologists and internists who treat CKI and CHF, should be made aware of the dangers of anemia in CKI and CHF and should work with nephrologists to correct it.

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Iron; Kidney Failure, Chronic

In recent years, rapid growth in the understanding of the pathophysiology of chronic heart failure has allowed for insights into many potential new therapeutic strategies. Yet until now, despite sound biological basis for efficacy and success in early-Phase studies, novel agents have not stood up to the scrutiny of late-Phase clinical trials. Indeed, remarkably negative results have been observed for vasopeptidase inhibitors, endothelin receptor antagonists and agents which block immune activation. However, efficacy data from other novel agents are still awaited, including the selective aldosterone receptor antagonist eplerenone, arginine vasopressin inhibitors, erythropoietin and hydroxy-methyl-glutaryl coenzyme A reductase inhibitors. Other classes of drugs which may enter clinical development include cardiac metabolic agents, matrix metalloproteinase inhibitors and advanced glycation end product antagonists. That the mortality and morbidity of patients with chronic heart failure remain unacceptably high makes the ongoing commitment to exploration of new drug therapies for the condition critical.

Topics: Arginine Vasopressin; Cardiovascular Agents; Clinical Trials as Topic; Endothelin Receptor Antagonists; Erythropoietin; Glycation End Products, Advanced; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Matrix Metalloproteinase Inhibitors; Mineralocorticoid Receptor Antagonists

Chronic heart failure (CHF) is a leading cause of morbidity and mortality. Although a precise definition for a cut-off value of hemoglobin level for anemia is still lacking, it has recently been found to be a common complication in CHF, occurring in 10-20% of patients. There are several possible pathogenetic mechanisms for anemia in CHF, and a precise underlying cause is found in only a minority of patients. In CHF, more than 50% of anemia cases are considered to be 'anemia in chronic illness'. In CHF patients, low hemoglobin values directly relate to poor peak oxygen consumption, disabling symptoms, and impaired survival. Recent pilot studies showed that correction of anemia with erythropoietin and iron may lead to improvement in symptoms and exercise capacity. These issues need to be tested in larger, double-blind, randomized, placebo-controlled trials before anemia treatment becomes routine in patients with CHF.

Topics: Anemia; Erythropoietin; Heart Failure; Hemoglobins; Humans; Iron

Erythropoietin is a hypoxia-induced hormone that is essential for normal erythropoiesis. The production of recombinant human erythropoietin (rHuEpo) has revolutionized the treatment of anemia associated with chronic renal failure and chemotherapy, and has been used as prophylaxis to prevent anemia after surgery. The erythropoietin receptor is widely distributed in the cardiovascular system, including endothelial cells, smooth muscle cells and cardiomyocytes. Epo has potentially beneficial effects on the endothelium including anti-apoptotic, mitogenic and angiogenic activities. On the other hand, some reports suggest that rHuEpo may have pro-thrombotic or platelet-activating effects. Hypertension develops in 20-30% of renal patients treated with rHuEpo. Many patients with heart failure have anemia. Despite some potential adverse effects, early studies in heart failure patients with anemia suggest that rHuEpo therapy is safe and effective in reducing left ventricular hypertrophy, enhancing exercise performance and increasing ejection fraction. Further studies are warranted to define the role of rHuEpo in chronic heart failure and other cardiovascular settings.

Topics: Anemia; Cardiovascular System; Cell Division; Chromogranins; Endothelium, Vascular; Erythropoietin; GTP-Binding Protein alpha Subunits, Gs; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Muscle, Smooth, Vascular; Myocytes, Cardiac; Nerve Tissue Proteins; Platelet Activation; Receptors, Erythropoietin; Recombinant Proteins; Thrombosis

Up to 64% of patients referred to nephrologists with chronic kidney insufficiency (CKI) have evidence of congestive heart failure (CHF), and most of these patients are also anemic. We have called this triad of anemia, CKI, and CHF the cardio renal anemia (CRA) syndrome. The 3 components of this syndrome form a vicious circle, with each one capable of causing or worsening the other 2. Anemia is found in one-third to one-half of CHF patients and can either cause or worsen the CHF, and can increase the mortality, hospitalization, and malnutrition in this condition. Anemia is also associated with a worsening of renal function in CHF and CKI, causing a more rapid progression to dialysis than is found in those without anemia. Uncontrolled CHF can cause rapid deterioration of renal function and may also cause anemia. Chronic kidney insufficiency can cause anemia and worsen the CHF.. Aggressive therapy of CHF with all the accepted CHF medications in the accepted doses will often fail to improve the CHF if anemia is also present but is not corrected. However, when the anemia was corrected with subcutaneous erythropoietin and, in some cases, with intravenous iron, the cardiac and patient function and quality of life improved, the need for hospitalization and for high-dose oral and intravenous diuretics was strikingly reduced, and renal function, which had previously been deteriorating, stabilized.. Nephrologists should carefully assess the cardiac status of all CKI patients, including routinely getting an echocardiogram and possibly measuring B-type natriuretic peptide. Where CHF is present, the indicated CHF agents in the indicated doses should be used.. Studies show that most cardiologists and internists do not recognize, investigate, or treat the anemia frequently seen in their CHF patients. In our experience cooperation between nephrologists and these specialists has increased their awareness about anemia, resulting in its earlier correction, and thus preventing the deterioration of the CHF, the CKI, and the anemia itself.

Topics: Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic

Topics: Anemia; Erythropoietin; Exercise; Heart Failure; Humans

About half of all the patients with CHF are anemic (they have a hemoglobin of < 12 g%). The prevalence and severity of this anemia increase with increasing severity of the CHF. The anemia is caused by a combination of poor nutrition, associated renal insufficiency causing inappropriately low Erythropoietin (EPO) levels, bone marrow depression and EPO resistance caused by excessive TNF alpha and other factors, gastrointestinal blood loss caused by aspirin, ACE inhibitors, EPO loss in the urine with proteinuria, and hemodilution caused by the excessive plasma volume. Studies have shown that the anemia is an independent risk factor for death in CHF, almost doubling the mortality rate. Correction of the anemia with subcutaneous EPO and IV iron improves cardiac function and functional capacity, helps prevent the progression of renal failure, markedly reduces hospitalization and diuretic doses, and improves self assessed quality of life. This so-called Cardio Renal Anemia Syndrome is very common in CHF. Its successful treatment demands close cooperation between cardiologists and nephrologists.

Topics: Anemia, Iron-Deficiency; Comorbidity; Erythropoietin; Female; Heart Failure; Humans; Incidence; Iron Compounds; Male; Prognosis; Recombinant Proteins; Risk Factors; Severity of Illness Index; Survival Rate; Treatment Outcome

Topics: Adaptation, Physiological; Anemia; Cardiovascular System; Cognition Disorders; Drug Costs; Epoetin Alfa; Erythropoietin; Exercise; Heart Failure; Hematocrit; Hemodynamics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Iron; Kidney Failure, Chronic; Multicenter Studies as Topic; Practice Guidelines as Topic; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Reference Values; Renal Dialysis; Risk; Thrombophilia; Treatment Outcome

The heart and the kidney exert a reciprocal control of their function in order to maintain a steady state of haemodynamics, both in physiological and pathological conditions. The functional relationship between the two organs becomes particularly evident during heart failure. The knowledge of such relationship may play an important role in the management of heart failure. We also report here our experience in the treatment of congestive heart failure with depletive techniques vicarious of kidney function.

Topics: Blood Pressure; Erythropoietin; Heart Failure; Humans; Hypertension; Kidney Diseases; Natriuretic Agents

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Morbidity; Recombinant Proteins; Renal Replacement Therapy; Risk Factors

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Kidney Diseases; Recombinant Proteins; Renal Dialysis

Background In patients with chronic heart failure and chronic kidney disease, correction of anemia with erythropoietin-stimulating agents targeting normal hemoglobin levels is associated with an increased risk of cardiovascular morbidity and mortality. Emerging data suggest a direct effect of erythropoietin on fibroblast growth factor 23 (FGF23), elevated levels of which have been associated with adverse outcomes. We investigate effects of erythropoietin-stimulating agents in patients with both chronic heart failure and chronic kidney disease focusing on FGF23. Methods and Results In the EPOCARES (Erythropoietin in CardioRenal Syndrome) study, we randomized 56 anemic patients (median age 74 [interquartile range 69-80] years, 66% male) with both chronic heart failure and chronic kidney disease into 3 groups, of which 2 received epoetin beta 50 IU/kg per week for 50 weeks, and the third group served as control. Measurements were performed at baseline and after 2, 26, and 50 weeks. Data were analyzed using linear mixed-model analysis. After 50 weeks of erythropoietin-stimulating agent treatment, hematocrit and hemoglobin levels increased. Similarly, C-terminal FGF23 levels, in contrast to intact FGF23 levels, rose significantly due to erythropoietin-stimulating agents as compared with the controls. During median follow-up for 5.7 (2.0-5.7) years, baseline C-terminal FGF23 levels were independently associated with increased risk of mortality (hazard ratio 2.20; 95% CI, 1.35-3.59; P=0.002). Conclusions Exogenous erythropoietin increases C-terminal FGF23 levels markedly over a period of 50 weeks, elevated levels of which, even at baseline, are significantly associated with an increased risk of mortality. The current results, in a randomized trial setting, underline the strong relationship between erythropoietin and FGF23 physiology in patients with chronic heart failure and chronic kidney disease. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00356733.

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Heart Failure; Hematinics; Hemoglobins; Humans; Male; Peptide Fragments; Recombinant Proteins; Renal Insufficiency, Chronic; Treatment Outcome

Anemia aggravates the disease course and the survival rate of chronic heart failure (CHF) patients. The purpose of the study was to investigate the level of erythropoietin (EPO) in CHF patients with anemic syndrome, with the aim to more accurately assess the severity of the disease and its treatment, depending on the anemia degree.. Patients with ischemic CHF of I-IV functional class (FC) with and without anemia were examined (total number of patients=208, patients with anemia=174). The EPO was determined using the enzyme-linked immunosorbent assay. Before treatment, the patients underwent the following medical therapy: angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, long-acting nitrates, diuretics, digoxin, and beta-blockers at individual doses. Depending on the plasma EPO level, the CHF patients with anemia were divided into four randomized groups in terms of treatment.. Normal erythropoietinemia was found in 36.2% of the CHF patients with anemic syndrome (I-III FC), hypoerythropoietinemia in 44.8% (III-IV FC), and hypererythropoietinemia in 18.96% (III-V FC). The EPO level in the blood plasma of the patients with I-II FC CHF with hypoerythropoietinemia, who were treated with methoxy polyethylene glycol-epoetin β (MEB), increased by 2.2 times. Combination therapy with disease-modifying drugs and MEB led to a significant increase in the plasma EPO level in the CHF patients with hypoerythropoietinemia.. It was shown that the EPO level in patients with CHF and anemia did not always drop. Hypererythropoietinemia in patients with CHF and anemia leads to an unfavorable treatment prediction. This necessitates the investigation of the EPO level in all patients with CHF before and after treatment, with the aim of correcting the anemic syndrome. The research showed that the combined therapy of patients with CHF and anemia using MEB medication and iron with regard to the EPO level in the blood plasma improved their overall physical condition, reduced heart failure symptoms and hospitalization frequency, and demonstrated a clear tendency to reduce the general mortality rate.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Anemia; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Digoxin; Diuretics; Erythropoietin; Female; Heart Failure; Humans; Male; Middle Aged; Nitrates; Severity of Illness Index

To study correlation between concentration of pathological cytokines and erythropoietin inpatients with chronic heart failure anemic syndrome and also to prove importance of this communication for need of appointment erythropoietin excitants.. 94 patients with chronic heart failure of New York Heart Association (NYHA) class III-IV a left ventricular ejection fraction of 40% or less withanemia w ere idied in inveslain (58 males, 36 females). Anemia was detected when hemoglobin (b) was less than 120 g/l in males and less than in females. 46 patients received traditional treatment of CHF (I group) and 48 patients were treated additionally with erythropoietin (EPO) (II group). Percutaneous EPO 50 IU monthly to patients without iron deficiency for a period of 6 months. Echocardiography parameters, plasma NT and pro-BNP, cytokines, EPO, feritin and 6-minute walking test were assessed at baseline and after treatment.. in patients with CHF and anemia in II group erythropoietin treatment increased Hb levels by 22.4% (p < 0.05) and erythropoietin serum levels by 29.3 +/- 14.3 IU/ml (p < 0.001). Increased erythropoietin level was associated with decrease of cytokines levels: IL 1 by 36.6% (p < 0.001), IL 6 by 54.3% (p < 0.05), TNF alpha by 48.3% (p < 0.05) compared with patients in I group. In erythropoietin-treated patients there is a significant increase of LVEF by 19.04% (p < 0.05) compared with patients from I group. A greater 6-minute distance walked on exercise testing increased by 76.6% (p < 0.05) after treatment with erythropoieitin.. Correction of anemia in patients with chronic heart failure with percutaneous erythropoietin injections 50 IU monthly for 6 month period to improve erythropoietin deficit and cytokines aggression and associated anemia, symptoms and quaity of life.

Topics: Anemia; Chronic Disease; Cytokines; Epoetin Alfa; Erythropoietin; Exercise Test; Female; Heart Failure; Hemoglobins; Humans; Interleukin-1; Male; Middle Aged; Recombinant Proteins; Treatment Outcome; Tumor Necrosis Factor-alpha; Ventricular Function, Left

Recombinant erythropoietin has become a routine component of care of patients with chronic kidney disease reducing the need for blood transfusions but raising the risks for cardiovascular events. We undertook this secondary analysis of subjects enrolled in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial to examine the interrelationships between epoetin-alfa maintenance doses utilized and achieved hemoglobin (Hb) irrespective of treatment target and randomized allocation.. We performed a post hoc analysis from the CHOIR trial. Inclusion criteria were Hb <11.0 g/dl and estimated glomerular filtration rates of 15-50 ml/min/1.73 m(2). To be included in the present analysis, subjects needed to be free of the composite event at 4 months, receive epoetin-alfa, and have ≥1 postbaseline Hb measurement. The mean weekly dose of epoetin-alfa received up to the time of first event or censure was the main exposure variable, while the achieved Hb at month 4 was the confounder representing the subject's underlying response to treatment. The primary outcome was the composite of death, heart failure hospitalization, stroke, or myocardial infarction. A Cox proportional hazard regression model was used in time-to-event analysis.. Among 1,244 subjects with complete data, the average weekly dose of epoetin-alfa ranged 143.3-fold from 133 to 19,106 units/week at the time of first event or censure. Cox proportional hazard analysis found that those in the middle tertile of Hb achieved (>11.5 to <12.7 g/dl) and the lowest tertile of epoetin-alfa dose exposure level (<5,164 units/week) had the lowest risk. Irrespective of Hb achieved, the relative risk in the highest tertile (>10,095 units/week) of epoetin-alfa dose exposure level was significantly escalated (hazard ratios ranged from 2.536 to 3.572, p < 0.05, when compared to the group of middle Hb tertile and lowered dose tertile). In a multivariable model that adjusted for achieved Hb, albumin, cholesterol, age, prior heart failure, prior stroke, prior deep venous thrombosis, atrial fibrillation or malignancy, the average weekly dose had a significant (p = 0.005) relative risk of 1.067 per 1,000 units of epoetin-alfa for the primary end point.. In the CHOIR trial, average epoetin-alfa doses >10,095 units/week were associated with increased risks for cardiovascular events irrespective of the Hb achieved within the first 4 months of treatment. These data suggest the weekly epoetin-alfa dose and not the Hb achieved was a principal determinant in the primary outcome observed implicating a cardiovascular toxicity of this erythrocyte-stimulating agent.

Topics: Aged; Aged, 80 and over; Anemia; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Recombinant Proteins; Renal Insufficiency, Chronic; Risk Factors; Stroke; Treatment Outcome

Hyporesponders to erythropoietin-stimulating agents (ESAs) have been associated with an increased subsequent risk of death or cardiovascular events. We hypothesized that subjects who are hyporesponsive to erythropoietin alfa would have higher plasma volumes and lower red cell deficits than subjects who are responsive to therapy.. As part of a prospective, single blind, randomized, placebo-controlled study comparing erythropoietin alfa with placebo in older adults (n = 56) with heart failure and a preserved ejection fraction (HFPEF), we performed blood volume analysis with the use of an indicator dilution technique with (131)iodine-labeled albumin. We evaluated differences in plasma volumes and red cell volumes in hyporesponders (eg, <1 g/dL increase in hemoglobin within the first 4 weeks of treatment with erythropoetin alfa) compared with subjects who were responders and controls.. Nine of 28 subjects (32%) assigned to ESA were hyporesponders. Hyporesponders did not differ from responders nor control subjects by any baseline demographic, clinical, or laboratory parameter, including hemoglobin. Hyporesponders had a greater total blood volume expansion (1,264.7 ± 387 vs 229 ± 206 mL; P = .02) but less of a red cell deficit (-96.2 ± 126 vs -402.5 ± 80.6 mL; P = .04) and a greater plasma volume expansion (+1,360.8 ± 264.5 vs +601.1 ± 165.5 mL; P = .01). Among responders, the increase in hemoglobin with erythropoietin alfa was associated primarily with increases in red cell volume (r = 0.91; P < .0001) as well as a decline in plasma volume (r = -0.55; P = .06).. Among older adults with HFPEF and anemia, hyporesponders to erythropoietin alfa had a hemodilutional basis of their anemia, suggesting that blood volume analysis can identify a cohort likely to respond to therapy.

Topics: Aged; Aged, 80 and over; Anemia; Blood Volume; Epoetin Alfa; Erythrocyte Volume; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Male; Middle Aged; Plasma Volume; Prospective Studies; Recombinant Proteins; Retrospective Studies; Single-Blind Method; Stroke Volume; Treatment Outcome

Erythropoietin stimulating agents (ESAs) is an active area of clinical investigation in heart failure (HF) but can cause hypertension and higher hemoglobin concentrations (Hb) that have been associated with adverse outcomes. We evaluated a dosing algorithm and potential confounders' effect on Hb and blood pressure (BP) in a clinical trial.. In an ongoing randomized, placebo controlled, single blind clinical trial of ESA (epoetin alfa) in anemic patients with HF and a preserved ejection fraction (HFPEF), Hb was measured weekly as was BP, weight and concomitant medical therapy. A repeated measure mixed model evaluated determinants of weekly changes in Hb and BP.. Among 45 subjects (78 ± 11 years, 67% women, EF = 57 ± 9%) with a total of 780 repeated weekly Hb measures, Hb significantly increased over time in those assigned to ESA (β = 0.933, P < 0.0001), compared to placebo. Dose (β = -0.108, P < 0.0001), patient weight (β = -0.016, P = 0.0037), diuretic use (β = -0.124, P = 0.0389), and time (β = 0.003, P = 0.0331), were all significantly associated with Hb change. Increased diuretic dose and weight change were significantly inversely associated with changes in Hb. ESA administration and dose were not significant determinants of absolute BP or changes in BP from baseline.. In addition to ESA dose and duration of therapy, factors indicative of volume status including weight and diuretic use are determinants of hemoglobin levels in HF subjects.. The currently employed dosing algorithm, which adjusts the administration of ESA based on the absolute hemoglobin and weekly change in hemoglobin increases Hb with relatively a low weekly dose of ESA without significant effects on BP.

Topics: Aged; Aged, 80 and over; Algorithms; Anemia; Biomarkers; Blood Pressure; Blood Volume; Confounding Factors, Epidemiologic; Diuretics; Drug Administration Schedule; Drug Dosage Calculations; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Hematinics; Hemoglobins; Humans; Male; Multivariate Analysis; New York City; Recombinant Proteins; Single-Blind Method; Stroke Volume; Time Factors; Treatment Outcome

Anemia is a common comorbidity in older adults with heart failure and a preserved ejection fraction and is associated with worse outcomes. We hypothesized that treating anemia with subcutaneous epoetin alfa would be associated with reverse ventricular remodeling and improved exercise capacity and health status compared with placebo.. Prospective, randomized, single-blind, 24-week study with blinded end point assessment among anemic (average hemoglobin of 10.4±1 g/dL) older adult patients (n=56; 77±11 years; 68% women) with heart failure and a preserved ejection fraction (ejection fraction=63±15%; B-type natriuretic peptide=431±366 pg/mL) was conducted. Treatment with epoetin alfa resulted in significant increases in hemoglobin (P<0.0001). Changes in end-diastolic volume (-6±14 versus -4±16 mL; P=0.67) at 6 months did not differ between epoetin alfa and placebo, but declines in stroke volume (-5±8 versus 2±10 mL; P=0.09) without significant changes in left ventricular mass were observed. Changes in 6-minute walk distance (16±11 versus 5±12 m; P=0.52) did not differ. Although quality of life improved by the Kansas City Cardiomyopathy Questionnaire and the Minnesota Living with Heart Failure Questionnaire in both cohorts, there were no significant differences between groups.. Administration of epoetin alfa to older adult patients with heart failure and a preserved ejection fraction compared with placebo did not change left ventricular end-diastolic volume and left ventricular mass nor did it improve submaximal exercise capacity or quality of life.. URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT00286182.

Topics: Age Factors; Aged; Aged, 80 and over; Anemia; Biomarkers; Chi-Square Distribution; Comorbidity; Epoetin Alfa; Erythropoietin; Exercise Test; Exercise Tolerance; Female; Heart Failure; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; New York City; Prospective Studies; Quality of Life; Recombinant Proteins; Recovery of Function; Single-Blind Method; Stroke Volume; Surveys and Questionnaires; Time Factors; Treatment Outcome; Ventricular Remodeling; Walking

This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes.. Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate < 60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106-117) g/L.. The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity.

Topics: Aged; Aged, 80 and over; Anemia; Cause of Death; Clinical Trials as Topic; Comorbidity; Darbepoetin alfa; Demography; Double-Blind Method; Erythropoietin; Female; Heart Failure; Hematinics; Hospitalization; Humans; Male; Middle Aged; Severity of Illness Index; Treatment Outcome

Combined heart and renal failure is associated with high cardiovascular morbidity and mortality. Anti-oxidant and anti-inflammatory, non-hematopoietic effects of erythropoietin (EPO) treatment have been proposed. Monocytes may act as biosensors of the systemic environment. We hypothesized that monocyte transcriptomes of patients with cardiorenal syndrome (CRS) reflect the pathophysiology of the CRS and respond to short-term EPO treatment at a recommended dose for treatment of renal anemia.. Patients with CRS and anemia (n = 18) included in the EPOCARES trial were matched to healthy controls (n = 12). Patients were randomized to receive 50 IU/kg/week EPO or not. RNA from CD14(+)-monocytes was subjected to genome wide expression analysis (Illumina) at baseline and 18 days (3 EPO injections) after enrolment. Transcriptomes from patients were compared to healthy controls and effect of EPO treatment was evaluated within patients.. In CRS patients, expression of 471 genes, including inflammation and oxidative stress related genes was different from healthy controls. Cluster analysis did not separate patients from healthy controls. The 6 patients with the highest hsCRP levels had more differentially expressed genes than the 6 patients with the lowest hsCRP levels. Analysis of the variation in log(2) ratios of all individual 18 patients indicated that 4 of the 18 patients were different from the controls, whereas the other 14 were quite similar. After short-term EPO treatment, every patient clustered to his or her own baseline transcriptome. Two week EPO administration only marginally affected expression profiles on average, however, individual gene responses were variable.. In stable, treated CRS patients with mild anemia, monocyte transcriptomes were modestly altered, and indicated imprints of inflammation and oxidative stress. EPO treatment with a fixed dose has hematopoietic effects, had no appreciable beneficial actions on monocyte transcription profiles, however, could also not be associated with undesirable transcriptional responses.

Topics: Aged; Anemia; Anti-Inflammatory Agents; Antioxidants; Biosensing Techniques; Cardio-Renal Syndrome; Cluster Analysis; DNA, Complementary; Erythropoietin; Female; Gene Expression Profiling; Heart Failure; Humans; Lipopolysaccharide Receptors; Male; Middle Aged; Monocytes; Oxidative Stress; Renal Insufficiency; Transcriptome

Atherosclerotic renal artery stenosis (ARAS) is common in cardiovascular diseases and associated with hypertension, renal dysfunction and/or heart failure. There is a paucity of data about the prevalence and the role of ARAS in the pathophysiology of combined chronic heart failure (CHF) and chronic kidney disease (CKD). We investigated the prevalence in patients with combined CHF/CKD and its association with renal function, cardiac dysfunction and the presence and extent of myocardial fibrosis.. The EPOCARES study (ClinTrialsNCT00356733) investigates the role of erythropoietin in anaemic patients with combined CHF/CKD. Eligible subjects underwent combined cardiac magnetic resonance imaging (cMRI), including late gadolinium enhancement, with magnetic resonance angiography of the renal arteries (MRA).. MR study was performed in 37 patients (median age 74 years, eGFR 37.4 ± 15.6 ml/min, left ventricular ejection fraction (LVEF) 43.3 ± 11.2%), of which 21 (56.8%) had ARAS (defined as stenosis >50%). Of these 21 subjects, 8 (21.6%) had more severe ARAS >70% and 8 (21.6%) had a bilateral ARAS >50% (or previous bilateral PTA). There were no differences in age, NT-proBNP levels and medication profile between patients with ARAS versus those without. Renal function declined with the severity of ARAS (p = 0.03), although this was not significantly different between patients with ARAS versus those without. Diabetes mellitus was more prevalent in patients without ARAS (56.3%) against those with ARAS (23.8%) (p = 0.04). The presence and extent of late gadolinium enhancement, depicting myocardial fibrosis, did not differ (p = 0.80), nor did end diastolic volume (p = 0.60), left ventricular mass index (p = 0.11) or LVEF (p = 0.15). Neither was there a difference in the presence of an ischemic pattern of late enhancement in patients with ARAS versus those without.. ARAS is prevalent in combined CHF/CKD and its severity is associated with a decline in renal function. However, its presence does not correlate with a worse LVEF, a higher left ventricular mass or with the presence and extent of myocardial fibrosis. Further research is required for the role of ARAS in the pathophysiology of combined chronic heart and renal failure.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Atherosclerosis; Cardio-Renal Syndrome; Chi-Square Distribution; Contrast Media; Erythropoietin; Female; Fibrosis; Glomerular Filtration Rate; Heart Failure; Hematinics; Humans; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Male; Meglumine; Middle Aged; Myocardium; Netherlands; Organometallic Compounds; Predictive Value of Tests; Prevalence; Prognosis; Renal Artery; Renal Artery Obstruction; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Severity of Illness Index; Stroke Volume; Ventricular Function, Left

Neutrophil-gelatinase associated lipocalin (NGAL), a tubular injury marker, is associated with iron metabolism in hemodialysis patients. We investigated whether serum NGAL levels reflect iron metabolism in combined chronic heart failure and chronic kidney disease (CHF/CKD) and whether treatment with low-dose erythropoietin stimulating agent (ESA) modulates NGAL levels.. In the EPOCARES trial (ClinTrialsNCT00356733) serum NGAL, hepcidin-25, transferrin saturation (TSAT), reticulocyte hemoglobin content (Ret-He) and endogenous erythropoietin (EPO) levels were measured.. Baseline serum NGAL levels correlated with cystatin C (r=0.767, p<0.001) and baseline EPO levels (r=-0.395, p=0.003). There was no correlation with baseline TSAT, Ret-He, and hepcidin-25 levels. After two weeks, NGAL levels decreased in the ESA-group (p=0.02), while there was no change in the no-ESA group (p=0.62). The magnitude in NGAL decrease in the ESA-group correlated with baseline EPO levels (r=0.431, p=0.01).. In contrast to in HD patients, in combined CKD/ CHF, serum NGAL levels did not correlate with iron metabolism, hence NGAL might reflect tubular damage in these patients. NGAL levels inversely correlated with baseline EPO levels and decreased in response to short-term ESA treatment, which might reflect an effect of ESA on tubular damage. These findings need to be confirmed and alternative explanations should be evaluated.

Topics: Acute-Phase Proteins; Aged; Aged, 80 and over; Anemia; Antimicrobial Cationic Peptides; Biomarkers; Chronic Disease; Comorbidity; Dose-Response Relationship, Drug; Erythropoietin; Female; Heart Failure; Hepcidins; Humans; Iron; Lipocalin-2; Lipocalins; Male; Prospective Studies; Proto-Oncogene Proteins; Regression Analysis; Renal Insufficiency, Chronic; Transferrin

Little is known about the effect of anemia correction with erythropoietin (EPO) on B-type natriuretic peptide (BNP) levels, NYHA class, and hospitalization rate. The aim of the study was to investigate, in patients with cardio-renal anemia syndrome, the effects of EPO on hemochrome and renal function parameters and BNP levels. We also analyzed the effect of EPO therapy on hospitalization rate and NYHA class after 12 months in comparison with a population undergoing to standard therapy. We performed a randomized double-blind controlled study of correction of the anemia with subcutaneous α (group A n = 13) or β (group B n = 14) EPO for 12 months in addition to standard therapy with oral iron in 27 subjects. Control group (n = 25 patients) received only oral iron. Significant increase in hemoglobin (Hb), hematocrit (Hct), and red blood cells (RBC) were revealed in EPO groups at 12 months; Hb, group A 12.3 ± 0.6; group B 11.7 ± 0.8; control group 10.6 ± 0.5 g/dl P < 0.0001; Hct group A 34.2 ± 2.3, group B 34 ± 2, control group 32.3 ± 1.8% P < 0.01; RBC, group A 3.9 ± 0.2, group B 3.8 ± 0.2, control group 3.3 ± 0.2, (P < 0.0001). Plasma BNP levels in EPO groups were significantly reduced after 12 months (group A: 335 ± 138 vs. group B: 449 ± 274 pg/ml control group 582 ± 209 pg/ml (P < 0.01). After 12 months of treatment, hospitalization rate and NYHA class were reduced in EPO groups with respect to control group (P < 0.05). Finally, an inverse correlation was observed between BNP and Hb levels in EPO Groups (r = -0.70 P < 0.001). EPO treatment reduces BNP levels and hospitalization rate in patients with cardio-renal anemia syndrome. The correction of anemia by EPO treatment appears able to improve clinical outcome in this subset of patients with heart failure.

Topics: Administration, Oral; Anemia; Erythropoietin; Heart Failure; Hemoglobins; Hospitalization; Humans; Injections, Subcutaneous; Iron; Kidney Diseases; Natriuretic Peptide, Brain; Severity of Illness Index; Treatment Outcome

Patients with cardiorenal syndrome (CRS) have high cardiovascular morbidity. Endothelial progenitor cells (EPC) constitute an endogenous vascular repairsystem, protecting against atherosclerosis development. Erythropoietin (EPO) treatment may have beneficial effects by mobilizing EPC from the bonemarrow. Our objective is to determine EPC levels and effects of EPO therapy on EPC levels in CRS patients.. Open-label randomized trial.. Part of the EPOCARES-trial, conducted in Utrecht (Netherlands).. Patients with CRS and anaemia and healthy controls were included. Interventions Patients were randomized to receive EPO therapy (50 IU/kg/wk) for 52 weeks or no EPO therapy.. CD34(+)KDR(+)-EPC, cultured EPC outgrowth and function at baseline, after 18 days and after 52 weeks.. Patients showed lower CD34(+)KDR(+)-cell numbers compared to controls (6(12) vs. 19(19) cells/10(5) granulocytes; p = 0.010), despite increased levels of stromal cell-derived factor-1α; (3.1(0.8) vs 2.6(0.3) ng/ml; p = 0.001). EPC outgrowth and function were not different between patients and controls. EPC levels did not change after 18 days with or without EPO treatment. CD34(+)KDR(+)-cells significantly declined after 52 weeks in the non-treated group (p = 0.028). Long-term EPO therapy did not significantly affect this reduction in CD34(+)KDR(+)-EPC levels.. CRS patients showed reduced CD34(+)KDR(+)-EPC levels compared to controls, consistent with a reduced vascular regenerative potential and despite upregulated SDF-1α levels. Over a one-year follow-up period a marked 68% further reduction in EPC levels was observed in the patient group without EPO treatment. In spite of promising experimental studies, our longitudinal, randomized study did not show significant influence of either short- or long-term EPO therapy on reduced EPC levels in CRS patients.

Topics: Anemia; Antigens, CD34; Cell Count; Cell Proliferation; Chemokine CXCL12; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Heart Failure; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Long-Term Care; Male; Recombinant Proteins; Stem Cells; Syndrome

Low-dose epoetin-β improved neo-angiogenesis and cardiac regeneration in experimental models of ischaemic cardiomyopathy without raising haemoglobin. No clinical study has tested this approach to date.. We performed a randomized, placebo-controlled, double-blind, single-centre study of 35 IU/kg body weight epoetin-β given subcutaneously once weekly for 6 months started within 3 weeks after successful percutaneous coronary intervention (PCI). Patients were included if they presented with a lesion within the proximal segment of the left anterior descending artery, the right coronary artery, or circumflex and had symptomatic heart failure. Patients with ST-segment elevation due to an acute myocardial infarct were excluded. The outcome variables were measured at baseline and at 6 months. Primary outcome measure was individual change in ejection fraction; secondary outcome was safety, change in N-terminal pro-brain natriuretic peptide, and peak VO(2). Twenty-four patients completed the 6-month treatment course. No adverse event related to the treatment occurred. Low-dose epoetin-β following PCI significantly improved global ejection fraction as measured by echocardiography (EPO: ΔEF 5.2 ± 2.0%, P= 0.013; placebo: ΔEF 0.3 ± 1.6%, P= 0.851; P= 0.019 for the inter-group difference) and cardiac magnetic resonance (EPO: ΔEF 3.1 ± 1.6%, P= 0.124; placebo: -1.9 ± 1.2%, P= 0.167; P= 0.042 for the inter-group difference). N-terminal pro-brain natriuretic peptide levels decreased in both groups without significant inter-group differences. Peak VO(2) levels increased significantly by 3.9 ± 1.1% (P< 0.05) in the EPO group, whereas in the placebo group the increase did not reach statistical significance (Δpeak VO(2) 3.0 ± 1.6, P = ns). No significant difference regarding peak VO(2) was observed between the EPO and placebo groups.. Low-dose epoetin-β treatment following PCI is safe and feasible, and has possible beneficial effects on global ejection fraction and measures of exercise capacity. Extended low-dose epoetin-β treatment warrants further mechanistic studies as well as larger clinical trials.. NCT00568542.

Topics: Algorithms; Angioplasty, Balloon, Coronary; Double-Blind Method; Erythropoietin; Exercise Tolerance; Female; Heart Failure; Hemoglobins; Humans; Male; Middle Aged; Myocardial Ischemia; Oxygen Consumption; Pilot Projects; Recombinant Proteins; Stroke Volume; Ventricular Function, Left

Studies have shown that red cell distribution width (RDW) is related to outcome in chronic heart failure (CHF). The pathophysiological process is unknown. We studied the relationship between RDW and erythropoietin (EPO) resistance, and related factors such as erythropoietic activity, functional iron availability and hepcidin.. In the Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome (EPOCARES) study, which investigates the role of EPO in 54 iron-supplemented anemic patients with CHF and chronic kidney disease (CKD) (n = 35 treated with 50 IU/kg/wk Epopoetin beta, n = 19 control), RDW was not associated with EPO resistance. We defined EPO resistance by EPO levels (r = 0.12, P = .42), the observed/predicted log EPO ratio (r = 0.12, P = .42), the increase in reticulocytes after 2 weeks of EPO treatment (r = -0.18, P = .31), and the increase of hemoglobin after 6 months of EPO treatment (r = 0.26, P = .35). However, RDW was negatively correlated with functional iron availability (reticulocyte hemoglobin content, r = -0.48, P < .001, and transferrin saturation, r = -0.39, P = .005) and positively with erythropoietic activity (soluble transferrin receptor, r = 0.48, P < .001, immature reticulocyte fraction, r = 0.36, P = .01) and positively with interleukin-6 (r = 0.48, P < .001). No correlation existed between hepcidin-25 and RDW.. EPO resistance was not associated with RDW. RDW was associated with functional iron availability, erythropoietic activity, and interleukin-6 in anemic patients with CHF and CKD.

Topics: Aged; Aged, 80 and over; Anemia; Cell Size; Drug Resistance; Erythrocyte Indices; Erythrocytes; Erythropoietin; Female; Heart Failure; Humans; Kidney Failure, Chronic; Male; Prospective Studies

The effects of erythropoietin administration on mitral regurgitation in patients with congestive heart failure have not yet been examined. After 2 months, erythropoietin treatment results in a significant reduction in left ventricular volumes and mitral regurgitation severity and improves hemodynamics.

Topics: Erythropoietin; Heart Failure; Humans; Mitral Valve Insufficiency; Prospective Studies; Therapeutics; Ventricular Function, Left; Ventricular Remodeling

To assess the prevalence of Restless Legs Syndrome (RLS) in anemic patients with Congestive Heart Failure (CHF) and Chronic Renal Failure (CRF) and to evaluate the effect of anemia treatment on RLS.. 38 anemic CHF-CRF patients were treated with subcutaneous Erythropoietin (EPO) and intravenous (IV) iron over 1 year. They were questioned initially and at 3 months post treatment about symptoms of RLS according to standard criteria. They were also contacted by telephone about RLS symptoms 12 months after onset of anemia treatment.. RLS was found in 15 (39.5%) of the 38 patients. In 10 (66.7%) patients it was present at least 6 days a week. The prevalence of the RLS initially was not related to Hb, to serum iron or % Transferrin Saturation. Diabetes and lower serum ferritin were more common in the RLS group (p<0.05). After 3 months of treatment, Hb increased from 10.4+/-0.8 to 12.3+/-1.2 g/dl, but RLS symptoms did not change. By 12 months the prevalence and frequency of RLS complaints was similar to what it had been initially.. RLS is common and often undiagnosed and untreated in anemic CHF-CRF patients. Unfortunately, successful treatment of anemia with EPO and IV iron did not improve this condition.

Topics: Aged; Anemia; Erythropoietin; Female; Heart Failure; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Prevalence; Restless Legs Syndrome

The CHOIR trial in anemic patients with chronic kidney disease compared epoetin-alfa treatment with low (11.3 g/l) and high (13.5 g/l) hemoglobin targets on the composite end point of death, hospitalization for heart failure, stroke, and myocardial infarction. However, other anemia management trials in patients with chronic kidney disease found there was increased risk when hemoglobin is targeted above 13 g/dl. In this secondary analysis of the CHOIR trial, we compared outcomes among the subgroups of patients with diabetes and heart failure to describe the comparative relationship of treatment to these two different hemoglobin goals. By Cox regression analysis, there was no increased risk associated with the higher hemoglobin target among patients with heart failure. In patients without heart failure, however, the hazard ratio (1.86) associated with the higher target was significant. Comparing survival curves in an unadjusted model, patients with diabetes did not have a greater hazard associated with the higher target. Subjects without diabetes had a significantly greater hazard in the high as compared to the low target, but the interaction between diabetes and the target was not significant. We suggest that the increased risks associated with higher hemoglobin targets are not clinically apparent among subgroups with greater mortality risk. These differential outcomes underscore the need for dedicated trials in these subpopulations.

Topics: Aged; Aged, 80 and over; Anemia; Chronic Disease; Comorbidity; Diabetes Mellitus; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Regression Analysis; Retrospective Studies; Survival Analysis; Treatment Outcome

Erythropoietin (EPO) resistance, an important cause of anaemia in patients with heart and renal failure, is associated with increased mortality. The hypothesis of the present study was that exogenous EPO decreases hepcidin levels and that the decrease in hepcidin levels upon EPO treatment is related to the bone marrow response.. In the EPOCARES trial, patients with renal failure (glomerular filtration rate 20-70 mL/min), heart failure, and anaemia were randomized to receive 50 IU/kg/week EPO (n = 20) or not (n = 13). Haemoglobin (Hb), hepcidin-25, ferritin, reticulocytes, serum transferrin receptor (sTfR), IL-6, and high-sensitivity C-reactive protein were measured at baseline and during treatment. Hepcidin-25 was measured by weak cation exchange chromatography/matrix assisted laser desorption ionization time-of-flight mass spectrometry. Baseline hepcidin levels were increased compared with a healthy reference population and were inversely correlated with Hb (r(2) = 0.18, P = 0.02), and positively with ferritin (r(2) = 0.51, P < 0.001), but not with renal function, high-sensitivity C-reactive protein or IL-6. Erythropoietin treatment increased reticulocytes (P < 0.001) and sTfR (P < 0.001), and decreased hepcidin (P < 0.001). Baseline hepcidin levels and the magnitude of the decrease in hepcidin correlated with the increase in reticulocytes (r(2) = 0.23, P = 0.03) and sTfR (r(2) = 0.23, P = 0.03) and also with the Hb response after 6 months (r(2) = 0.49, P = 0.001).. In this group of patients with combined heart and renal failure and anaemia, increased hepcidin levels were associated with markers of iron load and not with markers of inflammation. The (change in) hepcidin levels predicted early and long-term bone marrow response to exogenous EPO. In our group hepcidin seems to reflect iron load and response to EPO rather than inflammation and EPO resistance.

Topics: Aged; Aged, 80 and over; Anemia; Antimicrobial Cationic Peptides; Biomarkers; Drug Resistance; Erythropoietin; Female; Follow-Up Studies; Heart Failure; Hemoglobins; Hepcidins; Humans; Kidney Failure, Chronic; Male; Mass Spectrometry; Middle Aged; Prognosis; Recombinant Proteins

Increased oxidative and nitrosative stress are important mediators of left ventricular (LV) and vascular dysfunction in patients with chronic heart failure (CHF). This study investigated the effects of darbepoetin alfa on plasma markers of oxidative and nitrosative stress in patients with CHF with anemia. Thirty patients with CHF (LV ejection fraction [LVEF] <40%, hemoglobin <12.5 g/dl, and serum creatinine <2.5 mg/dl) were randomly assigned (1:1) to receive either a 3-month darbepoetin alfa regimen at 1.5 microg/kg every 20 days plus oral iron or placebo plus oral iron. Plasma B-type natriuretic peptide (BNP), markers of oxidative (oxidative, malondialdehyde, carbonyl proteins; antioxidative, glutathione) and nitrosative (nitrotyrosine) stress, LVEF, and 6-minute walked distance were assessed at baseline and after treatment. A significant improvement in LVEF and 6-minute walked distance was observed in only darbepoetin-treated patients. Plasma BNP (F = 14.8, p = 001), malondialdehyde (F = 9.4, p = 0.006), protein carbonyl (F = 9.2, p = 0.006), and nitrotyrosine (F = 4.4, p = 0.045) were significantly decreased, along with an increase in antioxidative glutathione (F = 4.2, p = 0.049) after darbepoetin alfa treatment. These factors were unaffected in placebo-treated patients. Darbepoetin-induced percentages of change in carbonyl protein significantly correlated with respective changes in plasma BNP (r = 0.55, p <0.05) and LVEF (r = -0.46, p <0.05). Finally, a drug-induced percentage of decrease in nitrotyrosine significantly correlated with the respective improvement in 6-minute walked distance (r = -0.63, p <0.05). In conclusion, darbepoetin alfa attenuated deleterious effects of oxidative and nitrosative stress into the cardiovascular system of anemic patients with CHF, improving also cardiac function and exercise capacity.

Topics: Aged; Anemia; Cardiomyopathies; Chronic Disease; Darbepoetin alfa; Erythropoietin; Exercise Tolerance; Female; Heart Failure; Hematinics; Humans; Male; Middle Aged; Nitrosation; Oxidative Stress

Anemia in heart failure is related to advanced New York Heart Association classes, severe systolic dysfunction, and reduced exercise tolerance. Although anemia is frequently found in congestive heart failure (CHF), little is known about the effect of its' correction with erythropoietin (EPO) on cardiac structure and function. The present study examines, in patients with advanced CHF and anemia, the effects of beta-EPO on left ventricular volumes, left ventricular ejection fraction (LVEF), left and right longitudinal function mitral anular plane systolic excursion (MAPSE), tricuspid anular plane excursion (TAPSE), and pulmonary artery pressures in 58 patients during 1-year follow-up in a double-blind controlled study of correction of anemia with subcutaneous beta-EPO. Echocardiographic evaluation, B-Type natriuretic peptide (BNP) levels, and hematological parameters are reported at 4 and 12 months. The patients in group A after 4 months of follow-up period demonstrated an increase in LVEF and MAPSE (P < 0.05 and P < 0.01, respectively) with left ventricular systolic volume reduction (P < 0.02) with respect to baseline and controls. After 12 months, results regarding left ventricular systolic volume LVEF and MAPSE persisted (P < 0.001). In addition, TAPSE increased and pulmonary artery pressures fell significantly in group A (P < 0.01). All these changes occurred together with a significant BNP reduction and significant hemoglobin increase in the treated group. Therefore, we revealed a reduced hospitalization rate in treated patients with respect to the controls (25% in treated vs. 54% in controls). In patients with anemia and CHF, correction of anemia with beta-EPO and oral iron over 1 year leads to an improvement in left and right ventricular systolic function by reducing cardiac remodeling, BNP levels, and hospitalization rate.

Topics: Anemia; Blood Pressure; Double-Blind Method; Drug Therapy, Combination; Erythropoietin; Ferrous Compounds; Heart Failure; Hematinics; Hospitalization; Humans; Injections, Subcutaneous; Natriuretic Peptide, Brain; Pulmonary Artery; Recombinant Proteins; Ventricular Dysfunction, Left; Ventricular Dysfunction, Right; Ventricular Remodeling

Patients with heart failure (HF) and anaemia have greater functional impairment, worse symptoms, increased rates of hospital admission, and a higher risk of death, compared with non-anaemic HF patients. Whether correcting anaemia can improve outcomes is unknown.. The Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF; Clinical Trials.gov NCT 003 58215) was designed to evaluate the effect of the long-acting erythropoietin-stimulating agent darbepoetin alfa on mortality and morbidity (and quality of life) in patients with HF and anaemia.. Approximately 2600 patients with New York Heart Association class II-IV, an ejection fraction < or =40%, and a haemoglobin (Hb) consistently < or =12.0 g/dL but > or =9.0 g/dL will be enrolled. Patients are randomized 1:1 to double-blind subcutaneous administration of darbepoetin alfa or placebo. Investigators are also blinded to Hb measurements and darbepoetin alfa is dosed to achieve an Hb concentration of 13.0 g/dL (but not exceeding 14.5 g/dL) with sham adjustments of the dose of placebo. The primary endpoint is the time to death from any cause or first hospital admission for worsening HF, whichever occurs first. The study will complete when approximately 1150 subjects experience a primary endpoint.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Double-Blind Method; Erythropoietin; Female; Heart Failure; Hematinics; Humans; Male; Middle Aged; Research Design; Stroke Volume; Surveys and Questionnaires; Ventricular Function, Left

Anemia is a frequent comorbidity in chronic heart failure (CHF) adversely affecting patients' prognosis. Erythropoietin seems to improve exercise capacity in CHF patients. This study investigates the effects of recombinant human erythropoietin analog darbepoetin-alpha on quality of life and emotional stress, evaluated by relevant questionnaires in patients with CHF and anemia.. Forty-one CHF patients [New York Heart Association class: II-III; left ventricular (LV) ejection fraction (EF)<40%; hemoglobin<12.5 g/dl; serum creatinine<2.5 mg/dl] were randomized (1:1) to receive either 3-month darbepoietin-alpha at 1.5 microg/Kg every 20 days plus iron orally (n=21) or placebo plus iron orally (n=20). Echocardiographic LVEF, questionnaires addressing quality of life (Kansas City Cardiomyopathy Questionnaire, functional and overall, Duke's Activity Status Index) and emotional stress [Zung self-rating depression scale (SDS), Beck Depression Inventory], as well as plasma b-type natriuretic peptide and 6-min walking distance (6MWT as a marker of exercise capacity) were assessed at baseline and posttreatment.. A significant improvement in LVEF (32+/-6 from 26+/-6%, P<0.001), 6MWT (274+/-97 from 201+/-113 m, P<0.01), hemoglobin (12.8+/-1.4 from 10.9+/-1.0 g/dl, P<0.001) and plasma b-type natriuretic peptide (517+/-579 from 829+/-858 pg/ml, P=0.002) was observed posttreatment only in darbepoetin-treated group. Kansas City Cardiomyopathy Questionnaire functional (78+/-14 from 57+/-24%, P<0.01) and overall (68+/-20 from 47+/-22, P<0.001), Duke's Activity Status Index (19+/-11 from 14+/-9, P<0.05), Zung SDS (38+/-10 from 47+/-11, P<0.05) and Beck Depression Inventory (11+/-9 from 16+/-10, P<0.05) scores also improved in darbepoetin-treated patients, whereas they remain unchanged in the placebo group except for the Zung SDS which worsened (P<0.05). A significant correlation between drug-induced percent changes in 6MWT and Zung SDS (r=-0.627, P<0.05) was also observed.. Darbepoetin-alpha improves quality of life and emotional stress in CHF patients with anemia, with a parallel increase in exercise capacity.

Topics: Aged; Anemia; Cohort Studies; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Exercise Tolerance; Female; Heart Failure; Hematinics; Humans; Male; Middle Aged; Quality of Life; Single-Blind Method; Stress, Psychological; Surveys and Questionnaires

Pro-inflammatory cytokine over-expression may be implicated to the pathogenesis of anemia in chronic heart failure (CHF) through the suppression of bone marrow erythropoiesis. Erythropoietin administration has anti-inflammatory and anti-apoptotic properties in experimental CHF models and improves exercise capacity in anemic CHF patients. The present study investigates the effects of recombinant human erythropoietin analogue darbepoetin-alpha on circulating pro-inflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with CHF and anemia. Forty-one CHF patients (NYHA class: II-III; left ventricular (LV) ejection fraction (EF) <40%; hemoglobin <12.5g/dl; serum creatinine <2.5mg/dl) were randomized to receive either 3-month darbepoietin-* at 1.5 microg/kg every 20 days plus iron orally (n=21) or placebo plus iron orally (n=20). LV systolic function, plasma B-type natriuretic peptide (BNP), inflammatory markers (TNF-*, IL-6, CRP), anti-inflammatory cytokine IL-10, endothelial adhesion molecules (soluble ICAM-1 and VCAM-1) and soluble apoptosis mediators (soluble Fas, soluble Fas ligand), and 6-min walking distance were assessed at baseline and 3 months post-treatment. In darbepoetin-* treated patients, plasma BNP (451 (62-2770) from 802 (476-4440) pg/ml, p=0.002), IL-6 (6.5+/-4.7 from 10.5+/-7.8 pg/ml, p=0.013) and soluble Fas ligand (53.2+/-16.6 from 59.2+/-17.9 pg/ml, p=0.023) decreased significantly, while LVEF (32+/-6 from 26+/-6%, p<0.001), hemoglobin (12.8+/-1.4 from 10.9+/-1.0 g/dl, p<0.001) and 6-min walked distance (274+/-97 from 201+/-113m, p<0.01) increased significantly. No significant changes were observed in the placebo arm, except for a worsening in 6-min walked distance (p=0.044). In conclusion, darbepoetin-alpha reduces circulating pro-inflammatory cytokine IL-6 and apoptotic mediator soluble Fas ligand in CHF patients with anemia, with a parallel improvement of cardiac performance and exercise capacity.

Topics: Aged; Anemia; Biomarkers; C-Reactive Protein; Chronic Disease; Cytokines; Darbepoetin alfa; Erythropoietin; Fas Ligand Protein; fas Receptor; Female; Heart Failure; Hematinics; Humans; Intercellular Adhesion Molecule-1; Interleukin-10; Interleukin-6; Male; Middle Aged; Solubility; Treatment Outcome; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Substantial evidence suggests that anemia is an independent risk factor for worse outcomes in patients with heart failure (HF). The Study of Anemia in Heart Failure Trial (STAMINA-HeFT) is the largest multicenter, randomized, double-blind, placebo-controlled trial to date evaluating the effect of treating anemia in HF.. Patients (N=319) with symptomatic HF, left ventricular ejection fraction < or = 40%, and hemoglobin > or = 9.0 g/dL and < or = 12.5 g/dL were randomized (double-blind) to placebo (N=157) or darbepoetin alfa (N=162) subcutaneously every 2 weeks for 1 year (target hemoglobin, 14.0+/-1.0 g/dL). The primary end point was change from baseline to week 27 in treadmill exercise time. Secondary end points were change from baseline in New York Heart Association class and quality of life at week 27. An additional prespecified efficacy analysis included the time to death by any cause or first HF-related hospitalization by 1 year. At baseline, the median (interquartile range) hemoglobin was 11.4 (10.9, 12.0) g/dL. At week 27, darbepoetin alfa treatment increased median (interquartile range) hemoglobin by 1.8 (1.1, 2.5) g/dL (placebo, 0.3 [-0.2, 1.0] g/dL; P<0.001). Of the patients treated with darbepoetin alfa, 85% achieved 2 consecutive hemoglobin levels of 14.0+/-1.0 g/dL during the study and experienced a hemoglobin increase of > or = 1.0 g/dL from baseline. By intent-to-treat analysis, darbepoetin alfa treatment did not significantly improve exercise duration, New York Heart Association class, or quality of life score compared with placebo. A nonsignificant trend was observed toward a lower risk of all-cause mortality or first HF hospitalization in darbepoetin alfa-treated patients compared with placebo (hazard ratio, 0.68; 95% CI, 0.43, 1.08; P=0.10). Occurrences of adverse events were similar in both treatment groups.. In this study of patients with symptomatic HF and anemia, treatment with darbepoetin alfa was not associated with significant clinical benefits. Darbepoetin alfa treatment was well tolerated and effectively raised hemoglobin. A trend of lower risk of morbidity and mortality was observed.

Topics: Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Double-Blind Method; Erythropoietin; Exercise Tolerance; Female; Heart Failure; Hemoglobins; Humans; Male; Middle Aged; Quality of Life; Stroke Volume; Survival Rate

Anemia is a frequent condition in chronic heart failure (CHF) that affects adversely long-term cardiac outcomes. We sought to investigate the effects of recombinant human erythropoietin analogue darbepoetin alpha on left (LV) and right ventricular (RV) function and neurohormonal activation in patients with CHF and anemia.. Thirty-two CHF patients (New York Heart Association class II-III, LV ejection fraction [EF] <40%, hemoglobin level <12.5 g/dL, serum creatinine level <2.5 mg/dL) were randomized (2:1) to receive either a 3-month darbepoetin alpha regimen at 1.5 microg/kg every 20 days plus oral iron (n = 21) or placebo plus oral iron (n = 11). Echocardiographic indices of LV systolic and diastolic function and RV function, plasma B-type natriuretic peptide (BNP) and 6-minute walked distance were assessed at baseline and posttreatment.. Regarding LV function, only treatment with darbepoetin alpha caused a significant improvement in LVEF (F = 22.001, P < .001), end-systolic wall stress (F = 4.934, P = .034), mitral annulus systolic displacement (F = 6.710, P < .015), isovolumic relaxation time (F = 4.909, P = .035), and E/e ratio (F = 7.833, P = .009). The RV systolic pressure (F = 7.715, P = .009) as well as tricuspid annulus systolic displacement and RVEF (F = 9.264, P = .005) were significantly improved only in the darbepoetin alpha group. Darbepoetin alpha had also alpha beneficial effect on New York Heart Association class (F = 14.586, P = .001), plasma BNP (F = 14.781, P = .001), and 6-minute walk test (F = 19.926, P < .001), whereas these parameters did not significantly change in the placebo-treated patients.. Darbepoetin alpha improves both LV and RV performance and exercise capacity and counteracts neurohormonal activation in CHF patients with anemia. The drug effects on LV diastolic function, RV function, and LV end-systolic wall stress, in particular, are novel findings, with a potential important contribution to patients' symptomatic improvement.

Topics: Aged; Anemia; Cardiomyopathy, Dilated; Darbepoetin alfa; Drug Therapy, Combination; Echocardiography; Erythropoietin; Exercise Tolerance; Heart Failure; Hematinics; Hemodynamics; Humans; Injections, Subcutaneous; Single-Blind Method; Ventricular Function, Left; Ventricular Function, Right

This study sought to investigate whether darbepoetin alfa, an erythropoiesis-stimulating protein (ESP), improves exercise capacity in patients with symptomatic chronic heart failure (CHF) and anemia.. Anemia is common in patients with CHF.. In a multicenter, randomized, double-blind, placebo-controlled study, CHF patients with anemia (hemoglobin > or =9.0 to < or =12.0 g/dl) received subcutaneous placebo (n = 22) or darbepoetin alfa (n = 19) at a starting dose of 0.75 microg/kg every 2 weeks for 26 weeks. The primary end point was change in exercise tolerance from baseline to week 27 as measured by peak oxygen uptake (ml/min/kg body weight). Other end points included changes in absolute peak VO2 (ml/min), exercise duration, and health-related quality of life.. Differences (95% confidence interval) in mean changes from baseline to week 27 between treatment groups were 1.5 g/dl (0.5 to 2.4) for hemoglobin concentration (p = 0.005), 0.5 ml/kg/min (-0.7 to 1.7) for peak VO2 (p = 0.40), 45 ml/min (-35 to 127) for absolute peak VO2 (p = 0.27), and 108 s (-11 to 228) for exercise duration (p = 0.075). Patients receiving darbepoetin alfa compared with placebo had an improvement in self-reported Patient's Global Assessment of Change (79% vs. 41%, p = 0.01) but no significant differences in the Kansas City Cardiomyopathy and Minnesota Living with Heart Failure Questionnaire scores. Darbepoetin alfa was well tolerated.. In patients with symptomatic CHF and anemia, darbepoetin alfa increased and maintained hemoglobin concentrations and improved health-related quality of life. A trend toward increased exercise time but not peak VO2 was observed. (Impact of Darbepoetin Alfa on Exercise Tolerance and Left Ventricular Structure in Subjects With Symptomatic Congestive Heart Failure (CHF) and Anemia; http://clinicaltrials.gov/ct/show/NCT00117234?order = 1; NCT00117234).

Topics: Activities of Daily Living; Aged; Anemia; Body Weight; Darbepoetin alfa; Double-Blind Method; Erythropoietin; Exercise Test; Exercise Tolerance; Female; Heart Failure; Hematinics; Hemoglobins; Hospitalization; Humans; Injections, Subcutaneous; Male; Natriuretic Peptide, Brain; Oxygen Consumption; Quality of Life; Treatment Outcome

Anaemia is common in chronic heart failure (CHF) and associated with worse outcome. This randomized, double-blind, placebo-controlled study evaluated the effect of two darbepoetin alfa dosing regimens on haemoglobin (Hb) rate of rise and clinical effects in patients with CHF and anaemia.. Patients with CHF (>or=3 months), left ventricular ejection fraction (LVEF)

Topics: Administration, Cutaneous; Aged; Anemia; Chronic Disease; Darbepoetin alfa; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoietin; Exercise Test; Exercise Tolerance; Female; Heart Failure; Hematinics; Hemoglobins; Humans; Male; Patient Satisfaction; Stroke Volume; Surveys and Questionnaires; Treatment Outcome

Although anemia is frequently found in congestive heart failure (CHF), little is known about the effect of its correction with erythropoietin (EPO) on cardiac structure and function.. The present study examines in patients with advanced CHF, chronic renal insufficiency, and anemia the effects of beta-EPO on left ventricular (LV) systolic diameter and volume (LVSD and LVSV), LV diastolic diameter and volume (LVDD and LVDV), LV mass, LV ejection fraction (LVEF), pulmonary artery pressure (PAP), and B-type natriuretic peptide (BNP) levels.. Fifty-one consecutive subjects affected with advanced CHF and anemia were studied. We performed a randomized double-blind controlled study of correction of anemia with subcutaneous EPO for 4 months (group A, 26 patients) using saline as the placebo in the control group (group B, 25 patients). We then maintained the EPO treatment in the treated group for another 8 months. Both groups received oral iron throughout the total 12-month period. Echocardiographic evaluation, BNP levels, and hematological parameters are reported at 4 and 12 months.. The patients in group A during the double-blind phase (4 months) demonstrated an increase in LVEF and mild reduction in LVSD and LVSV with respect to baseline and to group B with no differences in PAP, LVDD, and LVDV. Over the 12-month period, the hemoglobin increased from 10.40.6 to 12.4 +/- 0.8 g/dL (P < .01) in group A but did not change in group B. Compared with group B, group A had lower LVDD, LVSD, LVDV, LVSV, LV mass, PAP, and BNP and higher LVEF. The serum creatinine and creatinine clearance remained unchanged in the 2 groups.. In anemic patients with CHF, correction of anemia with EPO and oral iron over 1 year lead to an improvement in LV systolic function, LV remodeling, BNP levels, and PAP compared with a control group in which only oral iron was used.

Topics: Aged; Anemia; Creatinine; Double-Blind Method; Erythropoietin; Female; Heart Failure; Humans; Kidney Failure, Chronic; Male; Myocardial Contraction; Natriuretic Peptide, Brain; Recombinant Proteins; Stroke Volume; Syndrome; Ventricular Remodeling

Anemia, a common complication of chronic kidney disease, usually develops as a consequence of erythropoietin deficiency. Recombinant human erythropoietin (epoetin alfa) is indicated for the correction of anemia associated with this condition. However, the optimal level of hemoglobin correction is not defined.. In this open-label trial, we studied 1432 patients with chronic kidney disease, 715 of whom were randomly assigned to receive a dose of epoetin alfa targeted to achieve a hemoglobin level of 13.5 g per deciliter and 717 of whom were assigned to receive a dose targeted to achieve a level of 11.3 g per deciliter. The median study duration was 16 months. The primary end point was a composite of death, myocardial infarction, hospitalization for congestive heart failure (without renal replacement therapy), and stroke.. A total of 222 composite events occurred: 125 events in the high-hemoglobin group, as compared with 97 events in the low-hemoglobin group (hazard ratio, 1.34; 95% confidence interval, 1.03 to 1.74; P=0.03). There were 65 deaths (29.3%), 101 hospitalizations for congestive heart failure (45.5%), 25 myocardial infarctions (11.3%), and 23 strokes (10.4%). Seven patients (3.2%) were hospitalized for congestive heart failure and myocardial infarction combined, and one patient (0.5%) died after having a stroke. Improvements in the quality of life were similar in the two groups. More patients in the high-hemoglobin group had at least one serious adverse event.. The use of a target hemoglobin level of 13.5 g per deciliter (as compared with 11.3 g per deciliter) was associated with increased risk and no incremental improvement in the quality of life. (ClinicalTrials.gov number, NCT00211120 [ClinicalTrials.gov].).

Topics: Aged; Anemia; Epoetin Alfa; Erythropoietin; Female; Glomerular Filtration Rate; Heart Failure; Hematinics; Hemoglobins; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Recombinant Proteins; Renal Insufficiency, Chronic; Stroke; Survival Analysis

Anemia is now recognized as being a common finding in CHF and is associated with increased mortality and morbidity. However, it is uncertain whether the anemia is actually causing the worse prognosis or is merely a marker of more severe cardiac disease. Previous intervention studies with subcutaneous (s.c.) beta-EPO in combination with iron have either been uncontrolled or case-controlled studies. We report a randomized, double-blind, placebo-controlled study of the combination of s.c. EPO and oral iron versus oral iron alone in patients with anemia and resistant CHF.. The present study examines, in patients with advanced congestive heart failure (CHF) and anemia, the effects of beta-erythropoietin (EPO) and oral iron on the anemia and on cardiac and renal functional parameters.. Forty consecutive subjects with moderate to severe CHF and anemia (hemoglobin [Hb] <11 g/dL) were studied. They were randomized to receive, in a double-blind fashion, either (a) (group A, the treatment group, 20 patients) s.c. beta-EPO for 3 months twice weekly, in addition to daily oral iron, or (b) (group B, the placebo group, 20 patients) normal saline in s.c. injections and daily oral iron. Two patients in group B were eventually excluded because of a fall of Hb <8 g/dL requiring transfusion, leaving 18 patients in group B. After the 3-months study, the group A patients were maintained on the same treatment for an additional 9 months, whereas in Group B, the placebo and oral iron were stopped.. In group A, after a mean of 3.5 +/- 0.8 months of treatment, there was a significant increase in Hb from 10.4 +/- 0.6 to 12.4 +/- 0.8 g/dL (P < .01); a significant improvement in New York Heart Association functional class from 3.5 +/- 0.6 to 2.8 +/- 0.5 (P < .05); a longer endurance time on exercise testing, from 5.8 +/- 2.2 to 7.8 +/- 2.5 minutes (P < .01); a greater distance walked on exercise testing, from 278 +/- 55 to 356 +/- 88 meters (P < .01); a significant increase in the peak oxygen consumption (VO2) from 12.8 +/- 2.8 to 15.1 +/- 2.8 mL/kg per minute (<.05); and the VO2 at the anaerobic threshold, from 9.2 +/- 2.0 to 13.2 +/- 3.6 mL/kg minute (P < .01). There was also a significant fall in plasma B-type natriuretic peptide levels from 568 +/- 320 to 271 +/- 120 pg/mL (P < .01), a significant reduction in serum creatinine (P < .01), and an increase in estimated creatinine clearance (P < .05). In group B, there were no significant changes in any of the above parameters over the study period. At the end of the 1-year study, the Hb was still higher in group A than group B, and the rate of hospital admissions/patients over the year averaged 0.8 +/- 0.2 in group A and 1.7 +/- 0.8 in group B (P < .01).. In anemic CHF patients, correction of anemia with EPO and oral iron leads to improvement in New York Heart Association status, measured exercise endurance, oxygen use during exercise, renal function and plasma B-type natriuretic peptide levels and reduces the need for hospitalization.

Topics: Aged; Aged, 80 and over; Anaerobic Threshold; Anemia; Creatinine; Double-Blind Method; Erythropoietin; Exercise Test; Female; Follow-Up Studies; Heart Failure; Hemoglobins; Hospitalization; Humans; Kidney; Male; Natriuretic Peptide, Brain; Oxygen Consumption; Physical Endurance; Severity of Illness Index

This randomized clinical trial is designed to assess whether the prevention and/or correction of anemia, by immediate versus delayed treatment with erythropoietin alfa in patients with chronic kidney disease, would delay left ventricular (LV) growth. Study design and sample size calculations were based on previously published Canadian data.. One hundred seventy-two patients were randomly assigned. The treatment group received therapy with erythropoietin alfa subcutaneously to maintain or achieve hemoglobin (Hgb) level targets of 12.0 to 14.0 g/dL (120 to 140 g/L). The control/delayed treatment group had Hgb levels of 9.0 +/- 0.5 g/dL (90 +/- 5 g/L) before therapy was started: target level was 9.0 to 10.5 g/dL (90 to 105 g/L). Optimal blood pressure and parathyroid hormone, calcium, and phosphate level targets were prescribed; all patients were iron replete. The primary end point is LV growth at 24 months.. One hundred fifty-two patients were eligible for the intention-to-treat analysis: mean age was 57 years, 30% were women, 38% had diabetes, and median glomerular filtration rate was 29 mL/min (0.48 mL/s; range, 12 to 55 mL/min [0.20 to 0.92 mL/s]). Blood pressure and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were similar in the control/delayed treatment and treatment groups at baseline. Erythropoietin therapy was administered to 77 of 78 patients in the treatment group, with a median final dose of 2,000 IU/wk. Sixteen patients in the control/delayed treatment group were administered erythropoietin at a median final dose of 3,000 IU/wk. There was no statistically significant difference between groups for the primary outcome of mean change in LV mass index (LVMI) from baseline to 24 months, which was 5.21 +/- 30.3 g/m2 in the control/delayed treatment group versus 0.37 +/- 25.0 g/m2 in the treatment group. Absolute mean difference between groups was 4.85 g/m2 (95% confidence interval, -4.0 to 13.7; P = 0.28). Mean Hgb level was greater in the treatment group throughout the study and at study end was 12.75 g/dL (127.5 g/L in treatment group versus 11.46 g/dL [114.6 g/L] in control/delayed treatment group; P = 0.0001). LV growth occurred in 20.1% in the treatment group versus 31% in the control/delayed treatment group (P = 0.136). In patients with a stable Hgb level, mean LVMI did not change (-0.25 +/- 26.7 g/m2), but it increased in those with decreasing Hgb levels (19.3 +/- 28.2 g/m2; P = 0.002).. This trial describes disparity between observational and randomized controlled trial data: observed and randomly assigned Hgb level and LVMI are not linked; thus, there is strong evidence that the association between Hgb level and LVMI likely is not causal. Large randomized controlled trials with unselected patients, using morbidity and mortality as outcomes, are needed.

Topics: Adult; Aged; Anemia; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium; Canada; Chronic Disease; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Heart Ventricles; Hemoglobins; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Diseases; Lipids; Male; Middle Aged; Organ Size; Parathyroid Hormone; Phosphates; Recombinant Proteins; Renal Dialysis; Single-Blind Method; Treatment Failure; Ultrasonography

A mild anaemia is often found in patients with congestive heart failure (CHF), but its significance is uncertain. In an open uncontrolled study we investigated the effect of correcting this anaemia [haemoglobin (Hb) 9.5-11.5 g%] with subcutaneous (s.c.) erythropoietin (Epo) and intravenous (i.v.) iron (Fe) in 179 patients, 84 type II diabetics and 95 non-diabetics, with moderate to severe CHF which was resistant to maximally tolerated doses of standard CHF medications.. Epo, s.c., was given every 1-3 weeks to achieve and maintain the Hb at 12.5 g%. Fe (Fe sucrose-Venofer) was added i.v. as necessary to maintain the Fe stores. Duration of treatment was 11.8 + 8.2 months.. With the Epo-Fe treatment the Hb increased from 10.41 +/- 1.0 to 13.1 +/- 1.3 g% in diabetics and from 10.5 +/- 1.0 to 12.9 +/- 1.2 g% in non-diabetics. Comparing the diabetics and non-diabetics, the New York Heart Association functional class improved by 34.8 and 32.4%, respectively. breathlessness and/or fatigue, as measured by a self-administered Visual Analogue Scale, improved by 69.7 and 67.4%, and the left ventricular ejection fraction improved by 7.4 and 11.5%, respectively. The number of hospitalizations fell by 96.4 and 95.3%, respectively, compared with the pre-treatment period. Although the glomerular filtration rate (GFR) was falling at a rate of approximately 1 ml/min/month before the study in both groups, neither the mean serum creatinine nor the GFR changed significantly during the study period. The mean dose of Epo needed, measured in IU/week/kg body weight, was similar in the two groups.. The correction of the mild anaemia that was found in diabetics and non-diabetics with resistant CHF and mild to moderate chronic renal failure improved the cardiac function and patient functional status, stabilized the renal function and markedly reduced the need for hospitalization.

Topics: Aged; Anemia; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Iron; Kidney Failure, Chronic; Male; Recombinant Proteins; Treatment Outcome

Patients with chronic heart failure (CHF) are frequently anemic. An increase in hemoglobin could enhance exercise performance by increasing oxygen delivery. We investigated the effect of erythropoietin (EPO) on exercise performance in anemic patients with CHF.. Twenty-six anemic patients aged 57+/-11 years were randomized to receive EPO (15 000 to 30 000 IU per week) or placebo for 3 months. Parameters measured at baseline and end therapy included blood parameters (hemoglobin, hematocrit, plasma volume), exercise parameters (peak oxygen consumption [VO2], exercise duration, 6-minute walk), muscle aerobic metabolism (half-time of VO2 and near infrared recovery), and forearm vasodilatory function. EPO was well tolerated by all patients. Twelve patients in the EPO group felt improvement versus 1 in the placebo group (P<0.05). There were significant increases in hemoglobin (11.0+/-0.5 to 14.3+/-1.0 g/dL, P<0.05), peak VO2 (11.0+/-1.8 to 12.7+/-2.8 mL. min(-1) x kg(-1), P<0.05) and exercise duration (590+/-107 to 657+/-119 s, P<0.004) in the EPO group but no significant changes in the control group. Resting and hyperemic forearm vascular resistance and indices of the rate of muscle oxidative capacity were unchanged in both groups.. EPO significantly enhances exercise capacity in patients with CHF. One mechanism of improvement in VO2 is increased oxygen delivery from increased hemoglobin concentration.

Topics: Anemia; Chronic Disease; Erythrocyte Volume; Erythropoietin; Exercise Test; Exercise Tolerance; Female; Forearm; Heart Failure; Hemodynamics; Hemoglobins; Humans; Male; Middle Aged; Muscle, Skeletal; Oxygen Consumption; Plasma Volume; Prospective Studies; Quality of Life; Single-Blind Method; Treatment Outcome; Vasodilation

Congestive heart failure is extremely common in octogenarians and is associated with severe fatigue, shortness of breath, recurrent hospitalizations, and death. These patients, many of whom are anemic, are often resistant to standard CHF therapy including angiotensin-converting enzyme inhibitors, beta-blockers and diuretics.. To examine whether correction of the anemia (hemoglobin < 12 g/dl) in CHF patients can improve their clinical condition.. Forty octogenarians with anemia and severe resistant CHF were administered a combination of subcutaneous erythropoietin and intravenous iron sucrose.. This combination therapy led to a marked improvement in cardiac function, shortness of breath and fatigue, a marked reduction in the rate of hospitalization and a stabilizing of renal function.. Anemia appears to be an important but ignored contributor to the progression of CHF, and its correction may improve cardiac and renal status as well as the quality of life in elderly patients.

Topics: Age Factors; Aged; Aged, 80 and over; Anemia; Drug Therapy, Combination; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glomerular Filtration Rate; Glucaric Acid; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Renal Insufficiency; Severity of Illness Index; Time Factors

This is a randomized controlled study of anemic patients with severe congestive heart failure (CHF) to assess the effect of correction of the anemia on cardiac and renal function and hospitalization.. Although mild anemia occurs frequently in patients with CHF, there is very little information about the effect of correcting it with erythropoietin (EPO) and intravenous iron.. Thirty-two patients with moderate to severe CHF (New York Heart Association [NYHA] class III to IV) who had a left ventricular ejection fraction (LVEF) of < or =40% despite maximally tolerated doses of CHF medications and whose hemoglobin (Hb) levels were persistently between 10.0 and 11.5 g% were randomized into two groups. Group A (16 patients) received subcutaneous EPO and IV iron to increase the level of Hb to at least 12.5 g%. In Group B (16 patients) the anemia was not treated. The doses of all the CHF medications were maintained at the maximally tolerated levels except for oral and intravenous (IV) furosemide, whose doses were increased or decreased according to the clinical need.. Over a mean of 8.2+/-2.6 months, four patients in Group B and none in Group A died of CHF-related illnesses. The mean NYHA class improved by 42.1% in A and worsened by 11.4% in B. The LVEF increased by 5.5% in A and decreased by 5.4% in B. The serum creatinine did not change in A and increased by 28.6% in B. The need for oral and IV furosemide decreased by 51.3% and 91.3% respectively in A and increased by 28.5% and 28.0% respectively in B. The number of days spent in hospital compared with the same period of time before entering the study decreased by 79.0% in A and increased by 57.6% in B.. When anemia in CHF is treated with EPO and IV iron, a marked improvement in cardiac and patient function is seen, associated with less hospitalization and renal impairment and less need for diuretics.

Topics: Aged; Anemia; Erythropoietin; Female; Heart Failure; Humans; Injections, Intravenous; Injections, Subcutaneous; Iron; Male; Prospective Studies; Severity of Illness Index

Transient ST-segment depression measured on ambulatory ECG monitors has been described as representing silent ischemia. Patients who demonstrate silent ischemia have been reported to show increased mortality compared to patients without silent ischemia. We undertook this study to determine if the correction of anemia in End Stage Renal Disease (ESRD) patients from (+/- = standard deviation) 30 +/- 3 to 42 +/- 3 with the use of Epoietin alfa would result in decreased silent ischemia in patients with clinically evident ischemic heart disease or congestive heart failure.. Thirty one ESRD patients with congestive heart failure or patients with clinically-evident ischemic heart disease were randomized into one of two arms. Patients in Group A had their hematocrit increased with the use of slowly escalating doses of Epoietin alfa to 42 +/- 3% and patients in Group B were maintained with a hematocrit of 30 +/- 3% throughout the course of the study. All patients had a 24 hour Holter monitor recording at baseline and at 28 weeks after randomization (when they had reached their target hematocrit). Significant silent ischemia was considered to be present if patients demonstrated at least 60 seconds of > or = 1 mm ST segment depression.. Fifteen patients were randomized to Group A and 16 patients were randomized to Group B. The mean hematocrit increased in group A from 29.1 +/- 2.4% to 40.8 +/- 5.2% after 30 weeks. The mean hematocrit in Group B remained stable at 30 +/- 3% throughout the course of the study. Ten patients demonstrated silent ischemia at baseline. At follow up patients in group A demonstrated a mean of 1.7 +/- 4.9 minutes of ischemia compared to 1.1 +/- 3.4 minutes in group B. These were not significantly different. A similar number of patients in group A and Group B required adjustments in their anti-anginal medication during the course of the study.. It is possible to increase hematocrit to near normal levels in hemodialysis with the administration of exogenous Epoietin alfa. The increase in hematocrit form 30 +/- 3% to 42 +/- 3% is not associated with a change in the level of silent ischemia these patients demonstrate.

Topics: Anemia; Electrocardiography; Electrocardiography, Ambulatory; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Hematinics; Hematocrit; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Ischemia; Prognosis; Recombinant Proteins; Renal Dialysis

In patients with end-stage renal disease, anemia develops as a result of erythropoietin deficiency, and recombinant human erythropoietin (epoetin) is prescribed to correct the anemia partially. We examined the risks and benefits of normalizing the hematocrit in patients with cardiac disease who were undergoing hemodialysis.. We studied 1233 patients with clinical evidence of congestive heart failure or ischemic heart disease who were undergoing hemodialysis: 618 patients were assigned to receive increasing doses of epoetin to achieve and maintain a hematocrit of 42 percent, and 615 were assigned to receive doses of epoetin sufficient to maintain a hematocrit of 30 percent throughout the study. The median duration of treatment was 14 months. The primary end point was the length of time to death or a first nonfatal myocardial infarction.. After 29 months, there were 183 deaths and 19 first nonfatal myocardial infarctions among the patients in the normal-hematocrit group and 150 deaths and 14 nonfatal myocardial infarctions among those in the low-hematocrit group (risk ratio for the normal-hematocrit group as compared with the low-hematocrit group, 1.3; 95 percent confidence interval, 0.9 to 1.9). Although the difference in event-free survival between the two groups did not reach the prespecified statistical stopping boundary, the study was halted. The causes of death in the two groups were similar. The mortality rates decreased with increasing hematocrit values in both groups. The patients in the normal-hematocrit group had a decline in the adequacy of dialysis and received intravenous iron dextran more often than those in the low-hematocrit group.. In patients with clinically evident congestive heart failure or ischemic heart disease who are receiving hemodialysis, administration of epoetin to raise their hematocrit to 42 percent is not recommended.

Topics: Aged; Anemia; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Hematocrit; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Prospective Studies; Recombinant Proteins; Renal Dialysis

As a component of the open-label, multicenter National Cooperative Recombinant Human Erythropoietin (Epo) Study, the health-related quality-of-life effects of Epo therapy were assessed in 484 dialysis patients who had not previously been treated with Epo therapy (New-to-Epo) and 520 dialysis patients who were already receiving Epo therapy at the time of study enrollment (Old-to-Epo). Using scales from the Medical Outcomes Study 36-item Short Form Health Survey (SF-36), health-related quality of life was assessed on study enrollment (baseline) and at an average of 99 days follow-up. At baseline, SF-36 scores for Old- and New-to-Epo patients were well below those observed in the general population, reflecting substantial impairments in functional status and well-being among patients with chronic renal failure. Significant improvements from baseline to follow-up were observed among New-to-Epo patients in vitality, physical functioning, social functioning, mental health, looking after the home, social life, hobbies, and satisfaction with sexual activity (P < 0.05 for each). The mean improvements in hematocrit values among New-to-Epo and Old-to Epo patients were 4.6 and 0.3, respectively. At the time of follow-up, SF-36 scores for New-to-Epo patients were comparable with those observed among Old-to-Epo patients, whose scores did not change significantly from baseline to follow-up. Analysis of the relationship between Epo therapy, hematocrit values, and health-related quality of life suggest that some of the beneficial quality-of-life effects of Epo are mediated through a change in hematocrit level.

Topics: Activities of Daily Living; Adult; Aged; Anemia; Comorbidity; Depressive Disorder; Erythropoietin; Female; Heart Failure; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Patient Acceptance of Health Care; Peritoneal Dialysis; Quality of Life; Racial Groups; Recombinant Proteins; Renal Dialysis; Self-Assessment

In 2011, the Centers for Medicare & Medicaid Services implemented bundling of all services for patients receiving dialysis, including erythropoietin-stimulating agents use, and the Food and Drug Administration recommended conservative erythropoietin-stimulating agent dosing.. This retrospective cohort study investigated anemia care and clinical outcomes before and after the Centers for Medicare & Medicaid Services bundled payment and the revised Food and Drug Administration-recommended erythropoietin-stimulating agent labeling for Medicare-insured adults receiving hemodialysis using data from the United States Renal Data System from January 1, 2006 to December 31, 2016. Clinical outcomes included major adverse cardiovascular event (stroke, acute myocardial infarction, and all-cause mortality), cardiovascular mortality, and heart failure. Measurements were compared between prepolicy (2006-2010) and postpolicy (2012-2016) implementation using interrupted time series and Cox proportional hazards regression models.. The Medicare reimbursement policy and Food and Drug Administration-recommended erythropoietin-stimulating agent dosing changes were associated with lower erythropoietin-stimulating agent use and lower hemoglobin levels. These changes in anemia care were associated with lower risks of major adverse cardiovascular event, stroke, mortality, and heart failure but higher risk of acute myocardial infarction among adults receiving hemodialysis.

Topics: Adult; Aged; Anemia; Epoetin Alfa; Erythropoietin; Heart Failure; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Medicare; Myocardial Infarction; Policy; Renal Dialysis; Retrospective Studies; Stroke; United States

Anemia is common in heart failure (HF) patients with chronic kidney disease (CKD) and is associated with worse outcomes. Iron supplementation improves symptoms and is associated with reduced risk of hospitalization for HF in iron-deficiency HF patients. However, iron deficiency is present in <30% of anemic HF patients. Erythropoiesis stimulating agents (ESAs) improve symptoms but are associated with increased risk of thromboembolic events in anemic HF patients with CKD. Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors are a new class of agents for the treatment of anemia. These agents work by stabilizing the HIF complex, thereby stimulating endogenous erythropoietin production. We hypothesized that HIF-PH inhibitors may be associated with reduced risk of cardiovascular outcomes compared with ESAs in anemic HF patients with CKD. Accordingly, we aim to perform the meta-analysis of studies on the efficacy and safety of HIF-PH inhibitors compared with ESAs in anemic HF patients with CKD.. This meta-analysis will include prospective cohort studies and randomized controlled trials on the effect of HIF-PH inhibitors compared with ESAs in anemic HF patients with CKD. Information of studies will be collected from PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov. The primary outcome will be cardiovascular death. The secondary outcomes will be all-cause death, hospitalization for HF, HF symptoms, exercise capacity, health-related quality of life, and hemoglobin levels.. This meta-analysis will evaluate the effect of HIF-PH inhibitors in anemic HF patients with CKD, providing evidence regarding the use of HIF-PH inhibitors in these patients.. INPLASY202230103.

Topics: Anemia; Erythropoietin; Heart Failure; Hematinics; Hemoglobins; Humans; Hypoxia; Hypoxia-Inducible Factor-Proline Dioxygenases; Iron; Meta-Analysis as Topic; Prolyl-Hydroxylase Inhibitors; Prospective Studies; Quality of Life; Renal Insufficiency, Chronic; Systematic Reviews as Topic

Abnormal endogenous erythropoietin (EPO) constitutes an important cause of anaemia in chronic diseases. We analysed the relationships between iron deficiency (ID) and the adequacy of endogenous EPO in anaemic heart failure (HF) patients, and the impact of abnormal EPO on 12-month mortality.. We investigated 435 anaemic HF patients (age: 74 ± 10 years; males: 60%; New York Heart Association class I or II: 39%; left ventricular ejection fraction: 43 ± 17%). Patients with EPO higher than expected for a given haemoglobin were considered EPO-resistant whereas those with EPO lower than expected - EPO-deficient. ID was defined as serum ferritin <100 µg/L or 100-299 µg/L with transferrin saturation <20%. EPO-resistant patients (22%) had more advanced HF whereas those with EPO deficiency (57%) were more frequently females and had worse renal function. Lower serum ferritin (indicating depleted body iron stores) was related to higher EPO observed/predicted ratio when adjusted for significant clinical confounders, including C-reactive protein. One year all-cause mortality was 28% in patients with EPO resistance compared to 17% in patients with EPO deficiency and 10% in patients with adequate EPO (log-rank test for the comparison EPO resistance vs. adequate EPO: P = 0.02). When adjusted for other prognosticators, there was still a trend towards increased 12-month mortality in patients with higher EPO level.. Anaemic HF patients with endogenous EPO deficiency vs. resistance have different clinical and laboratory characteristics. In such patients, ID contributes to EPO resistance independently of inflammation.

Topics: Aged; Aged, 80 and over; Anemia; Anemia, Iron-Deficiency; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Iron Deficiencies; Male; Middle Aged

Anemia and iron deficiency are highly prevalent in chronic kidney disease (CKD) and in chronic heart failure. Both may epidemiologically predict future renal and/or cardiovascular events. However, anemia treatment with either erythropoietin or erythropoiesis-stimulating agents failed to induce a prognostic benefit in either CKD or chronic heart failure. Instead, in the subgroup of chronic dialysis patients, liberal intravenous iron supplementation was beneficial, and ongoing clinical trials are testing the prognostic implication of intravenous iron supplementation in chronic heart failure. Finally, HIF stabilizers are a new treatment option for anemia in chronic kidney disease, and safety studies are currently ongoing in CKD patients. Whether patients suffering from chronic heart failure might also benefit from this treatment is currently unknown.. THERAPIE MIT EISENPRäPARATEN:  Mit PIVOTAL erschien 2018 die erste kardiovaskuläre Endpunktstudie zur Eisensubstitution bei Dialysepatienten, die eine prognostische Überlegenheit einer Hochdosiseisentherapie gegenüber einer restriktiveren Eisenapplikation aufzeigte. Mit AFFIRM-AHF, IRONMAN, FAIR-HF2 und HEART-FID überprüfen aktuell gleich 4 Studien die Bedeutung einer intravenösen Eisenapplikation auf kardiovaskuläre Endpunkte bei Patienten mit Herzinsuffizienz. AUSBLICK:  HIF-Stabilisatoren erlauben eine orale Anämie-Behandlung bei chronischer Nierenerkrankung. Erste klinische Studien zeigten eine „Nichtunterlegenheit“ von HIF-Stabilisatoren gegenüber der Behandlung mittels rekombinanten Erythropoetins (EPO)/Erythropoese-stimulierenden Agenzien (ESA) in Bezug auf den Hämoglobinanstieg. Finale Ergebnisse großer Studien mit kardiovaskulären Endpunkten sind aktuell noch ausstehend. In diesen Studien muss das Sicherheitsprofil von HIF-Stabilisatoren überprüft werden, da HIF-Stabilisatoren die Transkription zahlreicher Gene auch jenseits der Hämatopoese verändern. In der klinischen Kardiologie spielen HIF-Stabilisatoren aktuell (noch) keine Rolle. Unter der Therapie mittels SGLT-II-Inhibitoren konnte ein Anstieg des Hämatokrits beobachtet werden, welcher sich nicht allein durch diuretische Effekte erklären lässt. Die genaue pharmakodynamische Wirkweise ist noch offen.

Topics: Anemia, Iron-Deficiency; Chronic Disease; Erythropoietin; Heart Failure; Hematinics; Humans; Iron; Renal Dialysis; Renal Insufficiency, Chronic

Despite growing research interest in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), it remains unknown whether central hemodynamic alterations inherently present in this condition do affect blood pressure and blood volume (BV) regulation. The present study sought to determine hemodynamic and endocrine responses to prolonged orthostatic stress in HFpEF patients. Central venous pressure (CVP) assessed via the internal jugular vein (IJV) aspect ratio with ultrasonography, arterial pressure and heart rate were determined at supine rest and during 2 hours of moderate (25-30°) head-up tilt (HUT) in 18 stable HFpEF patients (71.2 ± 7.3 years), 14 elderly (EC), and 10 young (YC) healthy controls. Parallel endocrine measurements comprised main BV-regulating hormones: pro-atrial natriuretic peptide, copeptin, aldosterone, and erythropoietin (EPO). At supine rest, the IJV aspect ratio was higher (>30%) in HFpEF patients compared with EC and YC, while mean arterial pressure was elevated in HFpEF patients (98.0 ± 13.1 mm Hg) and EC (95.6 ± 8.3 mm Hg) versus YC (87.3 ± 5.0 mm Hg) (P < 0.05). HUT increased heart rate (+10%) and reduced the IJV aspect ratio (-52%), with similar hemodynamic effects in all groups (P for interaction ≥ 0.322). The analysis of endocrine responses to HUT revealed a group×time interaction for circulating EPO, which was increased in YC (+10%) but remained unaltered in HFpEF patients and EC. The EPO response to a given reduction in CVP is similarly impaired in HFpEF patients and elderly controls, suggesting an age-dependent dissociation of EPO production from hemodynamic regulation in the HFpEF condition.

Topics: Adult; Age Factors; Aged; Biomarkers; Case-Control Studies; Central Venous Pressure; Erythropoietin; Female; Heart Failure; Humans; Male; Middle Aged; Patient Positioning; Stroke Volume; Tilt-Table Test; Time Factors; Up-Regulation; Ventricular Function, Left; Young Adult

Impairment of cardiac function causes renal damage. Renal failure after heart failure is attributed to hemodynamic derangement including reduced renal perfusion and increased venous pressure. One mechanism involves apoptosis and is defined as cardiorenal syndrome type 1. Erythropoietin (EPO) is a cytokine that induces erythropoiesis under hypoxic conditions. Hypoxia inducible factor 1 alpha (HIF-1α) plays a regulatory role in cellular response to hypoxia. Protective effects of EPO on heart, kidney and nervous system are unrelated to red blood cell production. We investigated early changes in and effects of EPO on renal tissues of rats with myocardial infarction by morphology and immunohistochemistry. Coronary artery ligation was used to induce myocardial infarction in Wistar rats. Group 1 comprised sham operated rats; groups 2, 3 and 4 included rats after coronary artery ligation that were sacrificed 6 h after ligation and that were treated with saline, 5,000 U/kg EPO or 10,000 U/kg EPO, respectively; group 5 included rats sacrificed 1 h after ligation. Group 2 showed increased renal tubule damage. Significantly less tubule damage was observed in EPO treated groups. EPO and EPO receptor (EPO-R) immunostaining intensities increased slightly for group 5 and became more intense for group 2. EPO and EPO-R immunostaining was observed in the interstitial area, glomerular cells and tubule epithelial cells of EPO treated groups. HIF-1α immunostaining was observed in collecting tubules in the medulla only in group 2. Caspase-3 immunostaining is an indicator of apoptosis. Caspase-3 staining intensity decreased in renal medulla of EPO treated groups. EPO treatment may exert a protective effect on the renal tissues of patients with cardiorenal syndrome.

Topics: Animals; Apoptosis; Erythropoietin; Heart Failure; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Kidney; Male; Rats, Wistar

Topics: Algorithms; Anemia; Biomarkers; Erythropoietin; Female; Greece; Heart Failure; Hemoglobins; Humans; Male; Prevalence; Reproducibility of Results; Retrospective Studies

The European Medicines Agency recommends limiting the hemoglobin (Hb) concentration to 10 to 12 g/dL in adults with chronic kidney disease (CKD) receiving erythropoiesis-stimulating agents such as epoetin theta. This postauthorization study assessed the incidence and intensity of cardiovascular events, including ischemic stroke, in patients receiving epoetin theta for anemia associated with CKD. A secondary end point was adverse drug reactions, including pure red cell aplasia.. In this prospective, noninterventional, multinational cohort study, consecutive patients with advanced or end-stage renal disease and receiving epoetin theta were followed up for 6 months. Data on reportable adverse events (RAEs) (cardiac disorders, cardiac failure, myocardial infarction, and ischemic stroke and respective subterms), epoetin theta dosage, and Hb concentrations were collected. A post hoc exploratory analysis assessed the incidences of RAEs according to tertiles for individual mean Hb concentration (≤10.7, >10.7-11.47, and >11.47 g/dL for low, intermediate, and high, respectively) and mean weekly epoetin theta dosage (≤62, >62-125, and >125 IU/kg/wk for low, intermediate, and high).. Data from 1039 patients were included (577 men, 462 women; mean age, 68.7 years). A total of 101 RAEs were documented in 89 patients (8.6%), for an event rate of 0.1985/person-year. Sixty-four patients (6.1%) died; none of the deaths was considered related to epoetin theta use. The incidence of RAEs was lowest at intermediate Hb concentrations (6.2%) compared with low (11.3%) and high (7.8%) Hb concentrations. The incidence of ischemic stroke was 1.5% at high Hb concentrations versus 0.6% at both the low and intermediate Hb concentrations. The incidence of any RAE was greater in the high-dose group (10.1%) than in the intermediate-dose (8.0%) and low-dose (7.6%) groups. The risk for any cardiovascular RAE or ischemic stroke was greatest in the high-dose/high-Hb group (13.3%), followed by high dose/low Hb (12.6%) and low dose/low Hb (12.1%). The risks for RAEs were lowest at high dose/intermediate Hb (3.8%) and low dose/intermediate Hb (5.3%). The event rate of adverse drug reactions other than the predefined RAEs was 0.0161/person-year. No cases of pure red cell aplasia were reported.. The findings from the present study suggest that, for maintaining the optimal target Hb concentration (10-12 g/dL according to the current summary of product characteristics for epoetin theta; 10-11.5 g/dL according to the current guideline from Kidney Disease Improving Global Outcomes) in anemic adults with CKD, the lowest approved, effective dose epoetin theta should be used.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Cohort Studies; Erythropoietin; Female; Heart Failure; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic; Stroke; Young Adult

Studies suggest that in patients with heart failure (HF), high serum erythropoietin is associated with risk of recurrent HF and mortality. Trials of erythropoietin-stimulating agents in persons with kidney disease have also suggested an increased incidence of adverse clinical events. No large studies of which we are aware have evaluated the association of endogenous erythropoietin levels with clinical outcomes in the community-living older adults.. Erythropoietin concentration was measured in 2488 participants aged 70-79 years in the Health, Aging and Body Composition Study. Associations of erythropoietin with incident HF, coronary heart disease, stroke, mortality, and ≥ 30% decline in estimated glomerular filtration rate were examined using Cox proportional hazards and logistic regression over 10.7 years of follow-up. Mean (SD) age was 75 (3) years and median (quartile 1, quartile 3) erythropoietin was 12.3 (9.0, 17.2) mIU/mL. There were 503 incident HF events, and each doubling of serum erythropoietin was associated with a 25% increased risk of incident HF 1.25 (95% confidence interval 1.13, 1.48) after adjusting for demographics, prevalent cardiovascular disease, cardiovascular disease risk factors, kidney function, and serum hemoglobin. There was no interaction of serum erythropoietin with chronic kidney disease or anemia (P > 0.50). There were 330 incident coronary heart disease events, 161 strokes, 1112 deaths, and 698 outcomes of ≥ 30% decline in estimated glomerular filtration rate. Serum erythropoietin was not significantly associated with these outcomes.. Higher levels of endogenous erythropoietin are associated with incident HF in older adults. Studies need to elucidate the mechanisms through which endogenous erythropoietin levels associate with specific outcomes.

Topics: Age Factors; Aged; Aging; Biomarkers; Body Composition; Erythropoietin; Female; Glomerular Filtration Rate; Heart Failure; Humans; Incidence; Kaplan-Meier Estimate; Kidney; Logistic Models; Longitudinal Studies; Male; Multivariate Analysis; Prevalence; Prognosis; Proportional Hazards Models; Renal Insufficiency, Chronic; Risk Factors; Time Factors; United States; Up-Regulation

In patients with heart failure (HF), serum erythropoietin (EPO) levels are elevated and associated with disease severity and outcome. Whether endogenous EPO levels are prospectively associated with the development of HF or cardiovascular events in the general population is unknown.. Serum EPO levels were measured at baseline in 6686 subjects enrolled in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study. Mean age (±SD) was 53 ± 12 years, 49.8% were male, and the median (interquartile range) EPO level was 7.7 (5.9-10.2) IU/L. During a median follow-up of 8.3 (7.7-8.8) years, 209 (3.1%) subjects were newly diagnosed with HF, 97 (1.5%) died of a cardiovascular cause, and 386 (6.0%) subjects had a non-fatal cardiovascular event (277 cardiac events and 93 strokes). Each doubling of EPO level was multivariably associated with new-onset HF [hazard ratio (HR) 1.32, 95% confidence interval (CI) 1.03-1.69, P = 0.031]. EPO levels showed interaction with urinary albumin excretion (P = 0.006) and were only associated with HF in subjects with albuminuria (HR 1.51, 95% CI 1.13-2.03, P = 0.005). There was an independent association of EPO levels with stroke in women (HR 1.82, 95% CI 1.24-2.65, P = 0.002), but not in men. No association was observed for EPO levels with other cardiovascular events or cardiovascular mortality.. High serum EPO levels are independently associated with an increased risk of new-onset HF in subjects with albuminuria. More research into the pathophysiological mechanisms linking EPO levels to HF is needed to understand this association.

Topics: Adult; Aged; Albuminuria; Cardiovascular Diseases; Erythropoietin; Female; Heart Failure; Humans; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Myocardial Ischemia; Myocardial Revascularization; Netherlands; Prognosis; Proportional Hazards Models; Sex Factors; Stroke

Although previous reports suggest that an elevated endogenous erythropoietin (EPO) level is associated with worse clinical outcomes in chronic heart failure (HF) patients, the prognostic implication of EPO in patients with acute decompensated HF (ADHF) and underlying mechanisms of the high EPO level in severe HF patients who have a poor prognosis remain unclear.. We examined 539 consecutive ADHF patients with EPO measurement on admission from our registry. During a median follow-up period of 329 days, a higher EPO level on admission was independently associated with worse clinical outcomes [hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.06-1.48, P = 0.008], and haemoglobin level was the strongest determinant of EPO level (P < 0.001), whereas estimated glomerular filtration rate (eGFR) was not significant in multivariate regression analysis. In the anaemic subgroup of 318 patients, a higher EPO level than expected on the basis of their haemoglobin level was related to increased adverse events (HR 1.63, 95% CI 1.05-2.49, P = 0.028). Moreover, estimated plasma volume excess rate was positively associated with EPO level (P = 0.003), and anaemic patients with a higher than expected EPO level tended to have a higher estimated plasma volume excess rate and plasma lactate level, and lower systemic oxygen saturation level with the preservation of the reticulocyte production index than those with a lower than expected EPO level.. A high EPO level predicts long-term worse clinical outcomes in ADHF patients, independent of anaemia and impaired renal function. Anaemia and hypoxia due to severe congestion may synergistically contribute to a high EPO level in high-risk HF patients.

Topics: Acute Disease; Aged; Aged, 80 and over; Anemia; Cause of Death; Cohort Studies; Disease Progression; Erythropoietin; Female; Glomerular Filtration Rate; Heart Failure; Hemoglobins; Humans; Lactic Acid; Male; Middle Aged; Mortality; Multivariate Analysis; Oximetry; Plasma Volume; Prognosis; Proportional Hazards Models; Prospective Studies; Registries; Renal Insufficiency

Mitomycin C (MMC) is one of the most effective chemotherapeutic drugs. However, the dose of MMC is greatly limited by its toxicity in normal tissues. Recombinant human erythropoietin (rhEPO), an erythropoietic hormone, has also been shown to exert tissue protective effects. The purpose of this study was to explore the protective effect of rhEPO against MMC-induced heart, liver, and renal dysfunction. Adult male Wistar rats were divided into six groups (with six animals each), namely control, rhEPO alone group, MMC alone group, and rhEPO + MMC group (pre-, co-, and posttreatment conditions). The results showed that MMC induced a marked cardiac, renal, and liver failure characterized by a significant decrease in body weight, organs weight, and organs ratio and a significant increase in creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, and conjugated and total bilirubin levels in serum. Histological examination showed that MMC caused liver alterations. rhEPO treatment restored body weight, organs weight, and organs ratio as well as serum biochemical parameters and histological damage caused by MMC exposure.

Topics: Animals; Antibiotics, Antineoplastic; Cardiotoxicity; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Erythropoietin; Heart Failure; Kidney Function Tests; Liver Function Tests; Male; Mitomycin; Organ Size; Rats, Wistar; Recombinant Proteins; Renal Insufficiency

Anemia is a common comorbidity of patients with heart failure, and iron deficiency is known as one of the causes of anemia in heart failure. Recent studies have shown that iron deficiency alone, without overt anemia, is associated with poor outcomes in patients with heart failure. Thus, to minimize the mortality in patients with heart failure, it is important to understand the link between iron deficiency and cardiac function. Chronic untreated iron deficiency results in cardiac remodeling, and we have previously reported that erythropoietin (Epo) and cardiac Epo receptor (EpoR) signaling may be associated with its remodeling. However, the link between EpoR signaling and its remodeling remains to be elucidated. Herein, we investigated the role of EpoR signaling on cardiac remodeling in response to chronic iron deficiency.. Wild-type mice and transgene-rescued EpoR-null mutant mice, which express EpoR only in the hematopoietic lineage (EpoR-restricted mice), were fed with either a normal or an iron-restricted diet, and the molecular mechanisms were investigated.. Dietary iron restriction gradually induced anemia, Epo secretion, and cardiac hypertrophy in wild-type mice. In contrast, EpoR-restricted mice fed with an iron-restricted diet exhibited anemia, left ventricular dilatation, and cardiac dysfunction compared with wild-type mice. Interestingly, altered cardiac mitochondrial biogenesis was observed in EpoR-restricted mice following iron deficiency. Moreover, cardiac p53 expression was increased in EpoR-restricted mice compared with wild-type mice following iron deficiency.. These data indicate that EpoR signaling is associated with cardiac remodeling following chronic iron deficiency.

Topics: Anemia, Iron-Deficiency; Animals; Chronic Disease; Disease Models, Animal; Erythropoietin; Heart Failure; Iron Deficiencies; Male; Mice; Mice, Knockout; Myocardium; Receptors, Erythropoietin; Signal Transduction

Topics: Anemia; Erythropoiesis; Erythropoietin; Heart Failure; Hematinics; Humans; Kidney Failure, Chronic

The effect of cell culturing protocol with various adhesion proteins and different culture time on the profile of cytokine and growth factors produced by endothelial progenitor cells harvested after mobilization with granulocyte colony-stimulating factor was examined in patients with chronic heart failure. The endothelial progenitor cells cultured on fibronectin or gelatin produced a broad and overall similar spectrum of cytokines and growth factors, the levels of which depended on the culture time. On culture day 16, the cells grown on fibronectin diminished the production of cytokines and growth factors (IL-10, IL-18, IL-8, erythropoietin, and VEGF), while the cells grown on gelatin down-regulated the synthesis of TNF-α, IL-8, and erythropoietin, although they up-regulated the production of IL-10, IL-18, and VEGF.

Topics: Cells, Cultured; Cytokines; Endothelial Progenitor Cells; Erythropoietin; Granulocyte Colony-Stimulating Factor; Heart Failure; Humans; Interleukin-10; Interleukin-18; Interleukin-8; Vascular Endothelial Growth Factor A

Anemia and chronic kidney disease are common disorders in heart failure (HF) patients and are associated with increased morbidity and mortality. This study assessed clinical outcomes associated with erythropoietin (EPO) treatment in this cardiorenal anemia syndrome (CRAS) population.. This was a retrospective cohort study of Veterans Affairs patients with CRAS from January 2003 to December 2006. The primary outcome was a composite of death, acute coronary syndrome (ACS), HF, and stroke. Multiple Cox regression modeling was used to evaluate the outcome in patients prescribed (n = 213) and not prescribed EPO (n = 1845). Adjusted incidence of mortality was statistically significantly higher in EPO than in non-EPO users (33.8% vs 19.7%; hazard ratio 1.40, 95% confidence interval 1.06-1.85; P = .02). The unadjusted composite of cardiovascular events/death was higher in the EPO group, but not statistically significant when adjusted for confounders (P = .12). Crude ACS events were documented in 18.8% and 10.8% patients (P = .001), and stroke events occurred in 22.5% and 18.3% patients (P = .14) in EPO and non-EPO groups, respectively.. We found that in CRAS patients, EPO use was associated with increased risk of mortality and a trend toward increased cardiovascular events. Therefore, clinicians considering EPO use in CRAS patients should assess whether any potential benefits outweigh the risks of use.

Topics: Aged; Aged, 80 and over; Anemia; Cohort Studies; Disease-Free Survival; Erythropoietin; Female; Heart Failure; Humans; Male; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Treatment Outcome

Lymphocytopenia is associated with an adverse prognosis in heart failure (HF). The present study investigated whether lymphocytopenia results from activated lymphocyte autophagy/apoptosis, which reflects haemodynamic inefficiency and functional aerobic impairment in patients with HF. One hundred and twenty-seven patients with HF were divided into three groups: HF with non- (lymphocytes ≥2000 cells/μl; n=45), mild (lymphocytes between ≥1500 cells/μl and <2000 cells/μl; n=39) and severe (lymphocytes <1500 cells/μl; n=43) lymphocytopenia. Lymphocyte autophagy/apoptosis, ventilatory/haemodynamic efficiencies and generic/disease-specific quality of life were analysed in these patients with HF and 35 normal counterparts. The results demonstrated that patients with HF with severe lymphocytopenia had (i) increased G-protein-coupled receptor kinase-2 (GRK-2) levels, (ii) lower mammalian target of rapamycin (mTOR) levels with higher lysosome-associated membrane protein-2 (LAMP-2) expression and Acridine Orange (AO) staining, (iii) lower mitochondrial transmembrane potential with higher caspase-3 activation and phosphatidylserine (PS) exposure, and (iv) greater extents of adrenaline (epinephrine)-induced apoptosis in lymphocytes, and higher plasma noradrenaline (norepinephrine)/adrenaline, myeloperoxidase and interleukin-6 concentrations than patients with HF without lymphocytopenia and normal counterparts did. Moreover, lymphocyte caspase-3 activation was an effect modifier, which modulated the correlation status between lymphocyte count and GRK-2 level. Lymphocyte count was positively correlated with peak cardiac output and peak oxygen consumption (VO2peak) in patients with HF. In addition, HF with lymphocytopenia was accompanied by lower Short Form-36 physical/mental component scores and increased Minnesota Living with Heart Failure Questionnaire scores. Therefore, we conclude that increased sympathetic activation and oxidative stress/pro-inflammatory status cause lymphocytopenia by activating programmed lymphocyte death in patients with HF. Moreover, a low lymphocyte count correlates with reduced haemodynamics and aerobic capacity, which reflects poor generic/disease-specific quality of life in patients with HF.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Autophagy; Catecholamines; Cytokines; Erythropoietin; Female; G-Protein-Coupled Receptor Kinase 2; Heart Failure; Hemodynamics; Humans; Lymphocytes; Lymphopenia; Lysosomal-Associated Membrane Protein 2; Male; Membrane Potential, Mitochondrial; Middle Aged; Oxygen Consumption; Peroxides; Quality of Life; Regression Analysis; Surveys and Questionnaires; TOR Serine-Threonine Kinases

Donation after circulatory death (DCD) offers a potential additional source of cardiac allografts. We used a porcine asphyxia model to evaluate viability of DCD hearts subjected to warm ischemic times (WIT) of 20–40 min prior to flushing with Celsior (C) solution. We then assessed potential benefits of supplementing C with erythropoietin, glyceryl trinitrate and zoniporide (Cs), a combination that we have shown previously to activate ischemic postconditioning pathways. Hearts flushed with C/Cs were assessed for functional, biochemical and metabolic recovery on an ex vivo working heart apparatus. Hearts exposed to 20-min WIT showed full recovery of functional and metabolic profiles compared with control hearts (no WIT). Hearts subjected to 30- or 40-min WIT prior to C solution showed partial and no recovery, respectively. Hearts exposed to 30-min WIT and Cs solution displayed complete recovery, while hearts exposed to 40-min WIT and Cs solution demonstrated partial recovery. We conclude that DCD hearts flushed with C solution demonstrate complete recovery up to 20-min WIT after which there is rapid loss of viability. Cs extends the limit of WIT tolerability to 30 min. DCD hearts with ≤30-min WIT may be suitable for transplantation and warrant assessment in a transplant model.

Topics: Animals; Death; Disease Models, Animal; Edema; Erythropoietin; Guanidines; Heart; Heart Failure; Heart Transplantation; Ischemic Preconditioning; Lactates; Myocardium; Nitroglycerin; Oxygen Consumption; Perfusion; Pyrazoles; Swine; Time Factors; Transplantation, Homologous; Troponin; Warm Ischemia

Topics: Adult; Anemia; Controlled Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Prognosis; Treatment Outcome

Topics: Anemia; Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Heart Failure; Hematinics; Hospitalization; Humans; Quality of Life; Treatment Outcome

Topics: Chronic Disease; Erythropoietin; Heart Failure; Humans; Neurotransmitter Agents; Renin-Angiotensin System; Sympathetic Nervous System

Topics: Anemia; Erythropoietin; Female; Heart Failure; Heart Failure, Systolic; Hematinics; Hemodilution; Humans; Male

Topics: Anemia; Erythropoietin; Heart Failure; Hematinics; Humans

Two of the most ethically complex situations in pediatrics are those involving families whose religious beliefs preclude the provision of life-sustaining treatment and those involving young adults who have reached the age of legal majority and who face decisions about life-sustaining treatment. This month's "Ethics Rounds" presents a case in which these 2 complexities overlapped. An 18-year-old Jehovah's Witness with sickle cell disease has life-threatening anemia. She is going into heart failure. Her doctors urgently recommend blood transfusions. The young woman and her family adamantly refuse. Should the doctors let her die? Is there any alternative?

Topics: Adolescent; Anemia, Sickle Cell; Blood Transfusion; Combined Modality Therapy; Critical Care; Erythropoietin; Ethics Committees, Clinical; Ethics, Medical; Female; Heart Failure; Hemoglobinometry; Humans; Hydroxyurea; Informed Consent; Jehovah's Witnesses; Patient Care Team; Professional-Family Relations; Professional-Patient Relations; Prognosis; Recombinant Proteins; Religion and Medicine; Treatment Refusal; Trust

Topics: Anemia; Erythropoietin; Heart Failure; Hematinics; Humans

Chronic heart failure (CHF) patients are frequently anaemic despite elevated endogenous erythropoietin (Epo) levels. We tested the hypothesis that this might be due to Epo resistance and investigated whether any defects apparent were due to Epo receptor (EpoR) downregulation and/or impaired Epo-induced signal transduction.. We studied 28 CHF patients (age 64 ± 10 yrs, LVEF 29 ± 9%, 89% male) and 12 healthy controls (65 ± 11 yrs, 75% male). Circulating erythroid progenitors (BFU-E) were cultured with 0, 1, 3 and 9 U/mL Epo. Circulating erythroblast surface EpoR and intracellular phosphorylated Signal Transducer and Activator of Transcription (phosphoSTAT)-5 expression were determined by flow cytometry.. Whilst BFU-E from control and non-anaemic subjects required only 3 U/mL Epo to significantly increase their numbers from baseline (1 U/mL), those from anaemic patients required 9 U/mL Epo. Lower Epo sensitivities related to higher interleukin-6 (r=-0.41, P=0.01) and soluble tumour necrosis factor receptor 2 (r=-0.38, P=0.02) levels. EpoR-positive cells were more abundant in anaemic patients (P<0.001). Although erythroblasts from anaemic patients exhibited higher baseline EpoR and phosphoSTAT5 expression (all P<0.05), Epo stimulation triggered significant increases in phosphoSTAT5 levels only in erythroblasts from control subjects and not in those from anaemic patients.. The responsiveness of erythroid cells to Epo is diminished in anaemic CHF patients. This is not due to EpoR downregulation but relates to a profound blunting of Epo-induced JAK-STAT signalling. Whilst residual Epo sensitivity can be exploited clinically with erythropoietic agents, targeting the mechanisms underlying Epo resistance in CHF may provide greater efficacy.

Topics: Aged; Anemia; Cells, Cultured; Chronic Disease; Down-Regulation; Drug Resistance; Erythroid Precursor Cells; Erythropoietin; Female; Flow Cytometry; Heart Failure; Humans; Janus Kinases; Male; Middle Aged; Receptors, Erythropoietin; Signal Transduction; STAT5 Transcription Factor

Anemia is a prevalent condition in heart failure with multiple potential causes. The complex interaction between iron stores, hepcidin, inflammation and anemia is poorly comprehended. We tested the hypothesis that, in stable heart failure patients with anemia, hepcidin is associated with iron deficiency status irrespective of inflammation.. Stable systolic heart failure outpatients with and without anemia underwent a complete iron panel, erythropoietin, hepcidin and tumor necrosis factor (TNF)-α assessment. Sixty outpatients were studied. Anemic patients (n = 38, mean hemoglobin 11.4 ± 1 g/dl) were older (69.6 ± 9.6 vs. 58 ± 10.8 years old, p < 0.01) compared with nonanemic patients (n = 22, mean hemoglobin 13.8 ± 1.1 g/dl). Iron deficiency was present in 42% of patients with anemia. TNF-α and hepcidin were 29 and 21% higher in patients with anemia, respectively, compared to nonanemic patients; however, no correlations were found between hepcidin and TNF-α levels. Hepcidin levels in the lower tertile (<31.7 ng/ml) were strongly associated with iron deficiency (OR 16.5, 95% CI 2.2-121.2; p < 0.01).. In stable heart failure patients with anemia, hepcidin levels may be more importantly regulated by patients' iron stores than by inflammation.

Topics: Aged; Aged, 80 and over; Anemia, Iron-Deficiency; Antimicrobial Cationic Peptides; Cross-Sectional Studies; Erythropoietin; Female; Heart Failure; Hemoglobins; Hepcidins; Humans; Iron; Male; Middle Aged; Odds Ratio; Outpatients; Receptors, Transferrin; Tumor Necrosis Factor-alpha

We investigated the effects of asialoerythropoietin (asialoEPO), a nonerythrogenic erythropoietin derivative, on 3 murine models of heart failure with different etiologies.. Doxorubicin (15 mg/kg) induced heart failure within 2 weeks (toxic cardiomyopathy). Treatment with asialoEPO (6.9 μg/kg) for 2 weeks thereafter attenuated the associated left ventricular dysfunction and dilatation. In addition, the asialoEPO-treated heart showed less myocardial fibrosis, inflammation, and oxidative damage, and diminished atrophic cardiomyocyte degeneration, which was accompanied by restored expression of GATA-4 and sarcomeric proteins. Mice with large 6-week-old myocardial infarctions exhibited marked left ventricular dysfunction with adverse remodeling (ischemic cardiomyopathy). AsialoEPO treatment for 4 weeks significantly mitigated progression of the dysfunction and remodeling and reduced myocardial fibrosis, inflammation, and oxidative damage. Finally, 25-week-old δ-sarcoglycan-deficient mice (genetic cardiomyopathy) were treated with asialoEPO for 5 weeks. AsialoEPO mitigated the progressive cardiac remodeling and dysfunction through cardiomyocyte hypertrophy, and upregulated expression of GATA-4 and sarcomeric proteins. AsialoEPO appears to act by altering the activity of the downstream erythropoietin receptor signals extracellular signal-regulated protein kinase, Akt, signal transducer, and activator of transcription 3 and 5 in a model-specific manner.. The findings suggest that asialoEPO exerts broad cardioprotective effects through distinct mechanisms depending on the model, which are independent of the erythrogenic action. This compound may be promising for the treatment of heart failure of various etiologies.

Topics: Animals; Asialoglycoproteins; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoietin; Follow-Up Studies; Heart Failure; Mice; Mice, Inbred C57BL; Treatment Outcome; Ventricular Function, Left; Ventricular Remodeling

Topics: Chronic Disease; Epoetin Alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Kidney Diseases; Patient Education as Topic; Physician-Patient Relations; Recombinant Proteins; Renal Dialysis; Risk Assessment; Risk Factors; Risk Management; Stroke; United States; United States Food and Drug Administration

Patients with chronic kidney disease (CKD) frequently suffer from heart disease as well. The combination of the two processes can exacerbate inflammation, resulting in increases in both resistance to erythropoietin (EPO) and mortality.. The aim of this study was to determine the prevalence of heart disease in a representative group of non-dialysis patients with stage 4-5 CKD, and the influence of that entity on EPO requirements and on mortality during a period of 36 months.. 134 patients (68% on EPO at the beginning, increasing to 72.3% during follow-up) were monitored for 36 months. To evaluate the dose-response effect of EPO therapy, we used the erythropoietin resistance index (ERI) calculated as the weekly weight-adjusted dose of EPO divided by the haemoglobin level. The ERI was determined both initially and during the last six months before the end of the study.. 39 patients (29.1%) had history of heart disease; 22 (16.4%) had suffered from heart failure (HF). The ERI was higher in patients with a history of heart disease or HF and those treated with drugs acting on the renin-angiotensin system (ACE inhibitors or ARBs). Using ERI as the dependent variable in the multivariate analysis, the variables that composed the final model were ferritin, haemoglobin, glomerular filtration rate and history of HF. The 36 month mortality rate (n=39 patients) was higher in the group having ERI above the median (2.6IU/week/kg/gram of haemoglobin in 100ml) (P=.002), and in the groups with heart disease (P=.001) or HF (P=.001) according to the Kaplan-Meier survival analysis.. Patients with history of heart disease or HF have a higher ERI, and all of these characteristics are associated with lower survival. ERI can be considered a marker for risk of death in the short to-medium term.

Topics: Aged; Aged, 80 and over; Anemia; Autoimmune Diseases; Cardio-Renal Syndrome; Cardiovascular Agents; Comorbidity; Cross-Sectional Studies; Dose-Response Relationship, Drug; Drug Resistance; Erythropoietin; Female; Ferritins; Glomerular Filtration Rate; Heart Diseases; Heart Failure; Hemoglobins; Humans; Kaplan-Meier Estimate; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Severity of Illness Index

The number of patients with chronic cardiac failure (CCF) grows continuously in the last decades especially among aged subjects compared with younger ones. Mortality and hospitalization rates among elderly subjects are also higher Hence, the importance of early diagnosis and treatment of concomitant diseases aggravating CCF, e.g. anemia. Reduced hemoglobin level may cause progression of CCF and deteriorate its prognosis. Correction of anemia with stimulators of erythropoiesis (erythropoietin, intravenous iron preparations) may be a useful auxiliary therapy for patients refractory to standard treatment. Oral iron preparations do not produce the desirable effect whereas combination of intravenous iron and erythropoietin has been reported to increase ejection fraction, reduce requirements for high-dose diuretics and necessity of repeated hospitalization, improve renal function, and decreases left ventricular hypertrophy. In other words, correction of anemia has beneficial effect on the clinical course of CCF and improves its prognosis.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Heart Failure; Humans; Iron; Male; Middle Aged

Anaemia in heart failure (HF) is associated with a poor prognosis. Although inflammation is assumed to be an important cause of anaemia, the association between anaemia and inflammatory markers in patients with HF has not been well established.. Data from a multicentre randomised clinical trial, in which patients were eligible if they were >18 years of age and admitted for HF (New York Heart Association II-IV), were used. In a subset of 326 patients, haemoglobin (Hb), haematocrit, high sensitivity C-reactive protein (hsCRP), interleukin-(IL) 6, soluble tumour necrosis factor receptor (sTNFR)-1 and erythropoietin (Epo) were measured at discharge and the primary endpoint was all-cause mortality. Follow-up was 18 months.. Anaemia (Hb <13 g/dl (men) and <12 g/dl (women)) was present in 40% (130/326) of the study population. Median levels of IL-6, hsCRP and sTNFR-1 were significantly higher in anaemic patients than in non-anaemic patients. Logistic regression demonstrated that each increase in hsCRP values (OR 1.58 per SD log hsCRP; 95% CI 1.09 to 2.29; p=0.016) and each increase in sTNFR-1 values (OR 1.62 per SD log sTNFR-1; 95% CI 1.24 to 2.11; p<0.001) were independently associated with anaemia. Epo (HR 1.31 per log Epo; 95% CI 1.01 to 1.69; p=0.041) and sTNFR-1 (HR 1.47 per log sTNFR-1; 95% CI 1.16 to 1.86; p=0.001) levels were independently associated with outcome.. Anaemia is present in 40% of patients hospitalised for HF and is independently associated with inflammation.

Topics: Aged; Aged, 80 and over; Anemia; Biomarkers; C-Reactive Protein; Chi-Square Distribution; Erythropoietin; Female; Heart Failure; Hematocrit; Hemoglobins; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Logistic Models; Male; Middle Aged; Multicenter Studies as Topic; Multivariate Analysis; Netherlands; Odds Ratio; Prognosis; Proportional Hazards Models; Randomized Controlled Trials as Topic; Receptors, Tumor Necrosis Factor, Type I; Retrospective Studies; Risk Assessment; Risk Factors; Survival Analysis; Time Factors

Topics: Anemia, Iron-Deficiency; Drug Therapy, Combination; Erythropoietin; Female; Heart Failure; Humans; Injections, Intravenous; Iron; Male; Middle Aged; Treatment Outcome

Heart failure (HF)-associated anemia is common and has a poor outcome. Because bone marrow (BM) dysfunction may contribute to HF-associated anemia, we first investigated mechanisms of BM dysfunction in an established model of HF, the transgenic REN2 rat, which is characterized by severe hypertrophy and ventricular dilatation and SD rats as controls. Secondly, we investigated whether stimulation of hematopoiesis with erythropoietin (EPO) could restore anemia and BM dysfunction. After sacrifice, erythropoietic precursors (BFU-E) were isolated from the BM and cultured for 10 days. BFU-E were quantified and transcript abundance of genes involved in erythropoiesis were assayed. Number of BFU-E were severely decreased in BM of REN2 rats compared to SD rats (50 ± 6.2 vs. 6.4 ± 1.7, p < 0.01). EPO treatment increased hematocrit in the SD-EPO group (after 6 weeks, 49 ± 1 vs. 58 ± 1%, p < 0.01); however, in the mildly anemic REN2 rats, there was no effect (43 ± 1 vs. 44 ± 1%). This was paralleled by a 67% decrease in BFU-E in BM of REN2 rats compared to SD (p < 0.01). EPO significantly improved BFU-E in both SD and REN2 but could not restore this to control levels in the REN2 rats. Expression of several genes involved in differentiation (LMO2), mobilization (SDF-1), and iron incorporation (transferrin receptor) of the BM were differentially expressed in REN2 rats compared to SD rats, and EPO did not normalize this. Altogether, these results suggest that BM dysfunction is an important contributor to HF-associated anemia and that EPO is not an effective agent to treat HF-associated anemia.

Topics: Anemia; Animals; Bone Marrow; Cell Differentiation; Erythroid Cells; Erythropoietin; Gene Expression Regulation; Heart Failure; Hematopoiesis; Hematopoietic Stem Cells; Hypertension; Iron; Male; Random Allocation; Rats; Rats, Sprague-Dawley

Topics: Anemia; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Heart Failure; Hematinics; Humans; Iron; Iron Deficiencies; Kidney Failure, Chronic

Topics: Animals; Apoptosis; Cardiotonic Agents; Cell Survival; Erythropoietin; Heart Failure; Humans; Inhibitor of Apoptosis Proteins; Myocytes, Cardiac; Peptides; Signal Transduction; Structural Homology, Protein

Erythropoietin, the red blood cell-making cytokine, is also a potential cytoprotective agent in heart disease. In this issue of Cell Stem Cell, Hoch et al. (2011) use two heart failure models, including chemotherapeutic cardiotoxicity, to reveal a mechanistic connection between reduced cardiomyocyte production of erythropoietin and neoangiogenesis by cardiac progenitors.

Topics: Animals; Antineoplastic Agents; Cell Differentiation; Endothelial Cells; Erythropoietin; Heart Failure; Humans; Myocardium; Stem Cells

Anticancer therapies, such as targeting of STAT3 or the use of anthracyclins (doxorubicin), can induce cardiomyopathy. In mice prone to developing heart failure as a result of reduced cardiac STAT3 expression (cardiomyocyte-restricted deficiency of STAT3) or treatment with doxorubicin, we observed impaired endothelial differentiation capacity of Sca-1(+) cardiac progenitor cells (CPCs) in conjunction with attenuated CCL2/CCR2 activation. Mice in both models also displayed reduced erythropoietin (EPO) levels in the cardiac microenvironment. EPO binds to CPCs and seems to be responsible for maintaining an active CCL2/CCR2 system. Supplementation with the EPO derivative CERA in a hematocrit-inactive low dose was sufficient to upregulate CCL2, restore endothelial differentiation of CPCs, and preserve the cardiac microvasculature and cardiac function in both mouse models. Thus, low-dose EPO treatment could potentially be exploited as a therapeutic strategy to reduce the risk of heart failure in certain treatment regimens.

Topics: Adipocytes; Animals; Antigens, Ly; Antineoplastic Agents; Capillaries; Cell Differentiation; Doxorubicin; Endothelial Cells; Erythropoietin; Fibroblasts; Gene Deletion; Heart Failure; Heart Function Tests; Humans; Membrane Proteins; Mice; Mice, Knockout; Myocardium; Organ Specificity; Pericytes; Receptors, CCR2; Receptors, Erythropoietin; STAT3 Transcription Factor; Stem Cells; Survival Analysis; Vascular Endothelial Growth Factor Receptor-2

Structurally-functional myocardium parameters and their interconnection with erythropoietin and tumour necrosis factor-alpha levels in blood plasma of patients with heart failure were analysed. Prevalence of erythropoietin over tumour necrosis factor-alpha in blood had positive effect on myocardium-contraction ability under acute heart failure. Improvement of pumped cardiac function was not registered under prevalence of erythropoietin over tumour necrosis faetor-a in blood of patients with chronic heart failure.

Topics: Aged; Aged, 80 and over; Cardiac Output; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Contraction; Myocardial Infarction; Organ Size; Tumor Necrosis Factor-alpha; Ventricular Remodeling

The hormone erythropoietin (EPO) has been demonstrated to have cardioprotective properties. The present study investigates the role of EPO to prevent heart failure following cancer treatment with doxorubicin [adriamycin (AD)]. Male Wistar rats (150 ± 10 g) were treated with saline (vehicle control group); with EPO, subcutaneously at 1,000 IU/kg body wt, three times per week for 4 wk (EPO group); with adriamycin, intraperitoneally at 2.5 mg/kg body wt, three times per week for 2 wk (AD group); and with adriamycin and EPO (EPO-AD group). Echocardiographic measurements showed that EPO-AD treatment prevented the AD-induced decline in cardiac function. Each of the hearts was then exposed to ischemia and reperfusion during Langendorff perfusion. The percentage of recovery after ischemia-reperfusion was significantly greater in EPO-AD than the AD-treated group for left ventricular developed pressure, maximal increase in pressure, and rate pressure product. The level of oxidative stress was significantly higher in AD (5 μM for 24 h)-exposed isolated cardiomyocytes; EPO (5 U/ml for 48 h) treatment prevented this. EPO treatment also decreased AD-induced cardiomyocyte apoptosis, which was associated with the decrease in the Bax-to-Bcl2 ratio and caspase-3 activation. Immunostaining of myocardial tissue for CD31 showed a significant decrease in the number of capillaries in AD-treated animals. EPO-AD treatment restored the number of capillaries. In conclusion, EPO treatment effectively prevented AD-induced heart failure. The protective effect of EPO was associated with a decreased level of oxidative stress and apoptosis in cardiomyocytes as well as improved myocardial angiogenesis.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Capillaries; Cardiotonic Agents; Caspase 3; Cells, Cultured; Disease Models, Animal; Doxorubicin; Enzyme Activation; Erythropoietin; Heart Failure; Immunohistochemistry; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Neovascularization, Physiologic; Oxidative Stress; Perfusion; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Recovery of Function; Time Factors; Ultrasonography; Ventricular Function, Left; Ventricular Pressure

Topics: Animals; Antineoplastic Agents; Erythropoietin; Heart Failure; Humans; Risk

The etiology of anemia is still unclear in patients with chronic heart failure (CHF). Hepcidin is an iron regulatory peptide that is synthesized in the liver to suppress iron absorption and utilization. Hepcidin synthesis is suppressed by anemia, hypoxia and erythropoiesis, and induced by inflammation. Inflammatory cytokines, such as interleukin-6 (IL-6), increase the synthesis of hepcidin, resulting in anemia of inflammation (AI). The serum hepcidin concentration in CHF patients with anemia was measured in order to better understand anemia in CHF.. Serum hepcidin-25, erythropoietin (EPO), ferritin and IL-6 concentrations were measured in 61 CHF patients. Among these patients, 36 patients had anemia. A group of 16 patients without cardiac disease or anemia were recruited as controls. Serum IL-6 and EPO were higher and hepcidin-25 was lower in CHF patients with anemia than in controls. Hepcidin-25 correlated with EPO and ferritin but not with IL-6. Results of multivariable regression analysis showed that independent predictors of serum hepcidin-25 included EPO and ferritin but not IL-6.. Serum hepcidin-25 concentrations were regulated by iron storage and erythropoiesis but not by IL-6 in CHF patients with anemia. These findings might indicate that AI is a minor cause of anemia in CHF.

Topics: Aged; Aged, 80 and over; Anemia; Antimicrobial Cationic Peptides; Biomarkers; Case-Control Studies; Chronic Disease; Down-Regulation; Erythropoietin; Female; Ferritins; Heart Failure; Hepcidins; Humans; Inflammation Mediators; Interleukin-6; Linear Models; Male; Middle Aged; Prospective Studies

Topics: Anemia; Biomarkers; Erythropoietin; Heart Failure; Humans

Endogenous erythropoietin is increased in patients with heart failure (HF). Previous small-scale data suggest that these erythropoietin levels are related to prognosis. This study aims to analyze the clinical and prognostic value of erythropoietin levels in relation to hemoglobin in a large cohort of HF patients.. In patients hospitalized for HF, endogenous erythropoietin levels were measured at discharge and after 6 months. In anemic patients, the relation between erythropoietin and hemoglobin levels was determined by calculating the observed/predicted ratio of erythropoietin levels. We studied data from 605 patients with HF. Mean age was 71+/-11 years; 62% were male; and mean left ventricular ejection fraction was 0.33+/-0.14. Median erythropoietin levels were 9.6 U/L at baseline and 10.5 U/L at 6 months. Higher erythropoietin levels at baseline were independently related to an increased mortality at 18 months (hazard ratio, 2.06; 95% confidence interval, 1.40 to 3.04; P<0.01). In addition, persistently elevated erythropoietin levels (higher than median at baseline and at 6 months) were related to an increased mortality risk (hazard ratio, 2.24; 95% confidence interval, 1.02 to 4.90; P=0.044). The observed/predicted ratio was determined in a subset of anemic patients, 79% of whom had erythropoietin levels lower than expected and 9% had levels higher than expected on the basis of their hemoglobin. Multivariate Cox regression analysis revealed that a higher observed/predicted ratio was related to an increased mortality risk (hazard ratio, 3.52; 95% confidence interval, 1.53 to 8.12; P=0.003).. Erythropoietin levels predict mortality in HF patients, and persistently elevated levels have an independent prognostic value. In anemic HF patients, the majority had a low observed/predicted ratio. However, a higher observed/predicted ratio may be related to an independent increased mortality risk.

Topics: Aged; Aged, 80 and over; Anemia; Cohort Studies; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Male; Middle Aged; Mortality; Predictive Value of Tests; Prognosis; Stroke Volume

Anemia is common in chronic kidney disease (CKD). The CHOIR study found increased risk of a composite cardiovascular outcome when anemia was treated with epoetin-alfa to a target hemoglobin level of 13.5 as compared with 11.3 g/dl. Whether this increase applies to all patient subgroups equally is unclear. We discuss an analysis by Szczech and colleagues of the effects of the higher hemoglobin target in CKD patients with diabetes mellitus or congestive heart failure.

Topics: Anemia; Chronic Disease; Diabetes Mellitus; Epoetin Alfa; Erythropoietin; Heart Failure; Hemoglobins; Humans; Kidney Diseases; Recombinant Proteins

Topics: Anemia; Erythropoietin; Europe; Heart Failure; Humans; Iron Compounds; Renal Insufficiency

We intended to delineate the mechanisms of erythropoietin (EPO)-induced cardiac vascular endothelial growth factor (VEGF) production and to establish if VEGF is crucial for EPO-induced improvement of cardiac performance.. The effects of EPO on VEGF expression were studied in cultured cardiac cells and EPO-treated hearts. The role of VEGF in EPO-induced neovascularization was studied with two distinct VEGF-neutralizing antibodies or irrelevant control IgG in an aortic sprouting assay and in rats with heart failure (HF) after myocardial infarction (MI) treated with EPO. EPO-alfa (10 IU/mL) was used in vitro and darbepoetin alfa (40 microg/kg/3 weeks, starting 3 weeks after MI) in vivo. EPO stimulated VEGF mRNA expression through the signal transducers and activators of transcription-3 (STAT-3) pathway in neonatal rat cardiomyocytes, but not in endothelial cells or fibroblasts. Similarly, the direct effects of EPO on endothelial sprouting were modest and VEGF independent. In rats with HF, EPO increased VEGF protein expression predominantly in cardiomyocytes, associated with a 37% increase in capillary density and improved cardiac performance. Administration of VEGF-neutralizing antibodies abrogated the salutary effects of EPO on cardiac microvascularization and function. VEGF neutralization attenuated EPO-induced proliferation of myocardial endothelial cells and reduced myocardial incorporation of endothelial progenitor cells (EPCs) in rats with alkaline phosphatase-labelled bone marrow cells.. VEGF is crucial for EPO-induced improvement of cardiac function in HF. EPO fosters VEGF expression predominantly in cardiomyocytes, which in turn stimulates myocardial endothelial proliferation and incorporation of EPCs.

Topics: Animals; Animals, Newborn; Cardiotonic Agents; Cell Movement; Cell Proliferation; Cells, Cultured; Darbepoetin alfa; Disease Models, Animal; Endothelial Cells; Epoetin Alfa; Erythropoietin; Heart Failure; Humans; Male; Myocytes, Cardiac; Neovascularization, Physiologic; Paracrine Communication; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Recombinant Proteins; Recovery of Function; RNA, Messenger; STAT3 Transcription Factor; Stem Cell Transplantation; Stem Cells; Time Factors; Transcription, Genetic; Up-Regulation; Vascular Endothelial Growth Factor A; Ventricular Function, Left; Ventricular Remodeling

Topics: Anemia; Erythropoietin; Heart Failure; Hematinics; Hemoglobins; Humans

Topics: Comorbidity; Disease Progression; Erythropoietin; Heart Failure; Humans; Prevalence; Prognosis; Risk Factors; Sleep Apnea, Central

Central sleep apnoea (CSA) and increased serum erythropoietin (EPO) concentration have each been associated with adverse prognosis in heart failure (HF) patients. The aim of this study was to examine the relationship between nocturnal hypoxaemia due to CSA and the serum EPO concentration in patients with HF.. Heart failure subjects (n = 33) and healthy controls (n = 18) underwent polysomnography (PSG) for diagnosis of CSA and identification and quantification of hypoxaemia. Blood collection for measurement of EPO was performed immediately post-PSG. For the analysis, HF subjects were dichotomized into subgroups defined by the presence or absence of CSA and by HF severity. Multivariate analyses were performed to evaluate the relationships of hypoxaemia and advanced HF to EPO concentration. Mean EPO concentration was 62% higher for HF subjects with CSA than for healthy controls (P = 0.004). The magnitude of nocturnal hypoxaemia was significantly and positively related to EPO concentration (r = 0.45, P = 0.02). Advanced HF was also significantly and positively related to EPO concentration (r = 0.43, P = 0.02). On multivariate analysis, the presence of combined nocturnal hypoxaemia and advanced HF yielded greater correlation to EPO concentration than either factor alone (r = 0.57, P = 0.04 and P = 0.05, respectively). Linear regression demonstrated that the combination of New York Heart Association Class and CSA was strongly associated with EPO concentration (P < 0.0001).. In non-anaemic HF patients, advanced HF and hypoxaemia due to CSA may each be independently associated with increased serum EPO concentration.

Topics: Aged; Biomarkers; Case-Control Studies; Disease Progression; Erythropoietin; Female; Health Status Indicators; Heart Failure; Humans; Hypoxia; Linear Models; Male; Middle Aged; Multivariate Analysis; Oxygen Consumption; Polysomnography; Prognosis; Risk Factors; Severity of Illness Index; Sleep Apnea, Central; Statistics as Topic

Anemia is common in patients with chronic heart failure (HF) with an incidence ranging from 4% to 55% depending on the studied population. Several studies have highlighted that the prevalence of anemia increases with worsening heart failure as reflected by New York Heart Association classification. Additionally, several epidemiological studies have highlighted its role as a prognostic marker, linking it to worse outcomes including; malnutrition, increased hospitalizations, refractory heart failure and death. The pathophysiology of anemia is multifactorial and related to various factors including; hemodilution, iron losses from anti-platelet drugs, activation of the inflammatory cascade, urinary losses of erythropoietin and associated renal insufficiency. There are a host of epidemiological studies examining HF outcomes and anemia, but only a few randomized trials addressing this issue. The purpose of this article is to review the literature that examines the interrelationship of anemia and congestive HF, analyzing its etiology, impact on outcomes and also the role of associated kidney disease as well as cardiorenal syndrome both as a marker of morbidity and mortality.

Topics: Anemia; Chronic Disease; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Renal Dialysis

Topics: Anemia; Diabetes Complications; Endpoint Determination; Epoetin Alfa; Erythropoietin; Heart Failure; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Recombinant Proteins

Topics: Animals; Cardiotonic Agents; Darbepoetin alfa; Endothelial Cells; Epoetin Alfa; Erythropoietin; Heart Failure; Humans; Myocytes, Cardiac; Neovascularization, Physiologic; Paracrine Communication; Recombinant Proteins; Recovery of Function; Stem Cells; Up-Regulation; Vascular Endothelial Growth Factor A; Ventricular Remodeling

The combination of chronic kidney disease (CKD), chronic heart failure (HF), and anaemia, the so-called cardio-renal-anaemia syndrome (CRA) is associated with dysregulation of erythropoietin levels and inflammation. Both have been associated with the development of cancer. This study aimed to determine the cumulative incidence of cancer in patients with CRA, as compared with anaemic CKD and control patients.. Patients aged <80 years who attended the nephrology or cardiology outpatient clinics between March 2006 and November 2007 were eligible for inclusion in this retrospective case-control study if haemoglobin <8.1 mmol/L (13 g/dL) and serum creatinine >80 mmol/L (0.90 mg/dL). Medical records dating back to 1996 were reviewed. The relationship between cancer and CRA, chronic HF, CKD, and anaemia was analysed using logistic regression analysis. Data from 1087 patients were reviewed. We identified 348 patients with both CKD and anaemia, of whom 132(38.3%) had CRA. The control group included 264 patients attending the hypertension outpatient clinic. Patients with CRA had a 19% cumulative incidence of cancer compared with 11% for patients with anaemia, CKD and no chronic HF, and 11% in the control group. The odds ratio (OR) for cancer was 1.8(95% CI 1.0-3.2) for the CRA group compared with the control group. Chronic HF was an independent risk factor for cancer after correction for age and gender (adjusted OR 2.0; 95% CI 1.2-3.3, P = 0.007).. The cumulative incidence of cancer among patients with CRA is high compared with controls and to anaemic CKD patients without chronic HF. Chronic HF was an independent risk factor for cancer. These results stress the importance of clarifying the mechanisms involved in the development of cancer in CRA.

Topics: Aged; Anemia; Case-Control Studies; Confidence Intervals; Erythropoietin; Female; Heart Failure; Humans; Incidence; Kidney Failure, Chronic; Logistic Models; Male; Middle Aged; Neoplasms; Netherlands; Odds Ratio; Receptors, Erythropoietin; Retrospective Studies; Risk Factors; Syndrome

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Risk Factors

Topics: Erythropoietin; Heart Failure; Humans; Hypoxia; Prognosis; Pulmonary Disease, Chronic Obstructive; Risk Factors

It has been reported that erythropoietin (EPO) attenuates ischemia-induced damage in a variety of tissues. It is unknown whether EPO alters the left ventricular (LV) remodeling process after ischemic insult. Accordingly, we tested the potential benefits of carbamylated EPO (CEPO) on LV remodeling in rats with myocardial infarction (MI).. MI was induced by coronary artery ligation in adult male Sprague-Dawley rats. One hour after surgery, rats were randomly assigned to 1 of 2 groups: MI plus placebo injections (placebo, n = 21) and MI plus CEPO injection (CEPO, n = 22). CEPO (10 μg/kg) or placebo was given via tail vein in a blinded fashion daily for the first 3 days, followed by twice a week subcutaneous injection for 6 weeks. Sham surgery was performed in another group of rats (n = 18) without coronary artery ligation. Cardiac function was assessed by echocardiography, hemodynamic, and in vivo and ex vivo LV pressure-volume relationship measurements 6 weeks after MI.. In comparison to placebo-treated rats, CEPO significantly improved LV geometry (LV end systolic dimension: 8.6 ± 0.8 vs. 9.6 ± 1.0 mm; LV end systolic volume: 404 ± 83 vs. 516 ± 122 μL, both P < 0.05). CEPO therapy also reduced the decline of systolic function (fractional shortening: -3.7% ± 1.7% vs. -10.9% ± 2.3%; Emax 0.46 ± 0.20 vs. 0.25 ± 0.08 mm Hg/s, both P < 0.05). Passive diastolic properties of the LV were minimally improved by leftward shift in the ex vivo end diastolic pressure-volume relationship.. CEPO administration 1 hour after acute MI improves systolic performance and may attenuate the LV remodeling process. Further studies to determine the mechanism of CEPO responsible for its beneficial effects and optimize dosing and timing regimens are warranted.

Topics: Animals; Drug Administration Schedule; Echocardiography; Erythropoietin; Heart Failure; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Ventricular Function, Left; Ventricular Remodeling

This article provides information and a commentary on key trials relevant to the pathophysiology, prevention, and treatment of heart failure (HF) presented at the annual meeting of the European Society of Cardiology held in Stockholm in 2010. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. The SHIFT study supports the use of ivabradine in patients with HF due to left ventricular systolic dysfunction and resting sinus rhythm rate ≥70 b.p.m. despite treatment with beta-blockers or where beta-blockers are contra-indicated. Results from PEARL-HF suggest that the potassium binding polymer RLY5016 may be useful for both prevention and treatment of hyperkalaemia in HF patients with or without concomitant chronic kidney disease. The STAR-heart study provides encouraging observational data about the potential for intracoronary stem cell transplantation in patients with HF. Results from HEBE-III showed no effect of erythropoietin on ejection fraction measured 6 weeks post-MI; although there were fewer cardiovascular events in patients assigned to erythropoietin, the study was too small to provide conclusive evidence of effect.

Topics: Adrenergic beta-Antagonists; Benzazepines; Clinical Trials as Topic; Comorbidity; Cyclic Nucleotide-Gated Cation Channels; Drug Therapy, Combination; Erythropoietin; Heart Failure; Hematinics; Humans; Hyperkalemia; Ivabradine; Myocardial Infarction; Polymers; Renal Insufficiency; Stem Cell Transplantation

In chronic heart failure (CHF), several plasma biomarkers identify subjects at risk of death over the midterm. However, their long-term predictive value in the context of other candidate predictors has never been assessed. This information may prove valuable in the management of a chronic disease with a long natural history, as CHF is today.. We aimed to assess the very-long-term prognostic power of a set of biomarkers to identify CHF patients at highest risk for all-cause mortality.. A group of 106 consecutive outpatients with CHF (85 male and 21 female, median age 56 y) was followed for 15 years. Echocardiographic tracings and blood samples were collected at study entry to evaluate cardiac function, plasma atrial natriuretic peptide (ANP), aldosterone, and erythropoietin, and plasma renin activity. The relationships between biomarkers, clinical and echocardiographic variables, and mortality were assessed.. After 15 years, 86 of the 106 patients (81%) had died. Multivariate analysis showed that ANP was the best independent predictor of survival over several clinical, echocardiographic, and humoral variables (hazard ratio: 5.62, 95% confidence interval: 3.37-9.39, P < 0.001 for plasma levels < median value of 71 pg/mL). Plasma renin activity and erythropoietin provided prognostic information in univariate analysis, but lost their predictive power when adjusted for covariates.. The present study represents the longest available follow-up of patients with CHF evaluating the prognostic power of multiple biomarkers. It shows that a simple assessment of plasma ANP levels is the strongest long-term predictor of death in all stages of heart failure.

Topics: Aldosterone; Atrial Natriuretic Factor; Biomarkers; Chronic Disease; Erythropoietin; Female; Follow-Up Studies; Heart Failure; Humans; Italy; Kaplan-Meier Estimate; Male; Middle Aged; Prognosis; Proportional Hazards Models; Prospective Studies; Renin; Risk Assessment; Risk Factors; Survival Rate; Time Factors; Ultrasonography

Topics: Anemia; Animals; Asialoglycoproteins; Erythropoietin; Heart Failure; Humans; Receptors, Erythropoietin; Recombinant Proteins; Renal Insufficiency; Signal Transduction

We examined the effect of asialoerythropoietin (asialoEPO), a nonerythrogenic derivative of erythropoietin (EPO), on renal dysfunction-associated heart failure.. Although EPO is known to exert beneficial effects on cardiac function, the clinical benefits in patients with chronic kidney disease are controversial. It remains to be addressed whether previously reported outcomes were the result of relief of the anemia, adverse effects of EPO, or direct cardiovascular effects.. Mice underwent 5/6 nephrectomy to cause renal dysfunction. Eight weeks later, when renal dysfunction was established, anemia and cardiac dysfunction and remodeling were apparent. Mice were then assigned to receive saline (control), recombinant human erythropoietin (rhEPO) at 5,000 IU (714 pmol)/kg, or asialoEPO at 714 pmol/kg, twice/week for 4 weeks.. Although only rhEPO relieved the nephrectomy-induced anemia, both rhEPO and asialoEPO significantly and similarly mitigated left ventricular dilation and dysfunction. The hearts of rhEPO- or asialoEPO-treated mice showed less hypertrophy, reflecting decreases in cardiomyocyte hypertrophy and degenerative subcellular changes, as well as significant attenuation of fibrosis, leukocyte infiltration, and oxidative deoxyribonucleic acid damage. These phenotypes were accompanied by restored expression of GATA-4, sarcomeric proteins, and vascular endothelial growth factor and decreased inflammatory cytokines and lipid peroxidation. Finally, myocardial activation was observed of extracellular signal-regulated protein kinase and signal transducer and activator of transcription pathways in the treated mice.. EPO receptor signaling exerts direct cardioprotection in an animal model of renal dysfunction-associated heart failure, probably by mitigating degenerative, pro-fibrosis, inflammatory, and oxidative processes but not through relief of anemia.

Topics: Anemia; Animals; Asialoglycoproteins; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Heart Failure; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Receptors, Erythropoietin; Recombinant Proteins; Renal Insufficiency; Signal Transduction

In patients with chronic heart failure, erythropoietin (Epo) levels are increased and related to a poor prognosis. Furthermore, Epo levels in these patients show a weak correlation with hemoglobin levels.. This is a retrospective analysis of a subgroup of the OPTIMAAL (Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan) trial in which serum Epo levels were measured at baseline, at 1 month, and at 1 and 2 years in 224 patients with an acute myocardial infarction complicated by signs or symptoms of heart failure. We investigated the determinants and the prognostic role of elevated Epo levels in these patients, and we studied the change in Epo levels by either captopril or losartan.. The correlation between Epo and hemoglobin at baseline (r = 0.348, P < .001) and after 1 month (r = 0.272, P < .001) disappeared after 1 year of follow up (r = 0.129, P = .102). At 1 year, C-reactive protein was the only factor associated with Epo levels. Higher Epo levels at baseline were independently related to a higher mortality during 2 years of follow-up (hazard ratio 2.84, P = .014). In the captopril group, logEpo levels decreased from 1.19 (+/-0.26) to 0.95 (+/-0.20) mIU/mL, and in the losartan group from 1.19 (+/-0.27) to 1.01 (+/-0.17) mIU/mL (P = .036 between groups).. In this substudy of the OPTIMAAL trial, the correlation between Epo and hemoglobin disappeared in early post-acute myocardial infarction heart failure patients. Furthermore, elevated Epo levels at baseline predicted increased mortality.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Captopril; Erythropoietin; Female; Heart Failure; Humans; Losartan; Male; Myocardial Infarction; Prognosis; Retrospective Studies

Anemia is common in patients with chronic heart failure and an independent predictor of poor prognosis. Chronic anemia leads to left ventricular (LV) hypertrophy and heart failure, but its molecular mechanisms remain largely unknown. We investigated the mechanisms, including the molecular signaling pathway, of cardiac remodeling induced by iron deficiency anemia (IDA). Weanling Sprague-Dawley rats were fed an iron-deficient diet for 20 wk to induce IDA, and the molecular mechanisms of cardiac remodeling were evaluated. The iron-deficient diet initially induced severe anemia, which resulted in LV hypertrophy and dilation with preserved systolic function associated with increased serum erythropoietin (Epo) concentration. Cardiac STAT3 phosphorylation and VEGF gene expression increased by 12 wk of IDA, causing angiogenesis in the heart. Thereafter, sustained IDA induced upregulation of cardiac hypoxia inducible factor-1alpha gene expression and maintained upregulation of cardiac VEGF gene expression and cardiac angiogenesis; however, sustained IDA promoted cardiac fibrosis and lung congestion, with decreased serum Epo concentration and cardiac STAT3 phosphorylation after 20 wk of IDA compared with 12 wk. Upregulation of serum Epo concentration and cardiac STAT3 phosphorylation is associated with a beneficial adaptive mechanism of anemia-induced cardiac hypertrophy, and later decreased levels of these molecules may be critical for the transition from adaptive cardiac hypertrophy to cardiac dysfunction in long-term anemia. Understanding the mechanism of cardiac maladaptation to anemia may lead to a new strategy for treatment of chronic heart failure with anemia.

Topics: Adaptation, Physiological; Anemia, Iron-Deficiency; Animals; Blood Pressure; Body Weight; Disease Models, Animal; Erythropoietin; Heart; Heart Failure; Heart Rate; Hypertrophy, Left Ventricular; Hypoxia-Inducible Factor 1, alpha Subunit; Iron; Kidney; Male; Myocardial Contraction; Myocardium; Neovascularization, Physiologic; Phosphorylation; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; STAT3 Transcription Factor; Time Factors; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Ventricular Function, Left; Ventricular Pressure; Ventricular Remodeling

Topics: Adaptation, Physiological; Anemia, Iron-Deficiency; Animals; Erythropoietin; Heart Failure; Hemodynamics; Humans; Hypertrophy, Left Ventricular; Myocardial Contraction; Myocardium; Neovascularization, Physiologic; Phosphorylation; Receptors, Erythropoietin; STAT3 Transcription Factor; Time Factors; Ventricular Function, Left; Ventricular Remodeling

Erythropoietin level was studied in blood plasma of humans from different age groups and in patients with chronic hearts failure of ishemic genesis. It was determined that there was no statistically significant difference of erythropoietin level among the age groups. Erythropoietin level in patients with chronic heart failure was 16-fold greater (102.86 +/- 29.04 mU/ml) than in the studied elder aged groups (6.38 +/- 1.82 mU/ml). The data obtained indicate that elderly (60 to 85 years) persons' organisms retain the ability of response to hypoxia by intensive erythropoietin production.

Topics: Adult; Aged; Aged, 80 and over; Aging; Chronic Disease; Erythropoietin; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Ischemia

The cardiorenal syndrome is a clinical and pathophysiological concept illustrating the relationship between the two organs, and is mainly based on the control of volemia. Heart failure is an example of this entity: when congestive heart failure becomes refractory, ultrafiltration by various modes of dialysis is needed. Ambulatory peritoneal ultrafiltration is a good alternative for the management of treatment-resistant congestive heart failure. Erythropoietin is the main treatment of anaemia of chronic renal failure for dialysed and predialysed patients, or patients with congestive heart failure and renal insufficiency. Correction of anaemia needs to be controlled at a maximal haemoglobin level of 12 g/dl.

Topics: Anemia, Iron-Deficiency; Clinical Trials as Topic; Erythropoietin; Heart Failure; Hemoglobins; Humans; Kidney Failure, Chronic

The aim of this work was to elucidate the relationship between the serum erythropoietin level, the degree of heart involvement in patients with chronic cardiac failure (CCF), characteristics of peripheral red blood cells and iron metabolism. A total of 77 patients with ischemic CCF were enrolled in the study. The control group comprised 13 subjects free from cardiovascular disorders. The analyses encompassed peripheral blood, serum iron, iron-binding capacity of serum, creatinine clearance, erythropoietin and TNF-alpha levels, echoCG data. The patients with CCF were divided into three groups based on the level of erythropoietin. Statistical analysis revealed the relationship between anemia, structural-functional changes in myocardium and erythropoietin production. Anemia appeared to be an additional stimulus for biosynthesis of erythropoietin in these patients.

Topics: Aged; Aged, 80 and over; Anemia; Biopsy; Dose-Response Relationship, Drug; Echocardiography; Erythropoietin; Female; Follow-Up Studies; Heart Failure; Humans; Iron; Male; Myocardium; Retrospective Studies; Treatment Outcome; Tumor Necrosis Factor-alpha

The most important predictors of long-term survival in patients with cardiac ischemic disease are left ventricular ejection fraction, left ventricular volumes, infarction size, presence and extent of residual myocardial ischemia. One of the most important recent developments in single photon emission computed tomography (SPECT) myocardial perfusion imaging is the ability to acquire these studies in conjunction with electrocardiogram (ECG) gating (G-SPECT). The ability to asses radionuclide myocardial perfusion and function with ECG G-SPECT imaging has revolutionized this field of nuclear cardiology. Study with G-SPECT development algorithms permits to quantify measures of left ventricular (LV) volume, ejection fraction (LVEF) and even regional myocardial wall motion and thickening. The American Society of Nuclear Cardiology (ASNC) in its position paper from March 1999 recommends the routine incorporation of G-SPECT during cardiac perfusion scintigraphy.. We presented a 70-year-old male with ischemic heart disease (dilatative, cardiomyopathy and absolute arrhythmia). He was few times hospitally treated by medicamentous therapy with no evidence of improvement. After hospital treatment, we included hyperbaric oxygenation (HBO) and erythropoietin injections. Hyperbaric oxygenation was carried out in a monoplace hyperbaric chamber, BLK S-303, by a graduated protocol for patients with severe heart insufficiency, totally 15 treatments. Recombinant erythropoietin beta (RecormonR F. Hoffmann-La Roche) was applied deeply subcutaneously, every second day from 2000 IU to totally 16000 IU. Before the therapy G-SPECT study was performed with 99m technetium-MIBI, and we obtained the functional parameters and perfusion of the left ventricle to follow-up the therapy effects. The study was performed by an ADAC-VERTEX PLUS-EPIC two-head gamma camera with dedicated quantitatively algorithm Auto-QUANT. The results of LVEF were 15%, with severity abnormal motion and wall thickening for all segments. Left ventricle end-diastolic volume was 393 ml (normal < 142 ml), and LV end-systolic volume was 334 ml (normal < 65 ml). Four months after the therapy G-SPECT showed improvement in any parameters; LVEF 25%, with improvement in wall motion (normalized wall motion in the anterior, lateral area, and proximal septum) and wall thickening, LV end-diastolic volume was 390 ml, LV end-systolic volume was 289 ml.. Using G-SPECT method before and after the therapy with hyperbaric oxygenation and erythropoietin we obtained objective improvement and good therapy effects in the treatment of chronic heart insufficiency.

Topics: Aged; Electrocardiography; Erythropoietin; Heart Failure; Humans; Hyperbaric Oxygenation; Male; Myocardial Perfusion Imaging; Recombinant Proteins; Tomography, Emission-Computed, Single-Photon; Ventricular Function, Left

The aim of this study was to analyse the prognostic impact of anaemia in patients receiving long-term left ventricular assist device (LVAD) support.. We reviewed the data of 65 consecutive patients who underwent LVAD support for at least 6 months. Anaemia was defined as haemoglobin levels <12.0 g/dL. Follow-up was performed 15 months after implantation. Anaemia was present in 30/65 patients (46%) after 6 months of LVAD support. Anaemic patients had higher levels of pre-implant creatinine (1.8 +/- 0.8 vs. 1.4 +/- 0.5 mg/dL; P = 0.04). The presence of anaemia after 6 months correlated with higher levels of creatinine and blood urea nitrogen and lower levels of albumin. Multivariate Cox proportional hazards regression analysis revealed that levels of haemoglobin <12 g/dL [risk ratio (RR), 8.94; 95% confidence interval (CI), 1.09-73.01; P = 0.04], creatinine >1.4 mg/dL (RR, 5.39; 95% CI, 1.78-16.30; P = 0.003), and albumin <1.5 g/L (RR, 3.23; 95% CI, 1.10-9.51; P = 0.03) were associated with all-cause mortality at 15 months. Long-term survival evaluated by Kaplan-Meier analysis was two times higher in non-anaemic patients after 6 months of LVAD support than in anaemic patients (P = 0.01).. Anaemia is related to adverse outcomes in patients receiving prolonged LVAD support.

Topics: Adult; Age Factors; Aged; Analysis of Variance; Anemia; Blood Chemical Analysis; Cohort Studies; Erythropoietin; Female; Follow-Up Studies; Heart Failure; Heart-Assist Devices; Humans; Incidence; Long-Term Care; Male; Middle Aged; Multivariate Analysis; Probability; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Severity of Illness Index; Sex Factors; Survival Analysis; Time Factors

To assess the safety and tolerability of darbepoetin alfa (DA) in the treatment of anaemia in heart failure (HF).. In this pooled analysis of three randomized, double-blind, placebo-controlled studies of anaemic [haemoglobin (Hb) < or =12.0 g/dL or < or =12.5 g/dL] symptomatic HF subjects, DA was administered subcutaneously once every 2 weeks and titrated to achieve and maintain a target Hb of 14.0 +/- 1.0 g/dL. In total, 516 subjects were randomized; 231 (44.8%) to placebo, 285 (55.2%) to DA. Darbepoetin alfa was well tolerated, with an adverse event (AE) profile similar to placebo. Most subjects (placebo, 85%; DA, 87%) experienced at least one AE. There was a lower incidence of serious AEs in the DA group (placebo, 43%; DA, 37%) with the most frequent being worsening HF (placebo, 19%; DA, 11%). Treatment-related AEs were reported for 9% and 12% in placebo and DA subjects, respectively. Fewer deaths were reported in DA group (6%) vs. placebo (8%).. Darbepoetin alfa was well tolerated with an AE profile similar to placebo in HF subjects treated to a target Hb of 14.0 +/- 1.0 g/dL. Contrary to recent data in other patient populations, there was no evidence of increased risk of mortality or cardiovascular events.

Topics: Aged; Anemia; Darbepoetin alfa; Erythropoietin; Female; Heart Failure; Hematinics; Hemoglobins; Humans; Male; Randomized Controlled Trials as Topic; Survival Analysis

Topics: Adrenergic beta-Antagonists; Anemia; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Drug Resistance; Erythropoietin; Heart Failure; Humans; Kidney Diseases

The prognosis in elderly patients with advanced chronic heart failure (CHF) and cardio-renal anemia syndrome (CRAS) is ominous, and treatment alternatives in this subset of patients are scarce.. To assess the long-term influence of combined therapy with intravenous (IV) iron and erythropoietin (rHuEPO) on hemoglobin (Hb), natriuretic peptides (NT-proBNP), and clinical outcomes in elderly patients with advanced CHF and mild-to-moderate renal dysfunction and anemia (CRAS) who are not candidates for other treatment alternatives, 487 consecutive patients were evaluated. Of them, 65 fulfilling criteria for entering the study were divided into 2 groups and treated in an open-label, nonrandomized fashion: intervention group (27, combined anemia therapy) and control group (38, no treatment for anemia). At baseline, mean age was 74 +/- 8 years, left ventricular ejection fraction was 34.5 +/- 14.1, Hb was 10.9 +/- 0.9 g/dL, creatinine was 1.5 +/- 0.5 mg/dL, NT-proBNP was 4256 +/- 4952 pg/mL, and 100% were in persistent New York Heart Association (NYHA) Class III or IV. At follow-up (15.3 +/- 8.6 months), patients in the intervention group had higher levels of hemoglobin (13.5 +/- 1.5 vs. 11.3 +/- 1.1; P < .0001), lower levels of natural log of NT-proBNP (7.3 +/- 0.8 vs. 8.0 +/- 1.3, P = .016), better NYHA functional class (2.0 +/- 0.6 vs. 3.3 +/- 0.5; P < .001), and lower readmission rate (25.9% vs. 76.3%; P < .001). In the multivariate Cox proportional hazards model, combined therapy was associated with a reduction of the combined end point all-cause mortality or cardiovascular hospitalization (HR 95%CI 0.2 [0.1-0.6]; P < .001).. Long-term combined therapy with IV iron and rHuEPO may increase Hb, reduce NT-proBNP, and improve functional capacity and cardiovascular hospitalization in elderly patients with advanced CHF and CRAS with mild to moderate renal dysfunction.

Topics: Aged; Aged, 80 and over; Anemia; Chronic Disease; Cohort Studies; Drug Evaluation; Drug Therapy, Combination; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Follow-Up Studies; Glucaric Acid; Heart Failure; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Neurotransmitter Agents; Pilot Projects; Prospective Studies; Recombinant Proteins; Survival Rate; Syndrome; Time Factors; Treatment Outcome

Anemia is common in congestive heart failure (CHF) and is associated with an increased mortality and morbidity. The most likely causes of anemia are chronic kidney disease (CKD) and excessive cytokine production, both of which can cause depression of erythropoietin (EPO) production and bone marrow activity. The cytokines also induce iron deficiency by both reducing gastrointestinal iron absorption and iron release from iron stores located in the macrophages and hepatocytes. Iron deficiency can cause thrombocytosis which might also contribute to cardiovascular complications in both CHF and CKD and is partially reversible with iron treatment. Thus attempts to control this anemia will have to consider both the use of erythropoiesis-stimulating agents (ESA), such as EPO, as well as oral and, probably more importantly, intravenous (IV) iron. The many studies on anemia in CHF patients treated with ESA and oral or IV iron, and even with IV iron without ESA have up to now shown a quite consistent positive effect on hospitalization, fatigue, shortness of breath, quality of life, exercise capacity, and beta-natriuretic peptide reduction, in the absence of increased cardiovascular damage related to the therapy. Adequately powered long-term placebo-controlled studies of ESA and/or IV iron are currently being carried out and their results are eagerly awaited.

Topics: Anemia; Erythropoietin; Heart Failure; Hemoglobins; Humans; Prevalence; Thrombocytosis

Anemia is frequently observed in patients with chronic heart failure (CHF) and is related to an impaired outcome. The origin of anemia in CHF is diverse and is associated with several factors including renal failure, resistance of the bone marrow to erythropoietin (EPO), hematinic deficiencies, and medication use. Recently, several small-scale clinical trials have shown that EPO treatment might improve clinical parameters in anemic heart failure patients. In addition, several preclinical studies have shown that EPO possesses non-hematopoietic effects. This current review focuses on the etiology, consequences, and treatment of anemia in heart failure patients. The pleiotropic effects of EPO in an experimental setting will also be discussed. Heart Fail Monit 2008;6(1):28-33.

Topics: Anemia; Bone Marrow; Chronic Disease; Epoetin Alfa; Erythropoietin; Heart Failure; Humans

We evaluated the relation between serum erithropoietin level and the severity of disease and mortality in patients with chronic heart failure (CHF).. We enrolled 96 CHF patients and 50 age- and sex-matched control subjects. Haemoglobin, haemotocrit, N terminal pro-B type natriuretic peptide (NT-proBNP) and erythropoietin levels and echocardiographic parameters were measured. The patients were contacted 1 year after the evaluations to determine survival.. The patients had lower haemoglobin and haematocrit but higher serum erythropoietin and NT-proBNP levels than the control subjects. Serum erythropoietin and NT-proBNP levels increased with worsening functional class. The serum erythropoietin level correlated negatively with left ventricular ejection fraction (r = -0.404, P < 0.001), haemoglobin (r = -0.530, P < 0.001) and haematocrit (r = -0.496, P < 0.001) levels. The patients who died (n = 17) had lower haemoglobin and haematocrit levels and significantly higher erythropoietin and NT-proBNP levels. However, multivariate logistic regression analysis showed that only NT-proBNP level was an independent predictor of mortality (P = 0.002).. Anaemia and resistance to erythropoietin develop proportionately to disease severity and left ventricular systolic dysfunction in patients with CHF. Although serum erythropoietin level seems related with mortality, this observation needs to be confirmed by studies with more patients and longer follow-up.

Topics: Biomarkers; Chronic Disease; Echocardiography; Erythropoietin; Female; Follow-Up Studies; Heart Failure; Hematocrit; Humans; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Protein Precursors; Severity of Illness Index; Survival Rate; Time Factors; Turkey

Aims Chronic heart failure (CHF) is frequently associated with a decreased haemoglobin level, whereas the mechanism remains largely unknown. Methods and results One hundred consecutive CHF patients without anaemia or renal dysfunction based on non-cardiac reasons were enrolled. We explored determinants of anaemia (as iron parameters, erythropoietin, hepcidin and kidney function) including red cell volume (RCV) (by a 51 Cr assay) as well as related markers and plasma volume. The influence of each factor on haemoglobin concentrations was determined in a multiple regression model. Mean haemoglobin concentrations were 11.7 +/- 0.8 mg/dL in anaemic CHF patients and 14.4 +/- 1.2 mg/dL in non-anaemic patients. Corrected reticulocytes were lower in anaemic patients (35.1 +/- 15.7 vs. 50.3 +/- 19.2 G/L, P = 0.001), but the RCV was not reduced (1659.3 +/- 517.6 vs. 1826.4 +/- 641.3 mL, P = 0.194). We found that plasma volumes were significantly higher in anaemic CHF patients (70.0 +/- 2.4 vs. 65.0 +/- 4.0%, P < 0.001). Plasma volume was the best predictor of haemoglobin concentrations in the regression model applied (B = -0.651, P < 0.001, R(2) = 0.769). Conclusion Haemodilution appears to be the most potent factor for the development of low haemoglobin levels in patients with CHF. Our data support an additional independent, but minor influence of iron deficiency on haemoglobin concentrations in CHF patients.

Topics: Anemia, Iron-Deficiency; Chronic Disease; Cross-Sectional Studies; Erythrocyte Volume; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Iron; Male; Middle Aged; Plasma Volume

Erythropoietin (EPO), traditionally known as a hematopoietic hormone, has recently been shown to have effects beyond hematopoiesis such as prevention of neuronal and cardiac apoptosis secondary to ischemia and induction of neoangiogenesis. Patients with congestive heart failure (CHF) suffer considerable morbidity and mortality despite advances in therapy. Anemia, CHF, and chronic kidney insuficiency often coexist and interact to cause or worsen each other in the so-called cardio-renal anemia syndrome. Treatment with EPO has shown promise in such patients. The paper reviews a case of a successful recovery of cardiac function in a patient with a severe CHF during the treatment with EPO.

Topics: Anemia; Erythropoietin; Female; Heart Failure; Humans; Middle Aged; Renal Insufficiency, Chronic

Topics: Biomarkers; Erythropoietin; Heart Failure; Hemoglobins; Humans

In anemic patients with heart failure (HF), erythropoietin-type drugs can elicit clinical improvement. This study examined the effects of chronic monotherapy with darbepoetin-alpha (DARB) on left ventricular (LV) function and remodeling in nonanemic dogs with advanced HF. HF [LV ejection fraction (EF) approximately 25%] was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to once a week subcutaneous injection of DARB (1.0 microg/kg, n=7) or to no therapy (HF, n=7). All procedures were performed during cardiac catheterization under general anesthesia and under sterile conditions. LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF were measured before the initiation of therapy and at the end of 3 mo of therapy. mRNA and protein expression of caspase-3, hypoxia inducible factor-1alpha, and the bone marrow-derived stem cell marker c-Kit were determined in LV tissue. In HF dogs, EDV and ESV increased and EF decreased after 3 mo of followup. Treatment with DARB prevented the increase in EDV, decreased ESV, and increased EF. DARB therapy also normalized the expression of HIF-1alpha and active caspase-3 and enhanced the expression of c-Kit. We conclude that chronic monotherapy with DARB prevents progressive LV dysfunction and dilation in nonanemic dogs with advanced HF. These results suggest that DARB elicits beneficial effects in HF that are independent of the presence of anemia.

Topics: Anemia; Animals; Bone Marrow Cells; Cardiotonic Agents; Caspase 3; Darbepoetin alfa; Disease Models, Animal; Disease Progression; Dogs; Erythropoietin; Heart Failure; Hematinics; Hematopoietic Stem Cells; Hypoxia-Inducible Factor 1, alpha Subunit; Injections, Subcutaneous; Myocardium; Proto-Oncogene Proteins c-kit; RNA, Messenger; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Remodeling

The present study investigated the immunohistochemical distributions and mRNA expressions of myocardial hypoxia-inducible factor (HIF)-1 alpha and its downstream factors, erythropoietin (Epo) and vascular endothelial growth factor (VEGF), in cardiac deaths. Medico-legal autopsy cases (n=114, within 48-h postmortem) of cardiac deaths (n=58) and control cases (n=56) were examined. Immunohistochemical positivities of HIF-1 alpha, Epo and VEGF were patchily observed in cardiomyocytes in the acute ischemic lesions of myocardial infarction (n=37), showing a relationship to morphological cardiomyocyte damage: the staining was intense in the regions with early ischemic changes and weak in the necrotic regions. Immunopositivities were sporadically detected in cardiomyocytes in some cases of sudden cardiac death without infarction (SCD, n=13). In chronic congestive heart disease (CHD, n=8), weak positivities were diffusely observed in the cardiomyocytes. However, there were no such findings in cases of mechanical asphyxiation (n=16) or drowning (n=18). HIF-1 alpha, Epo and VEGF mRNA expressions, as measured by real-time reverse transcription-polymerase chain reaction (RT-PCR), showed localized elevations related to acute myocardial infarction (AMI) lesions, whereas such findings were mild in recurrent myocardial infarction (RMI) and SCD cases. CHD showed significant elevations of these mRNAs irrespective of the sampling site. The mRNA expressions were significantly lower in cases of drowning. These findings suggest that focal immunopositivities and increased mRNAs of these factors are indicative of short and substantial duration of myocardial ischemia, respectively. The combined analyses may not only be useful for investigating the site, phase and severity of acute myocardial ischemia and the severity of chronic ischemic stress, but also contribute to differentiating cardiac deaths from asphyxiation and drowning or interpreting the possible contribution of cardiac disease in traumatic death.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Death, Sudden, Cardiac; Erythropoietin; Female; Forensic Pathology; Heart Failure; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Male; Middle Aged; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sensitivity and Specificity; Vascular Endothelial Growth Factor A

Carnitine improves erythropoetin (EPO) response and anaemia in haemodialysis patients (HD); however, the mechanism(s) responsible remain unidentified. We have reported that carnitine induces haem oxygenase (HO)-1, which is an antioxidant and antiapoptotic that acts via pathways shared with EPO. Therefore carnitine's effect on these pathways may account for the improved EPO response. This study evaluates carnitine's effect on protein expression of HO-1 in unexplained EPO resistant HD. Carnitine's effect was assessed by HO-1 expression in patients and compared to its antiapoptotic effect via HO-1 induction in a rat model of carnitine-treated heart failure.. Unexplained EPO resistant HD mononuclear cell HO-1 and rat gastrocnemious muscle HO-1 and Bcl-2 protein expression were evaluated by western blot.. HD's haemoglobin (Hb) and haematocrit (Ht) were not different before carnitine treatment: 8.8 +/- 0.4 mg/dl versus 8.98 +/- 0.13 and 30.20% +/- 0.84 versus 30.72 +/- 1.14, respectively. Carnitine increased HO-1, Hb and Ht compared with patients not treated with carnitine: 2.40 +/- 0.58 versus 1.49 +/- 0.41, P = 0.02; 11.22 +/- 0.54 versus 8.90 +/- 0.15, P < 0.0001; 32.72 +/- 1.77 versus 30.66 +/- 0.43, P = 0.035, respectively. Carnitine-treated HD's HO-1 significantly correlated with haemoglobin. HO-1 and Bcl-2 protein levels in untreated heart failure rat's gastrocnemious muscle were reduced when compared with controls: 3.41 +/- 0.49 versus 5.32 +/- 0.38 and 0.69 +/- 0.11 versus 1.65 +/- 0.37, respectively, but were higher in carnitine-treated heart failure rats: 4.8 +/- 0.32 versus 3.41 +/- 0.49, P < 0.0002 and 1.09 +/- 0.08 versus 0.69 +/- 0.11, P = 0.0007, respectively.. These results are consistent with an involvement of HO-1 in carnitine's effect on erythropoiesis. The initial signals or effectors responsible for carnitine's effect remain to be identified.

Topics: Animals; Apoptosis; Carnitine; Disease Models, Animal; Erythropoiesis; Erythropoietin; Heart Failure; Hematocrit; Heme Oxygenase-1; Hemoglobins; Humans; Leukocytes, Mononuclear; Male; Monocrotaline; Muscle, Skeletal; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Rats; Renal Dialysis; Signal Transduction

Anaemia is common following renal transplantation and is associated with the development of congestive heart failure (CHF). However the prevalence of anaemia in the first year following transplantation and the association between anaemia occurring early and the development of CHF have been understudied.. In this study, 132 incident patients undergoing tacrolimus and mycophenolate mofetil-based renal transplantation were studied for the prevalence of, and risk factors for, anaemia and CHF in the early period post transplantation.. Anaemia occurred in 94.5% and 53.1% of patients at 1 week and 12 months, respectively, and was associated with allograft dysfunction, hypoalbuminaemia, higher mycophenolic acid (MPA) levels, bacterial infection and hypoalbuminaemia. The association with hypoalbuminaemia may reflect the presence of chronic inflammation post-transplantation. Of patients displaying haemoglobin <11 g/dl, 41.1% and 29.4% were treated with erythropoiesis stimulating agents (ESAs) at 1 and 12 months respectively. CHF developed in 26 patients beyond 1 month post-transplantation, with echocardiographic left ventricular systolic function preserved in all but one. CHF was associated with anaemia and lower haemoglobin, allograft dysfunction, duration of dialysis and left ventricular hypertrophy on echocardiography prior to transplantation, suggesting the aetiology of CHF may involve the interplay of diastolic cardiac dysfunction, pre-load mismatch and after-load mismatch.. Modification of risk factors may improve anaemia management post transplantation. Reducing the prevalence of anaemia may in turn reduce the incidence of CHF-these observations support the need for clinical trials to determine how anaemia management may impact CHF incidence.

Topics: Adult; Anemia; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Hypoalbuminemia; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recombinant Proteins; Risk Factors; Tacrolimus; Time Factors

Erythropoietin (EPO) may improve cardiac function and induce neovascularisation in experimental models of chronic heart failure (CHF). However, the increased haematocrit associated with EPO treatment might exert concomitant deleterious effects.. To investigate the haematocrit independent effects of EPO on cardiac function.. Rats underwent permanent coronary artery ligation to induce myocardial infarction (MI) or sham surgery. Three weeks after MI, rats were randomly allocated to treatment with vehicle (MI) or the long-acting EPO analogue darbepoetin alfa administered in a high (40 microg/kg/3 weeks, MI-EPO-high) or a low-dose (0.4 microg/kg/3 weeks, MI-EPO-low). After 9 weeks, haemodynamic parameters, myocardial histology and Myosin Heavy Chain (MHC) isoforms were determined. High-dose EPO resulted in a significant increase in haematocrit (p<0.01) while low-dose EPO had no effect on haematocrit levels. EPO significantly improved cardiac function in both EPO groups, reflected by increased left ventricular (LV)-developed pressure and improved contractility (dP/dt(max)) and relaxation (dP/dt(min)) indices of the LV at 9-weeks (all p<0.05 compared to MI). The improved cardiac function was associated with increased capillary growth (38% in MI-EPO-high (p<0.01) and 27% in MI-EPO-low (p<0.05)) and an attenuated switch to slow beta-MHC isoforms in both EPO groups.. EPO improves cardiac function and induces neovascularisation at a dose that does not increase haematocrit, thereby circumventing the possible deleterious effects of increased erythropoiesis.

Topics: Animals; Apoptosis; Capillaries; Coronary Vessels; Darbepoetin alfa; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoietin; Heart Failure; Hematinics; Hematocrit; Male; Myocardial Contraction; Neovascularization, Physiologic; Random Allocation; Rats; Rats, Sprague-Dawley; Treatment Outcome

Topics: Anemia, Iron-Deficiency; Darbepoetin alfa; Double-Blind Method; Erythropoietin; Ferric Compounds; Heart Failure; Hematinics; Homeostasis; Humans; Multicenter Studies as Topic; Randomized Controlled Trials as Topic

Topics: Anemia; Epoetin Alfa; Erythropoietin; Follow-Up Studies; Heart Failure; Hematocrit; Humans; Kidney Failure, Chronic; Myocardial Infarction; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Survival Analysis

Topics: Anemia; Chronic Disease; Erythropoietin; Heart Failure; Hematinics; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Myocardial Contraction; Natriuretic Peptide, Brain; Recombinant Proteins; Stroke Volume; Syndrome; Systole; Ventricular Function, Left; Ventricular Remodeling

We aimed to evaluate whether ischemia is required for erythropoietin (EPO) induced stimulation of endothelial progenitor cells (EPCs) and their related effects on endothelial and cardiac function.. Bone marrow of rats was replaced by transgenic cells to allow tracking of EPCs. Ischemic heart failure was induced by left coronary artery ligation to induce myocardial infarction (MI) and control rats received a sham procedure. Three weeks after surgery, rats were randomized to receive EPO (darbepoetin alfa 40 microg/kg per 3 weeks) or vehicle and were sacrificed 9 weeks after surgery.. In all treated groups, EPO significantly increased circulating EPCs and their incorporation into the endothelium of the ischemic and non-ischemic hearts as well as in the control organs; kidney and liver. This was associated with significantly improved endothelial function, which was strongly correlated with circulating EPCs (R = 0.7, p < 0.01). However, additional EPCs preferentially homed to the ischemic MI borderzone (p < 0.01) resulting in specific EPO-induced improvement of cardiac microvascularization and performance only in ischemic hearts (all p < 0.05). The differential stimulation of neovascularization by EPO was associated with increased EPO-receptor and VEGF expression in ischemic hearts only.. In general, EPO stimulates normal endothelial progenitor cell-mediated endothelial turnover, but improves cardiac microvascularization and function only in the presence of ischemia.

Topics: Alkaline Phosphatase; Angiogenesis Inducing Agents; Animals; Bone Marrow Transplantation; Capillaries; Cell Movement; Coronary Vessels; Darbepoetin alfa; Disease Models, Animal; Endothelial Cells; Erythropoietin; GPI-Linked Proteins; Heart Failure; Humans; Isoenzymes; Male; Myocardial Contraction; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Rats; Rats, Inbred F344; Rats, Transgenic; Stem Cells; Vasodilation; Ventricular Function, Left; Ventricular Pressure

In 2007, several international studies brought useful information for the daily work of internists in hospital settings. This summary is of course subjective but reflects the interests and questions of the chief residents of the Department of internal medicine who wrote this article like an original trip in medical literature. This trip will allow you to review some aspects of important fields such as heart failure, diabetes, endocarditis, COPD, and quality of care. Besides the growing diversity of the fields covered by internal medicine, these various topics underline also the uncertainty internists have to face in a practice directed towards evidence.

Topics: Accidental Falls; Aged; Albuterol; Anemia; Anticoagulants; Antidiuretic Hormone Receptor Antagonists; Atrial Fibrillation; Attitude of Health Personnel; Benzazepines; Bronchitis, Chronic; Bronchodilator Agents; Cardiac Pacing, Artificial; Diabetes Mellitus; Endocarditis, Bacterial; Erythropoietin; Heart Failure; Heparin; Humans; Internal Medicine; Interprofessional Relations; Medical Staff, Hospital; Myocardial Infarction; Recombinant Proteins; Risk Management; Rosiglitazone; Salmeterol Xinafoate; Thiazolidinediones; Thromboembolism; Tolvaptan; Vasodilator Agents; Ventricular Dysfunction, Left; Workload

We examined the adequacy of endogenous erythropoietin (EPO) levels for the degree of anaemia in patients with chronic heart failure (CHF) and its relation to prognosis.. We studied 74 anaemic CHF patients from a cohort of 240 patients. The adequacy of endogenous EPO levels was assessed by derived observed/predicted (O/P) ratio. A ratio value < 0.92 indicates EPO levels lower than expected, whereas a value > 1.09 indicates EPO levels higher than expected. The primary endpoint was mortality. During a median follow up of 4.9 years, 35 of the 74 (47.3%) anaemic patients died. EPO levels lower than expected were observed in 29 patients (39%), whereas EPO levels higher than expected were present in 22 anaemic patients (29%). The Kaplan-Meier analysis revealed that anaemic patients with EPO levels higher than expected had a significantly higher mortality rate compared to patients with EPO levels as expected or EPO levels lower than expected (log-rank: P = 0.024). A higher O/P ratio was an independent predictor of increased mortality risk adjusted for variables including age, sex, haemoglobin, NT-proBNP, and renal function; hazard ratio (HR): 1.020 95%CI (1.004-1.036), P = 0.012.. EPO levels higher than expected, suggesting resistance to the hormone, are common in CHF patients and are associated with a higher mortality.

Topics: Aged; Anemia, Iron-Deficiency; Biomarkers; Epidemiologic Methods; Erythropoietin; Female; Heart Failure; Humans; Male; Prognosis; Stroke Volume

Topics: Anemia, Iron-Deficiency; Biomarkers; Erythropoietin; Heart Failure; Humans; Prognosis

Endothelial progenitor cells (EPCs) circulate in the adult peripheral blood and contribute to neovascularization. EPCs are considered to be included in CD34 positive mononuclear cells (CD34+ MNCs). Kinetics of circulating EPCs in congestive heart failure (CHF) has not been fully investigated.. We determined the numbers of white blood cells (WBCs), plasma brain natriuretic peptide (BNP), serum erythropoietin, vascular endothelial growth factor (VEGF) and thrombomodulin levels in 16 mild CHF patients (NYHA I, II), 10 severe CHF patients with acute exacerbation (NYHA III, IV), and 22 control subjects. The number of CD34+ MNCs in peripheral blood was quantified by flow cytometry.. The ratio of CD34+ MNCs:10(3) WBCs in mild CHF patients was higher than that in control subjects (P<0.05). Interestingly, the ratio of CD34+ MNCs:10(3) WBCs in severe CHF patients at admission was significantly lower than that in control subjects (P<0.005) or in mild CHF patients (P<0.05). Levels of BNP and erythropoietin in severe CHF patients were significantly higher than those in mild CHF patients. However, VEGF and thrombomodulin levels were not different between mild and severe CHF patients. In addition, the ratio of CD34+ MNCs:10(3) WBCs in severe CHF patients increased in proportion to the amelioration of CHF during hospitalization, and this increase correlated with the decrease in BNP level.. The ratio of CD34+ MNCs:10(3) WBCs was decreased in severe CHF. These findings suggest that impaired EPC recruitment might be involved in the pathophysiology of severe CHF.

Topics: Aged; Antigens, CD34; Case-Control Studies; Erythropoietin; Female; Heart Failure; Humans; Leukocyte Count; Leukocytes, Mononuclear; Male; Middle Aged; Natriuretic Peptide, Brain; Severity of Illness Index; Thrombomodulin; Vascular Endothelial Growth Factor A

Anaemia is prevalent in the chronic heart failure (CHF) population, but its cause is often unknown. The present study aims to investigate the relation between anaemia, renal perfusion, erythropoietin production, and fluid retention in CHF patients.. We studied 97 patients with CHF, of which 15 had anaemia (Hb<13.0 g/dL in men and Hb<12.0 g/dL in women), without haematinic deficiencies. Glomerular filtration rate (GFR) and extracellular volume (ECV) were measured as the clearance and the distribution volume of constantly infused 125I-iothalamate, respectively. Effective renal plasma flow (ERPF) was determined as the clearance of 131I-hippuran. Anaemic CHF patients displayed significantly reduced GFR (P=0.002), ERPF (P=0.005) and EPO production (P=0.001), and an elevated ECV (P=0.015). Multivariable analysis demonstrated that lower GFR (P=0.003), lower ERPF (P=0.004), lower EPO production (P=0.006), and a higher ECV (P=0.001) were significant independent predictors of lower haemoglobin levels.. Anaemia in CHF is not only independently associated with impaired renal perfusion and blunted EPO production, but to fluid retention as well.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Cell Size; Chronic Disease; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Renal Circulation; Renal Plasma Flow, Effective; Water-Electrolyte Imbalance

Topics: Erythropoietin; Heart Failure; Humans; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Heart Failure; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous

Topics: Anemia; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Cohort Studies; Comorbidity; Diuretics; Erythropoietin; Forecasting; Heart Failure; Humans; Iron; Kidney Failure, Chronic; Prevalence; Prognosis; Stroke Volume

Topics: American Heart Association; Anemia; Arrhythmias, Cardiac; Catheter Ablation; Chicago; Darbepoetin alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Mesenchymal Stem Cell Transplantation; Myoblasts, Skeletal; Myocardial Infarction; Quality of Life; Stroke Volume

Erythropoietin (EPO) improves cardiac function and induces neovascularization in chronic heart failure (CHF), although the exact mechanism has not been elucidated. We studied the effects of EPO on homing and incorporation of endothelial progenitor cells (EPC) into the myocardial microvasculature and myocardial expression of angiogenic factors.. CHF was induced in rats by coronary artery ligation resulting in myocardial infarction (MI) after bone marrow had been replaced by human placental alkaline phosphatase (hPAP) transgenic cells. We studied the effects of darbepoetin alfa treatment (EPO, 40 microg/kg, every 3 weeks, starting 3 weeks after MI) on longitudinal changes in left ventricular (LV) function, circulating EPC, myocardial histology, and expression of vascular endothelial growth factor (VEGF) determined 9 weeks after MI. EPO prevented LV-dilatation and improved cardiac function (all P < 0.05), which was associated with 42% increased capillary growth (P < 0.01). EPO-induced mobilization of EPC from the bone marrow (P < 0.01), which resulted in a three-fold increased homing of EPC into the cardiac microvasculature. The percentage of the endothelium that consisted of bone marrow derived cells was significantly increased (3.9 +/- 0.5 vs. 11.4 +/- 1%, P < 0.001) comprising 30% of the newly formed capillaries. In addition, EPO treatment resulted in a 4.5-fold increased myocardial expression of VEGF, which correlated strongly with neovascularization (r = 0.67; P < 0.001). VEGF was equally expressed by endothelial cells of myocardial and bone marrow origin.. EPO-induced neovascularization in post-MI heart failure is mediated through a combination of EPC recruitment from the bone marrow and increased myocardial expression of VEGF.

Topics: Animals; Capillaries; Collateral Circulation; Darbepoetin alfa; Echocardiography; Endothelial Cells; Endothelium, Vascular; Erythropoietin; Heart Failure; Male; Myocardial Infarction; Neovascularization, Physiologic; Rats; Rats, Inbred F344; Stem Cells; Up-Regulation; Vascular Endothelial Growth Factor A; Ventricular Dysfunction, Left

Topics: Anemia; Chronic Disease; Erythropoietin; Heart Failure; Hematinics; Humans; Recombinant Proteins

Topics: Anemia; Erythropoietin; Female; Heart Failure; Humans; Male; Severity of Illness Index

Topics: Anemia, Iron-Deficiency; Erythropoietin; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Heart Failure; Hematinics; Humans; Infusions, Intravenous; Natriuretic Peptide, Brain; Peptide Fragments; Treatment Outcome

Topics: Anemia, Iron-Deficiency; Erythropoietin; Heart Failure; Humans; Iron Compounds; Length of Stay; Prevalence; Prognosis; Sleep Apnea Syndromes; Survival Rate

Central sleep apnea (CSA) (with or without Cheyne-Stokes breathing) or obstructive sleep apnea (OSA) are common in congestive heart failure (CHF). Correction of anemia may improve CHF. We hypothesized that correction of anemia might also improve sleep-related breathing disorders (SRBDs) in CHF.. Thirty-eight patients with CHF and anemia (hemoglobin level < 12 g/dL) were treated with erythropoietin and intravenous iron to a target hemoglobin level of 13 g/dL. Home sleep recordings were done before and after 3 months of treatment.. Thirty-seven patients had SRBD (Apnea Hypopnea Index [AHI] of > or = 10). Hemoglobin level increased from 10.4 +/- 0.8 to 12.3 +/- 1.2 g/dL (P < .001). Total AHI values decreased from 35.9 +/- 12.2 to 24.9 +/- 12.2 (P < .001). The AHI of CSA, OSA and Cheyne-Stokes breathing decreased from 26.5 +/- 14.6 to 18.6 +/- 7.7, from 9.4 +/- 10.9 to 6.9 +/- 9.8, and from 13.1 +/- 16.4 to 9.0 +/- 12.2, respectively (all P < .05). Sleep minimal oxygen saturation (SaO2) increased from 62% +/- 12% to 71% +/- 11%; Epworth Sleepiness Scale score improved from 9.4 +/- 6.2 to 6.0 +/- 5.0 and New York Heart Association class improved from 2.9 +/- 0.4 to 1.7 +/- 0.7, all P < .001. Hemoglobin level improvement correlated with improvement in OSA+CSA, CSA, minimal SaO2, Epworth Sleepiness Scale score, and New York Heart Association class (all P < .001).. Improvement of anemia in CHF is associated with a reduction in SRBD and an improvement in daytime sleepiness.

Topics: Aged; Anemia, Iron-Deficiency; Dose-Response Relationship, Drug; Drug Therapy, Combination; Erythropoietin; Female; Ferric Compounds; Ferritins; Follow-Up Studies; Heart Failure; Hematinics; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Polysomnography; Retrospective Studies; Sleep; Sleep Apnea Syndromes; Treatment Outcome

Doxorubicin is a highly effective antineoplastic drug, but its clinical use is limited by its adverse side effects on the heart. We investigated possible protective effects of erythropoietin against doxorubicin-induced cardiomyopathy.. Cardiomyopathy was induced in mice by a single intraperitoneal injection of doxorubicin (15 mg/kg). In some cases, human recombinant erythropoietin (5000 U/kg) was started simultaneously. Two weeks later, left ventricular dilatation and dysfunction were apparent in mice given doxorubicin but were significantly attenuated by erythropoietin treatment. Erythropoietin also protected hearts against doxorubicin-induced cardiomyocyte atrophy and degeneration, myocardial fibrosis, inflammatory cell infiltration, and downregulation of expression of GATA-4 and 3 sarcomeric proteins, myosin heavy chain, troponin I, and desmin. Cyclooxygenase-2 expression was upregulated in doxorubicin-treated hearts, and that, too, was attenuated by erythropoietin. No doxorubicin-induced apoptotic effects were seen, nor were any changes seen in the expression of tumor necrosis factor-alpha or transforming growth factor-beta1. Antiatrophic and GATA-4 restoring effects of erythropoietin were demonstrated in the in vitro experiments with cultured cardiomyocytes exposed to doxorubicin, which indicated the direct cardioprotective effects of erythropoietin beyond erythropoiesis. Cardiac erythropoietin receptor expression was downregulated in doxorubicin-induced cardiomyopathy but was restored by erythropoietin. Among the downstream mediators of erythropoietin receptor signaling, activation of extracellular signal-regulated kinase was reduced by doxorubicin but restored by erythropoietin. By contrast, erythropoietin was ineffective when administered after cardiac dysfunction was established in the chronic stage.. The present study indicates a protective effect of erythropoietin against doxorubicin-induced cardiomyopathy.

Topics: Animals; Antibiotics, Antineoplastic; Cardiomyopathies; Caspase 3; Caspases; Cells, Cultured; Cyclooxygenase 2; Cytokines; Doxorubicin; Erythrocyte Count; Erythropoietin; GATA4 Transcription Factor; Heart Failure; In Situ Nick-End Labeling; Mice; Mice, Inbred C57BL; Myocardium; Myocytes, Cardiac; Receptors, Erythropoietin; Sarcomeres; Survival Rate; Ventricular Dysfunction, Left

Recent studies have suggested that endogenous erythropoietin (Epo) plays an important role in the mobilization of bone marrow-derived endothelial progenitor cells (EPCs). However, it remains to be elucidated whether the Epo system exerts protective effects on pulmonary hypertension (PH), a fatal disorder encountered in cardiovascular medicine.. A mouse model of hypoxia-induced PH was used for study. We evaluated right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in mice lacking the Epo receptor (EpoR) in nonerythroid lineages (EpoR(-/-) rescued mice) after 3 weeks of exposure to hypoxia. Those mice lack EpoR in the cardiovascular system but not in the hematopoietic system. The development of PH and pulmonary vascular remodeling were accelerated in EpoR(-/-) rescued mice compared with wild-type mice. The mobilization of EPCs and their recruitment to the pulmonary endothelium were significantly impaired in EpoR(-/-) rescued mice. By contrast, reconstitution of the bone marrow with wild-type bone marrow cells ameliorated PH in the EpoR(-/-) rescued mice. Hypoxia enhanced the expression of EpoR on pulmonary endothelial cells in wild-type but not EpoR(-/-) rescued mice. Finally, hypoxia activated endothelial nitric oxide synthase in the lungs in wild-type mice but not in EpoR(-/-) rescued mice.. These results indicate that the endogenous Epo/EpoR system plays an important role in the recruitment of EPCs and prevents the development of PH during chronic hypoxia in mice in vivo, suggesting the therapeutic importance of the system for the treatment of PH.

Topics: Animals; Bone Marrow Transplantation; Cell Movement; Cells, Cultured; Chronic Disease; Endothelial Cells; Endothelium; Endothelium, Vascular; Enzyme Activation; Erythroid Precursor Cells; Erythropoietin; GATA1 Transcription Factor; Heart Failure; Hematopoietic Stem Cells; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Lung; Male; Mice; Mice, Knockout; Mice, Transgenic; Muscle, Smooth, Vascular; Nitric Oxide Synthase Type III; Organ Specificity; Radiation Chimera; Receptor, TIE-2; Receptors, Erythropoietin; Systole; Ventricular Dysfunction, Right

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the American College of Cardiology 55th Annual Scientific Session held in March 2006. All reports should be considered as preliminary data, as analyses may change in the final publication. Darbepoetin alfa increased haemoglobin levels in heart failure patients and improved some aspects of quality of life compared to placebo. In the ASTEROID study rosuvastatin significantly reduced LDL-cholesterol levels and induced regression of atherosclerosis in patients with CAD. Rosuvastatin also produced a significant reduction in LDL-cholesterol levels in heart failure patients in the UNIVERSE study, but had no effect on left ventricular remodelling compared to placebo. The paediatric carvedilol study failed to show a benefit of carvedilol in children with heart failure. Ultrafiltration produced a greater weight and fluid loss than intravenous diuretics in heart failure patients with volume overload in the UNLOAD study but did not exert a greater improvement in breathlessness; however, ultrafiltration did reduce readmission rates. The ICELAND MI study showed that CMR imaging was more sensitive than ECG or clinical criteria for detecting myocardial infarction.

Topics: Carbazoles; Carvedilol; Child; Cholesterol, LDL; Clinical Trials as Topic; Darbepoetin alfa; Diuretics; Erythropoietin; Fluorobenzenes; Heart Failure; Humans; Myocardial Infarction; Propanolamines; Pyrimidines; Rosuvastatin Calcium; Sulfonamides; Ultrafiltration

Topics: Animals; Erythropoietin; Heart Failure; Hematocrit; Humans; Myocardial Infarction; Neovascularization, Physiologic

Late treatment with erythropoietin (EPO), as well as the administration before the onset of or during the acute stage of myocardial infarction (MI), has recently been shown to mitigate post-MI heart failure. We investigated the mechanisms, including the downstream signaling pathways, for the beneficial effect of late treatment with EPO on chronic post-MI heart failure.. EPO (1500 U/kg, twice a week) was administered to mice beginning 6 weeks after induction of large MI. The EPO treatment for 4 weeks diminished left ventricular dilatation and improved function. It significantly reduced inflammatory cell infiltration and fibrosis, and increased vascular density in noninfarcted areas. The elevated levels of the inflammatory cytokines interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha and transforming growth factor-beta1 seen in the failing hearts were returned nearly to control levels by EPO treatment. Oxidative damage in surviving cardiomyocytes was also significantly attenuated by EPO. Expression of EPO receptor was upregulated in failing hearts, and EPO treatment led to myocardial activation of signal transducer and activator of transcription-3 (Stat3), Stat5, and Akt. These in vivo effects of EPO were confirmed in vitro in experiments that showed the anti-inflammatory and anti-oxidant effects of EPO to be mediated via Stat and Akt activation. Finally, the beneficial effects of EPO were found to persist for 4 weeks after discontinuing treatment.. It thus appears that Stat-mediated reduction of inflammation and cytokine production and Akt-mediated attenuation of oxidative stress accompany the beneficial effects of late treatment with EPO on chronic post-MI heart failure.

Topics: Animals; Blotting, Western; Cells, Cultured; Cytokines; Echocardiography; Erythropoietin; Fibroblasts; Heart Failure; Hematocrit; Hydrogen Peroxide; Immunohistochemistry; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Models, Animal; Myocardium; Myocytes, Cardiac; Oxidation-Reduction; Random Allocation; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction; Time; Ventricular Remodeling

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the European Society of Cardiology heart failure meeting held in June 2006. All reports should be considered as preliminary data, as analyses may change in the final publication. In a sub-group analysis of the TNT study, intensive treatment with high-dose atorvastatin significantly reduced hospitalisations for heart failure in patients with stable coronary heart disease, compared with low-dose atorvastatin; this benefit was most evident in patients with a history of heart failure at baseline. In a combined analysis of two studies of darbepoetin alfa, which included 475 patients, treatment increased and maintained haemoglobin levels and produced non-significant improvements in symptoms and morbidity in anaemic heart failure patients compared to placebo. In the FERRIC-HF study (n=35), intravenous iron sucrose therapy improved exercise capacity and symptom status in iron-deficient heart failure patients. In a combined analysis of two studies (n=186), the adenosine A(1) receptor antagonist KW-3902 showed diuretic properties and appeared to enhance response to loop diuretics in heart failure patients hospitalised with fluid overload.

Topics: Anemia; Atorvastatin; Cardiology; Clinical Trials as Topic; Congresses as Topic; Darbepoetin alfa; Diuretics; Erythropoietin; Europe; Exercise Tolerance; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Heart Failure; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyrroles; Societies, Medical; Xanthines

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Prognosis; Syndrome

Topics: Anemia; Cardiovascular Diseases; Epoetin Alfa; Erythropoietin; Heart Failure; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Recombinant Proteins; Renal Insufficiency, Chronic

Anaemia is frequently found in patients with chronic heart failure (CHF) and has been associated with an increase in mortality and morbidity, impaired cardiac and renal function and a reduced quality of life (QoL) compared with non-anaemic CHF patients. Correction of anaemia with recombinant human erythropoietin (epoetin) has been associated with an improvement in CHF in both controlled and uncontrolled studies. The present study describes our findings in a series of 78 consecutive patients with symptomatic CHF and anaemia (haemoglobin (Hb) level <12.0 g/dl) treated with epoetin beta and, if necessary, intravenous iron sucrose. Over a mean observation period of 20.7 +/- 12.1 months, mean Hb levels increased from 10.2 +/- 1.1 to 13.5 +/- 1.2 g/dl, p < 0.01. New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF) were significantly improved and the number of hospitalizations was significantly reduced with the period before treatment (all p < 0.01). Serum creatinine and creatinine clearance (CCr) were 2.2 +/- 0.9 mg/dl and 32.5 +/- 26.5 ml/min, respectively, at baseline, and remained stable over the observation period. Interestingly, >90% of the patients had concomitant mild-to-moderate chronic kidney disease at baseline and study end (CKD), as defined by the accepted diagnostic criterion of a CCr <60 ml/min.. The correction of the anaemia with epoetin beta together with initial intravenous iron supplementation, resulted in significant improvements in NYHA class and cardiac function, and a reduction in hospitalization rate. Moreover, renal function was maintained stable in most patients.

Topics: Aged; Aged, 80 and over; Anemia; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Heart Failure; Hospitalization; Humans; Kidney Diseases; Male; Recombinant Proteins

Topics: Anemia; Confounding Factors, Epidemiologic; Erythropoietin; Heart Failure; Hematinics; Humans

Topics: Anemia; Confounding Factors, Epidemiologic; Erythropoietin; Heart Failure; Hematinics; Hematocrit; Humans

Considerable morbidity and mortality are still associated with congestive heart failure (CHF) syndromes, despite improvement in therapy. Activation of neurohormonal, inflammatory, and oxidative mechanisms has been shown to contribute to the significant morbidity and mortality. Erythropoietin (EPO) is a cytokine known to regulate erythroid proliferation, attenuate apoptosis and oxidative stress, and promote angiogenesis. We prospectively evaluated the predictive value of baseline EPO, N-terminal pro-B-type natriuretic peptide, and C-reactive protein levels in patients with clinically controlled chronic CHF.. One hundred eighty-eight outpatients from a CHF clinic had baseline assessment of EPO, N-terminal pro-B-type natriuretic peptide, and C-reactive protein levels and a complete clinical data profile. These patients were followed up for 24 months for any hospitalization due to CHF or mortality.. Circulating EPO levels were higher in CHF patients and increased in subjects with higher New York Heart Association scores. Levels of EPO (at a cutoff of 23 mU/mL) and N-terminal pro-B-type natriuretic peptide (cutoff at the median of 1556 pg/mL) were found to be strong predictors of mortality and CHF hospitalization, whereas C-reactive protein levels (cutoff of 10 mg/L) predicted CHF hospitalizations but not mortality. Left ventricular ejection fraction was found to be a predictor of mortality but not of CHF hospitalizations. Serum levels of EPO were significantly correlated with N-terminal pro-B-type natriuretic peptide and C-reactive protein levels but not with left ventricular ejection fraction.. If confirmed in large-scale clinical studies, determination of circulating EPO levels may aid in predicting morbidity and mortality in patients with clinically controlled congestive CHF.

Topics: Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Erythropoietin; Female; Heart Failure; Humans; Israel; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Predictive Value of Tests; Prognosis; Prospective Studies; Survival Analysis

Anaemia is often observed in patients with chronic heart failure (CHF), and it may be associated with a worse prognosis. Aim of this study was to identify the individual mechanisms of anaemia in CHF patients.. One hundred and forty-eight consecutive patients with haemoglobin concentration <13 g/dL (if males) or <12 g/dL (if females) were enrolled. Factors responsible for anaemia were investigated by evaluating endogenous erythropoietin (Epo) production, serum cytokines levels, body iron status, and iron supply for erythropoiesis. Most patients (57%) presented anaemia of chronic disease and among them, 92% showed evidence of a defective endogenous Epo production. This was indicated by an observed/predicted log(serum Epo) ratio less than 0.8 and/or a defective iron supply for erythropoiesis diagnosed by low transferrin saturation and/or increased value of soluble transferrin receptor. According to regression analysis sex, renal failure, and serum Epo were correlated with anaemia.. According to our study, about half of anaemic CHF patients showed anaemia of chronic disease with blunted endogenous Epo production and/or a defective iron supply for erythropoiesis. Determination of the individual mechanisms of anaemia in CHF could justify a rational therapeutic approach to anaemia.

Topics: Anemia; Chronic Disease; Cytokines; Erythropoiesis; Erythropoietin; Female; Heart Failure; Humans; Iron Deficiencies; Male; Middle Aged; Receptors, Transferrin

Patients with congestive heart failure (CHF) suffer considerable morbidity and mortality despite advances in therapy. Treatment with erythropoietin (Epo) has shown promise in CHF patients, yet its mechanisms of action remain elusive. Endothelial progenitor cells (EPC) contribute to postnatal angiogenesis and vasculogenesis, and Epo was shown to promote EPC mobilization. We explored the effect of chronic treatment with Epo on the numbers and functional properties of EPC in CHF patients.. Twenty-eight patients with CHF treated with Epo for a mean period of 28 months were compared to a matched group (n = 28) with regard to the number of circulating hematopoietic and endothelial stem cells (either CD34+, CD34+/CD45+, CD34+/CD133+, CD34+/VEGF-R2+ or CD34+/CD133+/VEGF-R2+) as well as their proliferative and adhesive capacity. In vitro, Epo was added to cultured EPC from healthy subjects to test proliferation and adhesion. No differences were observed in circulating numbers of hematopoietic and endothelial stem cells between CHF patients chronically treated with Epo or untreated. EPC from Epo-treated patients exhibited enhanced proliferation as well as a trend towards adhesion to cultured endothelial cells prior to and following stimulation with TNF-alpha. Addition of Epo to EPC from healthy subjects dose-dependently increased their proliferation and adhesion to fibronectin, cultured endothelial cells, and cardiomyocytes. These effects were significantly reduced in the presence of phosphatidylinositol (PI) 3-kinase inhibitors.. Chronic Epo treatment is associated with an increase in the adhesive and proliferative properties of circulating EPC in patients with CHF.

Topics: Aged; Analysis of Variance; Case-Control Studies; Cell Adhesion; Cell Proliferation; Cells, Cultured; Endothelial Cells; Erythropoietin; Female; Fibroblasts; Fibronectins; Heart Failure; Humans; Male; Myocytes, Cardiac; Phosphatidylinositol 3-Kinases; Stem Cells; Stimulation, Chemical

This article provides information and a commentary on landmark trials presented at the European Society of Cardiology Heart Failure meeting held in June 2005, relevant to the pathophysiology, prevention and treatment of heart failure. All reports should be considered as preliminary data, as analyses may change in the final publication. The erythropoiesis stimulating protein, darbepoetin alfa, increased haemoglobin levels, improved quality of life and showed a trend for improved exercise duration in anaemic patients with symptomatic chronic heart failure. In the ECHOS study, the selective dopamine agonist nolomirole (CHF1035) showed no benefit in heart failure patients. Preliminary results of the ASCOT-BPLA study, which were reported at the American College of Cardiology meeting in March 2005, showed that in hypertensive patients, treatment with a calcium antagonist plus an ACE inhibitor was more effective at reducing cardiovascular outcomes than atenolol plus a diuretic.

Topics: Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Esters; Heart Failure; Humans; Tetrahydronaphthalenes

Topics: Anemia; Chronic Disease; Erythropoietin; Evidence-Based Medicine; Heart Failure; Humans; Iron; Recombinant Proteins

Congestive heart failure (CHF) and anemia were reported to affect resting energy expenditure (REE). The aim of this study was to evaluate the effect of the correction of anemia on REE in subjects with CHF.. Nine anemic patients with compensated CHF and CRF were studied before and after correction of anemia. REE was studied by an open circuit indirect calorimeter, body composition by dual-energy-X-ray absorption and total body and extracellular water by multi-frequency bioelectrical impedence. Four anemic and 5 non-anemic CHF patients who did not receive any new treatment served as controls.. After the correction of their anemia patients tended to increase weight (P<0.06), but no significant changes were observed in body composition. Daily caloric intake increased significantly (P<0.02). Ejection fraction increased (P<0.05) and pulse rate decreased significantly (P<0.001). REE and REEPP were in the normal range before correction but increased significantly afterwards (1402+/-256 vs. 1496+/-206 kcal/d, and 101+/-9 vs. 109+/-8, P<0.023 and P<0.006, respectively).. Correction of anemia in patients with CHF increases their REE. This can be related either to improved tissue oxygenation and/or to increased caloric intake.

Topics: Aged; Aged, 80 and over; Anemia; Basal Metabolism; Body Composition; Calorimetry, Indirect; Electric Impedance; Energy Intake; Erythropoietin; Female; Heart Failure; Humans; Iron; Male; Middle Aged; Oxygen Consumption; Weight Gain

This study aimed to investigate the prognostic importance of plasma erythropoietin (EPO) levels in chronic heart failure (CHF) patients.. Anemia is common and is associated with an impaired survival in patients with CHF. Erythropoietin is a hematopoietic growth factor, upregulated in anemic conditions. Little is known about the pathophysiology of anemia in CHF and the prognostic importance of plasma EPO levels in CHF patients.. In 74 patients with CHF (age, 61 +/- 2 years; left ventricular ejection fraction, 0.31 +/- 0.01; peak oxygen consumption, 19.1 +/- 0.6 [mean +/- SEM]) and in 15 control patients, hemoglobin levels and plasma concentrations of EPO and brain natriuretic peptide were measured.. During a mean follow-up of 3.0 years (range, 2.3 to 5.3 years), 22 patients (30%) died. Anemia was present in 24% of the patients. Multivariate analysis showed that plasma EPO (p = 0.026) and hemoglobin levels (p = 0.005) were independent predictors of survival in this CHF population. We observed only a mild inverse correlation between the logarithm of EPO and hemoglobin levels (r2 = 0.08, p = 0.02) in CHF patients, whereas the control group showed a clear significant inverse correlation (r2 = 0.44, p = 0.007).. Elevated plasma EPO levels are associated with an impaired prognosis independent of hemoglobin levels and other established markers of CHF severity. Furthermore, in the CHF patients, EPO levels poorly correlate with the hemoglobin levels, in contrast with the control group.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Chronic Disease; Erythropoietin; Female; Follow-Up Studies; Heart Failure; Hemoglobins; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Netherlands; Prognosis; Retrospective Studies; Severity of Illness Index; Statistics as Topic; Survival Analysis

Topics: Anemia; C-Reactive Protein; Coronary Artery Disease; Cytomegalovirus Infections; Erythropoietin; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Middle Aged; Treatment Outcome

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Risk Factors

Topics: Anemia; Erythropoietin; Heart Failure; Humans

Both Congestive Heart Failure (CHF) and Chronic Renal Failure (CRF) are increasing steadily in the community. We propose that there is a vicious circle established whereby CHF and CRF both cause anemia and the anemia then worsens both the CHF and CRF causing more anemia and so on. We call this the Cardio Renal Anemia (CRA) syndrome. By the combination of active treatment of the CHF and control of the anemia with subcutaneous erythropoietin and intravenous iron, the progression of both the CHF and the CRF can be slowed or stopped in most cases, the quality of life improved and the need for recurrent hospitalization reduced. This will involve cooperation between internists, cardiologists, and nephrologists to allow early and maximal therapy of both the CHF and the anemia.

Topics: Aged; Anemia; Disease Progression; Drug Therapy, Combination; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Heart Failure; Hospitalization; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Oxygen Consumption; Recombinant Proteins; Stroke Volume

Topics: Adenine; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Antihypertensive Agents; Antirheumatic Agents; Bone Resorption; Bosentan; Cephalosporins; Darbepoetin alfa; Diphosphonates; Drug Approval; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Heart Failure; Humans; Hypoglycemic Agents; Imidazoles; Indoles; Insulin; Insulin Aspart; Interleukin 1 Receptor Antagonist Protein; Natriuretic Agents; Natriuretic Peptide, Brain; Organophosphonates; Organophosphorus Compounds; Protein C; Recombinant Proteins; Serotonin Receptor Agonists; Sialoglycoproteins; Sulfonamides; Tenofovir; Tryptamines; Zoledronic Acid

The mechanisms controlling erythropoietin (EPO) synthesis by the kidney in patients with chronic obstructive lung disease (COLD) or congestive left heart failure (CLHF) remain incompletely understood. Renal dysfunction occurs as a consequence of decreased renal blood flow (RBF) in these diseases. Because alterations in renal haemodynamics may affect EPO synthesis and red blood cell production, we investigated the potential relationships between renal function and plasma EPO synthesis in patients with COLD or CLHF. Thirty-two patients with COLD and 13 with CLHF underwent determination of renal physiology parameters, plasma EPO levels and haemoglobin levels. Plasma EPO concentrations were increased in patients with COLD or CLHF as compared to normal subjects, and were inversely correlated to haemoglobin concentrations. In patients with COLD or CLHF, plasma EPO was negatively correlated with both RBF and renal oxygen delivery (ROD) and positively correlated with filtration fraction. Plasma EPO was not correlated with glomerular filtration rate, fractional excretion of sodium, PO2 or PCO2. Among the patients with COLD, those with polycythemia (haemoglobin > 150 g L-1) had lower plasma EPO and higher RBF and ROD values than those with normocythemia (haemoglobin < or = 150 g L-1). Taken together, our data suggest that in patients with COLD or CLHF the critical determinant for EPO production is impairment of renal haemodynamics.

Topics: Adult; Aged; Erythropoietin; Female; Heart Failure; Humans; Kidney; Lung Diseases, Obstructive; Male; Middle Aged; Oxygen; Regional Blood Flow

The prevalence of congestive heart failure (CHF) is increasing rapidly in the community. We and others have shown that the prevalence and severity of both anemia and chronic renal failure (CRF) increase steadily with increasing severity of CHF. We have also shown that CHF patients may be resistant to standard drug therapy for CHF as long as the associated anemia is not corrected, and that correction of the anemia with subcutaneous erythropoietin and intravenous iron sucrose (Venofer: Vifor International, St. Gallen, Switzerland) may improve both the CHF and CRF and markedly reduce hospitalizations without causing side effects. We report here our experience with correcting anemia in this manner in 126 cases of anemic-resistant CHF patients. As in our previous studies, correction of the anemia improved both CHF and CRF, and reduced hospitalizations. Our studies suggest that correction of even mild anemia in CHF may be an important addition to the treatment of patients with the combination of CHF and CRF.

Topics: Aged; Anemia; Disease Progression; Drug Therapy, Combination; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glomerular Filtration Rate; Glucaric Acid; Heart Failure; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Stroke Volume; Sucrose

This study evaluated the prevalence and severity of anemia in patients with congestive heart failure (CHF) and the effect of its correction on cardiac and renal function and hospitalization.. The prevalence and significance of mild anemia in patients with CHF is uncertain, and the role of erythropoietin with intravenous iron supplementation in treating this anemia is unknown.. In a retrospective study, the records of the 142 patients in our CHF clinic were reviewed to find the prevalence and severity of anemia (hemoglobin [Hb] <12 g). In an intervention study, 26 of these patients, despite maximally tolerated therapy of CHF for at least six months, still had had severe CHF and were also anemic. They were treated with subcutaneous erythropoietin and intravenous iron sufficient to increase the Hb to 12 g%. The doses of the CHF medications, except for diuretics, were not changed during the intervention period.. The prevalence of anemia in the 142 patients increased with the severity of CHF, reaching 79.1% in those with New York Heart Association class IV. In the intervention study, the anemia of the 26 patients was treated for a mean of 7.2 +/- 5.5 months. The mean Hb level and mean left ventricular ejection fraction increased significantly. The mean number of hospitalizations fell by 91.9% compared with a similar period before the study. The New York Heart Association class fell significantly, as did the doses of oral and intravenous furosemide. The rate of fall of the glomerular filtration rate slowed with the treatment.. Anemia is very common in CHF and its successful treatment is associated with a significant improvement in cardiac function, functional class, renal function and in a marked fall in the need for diuretics and hospitalization.

Topics: Aged; Anemia, Iron-Deficiency; Erythropoietin; Female; Glomerular Filtration Rate; Heart Failure; Hospitalization; Humans; Injections, Intravenous; Injections, Subcutaneous; Iron; Male; Prevalence; Retrospective Studies; Severity of Illness Index; Stroke Volume

Erythropoietin (Epo), a growth factor produced by the kidney, is important in heart failure patients to promote oxygen delivery to tissues. Seventy-two chronic heart failure (CHF) patients at our outpatient clinic were subjected to morning serum Epo-level measurements and classified according to NYHA criteria.. Forty-eight patients of classes III and IV had a significantly elevated serum Epo-level of 42.9+/-40.3 mIU/ml (mean+/-1 S.D.) when compared to the mean level of 24 patients of classes I and II who had a normal range mean value of 13.4+/-6.2 mIU/ml (P<0.05). Patients on angiotensin-converting enzyme (ACE) inhibitors showed a trend towards lower serum Epo-levels compared to patients treated with angiotensin-II type-1 receptor antagonists (AT(1) antagonists) (levels: 33.3+/-35.6 mIU/ml and 43.6+/-38.1 mIU/ml). This trend did not, however, reach statistical significance (P=0.36).. We suggest that a desirable Epo increase in class III and IV CHF patients could be achieved by either recombinant human Epo administration or, possibly, by appropriate selection of the concomitant medical therapy. A large prospective study shall investigate the possible advantage of AT(1) antagonists over ACE-inhibitors with regard to Epo effect.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Erythropoietin; Female; Heart Failure; Humans; Male; Middle Aged; Reference Values

In the present study, the relationship between the blood erythropoietin level and cardiac function was investigated in 15 patients on chronic hemodialysis who developed chronic heart failure. Another 45 patients without cardiac dysfunction were selected as a control group that was matched for gender, age, and the duration of dialysis. The erythropoietin level was 256.3 +/- 481.8 mU/ml in the heart failure group, which was significantly higher than that in the control group (17.0 +/- 10.0 mU/ml, P < 0.01). Eight of the 15 patients in the heart failure group maintained a hematocrit of more than 30% without receiving recombinant human erythropoietin therapy, whereas 29 of the 45 patients in the control group required erythropoietin. In the heart failure group, the erythropoietin level was significantly correlated with the levels of atrial natriuretic peptide and brain natriuretic peptide (P < 0.01). These results suggest that heart failure can increase the erythropoietin level in proportion to the severity of cardiac dysfunction, even in patients on long-term dialysis.

Topics: Adult; Aged; Atrial Natriuretic Factor; Chronic Disease; Erythropoietin; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Renal Dialysis

Erythropoietin is a hormone responsible for regulation of red blood cell production. Circulating erythropoietin values are regulated by renal oxygen supply, which is determined by hemoglobin concentration, hemoglobin oxygen saturation, and renal blood flow. Previous animal and human studies regarding erythropoietin regulation have assumed pulsatile renal blood flow. During cardiopulmonary bypass, non-pulsatile renal perfusion has been shown to result in decreased glomerular filtration rate and decreased renal blood flow in comparison to pulsatile perfusion. Repair of congenital heart disease during cardiopulmonary bypass is an attractive circumstance in which to study the effect of non-pulsatile blood flow on erythropoietin production. The hypothesis in this study was that non-pulsatile perfusion would result in increased erythropoietin production because of decreased renal oxygen supply. Fourteen children with congenital heart disease and without preoperative renal insufficiency or anemia were enrolled in the study. All patients underwent cardiopulmonary bypass with non-pulsatile flow. In addition, 10 control patients without congenital heart disease were enrolled. Six cardiopulmonary bypass patients had 1.5- to 6-fold increases in plasma erythropoietin concentrations from baseline. These patients had longer cardiopulmonary bypass times, more commonly performed under low flow deep hypothermic conditions. The remaining 8 patients with congenital heart disease, and all control patients, did not develop increased postoperative erythropoietin concentrations. The conditions under which cardiopulmonary bypass are performed appear to influence postoperative circulating erythropoietin concentrations.

Topics: Cardiopulmonary Bypass; Child; Child, Preschool; Erythropoietin; Female; Heart Failure; Humans; Infant; Male; Renal Circulation

Plasma levels of erythropoietin (mU/ml) were measured in patients with congestive heart failure (CHF) (n = 108) and in a control group of normal subjects (n = 45). In normal subjects, plasma levels of erythropoietin were 1.9 +/- 0.2. In patients with CHF, plasma levels of erythropoietin increased progressively according to New York Heart Association (NYHA) class (I: 1.4 +/- 0.2, n = 28; II: 5.4 +/- 0.8, n = 27; III: 9.6 +/- 2, n = 32; IV: 34 +/- 8, n = 21; F = 57.7, p < 0.001) and were significantly higher in NYHA classes II, III, and IV than in normal subjects. Plasma erythropoietin significantly decreased (from 43 +/- 14 to 12 +/- 3 mU/ml, p < 0.01) in patients with severe CHF (n = 9) when enalapril (20 mg/day administered orally) was added to long-term treatment for 3 weeks. Finally, in a subgroup of patients with NYHA class IV CHF (n = 9) and high plasma erythropoietin levels (37 +/- 9 mU/ml), packed red blood cell volume, assessed by the iodine-125-albumin dilution method, was higher than that in normal subjects (n = 11) (2,616 +/- 235 vs 2,028 +/- 119 ml, p < 0.05). The present study demonstrates that plasma erythropoietin levels are elevated in a large cohort of patients with CHF of varying etiology, and that this increase is related to the progression of the disease. The increase in circulating erythropoietin is associated with augmented packed red blood cell volume in patients with severe CHF. These results suggest a participation of erythropoietin in the complex neurohormonal response that occurs in CHF.

Topics: Adult; Aged; Analysis of Variance; Chi-Square Distribution; Erythropoietin; Female; Heart Failure; Hemodynamics; Hormones; Humans; Male; Middle Aged; Regression Analysis; Severity of Illness Index

In animal experiments reduction of renal perfusion can stimulate erythropoietin production. The relationship between renal haemodynamics and erythropoietin production is unknown in congestive heart failure.. The aim was to study the relationship between serum erythropoietin and renal haemodynamics, plasma renin activity and haematocrit in patients with congestive heart failure and in healthy control subjects.. Serum erythropoietin, renal plasma flow, glomerular filtration rate and plasma renin activity were determined in 14 patients with acyanotic congestive heart failure, and 36 healthy controls.. Serum erythropoietin was significantly elevated in congestive heart failure 26.6 U l-1 (median) compared with controls 17.0 U l-1 despite a normal haematocrit, and increased with the severity of congestive heart failure (New York Heart Association class II: 17 U l-1 [n = 4]; class III: 30 U l-1 [n = 5]; class IV: 45 U l-1 [n = 5]). Significant inverse correlations between serum erythropoietin and renal plasma flow (r = -0.60, P < 0.03), and between serum erythropoietin and glomerular filtration rate, were found in congestive heart failure but not in the control subjects. A significant positive correlation (r = 0.71, P < 0.03) was demonstrated between serum erythropoietin and plasma renin activity in congestive heart failure.. A severe reduction in renal perfusion in congestive heart failure appears to cause an increase in serum erythropoietin.

Topics: Adult; Aged; Analysis of Variance; Erythropoietin; Female; Glomerular Filtration Rate; Heart Failure; Hematocrit; Humans; Male; Middle Aged; Renal Circulation; Renin

Topics: Anemia; Arrhythmias, Cardiac; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Pericarditis; Quality of Life; Renal Dialysis; Sick Sinus Syndrome

Topics: Antihypertensive Agents; Erythropoietin; Heart Failure; Hemofiltration; Humans; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis

Topics: Aged; Amyloidosis; Anticoagulants; Chronic Kidney Disease-Mineral and Bone Disorder; Dialysis Solutions; Erythropoietin; Heart Failure; Humans; Hypotension; Kidney Diseases; Membranes, Artificial; Middle Aged; Renal Dialysis; Survival Rate

Eighteen patients with dilated cardiomyopathy (three female, mean age 57 years), were treated for 48 weeks with enalapril added to digoxin and diuretic therapy for congestive heart failure of New York Heart Association (NYHA) functional class II (three patients). III (eight patients) and IV (seven patients), respectively. Serum levels of erythropoietin (EPO) were raised at the start (37 +/- 12.8 pmol 1(-1); mean +/- SD) and were normalized during enalapril treatment (17.5 +/- 9.9 pmol 1(-1) at 48 weeks; P less than 0.001). Serum EPO correlated at the start with NYHA functional class (r = 0.68; P less than 0.05). Normalization of elevated serum EPO concentrations during treatment with enalapril paralleled clinical and haemodynamic improvement, and probably reflected relief from renal hypoxia.

Topics: Adult; Aged; Enalapril; Erythropoietin; Female; Heart Failure; Humans; Male; Middle Aged

The presence of more than one form of immunoreactive erythropoietin was suggested by discrepancies between the levels of immunologically detectable and biologically active erythropoietin in the sera of normal individuals and patients with end-stage renal disease. In both groups, the level of immunologically detectable hormone was significantly higher than that of bioactive hormone. Sera from end-stage renal disease patients and normal subjects were fractionated on a gel permeation column, and the immunoreactive erythropoietin in the fractions was measured by RIA. Three classes of immunoreactive erythropoietin were found in the sera: one eluting before the [125I]erythropoietin marker, one coinciding with the [125I]erythropoietin marker, and a third eluting after the labeled tracer in the region of the cytochrome c marker. The high and low mol wt components were more immunoreactive than the human urinary erythropoietin standard in the RIA. Biological activity, as determined in the in vitro rat bone marrow assay, was found only in the material eluting with the erythropoietin tracer. These studies show that immunoreactive erythropoietin in the serum consists of three components with different immunoreactivities: high and low mol wt components and a component with a mol wt similar to that of the native hormone.

Topics: Erythropoietin; Female; Heart Failure; Humans; Kidney Failure, Chronic; Male; Molecular Weight; Radioimmunoassay

Topics: Acute Disease; Erythropoietin; Feeding and Eating Disorders; Heart Failure; Hemorrhagic Disorders; Humans; Hypertension; Peripheral Nervous System Diseases; Renin; Uremia; Vomiting

Three cases of adult pure red cell aplasia (PRCA) ARE REPORTED. All patients proved refractory to various combinations of androgens and corticosteroids. The first case, harboring a thymoma, showed a complete clinical remission following cyclophosphamide therapy. The second and third responded similarly to either a combined cyclophosphamide + antilymphocyte globulin (ALG) treatment or to ALG administration preceded by a small dosage of cyclophosphamide, which had proved ineffective when administered alone. Serum IgG inhibitors to erythropoiesis were demonstrated in all cases by means of in vivo and/or in vitro techniques. The inhibitor(s), although directed against the erythroid marrow in both the first and third patients (PRCA type A), apparently functioned as an antibody to circulating erythropoientin (Ep) in the second case (PRCA type B). The inhibitor(s) was always absent in postremission samples. Additionally, experimental models for both types of human PRCA were established in normal rodents. The present studies support the contention that adult PRCA is an autoimmune disease. The therapeutic role of cytotoxic-immunodepressive agents in PRCA patients is confirmed. It is emphasized that ALG may represent an additional therapeutic tool in cases resistant to cyclophosphamide and/or steroids. In addition, cyclophosphamide proved effective in a patient harboring a thymoma not amenable to surgery. Finally, it is postulated that IgG serum autoantibodies, directed against either an early erythroid precursor (PRCA type A) or, more rarely, circulating Ep (PRCA type B), play a major role in the pathogenesis of the disease.

Topics: Aged; Anemia, Aplastic; Antibodies, Antinuclear; Antilymphocyte Serum; Autoantibodies; Blood Transfusion; Bone Marrow Examination; Cyclophosphamide; Dexamethasone; Diabetic Coma; Erythrocytes; Erythropoietin; Female; Heart Failure; Hematocrit; Hepatitis; Humans; Immunoglobulin G; Iron; Male; Middle Aged; Radiography, Thoracic; Sarcoma, Kaposi; Serum Globulins; Skin Manifestations; Thymoma

Topics: Aged; Arteries; Blood Gas Analysis; Erythrocytes; Erythropoietin; Heart Failure; Hematocrit; Humans; Hypoxia; Leukocyte Count; Lung Diseases; Middle Aged; Pulmonary Embolism; Pulmonary Fibrosis; Respiratory Insufficiency; Reticulocytes

Topics: Coronary Disease; Epoetin Alfa; Erythropoietin; Heart Failure; Hematocrit; Humans; Immunization, Passive; Leukocyte Count; Pulmonary Heart Disease; Reticulocytes; Rheumatic Heart Disease; Serum