losartan-potassium and Myocardial-Infarction

Ischemic heart disease is rapidly growing as the common cause of death in the world. It is a disease that occurs as a result of coronary artery stenosis and is caused by the lack of oxygen within cardiac muscles due to an imbalance between oxygen supply and demand. The conventional medical therapy is focused on the use of drug eluting stents, coronary-artery bypass graft surgery and anti-thrombosis. Gene therapy provides great opportunities for treatment of cardiovascular disease. In order for gene therapy to be successful, the development of proper gene delivery systems and hypoxia-regulated gene expression vectors is the most important factors. Several non-viral gene transfer methods have been developed to overcome the safety problems of viral transduction. Some of which include plasmids that regulate gene expression that is controlled by environment specific promoters in the transcriptional or the translational level. This review explores polymeric gene carriers that target the myocardium and hypoxia-inducible vectors, which regulate gene expression in response to hypoxia, and their application in animal myocardial infarction models.

Topics: Animals; Cell- and Tissue-Based Therapy; DNA; Erythropoietin; Gene Transfer Techniques; Humans; Myocardial Infarction; Myocardium; Polymers; Vascular Endothelial Growth Factor A

Erythropoietin (EPO) is the main hormone that regulates erythropoiesis. Beyond its well-known hematopoietic action, EPO has diverse cellular effects in non-hematopoietic tissues. It has been shown to inhibit apoptosis by activating pro-survival pathways in the myocardium, to mobilize endothelial progenitor cells and to inhibit migration of inflammatory cells. EPO has also been shown to have potent pro-angiogenic properties. Numerous experimental data support the cardioprotective effects of EPO in animal models of acute myocardial infarct (AMI). However, these findings are not supported by recent clinical trials designed to investigate the safety and efficacy of EPO in patients with AMI. In this article, we begin by providing a comprehensive review of the cardioprotective effects of EPO in experimental animal models and the molecular mechanisms underlying these effects. We then discuss the EPO data obtained through clinical trials. We compare similarities and differences between the animal and human studies as well as between the different clinical studies in terms of sample size and study design including the dose, the route and the timing of administration as well as confounding factors such as comorbidities and concomitant treatments. Finally, we question the gap between the experimental and the translational clinical data and propose further developments to address these discrepancies and clearly evaluate the role of EPO in the clinical setting of MI.

Topics: Animals; Cardiotonic Agents; Clinical Trials as Topic; Disease Models, Animal; Erythropoietin; Humans; Myocardial Infarction

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

Topics: Cardiovascular Agents; Data Interpretation, Statistical; Erythropoietin; Evidence-Based Medicine; Humans; Myocardial Infarction; Stroke Volume; Treatment Outcome; Ventricular Function, Left

We sought to perform a meta-analysis to evaluate the potential influence of high-dose erythropoietin (EPO) on cardiac function parameters in patients with acute ST-segment elevation myocardial infarction (STEMI).. By searching PubMed, EMBASE, and the Cochrane Library (up to December 2012), seven randomized controlled trials (RCTs) reporting cardiac functional parameters with a total of 1,250 acute STEMI patients were identified. When applied to patients with acute STEMI, high-dose EPO was relatively safe and no increase in all-caused death and severe adverse effects were indicated. Estimates were pooled from fixed or random effects models. Compared with controls, high-dose EPO resulted in a slight but significant improvement in left ventricular ejection fraction of 1.02 % [95 % confidence interval (CI) 0.17-1.88, P = 0.019, I (2) = 0 %] and an improvement in left ventricular end-systolic volume of -4.61 ml (95 % CI -7.64 to -1.58, P = 0.003, I (2) = 27.7 %).. Available evidence suggested that high-dose EPO has limited cardio-protective effects in patients with STEMI. However, considering the relatively short follow-up durations and small patient populations in the current RCTs, the effects of high-dose EPO on clinical outcomes in patients with STEMI need to be evaluated in larger prospective RCTs of longer duration.

Topics: Dose-Response Relationship, Drug; Erythropoietin; Humans; Myocardial Infarction; Randomized Controlled Trials as Topic

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

Current evidence suggests that erythropoiesis-stimulating agents (ESAs), including erythropoietin and darbepoetin, may have a direct cardio-protective effect. However, randomized controlled trials (RCTs) assessing the efficacy and safety of ESAs in patients with acute ST-segment elevation myocardial infarction (STEMI) have yielded heterogeneous results. Here, we performed a meta-analysis of RCTs to assess whether the administration of ESAs can improve cardiac functional parameters, such as left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and left ventricular end-diastolic volume (LVEDV), and attenuate infarct size in patients with acute STEMI.. The PubMed, EBSCO, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched for relevant RCT studies on ESAs published before May 13, 2011. A total of nine RCTs involving 1,244 participants were identified. The original data of these studies were aggregated using fixed effect models. Compared with controls, the administration of ESAs showed a slight but significant improvement in LVEF (1.38%; 95% confidence interval 0.38-2.37%; p = 0.007). However, no significant improvement in LVEDV, LVESV, and infarct size was observed, and no increase in all-cause severe adverse effect was indicated.. Our meta-analysis indicates that the superiority of ESAs over conventional therapy in patients with acute STEMI is limited using current procedures. However, there is evidence to suggest that the timing and dosing of ESA administration may be optimized. Moreover, the long-term cardio-protective effect of ESAs in this patient population may be beneficial and worth exploring.

Topics: Arrhythmias, Cardiac; Cardiac Output; Cardiotonic Agents; Darbepoetin alfa; Electrocardiography; Erythropoiesis; Erythropoietin; Hematinics; Humans; Middle Aged; Myocardial Infarction; Randomized Controlled Trials as Topic; Recombinant Proteins

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

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

Hematopoietic cytokines, traditionally known to influence cellular proliferation, differentiation, maturation, and lineage commitment in the bone marrow, include granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, stem cell factor, Flt-3 ligand, and erythropoietin among others. Emerging evidence suggests that these cytokines also exert multifarious biological effects on diverse nonhematopoietic organs and tissues. Although the precise mechanisms remain unclear, numerous studies in animal models of myocardial infarction (MI) and heart failure indicate that hematopoietic cytokines confer potent cardiovascular benefits, possibly through mobilization and subsequent homing of bone marrow-derived cells into the infarcted heart with consequent induction of myocardial repair involving multifarious mechanisms. In addition, these cytokines are also known to exert direct cytoprotective effects. However, results from small-scale clinical trials of G-CSF therapy as a single agent after acute MI have been discordant and largely disappointing. It is likely that cardiac repair following cytokine therapy depends on a number of known and unknown variables, and further experimental and clinical studies are certainly warranted to accurately determine the true therapeutic potential of such therapy. In this review, we discuss the biological features of several key hematopoietic cytokines and present the basic and clinical evidence pertaining to cardiac repair with hematopoietic cytokine therapy.

Topics: Animals; Bone Marrow Cells; Cell Movement; Cytokines; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Membrane Proteins; Models, Animal; Myocardial Infarction

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

Erythropoietin (EPO) is a hematopoietic hormone with extensive nonhematopoietic properties. The discovery of an EPO receptor outside the hematopoietic system has fuelled research into the beneficial effects of EPO for various conditions, predominantly in cardiovascular disease. Experimental evidence has revealed the cytoprotective properties of EPO, and it seems that the EPO-EPO receptor system provides a powerful backbone against acute myocardial ischemia, gaining from the different properties of EPO. There is an ongoing discussion about possible discrepancy between preclinical and clinical effects of EPO on the cardiovascular system. Large, randomized, placebo-controlled clinical trials are underway to give a final verdict on EPO treatment for acute coronary syndromes.

Topics: Acute Coronary Syndrome; Acute Disease; Anemia; Erythropoiesis; Erythropoietin; Humans; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Receptors, Erythropoietin; Syndrome

Cell based therapy has become a new and attractive option for the treatment of cardiac disease and heart failure. Although it has been demonstrated in vitro and in vivo that differentiation of non-differentiated cells (progenitor cells) into cardiomyocytes is able even in adult hearts the potential use of such transdifferentiation processes is limited by the small number of cells that home and engraft in the myocardium and complete the transdifferentiation process. Therefore, cell recruitment to the damaged heart is a major challenge to improve any cell based therapy. This process requires homing and engraftment of stem or progenitor cells. Major strategies to improve stem or progenitor cell homing are based on an improvement of stem or progenitor cell mobilization from the bone marrow. Strategies that have been shown to be successful are those that use granulocyte colony-stimulating factor (G-CSF). But although cell mobilization was indeed successful no major impact on hemodynamics was found. Alternatives are therefore needed and experimental studies use parathyroid hormone, statins, erythropoietin, and others in addition to or as an alternative to G-CSF. Although each of these procedures does have an impact on cell mobilization and homing none of these studies has provided a direct evidence that a major improvement on top of standard pharmacological therapy can be expected from such strategies. In conclusion, improvement of stem cell homing is a major challenge in the development of successful cell based therapies but not yet improved to a clinical relevant status. The underlying concepts of different strategies will be discussed here.

Topics: Animals; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Meta-Analysis as Topic; Myocardial Infarction; Parathyroid Hormone; Recombinant Proteins; Stem Cell Transplantation; Stem Cells; Treatment Outcome

Granulocyte colony-stimulating factor (G-CSF) and erythropoietin are two cytokines that have been demonstrated to improve cardiac function and perfusion in myocardial infarction. G-CSF was initially evaluated as a stem cell mobilizer and erythropoietin as a cytoprotective agent. However, both cytokines have direct cytoprotective effects and stem cell-mobilizing ability. Direct cytoprotective effects of both cytokines are commonly mediated by the Jak-STAT pathway. In preclinical study, G-CSF and erythropoietin improved cardiac function and perfusion by angiomyogenesis and protection of cardiomyocytes in myocardial infarction. However, results from recent clinical trials did not support beneficial effects of cytokine therapy with G-CSF or erythropoietin alone in patients with myocardial infarction. Further studies are required to elucidate the mechanism of action and to improve therapeutic efficacy by employing novel strategies, such as combined cytokines.

Topics: Animals; Cell- and Tissue-Based Therapy; Clinical Trials as Topic; Combined Modality Therapy; Disease Models, Animal; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Myocardial Infarction; Neovascularization, Physiologic; Regeneration; Sensitivity and Specificity; Severity of Illness Index; Treatment Outcome; Ventricular Remodeling

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

To improve clinical outcomes in patients presenting with an acute myocardial infarction, new strategies to limit infarct size and postinfarct remodelling are warranted. Recent animal studies have revealed that erythropoietin has the potential to achieve both these goals. Even more intriguing is the possibility that erythropoietin could protect the myocardium when administered well after the onset of reperfusion. In this article we review the evidence in favour of erythropoietin-induced cardioprotection and the proposed underlying mechanisms. Inhibition of apoptosis and inflammation, as well as stimulation of neovascularization, all could contribute to cardioprotection. Activation of the reperfusion injury salvage kinase pathway at the moment of reperfusion appears to be a pivotal mechanism in the infarct size-limiting effect. Now that recent evidence has proven that erythropoietin also can protect the human heart, studies currently are being undertaken to examine the effect of administration of erythropoietin in patients presenting with an acute myocardial infarction.

Topics: Animals; Apoptosis; Cardiotonic Agents; Erythropoietin; Humans; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Neovascularization, Physiologic; Recombinant Proteins; Ventricular Remodeling

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

Despite the well-recognized effects of erythropoietin (EPO) on augmenting red blood cell production, EPO exerts multiple additional effects in diverse tissues. Evidence indicating the potential for tissue protection is reviewed as is a description of a study now initiated, in which its potential benefit on the evolution of acute myocardial infarction in patients is being explored.. The literature demonstrating tissue-protective effects of EPO in experimental animals and patients is cited as is the protocol of the recently undertaken Vermont/Dubai study assessing the potential benefits conferred by EPO on the evolution of infarction in patients.. Compelling arguments can be made indicating that EPO and its congeners, some of which are devoid of erythropoietic effects, can protect tissue against injurious stimuli. Accordingly, the promise of EPO for favorably altering the evolution of acute myocardial infarction merits exploration. Congeners of erythropoietin or EPO itself may be beneficial in protecting the heart against injury induced by ischemia thereby favorably modifying infarct size. Rigorous testing of this hypothesis is now in progress in a study involving patients with acute myocardial infarction admitted to hospital within 6 h after the onset of chest pain in whom infarct size is being evaluated based on serial analyses of concentrations of creatine kinase in plasma and thrombolysis is induced pharmacologically as promptly as possible.. EPO is promising for myocardial protection. Its potential is being delineated in a clinical study of myocardial infarction treated with tenecteplase with or without concomitant EPO.

Topics: Acute Disease; Animals; Cardiotonic Agents; Clinical Trials as Topic; Dogs; Erythropoietin; Heart; Humans; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Recombinant Proteins; Tenecteplase; Time Factors; Tissue Plasminogen Activator

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

Recombinant erythropoietin (EPO) was introduced into clinical practice after the identification of EPO as the major haemopoietic growth factor determining survival and maturation of erythroid precursors. Advances in our understanding of the novel sites of action of EPO in the vasculature, brain, heart and kidney have opened new avenues of therapeutic potential for EPO, and have led to an increased understanding of the biological roles of EPO and its mechanisms of cell protection.

Topics: Animals; Disease Models, Animal; Erythropoietin; Humans; Myocardial Infarction; Recombinant Proteins

The major physiological function of erythropoietin is the induction of erythropoiesis. A growing body of evidence indicates, however, that this hormone has tissue-protective effects and prevents tissue damage during ischemia and inflammation. This review article summarizes the present knowledge on the cardiovascular and renal protective effects of erythropoietin and discusses the possible underlying mechanisms.

Topics: Anemia; Cell Differentiation; Cell Proliferation; Endothelial Cells; Erythropoietin; Humans; Kidney Diseases; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Recombinant Proteins; Signal Transduction; Stem Cells

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

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

Topics: Adult; Aged; Anemia; Child; Comorbidity; Drug Costs; Epoetin Alfa; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Multicenter Studies as Topic; Myocardial Infarction; Occupations; Peritoneal Dialysis; Physical Fitness; Practice Guidelines as Topic; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Reference Values; Renal Dialysis; Thrombophilia; Treatment Outcome

Arrhythmia is the foremost cause of sudden death after myocardial infarction (MI). Animal models have recently shown that erythropoietin (EPO) can reduce the incidence of arrhythmia after MI.. We investigated the effects of administrating 33,000 IU EPO on the occurrence of post-MI arrhythmia in 40 patients with ST-elevation MI who were randomly assigned in either EPO or placebo groups. Arrhythmias were blindly documented using full 12-lead configuration during 24 hours after percutaneous coronary intervention (PCI) by a cardiologist. Afterward, CK-MB, hematologic, and hemodynamic data were examined within 2 weeks after MI.. A comparison made between the 2 groups showed significant differences in the incidence of arrhythmias (20% in EPO group and 35% in placebo group, P = 0.043). However, no significant differences in type of arrhythmias were observed between the groups. There was no significant difference between levels of CK-MB in the 2 groups during 24 hours (P = 0.186). Hematologic and hemodynamic data showed no significant changes 2 weeks after PCI.. High-dose administration of EPO in patients with ST-elevation MI who have been treated by primary PCI and standard antiplatelet therapy reduces the occurrence of arrhythmias. For clinical interpretation of the results, further well-designed trials are required.

Topics: Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Biomarkers; Creatine Kinase, MB Form; Electrocardiography; Erythropoietin; Female; Hemodynamics; Humans; Iran; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Pilot Projects; Platelet Aggregation Inhibitors; Recombinant Proteins; Risk Factors; Time Factors; Treatment Outcome

Renin-angiotensin system (RAS) inhibition has proven to be helpful in reducing cardiovascular and kidney disease progression in the general population; whether kidney transplant patients would derive similar benefits is unknown. RAS inhibition also reduces posttransplantation erythrocytosis in kidney transplant recipients, but its effect on hemoglobin (Hb) levels in patients without posttransplantation erythrocytosis is unclear.. The Specific Management of Anemia and Hypertension in Renal Transplant (SMAhRT) recipients study was designed to examine the cardiovascular benefits of RAS blockade with telmisartan 80 mg versus placebo, and Hb management with darbepoetin α in a randomized, double-blind, single-center controlled trial in 2,000 patients over 3 years. The primary efficacy variable was a composite of all-cause mortality, myocardial infarction or stroke.. The SMAhRT study was stopped prematurely due to a lower than expected event rate. At that point, 136 patients were enrolled and were followed for a mean duration of 15 months. The use of RAS blockade was not associated with an increased risk of adverse events such as worsening anemia or hyperkalemia. Likewise, the correction of Hb with darbepoetin was not associated with any increase in thrombotic events.. This study provides insight into the safety of RAS inhibition and Hb correction with an erythrocyte-stimulating agent in kidney transplant recipients.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Benzimidazoles; Benzoates; Darbepoetin alfa; Double-Blind Method; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Kidney Transplantation; Male; Middle Aged; Myocardial Infarction; Renin-Angiotensin System; Stroke; Telmisartan; Treatment Outcome; Young Adult

Erythropoietin (EPO) protected the myocardium from ischemia and reperfusion injury in preclinical studies. However, whether EPO can reduce myocardial injury in patients with acute myocardial infarction (MI) is controversial. The inconsistent results of previous studies have been attributed to differences in the doses, timing, and routes of administration of EPO. In this study, we will evaluate intracoronary treatment with a long-acting EPO analog, darbepoetin-α, administered immediately before reperfusion in patients with acute anterior ST-segment elevation MI.. This trial will be a single-center, prospective, randomized, two-arm, controlled trial with blind evaluation of the endpoints. At the time of the primary percutaneous coronary intervention, 80 patients will randomly receive one of the following treatments immediately before the first ballooning: intracoronary darbepoetin-α (ARANESP®; Jeil-Kirin Pharm., Korea) 300μg (n=40) or saline (n=40), administered via the over-the-wire balloon system. The objectives of this study are to evaluate the safety and efficacy of intracoronary darbepoetin-α therapy.. This is the first study to evaluate the safety and efficacy of intracoronary darbepoetin-α treatment in patients with acute MI.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Coronary Vessels; Darbepoetin alfa; Electrocardiography; Erythropoietin; Hematinics; Humans; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Prospective Studies; Research Design

Several trials investigating erythropoietin as a novel cytoprotective agent in myocardial infarction (MI) failed to translate promising preclinical results into the clinical setting. These trials could have missed crucial events occurring in the first few minutes of reperfusion. Our study differs by earlier intracoronary administration of a longer-acting erythropoietin analogue at the onset of reperfusion.. To evaluate the ability of intracoronary administration of darbepoetin-alpha (DA) at the very onset of the reperfusion, to decrease infarct size (IS).. We randomly assigned 56 patients with acute ST-segment elevation MI to receive an intracoronary bolus of DA 150 μg (DA group) or normal saline (control group) at the onset of reflow obtained by primary percutaneous coronary intervention (PCI). IS and area at risk (AAR) were evaluated by biomarkers, cardiac magnetic resonance (CMR) and validated angiographical scores.. There was no difference between groups regarding duration of ischemia, Thrombolysis in Myocardial Infarction flow grade at admission and after PCI, AAR size and extent of the collateral circulation, which are the main determinants of IS. The release of creatine kinase was not significantly different between the two groups even when adjusted to AAR size. Between 3-7 days and at 3 months, the area of hyperenhancement on CMR expressed as a percentage of the left ventricular myocardium was not significantly reduced in the DA group even when adjusted to AAR size.. Early intracoronary administration of a longer-acting erythropoietin analogue in patients with acute MI at the time of reperfusion does not significantly reduce IS.

Topics: Adult; Aged; Biomarkers; Collateral Circulation; Coronary Angiography; Coronary Circulation; Creatine Kinase; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; France; Humans; Injections, Intra-Arterial; Magnetic Resonance Imaging; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion Injury; Percutaneous Coronary Intervention; Predictive Value of Tests; Prospective Studies; Single-Blind Method; Time Factors; Treatment Outcome

Erythropoietin (EPO) was hypothesized to mitigate reperfusion injury, in part via mobilization of endothelial progenitor cells (EPCs). The REVEAL trial found no reduction in infarct size with a single dose of EPO (60,000 U) in patients with ST-segment elevation myocardial infarction. In a substudy, we aimed to determine the feasibility of cryopreserving and centrally analyzing EPC levels to assess the relationship between EPC numbers, EPO administration, and infarct size. As a prespecified substudy, mononuclear cells were locally cryopreserved before as well as 24 and 48-72 h after primary percutaneous coronary intervention. EPC samples were collected in 163 of 222 enrolled patients. At least one sample was obtained from 125 patients, and all three time points were available in 83 patients. There were no significant differences in the absolute EPC numbers over time or between EPO- and placebo-treated patients; however, there was a trend toward a greater increase in EPC levels from 24 to 48-72 h postintervention in patients receiving ≥30,000 U of EPO (P = 0.099 for CD133(+) cells, 0.049 for CD34(+) cells, 0.099 for ALDH(br) cells). EPC numbers at baseline were inversely related to infarct size (P = 0.03 for CD133(+) cells, 0.006 for CD34(+) cells). Local whole cell cryopreservation and central EPC analysis in the context of a multicenter randomized trial is feasible but challenging. High-dose (≥30,000 U) EPO may mobilize EPCs at 48-72 h, and baseline EPC levels may be inversely associated with infarct size.

Topics: Adult; Aged; Aged, 80 and over; Endothelial Cells; Erythropoietin; Female; Hematopoietic Stem Cell Mobilization; Humans; Leukocyte Count; Leukocytes, Mononuclear; Male; Middle Aged; Myocardial Infarction; Stem Cells

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

The HEBE III trial showed that epoetin alfa administration in patients with a first ST-elevation myocardial infarction (STEMI) did not improve left ventricular function at 6 weeks after primary percutaneous coronary intervention (PCI). The long term effects of erythropoiesis- stimulating agents on cardiovascular morbidity and mortality are unknown, therefore we evaluated clinical events at 1 year after PCI.. A total of 529 patients with a first STEMI and successful primary PCI were randomized to standard optimal medical treatment (N = 266) or an additional bolus of 60,000 IU epoetin alfa administered intravenously (N = 263) within 3 h after PCI. Analyses were performed by intention to treat.. At 1 year after STEMI, 485 patients had complete follow-up. The rate of the composite end point of all-cause mortality, re-infarction, target vessel revascularization, stroke and/or heart failure was 6.4 % (N = 15) in the epoetin alfa group and 9.6 % (N = 24) in the control group (p = 0.18). Thromboembolic events were present in 1.3 % (N = 3) of patients in the epoetin alfa group and 2.4 % (N = 6) in the control group. There was no evidence of benefit from epoetin alfa administration in subgroups of patients.. Administration of a single bolus of epoetin alfa in patients with STEMI does not result in a reduction of cardiovascular events at 1 year after primary PCI. There was a comparable incidence of thromboembolic complications in both treatment groups, suggesting that epoetin alfa administration is safe at long term.

Topics: Aged; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Recombinant Proteins; Thromboembolism

Increased viscosity may increase the risk of thrombosis or thromboembolic events. Recombinant human erythropoietin (rHuEPO) is the key stone treatment in anemic ESRD patients with the thrombotic limiting side effect. We evaluated the influence of clinical and laboratory findings on plasma viscosity in MHD patients in the present study.. After applying exclusion criteria 84 eligible MHD patients were included (30 female, age: 54.7 ± 13.7 years).. Patients with high viscosity had longer MHD history, calcium × phosphorus product, and higher rHuEPO requirement (356.4 versus 204.2 U/kg/week, P: 0.006). rHuEPO hyporesponsiveness was also more common in hyperviscosity group. According to HD duration, no rHuEPO group had the longest and the low rHuEPO dosage group had the shortest duration. Despite similar Hb levels, 68% of patients in high rHuEPO dosage group; and 38.7% of patients in low rHuEPO dosage group had higher plasma viscosity (P: 0.001). Patients with hyperviscosity had higher rHuEPO/Hb levels (P: 0.021). Binary logistic regression analyses revealed that rHuEPO hyporesponsiveness was the major determinant of hyperviscosity.. We suggest that the hyperviscous state of the hemodialysis patients may arise from the inflammatory situation of long term HD, the calcium-phosphorus mineral abnormalities, rHuEPO hyporesponsiveness, and related high dosage requirements.

Topics: Adult; Aged; Anemia; Arteriovenous Shunt, Surgical; Blood Viscosity; Calcium; Drug Resistance; Erythropoietin; Female; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Phosphorus; Prospective Studies; Recombinant Proteins; Renal Dialysis; Thromboembolism

Topics: Adult; Aged; Cohort Studies; Erythropoietin; Female; Humans; Iron; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Pilot Projects; Prospective Studies; Treatment Outcome

Preclinical studies and pilot clinical trials have shown that high-dose erythropoietin (EPO) reduces infarct size in acute myocardial infarction. We investigated whether a single high-dose of EPO administered immediately after reperfusion in patients with ST-segment elevation myocardial infarction (STEMI) would limit infarct size.. A total of 110 patients undergoing successful primary coronary intervention for a first STEMI was randomized to receive standard care either alone (n = 57) or combined with intravenous administration of 1,000 U/kg of epoetin β immediately after reperfusion (n = 53). The primary end point was infarct size assessed by gadolinium-enhanced cardiac magnetic resonance after 3 months. Secondary end points included left ventricular (LV) volume and function at 5-day and 3-month follow-up, incidence of microvascular obstruction (MVO), and safety.. Erythropoietin significantly decreased the incidence of MVO (43.4% vs 65.3% in the control group, P = .03) and reduced LV volume, mass, and function impairment at 5-day follow-up (all P < .05). After 3 months, median infarct size (interquartile range) was 17.5 g (7.6-26.1 g) in the EPO group and 16.0 g (9.4-28.2 g) in the control group (P = .64); LV mass, volume, and function were not significantly different between the 2 groups. The same number of major adverse cardiac events occurred in both groups.. Single high-dose EPO administered immediately after successful reperfusion in patients with STEMI did not reduce infarct size at 3-month follow-up. However, this regimen decreased the incidence of MVO and was associated with transient favorable effects on LV volume and function.

Topics: Coronary Angiography; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Erythropoietin; Female; Follow-Up Studies; Humans; Injections, Intravenous; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Postoperative Care; Prospective Studies; Recombinant Proteins; Time Factors; Treatment Outcome

Erythropoietin improves myocardial function and enhances re-endothelialisation. Aim of this study was to analyse progenitor cell mobilisation and restenosis in patients from the Regeneration of Vital Myocardium in ST-Segment Elevation Myocardial Infarction by Erythropoietin (REVIVAL-3) study. Patients with STEMI undergoing percutaneous coronary intervention (PCI) were randomly assigned to Epoetin beta (EPO) (n=68) or placebo (n=70). Drug-eluting stents (DES) were utilised in 93% of patients receiving EPO and in 95% of patients receiving placebo (p=0.83). Serial venous blood samples were drawn; CD133+ progenitor cells were quantified by four-colour flow cytometry and cytokines interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12 and tumour necrosis factor (TNF) alpha were analysed by cytometric bead array. Forty-eight hours after PCI a significant increase in CD133+ progenitor cells was observed in the EPO group. Yet, no differences in plasma cytokines were found. Quantitative coronary angiography after six months revealed an increase in segment diameter stenosis in the EPO group (32 ± 19% vs. 26 ± 14%, p=0.046). However, this increase in neointima generation was not associated with progenitor cell mobilisation. EPO in patients with STEMI treated with PCI is associated with an increase in diameter stenosis that is not associated with circulating progenitor cells.

Topics: Angiography; Cytokines; Drug-Eluting Stents; Erythropoietin; Flow Cytometry; Hematopoietic Stem Cell Mobilization; Humans; Inflammation; Interleukins; Myocardial Infarction; Placebos; Recombinant Proteins; Stem Cells; Time Factors; Treatment Outcome

To determine whether newer combination cytokine treatment with granulocyte colony-stimulating factor (G-CSF) and darbepoetin can improve efficacy of stem cell therapy, we evaluated safety and peripheral blood stem/progenitor cell (PBSC) mobilizing effects of combination cytokine in comparison with G-CSF alone in patients with acute myocardial infarction (AMI). We randomized 60 patients with AMI into two groups under 2:1 ratio; combination treatment with darbepoetin and G-CSF (n = 41: Combicytokine group) and the G-CSF alone (n = 19: G-CSF group). After coronary angioplasty, G-CSF was treated for 3 days with dose of 10 μg/kg/day in both groups. Only in the combicytokine group, additional single intravenous injection of 4.5 μg/kg of darbepoetin was administrated immediate after coronary angioplasty. Combination cytokine treatment was well tolerated as was G-CSF alone. PBSCs were obtained by apheresis for intracoronary infusion after completion of cytokine treatment and were analyzed by flow cytometry. The purity of proangiogenic cells was higher in combination cytokine group than the G-CSF group. Specifically, proportion of CD34(+)/KDR(+) endothelial progenitor cells, CD3(+)/CD31(+) angiogenic T cells and Tie2(+)/CXCR4(+) cells in apheresis products were higher in the combicytokine group. These meant that the combicytokine treatment recruited PBSCs in higher purity and fewer unwanted inflammatory cells than G-CSF alone in apheresis products. Combination treatment with darbepoetin and G-CSF is safe and more efficient to mobilize and recruit proangiogenic cells than G-CSF alone in patients with AMI. (. www.ClinicalTrials. gov identifier: NCT00501917).

Topics: Acute Disease; Adult; Aged; Antigens, CD34; Blood Component Removal; Coronary Angiography; Darbepoetin alfa; Drug Therapy, Combination; Endothelium, Vascular; Erythropoietin; Female; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Male; Middle Aged; Myocardial Infarction; Receptor, TIE-2; Stem Cells; T-Lymphocytes

The development of novel pharmaceutical interventions to improve the clinical outcomes of patients with acute ST-segment elevation myocardial infarction (STEMI) is an unmet medical need worldwide. In animal models, a single intravenous administration of erythropoietin (EPO) during reperfusion improves left ventricular (LV) function in the chronic stage. However, the results of recent proof-of-concept trials using high-dose EPO in patients with STEMI are inconsistent. In our pilot study, low-dose EPO after successful percutaneous coronary intervention (PCI) improved the LV ejection fraction (EF) and did not trigger severe adverse clinical events in patients with STEMI. One possible reason for this discrepancy is the dose of EPO used.. We have started a double-blind, placebo-controlled, randomized, multicenter clinical trial (EPO-AMI-II) to clarify the safety and efficacy of low-dose EPO in patients with STEMI. STEMI patients who have a low LVEF (<50 %) will be randomly assigned to intravenous administration of placebo or EPO (6,000 or 12,000 IU) within 6 h after successful PCI. The primary endpoint is the difference in LVEF between the acute and chronic phases (6 months), as measured by single-photon emission computed tomography. The patient number needed for EPO-AMI-II is 600. The study will stop when superior efficacy or futility is detected by an interim analysis. This study has been approved by the Evaluation System of Investigational Medical Care.. EPO-AMI-II study will clarify the safety and efficacy of low-dose EPO in STEMI patients with LV dysfunction in a double-blind, placebo-controlled, multicenter study. (247 words).

Topics: Adult; Aged; Double-Blind Method; Erythropoietin; Humans; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Reperfusion Injury; Ventricular Dysfunction, Left; Young Adult

Mortality and morbidity after acute myocardial infarction (AMI) remain high even when myocardial reperfusion is successful. Erythropoietin (EPO) protects against experimental MI.. The aim of this single-centre study was to investigate the effects of short-term high-dose erythropoietin on peripheral blood cells (PBCs) and infarct size in 30 patients with a first uncomplicated AMI undergoing percutaneous coronary intervention (PCI) who were randomly assigned to treatment with EPO (33 × 10(3)IU before PCI, and 24 and 48 h after admission), or placebo. We considered short-term CD34+ cell mobilisation, quantitative PBC gene expression in the apoptotic, angiogenic and inflammatory pathways, and enzymatically estimated infarct size. Echocardiographic and cardiac magnetic resonance studies were performed in the acute phase and six months later.. CD34+ cell mobilisation 72 h after admission was greater in the EPO-treated patient group (93 cells/μl [36-217] vs 22 cells/μl [6-51]; p = 0.002), who also showed higher expression of the anti-apoptotic AKT and NFkB, the pro-angiogenic VEGFR-2, and the EPO-R genes, and lower expression of the pro-apoptotic CASP3 and TP53 and pro-inflammatory IL12a genes. Moreover, they showed smaller infarct size (30% reduction in CK-MB release; p = 0.025), and a favourable pattern of left ventricular remodelling.. Short-term high-dose EPO administration in patients with AMI treated by PCI and standard anti-platelet therapy increases the levels of circulating CD34+ cells, shifts PBC gene expression towards anti-apoptotic, pro-angiogenic and anti-inflammatory pathways, and decreases infarct size. The clinical relevance of these results needs to be confirmed in specifically tailored trials.

Topics: Adult; Aged; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Female; Humans; Male; Middle Aged; Myocardial Infarction; Pilot Projects; Receptors, Erythropoietin

After an acute myocardial infarction, the early restoration of coronary blood flow is mandatory for reducing infarct size. However, the process of reperfusion itself may also cause irreversible myocardial injury and contribute to the final infarct size. Recent animal studies have suggested that erythropoietin could protect the myocardium when administered after the onset of reperfusion. We investigated whether the administration of erythropoietin at the time of PCI would limit the size of the infarct during acute myocardial infarction by analysis of MRI and cardiac enzymes in this pilot study.. We randomly assigned 57 patients with acute, anterior wall ST-elevation myocardial infarction who were presented within 12h after the onset of chest pain to one group which was given an intravenous bolus of recombinant human erythropoietin (rhEPO, 50 U/kg) immediately before undergoing PCI or the control group without the IV treatment before PCI. Infarct size was assessed by measuring the release of cardiac enzymes (CK, CK-MB) and by performing MRI on day 4 after infarction.. The injection of erythropoietin did not result in thrombotic or hypertensive complications. The release of cardiac enzyme was not different between two groups. On day 4, the absolute infarct volume of the area of hyperenhancement on MRI did not differ between two groups (EPO group 52.4 ± 23.6 cm(3) vs. control group 54.8 ± 28.6 cm(3), p=0.74). Two groups did not differ in the percentage of total infarct volume over left ventricle volume (EPO group 34.4 ± 11.7% vs. 37.0 ± 13.8%, p=0.50).. Intravenous administration of erythropoietin was safe and was not associated with thrombotic or hypertensive side effects. However, it did not reduce the infarct size when assessed by MRI and cardiac enzyme. Further studies about the dose or routes of administration of EPO are needed (ClinicalTrials.gov Identifier NCT00882466).

Topics: Angioplasty, Balloon, Coronary; Erythropoietin; Female; Follow-Up Studies; Humans; Injections, Intravenous; Male; Middle Aged; Myocardial Infarction; Pilot Projects; Prospective Studies; Recombinant Proteins; Treatment Outcome

Bone marrow derived stem/progenitor cell transplantation after acute myocardial infarction is safe and effective for improving left ventricular systolic function. However, the improvement of left ventricular systolic function is limited. This study will evaluate novel stem/progenitor cell therapy with combination cytokine treatment of the long-acting erythropoietin analogue, darbepoetin, and granulocyte colony-stimulating factor (G-CSF) in patients with acute myocardial infarction.. The 'MAGIC Cell-5-Combination Cytokine Trial' is a multicenter, prospective, randomized, 3-arm, controlled trial with blind evaluation of the endpoints. A total of 116 patients will randomly receive one of the following three treatments: an intravenous darbepoetin infusion and intracoronary infusion of peripheral blood stem cells mobilized with G-CSF (n = 58), an intracoronary infusion of peripheral blood stem cells mobilized with G-CSF alone (n = 29), or conventional therapy (n = 29) at phase I. Patients with left ventricular ejection fraction < 45% at 6 months, in the patients who received stem cell therapy at phase I, will receive repeated cell therapy at phase II. The objectives of this study are to evaluate the safety and efficacy of combination cytokine therapy with erythropoietin and G-CSF (phase I) and repeated progenitor/stem cell treatment (phase II).. This is the first study to evaluate the safety and efficacy of combination cytokine based progenitor/stem cell treatment.. http://www.ClinicalTrials.gov identifier: NCT00501917.

Topics: Combined Modality Therapy; Cytokines; Darbepoetin alfa; Erythropoietin; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Hematinics; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Injections; Myocardial Infarction; Prospective Studies; Research Design

Acute ST-segment elevation myocardial infarction (STEMI) is a leading cause of morbidity and mortality. In experimental models of MI, erythropoietin reduces infarct size and improves left ventricular (LV) function.. To evaluate the safety and efficacy of a single intravenous bolus of epoetin alfa in patients with STEMI.. A prospective, randomized, double-blind, placebo-controlled trial with a dose-escalation safety phase and a single dose (60,000 U of epoetin alfa) efficacy phase; the Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) trial was conducted at 28 US sites between October 2006 and February 2010, and included 222 patients with STEMI who underwent successful percutaneous coronary intervention (PCI) as a primary or rescue reperfusion strategy.. Participants were randomly assigned to treatment with intravenous epoetin alfa or matching saline placebo administered within 4 hours of reperfusion.. Infarct size, expressed as percentage of LV mass, assessed by cardiac magnetic resonance (CMR) imaging performed 2 to 6 days after study medication administration (first CMR) and again 12 ± 2 weeks later (second CMR).. In the efficacy cohort, the infarct size did not differ between groups on either the first CMR scan (n = 136; 15.8% LV mass [95% confidence interval {CI}, 13.3-18.2% LV mass] for the epoetin alfa group vs 15.0% LV mass [95% CI, 12.6-17.3% LV mass] for the placebo group; P = .67) or on the second CMR scan (n = 124; 10.6% LV mass [95% CI, 8.4-12.8% LV mass] vs 10.4% LV mass [95% CI, 8.5-12.3% LV mass], respectively; P = .89). In a prespecified analysis of patients aged 70 years or older (n = 21), the mean infarct size within the first week (first CMR) was larger in the epoetin alfa group (19.9% LV mass; 95% CI, 14.0-25.7% LV mass) than in the placebo group (11.7% LV mass; 95% CI, 7.2-16.1% LV mass) (P = .03). In the safety cohort, of the 125 patients who received epoetin alfa, the composite outcome of death, MI, stroke, or stent thrombosis occurred in 5 (4.0%; 95% CI, 1.31%-9.09%) but in none of the 97 who received placebo (P = .04).. In patients with STEMI who had successful reperfusion with primary or rescue PCI, a single intravenous bolus of epoetin alfa within 4 hours of PCI did not reduce infarct size and was associated with higher rates of adverse cardiovascular events. Subgroup analyses raised concerns about an increase in infarct size among older patients.. clinicaltrials.gov Identifier: NCT00378352.

Topics: Adult; Age Factors; Angioplasty, Balloon, Coronary; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Injections, Intravenous; Magnetic Resonance Imaging; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Placebos; Recombinant Proteins; Stents; Stroke; Thrombosis; Treatment Outcome; Ventricular Function, Left; Ventricular Remodeling

to assess the safety and feasibility of combined granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) based intracoronary peripheral blood stem cells (PBSCs) therapy in patients with recent myocardial infarction (RMI) who had successful reperfusion therapy with drug-eluting stent.. a total of 18 patients diagnosed with anterior ST-segment elevation AMI who had successful percutaneous coronary intervention (PCI) with drug-eluting stent implantation within 15 days after onset of symptom were enrolled. PBSCs were harvested and injected into the infarct-related artery after 5 consecutive days of G-CSF administration. Recombinant human erythropoietin was administered at the time of intracoronary PBSCs injection.. there were no procedural and periprocedural complications, such as ventricular arrhythmia, visible thrombus formation, distal embolization, injury of the coronary artery associated with the cell infusion catheterization procedure or elevation of CK-MB of more than two-times. After PBSCs injection, all patients had grade III myocardial blush grade. At follow-up of 21.1±5.5 months (range 12 to 30 months) there was no death, no re-infarction, no target lesion revascularization nor re-hospitalization for heart failure. Paired cardiac MRI demonstrated no change in left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) at 3 months, but they increased significantly at one year. Despite this, left ventricular ejection fraction (LVEF), wall motion score index (WMSI) and perfusion score index (PSI) improved at 3 months and remained stable at one year. The percentage of late gadolinium enhancement to LV mass (%LGE) were continuously improved until one year. There was no correlation between the level of CD34+, CD 45+, other cell subtypes as well as total number of PBSCs injected to the changes of LVEDV, LVESV, LVEF, WMSI, PSI, and %LGE (p >0.05).. combined G-CSF and EPO based- intracoronary infusion of PBSCs in patients RAMI is safe and feasible.

Topics: Aged; Angioplasty, Balloon, Coronary; Drug-Eluting Stents; Erythropoietin; Feasibility Studies; Female; Granulocyte Colony-Stimulating Factor; Health Status Indicators; Humans; Male; Middle Aged; Myocardial Infarction; Peripheral Blood Stem Cell Transplantation; Prospective Studies; Stroke Volume; Time Factors; Ventricular Function, Left

The acute administration of high-dose erythropoietin (EPO) on reperfusing ischaemic myocardium has been reported to halve myocardial infarct (MI) size in preclinical studies, but its effect in ST elevation myocardial infarction patients undergoing primary percutaneous coronary intervention (PPCI) remains unknown. We investigated whether high-dose EPO administered as an adjunct to PPCI reduces MI size.. Double-blinded, randomised, placebo-controlled.. Single tertiary cardiac centre.. Fifty-one ST elevation myocardial infarction patients undergoing PPCI.. Patients were randomly assigned to receive either a single intravenous bolus of EPO (50,000 IU) prior to PPCI with a further bolus given 24 h later (n=26) or placebo (n=25).. MI size measured by 24 h area under the curve troponin T and cardiac magnetic resonance imaging performed on day 2 and at 4 months.. EPO treatment failed to reduce MI size (troponin T area under the curve: 114.6±78 μg/ml EPO vs 100.8±68 μg/ml placebo; infarct mass by cardiac magnetic resonance: 33±16 g EPO vs 25±16 g placebo; both p>0.05). Unexpectedly, EPO treatment doubled the incidence of microvascular obstruction (82% EPO vs 47% placebo; p=0.02) and significantly increased indexed left ventricular (LV) end-diastolic volumes (84±10 ml/m(2) EPO vs 73±13 ml/m(2) placebo; p=0.003), indexed LV end-systolic volumes (41±9 ml/m(2) EPO vs 35±11 ml/m(2) placebo; p=0.035) and indexed myocardial mass (89±16 g/m(2) EPO vs 79±11 g/m(2) placebo; p=0.03). At 4 months, there were no significant differences between groups.. High-dose EPO administered as an adjunct to PPCI failed to reduce MI size. In fact, EPO treatment was associated with an increased incidence of microvascular obstruction, LV dilatation and increased LV mass. Clinical Trial Registration Information http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=4058 Unique Identifier=Study ID 4058.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Biomarkers; Coronary Circulation; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Humans; Hypertrophy, Left Ventricular; Injections, Intravenous; London; Magnetic Resonance Imaging; Male; Microcirculation; Middle Aged; Myocardial Infarction; Myocardium; Placebo Effect; Recombinant Proteins; Stroke Volume; Time Factors; Treatment Outcome; Troponin T; Ventricular Function, Left

Erythropoietin (EPO) has been found to have anti-apoptotic and tissue protective effects on the myocardium. The aim of the present pilot study was to observe the safety and efficacy of EPO administration for patients with acute myocardial infarction (AMI).. Patients admitted with AMI had all undergone successful percutaneous coronary intervention (PCI). Patients were randomly assigned to 2 groups (control and EPO groups), and given 12,000 IU EPO iv or saline after PCI. The primary endpoints were the difference between the acute phase and chronic phase (6 months after the attack) regarding left ventricular function as measured on electrocardiogram-gated single-photon emission computed tomography. Thirty-six patients (control 16, EPO 20) were eligible for analysis. Left ventricular ejection fraction (LVEF) significantly increased in the EPO group (from 51.0+/-19.6% to 58.5+/-15.0%, P=0.0238), but not in the control group. Further analysis was separately undertaken in patients with occlusion in the left anterior descending artery (LAD) and others (non-LAD). LVEF was <50% in most patients in the LAD subgroup, and LVEF significantly increased in the EPO group (37.5+/-13.0 to 52.7+/-15.8, P=0.0049), but not in the control group. EPO administration did not trigger any adverse clinical events.. EPO administration is a promising treatment for AMI.

Topics: Aged; Angioplasty, Balloon, Coronary; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Female; Humans; Male; Middle Aged; Myocardial Infarction; Pilot Projects; Recombinant Proteins; Stroke Volume; Tomography, Emission-Computed, Single-Photon; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

Erythropoietin improves myocardial function in experimental models of myocardial infarction. The aim of the present study was to determine the value of erythropoietin in patients with acute ST-elevation myocardial infarction.. This randomized, double-blind study included 138 patients admitted with acute ST-elevation myocardial infarction and treated with primary percutaneous coronary intervention. Patients were randomly assigned to receive epoetin-β (3.33×104 U, n=68) or placebo (n=70) immediately and at 24 and 48 hours after percutaneous coronary intervention. The primary end point was left ventricular ejection fraction after 6 months measured by MRI. Other end points included infarct size at 5 days and 6 months. Clinical adverse events (death, recurrent myocardial infarction, stroke, and infarct-related artery revascularization) were investigated at 30 days and 6 months. Left ventricular ejection fraction at 6-month follow-up was 52.0±9.1% in the erythropoietin group compared with 51.8±9.3% in the placebo group (P=0.92). Five days after percutaneous coronary intervention, left ventricular ejection fraction was 49.4±8.0% in the erythropoietin group and 50.8±7.3% in the placebo group (P=0.32); infarct size was 26.8±20.9% and 28.3±24.4% (P=0.76) and decreased to 17.3±14.3% and 20.9±16.4% at 6-month follow-up (P=0.27). The cumulative 6-month incidence of death, recurrent myocardial infarction, stroke or target vessel revascularization was 13.2% in the erythropoietin group and 5.7% in the placebo group (hazard ratio, 2.36; 95% confidence interval, 0.73 to 7.66; P=0.15).. In patients with acute ST-elevation myocardial infarction treated with primary percutaneous coronary intervention, erythropoietin treatment did not improve left ventricular ejection fraction or reduce infarct size but may increase clinical adverse events.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00390832.

Topics: Aged; Angioplasty; Double-Blind Method; Electrocardiography; Erythropoietin; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Myocardium; Recurrence; Stroke; Stroke Volume; Survival Analysis; Treatment Outcome

Cardioprotective effects of erythropoietin (EPO) have been shown in experimental and smaller clinical studies. We performed a prospective, multicentre, randomized trial to assess the effects of a single high dose of EPO after primary coronary intervention (PCI) for an ST-elevation myocardial infarction (STEMI). Methods and results Patients with a successful PCI for a first STEMI were randomized to receive either standard medical care alone, or in combination with a single bolus with 60,000 IU i.v. of epoetin alfa within 3 h after PCI. Primary endpoint was left ventricular ejection fraction (LVEF) after 6 weeks, assessed by planar radionuclide ventriculography. Pre-specified secondary endpoints included enzymatic infarct size and major adverse cardiovascular events. A total of 529 patients were enrolled (EPO n = 263, control n = 266). At baseline (before EPO administration), groups were well-matched for all relevant characteristics. After a mean of 6.5 (± 2.0) weeks, LVEF was 0.53 (± 0.10) in the EPO group and 0.52 (± 0.11) in the control group (P = 0.41). Median area under the curve (inter-quartile range) after 72 h for creatinine kinase was 50 136 (28 212-76 664)U/L per 72 h in the EPO group and 53 510 (33 973-90 486)U/L per 72 h in the control group (P = 0.058). More major adverse cardiac events occurred in the control than in the EPO group (19 vs. 8; P = 0.032). Conclusion A single high dose of EPO after a successful PCI for a STEMI did not improve LVEF after 6 weeks. However, the use of EPO was related to less major adverse cardiovascular events and a favourable clinical safety profile.. NCT00449488; http://www.clinicaltrials.gov/ct2/show/NCT00449488?term=voors&rank=2.

Topics: Angioplasty, Balloon, Coronary; Combined Modality Therapy; Electrocardiography; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Radionuclide Ventriculography; Recombinant Proteins; Treatment Failure; Ventricular Dysfunction, Left

Erythropoietin (EPO) enhances re-endothelialization and anti-apoptotic action. Larger clinical studies to examine the effects of high-dose EPO are in progress in patients with acute myocardial infarction (AMI).. The aim of this multi-center pilot study was to investigate the effect of `low-dose EPO' (6,000 IU during percutaneous coronary intervention (PCI), 24 h and 48 h) in 35 patients with a first ST-elevated AMI undergoing PCI who was randomly assigned to EPO or placebo (saline) treatment. Neointimal volume, cardiac function and infarct size were examined in the acute phase and 6 months later (ClinicalTrials.gov identifier: NCT00423020). No significant regression in in-stent neointimal volume was observed, whereas left ventricular (LV) ejection fraction was significantly improved (49.2% to 55.7%, P=0.003) and LV end-systolic volume was decreased in the EPO group (47.7 ml to 39.0 ml, P=0.036). LV end-diastolic volume tended to be reduced from 90.2% to 84.5% (P=0.159), whereas in the control group it was inversely increased (91.7% to 93.7%, P=0.385). Infarction sizes were significantly reduced by 38.5% (P=0.003) but not in the control group (23.7%, P=0.051). Hemoglobin, peak creatine kinase values, and CD34(+)/CD133(+)/CD45(dim) endothelial progenitors showed no significant changes. No adverse events were observed during study periods.. This is a first study demonstrating that short-term `low-dose' EPO to PCI-treated AMI patients did not prevent neointimal hyperplasia but rather improved cardiac function and infarct size without any clinical adverse effects.

Topics: Aged; Angioplasty, Balloon, Coronary; Biomarkers; Cardiovascular Agents; Chi-Square Distribution; Coronary Angiography; Coronary Restenosis; Creatine Kinase; Endothelial Cells; Erythropoietin; Female; Hemoglobins; Humans; Hyperplasia; Japan; Male; Middle Aged; Myocardial Infarction; Myocardium; Pilot Projects; Placebo Effect; Prospective Studies; Recombinant Proteins; Stem Cells; Stroke Volume; Time Factors; Treatment Outcome; Ultrasonography, Interventional; Ventricular Function, Left; Ventricular Remodeling

This study aimed to apply a software to calculate myocardial infarction (MI) volume by single-photon emission computed tomography.. The cardioVol software has been developed to reconstruct 3D figures from sequential short axis images. We re-analyzed the data from the EPO/AMI-I Study. The MI volume at baseline correlated with maximum creatine kinase. The MI volume significantly decreased during the 6-month follow up in the erythropoietin (EPO) group, but not in the control group. The decrements of MI volume in the EPO group were significantly larger than those in the control group.. The efficacy of EPO was further confirmed by the software.

Topics: Cardiac-Gated Single-Photon Emission Computer-Assisted Tomography; Erythropoietin; Female; Follow-Up Studies; Humans; Male; Myocardial Infarction; Organotechnetium Compounds; Pilot Projects; Radiography; Radiopharmaceuticals; Software

Acute myocardial infarction (MI) remains a leading cause of death despite advances in pharmacologic and percutaneous therapies. Animal models of ischemia/reperfusion have demonstrated that single-dose erythropoietin may reduce infarct size, decrease apoptosis, and increase neovascularization, possibly through mobilization of endothelial progenitor cells.. REVEAL is a randomized, double-blind, placebo-controlled, multicenter trial evaluating the effects of epoetin α on infarct size and left ventricular remodeling in patients with large MIs. The trial comprises a dose-escalation safety phase and a single-dose efficacy phase using the highest acceptable epoetin α dose up to 60,000 IU. Up to 250 ST-segment elevation myocardial infarction patients undergoing primary or rescue percutaneous coronary intervention will be randomized to intravenous epoetin α or placebo within 4 hours of successful reperfusion. The primary study end point is infarct size expressed as a percentage of left ventricular mass, as measured by cardiac magnetic resonance imaging 2 to 6 days post study medication administration. Secondary end points will assess changes in endothelial progenitor cell numbers and changes in indices of ventricular remodeling.. The REVEAL trial will evaluate the safety and efficacy of the highest tolerated single dose of epoetin α in patients who have undergone successful rescue or primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction.

Topics: Aged; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Epoetin Alfa; Erythropoietin; Follow-Up Studies; Heart Ventricles; Hematinics; Humans; Injections, Intravenous; Magnetic Resonance Imaging, Cine; Myocardial Infarction; Recombinant Proteins; Recovery of Function; Treatment Outcome; United States; Ventricular Function, Left; Ventricular Remodeling

To determine whether the administration of erythropoietin (EPO) early after the onset of ischemia could enhance the preservation of jeopardized myocardium by reperfusion, 236 patients admitted <6 hours after the onset of chest pain indicative of acute coronary syndromes confirmed to be ST-segment elevation acute myocardial infarctions who were treated with tenecteplase to induce coronary thrombolysis were studied. Patients were randomized to standard care or standard care plus the administration of a single dose of EPO 30,000 IU intravenously immediately before the onset of treatment with tenecteplase. The primary end point was enzymatically estimated infarct size. The results indicated that infarct size index was virtually identical in the 2 groups, with a mean +/- SE of 13.2 +/- 0.1 creatine kinase-MB gram equivalents in controls and 12.4 +/- 0.9 creatine kinase-MB gram equivalents in patients treated with EPO. In conclusion, although the early administration of EPO was apparently safe, it did not enhance the preservation of jeopardized ischemic myocardium.

Topics: Creatine Kinase, MB Form; Dose-Response Relationship, Drug; Electrocardiography; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Fibrinolytic Agents; Follow-Up Studies; Humans; Injections, Intravenous; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Secondary Prevention; Tenecteplase; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome

Erythropoietin mitigates myocardial damage and improves ventricular performance after experimental ischemic injury. This study assessed safety and efficacy markers relevant to the biological activity of recombinant human erythropoietin (rHuEpo) in patients with acute myocardial infarction (MI).. We conducted a prospective, placebo-controlled, randomized, double-blind trial to determine the effects of intravenous rHuEpo (200 U/kg daily for 3 consecutive days) on measures of platelet and endothelial cell activation, soluble Fas ligand, and peripheral blood mononuclear cell (PBMC) expression of angiogenesis signaling proteins in 44 subjects with acute MI treated with aspirin and clopidogrel after successful percutaneous coronary intervention.. Recombinant human erythropoietin did not alter bleeding time, platelet function assay closure time, von Willebrand factor levels, soluble P-selectin, or soluble Fas ligand levels when compared with placebo. By contrast, rHuEpo significantly increased expression of erythropoietin receptor, vascular endothelial growth factor receptor Flt-1, and phosphorylated phosphatidylinositol 3-kinase in PBMCs when compared with placebo (all Ps < .05).. In acute MI patients treated with aspirin and clopidogrel, short-term administration of rHuEpo did not alter markers of platelet and endothelial cell activation associated with thrombosis, yet did increase expression of angiogenesis signaling proteins in PBMCs when compared with placebo. These data provide preliminary evidence of safety and biologic activity of rHuEpo at this dosing and support continued enrollment in ongoing efficacy trials.

Topics: Double-Blind Method; Erythropoietin; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Activation; Prospective Studies; Recombinant Proteins

A pilot study was performed to determine the effect of 40,000 IU Epo on myocardial damage in 51 patients with non-ST segment elevation acute coronary syndrome (non-STE ACS). No significant difference in myocardial damage was found, but an increased systolic blood pressure was noticed.

Topics: Acute Coronary Syndrome; Epoetin Alfa; Erythropoietin; Humans; Injections, Intravenous; Myocardial Infarction; Pilot Projects; Prospective Studies; Recombinant Proteins

Preclinical studies have consistently shown that erythropoietin (EPO), administered after an acute myocardial infarction (AMI), reduces infarct size and improves left ventricular function. Furthermore, EPO promotes endothelial progenitor cell growth, which increases angiogenesis. A recent pilot study in patients with AMI suggested that a single bolus of EPO was safe and well tolerated.. The HEBE III is a multicenter, prospective, randomized, open-label trial with blinded evaluation of the primary end point. The primary objective is to study the effect on left ventricular ejection fraction (LVEF) of a single bolus of EPO, administered directly after a primary percutaneous coronary intervention (PCI) for a first AMI. A total of 466 patients with thrombolysis in myocardial infarction 0/1 flow before the PCI procedure and 2/3 flow after a successful PCI are randomly assigned to either receive standard medical care or a single bolus with 60,000 IU of EPO on top of standard medical care within 3 hours of the PCI procedure. Primary end point of the study is LVEF after 6 weeks, assessed by planar radionuclide ventriculography.. If an improvement of LVEF with a single bolus of EPO is demonstrated, this simple approach might further improve clinical outcome of patients with AMI.

Topics: Angioplasty, Balloon, Coronary; Erythropoietin; Female; Hematinics; Humans; Male; Myocardial Infarction; Radionuclide Ventriculography; Stroke Volume

Besides stimulating hematopoiesis, erythropoietin (EPO) protects against experimental ischemic injury in the heart. The present study evaluated the safety and tolerability of EPO treatment in non-anemic patients with acute myocardial infarction (MI).. In this single-center, investigator-initiated, prospective study, patients with a first acute MI were randomized to one bolus of 300 microg darbepoetin alfa or no additional medication before primary coronary intervention. Twenty-two patients (mean age 59 +/- 2 years) were included. In the darbepoetin group, serum EPO-levels increased to 130-270 times that of controls, within the first 24 h. After darbepoetin administration, only small and non-significant changes in hematocrit levels were observed, while endothelial progenitor cells (EPCs, CD34+/CD45-) were increased at 72 h (2.8 vs. 1.0 cells/microl in control group, p < 0.01). No adverse events were recorded during the 30-day follow-up. After 4 months, left ventricular ejection fraction was similar in the two groups (52 +/- 3% in darbepoetin vs. 48 +/- 5% in control group, p = NS).. Intravenous single high-dose darbepoetin alfa in acute MI is both safe and well tolerated. Darbepoetin treatment after MI stimulates EPCs mobilization. The results of this first pilot study support a larger scale clinical trial to establish efficacy of EPO administration in patients after acute MI.

Topics: Angioplasty, Balloon, Coronary; Antigens, CD34; Blood Cell Count; Blood Platelets; Darbepoetin alfa; Electrocardiography; Erythropoietin; Feasibility Studies; Heart Conduction System; Hemoglobins; Humans; Injections, Intravenous; Leukocyte Common Antigens; Male; Mesenchymal Stem Cells; Middle Aged; Myocardial Infarction; Patient Selection; Prospective Studies; Reticulocytes; Tachycardia, Ventricular; Treatment Outcome

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

This Spanish single-arm, multicenter, prospective clinical trial assessed the maintenance of hemoglobin concentrations (Hb) between 10-13 g/dL with unit doses of darbepoetin alfa and the safety of the treatment in dialysis patients. Eight-hundred twenty-six patients with chronic renal failure (CRF) (94% receiving haemodialysis and 6% receiving peritoneal dialysis) previously maintained on stable recombinant human erythropoietin (r-HuEPO) therapy with stable hemoglobin (Hb) concentrations (mean Hb concentration = 11.7 g/dL) were switched to darbepoetin alfa at a reduced dosing frequency for 24 weeks (a 20-week titration phase plus a 4-week treatment evaluation phase). Subjects receiving r-HuEPO two or three times weekly were switched to darbepoetin alfa once weekly, and those. who were receiving r-HuEPO once weekly were switched to darbepoetin alfa once every two weeks. The initial dose of darbepoetin alfa was determined from the r-HuEPO dose at inclusion into the study using a formula equating the peptide mass of the two molecules and rounding to the nearest available prefilled syringe dose. Overall, 86.8% of patients completed the 24-weeks of study. Changing the treatment from r-HuEPO to darbepoetin alfa and increasing the dose interval did not result in any clinically significant change in the Hb concentration. From base-line to the evaluation phase, the mean Hb fell 0.09 (95% CI, -0.2; -0.0) g/dl, with an increase of 0.19 (95% CI, 0.0;0.3) g/dL i.v. and a decrease of 0.22 (95% CI, -0.3; -0.1) g/dL s.c.). This maintenance of the mean Hb concentration was accompanied by a mean 9.8% reduction of the darbepoetin alfa dose (19.7% (95% CI, -24.9; -14.2) i.v. and 4.7% (95% CI, -8.5; -0.7) s.c. Treatment with darbepoetin alfa was well tolerated and no unexpected adverse events were reported. In conclusion, the replacement of previous r-HuEPO treatment by darbepoetin alfa in the therapy of anemia secondary to chronic renal failure in diaiyzed patients was effective, well tolerated, and decreased the frequency of dose administration compared with the previous r-HuEPO treatment. Darbepoetin alfa administered once weekly or once every two weeks maintained the baseline Hb levels whilst allowing dose reduction, which was higher in patients receiving i.v. darbepoetin alfa.

Topics: Aged; Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Hemorrhage; Humans; Hypertension; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Peritoneal Dialysis; Prospective Studies; Recombinant Proteins; Renal Dialysis; Safety; Thrombosis; Treatment Outcome

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

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

Topics: Animals; Apoptosis; Arrhythmias, Cardiac; Erythropoietin; Male; Mitochondria; Mitochondrial Dynamics; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Rats; Rats, Wistar

This study tested the hypothesis that intramuscular injections of erythropoietin (EPO) and endothelial progenitor cells (EPC) to critical limb ischemia (CLI; primary treatment site) could also improve heart function in rat after acute myocardial infarction (AMI; remote ischemic organ).. Adult-male SD rats (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (CLI-AMI), group 3 [CLI-AMI + EPO (10 mg/kg)], group 4 [CLI-AMI + EPCs (1.2 × 10. By day 21 (end of study period), 2-D echo and Laser doppler showed that left-ventricular injection fraction (LVEF) and the ratio of ischemic to normal blood flow were highest in group 1, lowest in group 2, significantly higher in group 5 than in groups 3 and 4, but not different in the latter two groups (all p < 0.0001). Flow cytometry and ELISA demonstrated that circulating angiogenesis factors were significantly progressively increased from groups 1 to 5 (all p < 0.001). The number of small vessels and protein (CD31/eNOS)/cellular (vWF) expressions reflecting integrity of endothelium exhibited an identical pattern to LVEF whereas protein (VEGF/SDF-1α)/cellular (VEGF) expressions were significantly progressively increased from groups 1 to 5 in quadriceps and heart tissues (all p < 0.0001). Protein expressions of apoptotic (Bax/caspase-3/PARP)/inflammatory (MMP-9) and microscopic findings of ischemic/fibrotic/collagen-deposition areas and DNA-damage marker (γ-H2AX+) were lowest in group 1 and significantly progressively decreased from groups 2 to 5 in quadriceps and heart tissues (all p < 0.0001).. Direct injection of EPO-EPC into CLI effectively restored blood flow in the CLI area and also preserved remote heart function.

Topics: Animals; Apoptosis; Biomarkers; Blood Vessels; Collagen; DNA Damage; Endothelial Progenitor Cells; Erythropoietin; Heart Ventricles; Ischemia; Male; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Rats, Sprague-Dawley; Regional Blood Flow; Stroke Volume

To explore the molecular mechanism of the cardioprotective effect of erythropoietin (EPO) in the rats with acute myocardial infarction (AMI) via the c-Jun N-terminal kinase (JNK) pathway.. The rat AMI models were constructed and randomly divided into the EPO group, AMI group, and Sham group. At 2 weeks after successful modeling, the cardiac function-related indicators of rats were determined, and after the rats were sacrificed, the left ventricular weight (LVW) index was measured. The enzyme-linked immunosorbent assay (ELISA) and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were employed to determine the levels of the related serum inflammatory factors and myocardial apoptosis, respectively. The apoptosis and the expression levels of the JNK pathway-related messenger ribonucleic acids (mRNA) and proteins in the myocardial tissues of all groups of rats were determined via Real Time-Polymerase Chain Reaction (RT-PCR) and immunohistochemistry.. After intervention with EPO, the EPO group had a substantially lower left ventricular end-diastolic pressure, but a remarkably higher left ventricular systolic pressure than the AMI group (p<0.05), and the LVW and LVW/body weight (BW) notably declined in the EPO group compared with those in AMI group (p<0.05). According to the ELISA results, the inflammatory factors were substantially raised in the AMI group compared with those in the other two groups (p<0.05) and significantly lowered after treatment with EPO (p<0.05). The TUNEL assay results revealed that EPO treatment could reverse the pathological changes in AMI to decrease the apoptosis to a large extent. It was detected via RT-PCR and immunohistochemistry that, compared with those in the Sham group, the expression level of the anti-apoptosis gene B-cell lymphoma 2 (Bcl-2) was substantially decreased, but the expression levels of pro-apoptosis gene Bcl-2 associated X protein (Bax) and the JNK pathway-related JNK and c-Jun were evidently elevated in the AMI group (p<0.05). Moreover, the expression level of Bcl-2 was remarkably raised (p<0.05) and the expression levels of Bax, JNK, and c-Jun remarkably declined (p<0.05) in the EPO group after intervention with EPO.. EPO can inhibit the inflammatory responses and decrease the myocardial apoptosis to protect the heart of the AMI rats, and its mechanism of action is related to the inhibition of the expression of the JNK pathway.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Cardiotonic Agents; Enzyme-Linked Immunosorbent Assay; Erythropoietin; In Situ Nick-End Labeling; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Signaling System; Myocardial Infarction; Myocardium; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-jun; Rats; Rats, Sprague-Dawley

Myocardial remodeling includes inappropriate collagen deposition in the interstitium. Erythropoietin (EPO) may have cardioprotective effects. We aimed to assess the role of EPO on myocardial remodeling during the chronic phase. We studied 60 Wistar rats divided into the following groups: control (CT), control + EPO (CT + EPO), myocardial infarction + EPO (MI + EPO), and myocardial infarction (MI). The interstitial collagen volume fraction (ICVF) was quantified and echocardiography was performed. We quantified asymmetric dimethylarginine and glutathione by ELISA, and used real-time PCR to assess apoptosis and inflammation. Western blotting was used to evaluate inflammatory proteins and tissue inhibitors of metalloproteinases (TIMPs), and TUNEL staining was used to detect apoptosis. For matrix metalloproteinases (MMPs), we performed zymography. Parametric and nonparametric analyses were performed according to normality testing. ICVF was greater in MI groups (p < 0.001) and was attenuated by EPO (p = 0.05). The MMP-2 did not show any difference between groups. The TIMP-1 and TIMP-2 did not have difference between groups. The MI groups had worse fraction shortening (p < 0.001), without EPO protection (p = 0.666). The MI groups had increased left ventricle diastolic dimension (p < 0.001) without EPO attenuation (p = 0.79). EPO did not act on oxidative stress. Apoptosis and inflammation were not modulated by EPO. We concluded that EPO attenuated interstitial collagen accumulation, but did not protect from heart dilation or dysfunction.

Topics: Animals; Apoptosis; Arginine; Collagen; Diastole; Erythropoietin; Glutathione; Heart; Hematocrit; Hemoglobins; Male; Myocardial Infarction; Myocardium; Oxidative Stress; Rats

Tissue engineering offers an exciting possibility for cardiac repair post myocardial infarction. We assessed the effects of combined polyethylene glycol hydrogel (PEG), human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM), and erythropoietin (EPO) therapy in a rat model of myocardial infarction. PEG with/out iPSC-CMs and EPO; iPSC-CMs in saline; or saline alone was injected into infarcted hearts shortly after infarction. Injection of almost any combination of the therapeutics limited acute elevations in chamber volumes. After 10 weeks, attenuation of ventricular remodeling was identified in all groups that received PEG injections, while ejection fractions were significantly increased in the gel-EPO, cell, and gel-cell-EPO groups. In all treatment groups, infarct thickness was increased and regions of muscle were identified within the scar. However, no grafted cells were detected. Hence, iPSC-CM-encapsulating bioactive hydrogel therapy can improve cardiac function post myocardial infarction and increase infarct thickness and muscle content despite a lack of sustained donor-cell engraftment.

Topics: Animals; Cells, Cultured; Erythropoietin; Humans; Hydrogels; Induced Pluripotent Stem Cells; Injections, Intralesional; Male; Myocardial Infarction; Myocytes, Cardiac; Polyethylene Glycols; Rats; Rats, Nude; Stem Cell Transplantation

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

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

Chronic kidney disease (CKD) is known to increase myocardial infarct size after ischemia/reperfusion. However, a strategy to prevent the CKD-induced myocardial susceptibility to ischemia/reperfusion injury has not been developed. Here, we examined whether epoetin β pegol, a continuous erythropoietin receptor activator (CERA), normalizes myocardial susceptibility to ischemia/reperfusion injury by its effects on protective signaling and metabolomes in CKD. CKD was induced by 5/6 nephrectomy in rats (subtotal nephrectomy, SNx), whereas sham-operated rats served controls (Sham). Infarct size as percentage of area at risk after 20-minutes coronary occlusion/2-hour reperfusion was larger in SNx than in Sham: 60.0±4.0% versus 43.9±2.2%. Administration of CERA (0.6 μg/kg SC every 7 days) for 4 weeks reduced infarct size in SNx (infarct size as percentage of area at risk=36.9±3.9%), although a protective effect was not detected for the acute injection of CERA. Immunoblot analyses revealed that myocardial phospho-Akt-Ser473 levels under baseline conditions and on reperfusion were lower in SNx than in Sham, and CERA restored the Akt phosphorylation on reperfusion. Metabolomic analyses showed that glucose 6-phosphate and glucose 1-phosphate were reduced and malate:aspartate ratio was 1.6-fold higher in SNx than in Sham, suggesting disturbed flux of malate-aspartate shuttle by CKD. The CERA improved the malate:aspartate ratio in SNx to the control level. In H9c2 cells, mitochondrial Akt phosphorylation by insulin-like growth factor-1 was attenuated by malate-aspartate shuttle inhibition. In conclusion, the results suggest that a CERA prevents CKD-induced susceptibility of the myocardium to ischemia/reperfusion injury by restoration of Akt-mediated signaling possibly via normalized malate-aspartate shuttle flux.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Drug Administration Schedule; Erythropoietin; Injections, Subcutaneous; Male; Metabolome; Myocardial Infarction; Myocardial Reperfusion Injury; Nephrectomy; Phosphorylation; Polyethylene Glycols; Proto-Oncogene Proteins c-akt; Random Allocation; Rats; Reference Values; Renal Insufficiency, Chronic; Sensitivity and Specificity

Erythropoietin (EPO) has been shown to protect the heart against acute myocardial infarction in pre-clinical studies, however, EPO failed to reduce infarct size in clinical trials and showed significant safety problems. Here, we investigated cardioprotective effects of two selective non-erythropoietic EPO receptor ligand dimeric peptides (AF41676 and AF43136) lacking erythropoietic activity, EPO, and the prolonged half-life EPO analogue, darbepoetin in acute myocardial infarction (AMI) in rats. In a pilot study, EPO at 100U/mL significantly decreased cell death compared to vehicle (33.8±2.3% vs. 40.3±1.5%, p<0.05) in rat neonatal cardiomyocytes subjected to simulated ischemia/reperfusion. In further studies (studies 1-4), in vivo AMI was induced by 30min coronary occlusion and 120min reperfusion in male Wistar rats. Test compounds and positive controls for model validation (B-type natriuretic peptide, BNP or cyclosporine A, CsA) were administered iv. before the onset of reperfusion. Infarct size (IS) was measured by standard TTC staining. In study 1, 5000U/kg EPO reduced infarct size significantly compared to vehicle (45.3±4.8% vs. 59.8±4.5%, p<0.05). In study 2, darbepoetin showed a U-shaped dose-response curve with maximal infarct size-reducing effect at 5μg/kg compared to the vehicle (44.4±5.7% vs. 65.9±2.7%, p<0.01). In study 3, AF41676 showed a U-shaped dose-response curve, where 3mg/kg was the most effective dose compared to the vehicle (24.1±3.9% vs. 44.3±2.5%, p<0.001). The positive control BNP significantly decreased infarct size in studies 1-3 by approximately 35%. In study 4, AF43136 at 10mg/kg decreased infarct size, similarly to the positive control CsA compared to the appropriate vehicle (39.4±5.9% vs. 58.1±5.4% and 45.9±2.4% vs. 63.8±4.1%, p<0.05, respectively). This is the first demonstration that selective, non-erythropoietic EPO receptor ligand dimeric peptides AF41676 and AF43136 administered before reperfusion are able to reduce infarct size in a rat model of AMI. Therefore, non-erythropoietic EPO receptor peptide ligands may be promising cardioprotective agents.

Topics: Animals; Cardiotonic Agents; Erythropoietin; Ligands; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; Pilot Projects; Rats; Rats, Wistar

The mechanism through which the protein kinase Akt (also called PKB), protects the heart against acute ischaemia-reperfusion injury (IRI) is not clear. Here, we investigate whether Akt mediates its cardioprotective effect by modulating mitochondrial morphology. Transfection of HL-1 cardiac cells with constitutively active Akt (caAkt) changed mitochondrial morphology as evidenced by an increase in the proportion of cells displaying predominantly elongated mitochondria (73 ± 5.0 % caAkt vs 49 ± 5.8 % control: N=80 cells/group; p< 0.05). This effect was associated with delayed time taken to induce mitochondrial permeability transition pore (MPTP) opening (by 2.4 ± 0.5 fold; N=80 cells/group: p< 0.05); and reduced cell death following simulated IRI (32.8 ± 1.2 % caAkt vs 63.8 ± 5.6 % control: N=320 cells/group: p< 0.05). Similar effects on mitochondrial morphology, MPTP opening, and cell survival post-IRI, were demonstrated with pharmacological activation of Akt using the known cardioprotective cytokine, erythropoietin (EPO). The effect of Akt on inducing mitochondrial elongation was found to be dependent on the mitochondrial fusion protein, Mitofusin-1 (Mfn1), as ablation of Mfn1 in mouse embryonic fibroblasts (MEFs) abrogated Akt-mediated mitochondrial elongation. Finally, in vivo pre-treatment with EPO reduced myocardial infarct size (as a % of the area at risk) in adult mice subjected to IRI (26.2 ± 2.6 % with EPO vs 46.1 ± 6.5 % in control; N=7/group: p< 0.05), and reduced the proportion of cells displaying myofibrillar disarray and mitochondrial fragmentation observed by electron microscopy in adult murine hearts subjected to ischaemia from 5.8 ± 1.0 % to 2.2 ± 1.0 % (N=5 hearts/group; p< 0.05). In conclusion, we found that either genetic or pharmacological activation of Akt protected the heart against acute ischaemia-reperfusion injury by modulating mitochondrial morphology.

Topics: Animals; Cell Death; Cell Line; Disease Models, Animal; Enzyme Activation; Erythropoietin; GTP Phosphohydrolases; Male; Mice, Inbred C57BL; Mitochondria, Heart; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Mitochondrial Size; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Proto-Oncogene Proteins c-akt; Signal Transduction; Time Factors; Transfection

Remote ischemic preconditioning (RIPC) induced by transient limb ischemia is a powerful innate mechanism of cardioprotection against ischemia. Several described mechanisms explain how RIPC may act through neural pathways or humoral factors; however, the mechanistic pathway linking the remote organ to the heart has not yet been fully elucidated. This study aimed to investigate the mechanisms underlying the RIPC-induced production of Janus kinase (JAK)-signal transducer and activator of the transcription (STAT)-activating cytokines and cardioprotection by using mouse and human models of RIPC.. Screened circulating cardioprotective JAK-STAT-activating cytokines in mice unexpectedly revealed increased serum erythropoietin (EPO) levels after RIP induced by transient ischemia. In mice, RIPC rapidly upregulated EPO mRNA and its main transcriptional factor, hypoxia-inducible factor-1α (HIF1α), in the kidney. Laser Doppler blood flowmetry revealed a prompt reduction of renal blood flow (RBF) after RIPC. RIPC activated cardioprotective signaling pathways and the anti-apoptotic Bcl-xL pathway in the heart, and reduced infarct size. In mice, these effects were abolished by administration of an EPO-neutralizing antibody. Renal nerve denervation also abolished RIPC-induced RBF reduction, EPO production, and cardioprotection. In humans, transient limb ischemia of the upper arm reduced RBF and increased serum EPO levels.. Based on the present data, we propose a novel RIPC mechanism in which inhibition of infarct size by RIPC is produced through the renal nerve-mediated reduction of RBF associated with activation of the HIF1α-EPO pathway.

Topics: Animals; bcl-X Protein; Erythropoietin; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Ischemic Preconditioning, Myocardial; Janus Kinases; Kidney; Male; Mice; Mice, Inbred BALB C; Myocardial Infarction; Peripheral Nerves

Adequately powered studies directly comparing hard clinical outcomes of darbepoetin alfa (DPO) versus epoetin alfa (EPO) in patients undergoing dialysis are lacking.. Observational, registry-based, retrospective cohort study; we mimicked a cluster-randomized trial by comparing mortality and cardiovascular events in US patients initiating hemodialysis therapy in facilities (almost) exclusively using DPO versus EPO.. Nonchain US hemodialysis facilities; each facility switching from EPO to DPO (2003-2010) was matched for location, profit status, and facility type with one EPO facility. Patients subsequently initiating hemodialysis therapy in these facilities were assigned their facility-level exposure.. DPO versus EPO.. All-cause mortality, cardiovascular mortality; composite of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke.. Unadjusted and adjusted HRs from Cox proportional hazards regression models.. Of 508 dialysis facilities that switched to DPO, 492 were matched with a similar EPO facility; 19,932 (DPO: 9,465 [47.5%]; EPO: 10,467 [52.5%]) incident hemodialysis patients were followed up for 21,918 person-years during which 5,550 deaths occurred. Almost all baseline characteristics were tightly balanced. The demographics-adjusted mortality HR for DPO (vs EPO) was 1.06 (95% CI, 1.00-1.13) and was materially unchanged after adjustment for all other baseline characteristics (HR, 1.05; 95% CI, 0.99-1.12). Cardiovascular mortality did not differ between groups (HR, 1.05; 95% CI, 0.94-1.16). Nonfatal outcomes were evaluated among 9,455 patients with fee-for-service Medicare: 4,542 (48.0%) in DPO and 4,913 (52.0%) in EPO facilities. During 10,457 and 10,363 person-years, 248 and 372 events were recorded, respectively, for strokes and MIs. We found no differences in adjusted stroke or MI rates or their composite with cardiovascular death (HR, 1.10; 95% CI, 0.96-1.25).. Nonrandom treatment assignment, potential residual confounding.. In incident hemodialysis patients, mortality and cardiovascular event rates did not differ between patients treated at facilities predominantly using DPO versus EPO.

Topics: Aged; Ambulatory Care Facilities; Anemia; Cardiovascular Diseases; Cause of Death; Comorbidity; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemodialysis Units, Hospital; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Recombinant Proteins; Registries; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Stroke; Treatment Outcome; United States

to investigate hemostatic parameter changes, such as platelet aggregation, blood and plasma viscosity, prothrombin time, APTT, CRP and fibrinogen, before and after administration of stem cell therapy.. a total of 24 patients were enrolled. Peripheral blood stem cells (PBSCs) were harvested and injected into the infarct-related artery after 5 consecutive days of G-CSF administration. Recombinant human erythropoietin was administered at the time of intracoronary PBSCs injection.. we were able to evaluate 11 from 24 of patients regarding hemostatic status pre-post stem cell injection. There were no significant difference between baseline vs 3 months in spontaneous aggregation (p=0.350), PT (p=0.793), aPTT (p=0.255) and TT (p=0.254). There were also no significant difference between baseline vs 3 months in plasma viscosity (p=0.442) and blood viscosity (p=0.843). Nevertheless the patient who had their blood and plasma viscosity above or below normal laboratory range return to normal level after the treatment. Both PT and APTT also show normalization value. Both Fibrinogen and CRP level show significant decrease between baseline and 3 months after treatment (p=0.009) and (p=0.04) respectively.. combined G-CSF and EPO based-intracoronary infusion of PBSCs may open new perspective in the treatment of hypercoagulable state post AMI.

Topics: Adult; Aged; Blood Viscosity; C-Reactive Protein; Drug-Eluting Stents; Erythropoietin; Female; Fibrinogen; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Myocardial Infarction; Partial Thromboplastin Time; Percutaneous Coronary Intervention; Peripheral Blood Stem Cell Transplantation; Platelet Aggregation; Prothrombin Time; Transplantation, Autologous

Erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF) are both potential novel therapeutics for use after myocardial infarction (MI). However, their underlying mechanisms remain unclear and the efficacy of monotherapy with EPO or G-CSF is also controversial. Therefore, we investigated the effects of combined treatment with EPO and G-CSF on neovascularization and cardiac function in post-infarction rats and explored the potential mechanisms.. Four groups of rats were used: control (saline injection after MI, i.h.), EPO (a single dose of 5 000 IU/kg after MI, i.h.), G-CSF (a dose of 50 µg× kg(-1)× d(-1) for 5 days after MI, i.h.), and both EPO and G-CSF (EPO+G-CSF, using the same regiment as above). Cardiac function was assessed by echocardiography before and 1 day, 7 days, 14 days and 21 days after MI. CD34(+)/Flk-1(+) cells in the peripheral blood were evaluated by flow cytometry before and 3 days, 5 days and 7 days after MI. The infarct area and angiogenesis in the peri-infarct area were analyzed. The mRNA and protein expression of vascular endothelial growth factor (VEGF) and stromal-derived factor-1a (SDF-1α) in the peri-infarct area were detected by real-time quantitative RT-PCR and Western blotting.. Compared with the control and monotherapy groups, the EPO+G-CSF group had significantly increased CD34(+)/Flk-1(+) endothelial progenitor cells (EPCs) in the peripheral blood (P < 0.05), up-regulated VEGF and SDF-1α levels in the peri-infarct region (P < 0.05), enhanced capillary density (P < 0.05), reduced infarct size (P < 0.05) and improved cardiac structure and function (P < 0.05). G-CSF alone did not dramatically increase EPCs in the peripheral blood, enhance capillary density in the peri-infarct area or reduce infarct size compared with the control group.. Combined treatment with EPO and G-CSF increased EPCs mobilization, up-regulated VEGF and SDF-1α levels in the post-infarction microenvironment, subsequently enhanced neovascularization in the peri-infarct region and reduced infarct size. All factors contributed to its beneficial effects on cardiac function in post-infarction rats.

Topics: Animals; Blotting, Western; Chemokine CXCL12; Echocardiography; Erythropoietin; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Male; Myocardial Infarction; Neovascularization, Physiologic; Rats; Rats, Sprague-Dawley

The role of erythropoietin (Epo) in myocardial repair after infarction remains inconclusive. We observed high Epo receptor (EPOR) expression in cardiac progenitor cells (CPCs). Therefore, we aimed to characterize these cells and elucidate their contribution to myocardial regeneration on Epo stimulation. High EPOR expression was detected during murine embryonic heart development followed by a marked decrease until adulthood. EPOR-positive cells in the adult heart were identified in a CPC-enriched cell population and showed coexpression of stem, mesenchymal, endothelial, and cardiomyogenic cell markers. We focused on the population coexpressing early (TBX5, NKX2.5) and definitive (myosin heavy chain [MHC], cardiac Troponin T [cTNT]) cardiomyocyte markers. Epo increased their proliferation and thus were designated as Epo-responsive MHC expressing cells (EMCs). In vitro, EMCs proliferated and partially differentiated toward cardiomyocyte-like cells. Repetitive Epo administration in mice with myocardial infarction (cumulative dose 4 IU/g) resulted in an increase in cardiac EMCs and cTNT-positive cells in the infarcted area. This was further accompanied by a significant preservation of cardiac function when compared with control mice. Our study characterized an EPO-responsive MHC-expressing cell population in the adult heart. Repetitive, moderate-dose Epo treatment enhanced the proliferation of EMCs resulting in preservation of post-ischemic cardiac function.

Topics: Animals; Cell Differentiation; Cell Proliferation; Erythropoietin; Female; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocytes, Cardiac; Rats; Receptors, Erythropoietin; Signal Transduction

From our previous clinical trials, intracoronary infusion of granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells ((mob)PBMCs) proved to be effective in improving myocardial contractility and reducing infarct volume in acute myocardial infarction. We tested the effect of priming (mob)PBMCs with erythropoietin (EPO) to augment its therapeutic efficacy.. (mob)PBMCs were obtained from healthy volunteers after a 3-day subcutaneous injection of G-CSF (10 μg/kg). About 40% of (mob)PBMCs were EPO receptor (EPOR) (+) and responded to 6 h EPO-priming (10 IU/mL) by increasing the expression of vasculogenic factors (i.e. IL8, IL10, bFGF, PDGF, MMP9) and adhesion molecules (i.e. integrin αV, β1, β2, β8) through the JAK2 and Akt pathway. These responses were also observed in PBMCs from elderly patients with coronary disease. The conditioned media from EPO-primed (mob)PBMCs contained various cytokines such as IL8, IL10, TNFα, and PDGF, which enhanced the migration and tube formation capability of endothelial cells. EPO-primed (mob)PBMCs also showed increased adhesion on endothelial cells or fibronectin. Augmented vasculogenic potential of EPO-primed (mob)PBMCs was confirmed in a Matrigel plug assay, ischaemic hindlimb, and myocardial infarction models of athymic nude mice. There were two action mechanisms: (i) cellular effects confirmed by direct incorporation of human (mob)PBSCs into mouse vasculature and (ii) indirect humoral effects confirmed by the therapeutic effect of the supernatant of EPO-primed (mob)PBMCs.. Brief ex vivo EPO-priming is a novel method to augment the vasculogenic potential of human (mob)PBMCs, which would help to achieve better results after intracoronary infusion in myocardial infarction patients.

Topics: Angiogenic Proteins; Animals; Bone Marrow Cells; Case-Control Studies; Cell Adhesion; Cell Adhesion Molecules; Cells, Cultured; Coronary Artery Disease; Culture Media, Conditioned; Cytokines; Disease Models, Animal; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hindlimb; Humans; Injections, Subcutaneous; Ischemia; Janus Kinase 2; Leukocytes, Mononuclear; Male; Mice, Nude; Muscle, Skeletal; Myocardial Infarction; Neovascularization, Physiologic; Peripheral Blood Stem Cell Transplantation; Proto-Oncogene Proteins c-akt; Recombinant Proteins; Regeneration; Signal Transduction; Time Factors

Several studies substantiate the cardioprotective effects of erythropoietin (EPO). Our goal was to quantify the effects of EPO treatment on the early expression of the apoptosis marker phosphatidylserine as well as on the left ventricular volumes and function by means of small animal PET.. Myocardial infarction (MI) was induced in C57BL/6 mice. Animals were assigned to saline or EPO groups and underwent Annexin PET (day 2) and gated FDG PET (days 6 and 30). Annexin uptake was significantly higher in the infarction than in remote myocardium, with no differences between treatment groups. Infarct size showed a slight decrease in the EPO group and a slight increase in the controls, which did not reach statistical significance. Follow-up analyses revealed a significant increase of end-diastolic and end-systolic volumes in the EPO group, in which a stable left ventricular ejection fraction (LVEF) was maintained.. We find that deleterious effects of EPO can outweigh cardioprotective effects. The present EPO treatment did not significantly reduce apoptosis after MI, but seemingly provoked significant myocardial dilation while maintaining a stable LVEF. Molecular mechanisms of EPO treatment may need further elucidation to optimize therapy regimens.

Topics: Animals; Annexin A5; Cardiotonic Agents; Drug Monitoring; Erythropoietin; Fluorodeoxyglucose F18; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Treatment Outcome

Conditioning refers to endogenous mechanisms rendering the myocardium more tolerant against reperfusion injury. Application of brief ischemia-reperfusion cycles prior to the index ischemia has a beneficial effect and limits the infarct size. This is called preconditioning and is mainly mediated by activation of adenosine, bradykinin, opioid and other receptors, with subsequent activation of intracellular mediators leading to mitochondrial protection. A clinical equivalent of preconditioning is preinfarction angina. Benefits for the ischemic and reperfused myocardium are also provided by repetitive short-lived cycles of ischemia-reperfusion applied after the index ischemia. This is termed postconditioning, shares a common pathway with preconditioning, and is more useful and relevant in clinical practice. Finally, benefits are also derived from remote conditioning, i.e. ischemia applied in a remote vascular territory parallel with or immediately after the index myocardial ischemia. Several pharmacological interventions may interfere with these mechanisms leading to enhanced protection of the myocardium and limitation of the infarct size. Despite the huge interest and the great body of evidence that verify the effectiveness of conditioning, clinical application has remained limited due to controversies over the appropriate intervention protocol, but also interference of medication, comorbidities and other factors that may enhance or blur the protective effect.

Topics: Adenosine; Cyclosporine; Enzyme Activators; Erythropoietin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Insulin; Ischemic Postconditioning; Ischemic Preconditioning, Myocardial; Myocardial Infarction; Myocardial Reperfusion; Myocardial Reperfusion Injury; Nicorandil; Vasodilator Agents

We investigated the effect of cardiac-targeting erythropoietin (EPO)-encapsulated liposomes with sialyl Lewis(X) (SLX) on myocardial infarct (MI) size, left ventricular (LV) remodeling and function, and its molecular mechanism for repairing infarcted myocardium. In rabbits, MI was induced by 30 min of coronary occlusion followed by reperfusion. EPO-encapsulated liposomes with SLX (L-EPO group), EPO-encapsulated liposomes without SLX (L-EPO without SLX group), liposomes with SLX without EPO (L group), or saline (saline group) were intravenously administered immediately after MI. MI sizes and numbers of microvessels were assessed 14 days after MI. Prosurvival proteins and signals were assessed by Western blot analysis 2 and 14 days after MI. Confocal microscopy and electron microscopy showed the specific accumulation of liposomes with SLX in the infarcted myocardium. MI and cardiac fibrosis areas were significantly smaller in the L-EPO group than in the other groups. LV function and remodeling were improved in the L-EPO group. The number of CD31-positive microvessels was significantly greater in the L-EPO group than in the other groups. Higher expressions of EPO receptors, phosphorylated (p)Akt, pERK, pStat3, VEGF, Bcl-2, and promatrix metalloproteinase-1 were observed in the infarct area in the L-EPO group than in the other groups. EPO-encapsulated liposomes with SLX selectively accumulated in the infarct area, reduced MI size, and improved LV remodeling and function through activation of prosurvival signals and by exerting antifibrotic and angiogenic effects. EPO-encapsulated liposomes with SLX may be a promising strategy for active targeting treatment of acute MI.

Topics: Animals; Drug Delivery Systems; eIF-2 Kinase; Erythropoietin; Hematinics; Liposomes; Male; Matrix Metalloproteinase 1; Myocardial Infarction; Neovascularization, Physiologic; Oligosaccharides; Phosphorylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Rabbits; Sialyl Lewis X Antigen; STAT3 Transcription Factor; Vascular Endothelial Growth Factor A; Ventricular Function, Left; Ventricular Remodeling

The cardioprotective effects of two different doses of erythropoietin administration were analyzed in rats with experimental myocardial infarction. None, saline, standard-dose (5000Ukg(-1)) and high-dose (10,000Ukg(-1)) of human recombinant erythropoietin alpha were administered intraperitoneally in Wistar rats with myocardial infarction induced by coronary artery ligation. Infarct sizes measured after triphenyltetrazolium chloride staining, levels of biochemical markers, histopathology examined by light and electron microscopy, and immunohistochemical expressions of erythropoietin, erythropoietin receptor, hypoxia inducible factor-1α and caspase-3, were analyzed. Lower scores of infarction and hemorrhage, lower number of macrophages and higher score of vascularization surrounding the infarct area were observed in the erythropoietin administered groups (p<0.05). Erythropoietin administration after myocardial infarction reduced the area of infarction and hemorrhage. There were hypoxia inducible factor-1α and caspase-3 expressions in the marginal area, and erythropoietin and erythropoietin receptor expression in both marginal and normal areas (p<0.001). Vascularization, erythropoietin expression in the normal area and vascular erythropoietin expression were positively correlated with human erythropoietin levels. The cardioprotective effects of erythropoietin treatment were independent of endogenous erythropoietin/erythropoietin receptor activity. Moreover exogenous erythropoietin treatment did not suppress endogenous erythropoietin. Erythropoietin administration after myocardial infarction reduced caspase 3 expression (apoptotic activity) and induced neovascularization around the infarct area. Higher erythropoietin administration did not provide an additional benefit over the standard-dose in myocardial protection.

Topics: Animals; Cardiotonic Agents; Caspase 3; Drug Administration Schedule; Erythropoietin; Gene Expression; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Rats; Rats, Wistar; Receptors, Erythropoietin; Recombinant Proteins

Extensive research during the last decade demonstrated that a single systemic administration of -erythropoietin (EPO) lead to significant attenuation of myocardial infarction (MI) induced in animals, mostly small rodents, either by a myocardial ischemia followed by reperfusion or by a permanent ligation of a coronary artery. Both methods are critically reviewed with the aim of helping the reader in appreciating key issues in the translation of experimental results to the clinic. Results of several clinical trials in patients with acute MI completed to date failed to demonstrate beneficial effects of EPO, and thus put into question the validity of results obtained in animal models. Comprehensive review of design and results of animal experiments and clinical trials presented here allowed authors to postulate that therapeutic window for EPO during developing MI is very narrow and was possibly missed in negative clinical trials. This point was illustrated by the negative outcome of experiment in the rat model of MI in which timing of EPO administration was similar to that in clinical trials. The design of future clinical trials should allow for a narrow therapeutic window of EPO. Given current standards for onset-to-door and door-to-balloon time the optimal time for EPO administration should be just prior to PCI.

Topics: Animals; Erythropoietin; Humans; Myocardial Infarction; Myocytes, Cardiac; Reperfusion Injury

The cardioprotective properties of erythropoietin (EPO) in preclinical studies are well documented, but erythropoietic and prothrombotic properties of EPO preclude its use in chronic heart failure (CHF). We tested the effect of long-term treatment with a small peptide sequence within the EPO molecule, helix B surface peptide (HBSP), that possesses tissue-protective, but not erythropoietic properties of EPO, on mortality and cardiac remodeling in postmyocardial infarction-dilated cardiomyopathy in rats. Starting 2 weeks after permanent left coronary artery ligation, rats received i.p. injections of HBSP (60 µg/kg) or saline two times per week for 10 months. Treatment did not elicit an immune response, and did not affect the hematocrit. Compared with untreated rats, HBSP treatment reduced mortality by 50% (P < 0.05). Repeated echocardiography demonstrated remarkable attenuation of left ventricular dilatation (end-diastolic volume: 41 versus 86%; end-systolic volume: 44 versus 135%; P < 0.05), left ventricle functional deterioration (ejection fraction: -4 versus -63%; P < 0.05), and myocardial infarction (MI) expansion (3 versus 38%; P < 0.05). A hemodynamic assessment at study termination demonstrated normal preload independent stroke work (63 ± 5 versus 40 ± 4; P < 0.05) and arterioventricular coupling (1.2 ± 0.2 versus 2.7 ± 0.7; P < 0.05). Histologic analysis revealed reduced apoptosis (P < 0.05) and fibrosis (P < 0.05), increased cardiomyocyte density (P < 0.05), and increased number of cardiomyocytes in myocardium among HBSP-treated rats. The results indicate that HBSP effectively reduces mortality, ameliorates the MI expansion and CHF progression, and preserves systolic reserve in the rat post-MI model. There is also a possibility that HBSP promoted the increase of the myocytes number in the myocardial wall remote from the infarct. Thus, HBSP peptide merits consideration for clinical testing.

Topics: Animals; Blood Pressure; Cardiomyopathy, Dilated; Cell Size; Coronary Circulation; Coronary Vessels; Echocardiography; Erythropoietin; Hematocrit; Hemodynamics; Kaplan-Meier Estimate; Male; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Peptides; Rats; Rats, Wistar; Survival Analysis; Ventricular Remodeling

AIM--to develop pathogenetic methods for the correction of dysregulated erythropoesis in coronary heart disease (CHD). 20 patients with myocardial Q-infarction and 52 ones with chronic CHD. 26 patients of the CHD group suffered anemia. Ten volunteers without signs of cardiovascular pathology served as controls. Characteristics of peripheral blood and iron metabolism, serum levels of inflammation markers and erythropoietin (EPO) were measured. In most CHD patients elevated levels of TNF-alpha inhibited hepatic synthesis of EPO. Low hepcidin production was associated with increased EPO levels and low iron content in blood. Anemia developing in CHD patients may cause not only inflammation but also depletion of iron reserves. Correction of dysregulated erythropoesis in coronary heart in CHD must be performed with due regard for the above mechanisms on an individual basis.

Topics: Aged; Coronary Disease; Drug Therapy, Combination; Erythropoiesis; Erythropoietin; Female; Humans; Iron; Iron Deficiencies; Male; Middle Aged; Myocardial Infarction; Severity of Illness Index; Treatment Outcome

Considerable efforts have been made to exploit cardioprotective drugs and gene delivery systems for myocardial infarction (MI). The promising cardioprotective effects of recombinant human erythropoietin (rHuEPO) protein in animal experiments have not been consistently reproduced in clinical human trials of acute MI; however, the mechanisms underlying the inconsistent discrepancies are not yet fully understood. We hypothesized that the plasmid human erythropoietin gene (phEPO) delivered by our bioreducible polymer might produce cardioprotective effects on post-infarct cardiac remodeling. We demonstrated that intramyocardial delivery of phEPO by an arginine-grafted poly(disulfide amine) (ABP) polymer in infarcted rats preserves cardiac geometry and systolic function. The reduced infarct size of phEPO/ABP delivery was followed by decrease in fibrosis, protection from cardiomyocyte loss, and down-regulation of apoptotic activity. In addition, the increased angiogenesis and decreased myofibroblast density in the border zone of the infarct support the beneficial effects of phEPO/ABP administration. Furthermore, phEPO/ABP delivery induced prominent suppression on Ang II and TGF-β activity in all subdivisions of cardiac tissues except for the central zone of infarct. These results of phEPO gene therapy delivered by a bioreducible ABP polymer provide insight into the lack of phEPO gene therapy translation in the treatment of acute MI to human trials.

Topics: Animals; Arginine; Cardiotonic Agents; Erythropoietin; Gene Transfer Techniques; Male; Myocardial Infarction; Myocardium; Polyamines; Rats; Rats, Sprague-Dawley; Ventricular Remodeling

In a setting with two concurrent treatments, inverse-probability-of-treatment weights can be used to estimate the joint treatment effects or the marginal effect of one treatment while taking the other to be a confounder. We explore these two approaches in a study of intravenous iron use in hemodialysis patients treated concurrently with epoetin alfa (EPO).. We linked US Renal Data System data with electronic health records (2004-2008) from a large dialysis provider. Using a retrospective cohort design with 776,203 records from 117,050 regular hemodialysis patients, we examined a composite outcome: mortality, myocardial infarction, or stroke.. With EPO as a joint treatment, inverse-probability-of-treatment weights were unstable, confidence intervals for treatment effects were wide, covariate balance was unsatisfactory, and the treatment and outcome models were sensitive to omission of the baseline EPO covariate. By handling EPO exposure as a confounder instead of a joint treatment, we derived stable weights and balanced treatment groups on measured covariates.. In settings with concurrent treatments, if only one treatment is of interest, then including the other in the treatment model as a confounder may result in more stable treatment effect estimates. Otherwise, extreme weights may necessitate additional analysis steps.

Topics: Anemia; Confounding Factors, Epidemiologic; Drug Therapy, Combination; Epidemiologic Methods; Epoetin Alfa; Erythropoietin; Ferric Compounds; Hematinics; Humans; Kidney Failure, Chronic; Medicare; Myocardial Infarction; Outcome Assessment, Health Care; Recombinant Proteins; Renal Dialysis; Stroke; Transferrin; United States

To improve cellular cardiomyoplasty efficacy after myocardial infarction (MI), we postulated that combining mesenchymal stem cells (MSCs) transplantation with anti-apoptotic and angiogenic effects of erythropoietin (EPO) and vascular endothelial growth factor (VEGF) may provide better prognosis in an infarcted heart 48 rats, underwent left anterior descending artery ligation, were divided into eight groups and treated as follows: Group 1: MSC+EPO+VEGF, Group 2: MSC+EPO, Group 3: MSC+VEGF, Group 4: MSC, Group 5: EPO+VEGF, Group 6: EPO, Group 7: VEGF and Group 8: Control. After MI induction, EPO and VEGF were injected subcutaneously at the dose of 3000 U/kg and 3 µg/kg respectively. MSCs were transplanted one week after MI. In the fourteenth and sixteenth days after infarction, EPO was injected again. Echocardiography demonstrated that all treatments improved left ventricular function significantly (before vs. after treatment) but in control group ejection fraction deteriorated over the 2-months period. Percent of ejection fraction recovery in all treatment groups were significantly greater than control (P<0.05). Compared with the control group, all treatments attenuated cell death in peri-infarct areas significantly, except groups 6 and 7. Vascular density of all treatment groups were more than control group but this superiority was statistically significant only in group 1 (P<0.01). All of our treatments had beneficial effects to some extent but MSC transplantation combined with EPO and VEGF administration resulted in superior therapeutic outcome in enhancing cell survival and neovascularization.

Topics: Animals; Apoptosis; Cardiomyoplasty; Cell Culture Techniques; Cell Separation; Combined Modality Therapy; Electrocardiography; Erythropoietin; Male; Mesenchymal Stem Cell Transplantation; Myocardial Infarction; Myocytes, Cardiac; Necrosis; Neovascularization, Physiologic; Phenotype; Prognosis; Rats; Rats, Wistar; Treatment Outcome; Vascular Endothelial Growth Factor A

In reperfused acute myocardial infarction (RAMI), cardioprotective treatments may enhance myocardial salvage and hence reduce the area of necrosis. Based on studies showing that plasmid-mediated vascular endothelial growth factor (pVEGF) gene transfer reduces infarct size by combining angio-arteriogenic and cardiomyogenic effects and that erythropoietin (EPO) exerts anti-apoptotic actions in animal models of AMI, we aimed to assess if their association would reduce infarct size to a larger extent than any of them individually in a large mammalian model of RAMI.. Adult sheep subjected to 90-minute coronary artery occlusion received upon reperfusion intramyocardial pVEGF 3.8 mg plus intravenous EPO 1000 IU/kg (n=8), pVEGF (n=8), EPO (n=8) or placebo (n=8).. Fifteen days after treatment, infarct size was smaller in the 3 treatment groups (pVEGF+EPO: 8 ± 1 %; pVEGF: 16 ± 5 %; EPO: 13 ± 4 %) compared to placebo (25 ± 7 %, p<0.001). However, in the EPO+VEGF group infarct size was significantly smaller than in the groups receiving EPO or VEGF individually (p<0.05). DNA fragmentation, a hallmark of late apoptosis, was significantly lower in sheep receiving EPO. The combined treatment, while not affecting global left ventricular performance, improved regional peri-infarct function and prevented over-time expansion of the post-infarct perfusion defect.. Combined pVEGF and EPO treatment might be clinically useful to enhance the benefits of early revascularization in patients with acute myocardial infarction.

Topics: Animals; Drug Therapy, Combination; Erythropoietin; Gene Transfer Techniques; Humans; Male; Myocardial Infarction; Myocardial Reperfusion; Sheep, Domestic; Vascular Endothelial Growth Factor A; Ventricular Function, Left

A high level of endogenous erythropoietin (EPO) may be associated with a smaller infarct size determined by the release of necrosis markers. Sleep-disordered breathing (SDB) is a well-known risk factor for cardiovascular diseases. In contrast, protective effects of SDB have also been described. The potential role of increased levels of EPO and vascular endothelial growth factor (VEGF) is suggested in this process. The study aimed to explore the EPO and VEGF serum levels in SDB and non-SDB patients during the acute phase of myocardial infarction.. Thirty-seven patients undergoing successful primary percutaneous coronary intervention in the acute myocardial infarction have been examined for the levels of EPO, VEGF, and troponin I (Tn). In the following, patients had an overnight polysomnography to determine breathing disturbances during sleep.. Both on admission day (day 1) and day 3 of hospitalization, EPO levels showed statistically significant differences in both SDB-positive and SDB-negative patient groups (p = 0.003 and p = 0.018, respectively). There was no statistically significant difference in VEGF levels. No correlation was found between the EPO and Tn levels.. SDB patients tend to have higher levels of EPO during acute myocardial infarction. No statistically significant differences in VEGF levels were observed.

Topics: Erythropoietin; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Polysomnography; Sleep Apnea, Obstructive; Statistics as Topic; Troponin I; Vascular Endothelial Growth Factor A

Erythropoietin (EPO) was shown to have protective effects after myocardial infarction (MI) by neovascularization and antiapoptotic mechanisms. Beside direct receptor-dependent mechanisms, mobilization and homing of bone marrow-derived cells (BMCs) may play a pivotal role in this regard. In this study, we intended to track different subpopulations of BMCs and to assess serially myocardial perfusion changes in EPO-treated mice after MI. To allow tracking of BMCs, we used a chimeric mouse model. Therefore, mice (C57BL/6J) were sublethally irradiated, and bone marrow (BM) from green fluorescent protein transgenic mice was transplanted. Ten weeks later coronary artery ligation was performed to induce MI. EPO was injected for 3 days with a total dose of 5000 IU/kg. Subpopulations (CD31, c-kit, CXCR-4 and Sca-1) of EGFP(+) cells were studied in peripheral blood, bone marrow and hearts by flow cytometry. Myocardial perfusion was serially investigated in vivo by pinhole single-photon emission computed tomography (SPECT) at days 6 and 30 after MI. EPO-treated animals revealed an enhanced mobilization of BMCs into peripheral blood. The numbers of these cells in BM remained unchanged. Homing of all BMCs subpopulations to the ischaemic myocardium was significantly increased in EPO-treated mice. Among the investigated subpopulations, EPO predominantly affected migration of CXCR-4(+) (4.3-fold increase). Repetitively SPECT analyses revealed a reduction of perfusion defects after EPO treatment over time. Our study shows that EPO treatment after MI enhances the migration capacity of BMCs into ischaemic tissue, which may attribute to an improved perfusion and reduced size of infarction, respectively.

Topics: Animals; Bone Marrow Cells; Cell Movement; Cell Separation; Erythropoietin; Green Fluorescent Proteins; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction; Vascular Endothelial Growth Factor A

Several polymorphisms of vasoactive hormones have been implicated in hypertension. Erythropoietin (EPO) interacts with vasoactive substances, such as angiotensin II. Previously detected single nucleotide polymorphisms in the hypoxia-responsive element of EPO might be associated with hypertension and hypertensive end organ damages.. 400 hypertensive patients and 200 age- and gender-matched normotensive controls were genotyped for an EPO polymorphism [cytosine (C)/thymine (T) single nucleotide polymorphism] at position 3434. Patients were grouped according to their genotype into the CC group (CC genotype) and the CT/TT group (CT and TT genotype). BP was measured by ambulatory BP monitoring.. The CC genotype was present in 87% of hypertensive patients and in 78.5% of controls (p = 0.007). In addition, patients with the CC genotype had higher BP levels compared with CT/TT genotypes (BPsys 143.7 ± 20.4 vs. 136.1 ± 13.5 mm Hg, p = 0.01, and BPdias 85.8 ± 11.6 vs. 82.4 ± 8.9, p = 0.043) despite a nearly identical number of antihypertensive drugs (2.3 ± 1.5 vs. 2.3 ± 1.6; p = 0.257). 100% of the small number of patients with end-stage renal disease (n = 15) had the CC genotype.. The CC genotype of the EPO gene at position 3434 is more frequently found in patients with hypertension and is associated with higher BP levels.

Topics: Adult; Aged; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Erythropoietin; Female; Genotype; Homozygote; Humans; Hypertension, Renal; Hypoxia; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Stroke; Vascular Diseases

Erythropoietin (EPO) has recently been shown to confer cardioprotective effects via angiogenesis and antiapoptosis. The administration of EPO after myocardial infarction (MI) reduces infarct size and improves cardiac function in small animals. The purpose of this study is to investigate the protective effects of EPO in porcine MI. Each animal in the EPO group received four injections of recombinant human EPO (rhEPO; 6000 U per injection) at 2-day intervals, starting after coronary occlusion. Animals in the control group received saline. Left ventriculography was performed just after coronary occlusion and at 28 days. Time-course changes in serum levels of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and fibroblast growth factor (FGF) were measured. The number of vessels was calculated, and the mRNA expressions of VEGF and insulin-like growth factor (IGF) were examined. Left ventricular function was similar between the groups. The numbers of cells positive for anti-α-smooth muscle actin, von Willebrand factor, and c-kit were significantly higher in the EPO group than in the controls (P < 0.05). The EPO group exhibited significantly higher HGF and FGF concentrations (P < 0.05) and higher expression of VEGF and IGF mRNA (P < 0.05) compared with the controls. In conclusion, EPO accelerates angiogenesis via the upregulation of systemic levels such as HGF and FGF, and the local expression of VEGF and IGF, in porcine MI.

Topics: Angiogenesis Inducing Agents; Animals; Disease Models, Animal; Erythropoietin; Female; Fibroblast Growth Factors; Hepatocyte Growth Factor; Humans; Immunohistochemistry; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Recombinant Proteins; Recovery of Function; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Somatomedins; Stroke Volume; Sus scrofa; Time Factors; Vascular Endothelial Growth Factor A; Ventricular Function, Left

Nitrosative stress caused by ischemia contributes to poor functional recovery in hearts. A previous study showed that recombinant human erythropoietin (EPO) activates the Janus-tyrosine kinase 2/extracellular signal-regulated kinase (Jak2/ERK) pathway to protect myocardium against ischemia/reperfusion (IR) injury. However, it is not clear how pro-survival signals triggered by EPO affect the nitric oxide (NO) system in post-ischemic myocardial tissue.. Isolated rat hearts were subjected to IR injury and changes in protein expression in the myocardium were evaluated by immunostaining.. Compared with untreated hearts, EPO-treated IR hearts showed significant improvements in contractility and reduced myocardial injury and infarction; this was associated with attenuated caspase-3 activation. Excess formation of NO metabolites and nitrotyrosine, which cause nitrosative stress, was markedly suppressed by EPO. The mechanism underlying EPO-mediated alleviation of nitrosative stress was related to an increase in arginase II expression and to the suppression of heat shock protein 90 (HSP90)-dependent upregulation of endothelial and inducible NO synthase (NOS). Myocardial EPO content was restored after EPO treatment, which in turn recruited signal transducer and activator of transcription (STAT) 3 protein and induced ERK signaling downstream of Jak2, which increased arginase II levels and suppressed HSP90 expression, respectively. Inhibition of STAT3 and ERK specifically reversed the effects of EPO on arginase II and HSP90 expression.. These results indicate that EPO triggers the Jak2-STAT3/ERK pathway to restore the balance between arginase and NOS and, thus, reduces nitrosative stress. This may form the basis of myocardial protection following IR.

Topics: Animals; Arginase; Blotting, Western; Epoetin Alfa; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; Female; HSP90 Heat-Shock Proteins; Immunohistochemistry; In Vitro Techniques; Janus Kinase 2; Myocardial Infarction; Myocardial Ischemia; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Reactive Nitrogen Species; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction; STAT3 Transcription Factor

To test a hypothesis that in negative clinical trials of erythropoietin in patients with acute myocardial infarction (MI) the erythropoietin (rhEPO) could be administered outside narrow therapeutic window. Despite overwhelming evidence of cardioprotective properties of rhEPO in animal studies, the outcomes of recently concluded phase II clinical trials have failed to demonstrate the efficacy of rhEPO in patients with acute MI. However, the time between symptoms onset and rhEPO administration in negative clinical trials was much longer that in successful animal experiments.. MI was induced in rats either by a permanent ligation of a descending coronary artery or by a 2-hr occlusion followed by a reperfusion. rhEPO, 3000 IU/kg, was administered intraperitoneally at the time of reperfusion, 4 hrs after beginning of reperfusion, or 6 hrs after permanent occlusion. MI size was measured histologically 24 hrs after coronary occlusion. The area of myocardium at risk was similar among groups. The MI size in untreated rats averaged ~42% of area at risk, or ~24% of left ventricle, and was reduced by more than 50% (p<0.001) in rats treated with rhEPO at the time of reperfusion. The MI size was not affected by treatment administered 4 hrs after reperfusion or 6 hrs after permanent coronary occlusion. Therefore, our study in a rat experimental model of MI demonstrates that rhEPO administered within 2 hrs of a coronary occlusion effectively reduces MI size, but when rhEPO was administered following a delay similar to that encountered in clinical trials, it had no effect on MI size.. The clinical trials that failed to demonstrate rhEPO efficacy in patients with MI may have missed a narrow therapeutic window defined in animal experiments.

Topics: Animals; Clinical Trials, Phase II as Topic; Erythropoietin; Humans; Male; Myocardial Infarction; Rats; Rats, Wistar; Time Factors; Treatment Failure

Topics: Erythropoietin; Humans; Interleukins; Myocardial Infarction; Stem Cells

Endothelial progenitor cells (EPCs) participate in vascular repair and angiogenesis. Thus, EPC transplantation into ischemic myocardium might improve cardiac function; however, the vast majority of cells die within a short period. The present study was designed to investigate whether exogenous erythropoietin (EPO) delivery could improve the survival of transplanted EPCs and enhance the efficiency of EPC-based cell therapy.. Myocardial infarction was induced in wild-type mice by ligating the left anterior descending coronary artery. Enhanced green fluorescent protein-EPCs with or without EPO were transplanted into peri-infarct myocardium. Enhanced green fluorescent protein-EPCs were detected 7 and 28 d after surgery. The amount of circulating EPCs was analyzed 3 and 28 d after surgery. The stromal cell-derived factor-1α and vascular endothelial growth factor concentrations, microvessel density, apoptosis, fibrosis in the peri-infarct myocardium, and cardiac function were compared among the groups.. More enhanced green fluorescent protein-EPCs were found in the hearts treated with EPC + EPO than in those treated with EPC alone. The circulating EPC level was markedly elevated after EPC + EPO treatment compared with EPC application alone. Stromal cell-derived factor-1α and vascular endothelial growth factor were increased accordingly, along with increased microvessel density, decreased apoptosis, and reduced fibrosis in the peri-infarct myocardium. Left ventricular fractional shortening was greater and the interventricular septum was thicker after EPC + EPO treatment compared with EPC treatment alone.. EPO improved the efficiency of EPC therapy in mice with myocardial infarction. This effect was associated with enhanced transplanted EPC survival and autologous EPC mobilization.

Topics: Animals; Cell Movement; Cell Survival; Cell- and Tissue-Based Therapy; Chemokine CXCL12; Electrocardiography; Endothelium, Vascular; Erythropoietin; Green Fluorescent Proteins; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Mice, Transgenic; Models, Animal; Myocardial Infarction; Neovascularization, Physiologic; Treatment Outcome; Vascular Endothelial Growth Factor A

Revascularization of infarcted myocardium results in release of inflammatory cytokines mediating myocardial reperfusion injury and heart failure. Blockage of inflammatory pathways dampens myocardial injury and reduces infarct size. We compared the impact of the interleukin-1 receptor antagonist Anakinra and erythropoietin on myocardial ischemia/reperfusion injury. In contrast to others, we hypothesized that drug administration prior to reperfusion reduces myocardial damage.. 12-15 week-old Lewis rats were subjected to myocardial ischemia by a 1 hr occlusion of the left anterior descending coronary artery. After 15 min of ischemia, a single shot of Anakinra (2 mg/kg body weight (bw)) or erythropoietin (5000 IE/kg bw) was administered intravenously. In contrast to erythropoietin, Anakinra decreased infarct size (P < 0.05, N = 4/group) and troponin T levels (P < 0.05, N = 4/group).. One-time intravenous administration of Anakinra prior to myocardial reperfusion reduces infarct size in experimental ischemia/reperfusion injury. Thus, Anakinra may represent a treatment option in myocardial infarction prior to revascularization.

Topics: Animals; Cytokines; Erythropoietin; Interleukin 1 Receptor Antagonist Protein; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Rats; Rats, Inbred Lew; Receptors, Interleukin-1; Troponin T

Topics: Electrocardiography; Erythropoietin; Female; Humans; Male; Myocardial Infarction; Myocardial Reperfusion; Postoperative Care

Recent studies reported cardioprotective effects of erythropoietin (EPO) against ischemia-reperfusion (I/R) injury through activation of the reperfusion injury salvage kinase (RISK) pathway. As RISK has been reported to be impaired in diabetes and insulin resistance syndrome, we examined whether EPO-induced cardioprotection was maintained in rat models of type 1 diabetes and insulin resistance syndrome. Isolated hearts were obtained from three rat cohorts: healthy controls, streptozotocin (STZ)-induced diabetes, and high-fat diet (HFD)-induced insulin resistance syndrome. All hearts underwent 25 min ischemia and 30 min or 120 min reperfusion. They were assigned to receive either no intervention or a single dose of EPO at the onset of reperfusion. In hearts from healthy controls, EPO decreased infarct size (14.36 ± 0.60 and 36.22 ± 4.20% of left ventricle in EPO-treated and untreated hearts, respectively, p < 0.05) and increased phosphorylated forms of Akt, ERK1/2, and their downstream target GSK-3β. In hearts from STZ-induced diabetic rats, EPO did not decrease infarct size (32.05 ± 2.38 and 31.88 ± 1.87% in EPO-treated and untreated diabetic rat hearts, respectively, NS) nor did it increase phosphorylation of Akt, ERK1/2, and GSK-3β. In contrast, in hearts from HFD-induced insulin resistance rats, EPO decreased infarct size (18.66 ± 1.99 and 34.62 ± 3.41% in EPO-treated and untreated HFD rat hearts, respectively, p < 0.05) and increased phosphorylation of Akt, ERK1/2, and GSK-3β. Administration of GSK-3β inhibitor SB216763 was cardioprotective in healthy and diabetic hearts. STZ-induced diabetes abolished EPO-induced cardioprotection against I/R injury through a disruption of upstream signaling of GSK-3β. In conclusion, direct inhibition of GSK-3β may provide an alternative strategy to protect diabetic hearts against I/R injury.

Topics: Animals; Apoptosis; Cardiotonic Agents; Diabetes Mellitus, Experimental; Dietary Fats; Erythropoietin; Glucose; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hemodynamics; In Vitro Techniques; Insulin Resistance; MAP Kinase Signaling System; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Receptors, Erythropoietin

The objective of this study was to examine the hypothesis that hypertensive hypertrophy is vulnerable to infarction and defective in cytoprotective mechanisms by modification of intracellular signaling and mitochondrial proteins. Myocardial infarction was induced by 20-minute coronary occlusion/reperfusion in spontaneously hypertensive stroke-prone rats (SHR-SPs) and their controls (Wistar-Kyoto rats [WKYs]). Infarct size expressed as a percentage of area-at-risk was larger by 29% in SHR-SPs than in WKYs. Pretreatment with erythropoietin (EPO) significantly limited infarct size in WKYs but not in SHR-SPs. Ca(2+) retention capacity of mitochondria, an index of the threshold for opening of the mitochondrial permeability transition pore, on reperfusion was reduced in SHR-SPs compared with that in WKYs. Suppression of reactive oxygen species by N-(2-mercaptopropionyl)-glycine increased Ca(2+) retention capacity after reperfusion and limited infarct size in SHR-SPs to levels in WKYs. EPO induced phosphorylation of Akt, extracellular signal-related kinase, and glycogen synthase kinase-3β in the myocardium in both WKYs and SHR-SPs. EPO enhanced interaction of phospho-glycogen synthase kinase-3β and adenine nucleotide translocase on reperfusion in WKYs, although such an effect of EPO was not detected in SHR-SPs. The results suggest that enhanced opening of mitochondrial permeability transition pores by reactive oxygen species and modification of the signal downstream of phospho-glycogen synthase kinase-3β in the mitochondria underlie the increased vulnerability to infarction and the lack of anti-infarct tolerance by EPO, respectively, in hypertensive hypertrophied hearts.

Topics: Animals; Calcium; Cardiomegaly; Erythropoietin; Hypertension; Male; Mitochondria, Heart; Mitochondrial ADP, ATP Translocases; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocardial Infarction; Myocardium; Protein Serine-Threonine Kinases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reactive Oxygen Species; Risk Factors; Tiopronin

Erythropoietin (EPO) has been shown to have anti-inflammatory, antiapoptotic, and proangiogenic effects. This study investigated whether early EPO treatment effectively preserves left ventricular (LV) function in porcine acute myocardial infarction (AMI). Eighteen male mini-pigs divided into groups 1 (sham), 2 (AMI), and 3 (AMI with 2 consecutive EPO doses [7500 IU per animal each time] at 30 minutes and 24 hours after AMI induction) underwent echocardiography before and 14 days after AMI induction through left anterior descending artery (LAD) ligation with myocardium harvested for analysis. Larger infarcted areas (IA) were noted in group 2 than in group 3. In both IA and peri-IA, percentage of apoptotic nuclei and CD40-positive cells, messenger RNA expressions of IL-8, matrix metalloproteinase-9, caspase-3, and Bcl-2 associated x protein were highest, whereas proliferator-activated receptor-γ coactivator-1α, endothelial nitric oxide synthase and Bcl-2 were lowest in group 2. Oxidative stress and cytosolic cytochrome c in IA were increased (P < 0.001), whereas protein expression of connexin43, cytochrome c, and protein kinase C-ε; in mitochondria were reduced in group 2 than in other groups (P < 0.045). The fibrosis in IA was notably decreased in group 3 compared with that in group 2. The number of small arterioles and capillary density in IA was highest in group 3, whereas LV performance was lowest in group 2 (P < 0.045). In conclusion, the results demonstrated that early EPO administration in a porcine AMI model effectively limits infarct size, attenuates LV remodeling, and preserves LV function.

Topics: Animals; Disease Models, Animal; Erythropoietin; Humans; Male; Myocardial Infarction; Recombinant Proteins; Swine; Swine, Miniature; Time Factors; Ventricular Function, Left; Ventricular Remodeling

To evaluate the effects of erythropoietin (EPO) combined with granulocyte-colony stimulating factor (G-CSF) on left ventricular function and ventricular remodeling after acute myocardial infarction (AMI) and investigate the possible mechanism.. The experimental design consisted of 5 groups of rats, namely the sham, myocardial infarction (MI) model, MI with EPO treatment, MI with G-CSF treatment, and MI with EPO plus G-CSF treatment groups. Apoptosis of the cardiomyocytes was detected by TUNEL staining, and HE staining, Masson trichrome staining, scarlatinum staining, and VIII agent staining were used to evaluate the survival, scar collagen deposition, and angiogenic effects. The cardiac structure and function of the rats after the treatments were assessed by echocardiography and hemodynamic examination.. Echocardiography indicated that LVEF and FS were improved in all the intervention groups 7 days after MI, and the rats in EPO plus G-CSF treatment group showed the most obvious reduction of LVESD and LVESV (P<0.01). On day 28 after MI, all the intervention groups showed improvements in LVEF, FS, LVESD, LVEDD, LVESV and LVEDV, which were especially obvious in the combined treatment group; the interventions, especially the combined treatment, also resulted in decreased LVEDP and increased LVSP and +dP/dtmax. On day 1 after MI, the number of apoptotic cells was significantly greater in the MI model group than in EPO and G-CSF groups, and was the fewest in the combined treatment group (P<0.01). On day 28, the number of new vessels increased and the scar and collagen deposition reduced in the EPO and G-CSF groups, and these changes were more obvious in the combined treatment group.. EPO combined with G-CSF can prevent left ventricular remodeling and improve cardiac systolic and diastolic functions by inhibiting cardiomyocyte apoptosis, reducing tissue collagen deposition and inducing neovascularisation.

Topics: Animals; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Myocardial Infarction; Rats; Rats, Wistar; Ventricular Function, Left; Ventricular Remodeling

Erythropoietin (EPO) has protective effects on myocardial infarction (MI). This study was to test whether EPO administrated after MI is as effective as EPO administrated before MI and to determine the role of AMP-activated protein kinase (AMPK) in the cardioprotective effects of EPO. Recombinant human EPO (5000 IU/kg) was intraperitoneally injected 12 hours before MI (pretreatment) or 30 minutes after MI (posttreatment). The levels of serum enzymes were assayed at 24 and 72 hours after MI. The infarct size was determined by nitro blue tetrazolium staining. The microarchitecture damages were evaluated by electron microscopy. EPO receptor messenger RNA and protein levels were determined by RT-PCR and immunohistochemistry, respectively. Activation of AMPK and nuclear factor kappa B was determined by immunoblotting. An AMPK-specific inhibitor, compound C, was used to inhibit AMPK activation in vivo. The authors found that both pretreatment and posttreatment of EPO successfully attenuated the serum enzyme levels, reduced the infarct size and ameliorated the microarchitecture damage. Moreover, both pretreatment and posttreatment of EPO decreased the EPO receptor messenger RNA and protein expressions, which were up-regulated in MI. More importantly, under MI conditions, EPO further increased the phosphorylation of AMPK and suppressed the activation of nuclear factor kappa B. Moreover, when AMPK was blocked by compound C, the cardioprotective effect of EPO was significantly attenuated (P < 0.01). Thus, this study demonstrates that both pretreatment and posttreatment of EPO are cardioprotective in an AMPK-dependent manners, providing the first evidence that the AMPK signaling pathway is involved in the cardioprotective effects of EPO.

Topics: AMP-Activated Protein Kinases; Animals; Cardiotonic Agents; Erythropoietin; Immunoblotting; Male; Microscopy, Electron; Mitochondria, Heart; Myocardial Infarction; Myocardium; NF-kappa B; Rats; Rats, Wistar; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

In models of acute ischaemia, erythropoietin (EPO) administration has been found to attenuate vascular injury largely through reduced apoptosis, suppressed inflammation and increased nitric oxide availability. We studied the association between circulating endogenous EPO and no-reflow in patients with first ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI).. Blood sampling was performed before PPCI. Consecutive patients with (n = 24) or without (n = 24) evidence of angiographic no-reflow after PPCI were enrolled. Angiographic no-reflow was defined as Thrombolysis in Myocardial Infarction (TIMI) flow ≤ 2 or as TIMI flow = 3 but with myocardial blush grade < 2. We also assessed electrocardiographic (ECG) no-reflow as ≤ 50% resolution of maximal ST elevation 60 min after PPCI.. Baseline characteristics did not correlate significantly with EPO concentrations. In contrast, both angiographic and ECG no-reflow correlated with lower EPO levels at univariate analysis [median (interquartile): 4·2 (0·6-9·5) vs. 12·2 (5·2-20·3) mIU mL(-1), P = 0·001, and 4·0 (0·6-7·1) vs. 9·3 (1·0-12·6) mIU mL(-1), P = 0·01, respectively]. At multivariable analysis, decreasing EPO tertiles and left anterior descending as the infarct-related artery were the only factors that predicted both angiographic and ECG no-reflow (P = 0·017 and P = 0·02 for EPO; P < 0·005 and P > 0·05 for left anterior descending artery, respectively).. We found an independent, graded, inverse relation between endogenous EPO levels and angiographic and ECG no-reflow following PPCI. In animal models of ischaemia, EPO has been found to be protective. In humans, endogenous EPO may contribute to offset the mechanisms responsible for no-reflow.

Topics: Aged; Biomarkers; Coronary Angiography; Electrocardiography; Erythropoietin; Female; Humans; Male; Middle Aged; Myocardial Infarction; No-Reflow Phenomenon; Regression Analysis

Topics: Anemia; Angioplasty, Balloon, Coronary; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Magnetic Resonance Imaging; Myocardial Infarction; Myocardial Reperfusion; Randomized Controlled Trials as Topic; Recombinant Proteins; Ventricular Remodeling

Erythropoietin (EPO) has the potential to improve ischemic tissue by mobilizing endothelial progenitor cells and enhancing neovascularization. We hypothesized that combining EPO with human chorionic gonadotrophin (hCG) would improve post-myocardial infarction (MI) effects synergistically.. After MI, five to seven animals were randomly assigned to each of the following treatments: control; hCG; EPO; hCG + EPO, and prolactin (PRL) + EPO. Follow-up echocardiograms were performed to assess cardiac structure and function. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and western blot analysis for apoptosis-related proteins, and cell proliferation by immunostaining for Ki67 and c-kit cells.. The MI-mediated increased chamber systolic dimension (p < 0.05 in controls) was attenuated by hCG, EPO, and hCG + EPO (p < 0.05 vs. control) but not PRL + EPO. Similarly all treatment groups, except PRL + EPO, reduced MI-induced increases (p < 0.05 vs. control) in ejection fraction (EF). The functional improvement in the EPO-treated groups was accompanied by increased capillary density. Apoptosis was markedly reduced in all treated groups. Significantly more cardiac c-kit(+) cells were found in the hCG + EPO group.. Our findings revealed that EPO, hCG, or their combination ameliorate cardiac remodeling post-MI. Whereas EPO stimulates neovascularization only and hCG + EPO stimulates c-kit+ cell proliferation. These data suggest that combining mobilizing and proliferative agents adds to the durability and sustainability of cytokine-based therapies for remodeling post-MI.

Topics: Animals; Apoptosis; Cell Proliferation; Chorionic Gonadotropin; Echocardiography; Erythropoietin; Humans; In Situ Nick-End Labeling; Ki-67 Antigen; Male; Myocardial Infarction; Proto-Oncogene Proteins c-kit; Random Allocation; Rats; Rats, Wistar; Ventricular Remodeling

Over the past 5–10 years, the positive effects of erythropoietin on myocardial infarction have been reported in several experimental, animal models. However, the results of the REVEAL study call into question the beneficial effects of erythropoietin in humans presenting with myocardial infarction.

Topics: Animals; Cardiovascular Agents; Erythropoietin; Evidence-Based Medicine; Humans; Myocardial Infarction; Myocardium; Randomized Controlled Trials as Topic; Treatment Outcome; Ventricular Function, Left

Topics: Biomarkers; Endpoint Determination; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Magnetic Resonance Imaging; Myocardial Infarction; Recombinant Proteins; Treatment Outcome

Topics: Blood Pressure; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Hypertension; Myocardial Infarction; Myocardial Reperfusion; Recombinant Proteins; Stents; Thrombosis

Topics: Clinical Trials as Topic; Erythropoietin; Humans; Myocardial Infarction

Topics: Angioplasty, Balloon, Coronary; Erythropoietin; Female; Hematinics; Humans; Male; Myocardial Infarction; Recombinant Proteins

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; Erythropoietin; Humans; Male; Myocardial Infarction; Ventricular Remodeling

Topics: Animals; Erythropoietin; Heart; Humans; Myocardial Infarction

Erythropoietin has been related to adverse prognosis in patients with heart failure, but it is unknown whether it adds prognostic information in acute coronary syndrome.. Plasma erythropoietin was measured on admission with enzyme-linked immunosorbent assay in 627 patients. Patients were divided into three groups depending on their erythropoietin level and followed for myocardial infarction (MI) (median 6 months) and mortality (median 39 months). Cox regression models were used to evaluate erythropoietin compared to clinical variables; age, gender, diabetes, smoking, prior MI, heart failure, hypertension and revascularization. In a second Cox regression model, laboratory markers were assessed; hemoglobin, estimated glomerular filtration rate (eGFR), C-reactive protein (CRP), cardiac troponin T (cTnT) and N-terminal pro-brain-natriuretic peptide (NT-proBNP).. Patients with the highest erythropoietin level (>8.8 mU/mL, n=205) had a 47% increased mortality (HR 1.47, 95% CI 1.04-2.06, p=0.028) when adjusted for clinical variables. Compared to laboratory risk markers, erythropoietin added prognostic information (HR 1.59, 95% CI 1.05-2.38, p=0.027) when adjusted for hemoglobin, eGFR and CRP. Erythropoietin (HR 1.21, 95% CI 0.79-1.86, p=0.387) was no longer significantly associated with mortality when cTnT and NT-proBNP were added. Erythropoietin was not related to the risk of future MI (HR 1.24, 95% CI 0.65-2.33, p=0.513).. Elevated erythropoietin level was associated with increased mortality in patients admitted with possible ACS when adjusted for clinical variables, or for kidney function and hemoglobin. However, erythropoietin does not add prognostic information when markers of myocardial necrosis and dysfunction are available in ACS.

Topics: Acute Coronary Syndrome; Aged; C-Reactive Protein; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Risk Factors; Troponin T

A noninvasive assessment of infarct size and transmural extension of myocardial infarction (TEMI) is fundamental in experimental models of ischemia-reperfusion. Conventional echocardiography parameters are limited in this purpose. This study was designed to examine whether speckle tracking imaging can be used in a rat model of ischemia-reperfusion to accurately detect the reduction of infarct size and TEMI induced by erythropoietin (EPO) as early as 24 h after reperfusion. Rats were randomly assigned to one of three groups: myocardial infarction (MI)-control group, 45 min ischemia followed by 24 h of reperfusion; MI-EPO group, similar surgery with a single bolus of EPO administered at the onset of reperfusion; and sham-operated group. Short-axis two-dimensional echocardiography was performed after reperfusion. Global radial (GS(r)) and circumferential (GS(cir)) strains were compared with infarct size and TEMI assessed after triphenyltetrazolium chloride staining. As a result, ejection fraction, shortening fraction, GS(r), and GS(cir) significantly correlated to infarct size, whereas only GS(r) and GS(cir) significantly correlated to TEMI. EPO significantly decreased infarct size (30.8 + or - 3.5 vs. 56.2 + or - 5.7% in MI-control, P < 0.001) and TEMI (0.37 + or - 0.05 vs. 0.77 + or - 0.05 in MI-control, P < 0.001). None of the conventional echocardiography parameters was significantly different between the MI-EPO and MI-control groups, whereas GS(r) was significantly higher in the MI-EPO group (29.1 + or - 4.7 vs. 16.4 + or - 3.3% in MI-control; P < 0.05). Furthermore, GS(cir) and GS(r) appeared to be the best parameters to identify a TEMI >0.75 24 h after reperfusion. In conclusion, these findings demonstrate the usefulness of speckle tracking imaging in the early evaluation of a cardioprotective strategy in a rat model of ischemia-reperfusion.

Topics: Animals; Echocardiography, Doppler; Erythropoietin; Models, Animal; Myocardial Infarction; Myocardium; Necrosis; Rats; Rats, Wistar; Reperfusion Injury; Salvage Therapy; Time Factors

Erythropoietin reportedly has beneficial effects on the heart after myocardial infarction, but the underlying mechanisms of these effects are unknown. We here demonstrate that sonic hedgehog is a critical mediator of erythropoietin-induced cardioprotection in mice. Treatment of mice with erythropoietin inhibited left ventricular remodeling and improved cardiac function after myocardial infarction, independent of erythropoiesis and the mobilization of bone marrow-derived cells. Erythropoietin prevented cardiomyocyte apoptosis and increased the number of capillaries and mature vessels in infarcted hearts by upregulating the expression of angiogenic cytokines such as VEGF and angiopoietin-1 in cardiomyocytes. Erythropoietin also increased the expression of sonic hedgehog in cardiomyocytes, and inhibition of sonic hedgehog signaling suppressed the erythropoietin-induced increase in angiogenic cytokine expression. Furthermore, the beneficial effects of erythropoietin on infarcted hearts were abolished by cardiomyocyte-specific deletion of sonic hedgehog. These results suggest that erythropoietin protects the heart after myocardial infarction by inducing angiogenesis through sonic hedgehog signaling.

Topics: Angiogenesis Inducing Agents; Angiopoietin-1; Animals; Apoptosis; Bone Marrow Cells; Capillaries; Cytokines; Erythropoietin; Hedgehog Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction; Myocytes, Cardiac; Recombinant Proteins; Signal Transduction; Up-Regulation; Ventricular Remodeling

Erythropoietin (EPO) has generated interest as a novel therapy after myocardial infarction (MI), but the safety and efficacy of prolonged therapy have not been studied in a large animal model of reperfused MI.. MI was induced in pigs by a 90-minute balloon occlusion of the left anterior descending coronary artery. Sixteen animals were randomized to either EPO or saline (control group). Inflammatory markers, bone marrow cell mobilization, and left ventricular function (by both echocardiography and pressure-volume measurements) were assessed at baseline, 1 and 6 weeks post-MI. EPO therapy was associated with a significant increase in hemoglobin and mononuclear counts. D-dimer and C-reactive protein levels did not differ between groups. At week 6, EPO therapy prevented further deterioration of left ventricular ejection fraction (39 +/- 2% vs. 33 +/- 1%, P < .01) and improved wall motion score index (P < .02). Histopathology revealed increased areas of viable myocardium, vascular density, and capillary-to-myocyte ratio in the EPO therapy compared with the control (all P < .05).. Prolonged EPO therapy after MI in a large animal model is safe and leads to an increase in viable myocardium, increased vascular density, and prevents further deterioration of left ventricular function. These results support future clinical studies in post-MI patients.

Topics: Animals; Disease Models, Animal; Erythropoietin; Myocardial Infarction; Random Allocation; Swine; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left

Darbepoetin, a long-acting erythropoietin derivative, attenuates cardiomyocyte apoptosis and improves short-term (3 days) cardiac function, but the mechanisms responsible are unknown. We investigated potential mechanisms by which darbepoetin exerts cardioprotection following myocardial infarction in mice and the significance of the erythropoietin receptor (EPOR)-common beta-chain (c-beta-chain) heteroreceptor.. Mice underwent 60 min coronary occlusion followed by treatment with vehicle or a single dose of darbepoetin. Effects on gene expression, apoptosis and neutrophil accumulation in infarcted left ventricle were assessed 24 h later. Cardiac function, effects on vascularization and fibrosis were assessed 28 days later. The significance of EPOR-c-beta-chain heteroreceptor was examined 28 days after infarction using mice deficient in c-beta-chain.. Twenty-four hours after darbepoetin, mRNAs encoding haeme oxygenase-1 (HO-1), iNOS and brain natriuretic peptide (BNP) were markedly elevated only in infarcted regions, and the frequency of apoptotic cells attenuated. Inflammation was also attenuated with reductions in neutrophil numbers. Darbepoetin also elevated mRNAs encoding angiogenic factors: placental growth factor, monocyte chemoattractant protein-1 and interleukin-1beta. Twenty-eight days after treatment, CD31+ vessels in the infarct zone doubled and fibrosis reduced. Cardiac haemodynamics were improved. Darbepoetin also improved cardiac haemodynamics in c-beta-chain-deficient mice, increased HO-1 and iNOS expression and vessel numbers and attenuated fibrosis.. Darbepoetin stimulates expression of haeme oxygenase, iNOS, BNP and angiogenic factors specifically in infarcted left ventricle that attenuates inflammation, apoptosis and fibrosis; elevate vessel numbers; and improve cardiac function. The EPOR-c-beta-chain heteroreceptor is not essential for these effects.

Topics: Animals; Apoptosis; Cardiotonic Agents; Darbepoetin alfa; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoietin; Fibrosis; Gene Expression Regulation; Heme Oxygenase-1; Hemodynamics; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardium; Natriuretic Peptide, Brain; Neovascularization, Physiologic; Neutrophil Infiltration; Nitric Oxide Synthase Type II; Receptors, Erythropoietin; Time Factors; Ventricular Function, Left

Erythropoietin (EPO) and granulocyte colony stimulating factor (GCSF) are potential novel therapies after myocardial infarction (MI). We first established the optimal and clinically applicable dosages of these drugs in mobilizing hematopoietic stem cells (HSC), and then tested the efficacy of monotherapy and combination therapy post-MI.. Optimal doses were established in enhanced green fluorescent protein (eGFP) + chimeric mice (n = 30). Next, mice underwent MI and randomized into 4 groups (n = 18/group): 1) GCSF; 2) EPO; 3) EPO+GCSF; and 4) control. Left ventricular (LV) function was analyzed pre-MI, at 4 hours and at 28 days post-MI. Histological assessment of infarct size, blood vessels, apoptotic cardiomyocytes, and engraftment of eGFP+ mobilized cells were analyzed at day 28. LV function in the control group continued to deteriorate, whereas all treatments showed stabilization. The treatment groups resulted in less scarring, increased numbers of mobilized cells to the infarct border zone (BZ), and a reduction in the number of apoptotic cardiomyocytes. Both EPO groups had significantly more capillaries and arterioles at the BZ.. We have established the optimal doses for EPO and GCSF in mobilizing HSC from the bone marrow and demonstrated that therapy with these agents, either as monotherapy or combination therapy, led to improvement of cardiac function post-MI. Combination therapy does not seem to have additive benefit over monotherapy in this model.

Topics: Animals; Cytokines; Delayed-Action Preparations; Disease Models, Animal; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction; Myocytes, Cardiac; Radiation Chimera; Random Allocation; Ventricular Function, Left

We recently demonstrated that transfusion of anemic animals up to 100 g/L hemoglobin with fresh blood protects the heart from ischemic injuries following myocardial infarction. Erythropoietin has cardioprotective effects independent of its erythropoietic activity. The objective of this study was to compare the cardioprotective effects of erythropoietin treatment to fresh-blood transfusion in anemic rats after acute myocardial infarction.. Randomized animal study.. University laboratory.. Male Sprague-Dawley rats weighing 200-300 g.. Myocardial infarction was induced by coronary artery ligation in 76 rats, 55 of which were anemic (80-90 g/L) and 21 of which had normal hemoglobin levels. Animals were randomized to erythropoietin (2000 units/kg), fresh-blood transfusion to 100 g/L hemoglobin, or saline-treatment groups immediately following myocardial infarction.. At 24 hrs after myocardial infarction, cardiac function and infarct size were determined. Myocardial apoptosis was determined by caspase-3 activity and terminal deoxynucleotidyl transferase d-UTP nick end labeling (TUNEL) assay. Infarct size was significantly decreased in anemic rats treated with erythropoietin or blood transfusion compared to those in the saline-treatment group. Cardiac function, as measured by maximal positive and minimal negative first derivatives of left ventricular pressure, was better preserved in the normal hemoglobin groups and the erythropoietin- or transfusion-treated anemic animals compared to saline-treated anemic animals. Myocardial caspase-3 activity and TUNEL-positive nuclei were significantly increased in anemic rats but were decreased by erythropoietin treatment or red blood cell transfusion.. Erythropoietin treatment is equally effective as fresh-blood transfusion in anemic rats after acute myocardial infarction at reducing infarct size, myocardial apoptosis, and improving cardiac function.

Topics: Anemia; Animals; Apoptosis; Blood Pressure; Blood Transfusion; Cardiotonic Agents; Caspase 3; Erythropoietin; Heart; Heart Rate; Hemoglobins; In Situ Nick-End Labeling; Male; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley

Topics: Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Male; Myocardial Infarction; Recombinant Proteins

Erythropoietin (EPO) and granulocyte colony stimulating factor (GCSF) have generated interest as novel therapies after myocardial infarction (MI), but the effect of combination therapy has not been studied in the large animal model. We investigated the impact of prolonged combination therapy with EPO and GCSF on cardiac function, infarct size, and vascular density after MI in a porcine model.. MI was induced in pigs by a 90 min balloon occlusion of the left anterior descending coronary artery. 16 animals were treated with EPO+GCSF, or saline (control group). Cardiac function was assessed by echocardiography and pressure-volume measurements at baseline, 1 and 6 weeks post-MI. Histopathology was performed 6 weeks post-MI.. At week 6, EPO+GCSF therapy stabilized left ventricular ejection fraction, (41 ± 1% vs. 33 ± 1%, p < 0.01) and improved diastolic function compared to the control group. Histopathology revealed increased areas of viable myocardium and vascular density in the EPO+GCSF therapy, compared to the control. Despite these encouraging results, in a historical analysis comparing combination therapy with monotherapy with EPO or GCSF, there were no significant additive benefits in the LVEF and volumes overtime using the combination therapy.. Our findings indicate that EPO+GCSF combination therapy promotes stabilization of cardiac function after acute MI. However, combination therapy does not seem to be superior to monotherapy with either EPO or GCSF.

Topics: Animals; Bone Marrow Cells; Disease Models, Animal; Drug Therapy, Combination; Echocardiography; Erythropoietin; Granulocyte Colony-Stimulating Factor; Heart; Heart Ventricles; Myocardial Infarction; Myocardium; Stroke Volume; Swine

Expanded endothelial progenitor cells (eEPC) improve global left ventricular function in experimental myocardial infarction (MI). Erythropoietin beta (EPO) applied together with eEPC may improve regional myocardial function even further by anti-apoptotic and cardioprotective effects. Aim of this study was to evaluate intramyocardial application of eEPCs and EPO as compared to eEPCs or EPO alone in experimental MI.. In vitro experiments revealed that EPO dosed-dependently decreased eEPC and leukocyte apoptosis. Moreover, in the presence of EPO mRNA expression in eEPC of proangiogenic and proinflammatory mediators measured by TaqMan PCR was enhanced. Experimental MI was induced by ligation and reperfusion of the left anterior descending coronary artery of nude rats (n = 8-9). After myocardial transplantation of eEPC and EPO CD68+ leukocyte count and vessel density were enhanced in the border zone of the infarct area. Moreover, apoptosis of transplanted CD31 + TUNEL + eEPC was decreased as compared to transplantation of eEPCs alone. Regional wall motion of the left ventricle was measured using Magnetic Resonance Imaging. After injection of eEPC in the presence of EPO regional wall motion significantly improved as compared to injection of eEPCs or EPO alone.. Intramyocardial transplantation of eEPC in the presence of EPO during experimental MI improves regional wall motion. This was associated with an increased local inflammation, vasculogenesis and survival of the transplanted cells. Local application of EPO in addition to cell therapy may prove beneficial in myocardial remodeling.

Topics: Animals; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Endothelium; Erythropoietin; Humans; Inflammation; Male; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Rats; Rats, Nude; Recovery of Function; Stem Cell Transplantation; Stem Cells

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

Topics: Animals; Disease Models, Animal; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Myocardial Infarction; Swine

Erythropoietin (EPO) and its non-erythrogenic derivative, carbarmylated EPO (CEPO), have been reported to activate different receptors (homomeric EPO receptor vs. heteromeric receptor consisting of EPO receptor monomer and common β-subunit). The aim of this study was to examine differences between EPO and CEPO in efficacy of cardioprotection against infarction and in activation of pro-survival kinases.. In isolated rat hearts, infarction was induced by global ischemia followed by reperfusion. Infarct size was determined 2 h after reperfusion, and ventricular tissues for immunoblotting were sampled at 5 min after reperfusion.. Pretreatment with EPO (10 units/ml) before ischemia reduced infarct size (% of risk area; %IS/AR) from 47.0 ± 2.1% of the control after 20-min ischemia to 24.7 ± 4.3% and from 62.0 ± 3.0% after 25-min ischemia to 45.5 ± 4.1%. Desialylated EPO (asialoEPO, 100 ng/ml) mimicked the protection by EPO. However, CEPO (100 ng/ml) failed to reduce infarct size after 20-min ischemia (%IS/AR = 47.5 ± 5.9%) and that after 25-min ischemia (%IS/AR = 56.1 ± 4.2%). The infarct size-limiting effect of CEPO was not shown either by increasing CEPO dose to 500 ng/ml or by shortening ischemia to 15 min. Both EPO and CEPO enhanced phosphorylation of cytosolic GSK-3β upon reperfusion. In contrast, phosphorylation of GSK-3β, Akt, and PKC-ε in mitochondria upon reperfusion was significantly enhanced by EPO but not by CEPO.. EPO affords more potent protection against infarction than does CEPO by distinct activation of signaling leading to phosphorylation of pro-survival protein kinases in mitochondria upon reperfusion.

Topics: Animals; Cardiotonic Agents; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Male; Mitochondria; Myocardial Infarction; Myocardial Reperfusion Injury; Phosphorylation; Protein Kinase C-epsilon; Protein Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; Signal Transduction

Topics: Angioplasty, Balloon, Coronary; Cardiovascular Agents; Coronary Restenosis; Endothelial Cells; Erythropoietin; Humans; Hyperplasia; Myocardial Infarction; Myocardium; Recombinant Proteins; Stroke Volume; Time Factors; Treatment Outcome; 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

Whereas administration of erythropoietin (EPO) acutely after myocardial infarction (MI) reduces infarct size and chronic EPO therapy attenuates post-MI remodeling, the safety of chronic EPO therapy following MI is unknown. Therefore, we examined the thrombogenic effects of a chronic EPO therapy after MI.. Rats underwent coronary occlusion followed by reperfusion. They were assigned to one of the following groups: EPO-A, single injection of EPO 5,000 U/kg at the time of reperfusion; EPO-C, injection of EPO 5,000 U/kg at the time of reperfusion followed by 300 U/kg/week; PBS-C, injection of vehicle only. After eight weeks of treatment they were exposed to a validated prethrombotic test based on partial stenosis of the inferior vena cava.. As compared to the rats receiving vehicle only, the rats treated with EPO exhibited a significant reduction in MI size (28.7 +/- 2.1% and 25.8 +/- 1.9 vs. 39.8 +/- 3.0% in EPO-A, EPO-C and PBS-C, respectively; p < 0.05). Whereas the hematocrit was significantly increased in EPO-C (59.7 +/- 2.0% vs. 44.7 +/- 0.9% in EPO-A, p < 0.001), the proportion of rats in which a thrombus occurred was similar in all groups (p = 0.52).. Chronic EPO therapy added to the single high dose of EPO injected acutely did not induce venous pro-thrombotic effect in rats.

Topics: Animals; Disease Models, Animal; Erythropoietin; Hematocrit; Male; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; Venous Thrombosis; Ventricular Remodeling

Mobilization of bone marrow-derived stem cells (BMCs) was shown to have protective effects after myocardial infarction (MI). However, the classical mobilizing agent, granulocyte-colony stimulating factor (G-CSF) relapsed after revealing an impaired homing capacity. In the search for superior cytokines, erythropoietin (EPO) appears to be a promising agent. Therefore, we analyzed in a murine model of surgically induced MI the influence of EPO treatment on survival and functional parameters as well as BMC mobilization, homing, and effect on resident cardiac stem cells (CSCs). Human EPO was injected intraperitoneally after ligation of the left anterior descendens (LAD) for 3 days with a total dose of 5000 IU/kg 6 and 30 days after MI, and pressure volume relationships were investigated in vivo. Cardiac tissues were analyzed by histology. To show the effect on BMCs and CSCs, FACS analyses were performed. Homing factors were analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and ELISA. EPO-treated animals showed a significant improvement of survival post-MI (62 vs. 36%). At days 6 and 30, all hemodynamic parameters associated with attenuated remodeling, enhanced neovascularization, and diminished apoptotic cells in the peri-infarct area were improved. BMC subpopulations (CD31(+), c-kit(+), and Sca-1(+) cells) were mobilized, and homing of Sca-1(+) and CXCR4(+) BMCs toward an SDF-1 gradient into the ischemic myocardium was enhanced. However, there was no beneficial effect on CSCs. We have shown that EPO application after MI shows cardioprotective effects. This may be explained by mobilization of BMCs, which are homing via the CXCR-4/SDF-1 axis. However, EPO has no beneficial effects on resident CSCs. Therefore, new treatment regimes using EPO together with other agents may combine complementary beneficial effects preventing ischemic cardiomyopathy.

Topics: Animals; Antigens, CD34; Bone Marrow Cells; Cardiomegaly; Cell Movement; Chemokine CXCL12; Erythropoietin; Female; Immunohistochemistry; Leukocyte Common Antigens; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Receptors, CXCR4; Stem Cells; Survival Rate; Time Factors

We have recently demonstrated that erythropoietin (EPO) protects cardiomyocytes from apoptosis during myocardial ischemia-reperfusion (I/R). The objective of the present study was to investigate the role of heme oxygenase (HO)-1 in the antiapoptotic effects of EPO. Primary cultures of neonatal mouse cardiomyocytes were subjected to anoxia-reoxygenation (A/R). Pretreatment with EPO significantly reduced apoptosis in A/R-treated cells. This reduction in apoptosis was preceded by an increase in the mRNA and protein expression of HO-1. Selective inhibition of HO-1 using chromium mesoporphyrin (CrMP) significantly diminished the ability of EPO to inhibit apoptosis. Cotreatment of EPO with SB-202190, an inhibitor of p38 activation, blocked the EPO-mediated HO-1 expression and antiapoptotic effects, suggesting a p38-dependent mechanism. The in vivo significance of p38 and HO-1 as mediators of EPO's cardioprotection was investigated in mice subjected to myocardial I/R. Pretreatment with EPO decreased infarct size as well as I/R-induced apoptosis in wild-type mice. However, these effects were significantly diminished in HO-1(-/-) mice. Furthermore, EPO given during ischemia reduced infarct size in mice subjected to I/R, and this effect was blocked by CrMP treatment in wild-type mice. Moreover, inhibition of p38 diminished the cardioprotective effects of EPO. We conclude that upregulation of HO-1 expression via p38 signaling contributes to EPO-mediated cardioprotection during myocardial I/R.

Topics: Animals; Animals, Newborn; Apoptosis; Carbon Monoxide; Cardiotonic Agents; Caspase 3; Caspase 9; Cells, Cultured; Erythropoietin; Heart Ventricles; Heme Oxygenase-1; Hemoglobins; Immunohistochemistry; In Situ Nick-End Labeling; Mice; Mice, Knockout; Myocardial Infarction; Myocardial Reperfusion Injury; p38 Mitogen-Activated Protein Kinases; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Up-Regulation

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

Erythropoietin (EPO) is a potent cardioprotective agent in models of myocardial ischemia and reperfusion (I/R). It has been suggested recently that EPO may also reduce ventricular arrhythmia after I/R. The present study investigated the role of neuronal nitric oxide synthase (nNOS) on the antiarrhythmic effects of EPO. EPO treatment increased nNOS expression in isolated neonatal mouse ventricular myocytes. Cotreatment with the phosphatidylinositol 3 (PI3)-kinase inhibitor, LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride], or treatment of cardiomyocytes infected with a dominant negative adenovirus targeted to Akt1 (ADV-dnAkt1) blocked the effects of EPO on nNOS expression, suggesting that EPO regulates nNOS expression via PI3-kinase and Akt. To examine the in vivo antiarrhythmic effects of EPO, wild-type (WT) and nNOS(-/-) mice were anesthetized and, after a baseline measurement, subjected to myocardial I/R to provoke ventricular arrhythmias. Pretreatment with EPO 24 h before ischemia increased nNOS expression and significantly reduced the number of premature ventricular contractions (PVCs) and the incidence of ventricular tachycardia (VT) in WT mice. In contrast, treatment with EPO had no effect on PVCs or the incidence of VT in nNOS(-/-) mice. Furthermore, EPO treatment after ischemia significantly reduced the threshold dose of cesium chloride (CsCl) to induce VT. We conclude that EPO via nNOS protects the heart from spontaneous and CsCl-induced ventricular arrhythmia during myocardial I/R.

Topics: Animals; Arrhythmias, Cardiac; Cells, Cultured; Cesium; Chlorides; Electrocardiography; Enzyme Inhibitors; Erythropoietin; Gene Expression; Heart; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Nitric Oxide Synthase Type I; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Tachycardia, Ventricular; Ventricular Premature Complexes

Abuse of doping agents may pose a higher risk for heart disease including acute myocardial infarction. We report the case of a 50-year-old body-builder Caucasian man with a long-standing abuse of nandrolone and erythropoietin that developed a ventricular septal defect following acute myocardial infarction. This mechanical complication led to cardiogenic shock ultimately treated with the implantation of a circulatory support by means of extracorporeal membrane oxygenation. The patient subsequently underwent orthotopic heart transplantation. The association of intense isometric exercise, abuse of erythropoietin and nandrolone is likely to have predisposed to coronary thrombus formation and acute myocardial infarction, as the patient presented no traditional cardiovascular risk factors.

Topics: Anabolic Agents; Doping in Sports; Erythropoietin; Heart Septal Defects, Ventricular; Heart Transplantation; Humans; Male; Middle Aged; Myocardial Infarction; Nandrolone; Shock, Cardiogenic; Weight Lifting

Various studies demonstrate erythropoietin (EPO) as a cardioprotective growth hormone. Recent findings reveal EPO in addition might induce proliferation cascades inside myocardium. We aimed to evaluate whether a single high-dose intramyocardial EPO administration safely elevates early intracardiac cell proliferation after myocardial infarction (MI). Following permanent MI in rats EPO (3000 U/kg) in MI EPO-treatment group (n=99) or saline in MI control group (n=95) was injected along the infarction border. Intramyocardial EPO injection activated the genes of cyclin D1 and cell division cycle 2 kinase (cdc2) at 24 h after MI (n=6, P<0.05) evaluated by real time-PCR. The number of Ki-67+ intracardiac cells analyzed following immunohistochemistry was significantly enhanced by 45% in the peri-infarction zone at 48 h after EPO treatment (n=6, P<0.001). Capillary density was significantly enhanced by 17% as early as seven days (n=6, P<0.001). After six weeks, left ventricular performance assessed by conductance catheters was restored under baseline and dobutamine induced stress conditions (n=11-14, P<0.05). No thrombus formation was observed in the heart and in distant organs. No deleterious systemic adverse effects were apparent. Single high-dose intramyocardial EPO delivery proved safety and promoted early intracardiac cell proliferation, which might in part have contributed to an attenuated myocardial functional decline.

Topics: Animals; Capillaries; Cardiotonic Agents; CDC2 Protein Kinase; Cell Proliferation; Cyclin D1; Disease Models, Animal; Erythropoietin; Injections, Intralesional; Ki-67 Antigen; Male; Myocardial Contraction; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Rats; Rats, Inbred Lew; Recovery of Function; Time Factors; Ventricular Function, Left

Erythropoietin (EPO) has been thought to be capable of potentiating protection of jeopardized myocardium by reperfusion in evolving myocardial infarction. However, diversity in study design and measurements of infarct size in studies evaluating EPO has led to inconsistent results. We sought to characterize the effect of EPO on infarct size after myocardial ischemia and reperfusion with the use of assessment of left-ventricular (LV) creatine kinase (CK) depletion and echocardiography.. Acute coronary occlusion was induced in 10-week-old C57BL6 mice by left anterior descending coronary artery ligation for 3 h followed by 72 h of reperfusion. EPO (10,000 U/kg) or an equivalent amount of saline vehicle alone was injected intraperitoneally before ligation or immediately after the onset of reperfusion. Assays of residual LV CK activity and calculation of LV CK depletion were performed on LV homogenates harvested 72 h after onset of reperfusion for measurement of infarct size, and echocardiography was performed immediately before harvest of tissue for measurement of function.. Mice administered EPO before ligation had similar infarct size (37.1+/-4.1%) and echo scores (22.9+/-0.4) compared with those in corresponding control mice administered saline (35.29+/-1.9 and 21.3+/-1.1%, respectively). Mice administered EPO after reperfusion had similar infarct size (39.1+/-4.8%) and echo scores (19.5+/-1.0) compared with those in corresponding control mice administered saline (40.3+/-4.9 and 21.5+/-1.9%, respectively).. EPO does not protect ischemic myocardium such that reperfusion after 3 h can yield additional salvage.

Topics: Animals; Biomarkers; Creatine Kinase; Disease Models, Animal; Echocardiography, Doppler; Epoetin Alfa; Erythropoietin; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Myocardial Contraction; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Recombinant Proteins; Time Factors; Ventricular Function, Left

Erythropoietin (EPO) protects the myocardium from ischaemic injury and promotes beneficial remodelling. We assessed the therapeutic efficacy of intracardiac EPO injection and EPO-mediated stem cell homing in a rat myocardial infarction (MI) model. Following MI, EPO (3000 U/kg) or saline was delivered by intracardiac injection. Compared to myocardial infarction control group (MIC), EPO significantly improved left ventricular function (n =11-14, P < 0.05) and decreased right ventricular wall stress (n = 8, P < 0.05) assessed by pressure-volume loops after 6 weeks. MI-EPO hearts exhibited smaller infarction size (20.1 +/- 1.1% versus 27.8 +/- 1.2%; n = 6-8, P < 0.001) and greater capillary density (338.5 +/- 14.7 versus 259.8 +/- 9.2 vessels per mm2; n = 6-8, P < 0.001) than MIC hearts. Direct EPO injection reduced post-MI myocardial apoptosis by approximately 41% (0.27 +/- 0.03% versus 0.42 +/- 0.03%; n = 6, P= 0.005). The chemoattractant SDF-1 was up-regulated significantly assessed by quantitative realtime PCR and immunohistology. c-Kit(+) and CD34(+) stem cells were significantly more numerous in MI-EPO than in MIC at 24 hrs in peripheral blood (n = 7, P < 0.05) and 48 hrs in the infarcted hearts (n = 6, P < 0.001). Further, the mRNAs of Akt, eNOS and EPO receptor were significantly enhanced in MI-EPO hearts (n = 7, P < 0.05). Intracardiac EPO injection restores myocardial functions following MI, which may attribute to the improved early recruitment of c-Kit(+) and CD34(+) stem cells via the enhanced expression of chemoattractant SDF-1.

Topics: Animals; Apoptosis; Cell Survival; Chemokine CXCL12; Disease Models, Animal; Erythropoietin; Heart Function Tests; Hematocrit; Hematopoietic Stem Cell Mobilization; Humans; Injections; Matrix Metalloproteinase 2; Myocardial Infarction; Myocytes, Cardiac; Neovascularization, Physiologic; Rats; Receptors, CXCR4; Receptors, Erythropoietin; Recombinant Proteins; Troponin T; Up-Regulation

Hepcidin, a key iron-regulator secreted from the liver, consists of 25 amino acids (hepcidin-25), blocks iron release from macrophages via internalization and degradation of cellular iron exporter ferroportin, and restrains the use of iron in organs. Hepcidin mRNA and protein are also expressed in the human heart. A short form of hepcidin that lacks 5 amino-acid residues in the N-terminus (hepcidin-20) has been found in human serum, although its physiological role is unknown. Here, we successfully measured the serum levels of hepcidin-25 and hepcidin-20 in 12 patients with acute myocardial infarction (AMI) using surface-enhanced laser desorption ionization time of flight mass spectrometry. Among the selected 10 patients, whose blood samples were taken within 4 hours after a heart attack, all the patients showed elevated serum levels of hepcidin-20 [between 31.7 and 285.1 arbitrary unit (AU); normal level < 9.3 AU], while 8 patients showed high levels of hepcidin-25 (9.3-271.4; normal < 25.5 AU). The hepcidin-20 level was decreased to nearly the normal level on day 7 (range of 2.9 to 12.5 AU) in the 12 patients, whereas the hepcidin-25 level remained high on day 7 in 8 patients. Furthermore, the elevated levels of hepcidin-25 and hepcidin-20 were not correlated with the serum levels of markers for inflammation, interleukin-6 and C-reactive protein, in the patients with AMI. In conclusion, the serum hepcidin-20 is transiently elevated in response to acute cardiac ischemia. Measurement of serum hepcidin-20, rather than hepcidin-25, is helpful for diagnosis of acute myocardial infarction.

Topics: Acute Disease; Adult; Aged; Amino Acid Sequence; Antimicrobial Cationic Peptides; Biomarkers; C-Reactive Protein; Creatine Kinase; Erythropoietin; Female; Hepcidins; Humans; Inflammation; Insulin; Interleukin-6; Male; Middle Aged; Molecular Sequence Data; Myocardial Infarction; Peptide Fragments; Sequence Homology, Amino Acid; Time Factors

Erythropoietin (Epo) is a hematopoietic hormone produced mainly by the kidneys in response to hypoxia. Recent acquisitions in the fields of hematology, neurology, cardiology, and experimental medicine show cytoprotective, angiogenetic and antiinflammatory effects of Epo. Exogenous erythroPoietin in Acute Myocardial Infarction: New Outlook aNd Dose Association Study (EPAMINONDAS, EudraCTno. 200500485386) is one of four ongoing randomized controlled trials, each testing the effects of Epo in >or=100 patients with STEMI. EPAMINONDAS is a multicenter, prospective, double-blind, placebo-controlled, dose-finding study assessing intravenous moderate doses of human recombinant Epo (epoietin-alpha, 100 or 200 IU/kg/die) versus placebo, given on the first 3 days, in 102 patients with first ST-segment elevation myocardial infarction. Initial dosing is within 12 h of primary percutaneous coronary revascularization. The primary endpoint is infarct size, quantified by CK-MB time-concentration curve, left ventricular wall motion score index, and pattern of contrast-enhanced magnetic resonance imaging. Secondary endpoints are ischemic recurrences, ventricular remodelling, and safety events, assessed in-hospital and at 12 months' follow-up. The results of current phase II studies will help define the safety/efficacy profile of Epo for patients with STEMI.

Topics: Clinical Trials, Phase II as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoietin; Follow-Up Studies; Humans; Myocardial Infarction; Prospective Studies; Randomized Controlled Trials as Topic; Recombinant Proteins; Research Design

Erythropoietin (EPO) can protect myocardium from ischemic injury, but it also plays an important role in promoting polycythaemia, the potential for thrombo-embolic complications. Local sustained delivery of bioactive agents directly to impaired tissues using biomaterials is an approach to limit systemic toxicity and improve the efficacy of therapies. The present study was performed to investigate whether local intramyocardial injection of EPO with hydrogel could enhance cardioprotective effect without causing polycythaemia after myocardial infarction (MI). To test the hypothesis, phosphate buffered solution (PBS), alpha-cyclodextrin/MPEG-PCL-MPEG hydrogel, recombined human erythropoietin (rhEPO) in PBS, or rhEPO in hydrogel were injected into the infarcted area immediately after MI in rats. The hydrogel allowed a sustained release of EPO, which inhibited cell apoptosis and increased neovasculature formation, and subsequently reduced infarct size and improved cardiac function compared with other groups. Notably, there was no evidence of polycythaemia from this therapy, with no differences in erythrocyte count and hematocrit compared with the animals received PBS or hydrogel blank injection. In conclusion, intramyocardial delivery of rhEPO with alpha-cyclodextrin/MPEG-PCL-MPEG hydrogel may lead to cardiac performance improvement after MI without apparent adverse effect.

Topics: alpha-Cyclodextrins; Animals; Apoptosis; Biocompatible Materials; Cardiotonic Agents; Drug Carriers; Echocardiography; Erythropoietin; Hemodynamics; Humans; Hydrogels; Male; Materials Testing; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Polycythemia; Random Allocation; Rats; Rats, Sprague-Dawley; Stem Cells; Ventricular Remodeling

The purpose of this study was to assess the short- and long-term cardioprotective effects of darbepoetin-alpha (DA) in a rat myocardial ischemia and reperfusion model and to investigate the signaling pathway through which DA limits cardiomyocytes apoptosis. Rats were subjected to 40 minutes of coronary artery ligation followed by 72 hours or 4 weeks reperfusion and received either DA (3 or 30 microg/kg, DA3 and D30 groups) or vehicle (control) prior to ischemia. In the DA groups reperfused for 72 hours, left ventricular shortening fraction and left ventricular ejection fraction were higher than that in the control rats (P < 0.05), in agreement with a smaller left ventricular (LV) infarct size. DA treatment activated the JAK2/Akt signaling pathway, lowered cleaved caspase-3, and increased both phosphorylated-Bad and phosphorylated-GSK-3beta proteins. This was consistent with the decrease of reactive oxygen species production and the lowered binding of Bad to Bcl-xL and Bcl-2 in a DA30 group of rats. Similarly, in the DA-4-week group, LV function was greater compared to the control. Histology alterations implicated lower LV cardiac fibrosis and greater capillary density; furthermore, both Bcl-xL and Bcl-2 were upregulated. In conclusion, DA afforded short- and long-term cardioprotective effects. Antiapoptotic effects, through the activation of Akt that regulates the Bcl-2 family proteins and activates GSK-3beta, are central in the DA cardioprotective mechanism.

Topics: Animals; Apoptosis; Cardiotonic Agents; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Heart; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Rats; Rats, Wistar; Reactive Oxygen Species; Severity of Illness Index; Signal Transduction; Stroke Volume; Time Factors

Ischemic postconditioning (IPost) and erythropoietin (EPO) have been shown to attenuate myocardial reperfusion injury using similar signaling pathways. The aim of this study was to examine whether EPO is as effective as IPost in decreasing postischemic myocardial injury in both Langendorff-isolated-heart and in vivo ischemia-reperfusion rat models. Rat hearts were subjected to 25 min ischemia, followed by 30 min or 2 h of reperfusion in the isolated-heart study. Rats underwent 45 min ischemia, followed by 24 h of reperfusion in the in vivo study. In both studies, the control group (n=12; ischemia-reperfusion only) was compared with IPost (n=16; 3 cycles of 10 s reperfusion/10 s ischemia) and EPO (n=12; 1,000 IU/kg) at the onset of reperfusion. The following resulted. First, in the isolated hearts, IPost or EPO significantly improved postischemic recovery of left ventricular developed pressure. EPO induced better left ventricular developed pressure than IPost at 30 min of reperfusion (73.18+/-10.23 vs. 48.11+/-7.92 mmHg, P<0.05). After 2 h of reperfusion, the infarct size was significantly lower in EPO-treated hearts compared with IPost and control hearts (14.36+/-0.60%, 19.11+/-0.84%, and 36.21+/-4.20% of the left ventricle, respectively; P<0.05). GSK-3beta phosphorylation, at 30 min of reperfusion, was significantly higher with EPO compared with IPost hearts. Phosphatidylinositol 3-kinase and ERK1/2 inhibitors abolished both EPO- and IPost-mediated cardioprotection. Second, in vivo, IPost and EPO induced an infarct size reduction compared with control (40.5+/-3.6% and 28.9+/-3.1%, respectively, vs. 53.7+/-4.3% of the area at risk; P<0.05). Again, EPO decreased significantly more infarct size and transmurality than IPost (P<0.05). In conclusion, with the use of our protocols, EPO showed better protective effects than IPost against reperfusion injury through higher phosphorylation of GSK-3beta.

Topics: Animals; Cardiotonic Agents; Coronary Circulation; Darbepoetin alfa; Disease Models, Animal; Erythropoietin; Female; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Heart Rate; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Time Factors; Ventricular Function, Left; Ventricular Pressure

Erythropoietin (EPO) and carbamylated erythropoietin (CEPO) can protect tissue from injury; however, CEPO has its protective effect in the absence of erythropoietic stimulation. The mechanism whereby CEPO protects heart from acute ischemia/reperfusion (I/R) injury remains unknown.. BALB/c mice were subjected to myocardial ischemia for 45 min followed by reperfusion for 4 h, and they received a single dose of CEPO intraperitoneal at the onset of reperfusion. Myocardial infarct size and cardiac function were assessed. The association of erythropoietin receptor with beta common receptor (betacR) was examined. The level of Akt phosphorylation in the myocardium was assayed as well as a series of downstream target genes of PI3K/Akt,including p-GATA-4, GATA-4, MHC, and troponin I.. CEPO administration immediately before reperfusion decreased infarction by 40% and increased ejection fraction (27%) and fractional shortening (22%), compared with untreated ischemic hearts (P < .05 each). CEPO promoted association of the EPO receptor and betacR. Furthermore, CEPO administration increased the levels of phospho-Akt in the myocardium by 59% (P < .05). A PI3K inhibitor, wortmannin, blocked the beneficial effect of CEPO on infarct size and cardiac function and attenuated the CEPO-induced Akt phosphorylation. CEPO also increased the expression of p-GATA-4, GATA-4, myosin heavy chain, and troponin I.. A single dose of CEPO at the onset of reperfusion attenuated acute myocardial I/R injury in the mouse. CEPO-induced cardioprotection appears to be mediated through a PI3K/Akt-dependent mechanism.

Topics: Androstadienes; Animals; Cardiotonic Agents; Cytokine Receptor Common beta Subunit; Erythropoietin; GATA4 Transcription Factor; Male; Mice; Mice, Inbred BALB C; Myocardial Infarction; Myocardial Reperfusion Injury; Myosin Heavy Chains; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptors, Erythropoietin; Signal Transduction; Troponin I; Wortmannin

Alteration in endoplasmic reticulum (ER) stress in diabetic hearts and its effect on cytoprotective signaling are unclear. Here, we examine the hypothesis that ER stress in diabetic hearts impairs phospho-glycogen synthase kinase (GSK)-3beta-mediated suppression of mitochondrial permeability transition pore (mPTP) opening, compromising myocardial response to cytoprotective signaling.. A rat model of type 2 diabetes (OLETF) and its control (LETO) were treated with tauroursodeoxycholic acid (TUDCA) (100 mg . kg(-1) . day(-1) for 7 days), an ER stress modulator. Infarction was induced by 20-min coronary occlusion and 2-h reperfusion.. Levels of ER chaperones (GRP78 and GRP94) in the myocardium and level of nonphoshopho-GSK-3beta in the mitochondria were significantly higher in OLETF than in LETO rats. TUDCA normalized levels of GRP78 and GRP94 and mitochondrial GSK-3beta in OLETF rats. Administration of erythropoietin (EPO) induced phosphorylation of Akt and GSK-3beta and reduced infarct size (% risk area) from 47.4 +/- 5.2% to 23.9 +/- 3.5% in LETO hearts. However, neither phosphorylation of Akt and GSK-3beta nor infarct size limitation was induced by EPO in OLETF rats. The threshold for mPTP opening was significantly lower in mitochondria from EPO-treated OLETF rats than in those from EPO-treated LETO rats. TUDCA restored responses of GSK-3beta, mPTP opening threshold, and infarct size to EPO receptor activation in OLETF rats. There was a significant correlation between mPTP opening threshold and phospho-GSK-3beta-to-total GSK-3beta ratio in the mitochondrial fraction.. Disruption of protective signals leading to GSK-3beta phosphorylation and increase in mitochondrial GSK-3beta are dual mechanisms by which increased ER stress inhibits EPO-induced suppression of mPTP opening and cardioprotection in diabetic hearts.

Topics: Animals; Blood Glucose; Body Weight; Calcium; Diabetes Mellitus, Type 2; Endoplasmic Reticulum; Erythropoietin; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Immunoblotting; Intracellular Membranes; Male; Membrane Potential, Mitochondrial; Mitochondria, Heart; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Myocytes, Cardiac; Permeability; Phosphorylation; Rats; Rats, Inbred OLETF; Taurochenodeoxycholic Acid

The erythropoietin levels in the blood of 50 patients with myocardial infarction were studied. The control group consisted of 33 patients with gastroenterologic diseases. Increased erythropoietin production in patients with myocardial infarction was caused by blood hypoxia under conditions of keeping kidney erythropoietin function. No dependence was found between manifestation of heaviness of acute heart failure caused by acute myocardial ischemic and hormone production in patients without anemia.

Topics: Adult; Aged; Aged, 80 and over; Erythropoietin; Female; Gastrointestinal Diseases; Humans; Kidney; Male; Middle Aged; Myocardial Infarction

Erythropoietin (Epo) is a hormone which regulates erythrocyte production. It has recently become known that Epo enhances angiogenesis. However, since shear stress is an initiator of arteriogenesis, this increase with Epo may be due to increased shear stress from erythrocytosis. To clarify this, we compared the effects of Epo on both angiogenesis and arteriogenesis. Myocardial infarction was induced by LAD ligation in Wistar rats (Epo, G-CSF and control). Epo (1,000 IU/kg) was administered immediately after ligation of the LAD. G-CSF was administered at 100 microg/kg/day for 5 days after the coronary ligation. Four weeks later, coronary angiography was performed using synchrotron radiation coronary micro-angiography with a Langendorff apparatus. The number of vessels was investigated by microscopy. The numbers of capillaries and arterioles (> 100 microm in diameter) were measured. Microscopical examination: Capillary density in the twilight zone was 95 +/- 19 in the control group, 126 +/- 24 in the G-CSF group, and 142 +/- 32 in the EPO group (control versus Epo: P < 0.005, control versus G-CSF: P < 0.05). Arteriole numbers were 4.3 +/- 0.2 in the control group, 6.9 +/- 1.0 in the G-CSF, and 11.8 +/- 0.6 in the Epo group (control versus Epo: P < 0.00001, G-CSF versus Epo: P < 0.00001, control versus G-CSF: P < 0.00001). The ratios of arterioles and capillaries were 0.048 +/- 0.013 in the control group, 0.057 +/- 0.016 in the G-CSF group, and 0.088 +/- 0.019 in the Epo group (control versus Epo: P < 0.0005, G-CSF versus Epo: P < 0.05). Angiography: The number of crossing arterioles in the 2 mm lattice was 5.4 +/- 1.7 in the Epo group and 3.8 +/-0.4 in the control group (P < 0.05). The gray scale values for the evaluation of capillaries was 128 +/- 3.7 and 119 +/- 2.1 in the Epo and control groups, respectively (P < 0.00005). Epo enhanced arterioles more significantly than it did capillaries in this infarcted rat heart model.

Topics: Angiography; Animals; Arterioles; Capillaries; Coronary Angiography; Disease Models, Animal; Erythropoietin; Male; Myocardial Infarction; Rats; Rats, Wistar; Synchrotrons

It has been recently reported that release of erythropoietin could mediate the cardioprotective effects of remote renal preconditioning. However, the mechanism of erythropoietin-mediated cardioprotection in remote preconditioning is still unexplored. Therefore, the present study was designed to investigate the possible signal transduction pathway of erythropoietin-mediated cardioprotection in remote preconditioning in rats. Remote renal preconditioning was performed by four episodes of 5 min renal artery occlusion followed by 5 min reperfusion. Isolated rat hearts were perfused on Langendorff apparatus and were subjected to global ischemia for 30 min followed by 120 min reperfusion. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in coronary effluent to assess the degree of myocardial injury. Extent of myocardial infarct size and coronary flow rate was also measured. Remote renal preconditioning and erythropoietin preconditioning (5,000 IUkg(-1), i.p.) attenuated ischemia-reperfusion-induced myocardial injury and produced cardioprotective effects. However, administration of diethyldithiocarbamic acid (150 mg kg(-1) i.p.), a selective NFkB inhibitor, and glibenclamide (5 mg kg(-1) i.p.), a selective K(ATP) channel blocker, attenuated cardioprotective effects of remote preconditioning and erythropoietin preconditioning. However, administration of minoxidil (1 mg kg(-1) i.v.), a selective K(ATP) channel opener, restored the attenuated cardioprotective effects of remote preconditioning and erythropoietin preconditioning in diethyldithiocarbamic acid pretreated rats. These results suggest that K(ATP) channel is a downstream mediator of NFkB activation in remote preconditioning and erythropoietin preconditioning. Therefore, it may be concluded that erythropoietin preconditioning and remote renal preconditioning trigger similar signaling mechanisms for cardioprotection, i.e., NFkB activation followed by opening of K(ATP) channels.

Topics: Animals; Cardiotonic Agents; Coronary Circulation; Creatine Kinase; Erythropoietin; Heart Rate; Humans; In Vitro Techniques; Ischemic Preconditioning; Ischemic Preconditioning, Myocardial; Kidney; L-Lactate Dehydrogenase; Male; Myocardial Infarction; Myocardium; Rats; Rats, Wistar; Recombinant Proteins; Signal Transduction

We investigated the effect of an erythropoietin (EPO)-gelatin hydrogel drug delivery system (DDS) applied to the heart on myocardial infarct (MI) size, left ventricular (LV) remodelling and function.. Experiments were performed in a rabbit model of MI. The infarct size was reduced, and LV remodelling and function were improved 14 days and 2 months after MI but not at 2 days after MI in the EPO-DDS group. The number of cluster of differentiation 31(CD31)-positive microvessels and the expression of erythropoietin receptor (EPO-R), phosphorylated-Akt (p-Akt), phosphorylated glycogen synthase kinase 3beta (p-GSK-3beta), phosphorylated extracellular signal-regulated protein kinase (p-ERK), phosphorylated signal transducer and activator of transcription 3 (p-Stat3), vascular endothelial growth factor (VEGF), and matrix metalloproteinase-1 (MMP-1) were significantly increased in the myocardium of the EPO-DDS group.. Post-MI treatment with an EPO-DDS improves LV remodelling and function by activating prosurvival signalling, antifibrosis, and angiogenesis without causing any side effect.

Topics: Animals; Blotting, Western; Cardiovascular Agents; Cell Survival; Chemistry, Pharmaceutical; Disease Models, Animal; Dosage Forms; Drug Carriers; Erythropoietin; Fibrosis; Gelatin; Humans; Hydrogels; Immunohistochemistry; Injections, Subcutaneous; Intracellular Signaling Peptides and Proteins; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Rabbits; Recombinant Proteins; Signal Transduction; Time Factors; Ventricular Function, Left; Ventricular Remodeling

Topics: Animals; Autocrine Communication; Cell Differentiation; Cell Proliferation; Cell Survival; Disease Models, Animal; Erythropoietin; Genetic Therapy; Humans; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Paracrine Communication; Regeneration; Stromal Cells; Ventricular Function, Left

Topics: Animals; Cardiovascular Agents; Cell Survival; Chemistry, Pharmaceutical; Dosage Forms; Drug Carriers; Erythropoietin; Humans; Injections, Subcutaneous; Myocardial Infarction; Myocardium; Recombinant Proteins; Signal Transduction; Ventricular Function, Left; Ventricular Remodeling

Administration of erythropoietin (EPO) during or immediately after myocardial ischemia can reduce subsequent myocardial apoptosis, a key phenomenon in myocardial ischemia-reperfusion injury. In this study, we assessed the effect of EPO on (99m)Tc-annexin V myocardial uptake and whether the accumulation of (99m)Tc-annexin V can predict cardiac remodeling and functional deterioration.. Eighteen rats with left coronary artery (LCA) occlusion were randomized to receive either an intravenous injection of EPO (EPO group) or saline (nontherapy [nT] group) immediately after release of the occlusion. After 20 min of LCA occlusion and 30 min of reperfusion, the rats were injected with (99m)Tc-annexin V. One hour after (99m)Tc-annexin V injection, the LCA was reoccluded and (201)Tl was injected intravenously, and the rats were sacrificed 1 min later. The heart was removed and sectioned, and dual-tracer autoradiography was performed to evaluate the distribution of the area at risk (defined on the thallium autoradiograph) and the area of apoptosis (defined on the annexin autoradiograph). Adjacent histologic specimens had deoxyuridine triphosphate nick-end labeling (TUNEL) staining to confirm the presence of apoptosis and were compared with autoradiography. Another 16 rats were randomized to EPO and nT groups and underwent echocardiography immediately after release of the LCA occlusion and at 2 and 4 wk after surgery.. The areas of (99m)Tc-annexin V accumulation in the EPO group were smaller than those in the nT group, though the (201)Tl defect areas of these 2 groups were comparable (area ratio, 0.318 +/- 0.038 vs. 0.843 +/- 0.051, P < 0.001, for annexin and 24.8 +/- 2.1 vs. 25.9 +/- 2.6 mm(2), P = NS, for thallium). (99m)Tc-annexin V accumulation correlated with the density of TUNEL-positive cells (r = 0.886, P < 0.001). In the nT group, left ventricular end-diastolic dimension (Dd) increased from baseline at 2 wk by 34.7% +/- 3.8% and remained stable at 34.9% +/- 5.0% at 4 wk after coronary occlusion. In the EPO group, Dd increased by 8.5% +/- 2.1% (P < 0.01 vs. nT at 2 wk) and 13.2% +/- 2.8% (P < 0.01 vs. nT at 4 wk). In the nT group, the left ventricular percentage of fractional shortening decreased by 42.2% +/- 3.4% and 52.9% +/- 3.4% at 2 and 4 wk, respectively, whereas in the EPO group it decreased 9.0% +/- 1.9% at 2 wk (P < 0.01 vs. nT at 2 wk) and 11.1% +/- 6.7% at 4 wk (P < 0.01 vs. nT at 4 wk).. This study demonstrated that a single treatment with EPO immediately after release of coronary ligation suppressed cardiac remodeling and functional deterioration. (99m)Tc-annexin V autoradiographs and TUNEL staining confirm that this change is due to a decrease in the extent of myocardial apoptosis in the ischemic/reperfused region.

Topics: Animals; Annexin A5; Apoptosis; Autoradiography; Cardiotonic Agents; Coronary Vessels; Echocardiography; Erythropoietin; Hematocrit; Male; Myocardial Infarction; Radionuclide Imaging; Rats; Rats, Wistar; Reperfusion Injury; Technetium

Recent studies have shown that insulin growth factor-1 (IGF-1) and either erythropoietin (EPO) or the long-acting EPO analog Darbepoetin alfa (DA) protect the heart against ischemia/reperfusion (I/R) and myocardial infarction (MI). The present study examined the cardioprotective effect of simultaneous treatments with IGF-1 and DA in these models of cardiac injury. Rats were subjected to I/R or MI and were treated with IGF-1, DA, and a combination of IGF-1 and DA, or vehicle treatment. IGF-1 and DA treatments imparted similar protective effect by reducing infarct size. Moreover, these treatments led to improvement of cardiac function after I/R or MI compared to vehicle. In the reperfused heart, apoptosis was reduced with either or both IGF-1 and DA treatments as measured by reduced TUNEL staining and caspase-3 activity. In addition, after MI, treatment with IGF-1 or DA significantly induced angiogenesis. This angiogenic effect was enhanced significantly when IGF-1 and DA were given simultaneously compared to vehicle or either agents alone. These data indicate simultaneous pharmacological treatments with IGF-1 and DA protect the heart against I/R and MI injuries. This protection results in reduced infarct size and improved cardiac function. Moreover, this treatment reduces apoptosis and enhances angiogenesis in the ischemic heart.

Topics: Animals; Apoptosis; Caspase 3; Darbepoetin alfa; Erythropoietin; In Situ Nick-End Labeling; Insulin-Like Growth Factor I; Male; Models, Biological; Myocardial Infarction; Myocardial Ischemia; Myocardium; Neovascularization, Pathologic; Rats; Rats, Sprague-Dawley; Reperfusion Injury

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

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

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

1. The aim of the present study was to determine the critical timing of Akt activation and its interaction with the mitochondrial permeability transition pore (mPTP) in the mechanism of infarct size limitation by erythropoietin (Epo). 2. In an isolated, buffer-perfused preparation, rabbit hearts were subjected to 30 min ischaemia/2 h reperfusion. Infusion of Epo (1 unit/mL) before ischaemia reduced infarct size from 36.6 +/- 2.6% of the risk area to 15.4 +/- 3.2%, whereas a 10-fold higher dose of Epo infused for 65 min commencing 5 min before reperfusion failed to afford significant cardioprotection. The protection afforded by Epo pretreatment was abolished by coinfusion of 5 micromol/L LY294002, a phosphatidylinositol 3-kinase (PI3-K) inhibitor. Infusion of Epo induced phosphorylation of Akt, extracellular signal-regulated kinase, glycogen synthase kinase 3beta and p70s6 kinase before ischaemia and tended to enhance reperfusion-induced phosphorylation of these protein kinases. Erythropoietin increased phospho-Akt in the mitochondria and induced complex formation of Akt with adenine nucleotide translocase (ANT), a major subunit of mPTP, upon reperfusion. 3. In another series of experiments, cardiomyocytes were isolated from rat hearts and loaded with Rhod-2 to determine mitochondrial Ca(2+) levels. Increases in mitochondrial Ca(2+) levels following exposure to 1 mmol/L ouabain for 30 min were similar in untreated and Epo-pretreated cells. However, ouabain-induced hypercontracture was significantly suppressed from 45.1 +/- 1.6 to 39.2 +/- 1.9% by Epo. 4. In conclusion, activation of PI3-K-Akt signalling before ischaemia is crucial for Epo-induced myocardial protection and this protection may be achieved by complex formation of activated Akt with mPTP components upon reperfusion, leading to elevation of the threshold for opening of mPTP.

Topics: Animals; Erythropoietin; Male; Mitochondria, Heart; Myocardial Infarction; Myocardial Reperfusion Injury; Protein Transport; Proto-Oncogene Proteins c-akt; Rabbits

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

Mesenchymal stromal cells (MSCs) possess intrinsic features that identify them as useful for treating ischaemic syndromes. Poor in vivo survival/engraftment of MSCs, however, limits their overall effectiveness. In this work, we tested whether genetically engineering MSCs to secrete erythropoietin (Epo) could represent a better therapeutic platform than MSCs in their native form.. MSCs from C57Bl/6 mice were retrovirally transduced with either an empty vector or one that causes the production of Epo and were then analysed for the alterations in angiogenic and survival potential. Using a mouse model of myocardial infarction (MI), the regenerative potential of null MSCs and Epo-overexpressing MSCs (Epo+MSCs) was assessed using serial echocardiogram and invasive haemodynamic measurements. Infarct size, capillary density and neutrophil influx were assessed using histologic techniques. Using in vitro assays coupled with an in vivo Matrigel plug assay, we demonstrate that engineering MSCs to express Epo does not alter their immunophenotype or plasticity. However, relative to mock-modified MSCs [wild-type (WT)-MSCs], Epo+MSCs are more resilient to apoptotic stimuli and initiate a more robust host-derived angiogenic response. We also identify and characterize the autocrine loop established on MSCs by having them secrete Epo. Furthermore, in a murine model of MI, animals receiving intracardiac injections of Epo+MSCs exhibited significantly enhanced cardiac function compared with WT-MSCs and saline-injected control animals post-MI, owing to the increased myocardial capillary density and the reduced neutrophilia.. Epo overexpression enhances the cellular regenerative properties of MSCs by both autocrine and paracrine pathways.

Topics: Animals; Apoptosis; Autocrine Communication; Cell Differentiation; Cell Proliferation; Cell Survival; Cells, Cultured; Disease Models, Animal; Erythropoietin; Female; Genetic Therapy; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Neovascularization, Physiologic; Neutrophil Infiltration; Paracrine Communication; Regeneration; Stromal Cells; Transduction, Genetic; Ventricular Function, Left; Ventricular Remodeling

Aims were to explore if darbepoietin-alpha in mouse can induce angiogenesis and if moderate doses after myocardial infarction stimulates periinfarct capillary and arteriolar densities, cell proliferation, and apoptosis. Myocardial infarction was induced by ligation of LAD. Mouse aortic rings (0.8mm) were cultured in matrigel and the angiogenic sprouting was studied after addition of darbepoietin-alpha with and without VEGF-165. After 12 days the hemoglobin concentration was 25% higher in the darbepoietin-alpha treated mice than in the control group. No difference in capillary densities in the periinfarct or noninfarcted areas was seen with darbepoietin-alpha. Cell proliferation was about 10 times higher in the periinfarct area than in the noninfarcted wall. Darbepoietin-alpha treatment led to a decrease of cell proliferation (BrdU, (p<0.02)) and apoptosis (TUNEL, p<0.005) with about 30% in the periinfarct area. Darbepoietin-alpha and VEGF-165 both independently induced sprouting from aortic rings. The results suggest that darbepoietin-alpha can induce angiogenesis but that moderate doses after myocardial infarction are not angiogenic but antiapoptotic.

Topics: Angiogenesis Inducing Agents; Animals; Aorta; Apoptosis; Biological Assay; Capillaries; Cell Proliferation; Cells, Cultured; Darbepoetin alfa; Erythropoietin; Humans; Mice; Mice, Inbred C57BL; Myocardial Infarction; Neovascularization, Physiologic; Vascular Endothelial Growth Factor A

Recently we found that post-infarct remodeling disrupts PI3KAkt signaling triggered by erythropoietin (EPO) but an unknown compensatory mechanism preserves EPO-induced protection against infarction in those hearts. In this study, we examined the possibility that ERK-mediated signaling is the compensatory mechanism affording protection in post-infarct remodeled hearts. Four weeks after coronary ligation in situ (post-MI group, post-MI) or a sham operation (sham group, Sham), hearts were isolated, perfused and subjected to 25-min global ischemia/2-h reperfusion. Infarct size was expressed as a percentage of risk area size (%I/R), from which scarred infarct by coronary ligation was excluded. EPO infusion (5 U/ml) before ischemia reduced %I/R similarly in Sham and post-MI (from 62.0 +/- 5.1 to 39.4 +/- 4.8 in Sham and from 58.6 +/- 6.6 to 36.3 +/- 3.8 in post-MI). PD98059, a MEK1/2 inhibitor, abolished this EPO-induced protection in post-MI (%I/R = 60.7 +/- 4.9) but not in Sham (%I/R = 35.1 +/- 5.4). EPO induced PI3K-dependent phosphorylation of Akt in Sham but not in post-MI. EPO increased phosphorylation levels of ERK1/2 both in Sham and post-MI, but this phosphorylation was diminished by a PI3K inhibitor in Sham but not in post-MI. These results suggest that PI3K-independent activation of ERK compensates the lack of signal input from the PI3K-Akt pathway to achieve EPO-induced protection in the remodeled myocardium.

Topics: Animals; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Myocardial Infarction; Myocardium; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Ventricular Remodeling

We examined the cardiac effects of chronic erythropoietin (EPO) therapy initiated 7 days after myocardial infarction (MI) in rats. A single high dose of EPO has been shown to reduce infarct size by preventing apoptosis when injected immediately after myocardial ischemia. The proangiogenic potential of EPO has also been reported, but the effects of chronic treatment with standard doses after MI are unknown. In this study, rats underwent coronary occlusion followed by reperfusion or a sham procedure. Infarcted rats were assigned to one of three treatment groups: 1) 0.75 microg/kg darbepoetin (MI+darb 0.75, n = 12); 2) 1.5 microg/kg darbepoetin (MI+darb 1.5, n = 12); 3) vehicle (MI+PBS, n = 16), once a week from day 7 postsurgery. Sham rats received the vehicle alone (n = 10). After 8 wk of treatment, the animals underwent echocardiography, left ventricular pressure-volume measurements, and peripheral blood endothelial progenitor cell (EPC) counting. MI size and capillary density in the border zone and the area at risk (AAR) were measured postmortem. The AAR was similar in the three MI groups. Compared with MI+PBS, the MI+darb 1.5 group showed a reduction in the MI-to-AAR ratio (20.8% vs. 38.7%; P < 0.05), as well as significantly reduced left ventricle dilatation and improved cardiac function. This reduction in post-MI remodeling was accompanied by increased capillary density (P < 0.05) and by a higher number of EPC (P < 0.05). Both darbepoetin doses increased the hematocrit, whereas MI+darb 0.75 did not increase EPC numbers or capillary density and had no functional effect. We found that chronic EPO treatment reduces MI size and improves cardiac function only at a dose that induces EPC mobilization in blood and that increases capillary density in the infarct border zone.

Topics: Animals; Cardiotonic Agents; Cell Differentiation; Dose-Response Relationship, Drug; Drug Administration Schedule; Endothelial Cells; Erythropoietin; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Stem Cells; Treatment Outcome; Ventricular Remodeling

Transplantation of marrow stromal cells (MSC) has been shown to improve heart perfusion and cardiac function after ischemia. Erythropoietin (EPO) is capable of inducing angiogenesis and inhibiting cell apoptosis. The aim of this study was to investigate the effect of EPO on the therapeutic potency of MSC transplantation in a rat model of myocardial infarction.. MSC viability was detected by MTT and flow cytometry following culture in serum-free medium for 24 h with or without EPO. Release of vascular endothelial growth factor (VEGF) by MSC incubated with different doses of EPO was assayed using ELISA. Immediately after coronary ligation, autologous MSC (3 x 10(6) cells) were injected into the ischemic myocardium (MSC and MSC-EPO groups). EPO (3,000 U/kg body weight) was injected daily for 3 consecutive days starting 1 day prior to ligation. The same EPO dose was also injected for consecutive 3 days starting 15 days after surgery (EPO and MSC-EPO groups). Control animals were injected saline solution for the same time period. Cardiac function was assessed by echocardiography 2 and 21 days after surgery, respectively. Western blot and immunohistological assessments were performed to examine the effects of treatments.. In vitro, EPO inhibited MSC apoptosis induced by serum-free medium and increased vascular endothelial growth factor (VEGF) release by MSC. In vivo, cardiac infarct size was significantly smaller, cardiac function significantly improved, and capillary density obviously higher in the MSC and EPO groups than in the control group. Combined treatment with EPO infusion and MSC transplantation demonstrated a further decrease in infarct size, a further improvement in cardiac function, and a further increase in capillary density compared with MSC or EPO alone. Furthermore, a higher ratio of phosphorylated Akt to total Akt was measured by Western blot; Bcl-2 was upregulated and Bax was downregulated by immunohistochemistry in the MSC-EPO group compared to the other three groups.. Transplantation of MSC combined with EPO infusion is superior to MSC monotherapy for angiogenesis and cardiac function recovery.

Topics: Angiogenesis Inducing Agents; Animals; Bone Marrow Cells; Bone Marrow Transplantation; Disease Models, Animal; Erythropoietin; Male; Myocardial Infarction; Rats; Rats, Wistar; Stromal Cells; Transplantation, Autologous

The aim of this work was to investigate the effects of different recombinant human erythropoietin (rhEPO) doses on the infarction development and if rhEPO could protect against the deleterious consequences induced by a previous intermittent hypoxia (IH, FiO(2) 5%, 4h). First, isolated rat hearts were submitted to an ischemia-reperfusion. rhEPO was infused before or after ischemia, at different doses. Secondly, rats were exposed to of IH. Twenty-four hours later, hearts underwent the ischemia-reperfusion protocol. For some hearts, 5Uml(-1) rhEPO was infused as previously. We observed that rhEPO has a dose-dependant effect on infarct size since it was significantly reduced by rhEPO infusions before or after ischemia. We also showed that 4h of IH induced a higher sensitivity to the infarction which was prevented by rhEPO. In conclusion, rhEPO administration before or after ischemia can protect isolated rat myocardium in a dose dependent manner and efficiently prevents the higher sensitivity to the infarction induced by previous intermittent hypoxia.

Topics: Animals; Coronary Circulation; Erythropoietin; Heart Diseases; Heart Rate; Hypoxia; In Vitro Techniques; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Wistar; Recombinant Proteins; Ventricular Function, Left

The usefulness of sustained-release erythropoietin for improving left ventricular (LV) function without polycythemia was evaluated in a rat chronic myocardial infarction model.. Four weeks after left coronary artery ligation, 50 Sprague-Dawley rats were assigned to 5 groups (n=10, each). Control group had a gelatin sheet (20x20 mm) containing saline applied to the infarct area, whereas the 4 treatment groups had gelatin sheets incorporating erythropoietin 0.1 U, 1 U, 10 U and 100 U, respectively. Endpoint measurements performed at 8 weeks after the coronary ligation revealed that the fractional area change was larger for erythropoietin 1 U and 10 U than in the other 3 groups. The LV end-systolic elastance and the time constant of isovolumic relaxation were better for erythropoietin 1 U and 10 U than in the other 3 groups. The density of vessels larger than 50 microm in diameter was the highest in the erythropoietin 1 U group. The number of red blood cells was significantly increased in groups receiving erythropoietin 10 U and 100 U.. Gelatin hydrogel sheets incorporating 1 U erythropoietin improved LV function without inducing polycythemia in a rat chronic myocardial infarction model.

Topics: Animals; Delayed-Action Preparations; Disease Models, Animal; Dose-Response Relationship, Drug; Echocardiography; Erythropoietin; Gelatin; Heart; Male; Myocardial Infarction; Neovascularization, Physiologic; Polycythemia; Rats; Rats, Sprague-Dawley; Ventricular Dysfunction, Left; Ventricular Remodeling

Topics: Animals; Cell- and Tissue-Based Therapy; Cholesterol, LDL; Coronary Disease; Endothelial Cells; Erythropoietin; Extremities; Fibroblast Growth Factor 2; Humans; Ischemia; Lipid Metabolism Disorders; Myocardial Infarction; Niacin; Probucol

We postulated that combining erythropoietin (EPO) infusion with bone marrow mesenchymal stem cells (MSC) delivery may give better prognosis in a rat infarcted heart. Acute myocardial infarction (MI) model was developed by coronary artery ligation. Animals were grouped (n=18) to receive intramyocardial injection of 30 microl saline solution without cells (EPO and control groups) or with 3x10(6) MSC from transgenic green fluorescent protein (GFP)+ male mice (MSC and MSC-EPO groups). The animals received either 5000 U/kg body weight EPO (EPO and MSC-EPO groups) or saline solution (MSC and control groups) for 7 days after MI. Cardiac functions were measured by echocardiography and cardiac tissue was harvested for immunohistological studies 3 weeks after surgery. We observed regeneration of MSC in and around the infarcted myocardium in MSC and MSC-EPO groups. Capillary density was markedly enhanced with significantly smaller infarct size and reduced fibrotic area in MSC-EPO group as compared with other three groups. A smaller left ventricular (LV) diastolic dimension and a higher LV fractional shortening were observed in MSC-EPO group than in other three groups. Transplantation of MSC combined with cytokine EPO is superior to either of the monotherapy approach for angiomyogenesis and cardiac function recovery.

Topics: Animals; Bone Marrow Transplantation; Capillaries; Cell Differentiation; Cells, Cultured; Combined Modality Therapy; Echocardiography; Erythropoietin; Female; Fibrosis; Injections, Intralesional; Male; Mesenchymal Stem Cell Transplantation; Mice; Myocardial Infarction; Neovascularization, Physiologic; Rats; Rats, Wistar

We studied plasma erythropoietin (EPO) levels and their relation with CD34(+)VEGFR-2(+) (mature and progenitor endothelial cells) and CD34(+) CD133(+)VEGFR-2(+), or CD34(+) CD117(+)VEGFR-2(+) (early/immature endothelial progenitors) cells in patients with acute myocardial infarction (AMI).. Fifty AMI patients undergoing percutaneous coronary intervention (PCI) within 6 h of symptom onset were enrolled. EPO, measured by ELISA, and cell subsets, by cytofluorimetric analysis, were evaluated before PCI, 24 h and 7 days afterwards. Forty-five healthy subjects (CTRLs) were studied. Plasma EPO levels were higher in AMI patients at admission, 24 h, and 7 days (P = 0.04, P = 0.0001, P = 0.001, respectively) than in CTRLs. No correlation was evidenced between EPO and haemoglobin (Hb) or haematocrit at admission or 24 h after AMI. Differently, both Hb and haematocrit inversely correlated with EPO at day 7 (P = 0.0016, P = 0.029, respectively). Plasma EPO levels correlated with CD34(+)CD133(+)VEGFR-2(+) cells at day 7 (P = 0.03).. AMI patients have increased plasma EPO levels until day 7. In the early phase, plasma EPO levels are Hb-independent; at day 7, an Hb-modulated increase of EPO correlates with the percentage of CD34(+)CD133(+)VEGFR-2(+) cells.

Topics: Acute Disease; Antigens, CD34; Coronary Angiography; Erythroid Precursor Cells; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hemoglobins; Humans; Male; Middle Aged; Myocardial Infarction; Prognosis; Prospective Studies; Risk Factors; Time Factors; Vascular Endothelial Growth Factor A

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

Erythropoietin is known to stimulate red cell production and has recently been shown to protect the heart against injury from ischemia/reperfusion. However, it is unknown whether darbepoetin alfa (Dpa), a long-acting analog of erythropoietin, can play a protective role against myocardial infarction. We assessed the potential protective role of Dpa in an in vivo rat model of myocardial ischemia/reperfusion and the underlying mechanisms. We found that a single intravenous Dpa treatment immediately before 30 minutes of regional ischemia reduced myocardial necrosis following 120 minutes of reperfusion in a dose-dependent manner. Optimal protection with Dpa against myocardial infarction was manifest at a dose of 2.5 microg/kg. Dpa conferred cardioprotection when administered after the onset of ischemia and at the start of reperfusion. Dpa (2.5 microg/kg) also reduced infarct size and Troponin I leakage 24 hours after reperfusion. Inhibition of p42/44 MAPK (PD98059), p38 MAPK (SB203580), mitochondrial ATP-dependent potassium (KATP) channels (5-HD), sarcolemmal KATP channels (HMR 1098), but not phosphatidylinositol-3 (PI3) kinase/Akt (Wortmannin and LY 294002) abolished Dpa-induced cardioprotection. Dpa confers immediate and sustained cardioprotection in rats, suggesting a potential therapeutic role of this long-acting erythropoietin analog for the treatment of acute myocardial infarction.

Topics: Animals; Cardiotonic Agents; Darbepoetin alfa; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Erythropoietin; Heart; Male; Mitogen-Activated Protein Kinase Kinases; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Potassium Channels; Rats; Rats, Sprague-Dawley

Erythropoietin (Epo) has anti-apoptotic and pro-angiogenic effects in rodent models of myocardial infarction (MI). We tested the hypothesis that a long-acting Epo derivative (darbepoetin) has a beneficial effect on infarct size and peri-infarct remodeling in a clinically relevant large animal model of ischemia-reperfusion. A human acute MI scenario was simulated in 16 domestic pigs by inflating an angioplasty balloon in the proximal left circumflex (LCx) artery for 60 min. The animals were randomized to darbepoetin 30 microg/kg i.v. or placebo (saline) at the time of reperfusion. Treatment with darbepoetin did not lead to a reduction in the infarct size at 2 weeks as assessed by histology (30.3+/-1.8% of the volume at risk for placebo vs. 33.2+/-2.5% for darbepoetin). However, significant effects were seen in the peri-infarct region. Histological evaluation revealed decreased interstitial fibrosis (6.8+/-0.7% of myocardial sections area vs. 9.6+/-0.7%, p=0.02) and increased average capillary area (106+/-3% of the non-infarcted myocardium vs. 89+/-4%, p=0.003) in the treatment arm in the absence of significant cardiac hypertrophy. This resulted in preserved regional wall motion as assessed by tissue Doppler-derived radial strain (subepicardial radial strain 90.1+/-21.2% for darbepoetin vs. 20.3+/-10.1% for placebo, p<0.05). However, this did not translate to improved wall thickening (126.5+/-6.0% of diastolic thickness for darbepoetin vs. 119.8+/-5.4% for placebo, p=NS). Beneficial effects of darbepoetin to peri-infarct remodeling were observed in a clinically relevant model of ischemia-reperfusion. Although the infarct size was not reduced, there was a limited decrease in interstitial fibrosis, increased capillary area and regional functional improvement in darbepoetin-treated animals.

Topics: Animals; Capillaries; Darbepoetin alfa; Disease Models, Animal; Echocardiography; Erythropoietin; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Receptors, Erythropoietin; Swine; Ventricular Remodeling

Topics: Acute Disease; Endothelium; Erythroid Precursor Cells; Erythropoietin; Humans; Myocardial Infarction; Prognosis; Time Factors

The benefits of skeletal myoblast transplantation are limited by the high rate of early cell death which is partly of ischemic origin. We, therefore, assessed whether graft survival could be improved by the additional use of the angiogenic cytokine erythropoietin (EPO). Thirty-five Lewis rats underwent coronary artery ligation and, two weeks later, were randomized to receive in-scar injections of control medium, skeletal myoblasts (5x10(6)) or skeletal myoblasts with EPO started the day before transplantation and continued for two weeks (500 U/kg three times a week). A fourth group was treated by EPO alone without injections. Function was assessed by 2D echocardiography before transplantation and one month thereafter. Compared with controls and hearts treated by EPO-alone, those transplanted with myoblasts yielded a significantly better recovery of LV ejection fraction, irrespective of whether they had received EPO or not. Neither the area of myoblast engraftment, nor angiogenesis differed between the myoblast-alone and the myoblast+EPO groups. Apoptosis was hardly detectable and, therefore, unaffected by EPO therapy. In this model, EPO failed to improve myoblast engraftment and postinfarction LV function. These negative findings justify to pursue the search for alternate cell survival-enhancing strategies.

Topics: Analysis of Variance; Animals; Apoptosis; Cell Survival; Cell Transplantation; Cells, Cultured; Echocardiography; Erythropoietin; Hematocrit; In Situ Nick-End Labeling; Myoblasts; Myocardial Infarction; Rats; Rats, Inbred Lew; Ventricular Function, Left

Topics: Animals; Apoptosis; Cell Survival; Cell Transplantation; Cells, Cultured; Echocardiography; Erythropoietin; Hematocrit; In Situ Nick-End Labeling; Myoblasts; Myocardial Infarction; Rats; Rats, Inbred Lew; Ventricular Function, Left

Topics: Animals; Apoptosis; Cell Survival; Cell Transplantation; Cells, Cultured; Echocardiography; Erythropoietin; Hematocrit; In Situ Nick-End Labeling; Myoblasts; Myocardial Infarction; Rats; Rats, Inbred Lew; Ventricular Function, Left

To evaluate the potential protective affects of Epo on left ventricular (LV) function and remodeling after acute myocardial infarction (MI).. Epo was injected into the peritoneum of male Wistar rats (250 g) during 6 weeks post induction of MI. Rats were divided into five groups: MI treated with single high dose (MT1, 5,000 U/kg, n=10), single high dose (5,000 U/kg) and repeated high doses (MTHi, 1,000 U/kg twice a week; n=8), or single high dose (5,000 U/kg) and repeated low doses (MTLo, 750 U/kg once a week, n=10), MI non-treated (MNT, n=10), sham (S, n=5). Echocardiography was performed 3.6+/-1.5 days and 43.7+/-2.3 days post MI. Collagen deposition and infarct size were measured on histological sections using computerized image analysis. Apoptosis was assessed by ApopTag staining.. Baseline fractional shortening (FS) was similar between groups. Six weeks after MI the FS of MTLo (26.9%) was significantly higher compared to MNT (17.8%), MT1 (19.5%) and MTH (22.3%) (p=0.01). However, remodeling indices (end diastolic and end systolic areas, LV circumference) did not improve in the Epo groups, and even worsened in the MTHi group. There was significantly less collagen staining in non-infarct areas in MT1 and MTHi groups compared to MNT and MTLo (0.38+/-0.3%, 0.49+/-0.34%, vs 0.89+/-0.41%, 0.95+/-0.33%, respectively, p<0.001). The number of ApopTag positive nucleus was significantly higher in the MNT group compared to the MT1, MTHi, MTLo groups (14.4+/-8, 7.6+/-4, 5.8+/-7, 4.8+/-5, respectively, p=0.01 for trend).. Repeated low doses of Epo after MI improved LV function, but the role of Epo on remodeling is not clear. It did not reduce left ventricular indices, but reduces fibrosis and apoptosis. High Epo doses reduced LV function and aggravated remodeling.

Topics: Acute Disease; Animals; Apoptosis; C-Reactive Protein; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Erythropoietin; Hemoglobins; Male; Myocardial Infarction; Rats; Rats, Wistar; Survival Rate; Ventricular Function, Left; Ventricular Remodeling

In view of the emerging role of recombinant human erythropoietin (rhEPO) as a novel therapeutical approach in myocardial ischemia, we performed the first two-way parallel comparison to test the effects of rhEPO pretreatment (1000 U/kg, 12h before surgery) versus EPO transgenic overexpression in a mouse model of myocardial infarction. Unlike EPO transgenic mice who doubled their hematocrit, rhEPO pretreated mice maintained an unaltered hematocrit, thereby offering the possibility to discern erythropoietic-dependent from erythropoietic-independent protective effects of EPO. Animals pretreated with rhEPO as well as EPO transgenic mice underwent permanent left anterior descending (LAD) coronary artery ligation. Resulting infarct size was determined 24h after LAD ligation by hematoxylin/eosin staining, and morphometrical analysis was performed by computerized planimetry. A large reduction in infarction size was observed in rhEPO-treated mice (-74% +/- 14.51; P = 0.0002) and an even more pronounced reduction in the EPO transgenic group (-87% +/- 6.31; P < 0.0001) when compared to wild-type controls. Moreover, while searching for novel early ischemic markers, we analyzed expression of hypoxia-sensitive Wilms' tumor suppressor gene (WT1) in infarcted hearts. We found that its expression correlated with the infarct area, thereby providing the first demonstration that WT1 is a useful early marker of myocardial infarction. This study demonstrates for the first time that, despite high hematocrit levels, endogenously overexpressed EPO provides protection against myocardial infarction in a murine model of permanent LAD ligation.

Topics: Animals; Biomarkers; Coronary Vessels; Disease Models, Animal; Erythropoietin; Hematocrit; Humans; Mice; Mice, Transgenic; Myocardial Infarction; Recombinant Proteins; WT1 Proteins

To study the cardioprotective effects of recombinant human erythropoietin (rhEPO) on heart with ischemia-reperfusion (I-R) injury and the possible mechanism.. 156 SD rats, except 36 in the sham operation group, underwent ligation of the left descending coronary artery for 30 minutes and then reperfusion for 3 hours. 108 rats were randomly divided into 3 equal groups IR + rhEPO group (Group C, intraperitoneally injected with rhEPO 5000 U/kg 24 h before IR insult), IR group (Group B), and sham-operation group (Group A). By the end of reperfusion blood sample were collected by cardiac puncture to detect the plasma content of MB isoenzyme of creatine kinase (CK-MB). Before ischemia, after ischemia, and 30, 60, 120, and 180 min after reperfusion the hearts of 6 rats from each group were killed respectively with their hearts taken out. Another 12 rats were randomly divided into Groups B and C as described above to undergo IR insult, and underwent re-ligation, intravenous injection of Evans blue and pathological examination to observe the area of infarct size. Another 18 rats were divided into 3 equal groups: Groups A, B, and C as described above, and then underwent electron microscopy to observe the ultrastructure of the myocardium. Furthermore, another 18 rats were divided into 3 equal groups: Groups A, B, and C as described above to undergo pathological examination of the heart and neutrophil infiltration. Tumor necrosis-alpha (TNF-alpha) and interleukin-6 (IL-6) concentrations of left ventricle were analyzed by ELISA 1 h and 2 h after reperfusion respectively; and nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) levels were detected by electrophoretic mobility shift assay.. The ratio of infarct size to area at risk (IS%) of Group C was (28.0% +/- 1.3%), significantly lower than that of Group B [(43.3 +/- 2.5)%, P < 0.01]. The plasma CK-MB concentrations of Groups B and C were (2110 +/- 245) U/L and (1689 +/- 138) U/L respectively, both significantly higher than that of Group A [(933 +/- 88) U/L, both P < 0.01], however, the CK-MB level of Group C was significantly lower than that of Group B (P < 0.01). The pathological changes of Group C were remarkably milder than those of Group B. The semi-quantitative scale of Groups B and C were 3.65 +/- 0.51 and 2.37 +/- 0.49 respectively, both significantly higher than that of Group A (1.76 +/- 0.43), and the semi-quantitative scale of Groups C was significantly lower than that of Group B (P < 0.01). The degree of neutrophil infiltration of Group C was remarkably milder than that of Group B. In Group B there were 2 peaks of NF-kappaB expression: 30 min and 180 min after reperfusion, and the AP-1 expression increased 30 min after reperfusion and then gradually decreased. In Group C the expression levels of NF-kappaB and AP-1 increased 30 min after reperfusion in comparison with Group A, and then gradually decreased and were all significantly lower than those of Group B (all P < 0.01). The levels of TNF-alpha and IL-6 1 h after reperfusion of Groups B and C were all significantly higher than those of Group A (all P < 0.01) and the TNF-alpha and IL-6 of Group C were both significantly lower than those of Group B (both P < 0.01).. RhEPO pretreatment can elicit potent cardioprotection against I-R injury, which may due in part to the suppression of NF-kappaB and AP-1 activation and downregulation of the downstream proinflammatory cytokines.

Topics: Animals; Erythropoietin; Humans; Ischemic Preconditioning, Myocardial; Male; Microscopy, Electron, Transmission; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; NF-kappa B; Random Allocation; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Tumor Necrosis Factor-alpha

Erythropoietin (EPO), originally known for its role in stimulation of erythropoiesis, has recently been shown to have a dramatic protective effect in animal models of myocardial ischemia-reperfusion (I-R) injury. However, the precise mechanisms remain unclear. We tried to study the anti-inflammatory properties of recombinant human erythropoietin (rhEPO) using an in vivo myocardial I-R rat model, which was established by 30 min ligation of left descending coronary and 3 h reperfusion. rhEPO or saline solution was intraperitoneally injected 24 h before I-R insult. The infarct size was measured by triphenyltetrazolium chloride (TTC)-Evans blue technique. Myeloperoxidase (MPO) activity and tissue neutrophil infiltration were studied. Ultrastructural organizations were observed and semiquantitatively evaluated. Tumor necrosis-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-10 concentrations of left ventricle were analyzed by enzyme-linked immunosorbance assays; intercellular adhesion molecule-1 (ICAM-1) by reverse-transcription polymerase chain reaction; and nuclear factor-kappa B (NF-kappaB) and activator protein 1 (AP-1) by electrophoretic mobility shift assay, respectively. We found that a single bolus injection of 5000 units/kg of rhEPO 24 h before insult remarkably reduced infarct size and neutrophil infiltration. It greatly attenuated I-R-induced NF-kappaB and AP-1 activation with decreased TNF-alpha, IL-6, and ICAM-1 production, but enhanced IL-10 production. In conclusion, the cardioprotection of EPO may be due in part to the suppression of the inflammatory response via down-regulation of NF-kappaB and AP-1 induced by I-R. IL-10 was also suggested to play a protective role through another independent mechanism involved in cardioprotection of rhEPO.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiotonic Agents; Disease Models, Animal; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Humans; Male; Mitochondria, Heart; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Neutrophil Infiltration; Nuclear Proteins; Peroxidase; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction

Postinfarct remodeling impairs mechanisms of ischemic preconditioning. We examined whether myocardial response to activation of the erythropoietin (EPO) receptor is modified by postinfarct remodeling. Four weeks after induction of myocardial infarction (MI) by coronary ligation in post-MI group (post-MI) or a sham operation in sham group (sham), rat hearts were isolated and subjected to 25-min global ischemia/2-h reperfusion. Infarct size was expressed as a percentage of risk area (i.e., left ventricle) from which scarred infarct was excluded (%I/R). The heart weight was 15% larger in post-MI, but there was no intergroup difference in plasma EPO levels or myocardial EPO receptor levels. EPO infusion (5 U/ml) significantly reduced %I/R from 59.9 +/- 4.1 to 36.2 +/- 4.2 in sham and from 58.1 +/- 5.0 to 35.2 +/- 4.0 in post-MI. This EPO-induced protection was sensitive to a phosphatidylinositol 3-kinase (PI3K) inhibitor, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), in sham. However, neither LY294002 nor wortmannin inhibited the EPO-induced protection in post-MI. Phosphorylation of Janus kinase 2 by EPO was attenuated and phosphorylation of Akt was not detected in post-MI. A guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one, and a mitochondrial ATP-sensitive K(+) channel (mitoK(ATP) channel) blocker, 5-hydroxydecanoate, inhibited EPO-induced protection in both sham and post-MI. Suppressor of cytokine signaling (SOCS)-1 protein level was higher by 50% in post-MI than in sham, although SOCS-3 levels were similar. These findings suggest that postinfarct remodeling disrupts cellular signaling from the EPO receptor to PI3K, presumably by increased SOCS-1. However, in the remodeled myocardium, lack of PI3K/Akt activation by the EPO receptor seems to be compensated by a mechanism upstream of the guanylyl cyclase-mitoK(ATP) channel pathway to achieve EPO-induced protection.

Topics: Animals; Blood Cell Count; Cardiotonic Agents; Disease Models, Animal; Erythropoietin; Hemodynamics; Humans; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; Recombinant Proteins; Ventricular Remodeling

Topics: Angioplasty, Balloon, Coronary; Erythropoietin; Hemoglobins; Humans; Myocardial Infarction

The cytokine erythropoietin protects the heart from ischaemic injury, in part by preventing apoptosis. But appropriate dose of erythropoietin for the protection of injured heart has not been studied. While we were researching the cardiac protective effects of erythropoietin in acute myocardial infarction, we experienced two cases of accidental nearly ten times overdose administration of erythropoietin up to 318,000 units instead of 33,000 units on the second day of three scheduled days of treatment. So a total of 384,000 units of erythropoietin were administered during three days. In case 1, the ALT level soared up to 386 U/l on the second day of administration and decreased slowly. It was back to normal state 3 months later. The AST level increased slowly up to 391 U/l and normalized 3 months later. Haemoglobin level was elevated up to 15.7 g/dl (14.7 g/dl at admission) and, 3 months later, normalized to 14.8 g/dl. In case 2, the ALT level was elevated up to 98 U/l on the second day of administration and decreased slowly. Three months later, the ALT level was normalized. The AST level also increased slowly up to 71 U/l and normalized 3 months later. Haemoglobin level was elevated up to 15.6 g/dl (13.8 g/dl at admission) and, 3 months later, normalized to 13.6 g/dl. In these two cases reported, these patients, even after massive overdose, tolerated it relatively well and the only side-effects we found were elevated liver enzyme and haemoglobin levels.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Drug Overdose; Erythropoietin; Hemoglobins; Humans; Liver; Male; Middle Aged; Myocardial Infarction; Recombinant Proteins

The aim of this study was to determine whether erythropoietin (EPO) affords additional cardioprotection to the preconditioned myocardium by enhanced phosphorylation of Akt, STAT3, or glycogen synthase kinase-3beta (GSK-3 beta). Preconditioning (PC) with 5-min ischemia/5-min reperfusion and EPO (5,000 U/kg iv) reduced infarct size (as % of area at risk, %IS/AR) after 20-min ischemia in rat hearts in situ from 56.5 +/- 1.8% to 25.2 +/- 2.1% and to 36.2 +/- 2.8%, respectively. PC-induced protection was significantly inhibited by a protein kinase C inhibitor, chelerythrine (5 mg/kg), and slightly blunted by a phosphatidylinositol-3-kinase inhibitor, wortmannin (15 microg/kg). The opposite pattern of inhibition was observed for EPO-induced protection. The combination of PC and EPO further reduced %IS/AR to 8.9 +/- 1.9%, and this protection was inhibited by chelerythrine and wortmannin. The additive effects of PC and EPO on infarct size were mirrored by their effects on the level of phosphorylated GSK-3 beta at 5 min after reperfusion but not their effects on the level of phospho-Akt or phospho-STAT3. To mimic phosphorylation-induced inhibition of GSK-3 beta activity, SB-216763 (SB), a GSK-3 beta inhibitor, was administered before ischemia or 5 min before reperfusion. Infarct size was significantly reduced by preischemic injection (%IS/AR = 40.4 +/- 2.2% by 0.6 mg/kg SB and 34.0 +/- 1.8% by 1.2 mg/kg SB) and also by prereperfusion injection (%IS/AR = 32.0 +/- 2.0% by 1.2 mg/kg SB). These results suggest that EPO and PC afford additive infarct size-limiting effects by additive phosphorylation of GSK-3beta at the time of reperfusion by Akt-dependent and -independent mechanisms.

Topics: Animals; Blotting, Western; Cardiotonic Agents; Erythropoietin; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hemodynamics; Ischemic Preconditioning, Myocardial; Male; Myocardial Infarction; Myocardium; Organ Size; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor

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; Immunohistochemistry; Mice; Myocardial Infarction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Erythropoietin (EPO) has been suggested to have a cardioprotective effect against ischemia. The purpose of this study was to examine the effects of EPO on cardiac remodeling after myocardial infarction (MI). MI was induced by ligation of the coronary artery in Wistar rats. The rats with MI were randomly divided into untreated MI and two EPO-treated MI groups. EPO was administered subcutaneously by injection once a day for 4 days after MI at 5000 U/kg or 3 times a week for 4 weeks at 1000 U/kg. Five days after MI, EPO prevented the increase in activated caspase 3, matrix metalloproteinase-2, and transcriptional activation of activator protein-1 in non-infarcted myocardium. Four weeks after MI, left ventricular weight, left ventricular end-diastolic pressure, and left ventricular dimension were increased, and ejection fraction and E wave deceleration time were decreased. EPO significantly attenuated this ventricular remodeling and systolic and diastolic dysfunction. In addition, EPO significantly attenuated the interstitial fibrosis and remodeling-related gene expression in non-infarcted myocardium. Furthermore, EPO significantly enhanced angiogenesis and reduced apoptotic cell death in peri-infarcted myocardium. In conclusion, when administered after MI, EPO prevents cardiac remodeling and improves ventricular function with enhanced angiogenesis and reduced apoptosis.

Topics: Animals; Apoptosis; Blotting, Northern; Blotting, Western; Caspase 3; Caspases; Disease Models, Animal; Echocardiography, Doppler; Erythropoietin; In Situ Nick-End Labeling; Male; Matrix Metalloproteinase 2; Myocardial Infarction; Myocardium; Rats; Rats, Wistar; Recombinant Proteins; Transcription Factor AP-1; Ventricular Function, Left; Ventricular Pressure; Ventricular Remodeling

High-dose erythropoietin has been claimed to be cardioprotective in experimental acute myocardial infarction. In large mammals, however, results are controversial and long-term follow-up data are lacking. We thus assessed the long-term effects of high-dose erythropoietin on left ventricular infarct size and function in an ovine model of reperfused myocardial infarction. After 90 minutes of coronary occlusion followed by reperfusion, sheep received recombinant human erythropoietin (rhEPO) 3000 units/kg on 3 consecutive days (rhEPO group, n=7) or vehicle (placebo group, n=6). Ten weeks later, ventricular function was assessed by echocardiography and catheterization. Infarct size, evaluated as percent fibrotic myocardium (morphometry) and by hydroxyproline quantification, was similar in both groups (morphometry: rhEPO: 22.1 +/- 5.5%, placebo: 18.1 +/- 3.3%, P not significant; hydroxyproline: rhEPO: 6.6 +/- 1.3 microg/mg wet weight, placebo: 7.1 +/- 0.9 microg/mg, P not significant). Ventricular function was diminished in the rhEPO group, as indicated by lower septal wall thickening at the infarct border zone (rhEPO: -1.9 +/- 16.4%, placebo: 20.5 +/- 17%, P<0.04), higher end systolic volume (rhEPO: 47 +/- 14.3 mL, placebo: 32.6 +/- 7.3 mL, P<0.05), and higher end diastolic pressure (rhEPO: 17 +/- 6.5 mm Hg, placebo: 10.1 +/- 2.8 mm Hg, P<0.03). In the rhEPO group, left ventricular endocardial area was larger, suggesting dilatation. High-dose erythropoietin has no cardioprotective effects in sheep with reperfused myocardial infarction.

Topics: Animals; Blood Circulation; Blood Pressure; Cardiac Output; Cardiotonic Agents; Erythropoietin; Heart Rate; Heart Ventricles; Hematocrit; Male; Myocardial Infarction; Myocardial Reperfusion; Recombinant Proteins; Sheep; Time Factors; Ventricular Function, Left

We investigated the effects of erythropoietin (EPO) on neovascularization and cardiac function after myocardial infarction (MI).. Erythropoietin exerts antiapoptotic effects and mobilizes endothelial progenitor cells (EPCs).. We intravenously administered EPO (1,000 IU/kg) immediately [EPO(0) group], 6 h [EPO(6h) group], or 1 week [EPO(1wk) group] after the permanent ligation of the coronary artery in dogs. Control animals received saline immediately after the ligation.. The infarct size 6 h after MI was significantly smaller in the EPO(0) group than in the control group (61.5 +/- 6.0% vs. 22.9 +/- 2.2%). One week after MI, the circulating CD34-positive mononuclear cell numbers in both the EPO(0) and the EPO(6h) groups were significantly higher than in the control group. In the ischemic region, the capillary density and myocardial blood flow 4 weeks after MI was significantly higher in both the EPO(0) and the EPO(6h) groups than in the control group. Four weeks after MI, left ventricular (LV) ejection fraction in the EPO(6h) (48.6 +/- 1.9%) group was significantly higher than that in either the control (41.9 +/- 0.9%) or the EPO(1wk) (42.6 +/- 1.2%) group but significantly lower than that in the EPO(0) group (56.1 +/- 2.3%). The LV end-diastolic pressure 4 weeks after MI in both the EPO(0) and the EPO(6h) groups was significantly lower than either the control or the EPO(1wk) group. Hematologic parameters did not differ among the groups.. In addition to its acute infarct size-limiting effect, EPO enhances neovascularization, likely via EPC mobilization, and improves cardiac dysfunction in the chronic phase, although it has time-window limitations.

Topics: Animals; Antigens, CD34; Capillaries; Coronary Circulation; Dogs; Erythropoietin; Hemodynamics; Leukocytes, Mononuclear; Myocardial Infarction; Neovascularization, Physiologic; Vascular Endothelial Growth Factor A; Ventricular Dysfunction, Left

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

Topics: Animals; Erythropoietin; Humans; Mice; Mice, Knockout; Myocardial Infarction; Myocardial Reperfusion Injury; Signal Transduction

Topics: Animals; Anti-Inflammatory Agents; Erythropoietin; Humans; Models, Animal; Myocardial Infarction; Myocardium; Recombinant Proteins; Signal Transduction

Systemic application of recombinant human erythropoietin (rhEPO) greatly limits cardiac tissue damage and attenuates left ventricular (LV) remodeling after experimentally induced myocardial infarction (MI). However, multiple injections of rhEPO stimulate red blood cell production and elevate the hematocrit (Htc), which might negatively affect the outcome of acute MI. We compared the outcome of experimental MI in rats treated with a single or multiple doses of rhEPO.. Sprague-Dawley male rats were subjected to a permanent ligation of the left descending coronary artery (CL) or sham operation. Immediately after CL animals received either a single i.v. injection of 3,000 IU/kg of rhEPO, or a single injection plus additional injections of the same dose of rhEPO repeated daily for six more days. Echocardiography and blood collection for measurement of Htc were performed prior to, and at 2 and 4 weeks after CL; MI size was measured histologically 4 weeks after CL.. A single injection of rhEPO elevated Htc by 11% (p < 0.05) 1 week after CL, but after multiple rhEPO injections Htc increased by 40%. In untreated rats a 140 and 340% expansion in end-diastolic and end-systolic LV volumes, respectively, and 55% decline in ejection fraction (EF) occurred during the 4 week period following CL. A single rhEPO dose attenuated the LV remodeling and EF reduction by 50%. Repeated rhEPO injections did not elicit any additional benefits in respect to LV remodeling. Moreover, at the end of 4 weeks, MI size was significantly reduced (by 40%) by a single injection, while after repeated rhEPO injections the reduction of MI size was not statistically significant.. The results of this study indicate that multiple dosing of rhEPO after induced myocardial infarction in rats has no added therapeutic benefits over those achieved by a single dose.

Topics: Animals; Cardiotonic Agents; Echocardiography; Erythropoietin; Heart Ventricles; Hematocrit; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Ventricular Remodeling

To observe the treatment and it's mechanisms of rHu-EPO on acute myocardial infarction of SD rats in vitro and vivo.. Cardiomyocytes were isolated from neonatal Sprague-Dawley rats. Hypoxia condition and oxidative stress were used to induce apoptosis. rHu-EPO was added to the culture system. Apoptosis was assessed by using Hoechst 33258 dyeing. Apoptosis index (AI) was then calculated. Thirty two rats were divided into three groups including sham operation group (Sham), acute myocardial infarction group (MI) and treated group (MI + EPO). Acute myocardial infarction model was made by ligating the anterior descending coronary artery. rHu-EPO was administered i.p. in MI + EPO group at the dose of 5000 units/kg of body weight immediately after the ligation and the next six days. At the fourteenth day all animals underwent hemodynamic measurements and then executed, the samples were examined with hematoxylin and eosin (HE) stain, immunohistochemistry technique (Bcl-2, Bax) and TdT-mediated dUTP nick end labeling (TUNEL) dyeing.. rHu-EPO significantly down-regulated the apoptosis of cardiomyocytes which underwent hypoxia or oxidative stress. In vivo experiment rHu-EPO protected the hemodynamic function of the rats from myocardial infarction and down-regulated the ratio of the positive cells for TUNEL and Bax. The ratio of the positive cells for Bcl-2 was up-regulated by rHu-EPO.. These findings suggested rHu-EPO improve myocardial infarction by attenuating apoptosis. Potential mechanism is to up-regulated Bcl-2 expression and down-regulated Bax expression.

Topics: Animals; Animals, Newborn; Apoptosis; Cell Hypoxia; Cells, Cultured; Disease Models, Animal; Erythropoietin; Humans; In Situ Nick-End Labeling; Injections, Intraperitoneal; Male; Myocardial Infarction; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Erythropoietin (EPO) induces angiogenesis and inhibits apoptosis through the phosphatidylinositol-3-kinase/Akt (PI3-K/Akt) pathway. Transplantation of mesenchymal stromal cells (MSC) has been shown to improve heart perfusion and function post myocardial ischemia. We investigated whether EPO enhances the therapeutic potency of MSC transplantation in rats with experimental myocardial infarction (MI).. Wistar rats were divided into four groups (n=8 each): myocardial infarction (MI) group, EPO group, MSC group and MSC-EPO group. MI was made by ligating the anterior descending coronary artery. MSC was injected in the infarcted area immediately after ligation in MSC group and MSC-EPO group. EPO (3000 U/kg) was administered i.p. in EPO group and MSC-EPO group for 3 days post MI and on the 14th to 16th day post MI. Cardiac function was measured by echocardiography at 2 and 21 days after MI. MI size was measured, and the level of phosphorylated Akt was assessed by Western blot and immunohistology at 21 days post MI.. LVEF was significantly lower at 21 days than that at 2 days in MI group while significantly increased in other 3 groups, especially in MSC-EPO group at 21 days than that at 2 days. MI size was significantly lower (20.7%+/-2.3% vs. 24.0%+/-2.3%, 26.0%+/-0.9%, 28.1%+/-1.5%, all P<0.05), capillary density was significantly higher (12.95+/-2.11 vs. 10.78+/-0.99, 10.43+/-1.52 and 6.31+/-0.69, all P<0.05) in MSC-EPO group at 21 days than that in other groups and the ratio of phosphorylated Akt to total Akt measured by Western blot was also significantly higher in MSC-EPO group than other groups (0.36 vs. 0.32, 0.31 and 0.28, all P<0.05). Compared to other groups, Bcl-2 was significantly up-regulated and Bax down-regulated in MSC-EPO group.. Our results demonstrated that MSC transplantation and EPO infusion could improve cardiac function and EPO enhances the therapeutic potency of MSC transplantation via PI3-K/Akt pathways.

Topics: Animals; Bone Marrow Transplantation; Erythropoietin; Male; Mesenchymal Stem Cell Transplantation; Myocardial Infarction; Neovascularization, Pathologic; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar

We investigated whether a higher serum erythropoietin (EPO) level in patients with acute myocardial infarction (MI) subjected to successful primary percutaneous coronary intervention (PCI) can predict a smaller infarct size determined by creatine kinase (CK) release.. Erythropoietin has been shown to protect cardiomyocytes from ischemia-reperfusion injury in rodents.. We prospectively studied 101 patients with first MI who received successful primary PCI within 12 h from the onset of MI. Blood samples were collected to examine the serum EPO level after the primary PCI and within 24 h from the onset of MI.. The peak CK level and cumulative CK release were significantly lower in the above-median EPO group than in the below-median EPO group. Thrombolysis In Myocardial Infarction (TIMI) grades and collateral grades before PCI, infarct-related coronary arteries, time to the successful reperfusion from the onset of MI, and serum creatinine levels were similar in the two EPO groups. A stepwise multiple regression analysis revealed that the absolute serum EPO level (mU/ml) as well as TIMI grades after PCI and preinfarction angina was an independent predictor for the cumulative CK release.. These data suggest that a high endogenous EPO level can predict a smaller infarct size in patients with acute MI subjected to successful primary PCI. This might be attributed to the potentially protective effect of endogenous EPO against ischemia-reperfusion injury in humans.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Angiography; Creatine Kinase; Erythropoietin; Female; Humans; Linear Models; Male; Myocardial Infarction; Natriuretic Peptide, Brain; Postoperative Period; Predictive Value of Tests; Prospective Studies

Although recent studies suggest that erythropoietin (EPO) may reduce multiple features of the myocardial ischemia/reperfusion injury, the cellular mechanisms and the clinical implications of EPO-induced cardioprotection are still unclear. Thus, in this study, we clarified dose-dependent effects of EPO administered just before reperfusion on infarct size and the incidence of ventricular fibrillation and evaluated the involvement of the phosphatidylinositol-3 (PI3) kinase in the in vivo canine model. The canine left anterior descending coronary artery was occluded for 90 min followed by 6 h of reperfusion. A single intravenous administration of EPO just before reperfusion significantly reduced infarct size (high dose (1,000 IU/kg): 7.7 +/- 1.6%, low dose (100 IU/kg): 22.1 +/- 2.4%, control: 40.0 +/- 3.6%) in a dose-dependent manner. Furthermore, the high, but not low, dose of EPO administered as a single injection significantly reduced the incidence of ventricular fibrillation during reperfusion (high dose: 0%, low dose: 40.0%, control: 50.0%). An intracoronary administration of a PI3 kinase inhibitor, wortmannin, blunted the infarct size-limiting and anti-arrhythmic effects of EPO. Low and high doses of EPO equally induced Akt phosphorylation and decreased the equivalent number of TUNEL-positive cells in the ischemic myocardium of dogs. These effects of EPO were abolished by the treatment with wortmannin. In conclusion, EPO administered just before reperfusion reduced infarct size and the incidence of ventricular fibrillation via the PI3 kinase-dependent pathway in canine hearts. EPO administration can be a realistic strategy for the treatment of acute myocardial infarction.

Topics: Animals; Apoptosis; Blood Cell Count; Cardiotonic Agents; Coronary Circulation; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Erythropoietin; Humans; In Situ Nick-End Labeling; Myocardial Infarction; Myocardial Reperfusion; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Recombinant Proteins; Ventricular Fibrillation

The mechanisms of rHu-EPO attenuating the apoptosis after myocardial infarction in rats were studied. Thirty-two rats were divided into three groups: sham operation group (Sham), acute myocardial infarction group (MI) and rHu-EPO-treated group (MI+ EPO). Acute myocardial infarction model was made by ligating the anterior descending coronary artery. rHu-EPO was administered i. p. in MI+EPO group at the dose of 5 000 IU/kg body weight immediately after the ligation. Each rat in MI+EPO group received the same dose of rHu-EPO daily the next 6 days. On the 14th day all rats underwent hemodynamic measurements and then killed. The samples were examined with HE stain, immunohistochemistry technique (bcl-2, bax) and TUNEL dyeing. The results showed that hemodynamic function in MI+ EPO group was much better than in MI group. The number of the cells positive for bax and TUNEL in MI+ EPO group was less than that in MI group. The number of the cells positive for bcl-2 in MI+ EPO group was more than that in MI group. These findings suggested that rHu-EPO could treat myocardial infarction by preventing apoptosis and attenuating post-infarction deterioration in hemodynamic function.

Topics: Animals; Apoptosis; Erythropoietin; Male; Myocardial Infarction; Myocytes, Cardiac; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Ventricular Function

Erythropoietin (EPO), known for its role in stimulating erythropoiesis, has recently been shown to have a cardio-protective effect in animal models of myocardial ischemia-reperfusion (I-R) injury. The mechanism of the cardio-protective effect of EPO is unclear. Part of the mechanism for EPO-induced cardio-protection may involve inhibition of myocardial apoptosis and preservation of ATP levels in the ischemic myocardium. We studied the expression of heat shock protein 70 (Hsp70) and its possible links to the cardio-protective effect of EPO. A rat model of myocardial I-R injury was established by ligating the left descending coronary artery for 30 min and then reperfusing for 2 hr. Recombinant human EPO (rhEPO) was injected ip 24 hr before the ligation. The myocardial infarct size and the area at risk of ischemia were measured by staining with triphenyltetrazolium chloride (TTC) and Evans blue dye. Expression of Hsp70 in the left ventricle was analyzed by ELISA and that of nuclear factor-kappaB (NF-kappaB) was analyzed by electrophoretic mobility shift assay (EMSA). The results showed that a single ip injection of 3,000 units/kg of rhEPO at 24 hr pre-ligation enhanced the expression of Hsp70 and diminished the expression of NF-kappaB in rat myocardium, and that the myocardial infarct induced by I-R injury was remarkably reduced in size, compared to control rats that received an ip saline injection at 24 hr pre-ligation.

Topics: Animals; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Erythropoietin; HSP70 Heat-Shock Proteins; Humans; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; NF-kappa B; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Erythropoietin (EPO) is a hormone that is currently used to treat patients with renal failure and anaemia. However, it has also been shown to protect against ischaemia/reperfusion injury; this protection occurring via activation of the ERK 1/2 and PI3K pathways. Since we have previously shown activation of ERK 1/2 and PI3K to be important for protection against reperfusion-induced injury in the myocardium, this study was designed to investigate its effect in the myocardium using both an isolated perfused rat heart and an in vivo rat recovery model of ischaemia-reperfusion.. Using an in vitro isolated rat heart model of 35 minutes ischaemia and 2 hours reperfusion, EPO (50 ng/ml) was administered to the rat myocardium 5 minutes prior to reperfusion for 20 minutes. The in vivo open-chest rat model consisted of 40 minutes ischaemia followed by 24 hours reperfusion with EPO (5000 U/kg) being administered at the point of reperfusion.. In the isolated perfused heart studies 50 ng/ml EPO was found to provide protection with a % I/R of 22.9% +/- 6.4 vs 54.5% +/- 7.4 for the ischaemic control group. To examine the mechanistic pathways involved in EPO-mediated protection, we co-administered the ERK 1/2 inhibitor, U0126 (10 uM) or the PI3K inhibitors, wortmannin, (100 nM) and LY294002 (15 microM) at reperfusion. U0126, wortmannin and LY294002 all abrogated EPO-mediated protection (% I/R 49.2% +/- 5.6, 46.1% +/- 5.5 and 49.9% +/- 6.1 respectively, p < 0.05). In the in vivo open-chest rat model, the % I/R was significantly attenuated in EPO-treated animals from 53.6 % +/- 3.7 in the control to 32.5% +/- 2.9 (p < 0.05). Likewise, wortmannin abrogated EPO-mediated protection (% I/R 50.7 +/- 2.3 v EPO 32.5% +/- 2.9, p < 0.05).. We demonstrate that EPO, administered at the point of reperfusion, reduced infarct size in an isolated perfused rat heart, in an ERK and PI3K dependent manner; in addition the mechanism was also confirmed in a whole animal model of ischaemia-reperfusion. These results suggest that EPO may be able to directly protect the myocardium against lethal reperfusion-induced injury and so offer the myocardium an additional clinical advantage over and above its ability to improve the oxygen carrying capacity of the blood.

Topics: Animals; Erythropoiesis; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; In Vitro Techniques; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Phosphatidylinositol 3-Kinases; Rats; Rats, Sprague-Dawley

Langendorff-perfused rat hearts treated with EPO exhibited significantly improved postischemic recovery of left ventricular developed pressure (LVDP) and reduced infarct size compared with control hearts. Perfusion with the mitogen/extracellular signal-regulated kinase (MEK) inhibitor U0126 just before and concomitant with EPO treatment abolished EPO-induced phosphorylation of the MEK substrate extracellular signal-regulated kinase (ERK) but had no effect of EPO-mediated cardioprotection. EPO treatment of the perfused hearts induced translocation of protein kinase C (PKC) epsilon isoform to the membrane fraction of the hearts and the protective effect of EPO was significantly inhibited by the PKC catalytic inhibitor chelerythrine added before and concomitant with EPO. These data demonstrate that EPO-mediated activation of the PKC signaling pathway before or during ischemia is required for the cardioprotective effect of EPO during ischemia-reperfusion injury. Perfusion with the phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 or wortmannin just before and concomitant with EPO treatment attenuated EPO-induced phosphorylation of the PI3K substrate Akt but had no effect on EPO-mediated cardioprotection. However, when wortmannin was added during EPO treatment and continued during reperfusion, EPO-mediated cardioprotection was significantly inhibited. We also show that postischemia EPO treatment at the onset of reperfusion significantly improved recovery of LVDP and reduced infarct size. Postischemia cardioprotection by EPO required the PI3K pathway but was not affected by inhibition of PKC at the time of EPO treatment.

Topics: Alkaloids; Androstadienes; Animals; Benzophenanthridines; Chromones; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; Male; Morpholines; Myocardial Infarction; Myocardial Reperfusion Injury; Phenanthridines; Phosphatidylinositol 3-Kinases; Protein Kinase C; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Signal Transduction; Ventricular Function, Left; Wortmannin

We assessed the effects of erythropoietin (EPO) treatment in a rat model of post-myocardial infarction (MI) heart failure.. Erythropoietin, traditionally known as a hematopoietic hormone, has been linked to neovascularization. Whereas administration of EPO acutely after MI reduces infarct size and improves cardiac function, its role in the failing heart is unknown.. Rats underwent coronary ligation or sham surgery. Rats with MI were randomly assigned to: untreated (MI), a single bolus of EPO immediately after MI induction (MI-EPO-early), EPO treatment immediately after MI and once every three weeks (MI-EPO-early+late), and EPO treatment starting three weeks after induction of MI, once every three weeks (MI-EPO-late). After nine weeks, hemodynamics, infarct size, myosin heavy chain (MHC) isoforms, myocyte hypertrophy, and capillary density were measured.. Erythropoietin treatment started immediately after MI (MI-EPO-early and MI-EPO-early+late) resulted in a 23% to 30% reduction in infarct size (p < 0.01) and, accordingly, hemodynamic improvement. Erythropoietin treatment, started three weeks after MI (MI-EPO-late), did not affect infarct size, but resulted in an improved cardiac performance, reflected by a 34% reduction in left ventricular end-diastolic pressure (p < 0.01), and 46% decrease in atrial natriuretic peptide levels (p < 0.05). The improved cardiac function was accompanied by an increased capillary density (p < 0.01), an increased capillary-to-myocyte ratio (p < 0.05), and a partial reversal of beta-MHC (p < 0.05) in all treated groups.. In addition to its effect on infarct size reduction, EPO treatment improves cardiac function in a rat model of post-MI heart failure. This observation may be explained by neovascularization, associated with an increased alpha-MHC expression.

Topics: Animals; Atrial Natriuretic Factor; Cardiac Output; Cardiomyopathy, Dilated; Coronary Vessels; Darbepoetin alfa; Disease Models, Animal; Drug Administration Schedule; Erythropoietin; Male; Myocardial Infarction; Myosin Heavy Chains; Neovascularization, Physiologic; Rats; Rats, Sprague-Dawley

Erythropoietin (epo), initially recognized and used clinically to increase erythropoiesis, has been shown to have beneficial effects on various other tissues in the setting of hypoxia and ischemia. Epo has been shown to reduce apoptosis after myocardial infarction, but few studies have evaluated the long-term effects of epo treatment on left ventricular (LV) remodeling, cardiac function, and blood flow after healing of a permanent coronary artery occlusion. The aim of this study was to assess the effects of epo treatment on the healed heart 6 weeks after myocardial infarction. Anesthetized rats underwent coronary artery occlusion and were treated with erythropoietin (5000 units/kg/day, n=21) or saline (n=20) the day before surgery, the day of, then for 5 days. At 6 weeks LV ventriculography to assess LV volumes and ejection fractions and histologic assessment of infarct size and LV cavity and wall dimensions were performed. Overall epo had no effect on LV remodeling or cardiac function. There were no significant differences in infarct morphology, infarct size (44+/-3% of the LV circumference versus 39+/-3%), LV cavity area, scar thickness, LV systolic volume, or ejection fraction (44+/-3% versus 39+/-3%) between the epo and saline groups, respectively. However, for any given size of myocardial infarct, LV ejection fraction was significantly higher in erythropoietin hearts and LV systolic volumes lower. Thus, in our model, treatment with epo had no long-term beneficial effect on LV remodeling after myocardial infarction but may have exerted some positive effect on LV function.

Topics: Animals; Coronary Circulation; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Female; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Time Factors; Treatment Failure; Ventricular Function, Left; Ventricular Remodeling

Recombinant human erythropoietin (rhEPO) has been proposed to possess important tissue protective, apart from haematopoietic, effects. Cardioprotective effects have thus been reported in rodents exposed to myocardial ischaemia. Pathways common to the mediation of ischaemic preconditioning may be involved. Before clinical testing such possible cardioprotective effects needs assessment in an experimental large animal model with closer similarity to human ischaemic pathophysiology.. A control group and two rhEPO groups were studied. EPO1 pigs were given EPO corresponding to the early window and EPO2 pigs to the early and late window of ischaemic preconditioning in a closed chest, catheter-based, porcine coronary occlusion model (45 min of occlusion of the left anterior descending artery). Infarct size as a proportion of the ischaemic area (IS/AAR) was measured in vivo by myocardial perfusion imaging (MPI) and postmortem by a histochemical procedure (at 150 min of reperfusion).. IS/AAR did not differ significantly between control (C), EPO1 and EPO2 groups, neither measured by MPI (mean+/-SD for C: 0.87+/-0.13; EPO1: 0.92+/-0.08; EPO2: 0.87+/-0.11), nor histochemically (mean+/-SD for C: 0.64+/-0.20; EPO1: 0.75+/-0.17; EPO2: 0.80+/-0.07). In the EPO2 group mean arterial pulmonary pressure and dP/dtmax were increased compared with control group.. Despite promising results from studies in rodents, rhEPO did not reduce infarct size measured after 2.5 h of reperfusion in our porcine model.

Topics: Animals; Blood Pressure; Cardiac Output; Cardiotonic Agents; Coronary Stenosis; Disease Models, Animal; Erythropoietin; Myocardial Infarction; Myocardial Ischemia; Recombinant Proteins; Swine; Tomography, Emission-Computed, Single-Photon

Recombinant human erythropoietin (rhEPO) protects tissue from ischemic damage, but translation of this finding into useful guidelines with respect to human trials for myocardial infarction (MI) requires a determination of the minimum effective rhEPO dose and the therapeutic window following MI.. Serial echocardiography revealed that during four weeks following MI, induced by a permanent coronary ligation in rats, the LV end-diastolic and end-systolic volumes in untreated rats expanded from 0.35 +/- 0.01 and 0.14 +/- 0.01 ml to 0.84 +/- 0.04 and 0.61 +/- 0.06 ml, respectively, and ejection fraction (EF) reduced by 50%. A single i.v. injection of rhEPO immediately following MI in a dose of 150 IU/kg was as effective as 3,000 IU/kg in causing a 2-fold reduction of the number of apoptotic nuclei in the AAR 24-h later, a 2-fold reduction of the MI size measured 4 weeks later, attenuation of progressive LV dilatation and fall in EF. A 3000 IU/kg dose had similar therapeutic effects when delayed by 4, 8, or 12 h following MI, but was not effective after a 24-h delay. A single dose of 150 IU/kg was effective within 4 h post-MI, but was without effect if administered after an 8-h delay.. Cell death, final MI size, myocardial remodeling and functional decline are significantly reduced in rats by a single injection of rhEPO in a dose as low as 150 IU/kg if administered during the first 4 h after the ischemic event. Higher doses extend the therapeutic window up to 12 h.

Topics: Animals; Apoptosis; Cardiotonic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Echocardiography; Erythropoietin; Humans; Male; Myocardial Infarction; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Recombinant Proteins

It has been well established that erythropoietin (EPO) can limit myocardial ischemia/reperfusion injury in a variety of acute settings. However, despite EPO being used chronically to treat anemia the infarct limiting effects of long term treatment (chronic) have never been fully investigated. In this study we examined the effects of a 3 week treatment of EPO (5,000 IU/Kg) in male Sprague Dawley rats in limiting myocardial infarction after 35 min ischemia and 2 h reperfusion in an in vitro isolated heart perfusion model. Treating the animals 'once a week' failed to limit infarct size significantly compared to a saline control (54.1% +/- 3.5 v 52.3% +/- 4.4), whereas a '3 times a week' regime succeeded in significantly reducing infarct size (36.2% +/- 3.2 v 52.3% +/- 4.4, p < 0.05). To demonstrate that the effect was not due to improved oxygen supply caused by a raised hematocrit level, we also administered EPO 24 h prior to ischemia/reperfusion. This treatment again reduced infarct size compared to a saline control (39.9% +/- 4.4 v 58.4% +/- 5.0, p < 0.05). To examine the mechanism of protection we used the PI3K inhibitor wortmannin and the nitric oxide synthase inhibitor L-NAME to try to abrogate EPO mediated protection. Where wortmannin failed to block the effects of EPO (31.7% +/- 6.0 v 36.2% +/- 3.2), L-NAME did abrogate protection (51.6% +/- 5.6 v 36.2% +/- 3.2, p < 0.05). We demonstrate that chronic EPO treatment limits infarct size and that it does so in a nitric oxide dependent manner.

Topics: Animals; Cardiotonic Agents; Drug Administration Schedule; Enzyme Inhibitors; Erythropoietin; Heart; Hematocrit; In Vitro Techniques; Male; Models, Animal; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Perfusion; Rats; Rats, Sprague-Dawley

Topics: Acute Disease; Coronary Artery Disease; Erythropoietin; Humans; Insulin-Like Growth Factor I; Kidney Diseases; Myocardial Infarction; Myocardial Ischemia; Syndrome

Erythropoietin (EPO) is a hormone known to stimulate hematopoiesis. However, recent research suggests additional properties of EPO, such as protection against ischemia/reperfusion (I/R) injury in various tissues. We studied the effect of timing of EPO administration on cardioprotection during I/R in the heart. Male Sprague-Dawley rats were subjected to 45 minutes of coronary occlusion, followed by 24 hours of reperfusion. Animals were randomized to receive saline or single dose of EPO (5,000 IU/kg) either 2 hours before I/R, at the start of ischemia, or after the onset of reperfusion. The ratio of infarct area/area at risk (planimetry), left ventricular (LV) function (pressure development), and apoptosis (number of active caspase-3 positive cells) were determined after 24-hour reperfusion. Administration of EPO during different time points resulted in a 19 to 23% (P < 0.05) reduction in the infarct area/area at risk, which was accompanied by a trend toward better LV hemodynamic parameters. Apoptosis was significantly attenuated in groups treated with EPO at the start of ischemia (29% reduction) and after the onset of reperfusion (38%), and to a lesser extent (16%) in the group pre-treated with EPO. Thus, in vivo administration of EPO at different time points protects the myocardial structure and preserves cardiac function during I/R. Cardioprotective effect of EPO is associated with inhibition of apoptosis.

Topics: Animals; Apoptosis; Cardiotonic Agents; Cell Proliferation; Drug Administration Schedule; Erythropoietin; Hemodynamics; Ki-67 Antigen; Male; Myocardial Infarction; Myocytes, Cardiac; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Time Factors; Ventricular Function, Left

Erythropoietin (EPO), originally identified for its critical hormonal role in promoting erythrocyte survival and differentiation, is a member of the large and diverse cytokine superfamily. Recent studies have identified multiple paracrineautocrine functions of EPO that coordinate local responses to injury by maintaining vascular autoregulation and attenuating both primary (apoptotic) and secondary (inflammatory) causes of cell death. Experimental evidence also supports a role for EPO in repair and regeneration after brain and spinal cord injury, including the recruitment of stem cells into the region of damage. Tissue expression of the EPO receptor is widespread, especially during development, and includes the heart. However, it is currently unknown as to whether EPO plays a physiological function in adult myocardial tissue. We have assessed the potential protective role of EPO in vitro with adult rat cardiomyocytes, and in vivo in a rat model of myocardial infarction with reperfusion. The results show that EPO markedly prevents the apoptosis of cultured adult rat myocardiocytes subjected to 28 h of hypoxia (approximately 3% normal oxygen). Additional studies employing a rat model of coronary ischemia-reperfusion showed that the administration of recombinant human EPO (5,000 units/kg of body weight; i.p. daily for 7 days) reduces cardiomyocyte loss by approximately 50%, an extent sufficient to normalize hemodynamic function within 1 week after reperfusion. These observations not only suggest a potential therapeutic role for recombinant human EPO in the treatment of myocardial ischemia and infarction by preventing apoptosis and attenuating postinfarct deterioration in hemodynamic function, but also predict that EPO is likely a tissue-protective cytokine in other organs as well.

Topics: Acidosis; Animals; Apoptosis; Cell Hypoxia; Erythropoietin; Hemodynamics; Humans; In Vitro Techniques; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Erythropoietin (EPO), well known for its role in stimulation of erythropoiesis, has recently been shown to have a dramatic neuroprotective effect in animal models of cerebral ischemia, mechanical trauma of the nervous system, and excitotoxins, mainly by reducing apoptosis. We studied the effect of single systemic administration of recombinant human EPO (rhEPO) on left ventricular (LV) size and function in rats during 8 weeks after the induction of a myocardial infarction (MI) by permanent ligation of the left descending coronary artery. We found that an i.p. injection of 3,000 units/kg of rhEPO immediately after the coronary artery ligation resulted, 24 h later, in a 50% reduction of apoptosis in the myocardial area at risk. Eight weeks after the induction of MI, rats treated with rhEPO had an infarct size 15-25% of the size of that in untreated animals. The reduction in myocardial damage was accompanied by reductions in LV size and functional decline as measured by repeated echocardiography. Thus, a single dose of rhEPO administered around the time of acute, sustained coronary insufficiency merits consideration with respect to its therapeutic potential to limit the extent of resultant MI and contractile dysfunction.

Topics: Animals; Apoptosis; Coronary Vessels; Echocardiography, Doppler; Erythropoietin; Heart Ventricles; Hematocrit; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Erythropoietin (EPO) has been shown to protect neurons from ischemic stroke, but can also increase thrombotic events and mortality rates in patients with ischemic heart disease. We reasoned that benefits of EPO might be offset by increases in hematocrit and evaluated the direct effects of EPO in the ischemic heart. We show that preconditioning with EPO protects H9c2 myoblasts in vitro and cardiomyocytes in vivo against ischemic injury. EPO treatment leads to significantly improved cardiac function following myocardial infarction. This protection is associated with mitigation of myocyte apoptosis, translating into more viable myocardium and less ventricular dysfunction. EPO-mediated myocyte survival appears to involve Akt activation. Importantly, cardioprotective effects of EPO were seen without an increase in hematocrit (eliminating oxygen delivery as an etiologic factor in myocyte survival and function), demonstrating that EPO can directly protect the ischemic and infarcted heart.

Topics: Animals; Apoptosis; Cell Line; Erythropoietin; In Situ Nick-End Labeling; Mitogen-Activated Protein Kinases; Myocardial Infarction; Phosphatidylinositol 3-Kinases; Protective Agents; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats

The von Hippel-Lindau (VHL) tumor suppressor gene targets hypoxia-inducible transcription factors (HIFs) for proteasomal degradation. Erythrocytosis due to inappropriate production of erythropoietin (EPO), one of the HIF target genes, is a classic albeit rare finding in patients with renal cancer. We report the clinical to molecular analysis in a patient in whom a thrombotic myocardial infarction was the first manifestation of a clear cell renal carcinoma associated with an elevated serum EPO level (109 U/L) and erythrocytosis (hemoglobin 200 g/L [20 g/dL]). The tumor strongly expressed EPO messenger RNA and the 2 regulatory subunits HIF-1alpha and HIF-2alpha. Sequence analysis of tumor tissue identified a point mutation of the VHL gene (nucleotide 701 T > C) with a predicted amino acid exchange (Leu163Pro). This structural change, although located at distance to the HIF-binding region, was found to inhibit binding of HIF-1alpha to VHL, thus leading to accumulation of HIF, which drives EPO production.

Topics: Carcinoma, Renal Cell; Erythropoietin; Genes, Tumor Suppressor; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Neoplasms; Ligases; Male; Middle Aged; Myocardial Infarction; Point Mutation; Polycythemia; RNA, Messenger; Tomography, X-Ray Computed; Transcription Factors; Tumor Cells, Cultured; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; Von Hippel-Lindau Tumor Suppressor Protein

Myocardial infarction (MI) complicating pregnancy in a renal transplant recipient is described. Management challenges of MI in pregnancy and the possible predisposing roles of renal transplantation and erythropoietin (EPO) use are discussed.

Topics: Adult; Coronary Angiography; Electrocardiography; Erythropoietin; Female; Humans; Kidney Transplantation; Myocardial Infarction; Pregnancy; Pregnancy Complications, Cardiovascular

Peripheral vascular disease is a serious and frequent problem in diabetic patients. Since the beginning of the widespread use of erythropoietin (EPO), we have noted an increase in peripheral vascular disease in diabetic patients receiving peritoneal dialysis and erythropoietin. This prompted us to study the effects of erythropoietin on peripheral vascular disease in patients receiving peritoneal dialysis. We retrospectively reviewed medical records of all diabetic patients in our program who received peritoneal dialysis from 1990 to 1996. Demographic and laboratory data as well as EPO use data were collected. Hospital days and occurrence of vascular events (defined as peripheral vascular surgery, amputation, or recommendation of vascular surgery or amputation by a vascular surgeon) were determined for diabetic patients receiving peritoneal dialysis. Comparisons were made between those who received EPO and those who did not received EPO, as well as comparing vascular events in 28 patients who received peritoneal dialysis before and after beginning EPO. Patients who received erythropoietin were found to have a significantly shorter time to a first vascular event, a greater number of vascular events, and more hospital days associated with vascular disease than diabetic patients who did not receive erythropoietin. With multivariate analysis, significant risk factors for the development of peripheral vascular disease in these patients were erythropoietin use, erythropoietin dose, and smoking. Twenty-eight patients who initially performed peritoneal dialysis without receiving EPO, and later received EPO, had a significant increase in vascular events, including amputations only while receiving EPO. We found the use of erythropoietin to be associated with peripheral vascular events in diabetic patients who receive peritoneal dialysis. Further investigation is warranted.

Topics: Adult; Aged; Amputation, Surgical; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Ischemia; Kidney Failure, Chronic; Leg; Length of Stay; Male; Middle Aged; Myocardial Infarction; Peritoneal Dialysis; Recombinant Proteins; Retrospective Studies

It's know that cardiopulmonary function affects the kidney perfusion and that erythropoietin (EPO) release depends on it. We want to determine the plasma level of EPO in the acute phase of myocardial infarction (AMI).. A transversal trial was carried out in 37 male patients with AMI aged between 31 and 84. We studied the following variables: cardiovascular risk factors, time lapse from beginning of symptoms until hospital arrival, transcutaneous oxygen saturation (ST02) and EPO plasma levels. 16 healthy males were used as control group.. Patients with AMI have different EPO levels than control group (25/37 vs 0/16) (18.90 +/- 8.43 mUI/ml vs 9.70 +/- 3.48 mUI/ml respectively p < 0.001). Hyperintense patients have higher EPO levels than normotense ones (18.53 +/- 8.28 mUI/ml vs 12.88 +/- 7.29 mUI/ml p < 0.05). Hypercholesterolemic patients have higher EPO level than normocholesterolemic ones (19 +/- 8.88 mUI/ml vs 12.40 +/- 6.75 mUI/ml p < 0.01). There were no difference between smokers and no smokers. We didn't find correlation between time lapse and EPO levels.. The trial remarks EPO levels increase during the initial phase of AMI and it is higher in hypertensive and hypercholesterolemic patients.

Topics: Adult; Aged; Aged, 80 and over; Cross-Sectional Studies; Erythropoietin; Humans; Male; Middle Aged; Myocardial Infarction; Time Factors

An increase in blood pressure is common during treatment of renal anaemia with recombinant human erythropoietin (rhEPO). Concomitant findings of a decrease in cardiac output indicate that an increase in the peripheral flow resistance underlies the increase in blood pressure. The aim of this study was to elucidate the haemodynamic changes during rhEPO treatment in patients with ischaemic heart disease (IHD). Haemodynamic variables were assessed by impedance cardiography in 18 consecutive patients with renal anaemia before and after rhEPO treatment. IHD was found in eleven of these patients. The remaining seven served as controls. Before rhEPO treatment, the cardiac index was decreased in the group of patients with IHD, compared with controls and healthy subjects. Due to an increase in stroke index, the cardiac index increased during rhEPO treatment and reached values equal to those in the control group. The blood pressure increased and the increase in mean arterial pressure was correlated to the increase in cardiac index. Apparently the patients with IHD were unable to compensate for anaemia by increasing their cardiac index. Anaemia treatment increased cardiac index, which in turn caused an increase in blood pressure in these patients.

Topics: Adult; Aged; Anemia; Cardiac Output; Coronary Circulation; Coronary Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Hematocrit; Hemodynamics; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Recombinant Proteins; Renal Dialysis

Recombinant human erythropoietin is widely used in chronic dialysis patients. However, the long-term effect, especially on the incidence of cardiovascular disease, has not been critically evaluated. We observed the annual incidence of stroke and acute myocardial infarction from April 1988 through March 1993 in Okinawa, Japan. Until April 1990, erythropoietin was not generally used. Therefore, we have two periods: pre-erythropoietin, April 1988 through March 1990, and post-erythropoietin, April 1990 through March 1993. Two thousand one hundred and sixteen patients (1,219 males and 897 females) were on chronic dialysis during the study period by March 31, 1993. Every case of stroke and acute myocardial infarction during the study period was registered. The odds ratio was calculated using the data of the general population in each sex and age class obtained in the same area. A total of 86 cases of stroke and 15 cases of acute myocardial infarction were registered during the study period. The annual incidence, per 1,000 patient-years, of stroke was 12.5 (1988), 10.5 (1989), 12.7 (1990), 14.0 (1991), and 17.5 (1992). The incidence of stroke was increased in the post-erythropoietin period compared to the pre-erythropoietin period, odds ratio 1.22 and 95% confidence interval (95% CI 1.06-1.41, p < 0.01). The annual incidence of acute myocardial infarction was 1.0 (1988), 1.8 (1989), 0.8 (1990), 2.9 (1991) and 4.7 (1992). The incidence of acute myocardial infarction was increased significantly in the post-erythropoietin period compared to the pre-erythropoietin period, odds ratio 1.87 (95% CI 1.66-2.10, p < 0.01). The odds ratio of stroke to the general population was 4.25 (95% CI 3.10-5.82) in the pre-erythropoietin and 4.58 (95% CI 2.14-9.80) in the post-erythropoietin period. In acute myocardial infarction, it was 2.98 (95% CI 2.84-3.12) and 3.81 (95% CI 3.18-4.56). The odds ratio of acute myocardial infarction was significantly increased (p < 0.01). The introduction of erythropoietin was associated with an increased risk of cardiovascular disease, especially acute myocardial infarction. Erythropoietin may unmask the sclerotic lesion in chronic dialysis patients.

Topics: Cardiovascular Diseases; Cerebrovascular Disorders; Diabetes Mellitus; Erythropoietin; Female; Humans; Japan; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Myocardial Infarction; Renal Dialysis; Risk Factors

Topics: Adult; Aged; Aged, 80 and over; Aortic Valve Insufficiency; Aortic Valve Stenosis; Cardiac Surgical Procedures; Christianity; Coronary Artery Bypass; Erythropoietin; Female; Heart Septal Defects, Atrial; Humans; Hypertension, Pulmonary; Middle Aged; Mitral Valve Insufficiency; Myocardial Infarction; Pulmonary Valve Stenosis; Religion and Medicine; Rheumatic Heart Disease; Tricuspid Valve Insufficiency