losartan-potassium and Ventricular-Dysfunction--Left

Advances in cancer treatment have greatly improved survival rates of children with cancer. However, these same chemotherapeutic or radiologic treatments may result in long-term health consequences. Anthracyclines, chemotherapeutic drugs commonly used to treat children with cancer, are known to be cardiotoxic, but the mechanism by which they induce cardiac damage is still not fully understood. A higher cumulative anthracycline dose and a younger age of diagnosis are only a few of the many risk factors that identify the children at increased risk of developing cardiotoxicity. While cardiotoxicity can develop at anytime, starting from treatment initiation and well into adulthood, identifying the best cardioprotective measures to minimize the long-term damage caused by anthracyclines in children is imperative. Dexrazoxane is the only known agent to date, that is associated with less cardiac dysfunction, without reducing the oncologic efficacy of the anthracycline doxorubicin in children. Given the serious long-term health consequences of cancer treatments on survivors of childhood cancers, it is essential to investigate new approaches to improving the safety of cancer treatments.

Topics: Adiponectin; Age Factors; Angiotensin-Converting Enzyme Inhibitors; Anthracyclines; Antibiotics, Antineoplastic; Antioxidants; Carbazoles; Cardiolipins; Cardiotonic Agents; Carvedilol; Doxorubicin; Erythropoietin; Heart; Heart Diseases; Humans; Lipid Peroxidation; Liposomes; Neoplasms; Piperazines; Propanolamines; Purines; Razoxane; Risk Factors; Sildenafil Citrate; Sulfones; Survivors; Ventricular Dysfunction, Left

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

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

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

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

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

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

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

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

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

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

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

Recent studies revealed that erythropoietin (EPO) has tissue-protective effects in the heart by increasing vascular endothelial growth factor (VEGF) expression and attenuating myocardial fibrosis in ischemia models. In this study, we investigated the effect of EPO on ventricular remodeling and blood vessel growth in diabetic rats.. Male SD rats were randomly divided into 3 groups: control rats, streptozotocin (STZ)-induced diabetic rats, and diabetic rats treated with 1000 U/kg EPO by subcutaneous injection once per week. Twelve weeks later, echocardiography was conducted, and blood samples were collected for counting of peripheral blood endothelial progenitor cells (EPCs). Myocardial tissues were collected, quantitative real-time PCR (RT-PCR) was used to detect the mRNA expression of VEGF and EPO-receptor (EPOR), and Western blotting was used to detect the protein expression of VEGF and EPOR. VEGF, EPOR, transforming growth factor beta (TGF-β), and CD31 levels in the myocardium were determined by immunohistochemistry. To detect cardiac hypertrophy, immunohistochemistry of collagen type I, collagen type III, and Picrosirius Red staining were performed, and cardiomyocyte cross-sectional area was measured.. After 12 weeks STZ injection, blood glucose increased significantly and remained consistently elevated. EPO treatment significantly improved cardiac contractility and reduced diastolic dysfunction. Rats receiving the EPO injection showed a significant increase in circulating EPCs (27.85 ± 3.43%, P < 0.01) compared with diabetic untreated animals. EPO injection significantly increased capillary density as well as EPOR and VEGF expression in left ventricular myocardial tissue from diabetic rats. Moreover, EPO inhibited interstitial collagen deposition and reduced TGF-β expression.. Treatment with EPO protects cardiac tissue in diabetic animals by increasing VEGF and EPOR expression levels, leading to improved revascularization and the inhibition of cardiac fibrosis.

Topics: Animals; Blotting, Western; Collagen Type I; Collagen Type III; Diabetes Mellitus, Experimental; Endothelial Cells; Erythropoietin; Fibrosis; Gene Expression Regulation; Hypertrophy, Left Ventricular; Immunohistochemistry; Injections, Subcutaneous; Male; Myocardial Contraction; Myocardium; Neovascularization, Physiologic; Platelet Endothelial Cell Adhesion Molecule-1; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, Erythropoietin; Recovery of Function; RNA, Messenger; Stem Cells; Time Factors; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Cardiac resynchronization therapy (CRT) is an effective treatment strategy in patients with severe left ventricular dysfunction and those with evidence of electro-mechanical dyssynchrony. A prospective observational study was conducted in patients with severe symptomatic heart failure undergoing CRT implantation. Thirty patients were classified as either responders (9 patients), or non-responders (21 patients). The association between functional status, quality of life scores and CRT responder status with erythropoietin (EPO) levels was determined. The mean EPO levels among responders were 28.8±3.6 and 11.4±1.7 mIU/ml among non-responders. Elevated EPO levels in the absence of anemia and renal insufficiency effectively correlate with functional impairment and severe symptoms, which impair quality of life in patients undergoing CRT.

Topics: Aged; Biomarkers; Cardiac Resynchronization Therapy; Erythropoietin; Female; Humans; Male; Middle Aged; Treatment Outcome; Ventricular Dysfunction, Left

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

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

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

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

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

Erythropoietin (Epo) receptors (EpoRs) are expressed in the heart. We have recently demonstrated that the endogenous Epo-EpoR system plays an important protective role in myocardial ischemia in mice and humans. In the present study, we tested our hypothesis that the endogenous Epo-EpoR system in nonhematopoietic cells also plays a protective role against pressure overload-induced cardiac dysfunction in vivo.. Transgene-rescued EpoR-null mutant mice (EpoR-/-(rescued)) that express EpoR exclusively in the hematopoietic cells were subjected to transverse aortic constriction (TAC). At 1 week after TAC, left ventricular weight and lung weight were significantly increased in EpoR-/-(rescued) mice compared with wild-type mice, although the fibrotic area was comparably increased after TAC in the 2 genotypes. In the EpoR-/-(rescued) mice with TAC, left ventricular end-diastolic diameter was significantly increased, left ventricular fractional shortening was significantly decreased, and survival rate was significantly decreased compared with wild-type mice with TAC. Phosphorylation of STAT3 at 5 hours and 1 week after TAC and that of p38 at 5 hours after TAC were significantly increased in wild-type mice but not in EpoR-/-(rescued) mice. Vascular endothelial growth factor protein expression and capillary density in left ventricular myocardium were significantly decreased in EpoR-/-(rescued) mice with TAC compared with wild-type mice with TAC.. These results suggest that the endogenous Epo-EpoR system in the nonhematopoietic cells plays an important protective role against pressure overload-induced cardiac dysfunction in vivo.

Topics: Animals; Aorta; Blood Pressure; Blotting, Northern; Echocardiography; Erythropoietin; Gene Transfer Techniques; Heart Rate; Mice; Mice, Mutant Strains; Mice, Transgenic; Organ Size; Receptors, Erythropoietin; Survival Rate; Ventricular Dysfunction, Left

To investigate the effect of erythropoietin for the management of postresuscitation myocardial dysfunction following asphyxia-induced cardiac arrest. Male adult Wistar rats were used for the prospective controlled animal study. Asphyxia-induced cardiac arrest was performed by turning-off the ventilator and clamping the endotracheal tube. Cardiopulmonary resuscitation with an intravenous injection of 0.01 mg/kg epinephrine and mechanical ventilation were started after 6.5 minutes of asphyxia. The resuscitated animals received either erythropoietin (5000 U/kg) or equivalent volume of 0.9% saline as placebo intravenously 3 minutes after return of spontaneous circulation. The erythropoietin treatment produced better left ventricular dP/dt40 and -dP/dt in the invasive hemodynamic measurements, and left ventricular fraction shortening by echocardiography. Administration of erythropoietin also improved three days survival among those successfully resuscitated. The molecular effects of erythropoietin were shown by activation of its down streaming Akt and ERK 42/44 signaling pathways. EPO has the potential to improve postresuscitation myocardial dysfunction and short term survival in rats after asphyxia-induced cardiac arrest.

Topics: Animals; Asphyxia; Cardiopulmonary Resuscitation; Cardiotonic Agents; Disease Models, Animal; Erythropoietin; Heart; Heart Arrest; Male; Rats; Rats, Wistar; Recombinant Proteins; Signal Transduction; Ventricular Dysfunction, Left

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

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

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

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

Dysfunction of the cardiovascular system is a common complication of chronic renal insufficiency. Many factors can cause left ventricular hypertrophy (LVH), and hypertension and anemia are among them. They play an important role in the pathogenesis of LVH as well as in the development of cardiac dysfunction. Echocardiography enables early detection of functional macrocirculatory changes as well as adequate measuring of cardiac structures and LV mass. Anemia of end-stage chronic renal insufficiency (ESRD) is only one among its many complications and has complex pathogenesis; one of the primary factors causing anemia is insufficient production of erythropoietin, a leading factor in the production of erythropoiesis. Anemia correction with recombinant human erythropoietin (r-HuEPO) in ESRD has a positive effect on the cardiovascular system. In this study the authors examined the hemodynamic effect of erythropoietin in anemic patients undergoing hemodialysis and observed its positive effect on the cardiovascular system. Twenty-two patients were included in the study (13 men and 9 women) mean age x=39.5 years. All patients were dialyzed three times a week for 4 hours and were all (Abstract continued) treated, according to protocol, with r-HuEPO for 8 months. Left ventricular mass was measured by the Penn Convention formula. The authors noticed the effectiveness of this therapy through an increase of hemoglobin of 35% and of hematocrit of 34% and a direct effect on the cardiovascular system. Echocardiographic findings showed decrease of LV mass from 391 to 274 mg (30%). The correction of renal anemia with erythropoietin leads to structural microcirculatory changes and partial morphologic regression of preexistent LVH, which again leads to regression of cardiac dysfunctions and improved hemodynamic effect, physical capacity, and cardiopulmonary status, and ultimately better quality of life for dialyzed patients.

Topics: Adult; Erythropoietin; Female; Hematocrit; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Microcirculation; Middle Aged; Recombinant Proteins; Renal Dialysis; Ultrasonography; Ventricular Dysfunction, Left

We studied the effect of correction of anemia with erythropoietin on left ventricular systolic and diastolic function at rest and exercise in 17 chronic hemodialysis patients by means of maximum exercise testing and equilibrium gated radionuclide angiocardiography on three occasions: 1) initial--before erythropoietin administration, 2) intermediate--at the time when the target hemoglobin level reached 100 g/l, and 3) long-term--after 12 months of therapy. After correction of anemia, the patients showed a significant improvement in their response to exercise regarding maximal work load achieved, exercise duration and recovery time. Ejection fraction and peak ejection rate remained unchanged during therapy. At rest, peak filling rate was reduced from 2.62 +/- 1.0 (baseline) to 2.28 +/- 0.9 (intermediate) end-diastolic volume per second, p < 0.01, while no significant difference was observed during exercise. The time to peak filling rate was prolonged significantly during EPO therapy from 157 +/- 30 to 177 +/- 28 ms at rest, p < 0.05, and from 101 +/- 24 to 130 +/- 27 ms during exercise, p < 0.01. By the time of the late study, there were no significant differences between the late and intermediate study. In conclusion, amelioration of anemia with erythropoietin in hemodialysis patients produced improvement in exercise capacity, but diastolic function worsened with therapy and this effect was maintained during the long-term treatment, while systolic function at rest and exercise remained unchanged.

Topics: Adult; Anemia; Erythropoietin; Exercise; Female; Follow-Up Studies; Gated Blood-Pool Imaging; Heart Rate; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Contraction; Recombinant Proteins; Renal Dialysis; Rest; Stroke Volume; Ventricular Dysfunction, Left

Topics: Adult; Diabetic Nephropathies; Diastole; Echocardiography; Erythropoietin; Humans; Kidney Transplantation; Male; Systole; Ventricular Dysfunction, Left