losartan-potassium and Myocardial-Ischemia

Anemia has and will continue to be a central theme in medicine particularly as clinicians are treating a burgeoning population of complex multi-organ system processes. As a result of multiple randomized controlled trials (RCTs), meta-analyses, and societal recommendations overly restrictive paradigms and under-administration of erythropoiesis stimulating agents (ESAs) have likely been followed by clinicians among all specialties.. A review of anemia in the context of chronic kidney disease, hematologic malignancies, and cancer is presented with focus on the establishment of ESAs as integral in the treatment of anemia. Multiple RCTs and meta-analyses studying the use of ESAs are presented with focus upon their application to clinical practice. A 'compendium' is proffered describing the evolution, establishment, and implications of ESA administration initially among those with CKD with rapid subsequent application to the Hematology-Oncology population of patients. Literature search methodologies have included MEDLINE (1985-2020), PubMed (1996-2020), Cochrane Central Trials (1985-2020), EMBASE (2000-2020), and ClinicalTrials.gov (2000-2020).. Upon evaluation of risks and benefits of ESAs focused opinion and commentary is made supporting more liberal use of these agents and strongly suggesting that the current underlying treatment 'pendulum' has perhaps shifted too far to the 'under-treatment' side in many cases.

Topics: Anemia; Blood Transfusion; Combined Modality Therapy; COVID-19; Epoetin Alfa; Erythropoietin; Expert Testimony; Forecasting; Guideline Adherence; Hematinics; Hematologic Neoplasms; Hematopoiesis; Humans; Iron; Medicine; Meta-Analysis as Topic; Multicenter Studies as Topic; Myocardial Ischemia; Neoplasms; Observational Studies as Topic; Pandemics; Practice Guidelines as Topic; Practice Patterns, Physicians'; Randomized Controlled Trials as Topic; Receptors, Erythropoietin; Renal Dialysis; Renal Insufficiency, Chronic; SARS-CoV-2; Venous Thromboembolism

The findings of recent clinical trials have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors produce effects beyond glucose lowering and have demonstrated beneficial cardiovascular effects that have been observed across a broad range of patients with type 2 diabetes mellitus. In particular, the cardiovascular benefit results largely from substantial and early effects of SGLT2 inhibition on cardiovascular death and hospitalization for heart failure. Recent cardiovascular outcomes trials (CVOTs) have also shown that relative risk reductions in cardiovascular outcomes were observed with SGLT2 inhibition both in patients with current and prior heart failure. Since the observed reductions of cardiovascular outcomes with SGLT2 inhibitor therapy were observed much earlier than would be expected by an anti-atherosclerotic effect, these results have led to speculation about the potential underlying pathways. Suggested mechanisms include natriuresis and osmotic diuresis; reductions in inflammation, oxidative stress, and arterial stiffness; reductions in blood pressure and body weight; and possible renoprotective effects. These effects could produce cardiovascular benefits through a range of cardiac effects, including reduction in left ventricular load, attenuation of cardiac fibrosis and inflammation, and improved myocardial energy production. Other possible mechanisms include inhibition of sodium-hydrogen exchange, increases in erythropoietin levels, and reduction in myocardial ischemia or reperfusion injury. It is likely that a range of mechanisms underlie the observed cardiovascular benefits of SGLT2 inhibitors; further elucidation of these mechanisms will be answered by ongoing research.

Topics: Blood Pressure; Body Weight; Cardiovascular Diseases; Cardiovascular System; Diuresis; Erythropoietin; Heart; Humans; Inflammation; Kidney; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Natriuresis; Oxidative Stress; Sodium-Glucose Transporter 2 Inhibitors; Sodium-Hydrogen Exchangers; Vascular Stiffness

Topics: Acute Lung Injury; Adult; Anemia; Blood Preservation; Blood Specimen Collection; Brain Injuries; Critical Illness; Erythrocyte Transfusion; Erythropoietin; Hemorrhage; Humans; Myocardial Ischemia; Nervous System Diseases; Sepsis; Shock; Stroke; Subarachnoid Hemorrhage

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

Topics: Acidosis; Apoptosis; Brain Ischemia; Erythropoietin; Fever; Fibrinolytic Agents; Forecasting; Humans; Hyperglycemia; Myocardial Ischemia; Tissue Plasminogen Activator

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

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

Topics: Anemia; 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

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

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

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

Erythropoietin and its receptor, a cytokine hormone long-known for its pro-erythropoietic effect, has been found to be expressed on a variety of tissues, including the cardiovascular system. Recent experimental studies in the ischemia-reperfusion model have demonstrated that erythropoietin has a significant cardioprotective and pro-angiogenic effect. This effect is quantified by a reduction in the relative infarct and apoptosis area and improved recovery of mechanical function. Despite potentially detrimental effects, erythropoietin has been used extensively in the last decade for treatment of anemia associated with chronic renal failure, and it has been found to be a safe drug in humans. The potential role of erythropoietin in the treatment of ischemic heart disease in humans has yet to be demonstrated in preliminary clinical trials.

Topics: Anemia; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Myocardial Ischemia; Neovascularization, Physiologic

Erythropoietin (EPO) is a hypoxia-induced hormone produced in the kidneys that stimulates hematopoiesis in the bone marrow. However, recent studies have also shown important nonhematopoietic effects of EPO. A functional EPO receptor is found in the cardiovascular system, including endothelial cells and cardiomyocytes. In animal studies, treatment with EPO during ischemia/reperfusion in the heart has been shown to limit the infarct size and the extent of apoptosis. In the longer term, EPO may promote ischemia-induced neovascularization, either by stimulating endothelial cells in situ or by mobilizing endothelial progenitor cells from bone marrow. The effects of EPO in the ischemic heart support the concept of EPO as a pleiotropic, tissue-protective agent for other organs expressing the EPO receptor. We recently performed a first randomized clinical study showing the safety and feasibility of EPO administration in patients with acute myocardial infarction. Future clinical studies are warranted to translate the beneficial effects of EPO from basic experiments to cardiac patients.

Topics: Animals; Cardiotonic Agents; Cardiovascular System; Diffusion of Innovation; Erythropoietin; Heart; Humans; Myocardial Ischemia; Receptors, Erythropoietin; Time Factors

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

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

Several studies showed that anaemia is commonly observed in patients with Chronic Heart Failure (CHF) and is associated with worsened symptoms and survival. When anaemia in these patients is treated with erythropoietin (EPO), a significant improvement in cardiac function and symptoms was observed. Although it was originally believed that EPO specifically acted on haematopoietical cells, recent evidence demonstrated several non-haematopoietical effects. Ischaemia/reperfusion experiments in rat heart and brain showed large infarct reduction when treated with EPO. Other effects of EPO are related to its pro-angiogenic effects on endothelial cells, which could be of potential value in patients with ischaemic heart disease. These preclinical findings suggest that EPO may have potential effects in cardiovascular disease beyond correction of haemoglobin levels.

Topics: Anemia; Apoptosis; Cardiac Output, Low; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Humans; Kidney Failure, Chronic; Myocardial Ischemia; Neovascularization, Pathologic; Recombinant Proteins; Stroke

Erythropoietin (EPO) increases the number of circulating erythrocytes primarily by preventing apoptosis of erythroid progenitors. In addition to this proerythroid action, results of recent studies show that systemically administered EPO is protective in vivo, in several animal models of neuronal injury. In vitro, EPO prevents neuronal apoptosis induced by a variety of stimuli. This review summarizes the neuroprotective actions of EPO and discusses the underlying mechanisms in terms of signal transduction pathways involved. The understanding of these mechanisms will help differentiate the neuroprotective actions of EPO from its role in the bone marrow.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Cytokines; Cytoprotection; DNA-Binding Proteins; Endothelial Cells; Epithelial Cells; Erythropoietin; Hematopoiesis; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Kidney Tubules; Models, Biological; Myocardial Ischemia; Neurons; Neuroprotective Agents; Nuclear Proteins; Signal Transduction; Transcription Factors; Trauma, Nervous System

Replacement of injured endothelial cells by bone marrow derived endothelial progenitor cells (EPC's) is a new pathway of vascular repair after ischemia. Endothelial progenitor cells contribute less than 0.01% to the peripheral venous compartment of mononuclear cells. The detection of EPC's requires a demonstration of CD 34 and VEGFR-2 (vascular endothelial growth factor receptor-2) antigenic cell membrane determinants and proof of endothelial characteristics after outgrowth and differentiation in cell culture. The most important stimuli to the mobilization and proliferation of EPC's are VEGF, GM-CSF (granulocyte-macrophage colony stimulating factor), erythropoietin, HMG-CoA-reductase inhibitors and tissue ischemia. In vivo in patients EPC's appear to contribute to endothelialization of vascular grafts, the formation of collaterals of ischemic limbs and the healing of myocardial infarcts. The role of EPC's in uremia is currently under investigation.

Topics: Antigens, CD34; Cardiovascular Diseases; Endothelium, Vascular; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Myeloid Progenitor Cells; Myocardial Ischemia; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Cardiac surgery and cardiopulmonary bypass (CPB) induce ischemia-reperfusion and subsequent cellular injury with inflammatory reaction. Clinical and experimental studies suggest that recombinant human erythropoietin (EPO) independently of its erythropoietic effect may be used as a cytoprotective agent against ischemic injury. We tested the hypothesis that one large dose of EPO administered shortly before CPB prevents the elevation of cardiac and cerebral ischemic blood markers as well as the systemic inflammatory response induced by cardiac surgery with CBP through this randomized double-blind placebo-controlled pilot trial. Fifty patients scheduled for coronary artery bypass graft (CABG) surgery with CPB were randomly allocated to EPO or control groups. EPO (800 IU/kg intravenously) or placebo (saline) was administered before CPB. The primary end point was to study the effect of EPO administration on several blood markers of myocardial and cerebral ischemia in relation to CABG with CPB. In both groups, surgery increased plasma concentrations of cardiac (troponin T, NT-proBNP, and creatine kinase MB) and cerebral (S100β protein) markers ischemic as well as the pro-inflammatory marker interleukin-6. Compared with the placebo, EPO administration before CPB did not prevent an increase of all these markers following CPB. In conclusion, one large dose of EPO, given shortly before CPB, did not protect against cardiac and cerebral ischemia and inflammatory response occurring during CABG surgery with CPB. Although the long-term clinical implications remain unknown, the findings do not support use of EPO at this dose as a cytoprotective agent in patients undergoing cardiac surgery.

Topics: Aged; Biomarkers; Brain Ischemia; Cardiopulmonary Bypass; Cytokines; Cytoprotection; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Erythropoietin; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Myocardial Reperfusion Injury; Nerve Growth Factors; Pilot Projects; Recombinant Proteins; Reperfusion Injury; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Treatment Outcome; Troponin T

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

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

The clearest benefit of recombinant human erythropoietin (rHuEPO) in end-stage renal disease is a substantial reduction in transfusion dependency and an improved quality of life. In this report, we describe the efficacy of weekly subcutaneous administration of rHuEPO in 11 elderly patients with anemia secondary to chronic renal failure.. The role of rHuEPO therapy in increasing the patient's quality of life and in decreasing the hospitalization rates secondary to cardiac morbidity was verified in 11 elderly patients (age range between 66 and 85 years) with anemia due to chronic renal failure. The mean hemoglobin level at the beginning of the study was 8.2 +/- (SD) 0.7 g/dl, and the serum creatinine concentration was 4.8 +/- 1.36 mg/dl. The patients underwent baseline and annual echocardiography, in addition to an electrocardiogram.. Most patients experienced a partial regression of left ventricular hypertrophy, and no congestive heart failure was documented. The mean hemoglobin level during rHuEPO therapy increased to 11.3 +/- 1.2 g/dl, while the mean serum creatinine concentration did not change significantly.. Our results confirm that early anemia correction in aged chronic renal failure patients permits improvement of the quality of life, of exercise performance, and of cognitive functions. Reduced transfusion need and regression of left ventricular hypertrophy favor a minor incidence of cardiac morbidity and contribute to reduce health costs.

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Male; Myocardial Ischemia

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

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

Since the earliest reports of the use of Epoetin alfa in hemodialysis patients, it has been described that Epoetin alfa may exacerbate preexisting hypertension or induce hypertension in End Stage Renal Disease (ESRD) patients not previously hypertensive. We undertook this study to determine if the correction of anemia in ESRD patients with cardiac disease from a hematocrit of 30+/-3% to 42+/-3% with the use of Epoetin alfa would result in increased blood pressure. This study was a substudy of the "Normal hematocrit Study".. Thirty-one patients were randomized into one of two arms. Patients in Group A had their hematocrit increased with the use of slowly escalating doses of Epoetin alfa to 42+/-3% and patients in Group B were maintained with a hematocrit of 30+/-3% throughout the course of the study. All patients had their blood pressure recorded with a 24 hour ambulatory BP device at study entry and at 28 weeks following randomization when they had achieved their target hematocrit. Pre-dialysis systolic and diastolic BP was also recorded.. The mean hematocrit increased in Group A from 29.1+/-2.4% to 40.8+/-5.2% after 30 weeks. The hematocrit in Group B remained stable at 30+/-3% throughout the course of the study. There was no difference in mean daytime, mean nighttime or 24 hour systolic or diastolic blood pressure between Groups A and B at either baseline or follow-up. Neither was there a difference in mean pre-dialysis systolic or diastolic BP between Groups A or B at baseline or Follow-up. Four patients in Group A and 4 patients in Group B required an increase in their antihypertensive medication during the course of the study.. It is possible to increase hematocrit to normal levels in hemodialysis with the administration of Epoetin alfa. The increase in hematocrit from 30+/-3% to 42+/-3% is not associated with increased blood pressure.

Topics: Adult; Aged; Anemia; Blood Pressure Monitoring, Ambulatory; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Ischemia; Recombinant Proteins; Reference Values; Renal Dialysis; Treatment Outcome

Hemoglobin levels below 10 g/dL lead to left ventricular (LV) hypertrophy, LV dilation, a lower quality of life, higher cardiac morbidity, and a higher mortality rate in end-stage renal disease. The benefits and risks of normalizing hemoglobin levels in hemodialysis patients without symptomatic cardiac disease are unknown.. One hundred forty-six hemodialysis patients with either concentric LV hypertrophy or LV dilation were randomly assigned to receive doses of epoetin alpha designed to achieve hemoglobin levels of 10 or 13.5 g/dL. The study duration was 48 weeks. The primary outcomes were the change in LV mass index in those with concentric LV hypertrophy and the change in cavity volume index in those with LV dilation.. In patients with concentric LV hypertrophy, the changes in LV mass index were similar in the normal and low target hemoglobin groups. The changes in cavity volume index were similar in both targets in the LV dilation group. Treatment-received analysis of the concentric LV hypertrophy group showed no correlation between the change in mass index and a correlation between the change in LV volume index and mean hemoglobin level achieved (8 mL/m2 per 1 g/dL hemoglobin decrement, P = 0.009). Mean hemoglobin levels and the changes in LV mass and cavity volume index were not correlated in patients with LV dilation. Normalization of hemoglobin led to improvements in fatigue (P = 0.009), depression (P = 0.02), and relationships (P = 0.004).. Normalization of hemoglobin does not lead to regression of established concentric LV hypertrophy or LV dilation. It may, however, prevent the development of LV dilation, and it leads to improved quality of life.

Topics: Adult; Aged; Anemia; Cardiac Volume; Cardiomyopathy, Dilated; Echocardiography; Erythropoietin; Female; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Ischemia; Patient Satisfaction; Quality of Life; Renal Dialysis; Surveys and Questionnaires; Thrombosis

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

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

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

To investigate the effect and mechanism of recombinant human erythropoietin (rhEPO) on angiogenesis in chronic ischemic porcine myocardium.. A ameroid constrictor was placed around the proximal circumflex branch of the left coronary artery in 12 Bama miniatures' swine artery by thoracoscopy. Electrocardiogram and coronary angiography were used to confirm the establishment of myocardial ischemia. The animals were divided into rhEPO treatment group (n = 6) and negative control group (n = 6). Treatment group received subcutaneous injection of rhEPO at 1, 3, 7, 14, 21 days, control group received saline. The expression of vascular endothelial growth factor (VEGF) in serum was assessed by ELISA. Ultrasonography and coronary angiography were assessed 28 days after therapy. Western blot was used to detect the expression of VEGF, phosphorylated protein kinase B (p-Akt) and phosphorylated extracellular signal regulated kinases (p-Erk). The degree of angiogenesis was assessed by immunohistochemical analysis.. Serum VEGF rose significantly in both control and treatment groups, peaking at 3 days and then returning to the near-baseline level at 28 days, but the two groups showed no significant difference at each time point (P > 0.05). Echocardiographic measurements showed that the left ventricular systolic function of animals in treatment group increase significantly after rhEPO therapy. the expression levels of VEGF, p-Akt and p-Erk had markedly increased, which resulted in a 2.5-fold increased of VEGF, 1.1-fold increased of p-Akt, 1.5-fold increased of p-Erk (t = 37.721, 10.907, 12.957, all P = 0.000). there were significant increase in capillary density and arteriole density in the two groups ((944 ± 98) %/mm² vs. (569 ± 102) %/mm², (73 ± 13) %/mm² vs. (45 ± 10) %/mm², t = 4.214, 2.869, P = 0.016, 0.023).. rhEPO can promote angiogenesis and arteriogenesis and improve the left ventricular systolic function in porcine model of chronic myocardial ischemia. The potential mechanism is to up-regulated the expression of p-Akt and p-Erk.

Topics: Animals; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; Humans; Male; Myocardial Ischemia; Neovascularization, Physiologic; Proto-Oncogene Proteins c-akt; Recombinant Proteins; Swine; Swine, Miniature; Vascular Endothelial Growth Factor A

Topics: Animals; Cardiotonic Agents; Chemokine CXCL12; Enzyme Activation; Erythropoietin; Janus Kinase 2; Male; Mice; Mice, Inbred C57BL; Myocardial Ischemia; STAT3 Transcription Factor; Treatment Outcome; Up-Regulation

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

Erythropoietin provides cellular protection by inhibiting apoptosis. Myocardial damage related to the cardiac ischemia is more prominent especially in the first 6 h. In the present study, circulatory erythropoietin levels in response to cardiac ischemia were evaluated.. Patients with stable angina who underwent balloon angioplasty (study group, n = 55) and hospitalized for coronary angiography (as control group, n = 23) were enrolled into the study. Serum erythropoietin levels were measured in both groups in baseline, 6 and 18 h after the procedure.. Coronary balloon inflation time was accepted as duration of myocardial ischemia. Study group showed significant erythropoietin reduction at sixth hour compared to control group. Erythropoietin reduction at sixth hour was significantly correlated with duration of myocardial ischemia.. Decreased circulatory erythropoietin levels in the early phase of acute cardiac ischemia may accelerate the apoptotic activity. Recombinant erythropoietin replacement to prevent erythropoietin decrease following cardiac ischemia may have negative effect on myocyte loss.

Topics: Acute Disease; Erythropoietin; Female; Humans; Male; Middle Aged; Myocardial Ischemia

Increasing evidence indicates that high levels of serum erythropoietin (Epo) can lessen ischemia-reperfusion injury in the heart and multiple cardiac cell types have been suggested to play a role in this Epo effect. To clarify the mechanisms underlying this cardioprotection, we explored Epo treatment of coronary artery endothelial cells and Epo cardioprotection in a Mus musculus model with Epo receptor expression restricted to hematopoietic and endothelial cells (ΔEpoR). Epo stimulation of coronary artery endothelial cells upregulated endothelial nitric oxide synthase (eNOS) activity in vitro and in vivo, and enhanced nitric oxide (NO) production that was determined directly by real-time measurements of gaseous NO release. Epo stimulated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinase kinase (MEK)/extracellular signal regulated kinase (ERK) signaling pathways, and inhibition of PI3K, but not MEK activity, blocked Epo-induced NO production. To verify the potential of this Epo effect in cardioprotection in vivo, ΔEpoR-mice with Epo response in heart restricted to endothelium were treated with Epo. These mice exhibited a similar increase in eNOS phosphorylation in coronary artery endothelium as that found in wild type (WT) mice. In addition, in both WT- and ΔEpoR-mice, exogenous Epo treatment prior to myocardial ischemia provided comparable protection. These data provide the first evidence that endothelial cell response to Epo is sufficient to achieve an acute cardioprotective effect. The immediate response of coronary artery endothelial cells to Epo stimulation by NO production may be a critical mechanism underlying this Epo cardioprotection.

Topics: Animals; Coronary Vessels; Endothelial Cells; Erythropoietin; Fluorescent Antibody Technique; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Ischemia; Myocardial Reperfusion Injury; Nitric Oxide; Nitric Oxide Synthase Type III; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

Although endogenous erythropoietin secretion returns via the renal allograft a few hours following successful engraftment, anemia is a common early or late complication. In addition, anemia is a risk factor for ischemic heart disease and graft loss. We sought to determine risk factors for and the prevalence of severe anemia immediately posttransplantation (PTA).. This cross-sectional retrospective study performed between 2006 and 2009 enrolled 864 adult subjects of mean age 40.7±13.8 (range=6-75) years. On the basis of The World Health Organization criteria, a hemoglobin (Hb) level less than 11 g/dL for men and less than 10 g/dL for women was defined as severe anemia.. Severe anemia occurred frequently (62.7%) among these patients whose most common underlying disease was hypertension 311 (58.2%). Their mean Hb level was 9.9±1.8 g/dL at the time of hospital discharge, namely, almost 2 weeks after transplantation. More than 90% (n=778) of subjects received a kidney from a living donor. Immediate severe anemia associated with delayed graft function (DGF; P=.01), antithymocyte globulin (ATG)/antilymphocyte globulin (ALG) administration (P=.000), acute rejection (P=.000), recipient gender (P=.000), cold ischemic time (P=.01), pretransplant Hb (P=.000), posttransplant creatinine (P=.001), and acute rejection episodes (P=.000). Upon logistic regression analysis donor age (P=.04, confidence interval [CI]=0.7-0.9), recipient female gender (P=.009, CI=0.08-0.7), and ATG/ALG use (P=.009, CI=1.7-43.4) showed significant effects to cause severe PTA.. Immediate anemia after renal transplantation is a consequence of poor renal function. In addition, ATG/ALG use and DGF can induce severe PTA, which may play roles in ischemic heart disease and graft loss.

Topics: Adolescent; Adult; Aged; Anemia; Child; Cross-Sectional Studies; Erythropoietin; Graft Survival; Humans; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Myocardial Ischemia; Postoperative Complications; Risk; Risk Factors

Although hypoxia and ischemia are known to be involved in the pathogenesis of cardiovascular disease, specific therapeutic targets still remain elusive. To address this important issue, we have performed 2 series of experimental studies, aiming at erythropoietin (Epo)/Epo receptor (EpoR) based on the following backgrounds. Epo has long been regarded as a hematopoietic hormone that acts exclusively in the proliferation and differentiation of erythroid progenitors. Although recent studies have demonstrated that EpoR is expressed in the cardiovascular system, the potential protective role of the vascular Epo/EpoR system in vivo remains to be examined. We hypothesized that the vascular Epo/EpoR system plays an important protective role against the development of cardiovascular disease. Using vascular EpoR-deficient mouse, we demonstrated that the vascular Epo/EpoR system plays a crucial role for endothelial function and vascular homeostasis. The vascular Epo/EpoR system is important for the activation of the vascular endothelial growth factor/vascular endothelial growth factor receptor-2 system, inhibits hypoxia-induced pulmonary endothelial damage and promotes ischemia-induced angiogenesis in vivo. These results indicate that the vascular Epo/EpoR system plays an important protective role against hypoxia/ischemia, demonstrating that this system is a novel therapeutic target in cardiovascular medicine.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Drug Delivery Systems; Endothelium, Vascular; Erythropoietin; Homeostasis; Humans; Hypoxia; Mice; Mice, Knockout; Myocardial Ischemia; Receptors, Erythropoietin

A hypoxia-inducible VEGF expression system with the oxygen-dependent degradation (ODD) domain was constructed and tested to be used in gene therapy for ischemic myocardial disease.. Luciferase and VEGF expression vector systems were constructed with or without the ODD domain: pEpo-SV-Luc (or pEpo-SV-VEGF) and pEpo-SV-Luc-ODD (or pEpo-SV-VEGF-ODD). In vitro gene expression efficiency of each vector type was evaluated in HEK 293 cells under both hypoxic and normoxic conditions. The amount of VEGF protein was estimated by ELISA. The VEGF expression vectors with or without the ODD domain were injected into ischemic rat myocardium. Fibrosis, neovascularization, and cardiomyocyte apoptosis were assessed using Masson's trichrome staining, α-smooth muscle actin (α-SMA) immunostaining, and the TUNEL assay, respectively.. The plasmid vectors containing ODD significantly improved the expression level of VEGF protein in hypoxic conditions. The enhancement of VEGF protein production was attributed to increased protein stability due to oxygen deficiency. In a rat model of myocardial ischemia, the pEpo-SV-VEGF-ODD group exhibited less myocardial fibrosis, higher microvessel density, and less cardiomyocyte apoptosis compared to the control groups (saline and pEpo-SV-VEGF treatments).. An ODD-mediated VEGF expression system that facilitates VEGF-production under hypoxia may be useful in the treatment of ischemic heart disease.

Topics: Animals; Apoptosis; Cell Line; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Genetic Therapy; Genetic Vectors; Humans; Hypoxia; Immunohistochemistry; In Situ Nick-End Labeling; Luciferases; Male; Myocardial Ischemia; Myocardium; Oxygen; Plasmids; Protein Stability; Rats; Rats, Sprague-Dawley; Simian virus 40; Transfection; Vascular Endothelial Growth Factor A

This study was aimed to assess the pleiotropic effects of non-hematopoietic doses of erythropoietin (Epo) on post-ischemic microcirculatory dysfunction and inflammation in murine cardiac allografts.. Epo was given intraperitoneally 2 hours prior to explantation (Epo-donor) or 2 hours prior to the onset of reperfusion (Epo-recipient). Controls were not treated. Intravital fluorescence microscopy (IVM) was used to assess post-ischemic coronary microcirculatory dysfunction.. IVM exhibited decreasing capillary blood flow velocities and functional capillary densities (FCD) in controls. Capillary diameters and venular blood flow characteristics showed no significant changes over time. Epo-treatment had no effect on coronary microhemodynamics. Post-ischemic inflammation was characterized by augmented macromolecular leakage. Microvascular permeability decreased in the Epo-donor group (p < 0.05). Leukocyte rolling in coronary post-capillary venules decreased during reperfusion from 64 ± 16 to 19 ± 16 cells/min/mm, whereas firm adhesion increased from 333 ± 135 to 479 ± 154 cells/mm(2) in controls. Capillary leukocyte plugging remained stationary over time with approximately 4 to 6 cells/HPF. Firm adhesion was inhibited in the Epo-recipient group, resulting in 84 ± 34 cells/mm(2) at 6 hours of reperfusion (p < 0.05). Capillary leukocyte plugging was also reduced in the Epo-recipient group (p < 0.05). Epo exerted no effect on leukocyte rolling. Histology revealed significant myocardial edema formation in allografts, without any alteration by Epo treatment. Immunohistochemistry indicated the involvement of resident cardiac mast cells. Allograft rejection was not affected by Epo treatment.. We demonstrate that non-hematopoietic treatment with Epo inhibits acute post-ischemic myocardial leukocyte sequestration, without affecting microcirculatory dysfunction and allograft rejection.

Topics: Animals; Cardiotonic Agents; Cell Adhesion; Coronary Vessels; Erythropoietin; Graft Rejection; Heart Transplantation; Leukocytes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microcirculation; Myocardial Ischemia; Transplantation, Homologous

Ischemia-reperfusion (I/R) injury may influence graft function after transplantation. Erythropoietin (EPO) attenuates I/R injury in various animal organs such as intestine, brain, and kidney.. To evaluate the effects of pretreatment with recombinant human EPO (rhEPO) on I/R-induced heart injury.. A rat model of I/R injury was established by ligating the left descending coronary artery for 30 minutes, followed by reperfusion for 4 hours. Fifty Sprague-Dawley rats were divided into 5 groups: sham operation; I/R; I/R+rhEPO, 100 U/kg; I/R+rhEPO, 1000 U/kg; and I/R+rhEPO, 5000 U/kg. Electrocardiograms were assessed continuously to note arrhythmia caused by reperfusion. Serum concentrations of interleukin (IL)-6 and IL-8, and tumor necrosis factor-alpha were measured at 2 and 4 hours after reperfusion.. The rhEPO-treated animals exhibited dosage-dependent significant reduction in the incidence of ventricular arrhythmia caused by reperfusion, and markedly decreased serum concentrations of IL-6, IL-8, and tumor necrosis factor-alpha (P < .05) compared with the I/R group (P < .05).. The rhEPO attenuates myocardial I/R injury in rats, at least in part related to inhibition of the system inflammatory response.

Topics: Animals; Erythropoietin; Humans; Inflammation; Interleukin-6; Interleukin-8; Myocardial Ischemia; Myocardial Reperfusion Injury; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reperfusion Injury; Tumor Necrosis Factor-alpha

We have previously demonstrated that endothelium-derived hydrogen peroxide (H(2)O(2)) plays an important role in the canine coronary microcirculation as an endothelium-derived hyperpolarizing factor in vivo. However, it remains to be examined whether endogenous H(2)O(2) is involved in the dilatation of coronary collaterals during myocardial ischemia in vivo and, if so, whether erythropoietin (EPO) enhances the responses. Canine subepicardial native collateral small arteries (CSA; ≥ 100 μm) and arterioles (CA; <100 μm) were observed using an intravital microscope. Experiments were performed after left anterior descending coronary artery ischemia (90 min) under the following eight conditions (n = 5 each): control, EPO, EPO+catalase, EPO+N-monomethyl-l-arginine (l-NMMA), EPO+l-NMMA+catalase, EPO+l-NMMA+iberiotoxin [Ca(2+)-activated K(+) (K(Ca)) channel blocker], EPO+l-NMMA+apamin+charybdotoxin (K(Ca) channel blocker), and EPO+wortmannin (phosphatidylinositol 3-kinase inhibitor). Myocardial ischemia caused significant vasodilatation in CA but not in CSA under control conditions, which was significantly decreased by catalase in CA. After EPO, the vasodilatation was significantly increased in both sizes of arteries and was significantly decreased by catalase. The enhancing effect of EPO was reduced by l-NMMA but not by catalase in CSA and was reduced by l-NMMA+catalase in CA, where the greater inhibitory effects were noted with l-NMMA+catalase, l-NMMA+iberiotoxin, L-NMMA+apamin+charybdotoxin, or wortmannin. EPO significantly ameliorated ischemia-induced impairment of myocardial Akt phosphorylation, which was abolished by l-NMMA+catalase or wortmannin. EPO also ameliorated oxidative stress and myocardial injury, as assessed by plasma 8-hydroxydeoxyguanosine and troponin-T, respectively. These results indicate that EPO enhances H(2)O(2)-mediated dilatation of coronary collateral arterioles during myocardial ischemia in dogs in vivo.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Arterioles; Carbon Dioxide; Collateral Circulation; Coronary Circulation; Coronary Vessels; Deoxyguanosine; Disease Models, Animal; Dogs; Enzyme Inhibitors; Erythropoietin; Female; Hydrogen Peroxide; Male; Myocardial Ischemia; Nitric Oxide Synthase Type III; Oxygen; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Potassium Channel Blockers; Protein Kinase Inhibitors; Troponin T; Vasodilation; Vasodilator Agents

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

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

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

Circulating erythropoietin (EPO) is mainly produced in the kidneys, depending on blood oxygen level. The present study investigated the postmortem serum EPO levels with regard to the cause of death and survival time. Serial medicolegal autopsy cases of postmortem time within 48 h (n = 536) were examined. Serum EPO levels were within the clinical reference range in most cases. Uremic patients with medical administration of an EPO agent (n = 11) showed a markedly high level (140-4,850 mU/ml; median, 1,798 mU/ml). Otherwise, an elevation in serum EPO level (>30 mU/ml) was mainly seen in protracted deaths due to blunt injury and fire fatality, depending on the survival time (r = 0.69, p < 0.0001, and r = 0.45, p < 0.0001, respectively), and in subacute deaths from gastrointestinal bleeding and infectious diseases. However, mildly to moderately elevated serum EPO levels were sporadically found in acute deaths due to mechanical asphyxiation, fire fatality, and acute ischemic heart disease, and in fatal hypothermia cases, especially for elderly subjects. Protracted deaths due to mechanical asphyxiation and ischemic heart disease did not show any survival time-dependent increase in serum EPO level (p > 0.05). EPO was immunohistochemically detected in the tubular epithelia and interstitial cells, showing no evident difference among the causes of death, independent of survival time or serum level. These findings suggest that serum EPO can be used as a marker for investigating anemia and/or hypoxia as a consequence of fatal insult in subacute or prolonged deaths, or a predisposition to traumatic deaths or fatal heart attacks in acute deaths.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asphyxia; Biomarkers; Communicable Diseases; Drowning; Erythropoietin; Female; Fires; Forensic Pathology; Gastrointestinal Hemorrhage; Humans; Hypothermia; Immunohistochemistry; Kidney; Male; Middle Aged; Myocardial Ischemia; Postmortem Changes; Sensitivity and Specificity; Time Factors; Uremia; Wounds, Nonpenetrating; Young Adult

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

EPO (erythropoietin) has recently been shown to have protective actions upon the myocardium; however, the direct effects of EPO upon cardiac contractile and secretory functions are unknown and the signalling mechanisms are not well defined. In the present study, we provide the first evidence of direct cardiac contractile actions of EPO. In isolated perfused Sprague-Dawley rat hearts, a 30 min infusion of EPO significantly increased contractility in a dose-dependent fashion (maximal change 18+/-2% with 1 unit/ml EPO; P<0.005 compared with vehicle). Perfusate ET-1 (endothelin-1) increased transiently during EPO infusion, and the ET(A/)ET(B) antagonist bosentan abolished the inotropic response to EPO. BNP (B-type natriuretic peptide) secretion (28+/-8%; P<0.05) and nuclear transcription factor GATA-4 DNA-binding activity (51%; P<0.05) were both significantly increased by EPO and blocked by bosentan. In a model of global ischaemic injury, delivery of 1 unit/ml EPO during reperfusion significantly attenuated creatine kinase release (28+/-12%; P<0.05) and significantly improved contractile recovery (P<0.001), independent of ET(A) blockade. Apoptotic indices [assessed by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling)/cleaved caspase-3-positive cells] were significantly decreased (P<0.01) by 1 unit/ml EPO during reperfusion alone, coincident with significantly increased phosphorylation of myocardial JAK2 (Janus kinase 2) and STAT3 (signal transducer and activator of transcription 3). Thus EPO directly enhances cardiac contractility and BNP secretion and alleviates ischemia/reperfusion injury via ET-1-dependent and -independent mechanisms respectively.

Topics: Animals; Apoptosis; Bosentan; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Erythropoietin; Heart; Humans; Janus Kinase 2; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Natriuretic Peptide, Brain; Perfusion; Phosphorylation; Rats; Rats, Sprague-Dawley; Recombinant Proteins; STAT3 Transcription Factor; Stimulation, Chemical; Sulfonamides

Cardiovascular disease is an important burden in the Western world, with a prevalence that is increasing exponentially. Indeed, the lifetime risk of coronary artery disease at 40 years of age is 1 in 2 for men and 1 in 3 for women, and it is estimated that one-third of the population worldwide will die of cardiovascular disease, with a majority of these deaths related to MI (myocardial infarction) or the complications of MI. Recent research has suggested that EPO (erythropoietin), an endogenous erythropoietic hormone, may have pleiotropic effects well beyond the maintenance of red blood cells, and may have a cardiovascular role as well, including a potentially salutary effect on reperfusion injury. Although findings supportive of a role of EPO as a cardioprotective agent appear promising, the mechanisms behind the observed benefits remain elusive. In the present issue of Clinical Science, Piuhola and co-workers provide an interesting study that may shed light on the effects of EPO (and possibly related compounds) in the context of acute MI.

Topics: Erythropoietin; Female; Humans; Male; Myocardial Ischemia; Myocardial Reperfusion Injury

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

Recent studies from our lab and others have shown that the hematopoietic cytokine erythropoietin (EPO) can protect the heart from ischemic damage in a red blood cell-independent manner. Here we examined any protective effects of the long-acting EPO analog darbepoetin alfa (DA) in a rat model of ischemia-reperfusion (I/R) injury. Rats were subjected to 30-min ischemia followed by 72-h reperfusion. In a dose-response study, DA (2, 7, 11, and 30 mug/kg) or vehicle was administered as a single bolus at the start of ischemia. To determine the time window of potential cardioprotection, a single high dose of DA (30 mug/kg) was given at either the initiation or the end of ischemia or at 1 or 24 h after reperfusion. After 3 days, cardiac function and infarct size were assessed. Acute myocyte apoptosis was quantified by TUNEL staining on myocardial sections and by caspase-3 activity assays. DA significantly reduced infarct size from 32.8 +/- 3.5% (vehicle) to 11.0 +/- 3.3% in a dose-dependent manner, while there was no difference in ischemic area between groups. Treatment with DA as late as 24 h after the beginning of reperfusion still demonstrated a significant reduction in infarct size (17.0 +/- 1.6%). Consistent with infarction data, DA improved in vivo cardiac reserve compared with vehicle. Finally, DA significantly decreased myocyte apoptosis and caspase-3 activity after I/R. These data indicate that DA protects the heart against I/R injury and improves cardiac function, apparently through a reduction of myocyte apoptosis. Of clinical importance pointing toward a relevant therapeutic utility, we report that even if given 24 h after I/R injury, DA can significantly protect the myocardium.

Topics: Animals; Cardiotonic Agents; Darbepoetin alfa; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoietin; Hematinics; Humans; Male; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Treatment Outcome

This chapter describes a system using adeno-associated viral (AAV) vector to deliver hypoxia-inducible gene expression to ischemic hearts. The hypoxia induction of gene expression in this system is based on the accumulation of hypoxia-inducible factor-1 (HIF-1) in ischemic hearts and the use of hypoxia-response element (HRE) identified from the enhancers of genes, the expression of which can be induced by hypoxia. The methods of plasmid and AAV vector construction for hypoxia-inducible gene expression, viral vector production and purification, and viral titer determination are described. This chapter also illustrates the methods that can be used to test hypoxia-inducible gene expression in vitro and in vivo, including hypoxia treatment of cultured cells, generation of murine ischemic heart models, and analysis of gene expression.

Topics: 3T3 Cells; Animals; Base Sequence; Cell Line; Dependovirus; Erythropoietin; Gene Expression; Genetic Therapy; Genetic Vectors; HeLa Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lac Operon; Mice; Molecular Sequence Data; Myocardial Ischemia; Response Elements; Transcription Factors; Transfection; Vascular Endothelial Growth Factors

Recently we found that the level of anti-infarct tolerance afforded by ischemic preconditioning (IPC) and erythropoietin (EPO) infusion was closely correlated with the level of Ser9-phospho-GSK-3beta upon reperfusion in the heart. To get an insight into the mechanism by which phospho-GSK-3beta protects the myocardium from ischemia/reperfusion injury, we examined the effects of IPC and EPO on interactions between GSK-3beta and subunits of the mitochondrial permeability transition pore (mPTP) in this study. Rat hearts were subjected to 25-min global ischemia and 5-min reperfusion in vitro with or without IPC plus EPO infusion (5 units/ml) before ischemia. Ventricular tissues were sampled before or after ischemia/reperfusion to separate subcellular fractions for immunoblotting and immunoprecipitation. Reperfusion increased mitochondrial GSK-3beta by 2-fold and increased phospho-GSK-3beta level in all fractions examined. Major subunits of mPTP, adenine nucleotide translocase (ANT) and voltage-dependent anion channel (VDAC), were co-immunoprecipitated with GSK-3beta after reperfusion. Phospho-GSK-3beta was co-immunoprecipitated with ANT but not with VDAC. IPC+EPO significantly increased the levels of GSK-3beta and phospho-GSK-3beta that were co-immunoprecipitated with ANT to 145+/-8% and 143+/-16%, respectively, of baseline but did not induce phospho-GSK-3beta-VDAC binding. A PKC inhibitor and a PI3 kinase inhibitor suppressed the IPC+EPO-induced increase in the level of phospho-GSK-3beta-ANT complex. The level of cyclophilin D co-immunoprecipitated with ANT after reperfusion was significantly reduced to 39+/-10% of the control by IPC+EPO. These results suggest that reduction in affinity of ANT to cyclophilin D by increased phospho-GSK-3beta binding to ANT may be responsible for suppression of mPTP opening and myocardial protection afforded by IPC+EPO.

Topics: Animals; Disease Models, Animal; Erythropoietin; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; In Vitro Techniques; Intracellular Membranes; Kinetics; Mitochondria, Heart; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocardial Ischemia; Phosphorylation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Ventricular Function

The cardioprotection afforded by ischemic preconditioning (IPC) and ischemic postconditioning (PC) are receptor mediated. In this review, we will focus on the major ligand classes and receptors that contribute to IPC and PC-induced cardioprotection. Ligand classes discussed include adenosine, bradykinin, opioids, erythropoietin, adrenergics and muscarinics. The cardioprotective therapeutic window of each ligand class will also be summarized, with particular focus as to whether ligands are protective when administered at or close to the time of reperfusion. Information will primarily be directed at studies in which infarct size reduction is the gold standard to assess the efficacy of IPC and PC. Myocardial stunning is a less robust endpoint for assessing cardioprotection and the use of this endpoint is only limited to studies with human tissue where infarct size assessment is not possible. Receptor cross-talk between ligands and the common signaling pathways involved for these ligands will also be briefly discussed.

Topics: Adenosine; Adrenergic Agents; Bradykinin; Cholinergic Agents; Erythropoietin; Humans; Ischemic Preconditioning, Myocardial; Ligands; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Narcotics; Protein Binding

Apart from its well-known stimulation of erythropoiesis, erythropoietin (EPO) exhibits angiogenic and anti-apoptotic effects. These cellular protective effects have also been described in experimental acute myocardial infarction models. We investigated the effects of EPO in a porcine model of chronic progressive myocardial ischaemia.. At weeks 2 and 6 after implantation of a circumflex ameroid constrictor, endocardial electromechanical NOGA system (Biosense Webster, Inc., California, USA) mapping of the left ventricle, coronary and ventricular angiography, as well as echocardiography were performed. Two weeks after ameroid placement, 13 pigs were randomized with 7 pigs receiving 10.000 U EPO and 6 pigs receiving placebo into the ischaemic region using a NOGA guided percutaneous transendocardial injection catheter, MYOSTAR. After 6 weeks, histology (Masson's Trichrome) was analyzed.. Endocardial electromechanical mapping showed an increase of mean unipolar voltage (UV) amplitude in the ischaemic myocardial segments in the EPO-treated animals (8.5 mV pre and 10.6 mV post treatment) and a significantly reduced ischaemic surface area compared to the control group (19% vs. 41%) suggesting a decline in ischaemic injury. Echocardiography revealed 2,2 hypokinetic segments of the lateral wall in the EPO group vs. 3,3 in the control groups. The mean ejection fraction was 64% in the EPO group and 55% in the placebo group. Quantitative histological analysis of the ischaemic regions revealed a reduction of myocardial fibrosis (8% vs. 28%) in the EPO group.. Endocardial EPO injection may induce cardioprotective effects in hibernating myocardium and may attenuate the progression of ischaemic tissue damage.

Topics: Animals; Chronic Disease; Coronary Circulation; Disease Models, Animal; Disease Progression; Electrophysiologic Techniques, Cardiac; Endocardium; Erythropoietin; Image Processing, Computer-Assisted; Myocardial Contraction; Myocardial Ischemia; Myocardial Stunning; Swine; Ultrasonography

Bone marrow cell implantation (BMI) has been utilized to treat patients with limb and heart ischemia. BMI provides angiogenic precursors and angiogenic cytokine-producing cells, especially erythroid cells. In this study, we induced in vitro angiogenesis cultures and in vivo BMI simulation using a murine limb ischemia model to examine the role of erythroid cells and the effect of erythropoietin (EPO). Human erythroid colonies (BFU-e) induced capillary networks around the colonies in vitro. Erythroid cells in human bone marrow produced vascular endothelial growth factor and placental growth factor. The angiogenic effects of erythroid cells were further amplified in the presence of EPO. Limb-ischemic mice were treated with BMI +/- EPO, and limb survival, blood flow recovery, and muscle histology were analyzed. Treatment with whole bone marrow cells + EPO significantly improved limb survival and blood flow. The cumulative effects of EPO on BMI induced and increase in capillary number and artery enlargement. Erythroid cells were essential for the in vivo effects of BMI, and CD14-positive cells supported the biological effects. In addition to the direct effect of EPO on angiogenesis, EPO showed indirect effect on angiogenesis through amplifying the angiogenic effects by erythroid cells supported by CD14-positive cells.

Topics: Adult; Animals; Bone Marrow Cells; Bone Marrow Transplantation; Disease Models, Animal; Endothelium, Vascular; Erythroid Cells; Erythroid Precursor Cells; Erythropoietin; Female; Humans; Lipopolysaccharide Receptors; Male; Mice; Mice, Inbred ICR; Myocardial Ischemia; Neovascularization, Physiologic; Platelet Endothelial Cell Adhesion Molecule-1

Topics: Cardiotonic Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Humans; Myocardial Ischemia; Neovascularization, Physiologic; Reperfusion Injury; Ventricular Remodeling

Erythropoietin (EPO), a cytokine best known for its ability to increase red blood cell mass, has recently been shown to protect cardiomyocytes from apoptotic cell death. The objective of the present study was to investigate the role of endothelial nitric oxide synthase (eNOS) in the anti-apoptotic effects of EPO in cardiomyocytes.. Neonatal mouse ventricular cardiomyocytes were isolated and cultured from wild-type and eNOS(-/-) mice. Treatment with EPO significantly reduced apoptosis induced by norepinephrine (NE) in the wild-type cardiomyocytes. The reduction of apoptosis was associated with significant increases in eNOS expression, phosphorylation and NO production. However, the anti-apoptotic effects of EPO were significantly decreased in wild-type cardiomyocytes treated with L-NAME, which inhibits nitric oxide synthase activity. The results were further confirmed using eNOS(-/-) cardiomyocytes. To investigate the in vivo significance of eNOS in mediating the anti-apoptotic effects of EPO, wild-type and eNOS(-/-) mice were subjected to myocardial ischemia and reperfusion. EPO decreased myocardial apoptosis and infarct size in wild-type mice. However, the protective effects of EPO were significantly diminished in eNOS(-/-) mice.. EPO increases eNOS expression and NO production in cardiomyocytes. The anti-apoptotic effects of EPO in cardiomyocytes are mediated by eNOS-derived NO production.

Topics: Animals; Apoptosis; Caspase 3; Cells, Cultured; Erythropoietin; Glyceraldehyde-3-Phosphate Dehydrogenases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphorylation; Recombinant Proteins; Up-Regulation

Topics: Animals; Erythropoietin; Humans; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction

To study the cardioprotection of recombinant human erythropoietin (rhEPO) preconditioning (EPC) and to investigate the role and possible mechanism of cyclooxygenase (COX)-2 in the delayed phase of EPC.. In phase 1, myocardial ischaemia reperfusion (I-R) rat model was established by 30 minutes ligation of left descending coronary and three hours of reperfusion. Rats were given 0.9% saline solution or rhEPO 24 hours before I-R protocol. COX-2 selective inhibitor celecoxib was given for further investigation of the cardioprotection of EPC. At the end of I-R protocol, infarct sizes were measured and ultrastructural organisations were studied. In phase 2, myocardial COX-2 mRNA expressions and prostaglandins (PGs) contents were studied in different groups after euthanasia.. It was found that EPC could elicit potent cardioprotection against I-R injury, shown by reduction of infarct size and improvement of ultrastructural organisation; whereas administration of celecoxib resulted in complete loss of this protection. EPC resulted in robust increase in COX-2 mRNA and PGs levels that were also abrogated by celecoxib.. COX-2 plays an essential part in cardioprotection of the delayed phase of EPC in rats, which might be related to actions of PGE(2) or PGI(2), or both.

Topics: Animals; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Erythropoietin; Ischemic Preconditioning, Myocardial; Ligation; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Pyrazoles; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Sulfonamides

Accumulating studies demonstrate that the expressions of hypoxia-inducible factor 1 (HIF-1), erythropoietin (EPO) and vascular endothelial growth factor (VEGF) depend on cellular oxygen tension, which is involved in the pathological process of tissue hypoxia and/or ischemia. The present study investigated hypoxia-inducible factor-1alpha (HIF-1alpha), EPO and VEGF mRNA expressions in the kidney with regard to the cause of death in medicolegal autopsy. Relative quantifications of HIF-1alpha, EPO and VEGF mRNAs, based on real-time TaqMan reverse transcription-polymerase chain reaction (RT-PCR), were performed on tissue specimens obtained from consistent sites of the bilateral renal cortices. The cases (total, n=245, 6-48h postmortem) included fatal blunt/sharp instrument injuries (n=53/31), asphyxia (n=28: aspiration, n=8; strangulation/hanging, n=20), drowning (n=27), fire fatality (n=62), acute myocardial infarction/ischemia (AMI, n=39), and gastrointestinal hemorrhage (n=5). Both HIF-1alpha and EPO mRNA levels were significantly lower in drowning cases. More characteristic findings were found for VEGF mRNA: it showed higher expression levels for AMI, acute blunt/sharp instrument injury, and aspiration, whereas it was lower for neck compression (strangulation/hanging), drowning, fire fatality with higher blood carboxyhemoglobin (COHb) levels (>60%), peracute blunt injury, and gastrointestinal hemorrhage. Quantitative assays of renal HIF-1alpha, EPO and VEGF mRNA transcripts are potentially useful for investigating the pathophysiology of death, and VEGF mRNA may be especially useful as an indication of acute circulatory failure.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asphyxia; Child; Drowning; Erythropoietin; Female; Fires; Forensic Pathology; Gastrointestinal Hemorrhage; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Male; Middle Aged; Myocardial Ischemia; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vascular Endothelial Growth Factor A; Wounds, Nonpenetrating; Wounds, Penetrating

Topics: Animals; Cardiotonic Agents; Erythropoietin; Hematopoiesis; Humans; Myocardial Ischemia; Receptors, Erythropoietin; Recombinant Proteins

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

Overexpression of erythropoietin (Epo) in mice (Epo-tg6) leads to an increase in hematocrit and blood volume, and strongly reduces endurance upon exercise. It was the aim of this study to characterize the mechanisms underlying the reduced cardiac performance.. Left (LV) and right (RV) ventricular function was measured with and without norepinephrine (NE) stimulation in 12 anaesthetized Epo-tg6 and in 13 wild-type (WT) control mice.. There were no differences in heart function under baseline resting conditions. Stimulation with NE (10 microl bolus injections of 1-100 ng per mouse) in WT mice led to a dose-dependent increase in heart rate (HR), LV developed pressure (LVDP) and rate of rise in LV pressure (LV dP/dt(max)), while LV end-diastolic pressure (LVEDP) was unchanged. Except for HR, these parameters increased to a lesser extent in EPO-tg6 mice. Strikingly, LVEDP strongly increased in Epo-tg6 mice after NE (up to >20 mmHg). Eleven out of 13 Epo-tg6, but none of the WT mice died or required resuscitation after high-doses of NE. In these cases severe diastolic dysfunction became overt since the relative myocardial relaxation time was significantly prolonged and the duration of diastole was shortened. Moreover, the ECG showed a marked ST segment depression as well as deep negative T-waves. The NE-induced reduction in myocardial adenosin-triphosphate (ATP) content was more pronounced in Epo-tg6 mice after 10 min of continuous NE infusion (50 ng/min per mouse).. NE-induced stress in Epo-tg6 mice led to acute heart failure associated with diastolic dysfunction and myocardial ischemia.

Topics: Acute Disease; Adenosine Triphosphate; Animals; Diastole; Dose-Response Relationship, Drug; Electrocardiography; Erythropoietin; Heart Rate; Mice; Mice, Transgenic; Myocardial Ischemia; Myocardium; Norepinephrine; Stimulation, Chemical; Ventricular Pressure

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

Erythropoietin is protective against cardiac ischemia, but the underlying mechanisms are unknown. We determined whether erythropoietin (0.5 - 10.0 U/ml) confers acute cardioprotection in infant rabbit hearts and the contribution of protein kinases, nitric oxide synthase and potassium channels to the underlying mechanism. Hearts from normoxic infant New Zealand White rabbits (n=8/group) were isolated and perfused in the Langendorff mode. Biventricular function was recorded under steady-state conditions prior to 30 min global no-flow ischemia and 35 min reperfusion. Administration of erythropoietin for 15 min immediately prior to ischemia resulted in a concentration-dependent increase in recovery of left and right ventricular developed pressure in rabbit hearts following myocardial ischemia and reperfusion. The optimal concentration of erythropoietin that afforded maximum recovery of developed pressure was manifest at 1.0 U/ml. Erythropoietin (1.0 U/ml) treatment resulted in phosphorylation of PKC, p38 MAP kinase and p42/44 MAP kinase. The cardioprotective effects of erythropoietin were abolished by the protein kinase inhibitors SB203580 (p38 MAP kinase), PD98059 (p42/44 MAP kinase) and chelerythrine (PKC) as well as the potassium channel blockers glibenclamide, HMR 1098, 5-HD and Paxilline. Nitrite and nitrate release from hearts before (2.3 +/- 0.9 nmol/min/g) and after (2.4 +/- 1.9 nmol/min/g) 15 min treatment with erythropoietin (1.0 U/ml) were not different. L-NAME and L-NMA did not block the cardioprotective effect of erythropoietin. We conclude the rapid activation of potassium channels and protein kinases by erythropoietin represents an important new mechanism for increasing cardioprotection.

Topics: Animals; Blotting, Western; Dose-Response Relationship, Drug; Erythropoietin; Heart; Myocardial Ischemia; Nitric Oxide Synthase; Organ Culture Techniques; Potassium Channels; Protein Kinase Inhibitors; Protein Kinases; Rabbits; Reperfusion Injury; Signal Transduction

Parenteral administration of recombinant human erythropoietin (rhEPO) to rats induces protection against myocardial ischemia/reperfusion injury 24 hours later. However, the mechanisms by which rhEPO mediates protection have not been determined.. rhEPO was perfused into isolated rat hearts over 15 minutes immediately before 30 minutes of no-flow ischemia and 45 minutes of reperfusion. Compared with saline-perfused control hearts, recovery of left ventricular developed pressure was increased in rhEPO-perfused hearts. rhEPO also increased AKT activity and decreased apoptosis. All of these effects were blocked when the phosphatidylinositol-3-kinase inhibitor wortmannin was infused with rhEPO.. rhEPO provides immediate protection against ischemia/reperfusion injury in the isolated perfused rat heart that is mediated by the phosphatidylinositol-3-kinase pathway.

Topics: Androstadienes; Animals; Apoptosis; Cardiotonic Agents; Enzyme Inhibitors; Erythropoietin; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Signal Transduction; Wortmannin

Here we investigate the effects of erythropoietin (EPO) on the tissue/organ injury caused by hemorrhagic shock (HS), endotoxic shock, and regional myocardial ischemia and reperfusion in anesthetized rats. Male Wistar rats were anesthetized with thiopental sodium (85 mg/kg i.p.) and subjected to hemorrhagic shock (HS; i.e., mean arterial blood pressure reduced to 45 mmHg for 90 min, followed by resuscitation with shed blood for 4 h), endotoxemia (for 6 h), or left anterior descending coronary artery occlusion (25 min) and reperfusion (2 h). HS and endotoxemia resulted in renal dysfunction and liver injury. Administration of EPO (300 IU/kg i.v., n = 10) before resuscitation abolished the renal dysfunction and liver injury in hemorrhagic, but not endotoxic, shock. HS also resulted in significant increases in the kidney of the activities of caspases 3, 8, and 9. This increase in caspase activity was not seen in HS rats treated with EPO. In cultured human proximal tubule cells, EPO concentration-dependently reduced the cell death and increase in caspase-3 activity caused by either ATP depletion (simulated ischemia) or hydrogen peroxide (oxidative stress). In the heart, administration of EPO (300 IU/kg i.v., n = 10) before reperfusion also caused a significant reduction in infarct size. In cultured rat cardiac myoblasts (H9C2 cells), EPO also reduced the increase in DNA fragmentation caused by either serum deprivation (simulated ischemia) or hydrogen peroxide (oxidative stress). We propose that the acute administration of EPO on reperfusion and/or resuscitation will reduce the tissue injury caused by ischemia-reperfusion of the heart (and other organs) and hemorrhagic shock.

Topics: Animals; Blood Pressure; Disease Models, Animal; Erythropoietin; Heart Rate; Male; Myocardial Ischemia; Rats; Reperfusion Injury; Shock, Hemorrhagic

Therapeutic angiogenesis with gene encoding vascular endothelial growth factor (VEGF) is a new potential treatment in cardiovascular disease. However, unregulated VEGF-mediated angiogenesis has the potential to promote tumor growth, accelerate diabetic proliferative retinopathy, and promote rupture of atherosclerotic plaque. To be safe and effective, gene therapy with VEGF must be regulated. To limit the risk of pathological angiogenesis, we developed a hypoxia-inducible VEGF gene therapy system using the erythropoietin (Epo) enhancer and water-soluble lipopolymer (WSLP). pEpo-SV-VEGF or pSV-VEGF-Epo was constructed by insertion of the Epo enhancer upstream of the Simian Virus 40 (SV40) promoter or downstream of the poly(A) signal of pSV-VEGF. In vitro transfection showed that pEpo-SV-VEGF, not pSV-VEGF-Epo, induced the VEGF expression in hypoxic cells. In addition, the VEGF protein, which was produced from the Epo-SV-VEGF-transfected and hypoxia-incubated cells, was able to enhance the proliferation of the endothelial cells. Injection of the pEpo-SV-VEGF/WSLP complex showed that the expression of VEGF was induced in ischemic myocardium, compared to normal myo-cardium. Therefore, with the localized induction of VEGF and the low cytotoxicity of WSLP, the pEpo-SV-VEGF/WSLP system may be helpful to eventually treat ischemic heart disease.

Topics: Animals; Cell Division; Endothelial Growth Factors; Endothelium, Vascular; Enhancer Elements, Genetic; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Gene Expression; Genetic Engineering; Genetic Therapy; Humans; Hypoxia; Intercellular Signaling Peptides and Proteins; Liposomes; Luciferases; Lymphokines; Models, Animal; Myocardial Ischemia; Neovascularization, Physiologic; Polymers; Rabbits; Stem Cells; Transfection; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Apoptosis is a contributing cause of myocyte loss in ischemic heart disease. Recent work has shown that erythropoietin (EPO) offers protection against apoptosis in a wide variety of tissues. We demonstrate that the erythropoietin receptor (EPOR) is expressed in the neonatal rat ventricular myocyte (NRVM). Exposure of NRVMs to hypoxia, with recombinant human EPO, significantly decreased apoptosis as measured by TUNEL, flow cytometry, and caspase 3/7 like activity when compared to hypoxia treatment alone. EPO administered at the initiation of coronary artery occlusion in the rat significantly decreased apoptosis in the myocardial ischemic region. In the NRVM, EPO increased the activity of Akt. The anti-apoptotic effect of EPO was abrogated by co-treatment with LY294002, a specific blocker of phosphatidylinositol 3-kinase (PI3-K). Our study demonstrates that EPO inhibits apoptosis in the NRVM exposed to hypoxia, through an Akt-dependent pathway. EPO also inhibits apoptosis in the in vivo rat model of myocardial ischemia.

Topics: Animals; Apoptosis; Caspase 3; Caspase 7; Caspases; Erythropoietin; Flow Cytometry; Heart Ventricles; Hypoxia; Immunohistochemistry; In Situ Nick-End Labeling; Male; Myocardial Ischemia; Myocardium; Phosphatidylinositol 3-Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin

Intramyocardial injection of genes encoding angiogenic factors could provide a useful approach for the treatment of ischemic heart disease. However, uncontrolled expression of angiogenic factors in vivo may cause some unwanted side effects, such as hemangioma formation, retinopathy, and arthritis. It may also induce occult tumor growth and artherosclerotic plaque progression. Because hypoxia-inducible factor 1 is up-regulated in a variety of hypoxic conditions and it regulates gene expression by binding to a cis-acting hypoxia-responsive element (HRE), we propose to use HRE, found in the 3' end of the erythropoietin gene to control gene expression in ischemic myocardium. A concatemer of nine copies of the consensus sequence of HRE isolated from the erythropoietin enhancer was used to mediate hypoxia induction. We constructed two adeno-associated viral vectors in which LacZ and vascular endothelial growth factor (VEGF) expressions were controlled by this HRE concatemer and a minimal simian virus 40 promoter. Both LacZ and VEGF expression were induced by hypoxia and/or anoxia in several cell lines transduced with these vectors. The functions of these vectors in ischemic myocardium were tested by injecting them into normal and ischemic mouse myocardium created by occlusion of the left anterior descending coronary artery. The expression of LacZ gene was induced eight times and of VEGF 20 times in ischemic myocardium compared with normal myocardium after the viral vector transduction. Hence, HRE is a good candidate for the control of angiogenic factor gene expression in ischemic myocardium.

Topics: 3T3 Cells; Animals; Cell Line; Dependovirus; DNA-Binding Proteins; Endothelial Growth Factors; Erythropoietin; Gene Expression; Genetic Therapy; Genetic Vectors; HeLa Cells; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Lac Operon; Lymphokines; Mice; Myocardial Ischemia; Nuclear Proteins; Transcription Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Systemic hypertension may develop, or worsen, in 20-30% of haemodialysis patients treated with recombinant human erythropoietin (r-HuEPO). No particular group of patients, however, should be excluded from r-HuEPO treatment because of this increased risk. In the vast majority of cases, hypertension can be managed effectively by reducing dry weight, and by adding an antihypertensive agent if necessary. Only if these approaches are ineffective should the dose of r-HuEPO be reduced. Patients on dialysis are likely to be intolerant of cardiac ischaemia, as a result of coronary artery disease, microvascular occlusive disease, inadequate neo-vascularization in cardiac hypertrophy, or reduced glucose uptake (which impairs non-oxidative metabolism of the heart). Treatment with r-HuEPO can significantly reduce cardiac risk, as measured by surrogate endpoints such as left ventricular hypertrophy. More studies are urgently needed to investigate the potential beneficial effects of r-HuEPO on hard endpoints such as cardiac morbidity and mortality. In addition, dose-response data for target haematocrits in the range 30-40% are needed before an appropriate target haematocrit can be determined for patients with symptomatic vascular and cardiac disease.

Topics: Erythropoietin; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Myocardial Ischemia; Peripheral Vascular Diseases; Recombinant Proteins

Topics: Adult; Aged; Aged, 80 and over; Anemia; Angina Pectoris; Arrhythmias, Cardiac; Drug Evaluation; Erythropoietin; Female; Follow-Up Studies; Humans; Immunologic Factors; Incidence; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Ischemia; Recombinant Proteins; Renal Dialysis

From a total of 81 patients on maintenance hemodialysis who underwent coronary angiography, 8 patients fulfilled the criteria: significant coronary artery disease, hematocrit less than 27%, reproducible (ECG) positive treadmill test, no disturbance of repolarization in ECG at rest. Exercise stress testing was performed at a hematocrit of 25 +/- 2% and following erythropoietin therapy at a hematocrit of 34 +/- 0.5%. Symptom-limited exercise performance increased in all patients (1.10 +/- 0.3 W/kg b.w. vs. 1.44 +/- 0.31 W/kg b.w., p less than 0.01) as well as exercise duration (489 vs. 362 s, p +/- 0.01). ST segment depression during maximal exercise was reduced from a mean of 2.1 to 0.4 mm (p less than 0.01). It is concluded that amelioration of renal anemia by erythropoietin in dialysis patients with significant coronary artery disease reduces exercise-induced myocardial ischemia.

Topics: Adult; Anemia; Coronary Disease; Erythropoietin; Exercise; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Renal Dialysis