losartan-potassium and Cardiomyopathy--Dilated

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

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

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

Dilated cardiomyopathy (DCM) is considered as the final common response of myocardium to diverse genetic and environmental insults and characterized mainly by left ventricular systolic dysfunction. The current therapies for the treatment of DCM are costly high and outcomes are often unsatisfactory. To date, mesenchymal stem cells (MSCs) have been thought to be an ideal stem cell to repair damaged myocardium but was still within relatively small scales and few cases have been conducted in clinical trials. The use of erythropoietin (EPO), a growth factor produced in the kidneys have been found prevent cardiomyocyte apoptosis. This study was aimed to transplant MSCs into DCM rat bone marrow to express EPO in vivo and investigate the regulation of EPO on cell signaling pathways after transfection. The results found that transplantation of MSCs carrying EPO could significantly relief the cardiac dysfunctions of the DCM rat. This underylying mechanism involved with inhibiting p-NF-κB and p-P38, regulateing and promoting the anti-inflammatory balance, thereby alleviating tissue injury in DCM rats and exhibiting a protective role. Meanwhile, the MSCs + EPO treatment in DCM rat also activated the p-Akt pathway and thus protecting the myocardium from apoptosis in DCM rats. The study revealed an potential therapeutic effect of MSCs and EPO in clinical and provided a molecular mechanism of action for treating DCM.

Topics: Animals; Cardiomyopathy, Dilated; Erythropoietin; Heart Function Tests; Hemodynamics; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Myocardium; Phosphorylation; Rats, Inbred Lew

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

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

Dilated human cardiomyopathy is associated with suppression of the prosurvival phosphatidylinositol-3-kinase (PI3K)/Akt and STAT3 pathways. The present study was carried out to determine if restoration of the PI3K/Akt and STAT3 activity by darbepoetin alfa improved cardiac function or reduced cardiomyocyte apoptosis in rabbit autoimmune cardiomyopathy induced by a peptide corresponding to the second extracellular loop of the ss(1)-adrenergic receptor (ss(1)-EC(II)). We found that ss(1)-EC(II) immunization produced progressive LV dilation, systolic dysfunction and myocyte apoptosis as measured by TUNEL, single-stranded DNA antibody, and active caspase-3. These changes were associated with activation of p38 mitogen-activated protein kinase (MAPK), endoplasmic reticulum stress markers (GRP78 and CHOP), and increased cleavage of procaspase-12, as well as decreased phosphorylation of Akt and STAT3, and decreased Bcl2/Bax ratio. As expected, darbepoetin alfa treatment increased phosphorylation of Akt and STAT3. It also increased the myocardial expression of erythropoietin receptor which was reduced in the failing myocardium, and improved cardiac function in the ss(1)-EC(II)-immunized animals. The latter was associated with reductions of myocyte apoptosis and cleaved caspase-3, as well as reversal of increased phosphorylation of p38-MAPK, increased ER stress, and decline in Bcl2/Bax ratio. The anti-apoptotic effects of darbepoetin alfa via Akt and STAT activation were also demonstrated in cultured cardiomyocytes treated with the anti-ss(1)-EC(II) antibody. These effects of darbepoetin alfa in vitro were prevented by LY294002 and STAT3 peptide inhibitor. Thus, we conclude that darbepoetin alfa improves cardiac function and prevents progression of dilated cardiomyopathy probably by activating the PI3K/Akt and STAT3 pathways and reducing ER stress.

Topics: Animals; Animals, Newborn; Autoimmune Diseases; Cardiomyopathy, Dilated; Cardiotonic Agents; Cells, Cultured; Darbepoetin alfa; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Erythropoietin; Humans; Myocytes, Cardiac; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rabbits; Rats; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor

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

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