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      Impact of Recombinant Human Erythropoietin Treatment on Left Ventricular Hypertrophy and Cardiac Function in Dialysis Patients

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          Abstract

          The results of anemia correction by recombinant human erythropoietin (rHuEPO) therapy with regard to cardiac function and left ventricular hypertrophy in dialysis patients are controversially discussed. The aim of the study was to assess the effects of therapy rHuEPO on cardiac morphology and function in dialysis patients. We studied 11 clinically stable hemodialysis patients with severe renal anemia (hematocrit <27%) and increased left ventricular mass index (LVMi) with no history of coronary or valvular heart disease, systemic disease, severe hyperparathyroidism, hypertension stage 2 or higher, transfusion-dependent anemia, and concurrent rHuEPO treatment. The patients were treated with rHuEPO administered subcutaneously once or twice weekly at a mean dose of 80 ± 31 IU/kg week until the hematocrit was >30% and underwent a complete Doppler echocardiographic study at baseline and at follow-up (after 12.2 ± 2.9 months). At follow-up, ejection fraction and fractional shortening significantly increased from 62.7 ± 13.8 to 67.8 ± 9.7% (p < 0.05) and from 35.5 ± 9.8 to 39.4 ± 7.1% (p < 0.05), respectively, whereas mean velocity of circumferential fiber shortening demonstrated a trend towards amelioration from 1.18 ± 0.23 to 1.27 ± 0.27 circ/s (n.s.). LVMi and morphological data remained unchanged throughout the study. Nevertheless, LVMi changes showed two different behaviors with respect to baseline values: in 6 patients with higher baseline values, LVMi decreased from 229 ± 36 to 191 ± 45 g/m<sup>2</sup> (p < 0.05), while it worsened in 5 patients with less marked LVMi, increasing from 141 ± 32 to 186 ± 40 g/m<sup>2</sup> (p < 0.05). Our data demonstrate that partial correction of renal anemia with rHuEPO therapy seems to improve cardiac performance and to induce a regression of left ventricular hypertrophy, particularly in patients with greater baseline hypertrophy, ultimately confirming the multifactorial pathogenesis of left ventricular hypertrophy.

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          Mitogenic effect of erythropoietin on neonatal rat cardiomyocytes: signal transduction pathways.

          The mitogenic effect of recombinant human erythropoietin (rHuEpo) on primary cultures of neonatal rat cardiac myocytes was observed. rHuEpo triggered a dose-dependent increase in myocyte proliferation. The hormone effect over optimally grown control culture 1 day after addition was maximum with 0.5 U/ml and was inhibited with anti-rHuEpo. Inhibitors of enzymatic pathways known to be involved in the cytokines intracellular mechanism such as genistein (tyrosine kinase inhibitor), 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (phospholipase C [PLC] inhibitor), and 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (protein kinase C [PKC] inhibitor) prevented the mitogenic action of rHuEpo. Also the inhibition of Na(+)-K(+)-ATPase activity by ouabain blunted the stimulatory action of rHuEpo on cell proliferation. The mitogenic action of the hormone was correlated with cardiac membrane paranitrophenylphosphatase (pNPPase) and PKC activity, since concentrations of rHuEpo that stimulate DNA synthesis increased pNPPase and PKC activity. Moreover, the enzymatic inhibition of tyrosine kinase, PLC, and PKC attenuated the stimulatory action of rHuEpo upon cardiac pNPPase activity. In this paper we demonstrate a non-hematopoietic action of rHuEpo showing both mitogenic and enzymatic effect upon primary myocyte cell culture and on pNPPase activity of neonatal rat heart. These effects are related to the capacity of rHuEpo to stimulate Na(+)-K(+)-ATPase activity and appear to be secondary to the activation of tyrosine kinase and PKC, indicating that in the rHuEpo mediated mitogenic action on cardiomyocytes involves the activation of the same enzymatic pathways that have been described by other cytokines in different tissues.
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            Author and article information

            Journal
            BPU
            Blood Purif
            10.1159/issn.0253-5068
            Blood Purification
            S. Karger AG
            0253-5068
            1421-9735
            1998
            December 1998
            14 May 1999
            : 16
            : 6
            : 317-324
            Affiliations
            a Centro di Riferimento di Nefrologia e Dialisi, Azienda USL, b Divisione di Cardiologia, Ospedale di Belcolle, Azienda USL, Viterbo, Italia
            Article
            14351 Blood Purif 1998;16:317–324
            10.1159/000014351
            10343078
            © 1998 S. Karger AG, Basel

            Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

            Page count
            Figures: 1, Tables: 3, References: 30, Pages: 8
            Product
            Self URI (application/pdf): https://www.karger.com/Article/Pdf/14351
            Categories
            Original Paper

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