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Growth Hormone and the Heart

ENDOCRINE UPDATES Shlomo Melmed, MD., Series Editor

1. E.R. Levin and 1.L. Nadler (eds.): Endocrinology of Cardiovascular Function. 1998. ISBN: 0-7923-8217 -X

2. 1.A. Fagin (ed.): Thyroid Cancer. 1998. ISBN: 0-7923-8326-5

3. 1.S. Adams and B.P. Lukert (eds.): Osteoporosis: Genetics, Prevention and Treatment. 1998. ISBN: 0-7923-8366-4.

4. B.-A. Bengtsson (ed.): Growth Rormone. 1999. ISBN: 0-7923-8478-4

5. C. Wang (ed.): Male Reproductive Function. 1999. ISBN 0-7923-8520-9

6. B. Rapoport and S.M. McLachlan (eds.): Graves' Disease: Pathogenesis and Treatment. 2000. ISBN: 0-7923-7790-7.

7. W. W. de Rerder (ed.): Functional and Morphological Imaging of the Endocrine System. 2000. ISBN 0-7923-7923-9

8. R.G. Burger (ed.): Sex Rormone Replacement Therapy. 2001. ISBN 0-7923-7965-9

9. A. Giustina (ed.): Growth Rormone and The Reart. 2001. ISBN 0-7923-7212-3

Growth Hormone And The Heart

Editor

Andrea Giustina, M.D.

Assistant Editor

Filippo Manelli, M.D.

Endocrine Section Department of Internal Medicine

University of Brescia, Italy

SPRINGER scmNCE+BUSINESS MEDIA, LLC

Library of Congress Cataloging-in-Publication Data

Growth hormone and the heart / editor, Andrea Giustina; assistant editor, Filippo Manelli. p. ; cm.-{Endocrine updates; 9)

Includes bibliographical references and index. ISBN 978-1-4613-5624-0 ISBN 978-1-4615-1579-1 (eBook) DOI 10.1007/978-1-4615-1579-1 1. Somatotropin-Physiological effect. 2. Somatotropin-Pathophysiology. 3.

Heart-Diseases-Endocrine aspects. 1. Giustina, Andrea. II. Manelli, Filippo. III. Series. [DNLM: I.Heart Diseases-physiopathology. 2. Somatotropin-physiology. 3. Heart-physiology. 4. Somatotropin-therapeutic use. WG 210 G884 20011 QP572.S6 07584 2001 616.1 '207-dc21

Copyright II> 2001 by Springer Science+Business Media New York Origina1ly published by Kluwer Academic Publishers in 2001 Softcover reprint of the hardcover 1 st edition 2001

00-046037

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, photo-copying, record ing, or otherwise, without the prior written permission of the publisher, Springer Science+ Business Media, LLC.

Printed on acid-free pa per.

Table of Contents

List of Contributors

Preface Riccardo Vigneri

Introduction Andrea Giustina and Filippo Manelli

Growth hormone and the heart

I. The cellular and molecular basis for growth hormone action on the heart

2.

3.

4.

5

6.

7.

8.

9.

Antonio Cittadini and Pamela S. Douglas

Physiological effects of growth hormone on the heart Giovanni Lombardi and Annamaria Colao

The heart and the growth hormone deficiency syndrome Mary Lee Vance

Growth hormone replacement and cardiac function in the GHDaduits Lei/Thuesen and Jens S. Christiansen

The heart in acromegaly Marco Losa and Klaus Von Werder

Impact of growth hormone-lowering treatments on heart function in acromegaly Philippe Chanson

Growth hormone secretion in congestive heart failure Filippo Manelli, Maurizio Volterrani, Roberto Lorusso, Giuseppe Romanelli, Andrea Giustina

The growth hormone axis in cachectic patients with chronic heart failure: evidence for acquired growth hormone resistance Stefan D. Anker, Claus-Dieter Pflaum, Mariantonietta Cicoira, Christian J. Strasburger

Growth hormone treatment in experimental heart failure Jargen Isgaard and Bengt-Alce Bengtsson

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23

29

33

45

59

67

81

10. Acute growth honnone effects in human subjects with 87 heart failure Filippo Manelli, Maurizio Volterrani, Roberto Lorusso Giuseppe Romanelli, Andrea Giustina

11. Effect of chronic growth honnone treatment in heart failure 97 Maurizio Volterrani, Filippo Manelli, Andrea Giustina

12. Does the growth factor approach have a future in the 101 treatment of human heart failure? Luigi Sacca, Antonio Cittadini, Serafino Fazio

13. Exercise and growth honnone secretion III Johannes D. Veldhuis, and Arthur Weltman

14. Growth honnone and skeletal muscle function 125 Ettore C. Degli Uberti, Paola Franceschetti., Maria R. Ambrosio

15. Growth honnone and nutritional status 151 Massimo Scacchi, Angela I. Pinceili, Francesco Cavagnini

16. Effects of growth honnone on sodium homeostasis 165 Grace Y.W: Kam, Troels Wolthers, KenK.Y. Ho

17. Growth honnone and exercise perfonnance 175 William B. Wehrenberg, Lisa K. Conley, Filippo Manelli, Andrea Giustina

18. IGF-I and the heart 183 Marc Y. Donath and Juergen Zap!

19. Growth honnone-releasing peptides and the heart 195 Vittorio Locatelli, Giuseppe Rossoni, Antonio Torsel/o, Micaela Bernareggi, Elena Bresciani, Vito De Gennaro Colonna, Romano Deghenghi, Eugenio E. Miiller, Ferruccio Berti

Index 211

List of Contributors

Maria R. Ambrosio: Department of Biomedical Sciences and Advanced Therapies (Section of Endocrinology), University ofFerrara,-ltaly.

Stefan D. Anker Franz-Volhard-Klinik- (charite, Campus Berlin-Buch) at Max Delbruck-Centrum for Molecular Medicine, Berlin, Germany.

Bengt-Ake Bengtsson: Research Center for Endrocinology and Metabolism Sahlgrenska University Hospital, Goteborg, Sweden.

Micaela Bernareggi: School of Medicine, University of Milano-Bicocca, Milano, Italy

Fe"uccio Berti: School of Medicine, University ofMilano-Bicocca, Milano, ItaIy.

Elena Bresciani: Department of Pharmacology, University of Milan, Italy.

Francesco Cavagnini: Chair of Endocrinology, University of Milan, IRCCS Ospedale San Luca, Istituto Auxologico Italiano, Via Spagnoletto n. 3, 1-20149 Milan, Italy.

Philippe Chanson: Service d'Endocrinologie et des Maladies de la Reproduction, University Hospital Bicetre, Assistance Publique, Hopitaux de Paris and Facuite de Medicine Paris-Sud, Universite Paris X, Kremlin Bicetre, France.

Jens S. Christiansen: Department of Endocrinology and Diabetes, Aarhus University Hospital, Kommunehospitalet, DK-SOOO Aarhus C, Denmark.

Mariantonietta Cicoira: Cardiac Medicine, NHLI, Imperial College School of Medicine, London, UK.

Antonio Cittadini: Department ofIntemal Medicine and Cardiovascular Sciences, University Federico II, Naples, Italy.

Annamaria Colao: Department of Molecular and Clinical Endocrinology and Oncology, Frederico II University of Naples, Italy.

viii

Lisa K Conley: College of Agriculture, Forestry and Life Sciences, Clemson University, Clemson, South Carolina, USA.

Vito De Gennaro Colonna: Departinent of Pharmacology, University of Milan, Italy.

Romano Deghenghi: Europeptides Argenteuil, France

Ettore C. Degli Uberti: Department of Biomedical Sciences and Advanced Therapies (Sect-ion of Endocrinology), University of Ferrara, Italy.

Marc Y. Donath: Division of Endocrinology and Diabetes, Department of Medicine., University Hospital, Zurich, CH.

Pamela S. Douglas: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Serafino Fazio: Department of Internal Medicine and Cardiovascular Sciences, University Federico II, Naples, Italy.

Paola Franceschetti: Departinent of Biomedical Sciences and Advanced Therapies, (Section of Endocrinology), University of Ferrara, Italy.

Andrea Giustina: Endocrine Section, Department of Internal Medicine, University of Brescia, Italy.

KenKY.Ho: Pituitary Research Unit, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydnev, Australia.

Jorgen ]sgaard: Research Center for Endocrinology and Metabolism, Sahlgrenska University Hospital, Goteborg, Sweden.

Grace Y. W. Kam: Pituitary Research Unit, Garv Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia.

Vittorio Locatelli: School of Medicine, University of Milano-Bicocca, Milano, Italy.

Gaetano Lombardi: Department of Molecular and Clinical Endocrinology and Oncology, "Federico Ir' University of Naples, Italy.

Roberto Lorusso: II Cardiac Surgery, Spedali Civili di Brescia, 1-25125 Brescia, Italy.

Marco Losa: Department of Neurosurgery, IRCCS San Raffaele, Via Olgettina 60, 1-20132 Milano, Italy.

Filippo ManeUl: Endocrine Section, Department of Internal Medicine, University of Brescia, 1-25125 Brescia, Italy.

Eugenio E. Muller: Department of Ph anna co logy, University of Milan, Italy.

Claus-Dieter Pflaum: Medizinische Klinik, Ludwigs-Maxirnilian Universitiit, Munich, Germany.

Angela I. Pincelli: Chair, Endocrinology, University of Milan, IRCCS Ospedale San Luca, Istituto Auxologico Italiano, Milan, Italy.

Giuseppe Romanelli: Geriatric Section, Department ofInternal Medicine, University of Brescia, Italy.

Giuseppe Rossoni: Department of Ph anna co logy, University of Milan, Italy.

Luigi Sacca: Department of Internal Medicine and Cardiovascular Sciences, University Federico II, Naples, Italy.

Massimo Scacchi: Chair of Endocrinology, University of Milan, IRCCS Ospedale San Luca, Istituto Auxologico Italiano, Milan, Italy.

Christian J. Strasburger: Medizinische Klinik, Ludwigs-Maxirnilian Universitiit, Munich, Germany.

ix

x

Leif Thuesen: Department of Endocrinology and Diabetes, Aarhus University Hospital, Kommunehospitalet, Aarhus, Denmark.

Antonio Tonello: School of Medicine, University of Milan-Bicocca, Milan, Italy.

Mary Lee Vance: Division of Endocrinology and Metabolism, University of Virginia Health Sciences Center, Box 601, Charlottesville, VA 22908, USA.

Johannes D. Veldhuis: University of Virginia School of Medicine, General Clinical Research Center, Charlottesville, VA 22908, USA.

Maur;zio Volterrani: Fondazione "S. Maugeri", Department of Cardiology, Gussago Medical Center, 1-25125 Brescia, Italy.

Klaus Von Werder: Endocrinology-Dept. of Medicine, Schlosspark Klinik, Humboldt University, Berlin, Germany.

William B. Wehrenberg: College of Agriculture, Forestry and Life Sciences, Clemson University, Clemson, SC USA.

Arthur Weltman: University of Virginia School of Medicine, General Clinical Research Center, Charlottesville, VA 22908, USA.

Troe/s Wolthen: Pituitary Research Unit, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia.

Jiirgen Zapf: Division of Endocrinology and Diabetes, Department of Medicine, University Hospital ZUrich, CH-8091 ZUrich, Switzerland.

Preface - Riccardo Vigneri

The endocrine system is the major regulator of cardiac function: cathecolamines and thyroid hormones, for instance, play an important and well known role for the regulation of the cardiovascular function. In the last 10 years growth hormone and its peripheral mediator IGF-1 have also gained more and more attention for their action on the cardiovascular system. Today, large evidences demonstrate that the GH/IGF-l axis has great relevance for the regulation of cardiac growth, structure and function.

The mechanisms explaining GH effects on the cardiovascular system are multiple, complex and not yet fully understood. There is certainly a direct action of GH and IGF -Ion the heart, through the stimulation of specific receptors for both GH and IGF -1 in the cardiac myocytes, where they promote cell growth; these hormones also affect the cardiovascular stromal tissue biology. The GHlIGF-1 system has also an indirect effects on the heart, mainly a consequence of the peripheral vasodilatation. Particularly, IGF-I stimulates endothelial nitric oxide synthesis and, by this mechanism, causes endothelium-dependent vasodilatation which change myocardial hemodynamic work and cardiac performance.

This book provides an useful update of current understanding of the mechanisms of GH action on the heart. Moreover, it discusses the clinical use of GH, its stimulators and its inhibitors on the heart structure and function, from two different points of view. First, different qualified groups discuss the consequences of chronic GH deficiency or excess on heart function. In patients with either GH deficiency or excess an impaired cardiovascular function occurs in the long-term and may reduce life expectancy. The benefits of treatments that normalize hormone concentrations are also discussed. Second, the use of GH as an agent for treatment of chronic heart failure is discussed by researchers that have discovered and proposed this particular use of GH. This is a field of great interest, with a lot of unsolved questions concerning the dose and duration of the therapeutic use of GH in patients with severe cardiomyopathy, with the possibility of emerging adverse effects when treatment is prolonged.

As already mentioned, the complexity of the relationship between the GH/IGF-l system and cardiac performance is still incompletely understood. This book will provide the reader with updated information regarding the biology and pathology of different effects of GH/IGF-l on the heart. In addition, I believe that it will stimulate more interest and more research on areas of possible GH use like miocardial ischemia and heart energetic, both of great interest for possible clinical applications.

Introduction - Andrea Giustina and Filippo Manelli

Several hormonal systems regulate heart function in physiological and pathological states. These notions have been organized in a new research and clinical discipline which can be defmed "cardiovascular endocrinology". However, that the growth hormone (GR) - IGF-I system may be heavily involved in the regulation of cardiac structure and function, as suspected on the basis of several clinical observations from many years, has been demonstrated only very recently by solid experimental and clinical evidences. This book aims at structuring in a single publication knowledge that has been so far accumulated in the area of GH and the heart from basic to clinical studies, by research groups working on this topic throughout the world. Lessons from different experimental models and from several human diseases (acromegaly, adult GH deficiency, heart failure) suggest to both endocrinologists and cardiologists that not only GH may have a role in the physiology and pathophysiology of heart function but that GH itself may fmd a place in the treatment of primary heart diseases (such as dilated cardiomyopathy) or of cardiac complications of hypopituitarism. The influences that GH has on heart function are also important for understanding the potential role of GH in improving exercise performance. Therefore, we thought that it of interest for the many people who are interested in the study of exercise (cardiologists, endocrinologists, physiologists and others) to provide an update of studies of the effects of exercise and nutritional status on GH secretion as well as of GH effects on the skeletal muscle and fluid/electrolyte balance before addressing in its complexity the effects of GH on exercise performance. In fact, the current knowledge seems to support the view that endogenous GH may influence exercise performance not only via its positive effects on the cardiac system but also acting at the level of skeletal muscle, nutritional status and physical training. Finally, the last section of the book is a window on the role of other components of the somatotropic axis (IGF-I, GH secretagogues) in the regulation of heart structure and function. The role of these molecules is important also for their clinical and therapeutical potential as alternatives to GH in the treatment of heart dysfunction. In conclusion, we hope that this book will not only be a useful update of the research that has been very actively produced in the field of cardiovascular endocrinology but also the primary step in the recognition of the wide physiological and clinical significance of GH and the heart interactions.

Growth Hormone and the Heart