- Email: [email protected]
A network against failing hearts—Introducing the German “Competence Network Heart Failure”
Letters to the Editor
References [1] Sakamoto T, Kusukawa R, Maccanon DM, Luisada AA. Hemodynamic determinants of the amplitude of the first heart sound. Circ Res Jan 1965;16:45–57. [2] Bargiggia GS, Bertucci C, Recusani F, Raisaro A, de Servi S, Valdes-Cruz LM, et al. A new method for estimating left ventricular dP/dt by continuous wave Dopplerechocardiography. Validation studies at cardiac catheterization. Circulation Nov 1989;80(5):1287–92.
135
[3] Perloff JK, Harvey WP. Clinical recognition of tricusoid stenosis. Circulation Sep 1960;22:346–64. [4] Lakier JB, Bloom KR, Pocock WA, Barlow JB. Tricuspid component of first heart sound. Br Heart J Dec 1973;35(12):1275–9. [5] Coats AJ. Ethical authorship and publishing. Int J Cardiol Jan 9, 2009;131(2):149–50.
0167-5273/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2009.06.060
A network against failing hearts—Introducing the German “Competence Network Heart Failure” Felix Mehrhof a,⁎, Markus Löffler b, Götz Gelbrich b, Cemil Özcelik a, Maximilian Posch a, Hans-Werner Hense c, Ulrich Keil c, Thomas Scheffold d, Heribert Schunkert e, Christiane Angermann f, Georg Ertl f, Roland Jahns f, Burkert Pieske g, Rolf Wachter h, Frank Edelmann h, Kai C. Wollert i, Bernhard Maisch j, Sabine Pankuweit j, Raimund Erbel k, Till Neumann k, Wolfgang Herzog l, Hugo Katus m, Thomas Müller-Tasch l, Christian Zugck m, Hans-Dirk Düngen a, Vera Regitz-Zagrosek n, Elke Lehmkuhl n, Stefan Störk f, Uwe Siebert o,p,q, Jürgen Wasem r, Anja Neumann r, Alexander Göhler o,p,q, Stefan D. Anker a, Friedrich Köhler s, Martin Möckel a, Karl-Josef Osterziel t, Rainer Dietz a, Mathias Rauchhaus a and on Behalf of the Competence Network Heart Failure a
Charité University Medicine, Campus Virchow Klinikum, Dept. Cardiology, Berlin, Germany University Leipzig, Institute for Medical Informatics, Statistics and Epidemiology, Leipzig, Germany c University Münster, Institute for Epidemiology and Social Medicine, Münster, Germany d University Witten/Herdecke, Institute for Heart and Circulation Research, Dortmund, Germany e University Schleswig-Holstein, Cardiovascular and Pulmonary Medical Center, Lübeck, Germany f Julius-Maximilian University Würzburg, Dept. of Internal Medicine, Würzburg, Germany g University Graz, Dept. of Cardiology, Graz, Austria h Georg-August University Göttingen, Dept. Cardiology and Pneumology, Göttingen, Germany i Hannover Medical School, Dept. Cardiology and Angiology, Hannover, Germany j University Hospital Giessen and Marburg, Dept. Cardiology, Marburg, Germany k University Essen, West German Heart Center, Essen, Germany l University Hospital Heidelberg, General Internal and Psychosomatic Medicine, Heidelberg, Germany m University Hospital Heidelberg, Dept. of Cardiology, Heidelberg, Germany n Charité University Medicine, Center for Cardiovascular Research, Berlin, Germany o UMIT – University for Health Sciences, Medical Informatics and Technology, Department of Public Health, Information Systems and Health Technology Assessment, Hall i. T., Austria p Harvard Medical School, Cardiovascular Research Program, Institute for Technology Assessment and Department of Radiology, Massachsetts General Hospital, Boston, MA, USA q Harvard School of Public Health, Center for Health Decision Science, Department of Health Policy and Management, Boston, MA, USA r University Duisburg-Essen, Institute for Health Care Management, Essen, Germany s Charité University Medicine, Campu Charité Mitte, Dep. of Cardiology, Berlin, Germany t Cardiopraxis Amberg, Amberg, Germany b
a r t i c l e
i n f o
Article history: Received 26 June 2009 Accepted 27 June 2009 Available online 13 August 2009 Keywords: Heart failure Epidemiology of heart failure Molecular mechanisms of heart failure Pharmacological therapy of heart failure Management of heart failure Biomaterial banking
⁎ Corresponding author. Tel.: +49 30 450 676789; fax: +49 30 450 576962. E-mail address: [email protected] (F. Mehrhof).
The CNHF has been built around three infrastructural projects forming the backbone of the network and ensuring the operating structure. The central projects are surrounded by a subset of scientific projects each of which focuses on a specific area of research related to the HF syndrome. The sponsor in part defrays running expenses for scientific staff and materials in the infrastructural and scientific projects, however some co-payment is expected from institutions participating in the CNHF. Furthermore, several associated projects are closely attached to the CNHF and use its infrastructure, contributing to the scientific output of the network yet without savouring financial support. Fig. 1 depicts the organigram of the CNHF. The central office serves as a contact base for all network partners and also for the funding party. The foremost task of this service unit is the scientific and strategic development of the CNHF as well as public relation tasks. In addition, the central office is in charge of the main financial and regulatory management of all network projects. After foundation of the network, the installation of a telemetric platform run by the centre for study management has been one of the
136
Letters to the Editor
Fig. 1. Projects in the Competence Network Heart Failure.
first measures. It allows an internet-based network-wide data management and internal use of confidential information by all network partners. In conjunction with all scientific projects, a basic clinical dataset (BCD) containing 190 items in 16 categories (Table 1) has been developed. These parameters are collected from all patients within the CNHF; further parameters used in more than one study are modular components of the harmonised dataset, beyond that, any additional study specific data item might be collected. This approach allows for pooled data analysis of study results and makes data management more efficient. Standardised case report forms, centrally run data bases with automated revision and consistency checks and development of standard operating procedures for all pertinent workflows further support the process of high quality data collection and analysis. Individual studies benefit from intensive biometric advice from the centre for study management in the developmental as well as the operational and analytical phases of the studies. In order to be equipped with a high quality collection of biomaterial samples from a large cohort of well phenotyped HF patients, the
Table 1 Categories of the basic clinical dataset. Topics
No. of questions/items
Socio-demographic data Physical examination Framingham criteria for HF Classification of HF Risk factors Cardiac diagnosis Aetiology Cardiovascular Interventions Concomitant diseases Medication Laboratory ECG Echocardiography Coronary angiography Quality of Life Depression
6 4 5 17 7 14 7 9 10 24 6 11 16 9 36 9
launch of a central biomaterial bank (BMB) has been another principal aim of the CNHF. After having established a professional system for the pseudonymisation of blood samples and clear separation from clinical or personal related patient data, the necessary positive vote from the institutional review board and the responsible German and European data safety authorities was obtained shortly after the initiation of the network in 2003. Fig. 2 delineates the communication pathways between the network office, the study centre, the biomaterial bank and each of the projects. The BMB supplies the infrastructure and necessary hardware for the standardised collection, registration, storage and processing of blood and other biomaterials. The wellorganised and amply equipped facility thereby offers the possibility to supply biomaterials from large cohorts of patients with various disease aetiologies for researchers and clinicians [1]. Today the BMB holds a collection of approximately 100,000 serum-, plasma- and DNAsamples from more than approximately 12000 HF patients. Integration of this research facility into a network of other cardiovascular or life science-distincted biomaterial organisations is planned for the near future. The various scientific projects focus on specific areas of HF research — from epidemiological characteristics and aetiological features of the disease to diagnostic strategies and therapeutic options. Gender specific questions in HF epidemiology and treatment are an issue in many of the scientific projects as are the evaluation of patients' quality of life [2]. A specialised working group is assessing the economical background of HF and complements various studies with a healtheconomic evaluation and a decision-analytic model. This enables the estimation of certain interventional therapeutic or management procedures with regard to cost-effectiveness [3]. Epidemiology of heart failure is based on three large populationbased prospective cohorts in different areas of the country. Differentiation between systolic and diastolic dysfunction but also investigation of determinants leading to the development of HF is basis of the work-programme [4]. Diastolic dysfunction as a common but poorly understood form of HF with preserved left ventricular function is a matter of investigation in yet another scientific project of the CNHF. A prospective multicenter study will yield state of the art data on the
Letters to the Editor
137
Fig. 2. Data- and biomaterial-flow within the CNHF: biomaterial samples and related sample-IDs as well as clinical data (BCD) combined with the related personal studyidentification (Stud-PID) are saved on independent database servers. They can only be connected via encrypted communication to the identification (ID)-database, which is hosted in the central office and stored on a separated database server. Re-identification of a patient is related to the patient identification (PID), stored in electronical form in the patient list on yet another database server or via the Central Patient Sheet, deposited at an external custodian. Upon application on BCD and selected biomaterial samples can be provided.
epidemiology and pathophysiology, two related projects are evaluating therapeutic options for affected patients. Various projects within the CNHF address the sundry aetiologic entities of HF. The basis for a subproject focussing on molecular genetic diagnostics has been the network-wide recruitment of large cohorts of patients with hypertrophic cardiomyopathy (HCM) (n N 250) and dilated cardiomyopathy (DCM) (n N 500). Comprehensive clinical characterisation of these patients led to the establishment of a platform for a systematic molecular genetic evaluation of cardiomyopathies. Two other scientific projects explore autoimmune mechanisms in the aetiology of HF. One of them investigates the growing evidence for a pathogenetic significance of functionally active auto-antibodies being able to recognize and activate the cardiac beta1-adrenergic receptor (anti-beta1-AR) [5]. A related project specifically examines a potential link between autoimmune disease and inflammatory respectively familial DCM. To date, more than 300 index patients have been included in the study, blood samples and endomyocardial biopsies from all these patients are available and a one-year follow-up of clinical data is currently underway. The HIV–heart project aims to reveal the aetiology of HIV-associated cardiovascular disorders and has included more than 800 HIV-infected persons for a baseline evaluation. A two-year followup of these patients will turn the project into a longitudinal survey [6]. Focussing on treatment options in HF, the CIBIS-ELD-trial as a randomised controlled trial investigates the up-titration tolerability of two standard beta-blockers in older patients — a cohort that has been underrepresented in clinical HF trials so far [7]. A project educating general physicians in specialised diagnostic skills evaluates the possibilities to improve diagnostic tools and demonstrates the horizontal networking character of the organisation. This idea is even further implemented in a nurse-coordinated telephone-based disease management program, which is evaluated regarding its efficacy within a randomised trial (Interdisciplinary Network for Heart Failure (INH)trial) [8]. Complementary to the clinically oriented projects within the CNHF, the aim of the basic research focussed scientists within the CNHF is the development of innovative strategies in the field of molecular biology as a basis for novel therapeutic strategies in HF. Up to eight working groups make use of different complementary models, i.e. cell culture studies, engineered heart tissue, isolated preparations of human cardiomyocytes and trabecular specimens as well as transgenic animal models.
Various additional undertakings with independent funding cooperate with the CNHF in terms of patient data and biomaterial sampling. Among them are large projects evaluating telemonitoring of HF patients [9] and a randomised prospective controlled trial assessing the effects of antidepressant pharmacotherapy in HF patients with major depression in terms of hard somatic endpoints (MOOD-HFtrial) [10]. Other projects investigate warfarin versus aspirin as an anticoagulant in patients with reduced ejection fraction (WARCEFtrial) [11] or compare the effects of combined rate- and rhythm control treatment with nebivolol and electric cardioversion to rate-control in patients with atrial fibrillation (NEBICAR-trial). A prospective cohort study with long-term follow-up investigates the relationship between rheumatic diseases and the development of cardiovascular disease and HF. Recently an additional project could be associated to the CNHF, collecting regional data on CHF in a registry (TOP 40). This project is bound to extend also to the acute phase of the disease, thereby mirroring the complex situation of HF in the population. The CNHF was officially initiated in June 2003, two years after the first call for applications; two years later more than 3000 patients had been included in the various scientific projects. Approximately 12000 HF patients have so far been prospectively evaluated and were also included into the database by the end of the second funding period in July 2008. Regular meetings at national congresses and independent scientific symposia fundamentally demonstrate and support the networking idea of the CNHF; these public appearances also serve to improve public relations, yet another mission of the network. The establishment of an Internet domain with a German and English homepage support the visibility of the network (www.knhi.de and www.ghfn. eu). A monthly newsletter has been established to circulate network news, results and meeting announcements but also to report important news from the projects to the network community and beyond; so far it has been issued more than 50 times. In order to inform the public and keep in touch with patients, physicians and other health care providers, regular patient seminars, a patient guide and close cooperation with other scientific organisations and patient foundations are additional public relations management tools and increase the visibility of the network. From the beginning of this ambitious project, promotion of young clinicians and clinical scientists has been a concern of the CNHF. Facilitated exchange between different scientific projects enabled young academics to work in different groups and
138
Letters to the Editor
surroundings; a number of scholarships and awards have been issued for junior scientists to reward outstanding results and promising projects proposals. In the future, the CNHF is expecting fundamental changes, mostly in terms of financial support. The third funding period of the network is due to expire in 2011; therefore it is currently one major aim of the network management to recruit new sources of funding and partnerships and to establish a valuable business plan. A first step in this direction was the formation of an independent legal entity enabling the network to act as an autonomous business partner. The broad network connections will be utilised to attract private financial sources; the resources of the biomaterial bank as well as the clinical database should also enable the network to attract the pharmaceutical industry, physicians, clinics and research organisations for cooperative projects. Furthermore, the evolution of new diagnostic and therapeutic concepts is targeted in national and international projects. The ambitions of various European cardiac associations in developing a large registry for patients with chronic HF are currently taken into account in a German pilot project. These and other examples and efforts in the development of investigator-initiated research in Germany and Europe will carry forward the original idea of the CNHF —
• area of HF; • care; and •• to patients and public developments in research and therapy and tokeep keep patients andinformed publicof new informed of new developments in • to and and boost boost the efficiency of research of in research the area of in HF;the tocoordinate coordinate the efficiency
• to the the quality of patient care; and toincrease increase quality of patient
thereby playand a keytherapy role in implementing effective strategies. research and thereby playprevention a key role in implementing
effective prevention strategies. We thank all patients, physicians and health care personnel that have been involved in the work of the CNHF. The German Federal Ministry of Research and Education (BMBF) supports the CNHF (funding no. 01GI0205). The authors of this manuscript have certified
that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [12]. References [1] Posch M, Gelbrich G, Pieske B, et al. The biomaterial bank of the German Competence Network of Heart Failure (CNHF) is a valuable resource for biomaterial and genetic research. Int J Cardiol 2009;136:108–11. [2] Müller-Tasch T, Peters-Klimm F, Schellberg D, et al. Depression is a major determinant of quality of life in patients with chronic systolic heart failure in general practice. J Card Fail 2007;10:818–24. [3] Göhler A, Conrads-Frank A, Worrell SS, et al. Decision-analytic evaluation of the clinical effectiveness and cost-effectiveness of management programmes in chronic heart failure. Eur J Heart Fail 2008;10:1026–32. [4] Markus MR, Stritzke J, Lieb W, et al. Implications for persistent prehypertension for ageing related changes in left ventricular geometry and function: the MONICA/ KORA Augsburg study. J Hypertens 2008;26(10):2040–9. [5] Jahns R, Boivin V, Lohse MJ. Beta 1-adrenergic receptor-directed autoimmunity as a cause of dilated cardiomyopathy in rats. Int J Cardiol 2006;112:7–14. [6] Neumann T, Esser S, Potthoff A, et al. Prevalence and natural history of heart failure in outpatient HIV-infected subjects: rationale and design of the HIV–HEART study. Eur J Med Res 2007;12:243–8. [7] Düngen HD, Apostolovic S, Inkrot S, et al. Bisoprolol vs. carvedilol in elderly patients with heart failure: rationale and design of the CIBIS-ELD trial. Clin Res Cardiol 2008;97:578–86. [8] Störk S, Hense HW, Zentgraf C, et al. Pharmacotherapy according to treatment guidelines is associated with lower mortality in a community-based sample of patients with chronic heart failure: a prospective cohort study. Eur J Heart Fail 2008;10:1236–45. [9] Köhler F, Schieber M, Lücke S, et al. “Partnership for the Heart”—development and testing of a new remote patient monitoring system. Dtsch Med Wochenschr Mar. 2, 2007;132:458–60. [10] Angermann CE, Gelbrich G, Störk S, et al. Rationale and design of a randomised, controlled, multicenter trial investigating the effects of selective serotonin reuptake inhibition on morbidity, mortality and mood in depressed heart failure patients (MOOD-HF). Eur J Heart Fail 2007;9:1212–22. [11] Pullicino P, Thompson JL, Barton B, Levin B, Graham S, Freudenberger RS. Warfarin versus aspirin in patients with reduced cardiac ejection fraction (WARCEF): rationale, objectives, and design. J Card Fail Feb. 2006;12:39–46. [12] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.
0167-5273/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2009.06.061
Granulocyte colony-stimulating factor in patients with ST segment elevation myocardial infarction: A disappointment-stimulating factor? Turgay Celik a,⁎, Atila Iyisoy a, Ejder Kardesoglu b, Murat Celik a a b
Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, 06018 Etlik-Ankara, Turkey Gulhane Military Medical Academy, Haydarpasa Training Hospital, Department of Cardiology, Turkey
a r t i c l e
i n f o
Article history: Received 22 June 2009 Accepted 26 June 2009 Available online 3 August 2009 Keywords: G-CSF ST segment elevation myocardial infarction Stem cell mobilization
⁎ Corresponding author. Tel.: +90 312 3044268; fax: +90 312 3044250. E-mail address: [email protected] (T. Celik).
In their recently published very well-designed article, Engelmann et al. investigated the effect of granulocyte colony-stimulating factor (G-CSF) on left-ventricular ejection fraction (LVEF) and event-free survival in patients suffering from sub-acute ST segment elevation myocardial infarction (STEMI) [1]. In that study, 44 patients suffering from sub-acute STEMI with late revascularization achieved by percutaneous coronary intervention (PCI) were randomized to receive either G-CSF (Filgrastim) at a dose of 10 µg/kg body weight/day subcutaneously or placebo. Changes of global and regional cardiac function from baseline over 1 and 3 months to 12 months of follow-up were analyzed by magnetic resonance imaging. The authors found that G-CSF administration after sub-acute STEMI is feasible and safe but does not improve myocardial function or survival when used as a single substance. The feature of G-CSF to mobilize stem cells from bone marrow (CD34+ mononuclear blood stem cells) and increase their circulating levels has
References [1] Sakamoto T, Kusukawa R, Maccanon DM, Luisada AA. Hemodynamic determinants of the amplitude of the first heart sound. Circ Res Jan 1965;16:45–57. [2] Bargiggia GS, Bertucci C, Recusani F, Raisaro A, de Servi S, Valdes-Cruz LM, et al. A new method for estimating left ventricular dP/dt by continuous wave Dopplerechocardiography. Validation studies at cardiac catheterization. Circulation Nov 1989;80(5):1287–92.
135
[3] Perloff JK, Harvey WP. Clinical recognition of tricusoid stenosis. Circulation Sep 1960;22:346–64. [4] Lakier JB, Bloom KR, Pocock WA, Barlow JB. Tricuspid component of first heart sound. Br Heart J Dec 1973;35(12):1275–9. [5] Coats AJ. Ethical authorship and publishing. Int J Cardiol Jan 9, 2009;131(2):149–50.
0167-5273/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2009.06.060
A network against failing hearts—Introducing the German “Competence Network Heart Failure” Felix Mehrhof a,⁎, Markus Löffler b, Götz Gelbrich b, Cemil Özcelik a, Maximilian Posch a, Hans-Werner Hense c, Ulrich Keil c, Thomas Scheffold d, Heribert Schunkert e, Christiane Angermann f, Georg Ertl f, Roland Jahns f, Burkert Pieske g, Rolf Wachter h, Frank Edelmann h, Kai C. Wollert i, Bernhard Maisch j, Sabine Pankuweit j, Raimund Erbel k, Till Neumann k, Wolfgang Herzog l, Hugo Katus m, Thomas Müller-Tasch l, Christian Zugck m, Hans-Dirk Düngen a, Vera Regitz-Zagrosek n, Elke Lehmkuhl n, Stefan Störk f, Uwe Siebert o,p,q, Jürgen Wasem r, Anja Neumann r, Alexander Göhler o,p,q, Stefan D. Anker a, Friedrich Köhler s, Martin Möckel a, Karl-Josef Osterziel t, Rainer Dietz a, Mathias Rauchhaus a and on Behalf of the Competence Network Heart Failure a
Charité University Medicine, Campus Virchow Klinikum, Dept. Cardiology, Berlin, Germany University Leipzig, Institute for Medical Informatics, Statistics and Epidemiology, Leipzig, Germany c University Münster, Institute for Epidemiology and Social Medicine, Münster, Germany d University Witten/Herdecke, Institute for Heart and Circulation Research, Dortmund, Germany e University Schleswig-Holstein, Cardiovascular and Pulmonary Medical Center, Lübeck, Germany f Julius-Maximilian University Würzburg, Dept. of Internal Medicine, Würzburg, Germany g University Graz, Dept. of Cardiology, Graz, Austria h Georg-August University Göttingen, Dept. Cardiology and Pneumology, Göttingen, Germany i Hannover Medical School, Dept. Cardiology and Angiology, Hannover, Germany j University Hospital Giessen and Marburg, Dept. Cardiology, Marburg, Germany k University Essen, West German Heart Center, Essen, Germany l University Hospital Heidelberg, General Internal and Psychosomatic Medicine, Heidelberg, Germany m University Hospital Heidelberg, Dept. of Cardiology, Heidelberg, Germany n Charité University Medicine, Center for Cardiovascular Research, Berlin, Germany o UMIT – University for Health Sciences, Medical Informatics and Technology, Department of Public Health, Information Systems and Health Technology Assessment, Hall i. T., Austria p Harvard Medical School, Cardiovascular Research Program, Institute for Technology Assessment and Department of Radiology, Massachsetts General Hospital, Boston, MA, USA q Harvard School of Public Health, Center for Health Decision Science, Department of Health Policy and Management, Boston, MA, USA r University Duisburg-Essen, Institute for Health Care Management, Essen, Germany s Charité University Medicine, Campu Charité Mitte, Dep. of Cardiology, Berlin, Germany t Cardiopraxis Amberg, Amberg, Germany b
a r t i c l e
i n f o
Article history: Received 26 June 2009 Accepted 27 June 2009 Available online 13 August 2009 Keywords: Heart failure Epidemiology of heart failure Molecular mechanisms of heart failure Pharmacological therapy of heart failure Management of heart failure Biomaterial banking
⁎ Corresponding author. Tel.: +49 30 450 676789; fax: +49 30 450 576962. E-mail address: [email protected] (F. Mehrhof).
The CNHF has been built around three infrastructural projects forming the backbone of the network and ensuring the operating structure. The central projects are surrounded by a subset of scientific projects each of which focuses on a specific area of research related to the HF syndrome. The sponsor in part defrays running expenses for scientific staff and materials in the infrastructural and scientific projects, however some co-payment is expected from institutions participating in the CNHF. Furthermore, several associated projects are closely attached to the CNHF and use its infrastructure, contributing to the scientific output of the network yet without savouring financial support. Fig. 1 depicts the organigram of the CNHF. The central office serves as a contact base for all network partners and also for the funding party. The foremost task of this service unit is the scientific and strategic development of the CNHF as well as public relation tasks. In addition, the central office is in charge of the main financial and regulatory management of all network projects. After foundation of the network, the installation of a telemetric platform run by the centre for study management has been one of the
136
Letters to the Editor
Fig. 1. Projects in the Competence Network Heart Failure.
first measures. It allows an internet-based network-wide data management and internal use of confidential information by all network partners. In conjunction with all scientific projects, a basic clinical dataset (BCD) containing 190 items in 16 categories (Table 1) has been developed. These parameters are collected from all patients within the CNHF; further parameters used in more than one study are modular components of the harmonised dataset, beyond that, any additional study specific data item might be collected. This approach allows for pooled data analysis of study results and makes data management more efficient. Standardised case report forms, centrally run data bases with automated revision and consistency checks and development of standard operating procedures for all pertinent workflows further support the process of high quality data collection and analysis. Individual studies benefit from intensive biometric advice from the centre for study management in the developmental as well as the operational and analytical phases of the studies. In order to be equipped with a high quality collection of biomaterial samples from a large cohort of well phenotyped HF patients, the
Table 1 Categories of the basic clinical dataset. Topics
No. of questions/items
Socio-demographic data Physical examination Framingham criteria for HF Classification of HF Risk factors Cardiac diagnosis Aetiology Cardiovascular Interventions Concomitant diseases Medication Laboratory ECG Echocardiography Coronary angiography Quality of Life Depression
6 4 5 17 7 14 7 9 10 24 6 11 16 9 36 9
launch of a central biomaterial bank (BMB) has been another principal aim of the CNHF. After having established a professional system for the pseudonymisation of blood samples and clear separation from clinical or personal related patient data, the necessary positive vote from the institutional review board and the responsible German and European data safety authorities was obtained shortly after the initiation of the network in 2003. Fig. 2 delineates the communication pathways between the network office, the study centre, the biomaterial bank and each of the projects. The BMB supplies the infrastructure and necessary hardware for the standardised collection, registration, storage and processing of blood and other biomaterials. The wellorganised and amply equipped facility thereby offers the possibility to supply biomaterials from large cohorts of patients with various disease aetiologies for researchers and clinicians [1]. Today the BMB holds a collection of approximately 100,000 serum-, plasma- and DNAsamples from more than approximately 12000 HF patients. Integration of this research facility into a network of other cardiovascular or life science-distincted biomaterial organisations is planned for the near future. The various scientific projects focus on specific areas of HF research — from epidemiological characteristics and aetiological features of the disease to diagnostic strategies and therapeutic options. Gender specific questions in HF epidemiology and treatment are an issue in many of the scientific projects as are the evaluation of patients' quality of life [2]. A specialised working group is assessing the economical background of HF and complements various studies with a healtheconomic evaluation and a decision-analytic model. This enables the estimation of certain interventional therapeutic or management procedures with regard to cost-effectiveness [3]. Epidemiology of heart failure is based on three large populationbased prospective cohorts in different areas of the country. Differentiation between systolic and diastolic dysfunction but also investigation of determinants leading to the development of HF is basis of the work-programme [4]. Diastolic dysfunction as a common but poorly understood form of HF with preserved left ventricular function is a matter of investigation in yet another scientific project of the CNHF. A prospective multicenter study will yield state of the art data on the
Letters to the Editor
137
Fig. 2. Data- and biomaterial-flow within the CNHF: biomaterial samples and related sample-IDs as well as clinical data (BCD) combined with the related personal studyidentification (Stud-PID) are saved on independent database servers. They can only be connected via encrypted communication to the identification (ID)-database, which is hosted in the central office and stored on a separated database server. Re-identification of a patient is related to the patient identification (PID), stored in electronical form in the patient list on yet another database server or via the Central Patient Sheet, deposited at an external custodian. Upon application on BCD and selected biomaterial samples can be provided.
epidemiology and pathophysiology, two related projects are evaluating therapeutic options for affected patients. Various projects within the CNHF address the sundry aetiologic entities of HF. The basis for a subproject focussing on molecular genetic diagnostics has been the network-wide recruitment of large cohorts of patients with hypertrophic cardiomyopathy (HCM) (n N 250) and dilated cardiomyopathy (DCM) (n N 500). Comprehensive clinical characterisation of these patients led to the establishment of a platform for a systematic molecular genetic evaluation of cardiomyopathies. Two other scientific projects explore autoimmune mechanisms in the aetiology of HF. One of them investigates the growing evidence for a pathogenetic significance of functionally active auto-antibodies being able to recognize and activate the cardiac beta1-adrenergic receptor (anti-beta1-AR) [5]. A related project specifically examines a potential link between autoimmune disease and inflammatory respectively familial DCM. To date, more than 300 index patients have been included in the study, blood samples and endomyocardial biopsies from all these patients are available and a one-year follow-up of clinical data is currently underway. The HIV–heart project aims to reveal the aetiology of HIV-associated cardiovascular disorders and has included more than 800 HIV-infected persons for a baseline evaluation. A two-year followup of these patients will turn the project into a longitudinal survey [6]. Focussing on treatment options in HF, the CIBIS-ELD-trial as a randomised controlled trial investigates the up-titration tolerability of two standard beta-blockers in older patients — a cohort that has been underrepresented in clinical HF trials so far [7]. A project educating general physicians in specialised diagnostic skills evaluates the possibilities to improve diagnostic tools and demonstrates the horizontal networking character of the organisation. This idea is even further implemented in a nurse-coordinated telephone-based disease management program, which is evaluated regarding its efficacy within a randomised trial (Interdisciplinary Network for Heart Failure (INH)trial) [8]. Complementary to the clinically oriented projects within the CNHF, the aim of the basic research focussed scientists within the CNHF is the development of innovative strategies in the field of molecular biology as a basis for novel therapeutic strategies in HF. Up to eight working groups make use of different complementary models, i.e. cell culture studies, engineered heart tissue, isolated preparations of human cardiomyocytes and trabecular specimens as well as transgenic animal models.
Various additional undertakings with independent funding cooperate with the CNHF in terms of patient data and biomaterial sampling. Among them are large projects evaluating telemonitoring of HF patients [9] and a randomised prospective controlled trial assessing the effects of antidepressant pharmacotherapy in HF patients with major depression in terms of hard somatic endpoints (MOOD-HFtrial) [10]. Other projects investigate warfarin versus aspirin as an anticoagulant in patients with reduced ejection fraction (WARCEFtrial) [11] or compare the effects of combined rate- and rhythm control treatment with nebivolol and electric cardioversion to rate-control in patients with atrial fibrillation (NEBICAR-trial). A prospective cohort study with long-term follow-up investigates the relationship between rheumatic diseases and the development of cardiovascular disease and HF. Recently an additional project could be associated to the CNHF, collecting regional data on CHF in a registry (TOP 40). This project is bound to extend also to the acute phase of the disease, thereby mirroring the complex situation of HF in the population. The CNHF was officially initiated in June 2003, two years after the first call for applications; two years later more than 3000 patients had been included in the various scientific projects. Approximately 12000 HF patients have so far been prospectively evaluated and were also included into the database by the end of the second funding period in July 2008. Regular meetings at national congresses and independent scientific symposia fundamentally demonstrate and support the networking idea of the CNHF; these public appearances also serve to improve public relations, yet another mission of the network. The establishment of an Internet domain with a German and English homepage support the visibility of the network (www.knhi.de and www.ghfn. eu). A monthly newsletter has been established to circulate network news, results and meeting announcements but also to report important news from the projects to the network community and beyond; so far it has been issued more than 50 times. In order to inform the public and keep in touch with patients, physicians and other health care providers, regular patient seminars, a patient guide and close cooperation with other scientific organisations and patient foundations are additional public relations management tools and increase the visibility of the network. From the beginning of this ambitious project, promotion of young clinicians and clinical scientists has been a concern of the CNHF. Facilitated exchange between different scientific projects enabled young academics to work in different groups and
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Letters to the Editor
surroundings; a number of scholarships and awards have been issued for junior scientists to reward outstanding results and promising projects proposals. In the future, the CNHF is expecting fundamental changes, mostly in terms of financial support. The third funding period of the network is due to expire in 2011; therefore it is currently one major aim of the network management to recruit new sources of funding and partnerships and to establish a valuable business plan. A first step in this direction was the formation of an independent legal entity enabling the network to act as an autonomous business partner. The broad network connections will be utilised to attract private financial sources; the resources of the biomaterial bank as well as the clinical database should also enable the network to attract the pharmaceutical industry, physicians, clinics and research organisations for cooperative projects. Furthermore, the evolution of new diagnostic and therapeutic concepts is targeted in national and international projects. The ambitions of various European cardiac associations in developing a large registry for patients with chronic HF are currently taken into account in a German pilot project. These and other examples and efforts in the development of investigator-initiated research in Germany and Europe will carry forward the original idea of the CNHF —
• area of HF; • care; and •• to patients and public developments in research and therapy and tokeep keep patients andinformed publicof new informed of new developments in • to and and boost boost the efficiency of research of in research the area of in HF;the tocoordinate coordinate the efficiency
• to the the quality of patient care; and toincrease increase quality of patient
thereby playand a keytherapy role in implementing effective strategies. research and thereby playprevention a key role in implementing
effective prevention strategies. We thank all patients, physicians and health care personnel that have been involved in the work of the CNHF. The German Federal Ministry of Research and Education (BMBF) supports the CNHF (funding no. 01GI0205). The authors of this manuscript have certified
that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [12]. References [1] Posch M, Gelbrich G, Pieske B, et al. The biomaterial bank of the German Competence Network of Heart Failure (CNHF) is a valuable resource for biomaterial and genetic research. Int J Cardiol 2009;136:108–11. [2] Müller-Tasch T, Peters-Klimm F, Schellberg D, et al. Depression is a major determinant of quality of life in patients with chronic systolic heart failure in general practice. J Card Fail 2007;10:818–24. [3] Göhler A, Conrads-Frank A, Worrell SS, et al. Decision-analytic evaluation of the clinical effectiveness and cost-effectiveness of management programmes in chronic heart failure. Eur J Heart Fail 2008;10:1026–32. [4] Markus MR, Stritzke J, Lieb W, et al. Implications for persistent prehypertension for ageing related changes in left ventricular geometry and function: the MONICA/ KORA Augsburg study. J Hypertens 2008;26(10):2040–9. [5] Jahns R, Boivin V, Lohse MJ. Beta 1-adrenergic receptor-directed autoimmunity as a cause of dilated cardiomyopathy in rats. Int J Cardiol 2006;112:7–14. [6] Neumann T, Esser S, Potthoff A, et al. Prevalence and natural history of heart failure in outpatient HIV-infected subjects: rationale and design of the HIV–HEART study. Eur J Med Res 2007;12:243–8. [7] Düngen HD, Apostolovic S, Inkrot S, et al. Bisoprolol vs. carvedilol in elderly patients with heart failure: rationale and design of the CIBIS-ELD trial. Clin Res Cardiol 2008;97:578–86. [8] Störk S, Hense HW, Zentgraf C, et al. Pharmacotherapy according to treatment guidelines is associated with lower mortality in a community-based sample of patients with chronic heart failure: a prospective cohort study. Eur J Heart Fail 2008;10:1236–45. [9] Köhler F, Schieber M, Lücke S, et al. “Partnership for the Heart”—development and testing of a new remote patient monitoring system. Dtsch Med Wochenschr Mar. 2, 2007;132:458–60. [10] Angermann CE, Gelbrich G, Störk S, et al. Rationale and design of a randomised, controlled, multicenter trial investigating the effects of selective serotonin reuptake inhibition on morbidity, mortality and mood in depressed heart failure patients (MOOD-HF). Eur J Heart Fail 2007;9:1212–22. [11] Pullicino P, Thompson JL, Barton B, Levin B, Graham S, Freudenberger RS. Warfarin versus aspirin in patients with reduced cardiac ejection fraction (WARCEF): rationale, objectives, and design. J Card Fail Feb. 2006;12:39–46. [12] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.
0167-5273/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2009.06.061
Granulocyte colony-stimulating factor in patients with ST segment elevation myocardial infarction: A disappointment-stimulating factor? Turgay Celik a,⁎, Atila Iyisoy a, Ejder Kardesoglu b, Murat Celik a a b
Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, 06018 Etlik-Ankara, Turkey Gulhane Military Medical Academy, Haydarpasa Training Hospital, Department of Cardiology, Turkey
a r t i c l e
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Article history: Received 22 June 2009 Accepted 26 June 2009 Available online 3 August 2009 Keywords: G-CSF ST segment elevation myocardial infarction Stem cell mobilization
⁎ Corresponding author. Tel.: +90 312 3044268; fax: +90 312 3044250. E-mail address: [email protected] (T. Celik).
In their recently published very well-designed article, Engelmann et al. investigated the effect of granulocyte colony-stimulating factor (G-CSF) on left-ventricular ejection fraction (LVEF) and event-free survival in patients suffering from sub-acute ST segment elevation myocardial infarction (STEMI) [1]. In that study, 44 patients suffering from sub-acute STEMI with late revascularization achieved by percutaneous coronary intervention (PCI) were randomized to receive either G-CSF (Filgrastim) at a dose of 10 µg/kg body weight/day subcutaneously or placebo. Changes of global and regional cardiac function from baseline over 1 and 3 months to 12 months of follow-up were analyzed by magnetic resonance imaging. The authors found that G-CSF administration after sub-acute STEMI is feasible and safe but does not improve myocardial function or survival when used as a single substance. The feature of G-CSF to mobilize stem cells from bone marrow (CD34+ mononuclear blood stem cells) and increase their circulating levels has