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ISSN: 2210-2892 ― Volume 10, 2020

Inhibiting C-Reactive Protein Synthesis by Cardiac Glycosides in Humans



Jan Torzewski*, Matthias Graf, Katharina Weber, Myron Zaczkiewicz, Manuela Leier, Matthias Froehlich, Oliver Zimmermann
Cardiovascular Center Oberallgäu-Kempten, Robert Weixler Str. 50, 87439 Kempten, Germany

Abstract

The role of C-reactive protein (CRP) in cardiovascular disease has been controversially discussed for almost two decades. Specific CRP inhibition, followed by use of CRP inhibitors in controlled clinical trials may be the only way to prove or disprove a causative role for CRP in cardiovascular disease. Endogenous and plant-derived inhibitors of the Na(+)/K(+)-ATPase, i.e. the cardiac glycosides ouabain, digoxin and digitoxin, potently inhibit CRP synthesis in human hepatoma cells and primary human hepatocytes in vitro.

In the herein described single-center C-reactive protein-Digoxin Observational Study (C-DOS), 60 patients with decompensated heart failure, NYHA III-IV and severely reduced Left Ventricular Ejection Fraction (LVEF<40%), and elevated CRP plasma levels will be treated by either digoxin+conventional heart failure therapy (30 patients) or by conventional heart failure therapy alone (30 patients). Plasma CRP levels in both groups will be assessed for 21 days. Plasma CRP levels (day21-day0) will be compared by regression analysis in order to find out whether digoxin significantly lowers CRP plasma levels in humans.

The trial will not answer the question whether CRP is causative in cardiovascular disease but, by following a step by step approach, investigates for the first time whether cardiac glycosides lower CRP plasma levels in humans. The study hereby serves as a pilot study for subsequent phase III trials. Importantly, it is the first trial ever that systematically uses a direct CRP synthesis inhibitor in vivo in humans.

Keywords: C-reactive protein, C-reactive protein synthesis, cardiovascular disease, cardiac failure, clinical study, drug development.

Article Information


Identifiers and Pagination:

Year: 2016
Volume: 7
First Page: 7
Last Page: 11
Publisher Id: TOPROCJ-7-1-7
DOI: 10.2174/2210289201607010007

Article History:

Received Date: 8/9/2015
Revision Received Date: 28/11/2015
Acceptance Date: 12/1/2016
Electronic publication date: 14/3/2016
Collection year: 2016

© Torzewski et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Cardiovascular Center Oberallgäu-Kempten, Robert Weixler-Straße 50, 87439 Kempten, Germany; Tel/Fax: ++49-8323-910-8950, ++49-8323-910-395; Email: jan.torzewski@kv-keoa.de



1. INTRODUCTION

In this article we summarize background, design aspects, statistical analysis and ethical considerations of our C-reactive protein-Digoxin Observational Study (CDOS), that has been discussed in detail on Drug Discovery & Therapy World Congress 2015 (DDTWC 2015), Boston, MA, USA http://www.ddtwc.com/.

2. Background

Elevated plasma levels of C-reactive protein (CRP), the prototype acute-phase protein (APP), are predictive for future cardiovascular events [1Pearson, T.A.; Mensah, G.A.; Alexander, R.W.; Anderson, J.L.; Cannon, R.O., III; Criqui, M.; Fadl, Y.Y.; Fortmann, S.P.; Hong, Y.; Myers, G.L.; Rifai, N.; Smith, S.C., Jr; Taubert, K.; Tracy, R.P.; Vinicor, F. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation, 2003, 107(3), 499-511.
[http://dx.doi.org/10.1161/01.CIR.0000052939.59093.45] [PMID: 12551878] , 2Koenig, W. High-sensitivity C-reactive protein and atherosclerotic disease: from improved risk prediction to risk-guided therapy. Int. J. Cardiol., 2013, 168(6), 5126-5134.
[http://dx.doi.org/10.1016/j.ijcard.2013.07.113] [PMID: 23978367] ]. The role of CRP as a risk factor contributing to the pathogenesis of atherosclerosis is controversial [3Torzewski, J.T.; Fan, J.; Schunkert, H.; Szalai, A.; Torzewski, M. Special Issue. C-reactive protein and arteriosclerosis. Mediators Inflamm., 2014. Article ID 646817, 4Zimmermann, O.; Li, K.; Zaczkiewicz, M.; Graf, M.; Liu, Z.; Torzewski, J. C-Reactive Protein in human atherogenesis. Facts Fiction. Mediators Inflamm., 2014. Article ID 561428.]. Whereas initial experimental studies suggested a pathogenic role for CRP in atherogenesis [5Paul, A.; Ko, K.W.; Li, L.; Yechoor, V.; McCrory, M.A.; Szalai, A.J.; Chan, L. C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Circulation, 2004, 109(5), 647-655.
[http://dx.doi.org/10.1161/01.CIR.0000114526.50618.24] [PMID: 14744975] ], more recent genetic data from Mendelian randomization trials failed to provide evidence for a causative role of CRP in cardiovascular disease [6Zacho, J.; Tybjaerg-Hansen, A.; Jensen, J.S.; Grande, P.; Sillesen, H.; Nordestgaard, B.G. Genetically elevated C-reactive protein and ischemic vascular disease. N. Engl. J. Med., 2008, 359(18), 1897-1908.
[http://dx.doi.org/10.1056/NEJMoa0707402] [PMID: 18971492] , 7Elliott, P.; Chambers, J.C.; Zhang, W.; Clarke, R.; Hopewell, J.C.; Peden, J.F.; Erdmann, J.; Braund, P.; Engert, J.C.; Bennett, D.; Coin, L.; Ashby, D.; Tzoulaki, I.; Brown, I.J.; Mt-Isa, S.; McCarthy, M.I.; Peltonen, L.; Freimer, N.B.; Farrall, M.; Ruokonen, A.; Hamsten, A.; Lim, N.; Froguel, P.; Waterworth, D.M.; Vollenweider, P.; Waeber, G.; Jarvelin, M.R.; Mooser, V.; Scott, J.; Hall, A.S.; Schunkert, H.; Anand, S.S.; Collins, R.; Samani, N.J.; Watkins, H.; Kooner, J.S. Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA, 2009, 302(1), 37-48.
[http://dx.doi.org/10.1001/jama.2009.954] [PMID: 19567438] ]. Mendelian randomization trials, however, do have limitations [8Morita, H.; Nagai, R. Genetically elevated C-reactive protein and vascular disease. N. Engl. J. Med., 2009, 360(9), 934-935.
[PMID: 19256031] , 9Smith, G.D.; Ebrahim, S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int. J. Epidemiol., 2003, 32(1), 1-22.
[http://dx.doi.org/10.1093/ije/dyg070] [PMID: 12689998] ]. Also, experimental results from laboratories all over the world have been contradictory, partly because of species differences in CRP biology [4Zimmermann, O.; Li, K.; Zaczkiewicz, M.; Graf, M.; Liu, Z.; Torzewski, J. C-Reactive Protein in human atherogenesis. Facts Fiction. Mediators Inflamm., 2014. Article ID 561428.] (which may limit the value of animal models in this particular area of research) and partly because data were not accurately evaluated [10van den Berg, C.W.; Taylor, K.E.; Lang, D. C-reactive protein-induced in vitro vasorelaxation is an artefact caused by the presence of sodium azide in commercial preparations. Arterioscler. Thromb. Vasc. Biol., 2004, 24(10), e168-e171.
[http://dx.doi.org/10.1161/01.ATV.0000142807.92781.d9] [PMID: 15319265] , 11Taylor, K.E.; Giddings, J.C.; van den Berg, C.W. C-reactive protein-induced in vitro endothelial cell activation is an artefact caused by azide and lipopolysaccharide. Arterioscler. Thromb. Vasc. Biol., 2005, 25(6), 1225-1230.
[http://dx.doi.org/10.1161/01.ATV.0000164623.41250.28] [PMID: 15802626] ]. Compelling evidence suggests that CRP activates the complement system and binds to and activates Fcγ receptors in macrophages in atherosclerosis and thereby sustains a chronic inflammatory process in the arterial wall [4Zimmermann, O.; Li, K.; Zaczkiewicz, M.; Graf, M.; Liu, Z.; Torzewski, J. C-Reactive Protein in human atherogenesis. Facts Fiction. Mediators Inflamm., 2014. Article ID 561428., 14Szalai, AJ; McCrory, MA; Xing, D Inhibiting c-reactive protein for the treatment of cardiovascular disease: promising evidence from rodent models. Mediators Inflamm., 2014. Article ID 353614.].

By analogy with the history of low density lipoprotein, HMG-CoA-enzyme inhibitors and cardiovascular disease [12Taylor, F.C.; Huffman, M.; Ebrahim, S. Statin therapy for primary prevention of cardiovascular disease. JAMA, 2013, 310(22), 2451-2452.
[http://dx.doi.org/10.1001/jama.2013.281348] [PMID: 24276813] ], specific CRP inhibition, followed by use of CRP inhibitors in controlled clinical trials may be the only way to prove or disprove a causative role for CRP in cardiovascular disease [3Torzewski, J.T.; Fan, J.; Schunkert, H.; Szalai, A.; Torzewski, M. Special Issue. C-reactive protein and arteriosclerosis. Mediators Inflamm., 2014. Article ID 646817].

As a result of a high throughput screening assay (HTS) to investigate the effect on CRP transcription of well-defined classes of pharmacological agents, we have shown in 2010 that endogenous and plant derived inhibitors of the Na(+)/K(+)-ATPase, i.e. the cardiac glycosides ouabain, digoxin and digitoxin, inhibit IL-1beta- and IL-6-induced acute phase protein expression in human hepatoma cells and primary human hepatocytes at nanomolar concentrations [13Kolkhof, P.; Geerts, A.; Schäfer, S.; Torzewski, J. Cardiac glycosides potently inhibit C-reactive protein synthesis in human hepatocytes. Biochem. Biophys. Res. Commun., 2010, 394(1), 233-239.
[http://dx.doi.org/10.1016/j.bbrc.2010.02.177] [PMID: 20206126] ]. Whether this in vitro finding holds true in vivo in humans and is also detected at CRP plasma level needs to be tested.

3. The Need For a Trial

Specific CRP inhibition, followed by use of CRP inhibitors in controlled clinical trials may be the only way to prove or disprove a causative role for CRP in cardiovascular disease [3Torzewski, J.T.; Fan, J.; Schunkert, H.; Szalai, A.; Torzewski, M. Special Issue. C-reactive protein and arteriosclerosis. Mediators Inflamm., 2014. Article ID 646817, 4Zimmermann, O.; Li, K.; Zaczkiewicz, M.; Graf, M.; Liu, Z.; Torzewski, J. C-Reactive Protein in human atherogenesis. Facts Fiction. Mediators Inflamm., 2014. Article ID 561428.]. An effect of cardiac glycosides on CRP plasma levels in humans has never been reported. Notably, in a recent seminal meta-analysis digoxin has been demonstrated to be associated with a neutral effect on mortality in randomised trials and a lower rate of admissions to hospital across all study types [15Ziff, O.J.; Lane, D.A.; Samra, M.; Griffith, M.; Kirchhof, P.; Lip, G.Y.; Steeds, R.P.; Townend, J.; Kotecha, D. Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data. BMJ, 2015, 351, h4451.
[http://dx.doi.org/10.1136/bmj.h4451] [PMID: 26321114] ]

Patients with decompensated heart failure, NYHA III-IV and severely reduced Left Ventricular Ejection Fraction (LVEF<40%) will be assessed for eligibility. In these patients, the plasma CRP is elevated [16Matsumoto, M.; Tsujino, T.; Lee-Kawabata, M.; Naito, Y.; Sakoda, T.; Ohyanagi, M.; Masuyama, T. Serum interleukin-6 and C-reactive protein are markedly elevated in acute decompensated heart failure patients with left ventricular systolic dysfunction. Cytokine, 2010, 49(3), 264-268.
[http://dx.doi.org/10.1016/j.cyto.2009.11.006] [PMID: 20005739] ]. Such study is ethically justified, because cardiac glycosides have been used in cardiac insufficiency for 230 years [17Withering, W. An Account of the Foxglove and Some of its Medical Uses with Practical Remarks on Dropsy and Other Diseases; GGJ and J. Robinson: London, UK, 1785.
[http://dx.doi.org/10.5962/bhl.title.3869] ] and, according to the heart failure guidelines, still provide an additive treatment option in NYHA classes III and IV [18McMurray, J.J.; Adamopoulos, S.; Anker, S.D.; Auricchio, A.; Böhm, M.; Dickstein, K.; Falk, V.; Filippatos, G.; Fonseca, C.; Gomez-Sanchez, M.A.; Jaarsma, T.; Køber, L.; Lip, G.Y.; Maggioni, A.P.; Parkhomenko, A.; Pieske, B.M.; Popescu, B.A.; Rønnevik, P.K.; Rutten, F.H.; Schwitter, J.; Seferovic, P.; Stepinska, J.; Trindade, P.T.; Voors, A.A.; Zannad, F.; Zeiher, A. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European society of cardiology. Developed in collaboration with the heart failure association (HFA) of the ESC. Eur. Heart J., 2012, 33(14), 1787-1847.
[http://dx.doi.org/10.1093/eurheartj/ehs104] [PMID: 22611136] ]. Thus, treatment with cardiac glycosides in NYHA III and IV patients is in line with heart failure guidelines and ethically justified.

The proposed trial will not answer the question whether CRP is causative in cardiovascular disease but, following a step by step approach, investigates for the first time whether cardiac glycosides lower CRP plasma levels in humans. The study serves as a pilot study for subsequent phase III trials.

4. Justificiation of Design Aspects

The study design has been extensively discussed with the Ethical Review Committee of Ulm University. Whereas the study was initially designed as a blinded, randomized clinical trial with two groups (conventional heart failure therapy plus digoxin vs. conventional heart failure therapy alone), the Ethical Review Committee suggested to change the design in order to avoid that final medication (digoxin or not) depends on the patient`s participation in the study. Following the Ethical Review Committee`s advice we have designed an observational study/prospective cohort study, which was finally accepted by the Ethical Review Committee.

4.1. Controls/Comparators

CRP plasma levels of 30 patients with decompensated heart failure, NYHA III-IV, severely reduced Left Ventricular Ejection Fraction (LVEF<40%) and conventional heart failure therapy plus digoxin will be compared to CRP plasma levels of 30 patients with decompensated heart failure, NYHA III-IV, severely reduced Left Ventricular Ejection Fraction (LVEF<40%) and conventional heart failure therapy alone.

4.2. Inclusion and Exclusion Criteria

Inclusion: Age>18 yrs; NYHA III and NYHA IV; acute cardiac failure (acute worsening of dyspnoe, radiological signs of cardiac congestion); left ventricular ejection fraction<40% in echocardiography (2 observers, Teichholz and Simpson method)

Exclusion: Significant concomitant disease (acute coronary syndrome, infection, antibiotic therapy, acute renal failure, cancer, autoimmune disease); CRP>5mg/dl, leukocyte count>12000/µL, body temperature >38 °C; AV-block I-III (for Digoxin patients).

Explanation for exclusion criteria: An exclusion of CRP>5mg/dl, leukocyte count>12000/µL, body temperature >38°C avoids confounding influence of infection. Due to the expected significant proportion of patients that need to be excluded, ~800 patients will be assessed for eligibility. Due to the expected high drop-out rate, ~80 patients will be assigned to the trial, and only 60 patients will finally be included in the trial.

4.3. Outcome Measures

CRP (and digoxin) plasma levels at days: 0, 2, 4, 6, 8 and 21. Thus, Primary efficacy endpoint is CRP plasma level during follow-up (day21 – day0). Key secondary endpoint(s): NTproBNP plasma levels (day21 – day0).

Explanation for follow up period: CRP plasma half-life is about 19h in humans. Therapeutic blood concentration of digoxin is reached after 3 days. We assumed that, after 21 days, a potential effect of digoxin on CRP synthesis should be visible.

4.4. Methods Against Bias

Echocardiography (EF) will be analysed by two investigators via Teichholz and Simpson method. Multiple regression analysis will be used to adjust for potential confounding due to gender, age, cardiac rhythm or center-specific effects. CRP plasma levels will be assessed by the independent clinical laboratory (Clinic Association Kempten-Oberallgäu, Kempten, Germany) via routine CRP measurement. Per protocol analysis of n=60 (30 digoxin vs. 30 control) patients will be performed as well as intention-to-treat analysis of approximately 80 patients assigned to the trial. Blinding is not possible because intervention and control depends on clinical needs. Digoxin plasma levels need to be monitored for safety reasons because of the drug`s small therapeutic window.

4.5. Proposed Sample Size/Power Calculations

Power calculation was discussed with the Institute of Epidemiology and Medical Biometry of Ulm University. There has never been any study investigating the effect of cardiac glycosides on CRP plasma levels before and thus, biometrical classification of the study is “pilot study for subsequent phase III trials”. The sample size of 60 patients in total was evaluated as being adequate to apply the aforementioned multiple regression analysis with 4 confounders. The expected drop-out rate is high due to, for example, acquirement of lung infection following cardiac decompensation, other infectious diseases or bradycardia due to digoxin treatment. There was no data base to conduct a formal sample size calculation due to the lack of retrospective trials in the field.

4.6. Feasibility of Treatment

Decompensated heart failure is one of the most common diagnoses on admission in cardiovascular units [18McMurray, J.J.; Adamopoulos, S.; Anker, S.D.; Auricchio, A.; Böhm, M.; Dickstein, K.; Falk, V.; Filippatos, G.; Fonseca, C.; Gomez-Sanchez, M.A.; Jaarsma, T.; Køber, L.; Lip, G.Y.; Maggioni, A.P.; Parkhomenko, A.; Pieske, B.M.; Popescu, B.A.; Rønnevik, P.K.; Rutten, F.H.; Schwitter, J.; Seferovic, P.; Stepinska, J.; Trindade, P.T.; Voors, A.A.; Zannad, F.; Zeiher, A. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European society of cardiology. Developed in collaboration with the heart failure association (HFA) of the ESC. Eur. Heart J., 2012, 33(14), 1787-1847.
[http://dx.doi.org/10.1093/eurheartj/ehs104] [PMID: 22611136] ]. All the admitted patients will be screened for inclusion and exclusion criteria. Feasibility and safety of recruitment is definitely given, because cardiac glycosides have been used in cardiac insufficiency for 230 years [17Withering, W. An Account of the Foxglove and Some of its Medical Uses with Practical Remarks on Dropsy and Other Diseases; GGJ and J. Robinson: London, UK, 1785.
[http://dx.doi.org/10.5962/bhl.title.3869] ] and, according to the heart failure guidelines, still provide an additive treatment option in NYHA classes III and IV [18McMurray, J.J.; Adamopoulos, S.; Anker, S.D.; Auricchio, A.; Böhm, M.; Dickstein, K.; Falk, V.; Filippatos, G.; Fonseca, C.; Gomez-Sanchez, M.A.; Jaarsma, T.; Køber, L.; Lip, G.Y.; Maggioni, A.P.; Parkhomenko, A.; Pieske, B.M.; Popescu, B.A.; Rønnevik, P.K.; Rutten, F.H.; Schwitter, J.; Seferovic, P.; Stepinska, J.; Trindade, P.T.; Voors, A.A.; Zannad, F.; Zeiher, A. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European society of cardiology. Developed in collaboration with the heart failure association (HFA) of the ESC. Eur. Heart J., 2012, 33(14), 1787-1847.
[http://dx.doi.org/10.1093/eurheartj/ehs104] [PMID: 22611136] ]. Expected finalization of patient recruitment is December 2015 based on current recruitment rate.

5. Statistical Analysis

After final data acquisition, all variables will be descriptively analyzed. To assess the efficacy of the investigated treatment scheme, multiple regression analysis will be performed. The dependent variable is the difference of CRP plasma level at day 21 and baseline, the independent variables are the group status (digoxin vs. placebo) and the four confounding variables gender, age, cardiac rhythm, i.e. sinus rhythm vs. atrial fibrillation, and study center. The level of significance is set to 5% (two-sided). The analyses of all secondary endpoints will be conducted in an explorative manner. Analyses concerning safety issues will be done by evaluating the adverse events frequencies in both groups. The expected drop-out rate (50%) is high, due to, for example, potential acquirement of infection during follow-up. Per protocol analysis of n=60 (30 digoxin vs. 30 control) patients will be performed as well as intention-to-treat analysis of approximately 80 patients assigned to the trial.

CONCLUSION

This is the first trial ever that systematically uses a direct CRP synthesis inhibitor in vivo in humans.

CONFLICT OF INTEREST

The study is funded by the Clinic Association Kempten-Oberallgäu. There is no conflict of interest for any of the authors.

ACKNOWLEDGEMENTS

We gratefully acknowledge Dr. David Bowyer, University of Cambridge, Cambridge, UK, for critical reading and substantial improvement of the manuscript. All individuals listed as authors have contributed substantially to the design, performance, analysis, or reporting of the work.

REFERENCES
[1] Pearson, T.A.; Mensah, G.A.; Alexander, R.W.; Anderson, J.L.; Cannon, R.O., III; Criqui, M.; Fadl, Y.Y.; Fortmann, S.P.; Hong, Y.; Myers, G.L.; Rifai, N.; Smith, S.C., Jr; Taubert, K.; Tracy, R.P.; Vinicor, F. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation, 2003, 107(3), 499-511.
[http://dx.doi.org/10.1161/01.CIR.0000052939.59093.45] [PMID: 12551878]
[2] Koenig, W. High-sensitivity C-reactive protein and atherosclerotic disease: from improved risk prediction to risk-guided therapy. Int. J. Cardiol., 2013, 168(6), 5126-5134.
[http://dx.doi.org/10.1016/j.ijcard.2013.07.113] [PMID: 23978367]
[3] Torzewski, J.T.; Fan, J.; Schunkert, H.; Szalai, A.; Torzewski, M. Special Issue. C-reactive protein and arteriosclerosis. Mediators Inflamm., 2014. Article ID 646817
[4] Zimmermann, O.; Li, K.; Zaczkiewicz, M.; Graf, M.; Liu, Z.; Torzewski, J. C-Reactive Protein in human atherogenesis. Facts Fiction. Mediators Inflamm., 2014. Article ID 561428.
[5] Paul, A.; Ko, K.W.; Li, L.; Yechoor, V.; McCrory, M.A.; Szalai, A.J.; Chan, L. C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Circulation, 2004, 109(5), 647-655.
[http://dx.doi.org/10.1161/01.CIR.0000114526.50618.24] [PMID: 14744975]
[6] Zacho, J.; Tybjaerg-Hansen, A.; Jensen, J.S.; Grande, P.; Sillesen, H.; Nordestgaard, B.G. Genetically elevated C-reactive protein and ischemic vascular disease. N. Engl. J. Med., 2008, 359(18), 1897-1908.
[http://dx.doi.org/10.1056/NEJMoa0707402] [PMID: 18971492]
[7] Elliott, P.; Chambers, J.C.; Zhang, W.; Clarke, R.; Hopewell, J.C.; Peden, J.F.; Erdmann, J.; Braund, P.; Engert, J.C.; Bennett, D.; Coin, L.; Ashby, D.; Tzoulaki, I.; Brown, I.J.; Mt-Isa, S.; McCarthy, M.I.; Peltonen, L.; Freimer, N.B.; Farrall, M.; Ruokonen, A.; Hamsten, A.; Lim, N.; Froguel, P.; Waterworth, D.M.; Vollenweider, P.; Waeber, G.; Jarvelin, M.R.; Mooser, V.; Scott, J.; Hall, A.S.; Schunkert, H.; Anand, S.S.; Collins, R.; Samani, N.J.; Watkins, H.; Kooner, J.S. Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA, 2009, 302(1), 37-48.
[http://dx.doi.org/10.1001/jama.2009.954] [PMID: 19567438]
[8] Morita, H.; Nagai, R. Genetically elevated C-reactive protein and vascular disease. N. Engl. J. Med., 2009, 360(9), 934-935.
[PMID: 19256031]
[9] Smith, G.D.; Ebrahim, S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int. J. Epidemiol., 2003, 32(1), 1-22.
[http://dx.doi.org/10.1093/ije/dyg070] [PMID: 12689998]
[10] van den Berg, C.W.; Taylor, K.E.; Lang, D. C-reactive protein-induced in vitro vasorelaxation is an artefact caused by the presence of sodium azide in commercial preparations. Arterioscler. Thromb. Vasc. Biol., 2004, 24(10), e168-e171.
[http://dx.doi.org/10.1161/01.ATV.0000142807.92781.d9] [PMID: 15319265]
[11] Taylor, K.E.; Giddings, J.C.; van den Berg, C.W. C-reactive protein-induced in vitro endothelial cell activation is an artefact caused by azide and lipopolysaccharide. Arterioscler. Thromb. Vasc. Biol., 2005, 25(6), 1225-1230.
[http://dx.doi.org/10.1161/01.ATV.0000164623.41250.28] [PMID: 15802626]
[12] Taylor, F.C.; Huffman, M.; Ebrahim, S. Statin therapy for primary prevention of cardiovascular disease. JAMA, 2013, 310(22), 2451-2452.
[http://dx.doi.org/10.1001/jama.2013.281348] [PMID: 24276813]
[13] Kolkhof, P.; Geerts, A.; Schäfer, S.; Torzewski, J. Cardiac glycosides potently inhibit C-reactive protein synthesis in human hepatocytes. Biochem. Biophys. Res. Commun., 2010, 394(1), 233-239.
[http://dx.doi.org/10.1016/j.bbrc.2010.02.177] [PMID: 20206126]
[14] Szalai, AJ; McCrory, MA; Xing, D Inhibiting c-reactive protein for the treatment of cardiovascular disease: promising evidence from rodent models. Mediators Inflamm., 2014. Article ID 353614.
[15] Ziff, O.J.; Lane, D.A.; Samra, M.; Griffith, M.; Kirchhof, P.; Lip, G.Y.; Steeds, R.P.; Townend, J.; Kotecha, D. Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data. BMJ, 2015, 351, h4451.
[http://dx.doi.org/10.1136/bmj.h4451] [PMID: 26321114]
[16] Matsumoto, M.; Tsujino, T.; Lee-Kawabata, M.; Naito, Y.; Sakoda, T.; Ohyanagi, M.; Masuyama, T. Serum interleukin-6 and C-reactive protein are markedly elevated in acute decompensated heart failure patients with left ventricular systolic dysfunction. Cytokine, 2010, 49(3), 264-268.
[http://dx.doi.org/10.1016/j.cyto.2009.11.006] [PMID: 20005739]
[17] Withering, W. An Account of the Foxglove and Some of its Medical Uses with Practical Remarks on Dropsy and Other Diseases; GGJ and J. Robinson: London, UK, 1785.
[http://dx.doi.org/10.5962/bhl.title.3869]
[18] McMurray, J.J.; Adamopoulos, S.; Anker, S.D.; Auricchio, A.; Böhm, M.; Dickstein, K.; Falk, V.; Filippatos, G.; Fonseca, C.; Gomez-Sanchez, M.A.; Jaarsma, T.; Køber, L.; Lip, G.Y.; Maggioni, A.P.; Parkhomenko, A.; Pieske, B.M.; Popescu, B.A.; Rønnevik, P.K.; Rutten, F.H.; Schwitter, J.; Seferovic, P.; Stepinska, J.; Trindade, P.T.; Voors, A.A.; Zannad, F.; Zeiher, A. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European society of cardiology. Developed in collaboration with the heart failure association (HFA) of the ESC. Eur. Heart J., 2012, 33(14), 1787-1847.
[http://dx.doi.org/10.1093/eurheartj/ehs104] [PMID: 22611136]
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Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)

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