[Frontiers In Bioscience, Landmark, 24, 1037-1049, March 1, 2019]

Anti-ß1-Adrenoreceptor auto-Antibodies in elderly heart failure patients

Tobias D. Trippel1,2, Dominik N. Mueller3, Danilo Obradovic1, Frank Edelmann1,2,4, Elvis Tahirovic1,2, Nicola Wilck3,5, Gabriela Riemekasten6, Duska Dragun7, Andreas Busjahn8, Harald Heidecke9, Juliane Junker9, Burkert Pieske1,2, Hans-Dirk Dungen1,2, Ralf Dechend3,10

1Charite, Universitatsmedizin Berlin, Campus Virchow Klinikum, Department of Internal Medicine, Cardiology, Berlin, Germany, 2German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Germany, 3Experimental and Clinical Research Center, Charite, Universitatsmedizin Berlin, Campus Buch Berlin, Germany, 4Herzzentrum Gottingen, Universitatsklinikum Gottingen, Abteilung fur Kardiologie und Pneumologie, Gottingen, Germany, 5Charite, Universitatsmedizin Berlin, Campus Charite Mitte, Department of Internal Medicine, Cardiology/Angiology, Berlin, Germany, 6Universitatsklinikum Schleswig-Holstein, Campus Lubeck, Klinik fur Rheumatologie, Lubeck, Germany, 7Charite, Universitatsmedizin Berlin, Campus Campus Virchow Klinikum, Department of Nephrology and Intensive Care, Berlin, Germany, 8HealthTwist GmbH, Biomedizinischer Forschungscampus Berlin-Buch, Germany, 9CellTrend, Biotechnologiepark, Luckenwalde, Germany, 10HELIOS Klinikum Berlin-Buch GmbH, Klinik und Poliklinik fur Kardiologie und Nephrologie, Berlin-Buch, Germany

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Methods
3.1. Subjects and intervention
3.2. Data collection and definitions
3.3. Data analysis
3.4. Ethics
4. Results
5. Discussion
5.1. Study population
5.2. B1-adrenergic autoantibodies in heart failure
5.3. Ethiology of heart failure
5.4. Heart Rate
5.5. Beta blocker therapy
5.6. ELISA
6. Limitations
7. Conclusion
8. Acknowledgements
9. References

1. ABSTRACT

An autoimmune reaction directed against the cardiac b1-adrenergic receptor (ß1-ADR) leading to the generation of autoantibodies (AA) against this G-coupled receptor has been described in patients with heart failure (HF). Agonist-like ß1-ADR-AA are associated with morbidity in HF patients and even predict mortality. Standardised and valid diagnostic tools to detect ß1-ADR-AA in clinical routine are lacking. We used a novel ELISA approach to investigate ß1-ADR-AA in a cohort of 574 HF patients of the CIBIS-ELD trial with follow up. The CIBIS-ELD trial compared the titration of bisoprolol and carvedilol to recommended target doses in regard to BB tolerability in patients aged 65 years and older. Patient with left ventricular (LV) ejection fraction (EF) < 50% or LV diameter end diastolic (DED) >55 cm showed significantly higher levels of ß1-ADR-AA. Although not yet fully validated, this ELISA allowed for a negative correlation of ß1-ADR-AA with the EF at baseline and at the follow up, ß1-ADR-AA further correlated positively with basal heart rate at follow up 12 weeks later. ß1-ADR-AA levels thus determined significantly increased under titration with beta-blockers (p<0.0.1). Changes in ß1-ADR-AA between F-Up and baseline were significantly higher in patients who used beta blockers (p=0.0.16) before study inclusion. The type of beta-blocker (BB) titrated in this study did not affect log ß1-ADR-AA levels at baseline (p=0.1.32), follow-up (p=0.0.58), nor the change (p=0.4.26). ß1-ADR-AA levels were estimated using a novel, commercially available ELISA. Although not yet fully validated, this ELISA allowed for pathophysiological insights: ß1-ADR-AA levels thus determined significantly increased under titration with beta-blockers (p<0.0.1), irrespective of type of BB. Higher levels of ß1-ADR-AA at baseline are associated with higher heart rates, lower ejection fraction and enlarged left ventricles. The relevance of the ß1-ADR-AA biomarker should be further evaluated.

9. REFERENCES

1. DL Mann, DP Zipes, P Libby, RO Bonow: Braunwald’s Heart Disease: A Textbook of Cardiovasc Med. 10 th Edition. Saunders W.B. / Elsevier. (2015)

2. MJ Lohse, S Engelhardt, T Eschenhagen: What is the role of ß-adrenergic signalling in heart failure? Circ Res 93, 896-906 (2003)

3. P Ponikowski, AA Voors, SD Anker, H Bueno, JG Cleland, AJ Coats, V Falk, JR González-Juanatey, VP Harjola, EA Jankowska, M Jessup, C Linde, P Nihoyannopoulos, JT Parissis, B Pieske, JP Riley, GM Rosano, LM Ruilope, F Ruschitzka, FH Rutten, P van der Meer: 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 37(27), 2129-2200 (2016)
DOI: 10.1093/eurheartj/ehw128
PMid:27206819

4. B Bornholz, D Roggenbuck, R Jahns, F Boege: Diagnostic and therapeutic aspects of ß1-adrenergic receptor autoantibodies in human heart disease. Autoimmun Rev 13, 954-962 (2014)
DOI: 10.1016/j.autrev.2014.08.021
PMid:25149394

5. G Wallukat, I Schimke: Agonistic autoantibodies directed again G-protein-coupled receptors and their relationship to cardiovascular disease. Semin Immunopathol 36, 351-363 (2014)
DOI: 10.1007/s00281-014-0425-9
PMid:24777744

6. L Sterin-Borda, OM Cossio, MG Gimeno, AF Gimeno, C Diez, RP Laguens, PC Meckert, RM Arana: Effect of a chagasic sera on the rat isolated atrial preparation: immunological, morphological and function aspects. Cardiovasc Res 10, 613-622 (1976)
DOI: 10.1093/cvr/10.6.613
PMid:825225

7. SG Muñoz Saravia, A Haberland, S Bartel, R Araujo, G Valda, D Duchen, I Diaz Ramirez, AC Borges, G Wallukat, I Schimke: Distinct patterns of autoantibodies against G-protein-coupled receptors in Chagas’ cardiomyopathy and megacolon: their potential impact for early risk assessment in asymptomatic Chagas’ patients. J Am Coll Cardio. 56(6), 526-527 (2010)
DOI: 10.1016/j.jacc.2010.02.057
PMid:20670767

8. Y Magnusson, G Wallukat, F Waagstein, A Hjalmarson, J Hoebeke J: Autoimmunity in idiopathic dilated cardiomyopathy, Characterization of antibodies against the beta-1-adrenorecptor with positive chronotropic effect. Circulation 89, 2760-2767 (1994)
DOI: 10.1161/01.CIR.89.6.2760
PMid:8205690

9. W Mao, S Fukuoka, C Iwai, J Liu, VK Sharma, SS Sheu, F Fu, CS Liang CS: Cardiomyocyte apoptosis in autoimmune cardiomyopathy: mediated viaendoplasmic reticulum stress and exaggerated by norepinephrine. Am J Physiol Heart Circ Physiol 293, 1636–1645 (2007)
DOI: 10.1152/ajpheart.01377.2006
PMid:17545481

10. R Jahns, V Boivin, C Siegmund, G Inselmann, MJ Lohse, F Boege: Autoantibodies activating human beta1-adrenergic receptors are associated with reduced cardiac function in chronic heart failure. Circulation 99(5), 649-654 (1999)
DOI: 10.1161/01.CIR.99.5.649
PMid:9950662

11. R Jahns, V Boivin, C Siegmund, F Boege, MJ Lohse, G Inselmann: Activating beta-1-adrenoceptor antibodies are not associated with cardiomyopathies secondary to valvular or hypertensive heart disease. J Am Coll Cardiol 34(5), 1545-1551 (1999)
DOI: 10.1016/S0735-1097(99)00381-2

12. S Stork, V Boivin, R Horf, L Hein, MJ Lohse, CE Angermann, R Jahns: Stimulating autoantibodies directed against the cardiac beta1-adrenergic receptor predict increased mortality in idiopathic cardiomyopathy. Am Heart J 152, 697-704 (2006)
DOI: 10.1016/j.ahj.2006.05.004
PMid:16996841

13. R Jahns, V Boivin, L Hein, S Triebel, CE Angermann, G Ertl, MJ Lohse: Direct evidence for a beta 1-adrenergic receptor-directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy. J Clin Invest 113(10), 1419-1429 (2004)
DOI: 10.1172/JCI200420149
PMid:15146239 PMCid:PMC406525

14. J Müller, G Wallukat, M Dandel, H Bieda, K Brandes, S Spiegelsberger, E Nissen, R Kunze, R Hetzer: Immunoglobulin adsorption in patients with idiopathic dilated cardiomyopathy. Circulation 101(4), 385-391 (2000)
DOI: 10.1161/01.CIR.101.4.385
PMid:10653829

15. G Wallukat, J Muller, R Hetzer: Specific removal of beta1-adrenergic-autoantibodies from patients with idiopathic dilated cardiomyopathy. N Engl J Med 347, 1806 (2002)

16. S Matsui, M Persson, HM Fu, M Hayase, S Katsuda, K Teraoka, T Kurihara, ML Fu: Protective effect of bisoprolol on beta-1 adrenoceptor peptide-induced autoimmune myocardial damage in rabbits. Herz 25(3), 267-270 (2000)
DOI: 10.1007/s000590050018
PMid:10904850

17. A Haberland, G Wallukat, C Dahmen, A Kage, I Schimke I: Aptamer neutralization of beta1-adrenoreceptor autoantibodies isolated from patients with cardiomyopathies. Circ Res 109, 986-992 (2011)
DOI: 10.1161/CIRCRESAHA.111.253849
PMid:21868696

18. G Munch, V Boivin-Jahns, HP Holthoff, K Adler, M Lappo, S Truol, H Degen, N Steiger, MJ Lohse, R Jahns, M Ungerer: Administration of the cyclic peptide COR-1 in humans (phase I study): ex vivo measurements of anti-beta1-adrenergic receptor antibody neutralization and of immune parameters. Eur J Heart Fail 14(11), 1230-1239 (2012)
DOI: 10.1093/eurjhf/hfs118
PMid:22968742

19. K Zophel, D Roggenbuck, M Schott: Clinical review about TRAb assay’s history. Autoimmun Rev 9, 695-700 (2010)
DOI: 10.1016/j.autrev.2010.05.021
PMid:20594972

20. VO Nikolaev, V Boivin, S Störk, CE Angermann, G Ertl, MJ Lohse, R Jahns: A novel fluorescence method for the rapid detection of functional beta1-adrenergic receptor autoantibodies in heart failure. J Am Coll Cardiol 50(5), 423-431 (2007)
DOI: 10.1016/j.jacc.2007.03.051
PMid:17662395

21. HP Holthoff, S Zeibig, V Jahns-Boivin, J Bauer, MJ Lohse, S Kääb, S Clauss, R Jahns, A Schlipp, G Münch, M Ungerer: Detection of anti-β1-AR autoantibodies in heart failure by a cell-based competition ELISA. Circ Res 111(6), 675-684 (2012)
DOI: 10.1161/CIRCRESAHA.112.272682
PMid:22811559

22. N Deubner, D Berliner, A Schlipp, G Gelbrich, AL Caforio, SB Felix, M Fu, H Katus, CE Angermann, MJ Lohse, G Ertl, S Stork, R Jahns R: Etiology, Titre-Course Survival-Study, Group. Cardiac beta1-adrenoceptor autoantibodies in human heart disease: rationale and design of the Etiology, Titre-Course, and Survival (ETiCS) Study. Eur J Heart Fail 12(7), 753-762 (2010)
DOI: 10.1093/eurjhf/hfq072
PMid:20494925

23. HD Düngen, S Apostolovic, S Inkrot, E Tahirovic, A Topper, F Mehrhof, C Prettin, B Putnikovic, AN Neskovic, M Krotin, D Sakac, M Lainscak, F Edelmann, R Wachter, T Rau, T Eschenhagen, W Doehner, SD Anker, F Waagstein, C Herrmann-Lingen, G Gelbrich, R Dietz, Cibis-Eld investigators Project Multicentre Trials in the Competence Network Heart Failure: Titration to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure: the CIBIS-ELD trial. Eur J Heart Fail 13, 670-680 (2011)
DOI: 10.1093/eurjhf/hfr020
PMid:21429992 PMCid:PMC3101867

24. HD Düngen, S Apostolović, S Inkrot, E Tahirović, F Krackhardt, M Pavlović, B Putniković, M Lainscak, G Gelbrich, F Edelmann, R Wachter, T Eschenhagen, F Waagstein, F Follath, M Rauchhaus, W Haverkamp, KJ Osterziel, R Dietz, CIBIS-ELD Investigators, Subproject Multicenter Trials in the Competence Network Heart Failure: Bisoprolol vs. carvedilol in elderly patients with heart failure: rationale and design of the CIBIS-ELD trial. Clin Res Cardiol 97(9), 578-586 (2008)
DOI: 10.1007/s00392-008-0681-6
PMid:18542839

25. NJ Freedman, J Robert, RJ Lefkowitz: Anti–β1-adrenergic receptor antibodies and heart failure: causation, not just correlation. J Clin Invest 113, 1379–1382 (2004)
DOI: 10.1172/JCI21748
PMid:15146232 PMCid:PMC406535

26. U Nussinovitch, Y Shoenfeld: The Clinical Significance of Anti-Beta-1 Adrenergic Receptor Autoantibodies in Cardiac Disease. Clinic Rev Allerg Immunol 44, 75–83 (2013)
DOI: 10.1007/s12016-010-8228-9
DOI: 10.1007/s12016-010-8229-8
PMid:21207194

27. G Wallukat, A Wollenberger, R Morwinski, HF Pitschner: Anti-beta 1-adrenoceptor autoantibodies with chronotropic activity from the serum of patients with dilated cardiomyopathy: mapping of epitopes in the first and second extracellular loops. J Mol Cell Cardiol 27(1), 397-406 (1995)
DOI: 10.1016/S0022-2828(08)80036-3

28. Y Magnusson, S Marullo, S Hoyer, F Waagstein, B Andersson, A Vahlne, JG Guillet, AD Strosberg, A Hjalmarson, J Hoebeke: Mapping of a functional autoimmune epitope on the beta 1-adrenergic receptor in patients with idiopathic dilated cardiomyopathy. J Clin Invest 86(5), 1658-1663 (1990)
DOI: 10.1172/JCI114888
PMid:1700798 PMCid:PMC296916

29. V Boivin, N Beyersdorf, D Palm, VO Nikolaev, A Schlipp, J Müller, D Schmidt, V Kocoski, T Kerkau, T Hünig, G Ertl, MJ Lohse, R Jahns: Novel receptor-derived cyclopeptides to treat heart failure caused by anti-β1-adrenoceptor antibodies in a human-analogous rat model. PLoS One 10(2), e0117589 (2015)

30. Y Magnusson, A Hjialmarson, J Hoebeke: Beta 1-adrenoreceptor autoimmunity in cardiomyopathy. Int J Cardiol 54, 137-141 (1996)
DOI: 10.1016/0167-5273(96)02590-9

31. A Diaz, MG Bourassa, MC Guertin, JC Tardif: Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J 26, 967–974 (2005)
DOI: 10.1093/eurheartj/ehi190
PMid:15774493

32. L Wilhelmsen, G Berglund, D Elmfeldt, G Tibblin, H Wedel, K Pennert, A Vedin, C Wilhelmsson, L Werkö L: The multifactor primary prevention trial in Göteborg, Sweden. Eur Heart J 7, 279–288 (1986)
DOI: 10.1093/oxfordjournals.eurheartj.a062065
PMid:3720755

33. M Metra, S Nodari, A D’Aloia, C Muneretto, AD Robertson, MR Bristow, L Dei Cas: Beta-Blocker Therapy Influences the Hemodynamic Response to Inotropic Agents in Patients With Heart Failure A Randomized Comparison of Dobutamine and Enoximone Before and After Chronic Treatment With Metoprolol or Carvedilol. JACC 40(7), 1248–1258 (2002)
DOI: 10.1016/S0735-1097(02)02134-4

34. P Ping, R Gelzer-Bell, DA Roth, D Kiel, PA Insel, HK Hammond: Reduced ß-adrenergic receptor activation decreased G-protein expression and ß-adrenergic receptor kinase activity in porcine heart. J Clin Invest 95, 1271-1280 (1995)
DOI: 10.1172/JCI117777
PMid:7883975 PMCid:PMC441466

35. G Iacarrino, ED Thomhave, RJ Lefkowitz, WJ Koch: Reciprocal in invo regulation of myocardial G protein-coupled receptor kinase expression by ß-adrenergic receptor stimulation and blockade. Circulation 98, 1783-1789 (1998)

36. R Jahns, F Boege: Questionable Validity of Peptide-Based ELISA Strategies in the Diagnostics of Cardiopathogenic Autoantibodies That Activate G-Protein-Coupled Receptors. Cardiology 131(3), 149-150 (2015)

37. B Bornholz, B Hanzen, Y Reinke, SB Felix, R Jahns, I Schimke, G Wallukat, F Boege: Detection of DCM-associated β1-adrenergic receptor autoantibodies requires functional readouts or native human β1-receptors as targets. Int J Cardiol 202, 728-30 (2016)

38. B Bornholz, S Weidtkamp-Peters, S Schmitmeier, CA Seidel, LR Herda, SB Felix, H Lemoine, J Hescheler, F Nguemo, C Schäfer, MO Christensen, C Mielke, F Boege: Impact of human autoantibodies on β1-adrenergic receptor conformation, activity, and internalization. Cardiovasc Res 97(3), 472-80 (2013)

Key Words: Heart Failure, Beta Blockers, Beta Receptors, Autoantibodies, ELISA

Send correspondence to: Harald Heidecke, CellTrend GmbH, Im Biotechnologiepark, 14943 Luckenwalde, Germany, Tel: 49-3371-6199-600, Fax: 49-3371-6199-604, E-mail: Heidecke@CellTrend.de