[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


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


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.


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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