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Partial adenosine A1 receptor agonism: a potential new therapeutic strategy for heart failure

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Abstract

Heart failure (HF) represents a global public health and economic problem associated with unacceptable rates of death, hospitalization, and healthcare expenditure. Despite available therapy, HF carries a prognosis comparable to many forms of cancer with a 5-year survival rate of ~50 %. The current treatment paradigm for HF with reduced ejection fraction (EF) centers on blocking maladaptive neurohormonal activation and decreasing cardiac workload with therapies that concurrently lower blood pressure and heart rate. Continued development of hemodynamically active medications for stepwise addition to existing therapies carries the risk of limited tolerability and safety. Moreover, this treatment paradigm has thus far failed for HF with preserved EF. Accordingly, development of hemodynamically neutral HF therapies targeting primary cardiac pathologies must be considered. In this context, a partial adenosine A1 receptor (A1R) agonist holds promise as a potentially hemodynamically neutral therapy for HF that could simultaneous improve cardiomyocyte energetics, calcium homeostasis, cardiac structure and function, and long-term clinical outcomes when added to background therapies. In this review, we describe the physiology and pathophysiology of HF as it relates to adenosine agonism, examine the existing body of evidence and biologic rationale for modulation of adenosine A1R activity, and review the current state of drug development of a partial A1R agonist for the treatment of HF.

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Authors and Affiliations

  1. Division of Cardiology, Duke University Medical Center, Durham, NC, USA

    Stephen J. Greene

  2. Division of Cardiovascular Medicine, Department of Medicine, Henry Ford Hospital, Detroit, MI, USA

    Hani N. Sabbah

  3. Division of Cardiology, Stony Brook University, Stony Brook, NY, USA

    Javed Butler

  4. Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Adriaan A. Voors

  5. Departments of Heart Diseases and Medicinal Chemistry, Bayer Pharma AG Research Center, Wuppertal, Germany

    Barbara E. Albrecht-Küpper

  6. Department of Cardiology, Campus Virchow, Charite Universitätsmedizin Berlin, Berlin, Germany

    Hans-Dirk Düngen

  7. Department of Cardiology, HELIOS Clinic Wuppertal, University Hospital Witten/Herdecke, Wuppertal, Germany

    Wilfried Dinh

  8. Global Drug Discovery, Clinical Sciences, Experimental Medicine, Bayer Pharma AG, Wuppertal, Germany

    Wilfried Dinh

  9. Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, 201 East Huron, Galter 3-150, Chicago, IL, 60601, USA

    Mihai Gheorghiade

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  1. Stephen J. Greene
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Correspondence to Mihai Gheorghiade.

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Conflict of interest

Dr. Greene reports no conflicts. Dr. Sabbah has received research Grants and/or is consultant to Bayer Healthcare AG, Stealth Peptides, Inc., Amgen Corp., Johnson & Johnson, Inc., Novartis Corp., Merck, and Takeda Pharmaceuticals. Dr. Butler reports research support from the National Institutes of Health, European Union, and Health Resources Service Administration and is a consultant to Amgen, Bayer, BG Medicine, Cardiocell, Celladon, Gambro, GE Healthcare, Medtronic, Novartis, Ono Pharma, Takeda, Trevena, and Zensun. Dr Voors received consultancy fees and/or research Grants from: Alere, Amgen, Bayer, Boehringer, Cardio3Biosciences, Celladon, GSK, Merck/MSD, Novartis, Servier, Singulex, Sphingotec, Trevena, Vifor, ZS Pharma, and is supported by a Grant from the European Commission: FP7-242209-BIOSTAT-CHF. Drs. Albrecht-Küpper and Dinh are employees of Bayer Healthcare. Dr. Düngen has received research grants and/or is consultant to Bayer Healthcare AG, Amgen Corp., Novartis, Trevena, Celladon, AstraZeneca and reports research support from German Ministry of Education and Research. Dr. Gheorghiade has been a consultant for Abbott Laboratories, AstraZeneca, Bayer Schering Pharma AG, Cardiocell LLC, Cardiorentis Ltd, GlaxoSmithKline, Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Ono Pharmaceuticals USA, Otsuka Pharmaceuticals, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Stealth BioTherapeutics, Sticares InterACT, Takeda Pharmaceuticals North America, Inc and Trevena Therapeutics.

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Greene, S.J., Sabbah, H.N., Butler, J. et al. Partial adenosine A1 receptor agonism: a potential new therapeutic strategy for heart failure. Heart Fail Rev 21, 95–102 (2016). https://doi.org/10.1007/s10741-015-9522-7

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