Heart Failure Reviews

, Volume 21, Issue 1, pp 95–102 | Cite as

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

  • Stephen J. Greene
  • Hani N. Sabbah
  • Javed Butler
  • Adriaan A. Voors
  • Barbara E. Albrecht-Küpper
  • Hans-Dirk Düngen
  • Wilfried Dinh
  • Mihai Gheorghiade


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.


Adenosine Adenosine A1 receptor Partial agonist Therapy Heart failure Mitochondria 


Compliance with ethical standards

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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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Stephen J. Greene
    • 1
  • Hani N. Sabbah
    • 2
  • Javed Butler
    • 3
  • Adriaan A. Voors
    • 4
  • Barbara E. Albrecht-Küpper
    • 5
  • Hans-Dirk Düngen
    • 6
  • Wilfried Dinh
    • 7
    • 8
  • Mihai Gheorghiade
    • 9
  1. 1.Division of CardiologyDuke University Medical CenterDurhamUSA
  2. 2.Division of Cardiovascular Medicine, Department of MedicineHenry Ford HospitalDetroitUSA
  3. 3.Division of CardiologyStony Brook UniversityStony BrookUSA
  4. 4.Department of Cardiology, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
  5. 5.Departments of Heart Diseases and Medicinal ChemistryBayer Pharma AG Research CenterWuppertalGermany
  6. 6.Department of Cardiology, Campus VirchowCharite Universitätsmedizin BerlinBerlinGermany
  7. 7.Department of Cardiology, HELIOS Clinic WuppertalUniversity Hospital Witten/HerdeckeWuppertalGermany
  8. 8.Global Drug Discovery, Clinical Sciences, Experimental MedicineBayer Pharma AGWuppertalGermany
  9. 9.Center for Cardiovascular InnovationNorthwestern University Feinberg School of MedicineChicagoUSA

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