title: Partial adenosine A1 receptor agonism: a potential new therapeutic strategy for heart failure.
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.
authors.affiliation: Division of Cardiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Greene
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Hani N
authors.initials: HN
authors.lastname: Sabbah
authors.affiliation: Division of Cardiology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Javed
authors.initials: J
authors.lastname: Butler
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
authors.affiliation: Departments of Heart Diseases and Medicinal Chemistry, Bayer Pharma AG Research Center, Wuppertal, Germany.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Albrecht-Küpper
authors.affiliation: Department of Cardiology, Campus Virchow, Charite Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Hans-Dirk
authors.initials: HD
authors.lastname: Düngen
authors.affiliation: Department of Cardiology, HELIOS Clinic Wuppertal, University Hospital Witten/Herdecke, Wuppertal, Germany.|Global Drug Discovery, Clinical Sciences, Experimental Medicine, Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Dinh
authors.affiliation: Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, 201 East Huron, Galter 3-150, Chicago, IL, 60601, USA. m-gheorghiade@northwestern.edu.
authors.forename: Mihai
authors.initials: M
authors.lastname: Gheorghiade
mesh_terms: D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology; D054333:Drug Partial Agonism; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D013318:Stroke Volume / Q000502:physiology
chemical_list: D058907:Adenosine A1 Receptor Agonists; D002317:Cardiovascular Agents; D043682:Receptor, Adenosine A1
keywords: Adenosine; Adenosine A1 receptor; Heart failure; Mitochondria; Partial agonist; Therapy