β₂ AR agonists in treatment of chronic heart failure: long path to translation.
The main clinical manifestations of advanced chronic heart failure (CHF), e.g. in dilated cardiomyopathy (DCM), are reduced systolic and diastolic functions, increased arterial elastance and arterio-ventricular uncoupling, accompanied and exacerbated by an excessive sympathetic activation and extensive abnormalities in the βAR signaling. Loss of cardiomyocytes due to apoptosis is one mechanism that undoubtedly contributes to cardiac remodeling and functional deterioration associated with dilated cardiomyopathy (DCM). Research during the last decade on the single cardiomyocyte level strongly suggested that selective stimulation of β(1) AR activates the proapoptotic signaling pathways, while selective stimulation of β(2) AR is antiapoptotic, but its precise mechanisms remain to be elucidated. Extensive research in the rat model of DCM following induction of myocardial infarction (MI) showed that prolonged treatment with of β(2) AR agonist, fenoterol, in combination with a β(1) AR blocker, metoprolol, is more effective than β(1) AR blocker alone and as effective as β(1) AR blocker with ACE inhibitor with respect to survival and cardiac remodeling. This combined regimen of β(2) AR agonists and a β(1) AR blocker might be considered for clinical testing as alternative or adjunct therapy to currently acceptable CHF arsenal. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."
Talan
Mark I
MI
Laboratory of Cardiovascular Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA. talanm@grc.nia.nih.gov
Ahmet
Ismayil
I
Xiao
Riu-Ping
RP
Lakatta
Edward G
EG
D058666:Adrenergic beta-2 Receptor Agonists / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000627:therapeutic use; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000473:pathology; D000077261:Carvedilol; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006333:Heart Failure / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D058990:Molecular Targeted Therapy; D011412:Propanolamines / Q000627:therapeutic use; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D057170:Translational Research, Biomedical
D058666:Adrenergic beta-2 Receptor Agonists; D002227:Carbazoles; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D000077261:Carvedilol