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 beta AR 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 beta(1) AR activates the proapoptotic signaling pathways, while selective stimulation of beta(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 beta(2) AR agonist, fenoterol, in combination with a beta(1) AR blocker, metoprolol, is more effective than beta(1) AR blocker alone and as effective as beta(1) AR blocker with ACE inhibitor with respect to survival and cardiac remodeling. This combined regimen of beta(2) AR agonists and a beta(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." Published by Elsevier Ltd.