Adrenergic signaling in heart failure: a balance of toxic and protective effects

Heart failure with reduced ejection fraction involves activation of the sympathetic nervous system and chronic hyperactivation of the sympatho-adrenergic receptors (ARs) beta-ARs and alpha 1-ARs, which are thought to be cardiotoxic and worsen pathological remodeling and function. Concurrently, the failing heart manifests significant decreases in sympathetic nerve terminal density, decreased cardiac norepinephrine levels, and marked downregulation of beta-AR abundance and signaling. Thus, a state of both feast and famine coexist with respect to the adrenergic state in heart failure. For the failing heart, the hyperadrenergic state is toxic. However, the role of hypoadrenergic mechanisms in the pathophysiology of heart failure is less clear. Cardiotoxic effects are known to arise from the beta 1-AR subtype, and use of beta-AR blockers is a cornerstone of current heart failure therapy. However, cardioprotective effects arise from the beta 2-AR subtype that counteract hyperactive beta 1-AR signaling, but unfortunately, beta 2-AR cardioprotective signaling in heart failure is inhibited by beta-AR blocker therapy. In contrast to current dogma, recent research shows beta 1-AR signaling can also be cardioprotective. Moreover, for some forms of heart failure, beta 2-AR signaling is cardiotoxic. Thus for both beta-AR subtypes, there is a balance between cardiotoxic versus cardioprotective effects. In heart failure, stimulation of alpha 1-ARs is widely thought to be cardiotoxic. However, also contrary to current dogma, recent research shows that alpha 1-AR signaling is cardioprotective. Taken together, recent research identifies cardioprotective signaling arising from beta 1-AR, beta 2-AR, and alpha 1-ARs. A goal for future therapies will to harness the protective effects of AR signaling while minimizing cardiotoxic effects. The trajectory of heart failure therapy changed radically from the previous and intuitive use of sympathetic agonists, which unfortunately resulted in greater mortality, to the current use of beta-AR blockers, which initially seemed counterintuitive. As a cautionary note, if the slow adoption of beta-blocker therapy in heart failure is any guide, then new treatment strategies, especially counterintuitive therapies involving stimulating beta-AR and alpha 1-AR signaling, may take considerable time to develop and gain acceptance.