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

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Abstract

Heart failure with reduced ejection fraction involves activation of the sympathetic nervous system and chronic hyperactivation of the sympatho-adrenergic receptors (ARs) β-ARs and α1-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 β-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 β1-AR subtype, and use of β-AR blockers is a cornerstone of current heart failure therapy. However, cardioprotective effects arise from the β2-AR subtype that counteract hyperactive β1-AR signaling, but unfortunately, β2-AR cardioprotective signaling in heart failure is inhibited by β-AR blocker therapy. In contrast to current dogma, recent research shows β1-AR signaling can also be cardioprotective. Moreover, for some forms of heart failure, β2-AR signaling is cardiotoxic. Thus for both β-AR subtypes, there is a balance between cardiotoxic versus cardioprotective effects. In heart failure, stimulation of α1-ARs is widely thought to be cardiotoxic. However, also contrary to current dogma, recent research shows that α1-AR signaling is cardioprotective. Taken together, recent research identifies cardioprotective signaling arising from β1-AR, β2-AR, and α1-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 β-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 β-AR and α1-AR signaling, may take considerable time to develop and gain acceptance.

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Acknowledgements

Supported by a VA Merit Award and a grant-in-aid from the American Heart Association, Western States Affiliate. Figure 4 generously provided by Timothy D. O’Connell, University of Minnesota. Helpful discussion of the manuscript with Drs. Paul C. Simpson and Joel S. Karliner is gratefully acknowledged.

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  1. Veterans Affairs Medical Center, San Francisco and Department of Medicine, University of California, Cardiology Division (111C), 4150 Clement St, San Francisco, CA, 94121, USA

    Anthony J. Baker

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Baker, A.J. Adrenergic signaling in heart failure: a balance of toxic and protective effects. Pflugers Arch - Eur J Physiol 466, 1139–1150 (2014). https://doi.org/10.1007/s00424-014-1491-5

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  • DOI: https://doi.org/10.1007/s00424-014-1491-5

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