Since the 1970s,^, in observational trials, and more recently in placebo-controlled randomized trials,^, antagonizing beta-1 adrenergic receptors in the myocardium has been shown to mitigate the burden of heart failure with reduced ejection fraction (HFrEF). Mortality has been reduced by 34-65% according to these studies. However, inhibiting the action of the peripheral sympathetic nervous system (SNS) by blocking alpha1 or stimulating alpha-2 central receptors has shown negative results or even an increased mortality, despite reducing norepinephrine plasma levels.^– This indicates that SNS effects on myocardial receptors, more than in peripheral receptors, play a pivotal role in HFrEF pathophysiology.

Hyper-activation of the SNS and the renin-angiotensin-aldosterone axis, combined with an increase in load-dependent peptides and inflammatory cascades constitute the neuro-humoral theory on HFrEF progression. While the neuro-humoral response counteracts and compensates for an initial myocardial insult, in the long-term it contributes to the progression of the disease to the point that cardiovascular homeostasis eventually succumbs if not treated properly. Therapies targeting all these neuro-humoral responses have dramatically changed the natural history of HFrEF.

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