β₃-Adrenergic Signaling in Heart Failure: A Stage-Dependent Double-Edged Sword

Heart failure (HF) is a heterogeneous clinical syndrome in which abnormalities of myocardial relaxation, contractile performance, and neurohormonal activation contribute variably across disease phenotypes and stages. While advanced heart failure with reduced ejection fraction (HFrEF) is dominated by impaired systolic function and low cardiac output, heart failure with preserved ejection fraction (HFpEF) and earlier disease stages are primarily characterized by diastolic dysfunction, increased myocardial stiffness, and elevated filling pressures. These distinctions have important therapeutic implications, particularly with respect to lusitropic versus inotropic strategies.β₃-adrenergic receptors (β₃-ARs) exhibit signaling properties distinct from classical β₁- and β₂-receptors and are increasingly recognized as modulators of cardiovascular function under pathological conditions. β₃-AR activation preferentially engages nitric oxide–cyclic guanosine monophosphate pathways, promoting vasodilation, reducing oxidative stress, and enhancing myocardial relaxation, albeit with mild context-dependent negative inotropy. Experimental and early clinical data suggest that β₃-AR agonism may be beneficial in clinical settings dominated by impaired relaxation and elevated filling pressures, including HFpEF and pulmonary hypertension.Conversely, sustained β₃-AR signaling in advanced systolic HF may contribute to contractile depression, mitochondrial dysfunction, and energetic inefficiency. Preclinical and translational studies indicate that selective β₃-AR antagonism can improve systolic performance and myocardial energetics without increasing heart rate or adrenergic drive, positioning β₃ blockade as a potential “smart inotropic” strategy.This review proposes a physiology-guided, stage-dependent framework for β₃-adrenergic modulation in HF, in which agonism and antagonism represent complementary therapeutic approaches tailored to dominant pathophysiology rather than opposing strategies.