Neurohormonal Crosstalk in Heart Failure: Targeting the Sympathetic-RAAS Axis for Precision Therapeutics

Abstract

Heart failure (HF) is characterized by sustained autonomic imbalance marked by chronic sympathetic nervous system (SNS) activation and upregulation of the renin angiotensin aldosterone system (RAAS). While initially compensatory, persistent neurohormonal activation promotes adverse cardiac remodeling, arrhythmogenesis, renal sodium retention, and progressive ventricular dysfunction. Increasing evidence indicates that the SNS and RAAS function not as isolated pathways but as an integrated neurohormonal axis with bidirectional amplification mechanisms that accelerate HF progression.
This review synthesizes current understanding of sympathetic-RAAS crosstalk at molecular, cellular, and systemic levels. Mechanistic insights into β-adrenergic receptor desensitization, G protein-coupled receptor kinase 2 (GRK2) signaling, angiotensin II mediated sympathetic facilitation, aldosterone driven autonomic modulation, and renal sympathetic activation in congestion physiology are discussed. Established therapies including β blockers, angiotensin receptor neprilysin inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors are examined through the lens of autonomic modulation rather than solely haemodynamic effects.
Additionally, device based strategies such as renal denervation, baroreceptor activation therapy, and vagal nerve stimulation are evaluated, highlighting translational data and clinical trial outcomes
Finally, we explore emerging precision targets, including GRK2 inhibition, central RAAS modulation, and neuroimmune interactions, proposing a framework for individualized autonomic targeted therapy.
Understanding the integrated neurohormonal network may refine therapeutic strategies and improve outcomes across the HF spectrum.