Autonomic nervous system involvement in pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a chronic pulmonary vascular disease characterized by increased pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Autonomic nervous system involvement in the pathogenesis of PAH has been demonstrated several years ago, however the extent of this involvement is not fully understood. PAH is associated with increased sympathetic nervous system (SNS) activation, decreased heart rate variability, and presence of cardiac arrhythmias. There is also evidence for increased renin-angiotensin-aldosterone system (RAAS) activation in PAH patients associated with clinical worsening. Reduction of neurohormonal activation could be an effective therapeutic strategy for PAH. Although therapies targeting adrenergic receptors or RAAS signaling pathways have been shown to reverse cardiac remodeling and improve outcomes in experimental pulmonary hypertension (PH)-models, the effectiveness and safety of such treatments in clinical settings have been uncertain. Recently, novel direct methods such as cervical ganglion block, pulmonary artery denervation (PADN), and renal denervation have been employed to attenuate SNS activation in PAH. In this review, we intend to summarize the multiple aspects of autonomic nervous system involvement in PAH and overview the different pharmacological and invasive strategies used to target autonomic nervous system for the treatment of PAH.

Keywords: Autonomic nervous system; Pulmonary arterial hypertension; Renin angiotensin aldosterone system; Right ventricle; Sympathetic nervous system.

Fig. 1

Schematic diagram summarizing autonomic nervous system involvement in PAH and various therapeutic strategies targetting the activation of SNS and RAAS in PAH. PAH is associated with increased sympathetic nervous system (SNS) and renin-angiotensin-aldosterone-system (RAAS) activation. The central nervous system provides autonomic output to the lungs and heart mainly through cranial nerves IX and X. The parasympathetic nervous system (shown in blue) originates from cranial nerves III, VII, IX, and X and the sacral nerves S2-S4. The SNS (shown in red) originates from the thoracolumbar region of the spinal cord and modulates; i) vascular and airway reactivity in the lungs, ii) heart rate and contractility in the heart and iii) RAAS activation in the kidneys and adrenal glands. Consequently, RAAS activation generates vasoactive compounds that result in pulmonary vasoconstriction and vascular remodeling, hallmarks of PAH. These vasoactive compounds may result in a feedback loop to the nervous system. Various pharmacological (α/β blockers, ACE inhibitors, AT1R inhibitors), surgical (pulmonary artery denervation (PADN), renal artery denervation) and experimental (Superior cervical and stellate ganglion block (SGB) approaches for modulating autonomic nervous system and RAAS are also shown boxed in red

Fig. 2

Renin-angiontensin-aldosterone system (RAAS) activation in PAH. Renin cleaves angiotensinogen to angiotensin I, which is further processed by the angiotensin-converting enzyme (ACE) to the biologically active peptide angiotensin II and binds to angiotensin receptors AT1 and AT2. Angiotensin I and II may also undergoe further processing by ACE2 to yield angiotensin (1–7), which activates the Mas receptor. On the other hand, aldosterone activates the mineralocorticoid receptors. Both AT1 and mineralocorticoid receptor activation lead to pathological signaling in PAH, and targeting these pathways using receptor antagonists or ACE inhibitors improves PAH. On the other hand, AT2 and Mas signaling are protective, and promoting these signaling cascades using AT2 agonists or ACE2 activators improves autonomic nervous system imbalance seen in PAH