Autonomic nervous system involvement in pulmonary arterial hypertension

Vaillancourt et al. Respiratory Research Autonomic nervous system involvement in pulmonary arterial hypertension Mylène Vaillancourt 0 Pamela Chia 0 Shervin Sarji Jason Nguyen Nir Hoftman Gregoire Ruffenach Mansoureh Eghbali Aman Mahajan Soban Umar 0 Equal contributors Department of Anesthesiology and Perioperative Medicine, Division of Molecular Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA) , Los Angeles, CA BH 520A CHS , USA 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. Pulmonary arterial hypertension; Autonomic nervous system; Right ventricle; Sympathetic nervous system; Renin angiotensin aldosterone system Overview of the autonomic regulation of heart and lungs The autonomic nervous system The autonomic nervous system is composed of sympathetic and parasympathetic divisions and is often divided by neural and endocrine regulatory components. The sympathetic nervous system (SNS) originates from the thoracolumbar region of the spinal cord (Fig. 1). Short preganglionic fibers from the T1-L2 segments synapse on paravertebral or prevertebral ganglia, enabling long postganglionic fibers to innervate target organs such as the heart and lungs. On the other hand, the parasympathetic nervous system originates from cranial nerves III, VII, IX, and X and the sacral nerves S2-S4. In general, parasympathetics cause vasodilation of blood vessels including the pulmonary vasculature, and sympathetics cause vasoconstriction [ 1 ] (Table 1). Autonomic innervation of the pulmonary vasculature The pulmonary vasculature is innervated by sympathetic, parasympathetic, and sensory nerve fibers. Increased vascular resistance is mediated by α-adrenoreceptors upon sympathetic nerve stimulation [ 2 ]. Noradrenergic fibers are activated by baroreceptors in the pulmonary artery [ 3 ] and proximal airway segments [ 4 ]. Chemoreceptors respond to decreased arterial PO2 levels to increase sympathetic nerve stimulation by the sympathetic chain neurons [ 2, 5 ]. Parasympathetic activation via vagal stimulation results in cholinergic-mediated relaxation of pulmonary arteries [6]. Many other factors (i.e. non-adrenergic and non-cholinergic mediators, peptides, trophic factors, differential release of transmitters by high or low frequencies) are implicated in sympathetic and parasympathetic regulation of lung vasculature, though their functions have not entirely been elucidated [ 7 ] (Table 1). Autonomic innervation of the heart The heart is also innervated by both parasympathetic and sympathetic fibers (Fig. 1). The parasympathetic fibers are responsible for decreasing chronotropy, dromotropy, and inotropy via cholinergic action on cardiac M2 receptors. The SNS acts on β1 adrenergic receptors to increase chronotropy, dromotropy, and inotropy of the heart [ 8 ]. Interestingly, β-adrenergic stimulation has been shown to have a significantly greater positive inotropic effect on left ventricular (LV) contractility than on right ventricular (RV) contractility [ 9 ]. On the contrary, adrenergic stimulation of alpha 1 receptors result in increased inotropy in the LV but decreased inotropy in the RV [ 10 ] (Table 1). Patients with PAH often have normal systemic blood pressures and lung volumes. However, they may suffer from hypoxia, hypercarbia, acidosis, and, in later stages, RV hypertrophy and failure. Neural pathways controlling the heart and lungs are described in detail within current scientific literature [ 11 ]. Autonomic nervous system and RAAS involvement in PAH PAH is a clinical syndrome characterize (...truncated)