Another Piece to the Puzzle: Linking the Cardiac Nervous System to Atrial Fibrillation in Pulmonary Arterial Hypertension.

P ulmonary arterial hypertension (PAH) is a rare, debilitat-ing disease characterized by an occlusive pulmonary vas-culopathy, resulting in elevated pulmonary vascular resistance and subsequently death from right ventricular (RV) failure. 1 Current therapeutic options in PAH are limited to pulmonary vasodilator therapy, which have improved clinical outcomes but only target part of the underlying pathology. 2 Because of the persistent high mortality of this disease process, there is a need and an interest to develop novel therapeutic targets for PAH. Sympathetic and parasympathetic abnormalities are well identified in PAH. 3 Downregulation and desensitization of adr-enoreceptors have been observed in RV myocytes. 4 In patients with PAH, decreased RV β-adrenoreceptor density is associated with increased incidence of RV failure. 5 Although there are increased circulating catecholamine levels in patients with RV failure from PAH, the RV is less responsive to β-agonists. 6 These findings represent an adrenergic remodeling manifesting as an inability to augment RV function with catecholamine stimulation and demonstrate a potential need to develop interventions that can target sympathetic nervous abnormalities in the RV in PAH. It is provocative to think what the effects of a therapeutic intervention that targets both sympathetic overactivity and atrial arrhythmias could have on clinical outcomes in PAH. In this current issue of Hypertension, Huang et al 7 demonstrate the utility of anterior right ganglionated plexus ablation in the sensitivity of the right atrium to atrial fibrillation and atrial flutter in patients with PAH. The authors measured the atrial effective refractory period and atrial fibrillation and atrial flutter inducibility before and after anterior right ganglionated plexus ablation with sympathetic stimulation by left stellate ganglion or left renal sympathetic nerve in a canine model of PAH. Histological analysis identified the cellular substrate of increased β1-adrenergic receptors, as well as an increased heterogeneity of non-phosphorylated connexin 43 expression in the PAH canine group, thus, creating the perfect storm for an increased atrial tachyarrhythmia susceptibility in a sea of elevated sympathetic neurohormones. The combination of electrophysi-ological cellular remodeling and anterior right ganglionated plexus and left stellate ganglion stimulation increased vulnerability to atrial fibrillation and atrial flutter in canines with PAH. With ablation of the anterior right ganglionated plexus, the authors demonstrated a suppression of atrial arrhythmias in response to sympathetic stimulation. This showed that both intrinsic cardiac nerves, especially right atrial, as well as extrinsic nerves, contribute to atrial fibrillation and atrial flutter sensitivity in this PAH …