Effects of Intrinsic and Extrinsic Cardiac Nerves on Atrial Arrhythmia in Experimental Pulmonary Artery Hypertension

Abstract

S upraventricular arrhythmias, such as atrial fibrillation (AF) and atrial flutter (AFL), are common in patients with pulmonary arterial hypertension (PAH) and are associated with poor outcomes.1,2 In 1 study, restoration and maintenance of sinus rhythm were invariably associated with clinical improvement and recovery. 3 However, it is difficult to treat AF/AFL in patients with PAH because existing antiarrhythmic agents have substantial side effects in patients with PAH.Previous studies have suggested that increased sympathetic nerve activation could contribute to disease severity in patients with PAH. 4,5 A recent study by Chen et al 6 demonstrated that pulmonary artery denervation decreased pulmonary arterial pressure and increased functional capacity. Our previous study showed that renal denervation attenuates pulmonary vascular remodeling and decreases pulmonary arterial pressure in experimental PAH.7 In a dog model with rapid atrial or ventricular pacing, a reduction in sympathetic tone or cardiac sympathetic denervation achieved by ablating extrinsic cardiac or renal sympathetic nerves was shown to be useful for controlling atrial arrhythmia. [8][9][10] However, to the best of our knowledge, the effect of sympathetic nerve activity on vulnerability to atrial arrhythmia in PAH has not been evaluated. The purpose of this study was to test the hypothesis that the activity of intrinsic and extrinsic cardiac nerves has an important role in vulnerability to atrial arrhythmia in a model of PAH. MethodsAdditional methodological details for each of the sections below are described in the online-only Data Supplement.Abstract-Atrial arrhythmia, which includes atrial fibrillation (AF) and atrial flutter (AFL), is common in patients with pulmonary arterial hypertension (PAH), who often have increased sympathetic nerve activity. Here, we tested the hypothesis that autonomic nerves play important roles in vulnerability to AF/AFL in PAH. The atrial effective refractory period and AF/AFL inducibility at baseline and after anterior right ganglionated plexi ablation were determined during left stellate ganglion stimulation or left renal sympathetic nerve stimulation in beagle dogs with or without PAH. Then, sympathetic nerve, β-adrenergic receptor densities and connexin 43 expression in atrial tissues were assessed. The sum of the window of vulnerability to AF/AFL was increased in the right atrium compared with the left atrium at baseline in the PAH dogs but not in the controls. The atrial effective refractory period dispersion was increased in the control dogs, but not in the PAH dogs, during left stellate ganglion stimulation. The voltage thresholds for inducing AF/AFL during anterior right ganglionated plexi stimulation were lower in the PAH dogs than in the controls. The AF/AFL inducibility was suppressed after ablation of the anterior right ganglionated plexi in the PAH dogs. The PAH dogs had higher sympathetic nerve and β1-adrenergic receptor densities, increased levels of nonphosphorylated connexin 43, and heterogeneo...

Pathophysiology, incidence, management, and consequences of cardiac arrhythmia in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

“…There is biologic plausibility to this finding, given that the maladaptive response of the right heart is thought to predispose to atrial arrhythmias. 29,30…”

Atrial Arrhythmias in Pulmonary Hypertension: Pathogenesis, Prognosis and Management

“…27,28 Using a canine animal model, Zhao and colleagues performed EPSs in animals with PAH and controls. 29…”

Ganglionic GFAP+ glial Gq-GPCR signaling enhances heart functions in vivo

“…Sympathetic nerve activity (SNA) is elevated in old age (3) and in cardiovascular-related diseases (4) including hypertension (5,6), arrhythmias (7,8), obesity, obstructive sleep apnea, and congestive heart failure (9,10). An understanding of the diverse cellular and molecular components of SNS control of cardiovascular functions is needed to enhance the search for new targets of cardiovascular disease (CVD) drug therapies.…”