Effect of Renal Denervation on Neurohumoral Activation Triggering Atrial Fibrillation in Obstructive Sleep Apnea

Abstract

O bstructive sleep apnea (OSA) is associated with a high prevalence of cardiovascular diseases such as hypertension and atrial fibrillation (AF).1,2 OSA is characterized by repetitive total collapses of the upper airway, leading to intermittent hypoxia, forced inspiration-induced negative tracheal and thoracic pressure (NTP), postapneic blood pressure rises, 3 and increased sympathetic activation. 4 Stimulation of vascular and cardiac α-and β-adrenoceptors by the neurotransmitters of the sympathetic nervous system leads to neurohumoral activation and increased reactive oxygen species (ROS) generation via nicotinamide adenine dinucleotide phosphate-oxidase (NADPH-oxidase) 5 and mitochondria. 6 Furthermore, elevated NADPHoxidase activity is associated with permanent AF in mice and humans 7,8 and, in particular, with an early event in the natural history of postoperative AF. 9 Therefore, increased sympathetic activation may play an important role for the initiation and progression of AF in OSA.Modulation of the autonomic nervous system by renal sympathetic denervation (RDN) has been shown to be effective in reducing both renal norepinephrine spillover and muscle sympathetic nerve activity. [10][11][12] In a pig model mimicking OSA, 1-time applied NTP during 2 minutes of obstructive respiratory events increased inducibility of AF by premature electric stimuli, 13,14 which could be reduced by β-adrenoceptor blockade and RDN. 15 However, the role of sympathetic activation for spontaneous AF episodes and the reasons for the progression to permanent AF in OSA Abstract-Obstructive sleep apnea is characterized by repetitive collapses of the upper airway, negative thoracic pressure periods, and intermittent hypoxia, stimulating the autonomic nervous system. The increased sympathetic drive during obstructive sleep apnea results in postapneic blood pressure rises and neurohumoral activation potentially involved in the initiation and progression to permanent atrial fibrillation (AF). In a pig model mimicking obstructive sleep apnea, we studied the effects of repetitive obstructive respiratory events for 4 hours on the occurrence of spontaneous AF episodes, postapneic blood pressure rises, and neurohumoral activation. In addition, renal sympathetic denervation was performed to investigate the impact of the sympathetic nervous system. Repetitive obstructive respiratory events caused pronounced postapneic blood pressure rises, prolonged duration of spontaneous AF episodes triggered by spontaneous atrial beats, and increased plasma renin activity and aldosterone concentrations. This was associated with increased nicotinamide adenine dinucleotide phosphate-oxidase activity, reduced antioxidative capacity, and elevated expression of connective tissue growth factor, a redox-sensitive mediator of fibrosis. Renal sympathetic denervation inhibited postapneic blood pressure rises and decreased plasma renin activity and aldosterone concentrations. The occurrence and duration of spontaneous AF were reduced comparable with a comb...

Obstructive respiratory events and premature atrial contractions after cardioversion

“…OSA manoeuvres were characterised by intra-apnoeic negative thoracic pressure, hypoxia and hypercapnia and postapnoeic blood pressure rises (see reference [6]). OSA manoeuvres were performed 2 min after termination of AF induced by 30 min of atrial tachypacing.…”

“…Left renal flow was measured with a Doppler flow probe (transit time flowmeter module system; Transonic Systems Inc., Elsloo, The Netherlands) positioned on the blood vessels. Following surgical renal denervation (RDN), the animals were allowed to re-equilibrate for 1.5 h. Significant reduction of a reproducible postapnoeic blood pressure rise and the absence (<5% change) of a decrease in renal blood flow induced by tracheal occlusion for 2 min were taken as evidence of the completeness of RDN [5,6]. Sham surgical procedure with kidney exposition without RDN and vehicle for atropine and atenolol (DMSO plus PEG) was performed in 11 other pigs serving as a control.…”

“…Solutions were injected over 5 min before induction of AF. Atenolol was used in a concentration, which resulted in a maximal heart rate reduction in previous studies [5,6].…”

“…A progressive shortening of atrial refractoriness during the first few days of AF has been shown to increase both the inducibility and persistence of AF (electrical remodelling) [2,3]. In a pig model for OSA, negative thoracic pressure during acute obstructive respiratory events (OREs) resulted in a pronounced acute shortening of atrial refractoriness and increased susceptibility to AF in non-remodeled atria [4][5][6]. Therefore, OREs occurring directly after ECV may result in an additional post-cardioversion shortening of atrial refractoriness, which may enhance the vulnerability for reinduction of AF.…”

“…To test whether PACs could induce AF during OREs after termination of AF, the arrhythmogenic electrophysiological substrate for re-entry was investigated in a pig model [4][5][6]. By treating the animals with the beta-blocker atenolol, the muscarinergic receptor antagonist atropine and modulation of sympathetic nervous system by renal sympathetic denervation [7][8][9], the role of autonomic nervous system activation was specifically addressed.…”