Effects Of Low-Level Carotid Baroreflex Stimulation On Atrial Fibrillation And The Underlying Mechanisms

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and a major cause of morbidity and mortality.In China, the population of AF patients has been over 10 million. The prevalence of AF increases with age, from 0.1% in people aged less than 55 years to 8% in people over 80 years. Although the multi-factor mechanism underlying the genesis of AF has been the focus of many studies, it only remains partially understood. Triggering factors and AF substrates which include rapid firng oirginating from pulmonary veins, atrial electrical remodeling and structural remodeling, et al, interact with each other to promote the progress of AF. So far, anti-arrhythmic drugs, electrical cardioversion, and catheter ablation techniques have been used to treat AF, while the clinical outcomes are far from satisfactory. Catheter ablation of AF is now a realistic therapeutic option in a broad spectrum of patients, but they are at risks for potential recurrence. These limitations stimulate research toward the development of effective but less aggressive procedures for the treatment and prevention of AF.In recent years, the autonomic nervous system was validated to play an important role in the initiation and maintenance of AF. Varieties of interventions on modulation of the autonomic nervous system have shown potential of AF control. Carotid baroreceptor stimulation (CBS), which can inhibit the sympathetic activity and enhance the vagal activity, has been applied to treat resistant hypertension and chronic heart failure. The effects of CBS on atrial fibrillation remain unknown. As vagus nerve stimulation at high intensity contributes to the creation of arrhythmia substrates while low-level vagus nerve stimulation prevents AF, we assumed that low-level CBS (LL-CBS) which does not affect blood pressure or heart rate, could produce an anti-AF effect. This study includes three parts.Part I Effect of low-level carotid baroreflex stimulation on atrial electrophysiologyObjectives:To investigate the effects of low-level carotid baroreflex stimulation (LL-CBS) on atrial electrophysiology.Methods:In study protocol 1, rabbits underwent LL-CBS (n=10) or surgical exposure (n=6) for one hour. In study protocol 2, rabbits underwent three hours of rapid atrial pacing (RAP) with concomitant LL-CBS in the third hour (n=7) or 3h-RAP without LL-CBS (n=6). Electrodes in a silicon sheet surrounded the carotid baroreceptor allowed LL-CBS at 20% below the voltage required to reduce the systolic BP or slow the heart rate. Electrodes were attached to the left atria (LA) and left atria appendage (LAA) to give RAP stimulation, to induce atrial fibrillation (AF) and measure the effective refractory period (ERP). Monophasic action potential (MAP) was recorded at LA.Results:One hour of LL-CBS significantly prolonged the ERPs, MAPD90 and MAPD50 of LAA and LA (P<0.05). After 3h-RAP, the ERPs, MAPD90 and MAPD50 were significantly shortened (P<0.05) while the concomitant application of LL-CBS during the third hour of RAP reversed the changes due to RAP.Conclusions:LL-CBS can prolong atrial ERP and MAPD, and reverse the atrial electrical remodeling induced by rapid atrial pacing.Part ? Effect of low-level carotid baroreflex stimulation on atrial fibrillationObjectives:The aim of our study was to investigate effects of short term LL-CBS on atrial fibrillation (AF) canine model.Methods:Group 1:anesthetized dogs underwent 6 h of rapid atrial pacing (RAP) with concomitant LL-CBS in last three hours (LL-CBS group, n=7) or without (Control group, n=6). Effective refractory period (ERP), ERP dispersion, and window of vulnerability (WOV) to AF were determined. Group 2:In subgroup 1, sustained AF was induced by injecting acetylcholine (Ach,10 mM) into anterior right ganglionated plexus (ARGP) at baseline and after 3-h LL-CBS (n=7) or sham operation (n=6). In subgroup 2, ACh was applied to right atrial appendage. AF duration (AF-D) and the average AF cycle length (AF-CL) were determined in both subgroups.Results:Group 1:LL-CBS reversed the RAP-induced ERP shortening (taking left inferior pulmonary vein for example,137±12 ms at baseline; 123±12 ms, the 3rd hour; 139±15 ms, the 6th hour; P<0.05), increase of ERP dispersion (0.19±0.02 at baseline,0.21±0.02, the 3rd hour; 0.18±0.02, the 6th hour; P<0.05) and WOV (11± 7 ms, at baseline,103±26 ms, the 3rd hour; 19±13 ms, the 6th hour; P<0.05). Group 2:AF-D was shortened (295±52 vs.722±66 s in subgroup 1; 247±30 vs.39±10 s in subgroup 2) and AF-CL (128±3 vs.100±5 ms in subgroup 1; 53±5 ms vs.60± 8 ms in subgroup 2) was prolonged markedly (P<0.01 for both) by LL-CBS.Conclusions:LL-CBS can reverse RAP-induced atrial electrical remodeling, inhibit inducibility of AF and suppress AF induced by cholinergic stimulation.Part ? Mechanisms of low-level carotid baroreflex stimulation suppressing atrial fibrillationObjectives:To investigate the mechanisms of low-level carotid baroreflex stimulation (LL-CBS) suppressing atrial fibrillation (AF).Methods:In study protocol 1A, rabbits underwent LL-CBS (n=10) or surgical exposure (n=6) for one hour. In study protocol 1B, rabbits underwent three hours of rapid atrial pacing (RAP) with concomitant LL-CBS in the third hour (n=7) or 3h-RAP without LL-CBS (n=6). In both protocols, power spectral of heart rate variability (HRV) was analyzed at baseline as well as after interventions in all groups, respectively. In study protocol 2, anesthetized dogs underwent 6 h of rapid atrial pacing (RAP) with concomitant LL-CBS in last three hours (LL-CBS group, n=7) or without (Control group, n=6). Left stellate ganglion (LSG) neural activity and HRV was analyzed at baseline, at the end of the 3rd hour and the 6th hour, repsectively.Results:In study protocol 1A, HF components were increased while LF components and LF/HF were decreased (P<0.05) after 1h LL-CBS. In study protocol 1B, The increase of HF components and the decrease of LF components and LF/HF after 3h-RAP were reversed by LL-CBS (P<0.05). In study protocol 2, The activation of LSG, decrease of HF, increase of LF and LF/HF ratio induced by RAP were all reversed by LL-CBS (P<0.05 for all). After 6h-RAP, plasma norepinephrine and angiotensin II levels were significantly lower in LL-CBS than Control group (P< 0.05 for both).Conclusions:The mechanism of LL-CBS suppressing AF is attributed to inhibition of the LSG activity and attenuation of the autonomic nerve remodeling. The suppression of renin-angiotensin-aldosterone system may also account for the anti-AF effect.