Deep breathing induced HRV modulation and cardiovagal response to non-invasive vagal nerve stimulation in atrial fibrillation

Background Non-invasive vagal nerve stimulation is a promising therapy in atrial fibrillation (AF)1, 2. However, selecting patients with an adequate vagal activity increase to stimulation remains challenging. We investigated whether baseline heart rate variability (HRV) or HRV modulation during deep breathing is associated with cardiovagal response to auricular (aVNS) or cervical vagal nerve stimulation (cVNS). Methods Patients with paroxysmal or persistent AF in sinus rhythm underwent standardized autonomic testing (Figure 1). After a 5-minute rest, baseline heart rate variability (HRV) was recorded. Three randomized interventions followed (130 RR intervals each): paced deep breathing (10-s cycles, 4:6 inspiration/expiration), aVNS, and cVNS using a transcutaneous 20-Hz, 200-ms stimulator below the pain threshold. Five-minute washout phases separated interventions. Relative HRV indices changes (Δ%) were analyzed. Adequate cardiovagal response to aVNS and cVNS was defined as an increase in both tonic (standard deviation of RR intervals, SDNN) and phasic vagal activity (root mean square of successive RR interval differences, RMSSD) compared to baseline. Results Fifteen patients were included (median age 67 [57; 75] years; 47% female; 87% paroxysmal AF; median CHA2DS2-VA 2 [0; 4]; 27% with prior AF ablation). Comorbidities comprised hypertension (53%), coronary artery disease (33%), diabetes (20%), obesity (20%), and heart failure (13%). Deep breathing increased tonic vagal activity (median SDNN: baseline 16 ms vs. deep breathing 27 ms vs. aVNS 19 ms vs. cVNS 22 ms; p<0.001), while phasic vagal activity and heart rate were similar between interventions. Adequate cardiovagal response occurred in 67% during aVNS (median Δ%SDNNaVNS +16%; Δ%RMSSDaVNS +16%) and in 50% during cVNS (Δ%SDNNcVNS +20%; Δ%RMSSDcVNS +39%). Responders did not differ in baseline vagal activity or heart rate response during deep breathing. In contrast, the magnitude of HRV change during deep breathing was strongly associated with tonic vagal activity changes during aVNS (∆%SDNNaVNS, Figure 2A), including Δ%SDNNDB (R=0.81, p<0.001), Δ%RMSSDDB (R=0.77, p<0.001) and Δ%high-frequency powerDB (R=0.72, p=0.002), with inverse associations for Δ%heart rateDB (R=–0.60, p=0.02) and Δ%stress indexDB (R=–0.67, p=0.007). Phasic vagal activity changes showed similar associations (Figure 2B). During cVNS, vagal activity changes correlated only with Δ%high frequency powerDB during deep breathing (Δ%SDNNcVNS: R=0.87, p=0.001; Δ%RMSSDcVNS: R=0.82, p=0.004). No associations were observed with baseline HRV. Conclusion In AF patients, HRV modulation during deep breathing is strongly associated with acute cardiovagal responsiveness to non-invasive vagal nerve stimulation, whereas baseline HRV is not. Deep breathing may serve as a simple physiological maneuver to guide patient selection for aVNS or cVNS.Figure 1.MethodsFigure 2.Results