Sympathetic and Parasympathetic Coactivation Induces Perturbed Heart Rate Dynamics in Patients with Paroxysmal Atrial Fibrillation

Background: Recent evidence indicates that sympathetic/parasympathetic coactivation (CoA) is causally linked to changes in heart rate (HR) dynamics. Whether this is relevant for patients with atrial fibrillation (AF) is unknown. Material/Methods: In patients with paroxysmal AF (n=26) and age-matched controls, (n=10) we investigated basal autonomic outflow and HR dynamics during separate sympathetic (cold hand immersion) and parasympathetic activation (O-2-inhalation), as well as during CoA (cold face test). In an additional cohort (n=7), HR response was assessed before and after catheter-based pulmonary vein isolation (PVI). Ultra-high-density endocardial mapping was performed in patients (n=6) before and after CoA. Results: Sympathetic activation increased (control: 74 +/- 3 vs. 77 +/- 3 bpm, p=0.0098; AF: 60 +/- 2 vs. 64 +/- 2 bpm, p=0.0076) and parasympathetic activation decreased HR (control: 71 +/- 3 vs. 69 +/- 3 bpm, p=0.0547; AF: 60 +/- 1 vs. 58 +/- 2 bpm, p<0.0009), while CoA induced a paradoxical HR increase in patients with AF (control: 73 +/- 3 vs. 71 +/- 3 bpm, p=0.084; AF: 59 +/- 2 vs. 61 +/- 2 bpm, p=0.0006), which was abolished after PVI. Non-linear parameters of HR variability (SD1) were impaired during coactivation in patients with AF (control: 61 +/- 7 vs. 69 +/- 6 ms, p=0.042, AF: 44 +/- 32 vs. 32 +/- 5 ms, p=0.3929). CoA was associated with a shift of the earliest activation site (18 +/- 4 mm) of the sinoatrial nodal region, as documented by ultra-high-density mapping (3442 +/- 343 points per map). Conclusions: CoA perturbs HR dynamics and shifts the site of earliest endocardial activation in patients with paroxysmal AF. This effect is abolished by PVI, supporting the value of emerging methods targeting the intrinsic cardiac autonomic nervous system to treat AF. CoA might be a valuable tool to assess cardiac autonomic function in a clinical setting.