The goal of this clinical trial is to investigate the effects of non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) in patients with persistent atrial fibrillation. taVNS is a treatment through which a small electrical current is applied to a specific location of the left ear. The main question to answer is whether taVNS will reduce the heart rate in patients with persistent atrial fibrillation. After appropriate training, participants will self-administer taVNS for 30 minutes every day for two weeks. During one of the two weeks (randomized order), the clip electrode, delivering the electrical current will be attached to the cymba conchae of the left ear, while during the other week the clip electrode will be attached to the lobule of the left ear. During both weeks, the electrocardiogram (ECG) will be monitored continuously through a small ECG patch that is placed on the chest. Participants will meet with the investigators at the beginning of the study, after 7 days and at the end of the study (after 14 days). Researchers will compare the ECG obtained during the two weeks and evaluate if the heart rate differs between the two study weeks.

In a previous study (Dalgleish et al., 2021), the investigators found that taVNS lengthens the PQ-interval in healthy study participants with regular sinus rhythm. This finding indicates that taVNS slows AV-conduction. Thus, it is reasonable to assume that taVNS may lower ventricular rate in patients with persistent atrial fibrillation. This assumption is in line with a recent study (Stavarakis et al., 2020) demonstrating reduced atrial fibrillation burden in patients with paroxysmal atrial fibrillation in response to a 6-month taVNS intervention.

The investigators hypothesize that taVNS reduces ventricular rate in patients with persistent atrial fibrillation. This hypothesis is based on the finding that taVNS lengthens the PQ-interval in healthy individuals with sinus rhythm (Dalgleish et al., 2021), demonstrating that taVNS slows AV-nodal conduction. Thus, it is conceivable that taVNS reduces the number of atrial excitations that are transmitted into the ventricles in patients with persistent atrial fibrillation. This effect should result in a lower ventricular rate. Testing this hypothesis is significant, because if the hypothesis would be verified, taVNS would have the potential to elicit an additive effect to AV-nodal blocking agents, and thus, may allow to reduce the dose of such drugs, effectively reducing potential adverse effects.

The study is designed as a two-week randomized cross-over study. Participants will start with either taVNS or sham-taVNS (randomly assigned) during the first week and then switch to the other intervention during the second week of the study. Throughout the two-week study, ambulatory ECG will be recorded using an ECG patch that allows continuous ECG recording for up to 14 days. Participants will self-apply taVNS or sham-taVNS for 30 min every day throughout the 2-week study.

Participants will meet with the investigators 3 times throughout the 2-week study protocol: On the first study day, participants will be instrumented with the ECG patch and instructed in the use of the taVNS device. In addition, patients will be instructed to keep a diary to record the time of the taVNS/sham-taVNS application, the stimulation parameters, and any potential therapeutic or adverse effects. The second study visit will occur at the end of the first study week. During this meeting, the function of the ECG patch and taVNS device will be verified, the diary will be inspected to verify protocol adherence, and the intervention will be switched to either taVNS or sham-taVNS application (depending on randomization). The final study visit will occur at the end of the study (after 2 weeks). The ECG patch will be retrieved, and the diary inspected for protocol adherence.

Inclusion Criteria:

• At least 18 years of age
• Persistent atrial fibrillation
• On anti-coagulation throughout the study

Exclusion Criteria:

• Below 18 years of age
• Pregnancy
• Signs or history of vestibulocochlear neuronitis or nerve damage (e.g., hearing loss or tinnitus)
• Signs or history of epilepsy
• Not on anti-coagulation

We do not plan to make individual participant data available to other researchers.

Participants will not be told if the location of the clip electrode will be for active taVNS or for sham-taVNS.