Nervus X- Atrial Fibrillation trial (NX-AF)

Mortality, morbidity and health care costs due to atrial fibrillation (AF) are
worldwide growing problems and therapeutic interventions for AF are often not
effective. For many years, it has been suggested that the autonomic nervous
system plays an important role in AF pathogenesis. Only recently it has been
shown that neuromodulation, consisting of invasive low-level vagus nerve
stimulation (LLVS) decreases AF inducibility, incidence and burden. An
innovative and non-invasive (transcutaneous) route for t-LLVS is electrical
stimulation of the auricular branch of the vagus nerve by applying an ear clip
consisting of surface electrodes to the tragus of the external ear. Clinical
studies have provided evidence that (t-)LLVS - under the bradycardia threshold
- may be effective in suppressing (post-operative) AF episodes, however the
underlying electrophysiological mechanism and regional differences in the
effect (t-)LLVS are not known. Another way to apply t-LLVS is to stimulate the
cervical branch of the vagus nerve. This branch contains 5 times more
myelinated fibers than the auricular branch. Therefore it is possbile that the
effect between auricular t-LLVS and cervical t-LLVS is different. Also
differences between invasive and transcutaneous LLVS have not been clarified.
As a consequence, it is at present not possible to predict which patient will
benefit from (t-)LLVS. Prior mapping studies have demonstrated that conduction
disorders and electrical asynchrony between the endo- and epicardium (EEA) are
key elements of the substrate underlying persistence of AF. Whether (t-)LLVS
affects this substrate, still remains to be elucidated.

The primary objective is to examine the impact of t-LLVS on
electrophysiological properties of the atria and ventricles.
Secondary objectives are:
- to elucidate the correlation between proteostasis marker levels in serum and
atrial tissue, and the influence of CANS.
- to examine the difference between auricular t-LLVS and cervical t-LLVS on
atrial electrophysiology.
- to investigate the effect of (t-)LLVS on termination of other forms of
tachyarrhythmia.
- to investigate the effect of t-LLVS on heart rate variability and atrial and
ventricular ectopy/tachyarrhythmia in patients with congenital heart disease.

OR group: This study is designed as an interventional study, with the
intervention existing of performing transcutaneous and invasive LLVS
per-operatively in patients undergoing open chest cardiac surgery and in
patients undergoing a endovascular cardiac procedure. Pre-operatively a blood
sample will be obtained. Per-operatively pacing of the atrium will be performed
and a tissue sample of the atrium will be collected as frequently done during
other procedures and during our other on-going mapping studies (MEC 2010-054,
MEC 2014-393, MEC 2015-373). After open chest cardiac surgery patients will
also undergo transcutaneous LLVS on post-operative day 1-3 for 1 hour per day.
EP group: patients included at the emergency room, transcutaneous LLVS will be
administered for a maximum of 5 minutes before receiving standard treatment.
Poli group: a blood sample and 7-day holter will be obtained. Afterwards,
patients will receive t-LLVS for 1 hour a day during a period of 1 week to
maximum 4 weeks.

OR group: High-resolution cardiac mapping during sinus rhythm, spontaneous or
induced AF before and after applying transcutaneous or invasive LLVS. Blood
sample and tissue biopsy will be obtained during the surgery. When patients are
hemodynamically and respiratory stable, t-LLVS will also be performed on
post-operative day 1-3 for 1 hour per day. Patients who undergo endovascular
cardiac procedures are often discharges within one day, therefore these
patients will not undergo post-operative t-LLVS.

ER group: patients included at the emergency room will receive transcutaneous
LLVS for a maximum of 5 minutes before receiving standard treatment for the
tachyarrhythmia.

Poli group: Blood sample and 7-day Holter will be obtained after inclusion in
this study. T-LLVS will be performed for 1 hour per day starting with 1 week,
after inclusion of the first 25 patients we evaluate whether this needs to be
prolonged up to 4 weeks.
After the t-LLVS, again blood sample and 7-day Holter will be obtained.

Neither the patient, nor the investigators are in any way compensated for their
participation with regards to this study. The risks associated with
participation are known to be negligible, since epicardial mapping using the
non-investigational product (see Medical Device Dossier) in over 500 patients
in previous METC-approved studies (MEC 2010-054, MEC 2014-393, MEC 2015-373)
did not cause any complications. The duration of the surgical procedure is
minimally prolonged by the epicardial mapping procedure with an estimate of
10-15 minutes. Studies in different medical fields have shown that t-LLVS is a
safe treatment modality. A recent study (TREAT-AF), which is currently in press
in JACC EP, demonstrated no complications of t-LLVS applied by the Parasym
device in almost 60 ambulatory patients. Patients may benefit from this study
as t-LLVS has been shown to possibly reduce post-operative AF thereby reducing
post-operative complications and hospital stay. Moreover, this novel therapy
may serve as a base for treatment of AF in non-surgical patients.

Poli group: Patients will not be under anesthesia so they will be conscious
during the extra additional investigations/actions. Therefore the mental load
will be a little bit higher compared to the other patient groups in this study.
We still think that this load will be low, because of the very minimal invasive
nature of the investigations. Patients may benefit from this study as t-LLVS
has been shown to reduce the atrial fibrillation burden also in patients
without a cardiac surgery.