Study purpose was to verify the value of an Implanted Loop Recorder (ILR) in assessing the mechanism of syncope and the efficacy of ILR-guided therapy after documentation of syncope recurrence in patients with suspected or certain neurally-mediated syncope at initial evaluation.

Multi-center, prospective, observational study enrolling 400 patients with suspected or certain neurally-mediated syncope, who undergo carotid sinus massage, tilt testing and ILR implantation. In its second phase, which starts after the first ILR-documented syncope, the study will register the patient outcome after administration of ILR-guided therapy, which is left to the discretion of the physicians.

Main objective: To verify the value of ILR in assessing the mechanism of syncope and the efficacy of the ILR-guided therapy after syncope recurrence.

Secondary objectives:

1. To define the exact mechanism of syncope in patients with suspected or certain neurally-mediated syncope based on the initial evaluation;
2. To prospectively evaluate the correlation between tilt-induced syncope, ATP-induced asystolic response and/or carotid sinus hypersensitivity and ILR-documented spontaneous syncope associated with bradycardia and/or asystole;
3. To assess the relationship between asymptomatic and symptomatic asystoles;
4. To assess the effectiveness of pacing therapy for preventing syncope recurrence in patients implanted with a pacemaker after an ILR-documented syncope associated with asystole/bradycardia.

Inclusion criteria:

• Suspected or certain neurally-mediated syncope, based on the Guidelines of the ESC TF on Syncope.
• 3 syncope episodes in the last 2 years.
• Severe clinical presentation of syncope requiring treatment initiation in the judgement of the investigator.
• Age >30 years.
• Patients have undergone carotid sinus massage, and ILR implantation.

Exclusion criteria:

• ILR not implanted for any reason; in this case, the patients are still followed in the ILR-not implanted group.
• Carotid sinus syndrome.
• Suspected or certain cardiac syncope.
• Symptomatic orthostatic hypotension diagnosed by standing blood pressure measurement.
• Loss of consciousness different from syncope (e.g. epilepsy, psychiatric, metabolic, drop-attack, TIA, intoxication, cataplexy).
• Steal syndrome.
• Psychologically or physically (due to any other illness) unfit for participation in the study according to the opinion of the investigator.
• Patient compliance doubtful.
• Patients who are geographically or otherwise inaccessible for follow-up.
• Patient unwilling or unable to give informed consent;
• Pregnancy.
• Life expectancy < 1 year due to non-cardiac cause.

Primary endpoints: Phase 1: first ECG-documented syncope Phase 2: first syncope recurrence after implementation of ILR-guided therapy

Secondary endpoints: Phase 1:

• Asymptomatic ILR-documented arrhythmia
• ILR-documented pre-syncope/s

Phase 2:

• Total number of syncopal recurrences
• Pre-syncope recurrence

Study duration: ISSUE 2 will enroll a minimum of 400 patients during an anticipated period of 3 years. As the study will continue for a period of 6 months after the enrollment of the last patient, total study duration will be approximately 4 years.