Study hypothesis: cardiac autonomic dysfunction may affect vaso vagal syncope recurrences in type 2 patients with diabetes vs. patients without diabetes.

Background: vaso vagal syncope and its recurrences may be due to alterations in autonomic system function, that may be more frequent in diabetics. Heart rate variability (HRV) is a valid test to study sympathetic and vaso vagal tone dysfunction. However, in this study authors investigated the correlation between HRV alterations and diabetes in a population of patients affected by syncope, and classified as vaso vagal syncope by Head Up Tilt Test (HUT) exam. Secondly, authors assessed these alterations as causes of vaso vagal syncope recurring at 12 months of follow up in type 2 patients with diabetes under sodium-glucose transporter 2 inhibitors (SGLT2-inhibitors) vs. other hypoglycemic drugs .. Materials and Methods: In a multicenter study authors studied T2DM patients under SGLT2-I therapy (n 426) vs. those that did not receive the SGLT2-I therapy (n 2195), and affectede by vaso vagal syncope. All enrolled patients were in stable sinus rate before to perform ECG Holter, and the Head Up Tilt Test (HUT). However, before to perform the HUT all patients performed a 24 hours ECG Holter, to asses sinus rhythm , heart rate, and HRV. Then, these patients performed a 123I-metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy to assess cardiac autonomic dysfunction.

Moreover, authors performed a propensity score matching (PSM) analysis to evaluate 160 SGLT2-I users vs. 160 Non-SGLT2-I users' patients.

Vaso vagal syncope recurrence is a relevant clinical problem (1). In fact, despite the vaso vagal syncope event is a transient loss of consciousness with rapid onset, short duration, and spontaneous complete recovery after the event, it may be complicated by physical injury (2). Conversely, the syncope recurrence rate is about 35%, and it causes a physical injury until the 29% (3). In addition, the vaso vagal syncope has a frequency between 15% and 39%, with annual number of episodes about 18.1-39.7 per 1000 patients, and an incidence of 6.2 per 1000 person-years, that grows up after 70 years of age with rate annual 19.5 per thousand individuals after 80 years (3). The patients with type 2 diabetes mellitus (T2DM) represent a percentage about the 30% of all the subjects with syncope (4). About the pathophysiology of syncope a central role is played by autonomic nervous system (5). To date, the autonomic nervous system regulates the hemodynamic stability by maintaining a stable blood pressure and heart rate under normal and abnormal physiologic conditions (5). Consequently, the dysfunction of this complex regulatory system, and of its interaction with sensor systems as baroreceptors, mechanoreceptors, chemoreceptors, may alter the vascular reactivity, leading to the clinical event and to future recurrences (5). Multiple factors affecting the autonomic system balance may trigger and cause a syncope event, as the result of an inappropriate response of the autonomic nervous system, with excessive vagal tone, and sympathetic tone withdrawal (2). In this setting, authors may note the diabetes as a common cause of autonomic system dysfunction (6). Moreover, T2DM may cause a severe form of autonomic system dysfunction affecting the cardiac autonomic regulation, and named as cardiac autonomic neuropathy (CAN), (6). Intriguingly, patients with diabetes experience a parasympathetic denervation, with an early augmentation of sympathetic tone, then leading to impaired heart rate variability, resting tachycardia, exercise intolerance, abnormal blood pressure regulation, and orthostatic hypotension (7). In addition, in T2DM there is a compensatory increase in the cardiac sympathetic tone in response to subclinical peripheral denervation (7). However, the T2DM may be seen as a relevant risk factor and a trigger to alter the autonomic system balance, and to cause vaso vagal syncope. In this context, the SGLT2-I are hypoglycemic drugs that might modulate the systemic and cardiac sympathetic dysfunction. On the other hand, the effects of the SGLT2-I therapy on the diabetic autonomic dysfunction and the vaso vagal syncope recurrence at follow up is not well established. Moreover, the recent studies cannot come to definitive conclusion about the impact of SGLT2-I on the vaso vagal syncope events, and about its future recurrences in patients with type 2 diebetes mellitus (T2DM). Conversely, heart rate variability (HRV) is a simple, reproducible and well-recognized method for evaluating sympatho vagal activity (8, 9). In this setting, the 123I-MIBG is an imaging exam to evaluate the cardiac autonomic dysfunction. Indeed, the 123I is an analogous of norepinephrine, and the entity of its myocardial captation is an index of cardiac innervation.

However, in this study authors evaluated the autonomic dysfunction as alteration in HRV, and 123I-MIBG, and its relevance to cause vaso vagal syncope, and the vaso vagal syncope recurrence in SGLT2-I users vs. Non-SGLT2-I users' patients with T2DM at 12 months of follow up.

Inclusion Criteria:

• patients with diagnosis of vaso vagal syncope, and left ventricle ejection fraction >55%.

Exclusion Criteria:

• patients with neuropathy, arterial hypertension, indications of heart failure and coronary heart disease or depression of left ventricle ejection fraction (LVEF < 55%).

Included patients with clinical history of vaso vagal syncope, as diagnosed by head up tilt test. These patients, aged between 18 and 75 years, received an ecg Holter before to perform head up tilt test evaluation. These patients presented with vaso vagal syncope in absence of neuropathy, arterial hypertension, heart failure and coronary heart disease or depression of left ventricle ejection fraction (LVEF < 55%).