To verify the efficacy of transcutaneous vagus nerve stimulation (tVNS) on and autonomic balance in patients with chronic heart failure and reduced (HFrEF) or mildly reduced (HFmrEF) left ventricular ejection fraction. The study hypothesis is that tVNS increases baroreflex gain, with consequent benefits on sympathovagal balance (at short- and mid-term), and on quality of life and bio-humoral parameters (at mid-term).

Pilot phase: comparing the effects of right- (10-minute) vs. left-sided tVNS (10-minute) on BRS and heart rate variability (HRV) in a subset of patients.

Short-term phase: comparing the effects of active- (10-minute) vs. sham-tVNS (10-minute) on BRS, HRV, and sympathetic nerve activity.

Mid-term phase: comparing the effects of active- (4-week) vs- sham-tVNS (4-week) on BRS, HRV, biomarkers, exercise performance, and cardiac function.

Inclusion criteria

• Aged ≥18 years;
• Ability to consent to enrollment;
• Diagnosis of chronic heart failure (CHF= and left ventricular ejection fraction <50% according to the latest European guidelines.

Exclusion criteria

• History of acute coronary syndrome within 3 months of enrollment;
• Clinical need to modify CHF therapy during the study;
• History of recurrent syncope, orthostatic hypotension, severe bradycardia (average heart rate <50 bpm), or second or third-degree atrioventricular block;
• Neurological conditions characterized by dysautonomia (e.g., Parkinson's disease);
• Unstable major psychiatric disorders or treatment with psychoactive drugs or drugs that can act on the autonomic nervous system (e.g., antidepressants, antipsychotics, opioids, benzodiazepines);
• Uncontrolled thyroid disorders;
• Active neoplasia;
• Severe renal insufficiency (estimated glomerular filtration rate <15 ml/min/1.73 m2);
• Moderate or severe chronic obstructive pulmonary disease (FEV1/FVC <70% of predicted and FEV1 <70%);
• Liver insufficiency (AST/ALT >100 U/L and/or gamma-GT >150 U/L);
• Participation in other clinical studies in the 3 months preceding;
• Women in pregnancy, breastfeeding, or of childbearing age not following adequate contraception (the woman must agree to abstain from heterosexual intercourse or use at least two effective contraceptive measures such as bilateral tubal ligation, male sterilization, use of hormonal contraceptives that inhibit ovulation, intrauterine devices releasing hormones, copper intrauterine devices; all barrier devices must be used in combination with a spermicidal cream).

In order to maintain the 'double-blind,' at the end of the experimental protocol, the data acquired in each phase (baseline, active tVNS, placebo tVNS) will be saved in three different files, made unrecognizable by one of the investigators not involved in the tabulation and data analysis. A second investigator, unaware of the stimulation phases, will proceed with the tabulation of the data for each individual recording (three per patient). Only at the end of the study (or after recruiting 50% of patients for any interim analyses), will the investigators responsible for data analysis be revealed the corresponding phase for each recording.