Choosing Wisely in clinical practice: Embracing critical thinking, striving for safer care.

In recent years, the Choosing Wisely and Less is More campaigns have gained growing attention in the medical scientific community. Several projects have been launched to facilitate confrontation among patients and physicians, to achieve better and harmless patient-centered care. Such initiatives have paved the way to a new "way of thinking." Embracing such a philosophy goes through a cognitive process that takes into account several issues. Medicine is a highly inaccurate science and physicians should deal with uncertainty. Evidence from the literature should not be accepted as it is but rather be translated into practice by medical practitioners who select treatment options for specific cases based on the best research, patient preferences, and individual patient characteristics. A wise choice requires active effort into minimizing the chance that potential biases may affect our clinical decisions. Potential harms and all consequences (both direct and indirect) of prescribing tests, procedures, or medications should be carefully evaluated, as well as patients' needs and preferences. Through such a cognitive process, a patient management shift is needed, moving from being centered on establishing a diagnosis towards finding the best management strategy for the right patient at the right time. Finally, while "thinking wisely," physicians should also "act wisely," being among the leading actors in facing upcoming healthcare challenges related to environmental issues and social discrepancies.

Use of high flow nasal cannula in patients with acute respiratory failure in general wards under intensivists supervision: a single center observational study.

BACKGROUND: Few data exist on high flow nasal cannula (HFNC) use in patients with acute respiratory failure (ARF) admitted to general wards. RATIONALE AND OBJECTIVES: To retrospectively evaluate feasibility and safety of HFNC in general wards under the intensivist-supervision and after specific training. METHODS: Patients with ARF (dyspnea, respiratory rate-RR > 25/min, 150 < PaO2/FiO2 < 300 mmHg during oxygen therapy) admitted to nine wards of an academic hospital were included. Gas-exchange, RR, and comfort were assessed before HFNC and after 2 and 24 h of application. RESULTS: 150 patients (81 male, age 74 [60-80] years, SOFA 4 [2-4]), 123 with de-novo ARF underwent HFNC with flow 60 L/min [50-60], FiO2 50% [36-50] and temperature 34 °C [31-37]. HFNC was applied a total of 1399 days, with a median duration of 7 [3-11] days. No major adverse events or deaths were reported. HFNC did not affect gas exchange but reduced RR (25-22/min at 2-24 h, p < 0.001), and improved Dyspnea Borg Scale (3-1, p < 0.001) and comfort (3-4, p < 0.001) after 24 h. HFNC failed in 20 patients (19.2%): 3 (2.9%) for intolerance, 14 (13.4%) escalated to NIV/CPAP in the ward, 3 (2.9%) transferred to ICU. Among these, one continued HFNC, while the other 2 were intubated and they both died. Predictors of HFNC failure were higher Charlson's Comorbidity Index (OR 1.29 [1.07-1.55]; p = 0.004), higher APACHE II Score (OR 1.59 [1.09-4.17]; p = 0.003), and cardiac failure as cause of ARF (OR 5.26 [1.36-20.46]; p = 0.02). CONCLUSION: In patients with mild-moderate ARF admitted to general wards, the use of HFNC after an initial training and daily supervision by intensivists was feasible and seemed safe. HFNC was effective in improving comfort, dyspnea, and respiratory rate without effects on gas exchanges. Trial registration This is a single-centre, noninterventional, retrospective analysis of clinical data.

The Interplay between Autonomic Nervous System and Inflammation across Systemic Autoimmune Diseases.

The autonomic nervous system (ANS) and the immune system are deeply interrelated. The ANS regulates both innate and adaptive immunity through the sympathetic and parasympathetic branches, and an imbalance in this system can determine an altered inflammatory response as typically observed in chronic conditions such as systemic autoimmune diseases. Rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis all show a dysfunction of the ANS that is mutually related to the increase in inflammation and cardiovascular risk. Moreover, an interaction between ANS and the gut microbiota has direct effects on inflammation homeostasis. Recently vagal stimulation techniques have emerged as an unprecedented possibility to reduce ANS dysfunction, especially in chronic diseases characterized by pain and a decreased quality of life as well as in chronic inflammation.

Effects of bilateral lung transplantation on cardiac autonomic modulation and cardiorespiratory coupling: a prospective study.

BACKGROUND: Although cardiac autonomic modulation has been studied in several respiratory diseases, the evidence is limited on lung transplantation, particularly on its acute and chronic effects. Thus, we aimed to evaluate cardiac autonomic modulation before and after bilateral lung transplantation (BLT) through a prospective study on patients enrolled while awaiting transplant. METHODS: Twenty-two patients on the waiting list for lung transplantation (11 women, age 33 [24-51] years) were enrolled in a prospective study at Ospedale Maggiore Policlinico Hospital in Milan, Italy. To evaluate cardiac autonomic modulation, ten minutes ECG and respiration were recorded at different time points before (T0) and 15 days (T1) and 6 months (T2) after bilateral lung transplantation. As to the analysis of cardiac autonomic modulation, heart rate variability (HRV) was assessed using spectral and symbolic analysis. Entropy-derived measures were used to evaluate complexity of cardiac autonomic modulation. Comparisons of autonomic indices at different time points were performed. RESULTS: BLT reduced HRV total power, HRV complexity and vagal modulation, while it increased sympathetic modulation in the acute phase (T1) compared to baseline (T0). The HRV alterations remained stable after 6 months (T2). CONCLUSION: BLT reduced global variability and complexity of cardiac autonomic modulation in acute phases, and these alterations remain stable after 6 months from surgery. After BLT, a sympathetic predominance and a vagal withdrawal could be a characteristic autonomic pattern in this population.

Multicentre external validation of the Canadian Syncope Risk Score to predict adverse events and comparison with clinical judgement.

BACKGROUND: The Canadian Syncope Risk Score (CSRS) has been proposed for syncope risk stratification in the emergency department (ED). The aim of this study is to perform an external multicenter validation of the CSRS and to compare it with clinical judgement. METHODS: Using patients previously included in the SyMoNE database, we enrolled subjects older than 18 years who presented reporting syncope at the ED. For each patient, we estimated the CSRS and recorded the physician judgement on the patients' risk of adverse events. We performed a 30-day follow-up. RESULTS: From 1 September 2015 to 28 February 2017, we enrolled 345 patients; the median age was 71 years (IQR 51-81), 174 (50%) were men and 29% were hospitalised. Serious adverse events occurred in 43 (12%) of the patients within 30 days. The area under the curve of the CSRS and clinical judgement was 0.75 (95% CI 0.68 to 0.81) and 0.68 (95% CI 0.61 to 0.74), respectively. The risk of adverse events of patients at low risk according to the CSRS and clinical judgement was 6.7% and 2%, with a sensitivity of 70% (95% CI 54% to 83%) and 95% (95% CI 84% to 99%), respectively. CONCLUSION: This study represents the first validation analysis of CSRS outside Canada. The overall predictive accuracy of the CSRS is similar to the clinical judgement. However, patients at low risk according to clinical judgement had a lower incidence of adverse events as compared with patients at low risk according to the CSRS. Further studies showing that the adoption of the CSRS improve patients' outcomes is warranted before its widespread implementation.

Syncope Time Frames for Adverse Events after Emergency Department Presentation: An Individual Patient Data Meta-Analysis.

Background and Objectives: Knowledge of the incidence and time frames of the adverse events of patients presenting syncope at the ED is essential for developing effective management strategies. The aim of the present study was to perform a meta-analysis of the incidence and time frames of adverse events of syncope patients. Materials and Methods: We combined individual patients' data from prospective observational studies including adult patients who presented syncope at the ED. We assessed the pooled rate of adverse events at 24 h, 72 h, 7-10 days, 1 month and 1 year after ED evaluation. Results: We included nine studies that enrolled 12,269 patients. The mean age varied between 53 and 73 years, with 42% to 57% females. The pooled rate of adverse events was 5.1% (95% CI 3.4% to 7.7%) at 24 h, 7.0% (95% CI 4.9% to 9.9%) at 72 h, 8.4% (95% CI 6.2% to 11.3%) at 7-10 days, 10.3% (95% CI 7.8% to 13.3%) at 1 month and 21.3% (95% CI 15.8% to 28.0%) at 1 year. The pooled death rate was 0.2% (95% CI 0.1% to 0.5%) at 24 h, 0.3% (95% CI 0.1% to 0.7%) at 72 h, 0.5% (95% CI 0.3% to 0.9%) at 7-10 days, 1% (95% CI 0.6% to 1.7%) at 1 month and 5.9% (95% CI 4.5% to 7.7%) at 1 year. The most common adverse event was arrhythmia, for which its rate was 3.1% (95% CI 2.0% to 4.9%) at 24 h, 4.8% (95% CI 3.5% to 6.7%) at 72 h, 5.8% (95% CI 4.2% to 7.9%) at 7-10 days, 6.9% (95% CI 5.3% to 9.1%) at 1 month and 9.9% (95% CI 5.5% to 17) at 1 year. Ventricular arrhythmia was rare. Conclusions: The risk of death or life-threatening adverse event is rare in patients presenting syncope at the ED. The most common adverse events are brady and supraventricular arrhythmias, which occur during the first 3 days. Prolonged ECG monitoring in the ED in a short stay unit with ECG monitoring facilities may, therefore, be beneficial.

Diagnostic accuracy of ICD-9 code 780.2 for the identification of patients with syncope in the emergency department.

PURPOSE: Syncope is a common condition that affects individuals of all ages and is responsible for 1-3% of all emergency department (ED) visits. Prospective studies on syncope are often limited by the exiguous number of subjects enrolled. A possible alternative approach would be to use of hospital discharge diagnoses from administrative databases to identify syncope subjects in epidemiological observational studies. We assessed the accuracy of the International Classification of Diseases, Ninth Revision (ICD-9) code 780.2 "syncope and collapse" to identify patients with syncope. METHODS: Patients in two teaching hospitals in Milan, Italy with a triage assessment for ED access that was possibly related to syncope were recruited in this study. We considered the index test to be the attribution of the ICD-9 code 780.2 at ED discharge and the reference standard to be the diagnosis of syncope by the ED physician. RESULTS: The sensitivity, specificity, positive and negative predictive values of the ICD-9 code 780.2 to identify patients with syncope were 0.63 (95% confidence interval [CI] 0.58-0.67), 0.98 (95% CI 0.98-0.99), 0.83 (95% CI 0.79-0.87) and 0.95 (95% CI 0.94-0.95), respectively. CONCLUSIONS: The moderate sensitivity of ICD-9 code 780.2 should be considered when the code is used to identify patients with syncope through administrative databases.

Deprescribing strategies in older patients with heart failure.

Older patients with heart failure are particularly vulnerable due to a wide range of associated comorbidities, disability, and frailty. This population often receives multiple prescriptions, increasing the risk of adverse drug reactions, non-adherence, and drug interactions. Deprescribing, which involves reducing the number of medications to the lowest clinically reasonable limit, has the potential to decrease the risk of drug interactions and enhance patients' quality of life. Moreover, simplifying medication regimens may improve adherence to essential heart failure therapies. This scientific review aims to comprehensively examine deprescribing strategies in older patients with heart failure. It explores the rationale, challenges, benefits, and potential approaches to optimizing medication regimens in this vulnerable population. Furthermore, the review suggests a practical, step-by-step approach for performing deprescribing in older patients with heart failure.

Syncope in the Emergency Department: A Practical Approach.

Syncope is a common condition encountered in the emergency department (ED), accounting for about 0.6-3% of all ED visits. Despite its high frequency, a widely accepted management strategy for patients with syncope in the ED is still missing. Since syncope can be the presenting condition of many diseases, both severe and benign, most research efforts have focused on strategies to obtain a definitive etiologic diagnosis. Nevertheless, in everyday clinical practice, a definitive diagnosis is rarely reached after the first evaluation. It is thus troublesome to aid clinicians' reasoning by simply focusing on differential diagnoses. With the current review, we would like to propose a management strategy that guides clinicians both in the identification of conditions that warrant immediate treatment and in the management of patients for whom a diagnosis is not immediately reached, differentiating those that can be safely discharged from those that should be admitted to the hospital or monitored before a final decision. We propose the mnemonic acronym RED-SOS: Recognize syncope; Exclude life-threatening conditions; Diagnose; Stratify the risk of adverse events; Observe; decide on the Setting of care. Based on this acronym, in the different sections of the review, we discuss all the elements that clinicians should consider when assessing patients with syncope.

How to recognize pulmonary embolism in syncope patients: A simple rule.

BACKGROUND: Syncope can be the presenting symptom of Pulmonary Embolism (PE). It is not known wether using a standardized algorithm to rule-out PE in all patients with syncope admitted to the Emergency Departments (ED) is of value or can lead to overdiagnosis and overtreatment. METHODS: We tested if simple anamnestic and clinical parameters could be used as a rule to identify patients with syncope and PE in a multicenter observational study. The rule's sensitivity was tested on a cohort of patients that presented to the ED for syncopal episodes caused by PE. The clinical impact of the rule was assessed on a population of consecutive patients admitted for syncope in the ED. RESULTS: Patients were considered rule-positive in the presence of any of the following: hypotension, tachycardia, peripheral oxygen saturation ≤ 93 % (SpO2), chest pain, dyspnea, recent history of prolonged bed rest, clinical signs of deep vein thrombosis, history of previous venous thrombo-embolism and active neoplastic disease. The sensitivity of the rule was 90.3 % (95 % CI: 74.3 % to 98.0 %). The application of the rule to a population of 217 patients with syncope would have led to a 70 % reduction in the number of subjects needing additional diagnostic tests to exclude PE. CONCLUSIONS: Most patients with syncope due to PE present with anamnestic and clinical features indicative of PE diagnosis. A clinical decision rule can be used to identify patients who would benefit from further diagnostic tests to exclude PE, while reducing unnecessary exams that could lead to over-testing and over-diagnosis.

The environmental cost of unwarranted variation in the use of magnetic resonance imaging and computed tomography scans.

BACKGROUND: Pollution is a major threat to global health, and there is growing interest on strategies to reduce emissions caused by health care systems. Unwarranted clinical variation, i.e. variation in the utilization of health services unexplained by differences in patient illness or preferences, may be an avoidable source of CO2 when related to overuse. Our objective was to evaluate the CO2 emissions attributable to unwarranted variation in the use of MRI and CT scans among countries of the G20-area. METHODS: We selected seven countries of the G20-area with available data on the use of CT and MRI scans from the organization for Economic Co-operation and Development repository. Each nation's annual electric energy expenditure per 1000 inhabitants for such exams (T-Enex-1000) was calculated and compared with the median and lowest value. Based on such differences we estimated the national energy and corresponding tons of CO2 that could be potentially avoided each year. RESULTS: With available data we found a significant variation in T-Enex-1000 (median value 1782 kWh, range 1200-3079 kWh) and estimated a significant amount of potentially avoidable emissions each year (range 2046-175120 tons of CO2). In practical terms such emissions would need, in the case of Germany, 71900 and 104210 acres of forest to be cleared from the atmosphere, which is 1.2 and 1.7 times the size of the largest German forest (Bavarian National Forest). CONCLUSION: Among countries with a similar rate of development, unwarranted clinical variation in the use of MRI and CT scan causes significant emissions of CO2.

Social Isolation: A Narrative Review on the Dangerous Liaison between the Autonomic Nervous System and Inflammation.

Social isolation and feelings of loneliness are related to higher mortality and morbidity. Evidence from studies conducted during space missions, in space analogs, and during the COVID-19 pandemic underline the possible role of the autonomic nervous system in mediating this relation. Indeed, the activation of the sympathetic branch of the autonomic nervous system enhances the cardiovascular response and activates the transcription of pro-inflammatory genes, which leads to a stimulation of inflammatory activation. This response is adaptive in the short term, in that it allows one to cope with a situation perceived as a threat, but in the long term it has detrimental effects on mental and physical health, leading to mood deflection and an increased risk of cardiovascular disease, as well as imbalances in immune system activation. The aim of this narrative review is to present the contributions from space studies and insights from the lockdown period on the relationship between social isolation and autonomic nervous system activation, focusing on cardiovascular impairment and immune imbalance. Knowing the pathophysiological mechanisms underlying this relationship is important as it enables us to structure effective countermeasures for the new challenges that lie ahead: the lengthening of space missions and Mars exploration, the specter of future pandemics, and the aging of the population.

Remdesivir-induced bradycardia in patients hospitalized with SARS-CoV2 infection: a possible vagally-mediated mechanism.

Recently, case series studies on patients with SARS-CoV-2 infection reported an association between remdesivir (RDV) administration and incidental bradycardia. However, the phenomenon has not yet been described in detail. We conducted a retrospective case-control study to evaluate the occurrence of RDV-related bradycardia in patients hospitalized for SARS-CoV2 pneumoniae. We retrospectively evaluated 71 patients, hospitalized in six internal medicine wards of the Milan area, affected by mild-to-moderate COVID-19 who received RDV (RDV group) and 54 controls, matched for sex, age and disease severity on admission (CTR group). The mean heart rate value recorded during the first two days of hospitalization was considered as baseline heart rate (HRb). Heart rate values relative to the 5-days treatment and the 5-days post-treatment were extracted for RDV group, while heart rate values relative to 10 days of hospitalization were considered for the CTR group. ΔHR values were calculated as maximum HR drop versus HRb. Possible associations between ΔHR and clinical-demographic factors were assessed through regression analysis. The RDV group experienced a significantly higher incidence of bradycardia compared to the CTR group (56% vs 33%, OR 2.6, 95% CI 1.2-5.4, p value = 0.011). Moreover, the RDV group showed higher ΔHR values than the CTR group. The HR progressively decreased with daily administration of RDV, reaching the maximun drop on day six (-8.6±1.9 bpm). In RDV group, patients who experienced bradycardia had higher drop in HR, higher alanine aminotransferase (ALT) values at the baseline (bALT) and during the RDV administration period. ΔHR was positively associated with HRb (ß = 0.772, p < 0.001) and bALT (ß = 0.245, p = 0.005). In conclusion, our results confirmed a significant association between RDV administration and development of bradycardia. This effect was proportional to baseline HR and was associated with higher levels of baseline ALT, suggesting a possible interaction between RDV liver metabolism and a vagally-mediated effect on HR due to increased availability of RDV metabolites.

Cardiac autonomic control in Rett syndrome: Insights from heart rate variability analysis.

Rett syndrome (RTT) is a rare and severe neurological disorder mainly affecting females, usually linked to methyl-CpG-binding protein 2 (MECP2) gene mutations. Manifestations of RTT typically include loss of purposeful hand skills, gait and motor abnormalities, loss of spoken language, stereotypic hand movements, epilepsy, and autonomic dysfunction. Patients with RTT have a higher incidence of sudden death than the general population. Literature data indicate an uncoupling between measures of breathing and heart rate control that could offer insight into the mechanisms that lead to greater vulnerability to sudden death. Understanding the neural mechanisms of autonomic dysfunction and its correlation with sudden death is essential for patient care. Experimental evidence for increased sympathetic or reduced vagal modulation to the heart has spurred efforts to develop quantitative markers of cardiac autonomic profile. Heart rate variability (HRV) has emerged as a valuable non-invasive test to estimate the modulation of sympathetic and parasympathetic branches of the autonomic nervous system (ANS) to the heart. This review aims to provide an overview of the current knowledge on autonomic dysfunction and, in particular, to assess whether HRV parameters can help unravel patterns of cardiac autonomic dysregulation in patients with RTT. Literature data show reduced global HRV (total spectral power and R-R mean) and a shifted sympatho-vagal balance toward sympathetic predominance and vagal withdrawal in patients with RTT compared to controls. In addition, correlations between HRV and genotype and phenotype features or neurochemical changes were investigated. The data reported in this review suggest an important impairment in sympatho-vagal balance, supporting possible future research scenarios, targeting ANS.

Dysautonomia in Parkinson's Disease: Impact of Glucocerebrosidase Gene Mutations on Cardiovascular Autonomic Control.

Evidence from clinical practice suggests that PD patients with the Glucocerebrosidase gene mutations (GBA-PD) are characterized by more severe dysautonomic symptoms than patients with idiopathic PD (iPD). Therefore, an accurate assessment of cardiovascular autonomic control (CAC) is necessary to clarify the role of GBA mutations in the pathophysiology of PD. We evaluated the CAC at rest and during orthostatic challenge of 15 iPD, 15 GBA-PD and 15 healthy controls (CTR). ECG and respiration were recorded in supine position and during active standing. The analysis of Heart Rate Variability (HRV) was performed on ECG recordings using two different approaches, linear spectral analysis and non-linear symbolic analysis. GBA-PD patients presented more frequently an akinetic-rigid phenotype and cognitive dysfunction than iPD patients. Both iPD and GBA-PD group were characterized by a lower spectral HRV than CTR group. At rest, the GBA-PD group was characterized by a lower parasympathetic modulation and a shift of the sympathovagal balance toward a sympathetic predominance compared to the CTR group. Moreover, the GBA-PD patients presented a lower HR increment and a lower or absent reduction of the vagal modulation in response to the active standing than iPD patients. Lastly, the cardiovascular autonomic dysfunction in PD patients was associated with longer disease duration, and with the occurrence of REM sleep behavior disorder and constipation. Our findings suggest a more severe impairment of the CAC in PD patients with GBA mutations. These results and further studies on the role of GBA mutations could allow a stratification based on cardiovascular risk in PD patients and the implementation of specific prevention programs.

Obesity and sleep disturbances: The "chicken or the egg" question.

Obesity and sleep disturbances are common conditions in modern societies and accumulating evidence support a close bidirectional causal relationship between these two conditions. Indeed, from one side sleep loss seems to affect energy intake and expenditure through its direct effects on hormone-mediated sensations of satiety and hunger and through the influence on hedonic and psychological aspects of food consumption. Sleep deprived patients have been shown to experiment excessive daytime sleepiness, fatigue, and tiredness that, in a vicious circle, enhances physical inactivity and weight gain. On the other side, obesity is a well-known risk factor for several sleep disorders. This narrative review will discuss the main pathophysiological mechanisms that link sleep loss to obesity and metabolic syndrome with particular attention to the three most common sleep disorders (insomnia, obstructive sleep apnoea syndrome, restless leg syndrome).

Frequency of asymptomatic carriers of SARS-CoV-2 among children and adults after school reopening.

BACKGROUND: Children often develop an asymptomatic form of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), but it is debated if children are at higher risk than adults to be asymptomatic carriers of SARS-CoV-2, especially during the school reopening. The main aim of this study was to investigate the frequency of SARS-CoV-2 asymptomatic carriers in children and adults during the reopening of the schools in Milan, Italy. METHODS: We conducted a cross-sectional study at the pediatric and adult Emergency Department (ED) of the Ca' Granda Ospedale Maggiore Policlinico (Milan) between October 1 and 31, 2020, i.e. 3 weeks after the reopening of schools. Patients admitted to the ED short stay observation and without any sign or symptom consistent with a SARS-CoV-2 were eligible. These patients underwent a nasopharyngeal swab specimen for the detection of SARS-CoV-2. The odds ratio and its 95% confidence interval (CI) was calculated to assess the risk of asymptomatically carrying the SARS-CoV-2 infection in children and adults. RESULTS: A total of 69 (27 females, median age 8.7 years) children and 251 (107 females, median age 71 years) adults were enrolled. Pediatric and adult subjects tested positive for SARS-CoV-2 with a similar frequency (1/69 [1.4%] vs 4/251 [1.6%]). Children had an odds ratio to be a carrier of 0.91 (CI 0.02- 9.38) compared to adults. CONCLUSIONS: The frequency of asymptomatic SARS-CoV-2 carriers was similar among children and adults. Considering the emerging diffusion of new SARS-CoV-2 variants, the asymptomatic spread of SARS-CoV-2 infection among children and adults should be monitored.

Effects of transcutaneous auricular vagus nerve stimulation on cardiovascular autonomic control in health and disease.

Autonomic nervous system (ANS) dysfunction is a well-known feature of cardiovascular diseases (CVDs). Studies on heart rate variability (HRV), a non-invasive method useful in investigating the status of cardiovascular autonomic control, have shown that a predominance of sympathetic modulation not only contributes to the progression of CVDs but has a pivotal role in their onset. Current therapies focus more on inhibition of sympathetic activity, but the presence of drug-resistant conditions and the invasiveness of some surgical procedures are an obstacle to complete therapeutic success. On the other hand, targeting the parasympathetic branch of the autonomic nervous system through invasive vagus nerve stimulation (VNS) has shown interesting results as alternative therapeutic approach for CVDs. However, the invasiveness and cost of the surgical procedure limit the clinical applicability of VNS and hinder the research on the physiological pathway involved. Transcutaneous stimulation of the auricular branch of the vagus nerve (tVNS) seems to represent an important non-invasive alternative with effects comparable to those of VNS with surgical implant. Thus, in the present narrative review, we illustrate the main studies on tVNS performed in healthy subjects and in three key examples of CVDs, namely heart failure, hypertension and atrial fibrillation, highlighting the neuromodulatory effects of this technique.