Vagal nerve stimulation in myocardial ischemia/reperfusion injury: from bench to bedside

Candreva A., Buongiorno A.L., Matter M.A., Rizzini M.L., Giacobbe F., Ravetti E., Giannino G., Carmagnola L., Gilhofer T., Gallo D., Chiastra C., Stähli B.E., Iannaccone M., Morbiducci U., Porto I., et. al.

Background and aims Intracoronary pressure gradients and translesional flow patterns have been correlated with coronary plaque progression and lesion destabilization. In this study, we aimed to determine the relationship between endothelial shear stress and plaque progression and to evaluate the effect of shear forces on coronary plaque features. Methods A systematic review was conducted in medical on-line databases. Selected were studies including human participants who underwent coronary anatomy assessment with computational fluid dynamics (CFD)-based wall shear stress (WSS) calculation at baseline with anatomical evaluation at follow-up. A total of six studies were included for data extraction and analysis. Results The meta-analysis encompassed 31′385 arterial segments from 136 patients. Lower translesional WSS values were significantly associated with a reduction in lumen area (mean difference − 0.88, 95% CI -1.13 to −0.62), an increase in plaque burden (mean difference 4.32, 95% CI 1.65–6.99), and an increase in necrotic core area (mean difference 0.02, 95% CI 0.02–0.03) at follow-up imaging. Elevated WSS values were associated with an increase in lumen area (mean difference 0.78, 95% CI 0.34–1.21) and a reduction in both fibrofatty (mean difference − 0.02, 95% CI -0.03 to −0.01) and fibrous plaque areas (mean difference − 0.03, 95% CI -0.03 to −0.03). Conclusion This meta-analysis shows that WSS parameters were related to vulnerable plaque features at follow-up. These results emphasize the impact of endothelial shear forces on coronary plaque growth and composition. Future studies are warranted to evaluate the role of WSS in guiding clinical decision-making.

Jani N., van Weperen V., Hoang J.D., Herring N., Smith C., Vaseghi M.

Jin H., Li M., Jeong E., Castro-Martinez F., Zuker C.S.

AbstractThe body–brain axis is emerging as a principal conductor of organismal physiology. It senses and controls organ function1,2, metabolism3 and nutritional state4–6. Here we show that a peripheral immune insult strongly activates the body–brain axis to regulate immune responses. We demonstrate that pro-inflammatory and anti-inflammatory cytokines communicate with distinct populations of vagal neurons to inform the brain of an emerging inflammatory response. In turn, the brain tightly modulates the course of the peripheral immune response. Genetic silencing of this body–brain circuit produced unregulated and out-of-control inflammatory responses. By contrast, activating, rather than silencing, this circuit affords neural control of immune responses. We used single-cell RNA sequencing, combined with functional imaging, to identify the circuit components of this neuroimmune axis, and showed that its selective manipulation can effectively suppress the pro-inflammatory response while enhancing an anti-inflammatory state. The brain-evoked transformation of the course of an immune response offers new possibilities in the modulation of a wide range of immune disorders, from autoimmune diseases to cytokine storm and shock.

Dusi V., Angelini F., Baldi E., Toscano A., Gravinese C., Frea S., Compagnoni S., Morena A., Saglietto A., Balzani E., Giunta M., Costamagna A., Rinaldi M., Trompeo A.C., Rordorf R., et. al.

Abstract Background Percutaneous stellate ganglion block (PSGB) through single bolus injection and thoracic epidural anaesthesia (TEA) have been proposed for the acute management of refractory ventricular arrhythmias (VAs). However, data on continuous PSGB (C-PSGB) are scant. Aims To report our dual-center experience with C-PSGB and to perform a systematic review on C-PSGB and TEA. Methods Consecutive patients receiving C-PSGB at 2 centers were enrolled. The systematic literature review follows the latest PRISMA criteria. Results Our case series (26 patients, 88% male, 60±16 years, all with advanced structural heart disease, LVEF 23±11%, 32 C-PSGB performed, median duration 3 days) shows that C-PSGB is feasible and safe and leads to complete VAs suppression in 59% and to overall clinical benefit in 94% of cases. Overall, 61 patients received 68 C-PSGB and 22 TEA, with complete VAs suppression in 63% of C-PSGBs (61% of patients). Most TEA procedures (55%) were performed on intubated patients, as opposed to 28% C-PSGBs (p=0.02); 52% of patients were on full anticoagulation at C-PSGB, none at TEA (p<0.001). Ropivacaine and lidocaine were the most used drugs for C-PSGB, and the available data support a starting dose of 12 mg/h and 100 mg/h, respectively. No major complications occurred, yet TEA discontinuation rate due to side-effects was higher than C-PSGB (18% versus 1%, p=0.01). Conclusions C-PSGB seems feasible, safe, and effective for the acute management of refractory VAs. The antiarrhythmic effect may be accomplished with less concerns for concomitant anticoagulation compared to TEA, and with a lower side-effects related discontinuation rate.

González-González M.A., Conde S.V., Latorre R., Thébault S.C., Pratelli M., Spitzer N.C., Verkhratsky A., Tremblay M., Akcora C.G., Hernández-Reynoso A.G., Ecker M., Coates J., Vincent K.L., Ma B.

Bioelectronic Medicine stands as an emerging field that rapidly evolves and offers distinctive clinical benefits, alongside unique challenges. It consists of the modulation of the nervous system by precise delivery of electrical current for the treatment of clinical conditions, such as post-stroke movement recovery or drug-resistant disorders. The unquestionable clinical impact of Bioelectronic Medicine is underscored by the successful translation to humans in the last decades, and the long list of preclinical studies. Given the emergency of accelerating the progress in new neuromodulation treatments (i.e., drug-resistant hypertension, autoimmune and degenerative diseases), collaboration between multiple fields is imperative. This work intends to foster multidisciplinary work and bring together different fields to provide the fundamental basis underlying Bioelectronic Medicine. In this review we will go from the biophysics of the cell membrane, which we consider the inner core of neuromodulation, to patient care. We will discuss the recently discovered mechanism of neurotransmission switching and how it will impact neuromodulation design, and we will provide an update on neuronal and glial basis in health and disease. The advances in biomedical technology have facilitated the collection of large amounts of data, thereby introducing new challenges in data analysis. We will discuss the current approaches and challenges in high throughput data analysis, encompassing big data, networks, artificial intelligence, and internet of things. Emphasis will be placed on understanding the electrochemical properties of neural interfaces, along with the integration of biocompatible and reliable materials and compliance with biomedical regulations for translational applications. Preclinical validation is foundational to the translational process, and we will discuss the critical aspects of such animal studies. Finally, we will focus on the patient point-of-care and challenges in neuromodulation as the ultimate goal of bioelectronic medicine. This review is a call to scientists from different fields to work together with a common endeavor: accelerate the decoding and modulation of the nervous system in a new era of therapeutic possibilities.

Saglietto A., Baccega D., Esposito R., Anselmino M., Dusi V., Fiandrotti A., De Ferrari G.M.

BackgroundArtificial intelligence (AI) has shown promise in the early detection of various cardiac conditions from a standard 12-lead electrocardiogram (ECG). However, the ability of AI to identify abnormalities from single-lead recordings across a range of pathological conditions remains to be systematically investigated. This study aims to assess the performance of a convolutional neural network (CNN) using a single-lead (D1) rather than a standard 12-lead setup for accurate identification of ECG abnormalities.MethodsWe designed and trained a lightweight CNN to identify 20 different cardiac abnormalities on ECGs, using data from the PTB-XL dataset. With a relatively simple architecture, the network was designed to accommodate different combinations of leads as input (<100,000 learnable parameters). We compared various lead setups such as the standard 12-lead, D1 alone, and D1 paired with an additional lead.ResultsThe CNN based on single-lead ECG (D1) outperformed the one based on the standard 12-lead framework [with an average percentage difference of the area under the curve (AUC) of −8.7%]. Notably, for certain diagnostic classes, there was no difference in the diagnostic AUC between the single-lead and the standard 12-lead setups. When a second lead was detected in the CNN in addition to D1, the AUC gap was further reduced to an average percentage difference of −2.8% compared with that of the standard 12-lead setup.ConclusionsA relatively lightweight CNN can predict different classes of cardiac abnormalities from D1 alone and the standard 12-lead ECG. Considering the growing availability of wearable devices capable of recording a D1-like single-lead ECG, we discuss how our findings contribute to the foundation of a large-scale screening of cardiac abnormalities.

Giannino G., Braia V., Griffith Brookles C., Giacobbe F., D’Ascenzo F., Angelini F., Saglietto A., De Ferrari G.M., Dusi V.

The cardiac autonomic nervous system (CANS) plays a pivotal role in cardiac homeostasis as well as in cardiac pathology. The first level of cardiac autonomic control, the intrinsic cardiac nervous system (ICNS), is located within the epicardial fat pads and is physically organized in ganglionated plexi (GPs). The ICNS system does not only contain parasympathetic cardiac efferent neurons, as long believed, but also afferent neurons and local circuit neurons. Thanks to its high degree of connectivity, combined with neuronal plasticity and memory capacity, the ICNS allows for a beat-to-beat control of all cardiac functions and responses as well as integration with extracardiac and higher centers for longer-term cardiovascular reflexes. The present review provides a detailed overview of the current knowledge of the bidirectional connection between the ICNS and the most studied cardiac pathologies/conditions (myocardial infarction, heart failure, arrhythmias and heart transplant) and the potential therapeutic implications. Indeed, GP modulation with efferent activity inhibition, differently achieved, has been studied for atrial fibrillation and functional bradyarrhythmias, while GP modulation with efferent activity stimulation has been evaluated for myocardial infarction, heart failure and ventricular arrhythmias. Electrical therapy has the unique potential to allow for both kinds of ICNS modulation while preserving the anatomical integrity of the system.

Palma J.

To review the available evidence on the impact of muscarinic receptor modulation on cardiovascular control in humans. In this narrative Review we summarize data on cardiovascular endpoints from clinical trials of novel subtype-selective or quasi-selective muscarinic modulators, mostly PAMs, performed in the last decade. We also review the cardiovascular phenotype in recently described human genetic and autoimmune disorders affecting muscarinic receptors. Recent advancements in the development of compounds that selectively target muscarinic acetylcholine receptors are expanding our knowledge about the physiological function of each muscarinic receptor subtype (M1, M2, M3, M4, M5). Among these novel compounds, positive allosteric modulators (PAMs) have emerged as the preferred therapeutic to regulate muscarinic receptor subtype function. Many muscarinic allosteric and orthosteric modulators (including but not limited to xanomeline-trospium and emraclidine) are now in clinical development and approaching regulatory approval for multiple indications, including the treatment of cognitive and psychiatric symptoms in patients with schizophrenia as well as Alzheimer’s disease and other dementias. The results of these clinical trials provide an opportunity to understand the influence of muscarinic modulation on cardiovascular autonomic control in humans. While the results and the impact of each of these therapies on heart rate and blood pressure control have been variable, in part because the clinical trials were not specifically designed to measure cardiovascular endpoints, the emerging data is valuable to elucidate the relative cardiovascular contributions of each muscarinic receptor subtype. Understanding the muscarinic control of cardiovascular function is of paramount importance and may contribute to the development of novel therapeutic strategies for treating cardiovascular disease.

Elia E., Bruno F., Crimi G., Wańha W., Leonardi S., Mauro M., Roubin S.R., Fabris E., Giannino G., Mancone M., Severino P., Truffa A., De Filippo O., Huczek Z., Mazurek M., et. al.

Impact of gender on heart remodeling after acute coronary syndrome (ACS) and consequently on development of heart failure (HF) remains to be elucidated.CORALYS is a multicenter, retrospective, observational registry enrolling consecutive patients admitted for ACS and treated with percutaneous coronary intervention. HF hospitalization was the primary endpoint while all-cause mortality and the composite endpoint of incidence of first HF hospitalization and cardiovascular mortality were the secondary ones.Among 14,699 patients enrolled in CORALYS registry, 4578 (31%) were women and 10,121 (69%) males. Women were older, had more frequently hypertension and diabetes and less frequently smoking habit. History of myocardial infarction (MI), STEMI at admission and multivessel disease were less common in women. After median follow up of 2.9 ± 1.8 years, women had higher incidence of primary and secondary endpoints and female sex was an independent predictor of HF hospitalization (HR 1.26;1.05-1.50; p = 0.011) and cardiovascular death/HF hospitalization (HR 1.18;1.02-1.37; p = 0.022). At multivariable analysis women and men share as predictors of HF diabetes, history of cancer, chronic kidney disease, atrial fibrillation, complete revascularization and left ventricular ejection fraction. Chronic obstructive pulmonary disease (HR 2.34;1.70-3.22, p < 0.001) and diuretics treatment (HR 1.61;1.27-2.04, p < 0.001) were predictor of HF in men, while history of previous MI (HR 1.46;1.08-1.97, p = 0.015) and treatment with inhibitors of renin-angiotensin system (HR 0.69;0,49-0.96 all 95% CI, p = 0.030) in women.Women are at increased risk of HF after ACS and gender seems to be an outcome-modifier of the relationship between a variable and primary outcome.

Stavrakis S., Chakraborty P., Farhat K., Whyte S., Morris L., Abideen Asad Z.U., Karfonta B., Anjum J., Matlock H.G., Cai X., Yu X.

Low-level transcutaneous stimulation of the auricular branch of the vagus nerve at the tragus is antiarrhythmic and anti-inflammatory in animals and humans. Preliminary studies show that transcutaneous vagus nerve stimulation (tVNS) is beneficial in animal models of postural tachycardia syndrome (POTS). In this study the authors conducted a sham-controlled, double-blind, randomized clinical trial to examine the effect of tVNS on POTS over a 2-month period relative to sham stimulation. tVNS (20 Hz, 1 mA below discomfort threshold) was delivered using an ear clip attached to either the tragus (active; n = 12) or the ear lobe (sham; n = 14) for 1 hour daily over a 2-month period. Postural tachycardia was assessed during the baseline and 2-month visit. Heart rate variability based on 5-minute electrocardiogram, serum cytokines, and antiautonomic autoantibodies were measured at the respective time points. Mean age was 34 ± 11 years (100% female; 81% Caucasian). Adherence to daily stimulation was 83% in the active arm and 86% in the sham arm (P > 0.05). Postural tachycardia was significantly less in the active arm compared with the sham arm at 2 months (mean postural increase in heart rate 17.6 ± 9.9 beats/min vs 31.7 ± 14.4 beats/min; P = 0.01). Antiadrenergic autoantibodies and inflammatory cytokines were lower in the active arm compared with the sham arm at 2 months (P < 0.05). Heart rate variability was better in the active arm. No device-related side effects were observed. Our results support the emerging paradigm of noninvasive neuromodulation to treat POTS. Mechanistically, this effect appears to be related to reduction of antiautonomic autoantibodies and inflammatory cytokines, and improvement in autonomic tone. Further studies are warranted. (Autoimmune Basis for Postural Tachycardia Syndrome; NCT05043051).

Savastano S., Baldi E., Compagnoni S., Rordorf R., Sanzo A., Gentile F.R., Dusi V., Frea S., Gravinese C., Cauti F.M., Iannopollo G., De Sensi F., Gandolfi E., Frigerio L., Crea P., et. al.

Abstract Background and Aims An electrical storm (ES) is a clinical emergency with a paucity of established treatment options. Despite initial encouraging reports about the safety and effectiveness of percutaneous stellate ganglion block (PSGB), many questions remained unsettled and evidence from a prospective multicentre study was still lacking. For these purposes, the STAR study was designed. Methods This is a multicentre observational study enrolling patients suffering from an ES refractory to standard treatment from 1 July 2017 to 30 June 2023. The primary outcome was the reduction of treated arrhythmic events by at least 50% comparing the 12 h following PSGB with the 12 h before the procedure. STAR operators were specifically trained to both the anterior anatomical and the lateral ultrasound-guided approach. Results A total of 131 patients from 19 centres were enrolled and underwent 184 PSGBs. Patients were mainly male (83.2%) with a median age of 68 (63.8–69.2) years and a depressed left ventricular ejection fraction (25.0 ± 12.3%). The primary outcome was reached in 92% of patients, and the median reduction of arrhythmic episodes between 12 h before and after PSGB was 100% (interquartile range −100% to −92.3%). Arrhythmic episodes requiring treatment were significantly reduced comparing 12 h before the first PSGB with 12 h after the last procedure [six (3–15.8) vs. 0 (0–1), P &lt; .0001] and comparing 1 h before with 1 h after each procedure [2 (0–6) vs. 0 (0–0), P &lt; .001]. One major complication occurred (0.5%). Conclusions The findings of this large, prospective, multicentre study provide evidence in favour of the effectiveness and safety of PSGB for the treatment of refractory ES.

Thompson N., Ravagli E., Mastitskaya S., Challita R., Hadaya J., Iacoviello F., Shah Idil A., Shearing P.R., Ajijola O.A., Ardell J.L., Shivkumar K., Holder D., Aristovich K.

AbstractCardiac disease progression reflects the dynamic interaction between adversely remodeled neurohumoral control systems and an abnormal cardiac substrate. Vagal nerve stimulation (VNS) is an attractive neuromodulatory option to dampen this dynamic interaction; however, it is limited by off-target effects. Spatially-selective VNS (sVNS) offers a promising solution to induce cardioprotection while mitigating off-target effects by specifically targeting pre-ganglionic parasympathetic efferent cardiac fibers. This approach also has the potential to enhance therapeutic outcomes by eliminating time-consuming titration required for optimal VNS. Recent studies have demonstrated the independent modulation of breathing rate, heart rate, and laryngeal contraction through sVNS. However, the spatial organization of afferent and efferent cardiac-related fibers within the vagus nerve remains unexplored.By using trial-and-error sVNSin vivoin combination withex vivomicro-computed tomography fascicle tracing, we show the significant spatial separation of cardiac afferent and efferent fibers (179±55° SD microCT, p<0.05 and 200±137° SD, p<0.05 sVNS – degrees of separation across a cross-section of nerve) at the mid-cervical level. We also show that cardiac afferent fibers are located in proximity to pulmonary fibers consistent with recent findings of cardiopulmonary convergent neurons and circuits. We demonstrate the ability of sVNS to selectively elicit desired scalable heart rate decrease without stimulating afferent-related reflexes.By elucidating the spatial organization of cardiac-related fibers within the vagus nerve, our findings pave the way for more targeted neuromodulation, thereby reducing off-target effects and eliminating the need for titration. This, in turn, will enhance the precision and efficacy of VNS therapy in treating cardiac pathology, allowing for improved therapeutic efficacy.Condensed AbstractSpatially-selective vagus nerve stimulation (sVNS) presents a promising approach for addressing chronic heart disease with enhanced precision. Our study reveals significant spatial separation between cardiac afferent and efferent fibers in the vagus nerve, particularly at the mid-cervical level. Utilizing trial-and-error sVNS in vivo and micro-computed tomography fascicle tracing, we demonstrate the potential for targeted neuromodulation, achieving therapeutic effects like scalable heart rate decrease without stimulating afferent-related reflexes. This spatial understanding opens avenues for more effective VNS therapy, minimizing off-target effects and eliminating the need for titration, thereby expediting therapeutic outcomes in myocardial infarction and related conditions.TweetWith functional and structural imaging, we found organization of vagal efferent & afferent cardiac regions. We can selectively activate only cardiac efferents to achieve bradycardia; desired to reduce the effects of sympathetic overactivation associated with heart disease #VNS #Cardiac #VagusNerveKey PointsSpatially-selective vagus nerve stimulation (sVNS) presents a promising approach for addressing chronic heart disease with enhanced precision.Our study reveals significant spatial separation between cardiac afferent and efferent fibers in the vagus nerve, particularly at the mid-cervical level.Utilizing trial-and-error sVNS in vivo and micro-computed tomography fascicle tracing, we demonstrate the potential for targeted neuromodulation, achieving therapeutic effects like scalable heart rate decrease without stimulating afferent-related reflexes.This spatial understanding opens avenues for more effective VNS therapy, minimizing off-target effects and eliminating the need for titration, thereby expediting therapeutic outcomes in myocardial infarction and related conditions.

Xu Y., Lu X., Song Z., Lin H., Chen Y.

Aims: Myocardial ischemia-reperfusion (I/R) injury markedly undermines the protective benefits of revascularization, contributing to ventricular dysfunction and mortality. Due to complex mechanisms, no efficient ways exist to prevent cardiomyocyte reperfusion damage. Vagus nerve stimulation (VNS) appears as a potential therapeutic intervention to alleviate myocardial I/R injury. Hence, this meta-analysis intends to elucidate the potential cellular and molecular mechanisms underpinning the beneficial impact of VNS, along with its prospective clinical implications.Methods and Results: A literature search of MEDLINE, PubMed, Embase, and Cochrane Database yielded 10 articles that satisfied the inclusion criteria. VNS was significantly correlated with a reduced infarct size following myocardial I/R injury [Weighed mean difference (WMD): 25.24, 95% confidence interval (CI): 32.24 to 18.23, p &lt; 0.001] when compared to the control group. Despite high heterogeneity (I2 = 95.3%, p &lt; 0.001), sensitivity and subgroup analyses corroborated the robust efficacy of VNS in limiting infarct expansion. Moreover, meta-regression failed to identify significant influences of pre-specified covariates (i.e., stimulation type or site, VNS duration, condition, and species) on the primary estimates. Notably, VNS considerably impeded ventricular remodeling and cardiac dysfunction, as evidenced by improved left ventricular ejection fraction (LVEF) (WMD: 10.12, 95% CI: 4.28; 15.97, p = 0.001) and end-diastolic pressure (EDP) (WMD: 5.79, 95% CI: 9.84; −1.74, p = 0.005) during the reperfusion phase.Conclusion: VNS offers a protective role against myocardial I/R injury and emerges as a promising therapeutic strategy for future clinical application.

Yamaguchi T., Salavatian S., Kuwabara Y., Hellman A., Taylor B.K., Howard-Quijano K., Mahajan A.

Background: A myocardial ischemia/reperfusion (IR) injury activates the transient receptor potential vanilloid 1 (TRPV1) dorsal root ganglion (DRG) neurons. The activation of TRPV1 DRG neurons triggers the spinal dorsal horn and the sympathetic preganglionic neurons in the spinal intermediolateral column, which results in sympathoexcitation. In this study, we hypothesize that the selective epidural administration of resiniferatoxin (RTX) to DRGs may provide cardioprotection against ventricular arrhythmias by inhibiting afferent neurotransmission during IR injury. Methods: Yorkshire pigs (n = 21) were assigned to either the sham, IR, or IR + RTX group. A laminectomy and sternotomy were performed on the anesthetized animals to expose the left T2–T4 spinal dorsal root and the heart for IR intervention, respectively. RTX (50 μg) was administered to the DRGs in the IR + RTX group. The activation recovery interval (ARI) was measured as a surrogate for the action potential duration (APD). Arrhythmia risk was investigated by assessing the dispersion of repolarization (DOR), a marker of arrhythmogenicity, and measuring the arrhythmia score and the number of non-sustained ventricular tachycardias (VTs). TRPV1 and calcitonin gene-related peptide (CGRP) expressions in DRGs and CGRP expression in the spinal cord were assessed using immunohistochemistry. Results: The RTX mitigated IR-induced ARI shortening (−105 ms ± 13 ms in IR vs. −65 ms ± 11 ms in IR + RTX, p = 0.028) and DOR augmentation (7093 ms2 ± 701 ms2 in IR vs. 3788 ms2 ± 1161 ms2 in IR + RTX, p = 0.020). The arrhythmia score and VT episodes during an IR were decreased by RTX (arrhythmia score: 8.01 ± 1.44 in IR vs. 3.70 ± 0.81 in IR + RTX, p = 0.037. number of VT episodes: 12.00 ± 3.29 in IR vs. 0.57 ± 0.3 in IR + RTX, p = 0.002). The CGRP expression in the DRGs and spinal cord was decreased by RTX (DRGs: 6.8% ± 1.3% in IR vs. 0.6% ± 0.2% in IR + RTX, p < 0.001. Spinal cord: 12.0% ± 2.6% in IR vs. 4.5% ± 0.8% in IR + RTX, p = 0.047). Conclusions: The administration of RTX locally to thoracic DRGs reduces ventricular arrhythmia in a porcine model of IR, likely by inhibiting spinal afferent hyperactivity in the cardio–spinal sympathetic pathways.

Baig S.S., Kamarova M., Bell S.M., Ali A.N., Su L., Dimairo M., Dawson J., Redgrave J.N., Majid A.

Ischemic stroke is a leading cause of disability and there is a paucity of therapeutic strategies that promote functional recovery after stroke. Transcutaneous vagus nerve stimulation (tVNS) has shown promising evidence as a tool to reduce infarct size in animal models of hyperacute stroke. In chronic stroke, tVNS paired with limb movements has been shown to enhance neurological recovery. In this review, we summarize the current evidence for tVNS in preclinical models and clinical trials in humans. We highlight the mechanistic pathways involved in the beneficial effects of tVNS. We critically evaluate the current gaps in knowledge and recommend the key areas of research required to translate tVNS into clinical practice in acute and chronic stroke.

Hajjeh O., Rajab I., Bdair M., Saife S., Zahran A., Nazzal I., AbuZahra M.I., Jallad H., Abukhalil M.M., Hallak M., Al-Said O.S., Al-Braik R., Sawaftah Z., Milhem F., Almur O., et. al.

Kruchinova S., Gendugova M., Namitokov A., Sokolskaya M., Gilevich I., Tatarintseva Z., Karibova M., Danilov V., Simakin N., Shvartz E., Kosmacheva E., Shvartz V.

Background: Despite the vast evidence of the beneficial effect of vagus nerve stimulation on the course of myocardial infarction confirmed in studies using animal models, the introduction of this method into actual clinical practice remains uncommon. Objective: The objective of our study was to evaluate the effect of transcutaneous vagus nerve stimulation (tVNS) on in-hospital and long-term outcomes for patients with ST-elevation myocardial infarction. Materials and Methods: A blind, randomized, placebo-controlled clinical trial was conducted. The participants were randomly split into two groups. The Active tVNS group was subjected to stimulation of the tragus containing the auricular branch of the vagus nerve. The Sham tVNS group underwent stimulation of the lobule. Stimulation was performed immediately on admission before the start of the percutaneous coronary intervention (PCI). Then, tVNS continued throughout the entire PCI procedure and 30 min after its completion. The primary endpoints were hospital mortality and 12-month mortality. The secondary endpoints were in-hospital and remote non-lethal cardiovascular events. The combined endpoint consisted of major adverse cardiovascular events (MACEs)—recurrent myocardial infarction, stroke/TIA, and overall mortality. Results: A total of 110 patients were randomized into the Active tVNS group (n = 55) and the Sham tVNS group (n = 55). The incidences of hospital mortality, cardiogenic shock, and AV block 3 were statistically less common in the Active tVNS group than in the Sham tVNS group (p = 0.024*, p = 0.044*, and p = 0.013*, respectively). In the long-term period, no statistical differences were found in the studied outcomes obtained following the construction of Kaplan–Meyer survival curves. When comparing groups by total mortality, taking into account hospital mortality, we observed a tendency for the survival curves to diverge (Logrank test, p = 0.066). Statistical significance was revealed by the composite endpoint, taking into account hospital events (Logrank test, p = 0.0016*). Conclusions: tVNS significantly reduced hospital mortality (p = 0.024*), the level of markers of myocardial damage, and the frequency of severe cardiac arrhythmias in patients with acute myocardial infarction. In the long term, the prognostic value of tVNS was revealed by the composite endpoint major adverse cardiovascular events. Further studies with an expanded sample are needed for a more detailed verification of the data obtained to confirm the effectiveness of tVNS and allow an in-depth analysis of the safety and feasibility of its use in routine clinical practice. This clinical trial is registered with ClinicalTrials database under a unique identifier: NCT05992259.