Search Results (21)

The imbalance in the interaction between the autonomic nervous system and the immune system serves as a central mechanism in the onset and progression of cardiovascular diseases. The excessive activation of the sympathetic nervous system and suppression of vagal function contribute to chronic inflammation and cardiac remodeling. Precision medicine, by integrating multidimensional data such as genomics and metabolomics, offers a novel perspective for the personalized design of exercise interventions. This systematic review explores the bidirectional regulatory mechanisms of exercise interventions on the autonomic nervous system–immune axis and examines the potential applications of precision medicine in optimizing exercise prescriptions and clinical translation. Exercise significantly improves cardiovascular function through immunometabolic reprogramming, which includes suppressing sympathetic overactivity, enhancing vagal tone, and modulating the IL-6/IL-10 balance, as well as activating the short-chain fatty acid (SCFA)–Treg axis. Moreover, precision-medicine-driven ACE I/D gene typing provides a basis for selecting tailored exercise prescriptions, thereby significantly enhancing the efficacy of exercise interventions. By leveraging a multi-tiered “neuro–immune–metabolic” regulatory framework, exercise interventions contribute to improved cardiovascular health. The application of precision medicine technology overcomes individual variability constraints, advancing exercise prescription design from generalized recommendations toward personalized and dynamically adaptive strategies. Full article

Diabetes mellitus, especially type 2 diabetes mellitus (T2DM), is a major health problem worldwide and has become a leading cause of mortality. As a common complication of patients with T2DM, cardiac autonomic dysfunction (including sympathetic overactivation and reduced vagal tone) is associated with a higher risk of arrhythmia-related sudden cardiac death. Our previous study found that T2DM-elevated hydrogen peroxide (H₂O₂) levels in atrioventricular ganglion (AVG) neurons contribute to the decrease in cardiac vagal function and ventricular arrhythmogenesis through inhibition of N-type Ca²⁺ channels (Ca_v2.2). In the present study, treatment with exogenous H₂O₂ in differentiated NG108-15 cells increased REST expression and decreased Ca_v2.2-α expression. Adenoviral catalase gene transfection into the AVG neurons significantly reduced the REST levels elevated by a high-fat diet plus streptozotocin-induced T2DM. Lentiviral REST shRNA transfection markedly increased Ca_v2.2-α expression in the AVG neurons from T2DM rats. REST shRNA also activated N-type Ca²⁺ channels and increased cell excitability of AVG neurons in T2DM rats. Additionally, REST shRNA markedly improved cardiac vagal activation in T2DM rats. The present study suggests that the H₂O₂-REST-Ca_v2.2 channel signaling axis could be a potential therapeutic target to normalize cardiac vagal dysfunction and its related cardiac complications in T2DM. Full article

This paper presents a study undertaken to evaluate the sensor systems that were shortlisted to be used in the development of a portable respiratory-gated transcutaneous auricular vagus nerve stimulation (taVNS) system. To date, all published studies assessing respiratory-gated taVNS have been performed in controlled laboratory environments. This limitation arises from the reliance on non-portable sensing equipment, which poses significant logistical challenges. Therefore, we recognised a need to develop a portable sensor system for future research, enabling participants to perform respiratory-gated stimulation conveniently from their homes. This study aimed to measure the accuracy of an in-ear and a fingertip-based photoplethysmography (PPG) sensor in measuring cardiac vagal tone relevant heart rate variability (HRV) parameters of root mean square of successive R-R interval differences (RMSSDs) and the high-frequency (HF) component of HRV. Thirty healthy participants wore the prototype sensor equipment and the gold standard electrocardiogram (ECG) equipment to record beat-to-beat intervals simultaneously during 10 min of normal breathing and 10 min of deep slow breathing (DSB). Additionally, a stretch sensor was evaluated to measure its accuracy in detecting exhalation when compared to the gold standard sensor. We used Bland–Altman analysis to establish the agreement between the prototypes and the ECG system. Intraclass correlation coefficients (ICCs) were calculated to establish consistency between the prototypes and the ECG system. For the stretch sensor, the true positive rate (TPR), false positive rate (FPR), and false negative rate (FNR) were calculated. Results indicate that while ICC values were generally good to excellent, only the fingertip-based sensor had an acceptable level of agreement in measuring RMSSDs during both breathing phases. Only the fingertip-based sensor had an acceptable level of agreement during normal breathing in measuring HF-HRV. The study highlights that a high correlation between sensors does not necessarily translate into a high level of agreement. In the case of the stretch sensor, it had an acceptable level of accuracy with a mean TPR of 85% during normal breathing and 95% during DSB. The results show that the fingertip-based sensor and the stretch sensor had acceptable levels of accuracy for use in the development of the respiratory-gated taVNS system. Full article

Although the benefits of exercise training have been shown repeatedly in many studies, its relationship with the occurrence of atrial fibrillation (AF) in competitive athletes still remains controversial. In the present review, we sought to demonstrate a comprehensive report of the incidence, pathophysiology, and therapeutic approaches to AF in elite athletes. A 2 to 10 times higher frequency of AF has been shown in many studies in high-intensity endurance athletes compared to individuals who do not exercise. Moreover, a U-shaped relationship between male elite athletes and AF is demonstrated through this finding, while the type and the years of physical activity seem to relate to AF development. A strong correlation seems to exist among the type of exercise (endurance sports), age (>55 years), gender (males), and the time of exercise training, all contributing to an increased risk of AF. The pathophysiology of AF still remains unclear; however, several theories suggest that complex mechanisms are involved, such as bi-atrial dilatation, pulmonary vein stretching, cardiac inflammation, fibrosis, and increased vagal tone. Elite athletes with AF require a comprehensive clinical evaluation and risk factor optimization, similar to the approach taken for nonathletes. Although anticoagulation and rate or rhythm control are cornerstones of AF management, there are still no specific guidelines for elite athletes. Full article

Patients with cirrhosis often exhibit cardiac autonomic dysfunction (CAD), characterized by enhanced cardiac sympathetic activity and diminished cardiac vagal tone, leading to increased morbidity and mortality. This study delineates the cellular and molecular mechanisms associated with altered neuronal activities causing cirrhosis-induced CAD. Biliary and nonbiliary cirrhotic rats were produced by common bile duct ligation (CBDL) and intraperitoneal injections of thioacetamide (TAA), respectively. Three weeks after CBDL or TAA injection, the assessment of heart rate variability revealed autonomic imbalance in cirrhotic rats. We observed increased excitability in stellate ganglion (SG) neurons and decreased excitability in intracardiac ganglion (ICG) neurons in cirrhotic rats compared to sham-operated controls. Additionally, threshold, rheobase, and action potential duration exhibited opposite alterations in SG and ICG neurons, along with changes in afterhyperpolarization duration. A- and M-type K⁺ channels were significantly downregulated in SG neurons, while M-type K⁺ channels were upregulated, with downregulation of the N- and L-type Ca²⁺ channels in the ICG neurons of cirrhotic rats, both in transcript expression and functional activity. Collectively, these findings suggest that cirrhosis induces an imbalance between cardiac sympathetic and parasympathetic neuronal activities via the differential regulation of K⁺ and Ca²⁺ channels. Thus, cirrhosis-induced CAD may be associated with impaired autonomic efferent functions within the homeostatic reflex arc that regulates cardiac functions. Full article

Patients with major depressive disorder (MDD) have an increased risk for cardiac events. This is partly attributed to a disbalance of the autonomic nervous system (ANS) indicated by a reduced vagal tone and a (relative) sympathetic hyperactivity. However, in most studies, heart rate variability (HRV) was only examined while resting. So far, it remains unclear whether the dysbalance of the ANS in patients with MDD is restricted to resting or whether it is also evident during sympathetic and parasympathetic activation. The aim of this study was to compare the responses of the ANS to challenges that stimulated the sympathetic and, respectively, the parasympathetic nervous systems in patients with MDD. Forty-six patients with MDD (female 27 (58.7%), mean age 44 ± 17 years) and 46 healthy controls (female 26 (56.5%), mean age 44 ± 20 years) underwent measurement of time- and frequency-dependent domains of HRV at rest, while standing (sympathetic challenge), and during slow-paced breathing (SPB, vagal, i.e., parasympathetic challenge). Patients with MDD showed a higher heart rate, a reduced HRV, and a diminished vagal tone during resting, standing, and SPB compared to controls. Patients with MDD and controls responded similarly to sympathetic and vagal activation. However, the extent of modulation of the ANS was impaired in patients with MDD, who showed a reduced decrease in the vagal tone but also a reduced increase in sympathetic activity when switching from resting to standing. Assessing changes in the ANS during sympathetic and vagal activation via respective challenges might serve as a future biomarker and help to allocate patients with MDD to therapies like HRV biofeedback and psychotherapy that were recently found to modulate the vagal tone. Full article

These days, in vitro functional analysis of gene variants is becoming increasingly important for risk stratification of cardiac ion channelopathies. So far, such risk stratification has been applied to SCN5A, KCNQ1, and KCNH2 gene variants associated with Brugada syndrome and long QT syndrome types 1 and 2, respectively, but risk stratification of HCN4 gene variants related to sick sinus syndrome has not yet been performed. HCN4 is the gene responsible for the hyperpolarization-activated ‘funny’ current I_f, which is an important modulator of the spontaneous diastolic depolarization underlying the sinus node pacemaker activity. In the present study, we carried out a risk classification assay on those loss-of-function mutations in HCN4 for which in vivo as well as in vitro data have been published. We used the in vitro data to compute the charge carried by I_f (Q_f) during the diastolic depolarization phase of a prerecorded human sinus node action potential waveform and assessed the extent to which this Q_f predicts (1) the beating rate of the comprehensive Fabbri–Severi model of a human sinus node cell with mutation-induced changes in I_f and (2) the heart rate observed in patients carrying the associated mutation in HCN4. The beating rate of the model cell showed a very strong correlation with Q_f from the simulated action potential clamp experiments (R² = 0.95 under vagal tone). The clinically observed minimum or resting heart rates showed a strong correlation with Q_f (R² = 0.73 and R² = 0.71, respectively). While a translational perspective remains to be seen, we conclude that action potential clamp on transfected cells, without the need for further voltage clamp experiments and data analysis to determine individual biophysical parameters of I_f, is a promising tool for risk stratification of sinus bradycardia due to loss-of-function mutations in HCN4. In combination with an I_f blocker, this tool may also prove useful when applied to human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) obtained from mutation carriers and non-carriers. Full article

The nuance of autonomic cardiac control has been studied for more than 400 years, yet little is understood. This review aimed to provide a comprehensive overview of the current understanding, clinical implications, and ongoing studies of cardiac sympathetic modulation and its anti-ventricular arrhythmias’ therapeutic potential. Molecular-level studies and clinical studies were reviewed to elucidate the gaps in knowledge and the possible future directions for these strategies to be translated into the clinical setting. Imbalanced sympathoexcitation and parasympathetic withdrawal destabilize cardiac electrophysiology and confer the development of ventricular arrhythmias. Therefore, the current strategy for rebalancing the autonomic system includes attenuating sympathoexcitation and increasing vagal tone. Multilevel targets of the cardiac neuraxis exist, and some have emerged as promising antiarrhythmic strategies. These interventions include pharmacological blockade, permanent cardiac sympathetic denervation, temporal cardiac sympathetic denervation, etc. The gold standard approach, however, has not been known. Although neuromodulatory strategies have been shown to be highly effective in several acute animal studies with very promising results, the individual and interspecies variation between human autonomic systems limits the progress in this young field. There is, however, still much room to refine the current neuromodulation therapy to meet the unmet need for life-threatening ventricular arrhythmias. Full article

Second-degree atrioventricular (AV) block is the most common cardiac arrhythmia in horses, affecting 40–90% depending on breed. Usually, the AV blocks occur while the horses are resting and disappear upon exercise and are, therefore, considered to be uneventful for horses. However, if the AV blocks occur frequently, this may result in syncope and collapse. Identifying the cause of second-degree AV block is difficult and often subscribed to high vagal tone. In this report, we present an eight-year-old Quarter horse with a high burden of second-degree AV blocks and multiple collapses. The clinical examination, including neurological examination, blood analysis, 24-h ECG recording and cardiac echocardiography, did not reveal any signs of general or cardiovascular disease besides a high burden of second-degree AV blocks (~300 blocks per hour) and a hyperechoic area in the AV nodal region. An implantable loop recorder (ILR) was inserted to monitor the cardiac rhythm. The ILR detected several consecutive second-degree AV blocks and pauses above 5 s. However, unfortunately, no recordings were available during the collapses. Eventually, the horse was euthanized and the heart inspected. The aortic root was severely cartilaginous and appeared to penetrate the AV node, especially in the His bundle region, possibly explaining the hampered AV conduction. Nevertheless, it is still uncertain if the AV nodal disruption caused the collapses and more knowledge on AV nodal diseases in horses is warranted. Full article

It is proven that music listening can have a therapeutic impact in many clinical fields. However, to assume a curative value, musical stimuli should have a therapeutic logic. This study aimed at assessing short-term effects of algorithmic music on cardiac autonomic nervous system activity. Twenty-two healthy subjects underwent a crossover study including random listening to relaxing and activating algorithmic music. Electrocardiogram (ECG) and non-invasive arterial blood pressure were continuously recorded and were later analyzed to measure Heart Rate (HR) mean, HR variability and baroreflex sensitivity (BRS). Statistical analysis was performed using a general linear model, testing for carryover, period and treatment effects. Relaxing tracks decreased HR and increased root mean square of successive squared differences of normal-to-normal (NN) intervals, proportion of interval differences of successive NN intervals greater than 50 ms, low-frequency (LF) and high-frequency (HF) power and BRS. Activating tracks caused almost no change or an opposite effect in the same variables. The difference between the effects of the two stimuli was statistically significant in all these variables. No difference was found in the standard deviation of normal-to-normal RR intervals, LF_power in normalized units and LF_power/HF_power variables. The study suggests that algorithmic relaxing music increases cardiac vagal modulation and tone. These results open interesting perspectives in various clinical areas. Full article

Introduction: The aim of the study was to assess cardiac and autonomic function in patients with myasthenia gravis (MG) and to explore its relationship with disease outcomes. Methods: Thirty-eight patients with an MG were enrolled (median age 40.5 years; median disease duration 5.5 years). Cardiovascular parameters, baroreflex sensitivity (BRS), spectral indices of short-term heart rate (HRV), and systolic blood pressure variability (SBPV) were compared with age- and gender-matched controls (n = 30). Cardiac autonomic function was assessed during the response to standing (tilt) and deep breathing tests (expiration/inspiration ratio-E/I). Results: HR and BP responses to the tilt test were similar in both groups. MG patients, as compared to controls, were characterized by altered SBPV at rest, significantly reduced HR response to the deep breathing test (p < 0.001), increased sympathovagal balance after tilt (delta LF/HF-RRI, p = 0.037), and lower values of BRS (p = 0.007) and hemodynamic parameters, i.e., cardiac index, index contractility, left ventricular work index, at rest and during tilt. There was no association between disease duration and autonomic parameters. Disease severity, as determined by MGFA (Myasthenia Gravis Foundation of America) corrected for age and sex, was an independent predictor of diminished vagal tone (E/I ratio) and increased sympathetic response to tilt (delta LF/HF-RRI) as measured with HRV. Lower BRS was associated with greater disease severity and older age. Hemodynamic parameters were predominantly predicted by age and sex. Conclusion: Our results confirm cardiac autonomic dysfunction among MG patients with predominant parasympathetic impairment. Clinicians should consider evaluation of autonomic balance in MG patients with, or at risk for, cardiovascular disease. Full article

This study examines the associations between physical and emotional well-being and classroom climate, cardiac vagal response, and body mass index (BMI) in a sample of 6- to-8-year-olds. Specifically, we expected a direct link between classroom climate, vagal withdrawal, BMI and children’s physical and emotional comfort. Furthermore, we explored whether these individual and environmental characteristics influenced well-being in an interactive fashion. Participants were 142 (63 boys, 44%) first and second graders living in the North of Italy who were interviewed on their emotional and physical comfort. Heart rate and a measure of vagal influence on the heart (cardiac vagal tone) were recorded at rest and during an oral academic test. Height and weight were collected. Classroom climate was positively linked with physical well-being, whereas emotional well-being was negatively related with BMI. In addition, an inverted U-shaped effect of cardiac vagal withdrawal (i.e., cardiac vagal tone during stress minus resting vagal tone) on emotional well-being was found. Two regression models highlighted the role played by BMI when interacting with vagal withdrawal in predicting children’s physical and emotional well-being. The interplay between BMI and cardiac vagal withdrawal played an important role in primary school children’s well-being. From a clinical perspective, preventive training to improve autonomic regulation in concert with interventions promoting healthy eating attitudes might be critical for supporting primary school children’s emotional and physical health. Full article

(1) Polymyalgia rheumatica (PMR) is an inflammatory disease characterised by pain, morning stiffness, and reduced quality of life. Recently, vagus nerve stimulation (VNS) was shown to have anti-inflammatory effects. We aimed to examine the effect of transcutaneous VNS (t-VNS) on PMR. (2) Fifteen treatment-naïve PMR patients completed the study. Patients underwent a 5-day protocol, receiving 2 min of t-VNS stimulation bilaterally on the neck, three times daily. Cardiac vagal tone (CVT) measured on a linear vagal scale (LVS), blood pressure, heart rate, patient-reported outcome, and biochemical changes were assessed. (3) t-VNS induced a 22% increase in CVT at 20 min after initial stimulations compared with baseline (3.4 ± 2.2 LVS vs. 4.1 ± 2.9 LVS, p = 0.02) and was accompanied by a 4 BPM reduction in heart rate (73 ± 11 BPM vs. 69 ± 9, p < 0.01). No long-term effects were observed. Furthermore, t-VNS induced a 14% reduction in the VAS score for the hips at day 5 compared with the baseline (5.1 ± 2.8 vs. 4.4 ± 2.8, p = 0.04). No changes in CRP or proinflammatory analytes were observed. (4) t-VNS modulates the autonomic nervous system in patients with PMR, but further investigation of t-VNS in PMR patients is warranted. Full article

The renin–angiotensin–aldosterone system (RAAS) impacts cardiovascular homeostasis via direct actions on peripheral blood vessels and via modulation of the autonomic nervous system. To date, research has primarily focused on the actions of the RAAS on the sympathetic nervous system. Here, we review the critical role of the RAAS on parasympathetic nerve function during normal physiology and its role in cardiovascular disease, focusing on hypertension. Angiotensin (Ang) II receptors are present throughout the parasympathetic nerves and can modulate vagal activity via actions at the level of the nerve endings as well as via the circumventricular organs and as a neuromodulator acting within brain regions. There is tonic inhibition of cardiac vagal tone by endogenous Ang II. We review the actions of Ang II via peripheral nerve endings as well as via central actions on brain regions. We review the evidence that Ang II modulates arterial baroreflex function and examine the pathways via which Ang II can modulate baroreflex control of cardiac vagal drive. Although there is evidence that Ang II can modulate parasympathetic activity and has the potential to contribute to impaired baseline levels and impaired baroreflex control during hypertension, the exact central regions where Ang II acts need further investigation. The beneficial actions of angiotensin receptor blockers in hypertension may be mediated in part via actions on the parasympathetic nervous system. We highlight important unknown questions about the interaction between the RAAS and the parasympathetic nervous system and conclude that this remains an important area where future research is needed. Full article

Among the types of blood cancers, non-Hodgkin lymphoma is the most common. The usual treatments for this type of cancer can cause heart failure. A descriptive observational study was conducted that included 16 non-Hodgkin lymphoma survivors and 16 healthy controls matched by age and sex. Vagal tone was evaluated in the short term with a three-channel Holter device, and the time and frequency domains were analyzed following a previously accepted methodology to evaluate cardiac autonomic balance. The results of the analysis revealed that the standard deviation of the NN interval (F = 6.25, p = 0.021) and the square root of the mean of the sum of the differences between NN intervals (F = 9.74, p = 0.004) were significantly higher in healthy subjects than in lymphoma survivors. In the heart rate variability (HRV) index, there were no significant differences between the groups (F = 0.03, p = 0.85), nor in the parameters of the frequency domains LF (F = 1.94, p = 0.17), HF (F = 0.35, p = 0.55), and the ratio LF/HF (F = 3.07, p = 0.09). HRV values were lower in non-Hodgkin lymphoma survivors in the first year after treatment, resulting in autonomic imbalance compared to healthy paired subjects. Full article