Search Results (455)

Background/Objectives: Aortic stenosis is associated with autonomic nervous system (ANS) imbalance, while diabetes mellitus is a major contributor to cardiac autonomic neuropathy. Their coexistence may result in more pronounced autonomic dysfunction not fully captured by conventional assessment. This study aimed to compare ANS function in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement (TAVR), according to diabetes status. Methods: This cross-sectional study included 74 patients with severe aortic stenosis referred for TAVR, including 21 patients with diabetes mellitus. Autonomic function was evaluated using non-invasive ECG-based analysis, incorporating short-term and 24 h Holter-derived heart rate variability (HRV), nonlinear Poincaré plot indices, and deceleration and acceleration capacity. Ambulatory blood pressure monitoring and standard clinical and echocardiographic assessment were performed. Results: Patients with diabetes mellitus demonstrated significantly lower long-term HRV parameters and reduced nonlinear Poincaré plot indices compared with non-diabetic patients, indicating altered autonomic modulation. Short-term HRV showed similar trends without statistical significance. Echocardiographic severity of aortic stenosis and left ventricular systolic function were comparable between groups. Conclusions: Autonomic dysfunction appears to be more pronounced in patients with severe aortic stenosis and diabetes mellitus, predominantly affecting parasympathetic modulation. ECG-derived autonomic parameters may offer complementary insight into ANS involvement in this population and warrant further investigation. Full article

Background: In patients with severe atherosclerotic internal carotid artery stenosis (ICAS), the capacity of cerebral vasoreactivity (CVR)—an independent risk factor for cerebral ischemia—is reduced, and dysregulation of arterial blood pressure (ABP) may also be present. Thus, this study assessed the relationship between changes in cerebral blood flow velocity (BFV) in response to vasoactive stimuli (as measured by transcranial Doppler (TCD)), characterizing CVR and cardiovascular autonomic nervous system (CANS) function. Methods: Common carotid artery compression (CCC n = 26), hyperventilation (HV) and breath-holding (BH) tests (n = 31), and the Valsalva maneuver (VM n = 34) were used to assess CVR in patients with ICAS. In the middle cerebral arteries, BFV was monitored by TCD, whereas ABP was registered non-invasively. For statistical analysis, validated indices describing CANS function—namely, sympathetic index (SI), pressure recovery time (PRT), and Valsalva heart rate ratio (VHRR)—were selected based on the VM response. Several parameters were defined in order to evaluate CVR responses, including cerebral arterial resistance (CAR = ABP/BFV), which was correlated with the CVR indices using Spearman’s pairwise correlation and canonical correlation. Results: A significant correlation was found between several CVR indices of the HV-BH and VM tests and CANS indices of VM using Spearman’s pairwise correlation test. Regarding the HV-BH CVR and CANS indices of VM, a significant correlation was found between CAR values until it reached its maximum on the to-be-operated side (CAR_{timetomaxICAop}) and VHRR (p = 0.041). A significant correlation was also found between the time elapsed until the CAR minimum value (CAR_{timetominICAop}) and SI (p = 0.019). Concerning the CVR and CANS indices of the VM, a significant correlation was found between cerebrovascular Valsalva ratio on the to-be-operated side (CVAR_ICAop) and PRT (p = 0.002). Canonical correlation analysis confirmed that impairments of CANS and CVR may be associated. Conclusions: In patients with severe ICAS, the potentially concomitant dysregulation of cerebrovascular reactivity and the cardiovascular autonomic nervous system can further increase cerebral ischemic risk. Full article

Pregnanolone glutamate (PG) is a synthetic neurosteroid analog showing promise for treating ischemic brain injury, yet its blood–brain barrier (BBB) transport and metabolic fate remain unclear. We investigated the pharmacokinetics of PG in postnatal day 12 rats of both sexes subjected to endothelin-1 (ET-1)-induced focal hippocampal ischemia. Animals received PG (1 mg/kg intraperitoneal (i.p.)) or vehicle; serum and hippocampal steroidomes were profiled 60 min post-administration using gas chromatography-tandem mass spectrometry (GC-MS/MS) (hippocampus: n = 16 PG+, n = 27 PG−; multi-tissue subset: n = 6 PG+, n = 21 PG−). Our data revealed a “dual-fate” mechanism: PG undergoes systemic hydrolysis as a prodrug, as suggested by the tissue distribution pattern at 60 min post-administration, but also crosses the BBB intact, with significant parent conjugate accumulation in the hippocampus (42.3 pmol/g). The brain functioned as a “metabolic sink”, passively accumulating metabolites generated in peripheral organs—such as 17-hydroxypregnanolone—despite local absence of synthesizing enzymes (e.g., CYP17A1). Crucially, PG induced “metabolic segregation” within the central nervous system (CNS): the pharmacological 5β-pathway was saturated (~170-fold pregnanolone increase), while endogenous neuroprotective 5α-pathway (allopregnanolone) homeostasis remained preserved, contrasting with peripheral metabolic saturation. Preferential hippocampal accumulation of 3-oxo and 3β-isomers suggests autonomous regulatory buffering via oxidative 17β-hydroxysteroid dehydrogenase (HSD17B) enzymes, protecting against excessive GABAergic inhibition. This unique pharmacokinetic profile—combining metabolic segregation with active central buffering—defines PG as a dual-mechanism delivery system that generates central neuroactive metabolites—several with previously established GABAergic and neuroprotective activity—without disrupting endogenous neurosteroidogenesis, positioning it as a promising neurotherapeutic candidate minimizing physiological steroid homeostasis disruption. Importantly, the present study characterizes the pharmacokinetic and metabolic fate of PG; the neuroprotective efficacy of PG was demonstrated in our prior functional studies using the same model. Full article

Coronary artery spasm (CAS) is a common endotype in patients with angina with non-obstructive coronary arteries. Pathophysiologically, the presence of CAS among arteries is not normal, as evidenced by several interacting mechanisms involving CAS development, including the endothelium, vascular smooth muscle cells, adventitia, autonomic nervous system, local inflammation, and systemic inflammation. Clinically, CAS is a dynamic process with a threshold effect on presentation; it can present as silent ischemia, atypical chest pain, resting angina, chronic coronary syndrome, acute coronary syndrome, variant angina, and even sudden cardiac arrest. Incomplete intracoronary provocation testing to exclude CAS as the etiology of chronic or acute coronary syndrome leads to an incorrect diagnosis and, subsequently, inappropriate treatment. Identification of the correct endotypes of chronic and acute coronary syndromes is critical for the selection of appropriate therapy, which thus affects disease outcome. Therefore, it is essential to complete intracoronary provocation testing for both the right and left coronary arteries to reach a correct diagnosis regarding CAS, including epicardial vasospasm and microvascular spasm. If CAS is found not to be the cause of myocardial ischemia, then a microvascular functional assessment is the next step to identify the etiology of the ischemic event. A comprehensive assessment of CAS is essential before appropriate treatments can be started. Full article

Background: Chronic work-related stress, including exposure to mobbing, is associated with a wide range of psychological and somatic consequences. However, its potential impact on visual function, particularly in the absence of structural ocular damage, remains underexplored. This narrative review critically examines the evidence linking chronic stress, autonomic nervous system (ANS) dysregulation, and functional visual disorders, focusing on accommodative function and asthenopia. Methods: A qualitative narrative review of the literature published between 2000 and 2025 was conducted using major biomedical databases. Studies addressing chronic stress, ANS activity, accommodative function, digital eye strain, and functional ocular symptoms were identified and integrated into a coherent pathophysiological framework. Results: The ocular system, being richly innervated by the ANS, may represent a peripheral target of prolonged stress-related autonomic alterations. Available evidence suggests that chronic stress is associated with asthenopia, accommodative inefficiency, and ocular discomfort even in the absence of overt ocular pathology. In particular, altered parasympathetic control of the ciliary muscle emerges as a plausible mediating mechanism. Conclusions: Functional visual disorders may represent peripheral manifestations of stress-related ANS dysregulation. Although causality cannot be established conclusively, the proposed framework supports the need for multidisciplinary research to clarify the clinical and medico-legal relevance of stress-related visual dysfunction. Full article

Background/Objectives: Pulmonary embolism (PE) remains a significant cause of cardiovascular mortality, with risk stratification being critical for optimizing treatment decisions. Heart rate variability (HRV), a measure of autonomic nervous system function, had been explored as a prognostic index in various cardiovascular conditions, yet has received limited investigation regarding PE prognosis. Our objective was to evaluate the prognostic value of ultra-short HRV indices, obtained at the emergency department (ED), in patients presenting with PE. Methods: A retrospective cohort study, conducted at Rambam Health Care Campus, Haifa, Israel. All eligible patients diagnosed with acute PE at the ED, between the years 2010 and 2012 were included. Further, a subgroup analysis was performed to differentiate between oncological (n = 118) and non-oncological (n = 115) patient populations. Ten-seconds electrocardiogram was used to compute ultra-short HRV indices, specifically SDNN (standard deviation of normal-to-normal RR intervals) and RMSSD (root mean square of successive differences). Multivariate logistic regression models were created to assess HRV’s independent predictive value for 30-day and 90-day mortality. In addition, a survival analysis was carried out utilizing Cox regression and Kaplan-Meier curves. Results: 233 patients (42% male; age 65 ± 17) were included in the analysis. Ultra-short HRV indices did not significantly correlate with short-term mortality. However, in non-oncological patients (n = 115), multivariate analysis demonstrated that higher SDNN (as a continuous variable), was independently associated with increased 90-day mortality (AOR 1.018, 95% CI 1.000–1.037; p = 0.044). In contrast, HRV showed no predictive value for mortality in oncological patients. In both the entire cohort and the non-oncological sub-group, Kaplan-Meier plots established statistically significant differences, with lower HRV indices correlating with worse survival. This finding is paradoxical. The issue of context-dependent HRV (i.e., based on ECG obtained during rapid shallow breathing, which reduces HRV on the one hand, but is possibly adaptive during an acute PE, to increase oxygen supply and prevent shock in the short run, on the other hand), may explain these findings. Conclusions: Ultra-short HRV shows some promise in short term risk stratification of non-oncological PE patients. As for oncological patients, HRV was not found to have short term prognostic relevance. Full article

Background/Objectives: Wearable devices capable of capturing heart rate variability (HRV) enable continuous assessment of autonomic nervous system function in real-world settings. Because systemic inflammation disrupts autonomic balance through vagal withdrawal and sympathetic activation, HRV has been proposed as a non-invasive digital biomarker of inflammatory activity. Despite the rapid expansion of wearable sensor technologies, the accuracy and consistency for detecting systemic inflammatory states remain unclear. This systematic review aimed to evaluate the clinical relevance of wearable-derived HRV indices in relation to established inflammatory biomarkers. Methods: A systematic search of PubMed, Scopus, Web of Science, and the Cochrane Library was conducted through April 2025. Due to methodological heterogeneity, findings were synthesized using the Synthesis Without Meta-analysis (SWiM) framework with vote counting, effect-direction plots, and sign tests. Results: Eleven studies involving 2419 participants met the inclusion criteria. Vote counting demonstrated that SDNN showed a predominantly inverse association with CRP, with 83% of comparisons indicating reduced SDNN in the presence of elevated CRP (sign test p = 0.031). In contrast, associations between RMSSD and inflammatory cytokines were heterogeneous and largely non-significant. ECG-based wearable devices yielded more consistent associations than photoplethysmography-based devices, while recording duration and population characteristics contributed to variability across studies. Conclusions: Wearable-derived HRV, particularly SDNN from ECG-based devices, shows a consistent inverse association with CRP, supporting its role as a non-invasive physiological correlate of systemic inflammation. However, heterogeneity and the lack of diagnostic accuracy metrics limit conclusions regarding clinical utility. At present, wearable HRV should be considered an exploratory or adjunctive biomarker, pending validation in standardized longitudinal studies with formal diagnostic performance assessment. Full article

Post-stroke rehabilitation integrates technological feedback systems to enhance motor relearning and autonomic regulation. Among these, physiological biofeedback—based on electromyography (EMG), heart rate variability (HRV) and electrocardiography (ECG)—represents a multimodal approach for restoring neuromotor control and autonomic balance. EMG biofeedback enables patients to visualize and voluntarily modulate muscle activation, supporting cortical reorganization and improving movement precision through real-time feedback. Recent meta-analyses confirm that EMG biofeedback significantly improves upper- and lower-limb function in stroke survivors, particularly when combined with task-oriented physiotherapy. EMG biofeedback demonstrates improvements in swallowing function, motor control, and patient motivation. Beyond the motor domain, HRV biofeedback has shown substantial benefits lately, especially in regulating the autonomic nervous system (ANS) activity, improving vagal tone, and reducing sympathetic overdrive: a major contributor to fatigue and cardiovascular instability post-stroke. By targeting the sympathetic–parasympathetic balance, HRV biofeedback not only enhances autonomic flexibility but also supports emotional and cognitive recovery. Together, these modalities integrate neuromuscular and autonomic rehabilitation, offering a path toward individualized, feedback-driven recovery protocols. This narrative review synthesizes recent evidence on the mechanisms, the clinical outcomes, and translational potential of EMG- and HRV-based biofeedback in stroke rehabilitation, highlighting their role in advancing physiotherapy toward an adaptive, data-driven, and neuroplastic paradigm, as from now on, the emerging directions will include integrating physiological biofeedback with immersive or AI-driven platforms for enhanced personalization and motivation. Full article

The heart’s performance relies on its contractile and rhythmic properties, which are modulated not only by extrinsic autonomic inputs but also by the intrinsic cardiac nervous system (ICNS), a distributed network of intracardiac ganglia and neurons that integrates local sensory, autonomic, and inflammatory signals. Growing evidence indicates that cardiac fibrosis and neuronal remodeling are intertwined processes within this network. This review synthesizes current knowledge on molecular, structural, and functional remodeling of the ICNS to drive neurofibrosis, autonomic imbalance, and arrhythmogenesis. We outline ICNS anatomy and neurochemical diversity, then summarize core fibrotic mechanisms, fibroblast activation, extracellular matrix dynamics, and inflammatory signaling, and map these onto intracardiac ganglia. Across diabetes, myocardial infarction, heart failure, and neuroinflammatory states, shared pathways (e.g., IL-6/STAT3, TGF-β/SMAD, PI3K/AKT, MAPK/ERK, oxidative stress) suppress neuronal excitability, promote neuron–glia–fibroblast coupling, and culminate in neurofibrotic remodeling. We integrate functional data linking these changes to autonomic dysregulation and arrhythmia vulnerability. Future priorities involve constructing detailed human ICNS atlases and applying single-cell and spatial multi-omics to better characterize intracardiac neurons, their circuitry, and their interactions with fibroblasts and immune cells. These insights will be essential to inform targeted neuromodulation and anti-fibrotic interventions. The ICNS is a dynamic regulatory hub whose cells and circuits participate directly in cardiac fibrosis and electrical instability. Recognizing neurofibrosis as a companion process to myocardial fibrosis reframes therapeutic strategy toward preserving both neural and myocardial integrity. Full article

Background and Objectives: The aim of this study is to objectively evaluate the effects of a six-week intermittent hypoxic–hyperoxic exposure program on blood pressure, respiratory function, cardiac autonomic nervous activity and C Reactive Protein levels in older adults. Materials and Methods: A double-blinded randomized controlled clinical trial was conducted on twenty-two older adults. Heart rate variability, respiratory function, blood pressure, C Reactive Protein levels and oxygen saturation were measured at two time points: baseline and after 6 weeks of treatment. Results: The maximal inspiratory pressure variable increased significantly in the EG (+7.50 ± 1.72 cmH2O, p < 0.01, ES = 1.17), while no changes were observed in the CG. The LF/HF variable decreased significantly in the EG (−1.23 ± 0.34 n.u, p < 0.01, ES = 1.11), with no significant changes in the CG. The C Reactive Protein variable decreased significantly in the EG (−7.00 ± 3.07 mg/L, p < 0.01, ES = 1.4), with no significant changes in the CG. Conclusions: Six weeks of intermittent hypoxic–hyperoxic exposure was associated with trends toward improvements in blood pressure, respiratory function, cardiac autonomic nervous activity, and C Reactive Protein levels, compared with a placebo application of the same therapy. Full article

Plasticity is fundamental to the development, strengthening, and maintenance of healthy synaptic connections and recovery from injury in both the central and peripheral nervous systems. Yet, the processes involved are poorly understood. Herein, using a combination of patch-clamp electrophysiology and immuno-fluorescence confocal microscopy in adult mice, it is shown that blockade of synaptic transmission at submandibular ganglion junctions exposed to botulinum neurotoxin type A was accompanied by a rapid and striking decline in the abundance of synaptic vesicle markers—SV2, vesicle-associated membrane protein 2, and vesicular acetylcholine transporter—plus SNAP-25 (cleaved and intact) and postsynaptic α7 nicotinic acetylcholine receptors. Such alterations by the neurotoxin of parasympathetic synapses contrast starkly with the stability of postsynaptic proteins at nearby skeletal neuromuscular junctions. Both neurotransmission and the expression of SV2 and α7 nicotinic acetylcholine receptors remained depressed for 4 weeks, with full recovery of synaptic function delayed for more than 8 weeks. These novel findings may explain the relatively slow recovery of autonomic function after botulism or following therapeutic injections to alleviate hypersecretory disorders. Full article

Hereditary polyneuropathies represent a genetically and clinically heterogeneous group of disorders affecting the peripheral nervous system, characterized by progressive motor, sensory, and autonomic impairment. Advances in molecular genetics have identified key causative genes, including PMP22, MPZ, MFN2, TTR, EGR2, and CX32 (GJB1), which are implicated in Charcot–Marie–Tooth disease, Dejerine–Sottas syndrome, and related neuropathies. These conditions display substantial allelic and locus heterogeneity. Pathogenetically, mechanisms involve impaired myelin maintenance, disrupted axonal transport, mitochondrial dysfunction, and aberrant Schwann cell biology. Despite these insights, therapeutic options remain limited, and there is a pressing need to translate genetic findings into effective interventions. This review aims to provide a comprehensive synthesis of current knowledge compiling all known mutations resulting in hereditary polyneuropathies. In addition, it underscores the molecular pathomechanisms of hereditary polyneuropathies and evaluates emerging therapeutic strategies, including adeno-associated virus mediated RNA interference, CRISPR-based gene editing, antisense oligonucleotide therapy, and small-molecule modulators of axonal degeneration. Furthermore, the integration of precision diagnostics, such as next-generation sequencing and functional genomic approaches, is discussed in the context of personalized disease management. Collectively, this review underscores the need for patient-centered approaches in advancing care for individuals with hereditary polyneuropathies. Full article

Background and Objectives: Diabetes mellitus (DM) is a major risk factor for cardiovascular diseases (CVD), including acute myocardial infarction (MI), and is frequently associated with cardiac autonomic neuropathy (CAN). Post-MI autonomic dysfunction contributes to adverse outcomes, but data on prognostic markers in diabetic patients remain limited. This study aimed to (1) compare autonomic nervous system (ANS) function between patients with MI and DM (MI/DM), MI without DM, and DM without MI; (2) assess differences in MI/DM patients based on survival status; and (3) identify prognostic factors for all-cause mortality in diabetic patients following MI. Materials and Methods: This retrospective–prospective study included 375 patients: 93 MI/DM, 229 MI, and 53 DM. MI patients were treated with fibrinolytic or conservative therapy. All participants underwent cardiovascular reflex tests (CARTs) and 24 h Holter ECG with heart rate variability (HRV) analysis; DM patients without MI were tested in an outpatient setting. The primary endpoint was all-cause mortality during a median follow-up of 38 months. Univariable and multivariable Cox regression analyses were performed to determine mortality predictors. Results: Autonomic dysfunction was prevalent in all groups, with MI/DM patients showing the most pronounced impairment, particularly in parasympathetic function. MI/DM patients had significantly lower SDNN values and higher prevalence of definite parasympathetic dysfunction than other groups. In the MI/DM group, abnormal Valsalva maneuver (VM) was more frequent among non-survivors. Multivariable analysis identified abnormal VM and NSTEMI as predictors of overall mortality. Conclusions: Diabetic patients after MI exhibit the most severe autonomic impairment, predominantly parasympathetic, which may contribute to their increased cardiovascular risk. In this high-risk group, abnormal VM and NSTEMI presentations independently predict long-term mortality. Assessment of autonomic function, particularly VM, may provide valuable prognostic information and aid in risk stratification. Full article

Prader–Willi syndrome (PWS) is a rare, multisymptomatic genetic disorder caused by the absence or dysfunction of specific genes on chromosome 15. The genetic abnormality is anticipated to cause a dysfunction of the hypothalamus, which is also central in the regulation of the autonomic nervous system (ANS). Typical symptoms of PWS indicating a hypothalamic dysfunction include muscular hypotonia, poor growth, short stature, and feeding difficulties in infancy, which in early childhood are replaced by hyperphagia, leading to a high risk of obesity. Other characteristics, such as sleep difficulties, altered pain perception, delayed gastric emptying and constipation, blood pressure irregularities and dysregulated stress response, altered temperature regulation, delayed pupillary reaction, and urine retention and incontinence, all indicate a dysfunction of ANS. The ANS is usually divided into three parts: the sympathetic nervous system (SNS), which activates the fight-or-flight response during stress; the parasympathetic nervous system (PNS), which promotes calm and digestion; and the independent enteric nervous system (ENS), which regulates the gastrointestinal tract. Noradrenaline is the main neurotransmitter for the SNS, and acetylcholine for the PNS, while the ENS is regulated mainly by acetylcholine and serotonin. However, the ENS is modulated by both the SNS and the PNS, as well as many neuropeptides. Peptides regulating behavior, metabolism, appetite, and satiety have been extensively studied in PWS. However, studies of the role of neuropeptides in regulating other autonomic functions are limited and remain poorly understood. This review aims to synthesize current evidence from both animal models and human studies to explore potential mechanisms by which neuropeptides may contribute to autonomic dysfunction in individuals with PWS. Full article

The gut microbiota is crucial for metabolic homeostasis and cardiovascular health. Dysbiosis triggers a gut–brain–heart axis dysfunction: vagal signaling promotes neuroinflammation and cerebral damage, which in turn impairs cardiac function. This bidirectional cycle is further exacerbated by reduced cerebral perfusion. Trimethylamine-N-oxide (TMAO), a metabolite of dietary choline and L-carnitine, acts as a primary mediator in this network. Elevated TMAO levels—resulting from bacterial conversion and hepatic oxidation—are linked to atherosclerosis and heart failure. Mechanistically, TMAO activates the NLRP3 inflammasome, inhibits the SIRT3-SOD2 pathway, and promotes platelet hyperreactivity. Furthermore, it modulates the autonomic nervous system, enhancing sympathetic activity and cardiac arrhythmias. Clinical evidence suggests TMAO is a potent predictor of mortality in HF. While current HF therapies focus on end-organ response (beta-blockers) or humoral pathways (ACE inhibitors), directly targeting the microbiota and TMAO offers a novel therapeutic frontier. Integrating TMAO assessment into risk models and utilizing advanced in vitro gut–brain models will be essential for developing personalized, groundbreaking cardiovascular interventions. Within this framework, the main aim of the present review is to describe how cardiac autonomic control can be directly modulated by the microbiota and its byproducts like TMAO. This latter is a leading target candidate for novel HF prevention and therapy interventions. Full article