Search Results (1,421)

Heart rate variability (HRV) forms the basis of non-invasive autonomic nervous system assessment. However, its analysis is constrained by the non-stationary nature of physiological signals. Standard analytical methods, which assume stationarity within fixed time windows, fail to capture dynamical effects of interest, such as the response to a physiological stressor. This limitation obstructs the development of mechanistic hypotheses about autonomic control. Here, we address this challenge by introducing a probabilistic framework for modeling non-stationary HRV dynamics during transient, single-event perturbation-recovery paradigms. We propose a hypothesis-driven, generative model that transforms the physiological response into a continuous-time stochastic process controlled by a double-logistic function. This approach deconstructs the R-R interval (RRi) series into a set of interpretable parameters representing the latency, rate, and magnitude of distinct response and recovery phases. Through simulation, we show that the model achieves high-fidelity parameter recovery and describes these dynamics more accurately than conventional fixed-time window methods under conditions matching its own generative assumptions. We then apply the framework to an empirical exercise-recovery recording, generating a precise, falsifiable hypothesis of “dissonant autonomic recovery”, where the baseline RR interval and its variability recover to distinct extents. The biphasic autonomic non-stationary decomposition (BAND) framework provides a formal methodology for translating RRi time series into quantitative, testable estimates of their generative processes. Full article

Background/Objectives: Gastroparesis is a disorder in which individuals experience dysfunctional gastric motor symptoms, but the underlying etiology is unclear. This exploratory study investigates autoimmune, inflammatory, metabolic, autonomic, and enteric (AIMAE) abnormalities in patients with gastroparesis symptoms to provide new insights into pathophysiology. The aim of this study is to further elucidate the potential associations between the different AIMAE measurements. Methods: Twenty-one patients with gastroparesis symptoms underwent a series of testing including assays for measurement of autoimmune, inflammatory, and metabolic markers; measurement of the autonomic nervous system; electrogastrography recordings; and gastric emptying measurements. Associations were evaluated using Spearman’s rank correlation with pairwise-complete observations. Benjamini–Hochberg false-discovery-rate correction was applied separately within each prespecified statistical family, with q ≤ 0.05 defining statistical significance. Results: Across 3432 planned correlations in 10 prespecified families, four associations met the false-discovery-rate threshold. DFS-70 was positively associated with C-peptide (q= 0.000330). Low-resolution EGG S1 mean amplitude was positively associated with insulin (q = 0.000172). IL-6 was inversely associated with baseline sympathetic LFa modulation (q = 0.000172) and standing sympathetic LFa modulation (q = 0.000172). Conclusions: This prospective pilot study identified strong associations among autoimmune, inflammatory, metabolic, enteric, and autonomic measurements. The findings were robust to leave-one-out analyses and generally retained their direction and magnitude after excluding participants with diabetes or a gastric electrical stimulator. However, the results of this study should be interpreted as hypothesis-generating rather than causal due to its limitations including a small cohort and incomplete confounder information. Full article

Background: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by impaired glucose homeostasis, insulin resistance, and progressive β-cell dysfunction. Increasing evidence suggests that glucose homeostasis is regulated not only by peripheral metabolic organs but also by central nervous system and autonomic pathways. Photobiomodulation (PBM) has been reported to modulate mitochondrial function, oxidative stress, vascular responses, and neural activity; however, its potential influence on glycemic outcomes remains largely unexplored. Objective: This prospective pilot study aimed to evaluate the feasibility of applying multi-wavelength LED irradiation to a predefined cranial region and to explore preliminary glycemic outcomes in individuals with T2DM. Methods: Seven participants with physician-diagnosed T2DM receiving stable antidiabetic medication regimens were enrolled. Multi-wavelength LED irradiation (660, 850, and 940 nm) was applied bilaterally to the predefined S3 region of the skull. Irradiation parameters included an irradiance of 5 mW/cm² (0.005 W/cm²), an energy density of 4.5 J/cm², and an exposure duration of 900 s per session. Treatments were administered three times weekly for four weeks (12 sessions). Primary outcome measures included fasting blood glucose (Glucose AC) and glycated hemoglobin (HbA1c). Secondary outcomes included mean blood glucose, fasting insulin, C-peptide, homeostasis model assessment of insulin resistance (HOMA-IR), lipid profile, and C-reactive protein (CRP). Exploratory paired statistical analyses were performed following assessment of data normality using the Shapiro–Wilk test. Results: Following the four-week intervention, fasting blood glucose and mean blood glucose were significantly reduced (p = 0.026 and p = 0.044, respectively), whereas HbA1c demonstrated a borderline reduction (p = 0.051). Changes in fasting insulin, C-peptide, HOMA-IR, lipid profile, and CRP were variable and did not reach statistical significance. No intervention-related adverse events were observed, and all participants completed the study protocol. Conclusions: Multi-wavelength LED irradiation applied to the predefined S3 region of the skull was feasible, safe, and well tolerated in individuals with T2DM. The observed preliminary glycemic outcomes support the feasibility of further investigation in larger randomized controlled trials. However, because of the small sample size, absence of a control group, and exploratory study design, the present findings should be interpreted cautiously and should not be considered evidence of clinical efficacy or causal effects. Full article

Background/Objectives: Resistance exercise (RE) reduces heart rate variability (HRV) in healthy young individuals, reflecting increased cardiovascular demand and autonomic stress during recovery. Given that theacrine (TEA) acts on the central nervous system and may influence autonomic cardiovascular regulation, its effects on HRV metrics remain unclear and have not yet been investigated. Methods: Seventeen young, healthy resistance-trained participants (8 females) completed two RE sessions under TEA and placebo (PLA) conditions in a randomized, double-blind, crossover design. HRV indices related to vagal modulation (RMSSD and HFnu), systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were assessed at three time points: pre-supplementation, pre-exercise (90 min after supplementation), and 30 min post-exercise. Results: In the TEA condition, RMSSD increased at pre-exercise compared with pre-supplementation (p = 0.01), with no significant difference between pre-supplementation and post-exercise (p = 0.140). The PLA condition showed significant post-exercise reductions in RMSSD compared to both pre-supplementation and pre-exercise (p < 0.01). Similar patterns were observed for HFnu. SBP, DBP, and HR increased significantly after exercise in both conditions, with no between-condition differences. No significant time × condition interactions or sex effects were observed for any HRV or cardiovascular variable. Conclusions: Acute TEA supplementation did not significantly alter autonomic or cardiovascular responses compared with PLA following a single RE session. Although distinct post-exercise HRV patterns were observed between conditions, the time × condition interaction did not support a significant treatment effect. Larger studies are needed to clarify the potential effects of TEA on post-exercise autonomic recovery. Full article

Background: Memantine, an uncompetitive and voltage-dependent N-methyl-D-aspartate (NMDA) receptor antagonist, is clinically established for moderate-to-severe Alzheimer’s disease. Its pharmacodynamic profile, low-to-moderate affinity, rapid open-channel block, and strong voltage dependency allows selective inhibition of pathological NMDA overactivation while preserving physiological neurotransmission. Increasing evidence shows that these same mechanistic principles operate in the peripheral nervous system, where NMDA receptors contribute to excitotoxicity, oxidative stress, neuroinflammation, and maladaptive nociceptive signaling. Purpose: To synthesize emerging preclinical and clinical evidence demonstrating memantine’s modulatory and neuroprotective actions in peripheral neurons and glia and to outline implications for drug repurposing across neurology, pain medicine, oncology, supportive care, and ophthalmology. Methodology: A narrative integration of mechanistic studies, in vivo preclinical models, and heterogeneous clinical trials evaluating memantine’s effects on peripheral sensory neurons, autonomic neurons, Schwann cells, retinal ganglion cells, and neuromuscular junction physiology. Evidence was examined across conditions involving excitotoxicity, oxidative injury, mitochondrial dysfunction, apoptotic signaling, neuroinflammation, and neuropathic pain amplification. Results: Memantine consistently attenuates peripheral excitotoxic calcium influx, suppresses NOX-2–mediated ROS generation, stabilizes mitochondrial membrane potential, modulates Bax/Bcl-2 signaling, and reduces neuroinflammatory cytokine activity. It also inhibits dorsal horn wind-up selectively under neuropathic conditions. These convergent mechanisms yield protective effects across chemotherapy-induced peripheral neuropathy (CIPN), diabetic neuropathy, traumatic nerve injury, phantom limb pain, retinal ganglion cell excitotoxicity, and organophosphate-induced neuromuscular toxicity. Clinical evidence includes improved multimodal neuropathy outcomes in diabetic neuropathy when combined with gabapentin, reduced phantom limb pain prevalence and intensity at six months, and a five-fold reduction in post-mastectomy neuropathic pain with pre-emptive administration. Conclusions: Memantine should be conceptually reframed as a system-wide neuroprotective agent with substantial translational potential beyond the CNS. Priorities for future development include NR2B-selective peripheral NMDA antagonists, peripherally restricted formulations, single-cell transcriptomic mapping of peripheral NMDA receptor subtypes, and adequately powered PNS-specific randomized trials. Full article

Brain-derived neurotrophic factor (BDNF) impacts parasympathetic nervous system function by increasing the excitability of cardioinhibitory parasympathetic neurons in the brainstem, ultimately lowering heart rate (HR) and heightening resting parasympathetic tone. Yet, whether BDNF and its high-affinity receptor—tropomyosin receptor kinase B (TrkB)—also act more distally, i.e., at the level of cholinergic-sensitive intrinsic cardiac ganglia (ICGs), remains unclear. Hence, we conducted morphological and functional studies in neural crest-specific BDNF knockout mice (ncBDNF KO), a model that selectively ablates BDNF signaling in neural crest-derived autonomic structures, including the intrinsic cardiac nervous system. ncBDNF mice exhibited a significant rise in resting heart rate with unchanged baseline contractile performance, thus supporting the role of endogenous BDNF in maintaining physiological parasympathetic restraint. When examining the ICGs, immunofluorescence analysis revealed a highly compartmentalized organization, with BDNF being predominantly confined to cholinergic neuronal somata and TrkB mainly clustered instead in S100-positive satellite glial cells, thus unveiling a previously unrecognized neuron–glia BDNF/TrkB ICG pattern. Next, we directly infused BDNF in Langendorff-perfused isolated WT mouse hearts and observed a rapid and reproducible bradycardic response that was abrogated by atropine but potentiated by neostigmine, hence attesting to the cholinergic nature of such bradycardia. Of note, BDNF maintained its positive inotropic effects under muscarinic blockade, as witnessed by the enhanced left ventricular developed pressure, maximal dP/dt, and rate-pressure product, congruent with direct BDNF-evoked myocardial TrkB agonism. Thus, ICGs are additional relevant relay stations interposed between BDNF/TrkB signaling and parasympathetic modulation of heart function. Although through different molecular paths, BDNF-mediated modulation of ICG firing can coordinate with the previously reported BDNF positive inotropy/lusitropy to adapt cardiac performance to increased workload and/or stress conditions. Full article

The renin–angiotensin system (RAS) and vasopressin system (VAS) play an essential role in the regulation of multiple vital body functions. A survey of the literature provides evidence that the central and systemic RAS and VAS are activated during pregnancy and cooperate in the regulation of blood circulation and in the exchange of substrates and metabolites between the mother and fetus. The present review is focused on the engagement of the RAS and VAS in the regulation of blood circulation in healthy pregnant women and fetuses and in gestations complicated by cardiovascular, metabolic and psychogenic diseases. The presence of several components of the RAS and VAS, such as renin, angiotensin-converting enzymes (ACE1, ACE2), angiotensins [Ang II, Ang-(1–7)], angiotensin receptors (AT1R, AT2R), and AVP receptors (V1aR), in the placenta and the myometrium allows us to assume that the RAS and VAS play a prominent role in function of the maternal–placental–fetal unit. Gestation is also associated with the activation of components of the RAS and VAS in appropriate regions of the central nervous system that are involved in the regulation of blood pressure. Experimental studies suggest that the RAS and VAS participate in the autonomic control of blood circulation and in the regulation of emotional aspects of pregnancy and maternity. Abnormal functioning of the RAS and/or VAS was found in eclampsia, metabolic diseases (diabetes mellitus) and psychogenic disorders (anxiety, stress, and depression). Some of these abnormalities may have an immunological or genetic background. In eclampsia, the presence of specific agonistic angiotensin receptor autoantibodies (AT1-AA) and altered genotypes of AGT, ACE2, AT1R, and AT2R were reported. Polymorphism of the AVP promoter was also described. Inappropriate pharmacotherapy or toxic environmental pollution may disturb the regulation of the cardiovascular system of the mother and fetus by the RAS and VAS during gestation. Further studies are necessary to better recognize the mechanisms of action of the RAS and VAS in healthy and pathological pregnancies. Full article

Purpose: Acute exercise elicits coordinated neuroendocrine and autonomic responses that are strongly influenced by exercise modality and intensity. While cortisol and salivary alpha-amylase are widely used as peripheral indicators of hypothalamic–pituitary–adrenal (HPA) axis and sympathetic nervous system activation, respectively, salivary orexin remains an exploratory biomarker whose relationship with central orexinergic activity is not yet fully established, particularly in response to different exercise conditions. This study aimed to compare the acute salivary responses of orexin, alpha-amylase, and cortisol following distinct exercise modalities characterized by different physiological loads. Methods: A repeated-measures design was employed in a sample of physically active young women. Each participant completed four experimental sessions: high-intensity interval training (HIIT), combined exercise (CE), moderate-intensity continuous training (MICT), and yoga. Saliva samples were collected at baseline (T0), immediately post-exercise (T1), and during early recovery (T2 and T3). Biomarker concentrations were analyzed to assess temporal dynamics and modality-dependent differences. Results: All biomarkers showed modality-dependent responses. HIIT elicited the most pronounced increases in alpha-amylase and cortisol, reflecting robust sympathetic and HPA axis activation, whereas CE and MICT induced more moderate responses. Yoga was associated with minimal changes across all biomarkers. Orexin displayed a graded response across the exercise modalities, with higher post-exercise levels observed following HIIT compared to lower-intensity conditions. Temporal analyses revealed distinct kinetic profiles, with alpha-amylase peaking rapidly in the early post-exercise phase, whereas cortisol exhibited a more delayed response. Conclusions: These findings demonstrate that acute salivary responses of orexin, alpha-amylase, and cortisol are strongly modulated by exercise modality, supporting the importance of an integrated, multi-biomarker approach to characterize the physiological response to exercise. The inclusion of salivary orexin provides exploratory information on a potentially relevant arousal- and energy-regulation-related pathway, complementing established peripheral markers of autonomic and endocrine activation. This integrated perspective may contribute to a more comprehensive understanding of exercise-induced stress responses in young women. Full article

The enteric nervous system (ENS) can function semi-autonomously from the central nervous system (CNS) in regulating complex gastrointestinal processes and exhibits substantial developmental, epigenetic, neuroimmune, and adaptive plasticity. We propose the concept of Stress-Induced Long-term Epigenetic Implicit Memory (SLEIM) as a hypothesis-generating theoretical framework suggesting that prenatal maternal stress may contribute to persistent biological alterations within ENS-related pathways through interacting epigenetic, neuroimmune, neuronal, glial, and microbiota-associated mechanisms. The precise biological substrates and mechanisms underlying this proposed framework remain unknown. Through the microbiota–gut–brain axis (MGBA), such stress-related biological alterations may influence physiological communication between the ENS and CNS and in turn affect stress-response systems, including HPA axis activity, immune signalling, cortisol regulation, mast-cell activation, and cytokine balance. The frequent comorbidity of fibromyalgia (FM) and irritable bowel syndrome (IBS) suggests the existence of shared pathogenic mechanisms involving central sensitisation, neuroimmune processes, and MGBA dysfunction. In this study, we therefore also address dependency-related characteristics and autonomy vulnerabilities reported in some patients with FM and consider how developmental, psychological, neurobiological, and illness-related factors may contribute to these patterns. Within the proposed SLEIM framework, prenatal stress-related biological influences may represent a potential developmental pathway that contributes to vulnerability to IBS, FM, and related functional disorders later in life. However, these relationships remain hypothetical and require future empirical investigation. Full article

Background: The autonomic nervous system (ANS) in individuals with obsessive–compulsive disorder (OCD) is often characterized by heightened sympathetic tone and reduced parasympathetic flexibility. This exploratory pilot study aimed to provide a detailed, dynamic portrait of autonomic dysregulation. Methods: Heart rate variability (HRV), galvanic skin response (GSR), and oculomotor measures (pupil size, fixations, saccade velocity) were recorded in 31 participants with OCD (obsessive–compulsive disorder) and 46 healthy controls while viewing 18 videos, half of them designed to trigger specific OCD dimensions and half neutral or positive. Results: The OCD group exhibited a state of sympathetic hyperactivation, evidenced by significantly lower mean NN intervals (average interval between normal heartbeats) and a distinct GSR (galvanic skin response) pattern marked by a rising tonic component across the experiment. Healthy controls exhibited increases in SDNN (standard deviation of NN intervals) and RMSSD (root mean square of successive differences) following pleasant videos, whereas this response was less pronounced and emerged later in the OCD group, suggesting reduced autonomic flexibility. Oculomotor data revealed faster saccade velocities during video viewing in the OCD group; however, unlike controls, their eye movements did not correlate with the pleasantness of the content. Conclusions: These results support the theory that individuals with OCD may exhibit greater sympathetic activation and delayed parasympathetic engagement. The findings suggest that autonomic inflexibility may be a core, measurable feature of OCD. Full article

Trauma is a condition that overwhelms an individual’s capacity to cope, disrupting emotional regulation, cognitive functioning, and the sense of safety. Complex trauma, characterized by prolonged and interpersonal adverse experiences, is associated with significant psychological distress, including anxiety, dissociation, and difficulties in self-regulation. Neurobiological research highlights how trauma is encoded not only cognitively but also within the body, through autonomic nervous system dysregulation and procedural memory processes, often resulting in states of hyperarousal or hypoarousal and a narrowed window of tolerance. The aim of this narrative review is to synthesize and critically examine the current literature on somatic-based interventions for the treatment of trauma, with a particular focus on Sensorimotor Psychotherapy, Somatic Experiencing, and related body-oriented approaches. In this context, somatic-based interventions offer a bottom–up approach that directly targets physiological and sensorimotor processes. Modalities such as Sensorimotor Psychotherapy and Somatic Experiencing aim to restore autonomic balance, enhance body awareness, and support the integration of traumatic experiences. This narrative review synthesizes current evidence, suggesting that these approaches can improve emotional regulation, dissociation, and overall trauma-related symptoms, particularly in individuals with complex trauma. Despite promising findings, the literature is limited by methodological variability and a lack of rigorous trials. Further research is needed to strengthen the evidence base and clarify mechanisms of change. Overall, somatic interventions represent a valuable complement to traditional trauma therapies, supporting a more integrated and embodied approach to treatment. Full article

Virtual reality (VR) provides an effective experimental environment for the controlled investigation of autonomic physiological responses under different levels of virtual immersion. This study investigated heart rate variability (HRV) responses to mental stress induced by an interactive VR game. Two stereoscopic conditions were compared: low immersion using polarising glasses and high immersion using a VR headset. Additionally, the applicability of visual, mathematical, and machine learning approaches for analysing VR-related changes in the autonomic nervous system is evaluated. The experiment involved 42 healthy volunteers (37 men and 5 women; mean age 26 ± 7 years). The HRV analysis is based on RR-intervals and includes time, frequency, and nonlinear indicators. Within the nonlinear framework, visual-mathematical methods, including Poincaré diagrams, recurrence plots, and histogram analysis, were applied. For automated classification of physiological states, a Random Forest model using 17 selected HRV parameters was applied. The results show exposure to the VR game elicited significant changes in autonomic cardiac regulation and heart rate variability, with different stereoscopic technologies producing distinct physiological responses. Nonlinear methods and applied visual-mathematical analyses reveal complex dynamic characteristics of heart rate that classical HRV indicators cannot fully capture. ROC and confusion matrix analyses show that the Random Forest model has good discriminative ability in distinguishing between a resting state and different levels of virtual immersion. The results confirm the potential of the proposed integrated approach, combining virtual reality, linear and nonlinear HRV analyses, and machine learning, as a tool for the objective assessment and modelling of autonomic physiological responses during VR exposure. The study has several limitations, including the relatively small and homogeneous sample size and the absence of stress and psychological state assessment through validated questionnaires, which should be addressed in future research. Full article

Restorative environments have been widely associated with stress reduction, psychological recovery, and improved well-being; however, evidence regarding cognitive performance remains methodologically fragmented, particularly across sensory modalities and neurophysiological assessment approaches. This systematic review examined the relationship between restorative environments and cognitive performance, with specific attention to sensory modality, cognitive domain, and the neuroscientific and physiological methods used to assess these effects. The review was conducted in accordance with PRISMA 2020. Peer-reviewed studies published in English from 2000 onward were identified through PubMed, Web of Science, Scopus, ScienceDirect, and PsycINFO, with the final search conducted on 31 March 2026. Eligible studies involved healthy human participants exposed to restorative environmental conditions in built, natural, or simulated settings and included at least one objective measure of cognitive performance together with at least one central nervous system or autonomic nervous system measure. Due to substantial methodological heterogeneity, findings were synthesized narratively. Of the 517 records identified, 26 studies met the inclusion criteria: visual (n = 13), auditory (n = 1), thermal (n = 8), olfactory (n = 1), and multisensory (n = 3). Across the 26 included studies, study-level effect directions were predominantly mixed, comprising 13 mixed, 6 positive, 4 neutral, and 3 negative classifications. Visual studies showed the clearest recurring favorable pattern, particularly for attention-related performance and selected working-memory outcomes. Thermal effects were condition-dependent, whereas evidence for auditory, olfactory, and multisensory modalities remained limited and mixed. Overall, the strength and consistency of the findings varied substantially according to sensory modality, exposure design, and assessment method. The evidence base was uneven across sensory modalities and showed considerable heterogeneity in intervention design, exposure characteristics, cognitive tasks, and neurophysiological outcomes. These findings provide a structured, modality-specific map of how restorative environments have been linked with cognitive performance while highlighting the need for more methodologically consistent research, particularly on underexplored non-visual, tactile, and multisensory pathways. Full article

Background: During intrauterine life, the fetus is continuously exposed to rhythmic sensory stimuli; among these, the maternal heartbeat is one of the earliest and most biologically salient, contributing to the early organization of physiological regulation. This exploratory longitudinal observational study examined whether exposure to the maternal heartbeat influences neonatal autonomic activity and whether this response is moderated by prenatal maternal psychological distress. Methods: Sixteen dyads of mother–child were included in the analyses. Pregnant women were first assessed between 24 and 28 weeks of gestation: maternal distress was measured using the Depression Anxiety Stress Scales—21 (DASS-21), and maternal heartbeat recordings were obtained. At 3–4 weeks postpartum, neonates were exposed to recordings of their own mother’s heartbeat. Neonatal heart rate variability (HRV) was assessed using electrocardiography at rest and during the hearing of the maternal heartbeat. Results: Exposure to the heartbeat significantly reduced high-frequency (HF) HRV compared to baseline (p = 0.037), providing evidence for modulation of parasympathetic activity. Importantly, an interaction between condition and maternal distress was observed (p = 0.021), suggesting that neonatal autonomic responses differ as a function of maternal psychological state. Conclusions: Overall, these preliminary findings suggest that neonatal autonomic responses to maternal heartbeat exposure may not be uniform but may vary according to maternal psychological distress, highlighting the potential role of the maternal psychophysiological context in shaping early autonomic regulation. Full article

Cardioneuroablation (CNA), defined as endocardial catheter ablation of atrial ganglionated plexi within the intrinsic cardiac autonomic nervous system, has emerged as a mechanism-directed therapy for cardioinhibitory reflex syncope and functional bradyarrhythmias. By attenuating postganglionic parasympathetic input to the sinoatrial and atrioventricular nodes, CNA targets the autonomic substrate of cardioinhibition rather than merely treating its bradycardic consequence. Over the past two decades, the evidence base has progressed from pioneering single-center experiences to multicenter registries, systematic reviews, meta-analyses, and randomized clinical trials, with reported freedom from recurrent syncope of approximately 80–94% in carefully selected patients at medium-term follow-up. This state-of-the-art narrative review summarizes the rationale, anatomy, patient-selection principles, mapping and ablation strategies, procedural endpoints, clinical outcomes, safety profile, and emerging applications of CNA. Particular emphasis is placed on the unresolved questions that will define the future of the field: the absence, to date, of adequately powered sham-controlled efficacy data; the lack of a universally validated intraprocedural endpoint; the biological and clinical significance of vagal reinnervation; and the gap between expert-center and broader real-world outcomes. Current evidence supports CNA as a promising, anatomically grounded neuromodulatory therapy, but its transition from expert-center innovation to guideline-endorsed treatment will depend on rigorous patient selection, standardized procedural endpoints, and the results of ongoing randomized trials. Full article