Stellate ganglion neurons, important mediators of cardiopulmonary neurotransmission, are surrounded by satellite glial cells (SGCs), which are essential for the function, maintenance, and development of neurons. However, it remains unknown whether SGCs in adult sympathetic ganglia exhibit any functional diversity, and what role this plays in modulating neurotransmission. We performed single‐cell RNA sequencing of mouse stellate ganglia (n = 8 animals), focusing on SGCs (n = 11,595 cells). SGCs were identified by high expression of glial‐specific transcripts, S100b and Fabp7. Microglia and Schwann cells were identified by expression of C1qa/C1qb/C1qc and Ncmap/Drp2, respectively, and excluded from further analysis. Dimensionality reduction and clustering of SGCs revealed six distinct transcriptomic subtypes, one of which was characterized the expression of pro‐inflammatory markers and excluded from further analyses. The transcriptomic profiles and corresponding biochemical pathways of the remaining subtypes were analyzed and compared with published astrocytic transcriptomes. This revealed gradual shifts of developmental and functional pathways across the subtypes, originating from an immature and pluripotent subpopulation into two mature populations of SGCs, characterized by upregulated functional pathways such as cholesterol metabolism. As SGCs aged, these functional pathways were downregulated while genes and pathways associated with cellular stress responses were upregulated. These findings were confirmed and furthered by an unbiased pseudo‐time analysis, which revealed two distinct trajectories involving the five subtypes that were studied. These findings demonstrate that SGCs in mouse stellate ganglia exhibit transcriptomic heterogeneity along maturation or differentiation axes. These subpopulations and their unique biochemical properties suggest dynamic physiological adaptations that modulate neuronal function.

Hyperkalemia is a metabolic disturbance of the potassium balance that can cause potentially fatal cardiac arrhythmias. Kidney dysfunction and renin-angiotensin-aldosterone system inhibiting drugs are notorious for their tendency to induce hyperkalemia by decreasing the excretion of potassium. The role of dietary potassium intake in inducing hyperkalemia is less clear. We review and analyze the common presentation, laboratory, and electrocardiogram (ECG) findings and therapeutic options associated with dietary-induced hyperkalemia, and find evidence for hyperkalemia development in non-renal impaired patients. Thirty-five case reports including 44 incidences of oral intake-induced hyperkalemia were assessed, 17 patients did not suffer from kidney dysfunction. Mean age was 49 ± 20 years. Mean potassium concentration was 8.2 ± 1.4 mEq/l, most frequently caused by abundant intake of fruit and vegetables (n = 17) or salt substitutes (n = 12). In patients with normal kidney function, intake of salt substitutes or supplements was the main cause of hyperkalemia. Main symptoms encompassed muscle weakness (29.5%), vomiting (20.4%), and dyspnea (15.9%). When ECGs were performed (n = 30), abnormalities were present in 86.7% of cases. Treatment involved administration of insulin (n = 22), sodium/calcium polystyrene sulfonate (n = 14), and/or calcium gluconate (n = 14). Forty patients fully recovered. Three, non-renal impaired, patients passed away. These results offer insight into the clinical aspects of dietary-induced hyperkalemia and suggest that the common assumption that dietary-induced hyperkalemia is a condition of renal impaired patients might be incorrect.

Purpose This review aimed to provide a complete overview of the current stance and recent developments in antiarrhythmic neuromodulatory interventions, focusing on lifethreatening vetricular arrhythmias. Methods Both preclinical studies and clinical studies were assessed to highlight the gaps in knowledge that remain to be answered and the necessary steps required to properly translate these strategies to the clinical setting. Results Cardiac autonomic imbalance, characterized by chronic sympathoexcitation and parasympathetic withdrawal, destabilizes cardiac electrophysiology and promotes ventricular arrhythmogenesis. Therefore, neuromodulatory interventions that target the sympatho-vagal imbalance have emerged as promising antiarrhythmic strategies. These strategies are aimed at different parts of the cardiac neuraxis and directly or indirectly restore cardiac autonomic tone. These interventions include pharmacological blockade of sympathetic neurotransmitters and neuropeptides, cardiac sympathetic denervation, thoracic epidural anesthesia, and spinal cord and vagal nerve stimulation. Conclusion Neuromodulatory strategies have repeatedly been demonstrated to be highly effective and very promising anti-arrhythmic therapies. Nevertheless, there is still much room to gain in our understanding of neurocardiac physiology, refining the current neuromodulatory strategic options and elucidating the chronic effects of many of these strategic options.

In the anaesthetized, chronic atrioventricular block (CAVB) dog, ventricular ectopic beats and Torsade de pointes arrhythmias (TdP) are believed to ensue from an abrupt prolongation of ventricular repolarization and increased temporal dispersion of repolarization, quantified as short-term variability (STV). These TdP stop spontaneously or, when supported by substantial spatial dispersion of repolarization (SDR), degenerate into ventricular fibrillation. However, most studies involving ventricular arrhythmias do not quantify SDR by means of an electrophysiological parameter. Therefore, we reviewed the effects of 4 highly effective anti-arrhythmic drugs (flunarizine, verapamil, SEA-0400, and GS-458967) on the repolarization duration and associated STV. All drugs were tested as anti-arrhythmic strategies against TdP in CAVB dogs, their high anti-arrhythmic efficacy was defined as suppressing drug-induced TdP in 100% of the experiments. This comparison demonstrates that even though the anti-arrhythmic outcome was similar for all drugs, distinct responses of repolarization duration and associated STV were observed. Moreover, the aforementioned and commonly adopted electrophysiological parameters were not always sufficient in predicting TdP susceptibility, and additional quantification of the SDR proved to be of added value in these studies. The variability in electrophysiological responses to the different anti-arrhythmic drugs and their inconsistent adequacy in reflecting TdP susceptibility, can be explained by distinct modes of interference with TdP development. As such, this overview establishes the separate involvement of temporal and spatial dispersion in ventricular arrhythmogenesis in the CAVB dog model and proposes SDR as an additional parameter to be included in future fundamental and/or pharmaceutical studies regarding TdP arrhythmogenesis.

Ventricular arrhythmias, consisting of single ectopic beats (sEB), multiple EB (mEB), and Torsades de Pointes (TdP, defined as >5 beats with QRS vector twisting around isoelectric line) can be induced in the anesthetized chronic AV-block (CAVB) dog by dofetilide (IKr-blocker). The interplay between temporal dispersion of repolarization, quantified as short-term variability (STV), and spatial dispersion of repolarization (SDR) in the initiation and perpetuation of these arrhythmias remains unclear. Five inducible (>3 TdPs/10') CAVB dogs were observed for 10' from the start of dofetilide infusion (0.025mg/kg, 5'). An intracardiac decapolar electrogram (EGM) catheter and 30 intramural cardiac needles in the left ventricle (LV) were introduced. STVARI was derived from 31 consecutive activation recovery intervals (ARI) on the intracardiac EGM, using the formula: . The mean SDR3D in the LV was determined as the three-dimensional repolarization time differences between the intramural cardiac needles. Moments of measurement included baseline (BL) and after dofetilide infusion prior to first 1) sEB (occurrence at 100±35"), 2) mEB (224±96"), and 3) non self-terminating TdP (454±298"). STVARI increased from 2.15±0.32ms at BL to 3.73±0.99ms* prior to the first sEB and remained increased without further significant progression to mEB (4.41±0.45ms*) and TdP (5.07±0.84ms*) (*p<0.05 compared to BL). SDR3D did not change from 31±11ms at BL to 43±13ms prior to sEB, but increased significantly prior to mEB (68±7ms*) and to TdP (86±9ms*+) (+p<0.05 compared to sEB). An increase in STV contributes to the initiation of sEB whereas an increase in SDR is important for the perpetuation of non self-terminating TdPs.

IntroductionTorsade de pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog model result from proarrhythmic factors, which trigger TdP and/or reinforce the arrhythmic substrate. This study investigated electrophysiological and arrhythmogenic consequences of severe bradycardia for TdP.MethodsDofetilide (25 μg/kg per 5 min) was administered to eight anesthetized, idioventricular rhythm (IVR) remodeled CAVB dogs in two serial experiments: once under 60 beats per minute (bpm), right ventricular apex paced (RVA60) conditions, once under more bradycardic IVR conditions. Recordings included surface electrocardiogram and short-term variability (STV) of repolarization from endocardial unipolar electrograms. TdP inducibility (three or more episodes within 10 min after start of dofetilide) and arrhythmic activity scores (AS) were established. Mapping experiments in 10 additional dogs determined the effect of lowering rate on STV and spatial dispersion of repolarization (SDR) in baseline.ResultsIVR-tested animals had longer baseline RR-interval (1,403 ± 271 ms) and repolarization intervals than RVA60 animals. Dofetilide increased STV similarly under both rhythm strategies. Nevertheless, TdP inducibility and AS were higher under IVR conditions (6/8 and 37 ± 27 vs. 1/8 and 8 ± 12 in RVA60, respectively, both p &lt; 0.05). Mapping: Pacing from high (128 ± 10 bpm) to middle (88 ± 10 bpm) to experimental rate (61 ± 3 bpm) increased all electrophysiological parameters, including interventricular dispersion, due to steeper left ventricular restitution curves, and intraventricular SDR: maximal cubic dispersion from 60 ± 14 (high) to 69 ± 17 (middle) to 84 ± 22 ms (p &lt; 0.05 vs. high and middle rate).ConclusionIn CAVB dogs, severe bradycardia increases the probability and severity of arrhythmic events by heterogeneously causing electrophysiological instability, which is mainly reflected in an increased spatial, and to a lesser extent temporal, dispersion of repolarization.

Purpose Cardiac autonomic dysfunction is one of the main pillars of cardiovascular pathophysiology. The purpose of this review is to provide an overview of the current state of the art on the pathological remodeling that occurs within the autonomic nervous system with cardiac injury and available neuromodulatory therapies for autonomic dysfunction in heart failure. Methods Data from peer-reviewed publications on autonomic function in health and after cardiac injury are reviewed. The role of and evidence behind various neuromodulatory therapies both in preclinical investigation and in-use in clinical practice are summarized. Results A harmonic interplay between the heart and the autonomic nervous system exists at multiple levels of the neuraxis. This interplay becomes disrupted in the setting of cardiovascular disease, resulting in pathological changes at multiple levels, from subcellular cardiac signaling of neurotransmitters to extra-cardiac, extra-thoracic remodeling. The subsequent detrimental cycle of sympathovagal imbalance, characterized by sympathoexcitation and parasympathetic withdrawal, predisposes to ventricular arrhythmias, progression of heart failure, and cardiac mortality. Knowledge on the etiology and pathophysiology of this condition has increased exponentially over the past few decades, resulting in a number of different neuromodulatory approaches. However, significant knowledge gaps in both sympathetic and parasympathetic interactions and causal factors that mediate progressive sympathoexcitation and parasympathetic dysfunction remain. Conclusions Although our understanding of autonomic imbalance in cardiovascular diseases has significantly increased, specific, pivotal mediators of this imbalance and the recognition and implementation of available autonomic parameters and neuromodulatory therapies are still lagging.

The meticulous control of cardiac sympathetic and parasympathetic tone regulates all facets of cardiac function. This precise calibration of cardiac efferent innervation is dependent on sensory information that is relayed from the heart to the central nervous system. The vagus nerve, which contains vagal cardiac afferent fibers, carries sensory information to the brainstem. Vagal afferent signaling has been predominantly shown to increase parasympathetic efferent response and vagal tone. However, cardiac vagal afferent signaling appears to change after cardiac injury, though much remains unknown. Even though subsequent cardiac autonomic imbalance is characterized by sympathoexcitation and parasympathetic dysfunction, it remains unclear if, and to what extent, vagal afferent dysfunction is involved in the development of vagal withdrawal. This review aims to summarize the current understanding of cardiac vagal afferent signaling under in health and in the setting of cardiovascular disease, especially after myocardial infarction, and to highlight the knowledge gaps that remain to be addressed.