Impulse Conduction Research Articles

Empagliflozin treatment rescues abnormally reduced Na+ currents in ventricular cardiomyocytes from dystrophin-deficient mdx mice

Abstract Background Cardiac arrhythmias represent a major cause of death in Duchenne muscular dystrophy (DMD), a devastating muscle disease caused by dystrophin deficiency. An important source for arrhythmia vulnerability in DMD patients is impaired ventricular impulse conduction, which predisposes for ventricular asynchrony, and the development of reentrant circuits. Using the dystrophin-deficient mdx mouse model for DMD, we and others previously reported that the absence of dystrophin results in a significant peak Na+ current (INa) loss both in ventricular cardiomyocytes of the working myocardium, and in Purkinje fibers, ventricular myocytes specialized for rapid electrical impulse conduction. This finding provided a mechanistic explanation for ventricular conduction defects and concomitant arrhythmias in the dystrophic heart. Purpose In the present study, we tested the hypothesis that empagliflozin (EMPA), an inhibitor of sodium/glucose cotransporter 2 in clinical use to treat type II diabetes and nondiabetic heart failure, rescues the loss of peak INa in dystrophin-deficient ventricular cardiomyocytes. Methods In a first set of experiments, we treated a cohort of mdx mice with 15 mg/kg body weight/day EMPA via the drinking water. After 4 weeks of treatment, ventricular cardiomyocytes were isolated from these mice, as well as from untreated wild-type and mdx control mice, via Langendorff heart perfusion and enzymatic digestion. Peak INa was measured using the whole cell patch clamp technique. In a second experimental approach, peak INa was compared after a 24 hour exposure of isolated mdx ventricular cardiomyocytes with 1 µM EMPA, 10 µM of the Na+-H+ exchanger 1 inhibitor cariporide, or 10 µM cariporide in combination with 1 µM EMPA. In a third set of experiments, we superfused freshly isolated mdx ventricular cardiomyocytes with 1 or 10 µM EMPA in order to examine the acute action of the drug on peak INa. Results Consistent with the literature, we found peak INa of mdx ventricular cardiomyocytes to be substantially decreased compared to wild-type. Peak INa of ventricular cardiomyocytes derived from mdx mice, which had received EMPA for 4 weeks, was restored to wild-type level. Moreover, incubation of isolated mdx ventricular cardiomyocytes with EMPA for 24 hours significantly increased their peak INa. This effect did not depend on Na+-H+ exchanger 1 inhibition by the drug. The voltage dependencies of INa activation and fast inactivation were neither modified by long-term treatment nor incubation with EMPA. Finally, acute application of EMPA did not influence peak INa. Conclusion Our findings indicate that EMPA treatment can correct abnormally reduced peak INa of dystrophin-deficient ventricular cardiomyocytes. Long-term EMPA administration may diminish arrhythmia vulnerability in DMD patients.

Reduced Na current in dystrophin-deficient ventricular cardiomyocytes is rescued by tenascin-C inhibition

Abstract Background Duchenne muscular dystrophy (DMD) is an X-linked hereditary disease triggered by the deficiency of the structural protein dystrophin, which leads to muscular degeneration mainly affecting young males. Major contributors to early death in DMD patients are cardiac arrhythmias and dystrophic cardiomyopathy. One cause for arrhythmias is impaired ventricular impulse conduction, which leads to ventricular asynchrony and reentrant mechanisms. We recently showed that the disruption of dystrophin results in a significant reduction of Na current in ventricular cardiomyocytes (vCMs) of the dystrophin-deficient mdx mouse model for human DMD. Na current reduction provides a mechanistic explanation for the impaired ventricular conduction and accompanying arrhythmias in the dystrophic heart. The extracellular matrix protein tenascin-C (TN-C) is a significant remodeling factor in the injured and diseased heart and is strongly upregulated in dystrophic cardiomyopathy. To this date, it is unknown how the upregulation of TN-C in DMD patients affects dystrophic cardiomyopathy. Purpose In this study, we examined the effect of TN-C inhibition on diminished Na currents in dystrophin-deficient vCMs. Methods We compared four different mouse genotypes with each other, namely wild-type, dystrophin-deficient mdx, TN-C-deficient and dystrophin- plus TN-C-deficient mice. Furthermore, a cohort of mdx mice was injected with TN-C siRNA twice a week for 9 weeks to investigate the effect of TN-C knockdown. Hearts from adult male mice were enzymatically digested using a Langendorff system to isolate single vCMs. Na currents were then measured with the whole cell patch clamp technique. Results Na current densities were increased in TN-C deficient vCMs compared to wild-type vCMs. Accordingly, 24-hour incubation of wild-type vCMs with human recombinant TN-C resulted in a significant decrease in Na current. Na currents of vCMs from mdx mice were reduced, but restored to the wild-type level in vCMs from TN-C-deficient mdx mice. Moreover, vCMs of TN-C siRNA-treated mdx mice had significantly increased Na currents compared to control mdx vCMs. Conclusion Upregulation of TN-C in dystrophin-deficient vCMs reduces Na currents, whereas inhibition of TN-C prevents this reduction. Therefore, inhibition of TN-C in DMD patients may be considered as a potential new therapeutic strategy to improve ventricular conduction and reduce arrhythmia vulnerability.

Establishment of a Serum-Free Human iPSC-Derived Model of Peripheral Myelination.

Myelination and the formation of nodes of Ranvier are essential for the rapid conduction of nerve impulses along axons in the peripheral nervous system (PNS). While many animal-based and serum-containing models of peripheral myelination have been developed, these have limited ability when it comes to studying genetic disorders affecting peripheral myelination. We report a fully induced pluripotent stem cell (iPSC)-derived human model of peripheral myelination using Schwann cells (SCs) and motoneurons, cultured in a serum-free medium on patterned and nonpatterned surfaces. Results demonstrated iPSC-derived SC-expressed early growth response protein 2 (Egr2), a key transcription factor for myelination, and after ∼30 days in coculture, hallmark features of myelination, including myelin segment and node of Ranvier formation, were observed. Myelin segments were stained for the myelin basic protein, which surrounded neurofilament-stained motoneuron axons. Clusters of voltage-gated sodium channels flanked by paranodal protein contactin-associated protein 1, indicating node of Ranvier formation, were also observed. High-resolution confocal microscopy allowed for 3D reconstruction and measurement of myelin g-ratios of myelin segments, with an average g-ratio of 0.67, consistent with reported values in the literature, indicating mature myelin segment formation. This iPSC-based model of peripheral myelination provides a platform to investigate numerous PNS diseases, including Charcot-Marie Tooth disorder, Guillian-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and antimyelin-associated glycoprotein peripheral neuropathy, with the potential for greater translatability to humans for improving the applicability for drug-screening programs.

Establishing validated RT-qPCR workflow for the analysis of oligodendrocyte gene expression in the developing murine brain.

Myelination is essential for the proper conduction of impulses across neuronal networks. Mature, myelinating glia differentiate from progenitor cells through distinct stages that correspond to oligodendrocyte-specific gene expression markers. Reverse transcription quantiatative PCR (RT-qPCR) is a common technique used to quantify gene expression across cell development; however, a lack of standardization and transparency in methodology may lead to irreproducible data. Here, we have designed and validated RT-qPCR assays for oligodendrocyte genes and reference genes in the developing C57BL6/J mouse brain that align with the MIQE guidelines, including quality controls for primer specificity, temperature dependence, and efficiency. A panel of eight commonly used reference genes was ranked using a series of reference gene stability methods that consistently identified Gapdh, Sdha, Hmbs, Hprt1, and Pgk1 as the top candidates for normalization across brain regions. In the cerebrum, myelin genes peaked in expression at postnatal day 21, which corresponds to the peak of developmental myelination. The gene expression patterns from the brain homogenate were in agreement with previously reported RNA-seq and microarray profiles from oligodendrocyte lineage cells. The validated RT-qPCR assays begin to build a framework for future investigation into the molecular mechanisms that regulate myelination in mouse models of brain development, aging, and disease.

Glutamate, Gangliosides, and the Synapse: Electrostatics at Work in the Brain.

The synapse is a piece of information transfer machinery replacing the electrical conduction of nerve impulses at the end of the neuron. Like many biological mechanisms, its functioning is heavily affected by time constraints. The solution selected by evolution is based on chemical communication that, in theory, cannot compete with the speed of nerve conduction. Nevertheless, biochemical and biophysical compensation mechanisms mitigate this intrinsic weakness: (i) through the high concentrations of neurotransmitters inside the synaptic vesicles; (ii) through the concentration of neurotransmitter receptors in lipid rafts, which are signaling platforms; indeed, the presence of raft lipids, such as gangliosides and cholesterol, allows a fine tuning of synaptic receptors by these lipids; (iii) through the negative electrical charges of the gangliosides, which generate an attractive (for cationic neurotransmitters, such as serotonin) or repulsive (for anionic neurotransmitters, such as glutamate) electric field. This electric field controls the flow of glutamate in the tripartite synapse involving pre- and post-synaptic neurons and the astrocyte. Changes in the expression of brain gangliosides can disrupt the functioning of the glutamatergic synapse, causing fatal diseases, such as Rett syndrome. In this review, we propose an in-depth analysis of the role of gangliosides in the glutamatergic synapse, highlighting the primordial and generally overlooked role played by the electric field of synaptic gangliosides.

Numerical analysis of coupled dynamical biological networks: Modeling electrical information exchange among nerve cells using finite volume method

An innovative approach to modeling the conduction of electrical impulses via intricate neuronal structures is introduced in this paper, which offers a theoretical and computational examination of parameter estimation in a coupled FitzHugh–Nagumo model. With this goal in mind, we present a finite volume approach to solving the FitzHugh–Nagumo model and check the numerical method’s accuracy against previous findings. To further assess and contrast the efficacy and precision of the model’s outputs, a finite difference formulation is incorporated. To clarify the basic qualitative properties of the inhibitor–activator mechanism intrinsic to the coupled FitzHugh–Nagumo model, the analysis uses dynamical system approaches and linear stability analysis. The results show that the suggested schemes are very accurate, with conditional stability, reaching fourth-order spatial and second-order temporal precision. The results are given in both tabular and graphical forms. According to numerical results, the suggested finite volume method outperforms the finite difference method in accurately and efficiently solving the nonlinear coupled FitzHugh–Nagumo model. Neuronal activity and electrical communication are complex biological systems with a lot of investigated nonlinear differential equations; this research helps us understand more about these topics.

Effect of the Heaviness of Smoking Index (HSI) and Duration of Smoking on Central Neural Processing Using Brainstem Auditory Evoked Responses (BAERs).

Purpose of study The goal of this research was to find the correlation of nicotine dependence and duration of smoking with the status of central neuronal processing in chronic smokers. Our primary objective was to record brainstem auditory evoked responses (BAERs) in chronic smokers and further find their correlation to the Heaviness of Smoking Index (HSI) scores and years of non-abstained smoking of the subjects. We postulated that smoking leads to myelination abnormalities which in turn causes decreased impulse conduction velocity. Methods After obtaining informed consent, we conducted BAER on 60 male smokers who were further classified into groups based on their HSI scores (low, moderate, and high nicotine dependency) and 20 age-matched, non-smoking males. The obtained data was examined using the two-way ANOVA test and the Kruskal-Wallis test. Pearson's coefficient of correlationand the median (as a measure of central tendency) were calculated. Results We observed a non-significant negative correlation between wave I BAER latency and the degree of nicotine dependence. Wave II showed minimal correlation, whereas a positive correlation was seen in waves III, IV, and V. Interpeak latencies (IPL) I-III and III-V showed a non-significant positive correlation with the HSI score, whereas IPL I-V showed a significant positive correlation with the same. When correlated with the duration of smoking (years), the latencies (msec) of BAER waves I-V showed a pattern of progressively decreasing negative correlation, out of which waves I, II, and III were significantly affected. The IPL (msec) of waves I-III was non-significantly, yet positively, correlated, while the IPL of waves I-V and III-V showed a significant positive correlation to the duration of smoking. Conclusions The degree of nicotine dependence and duration of tobacco smoking progressively affected the latencies of BAER waves at the pontomedullary level of the brainstem. This indicates slower central neuronal processing at this level and an increased central transmission time, the extent of which is directly dependent on the extent of tobacco smoking. This is attributed to the myelination defects caused by direct and indirect effects of the toxic metabolites of tobacco smoke, chronic hypoxia, hypercapnia, and respiratory acidosis.

Exploring the Intersection of Sarcoidosis and Cardiac Arrhythmias

Sarcoidosis is a multi-organ granulomatous disease of uncertain origin, characterized by the formation of non-necrotizing granulomas in various organs, including the heart. Cardiac involvement in sarcoidosis is rare, with approximately 5% of sarcoidosis patients developing clinically apparent cardiac disease, which is associated with significant morbidity and mortality. Genetically predisposed individuals develop granuloma in myocardium musculature, leading to aberrant conduction of cardiac impulses and the development of various arrhythmias. Common arrhythmias range from atrial fibrillation to ventricular tachycardia and can lead to sudden cardiac death because of ventricular fibrillation. The diagnostic challenge results from high specificity but rather limited sensitivity of endomyocardial biopsy, which is the gold standard diagnostic test, making advanced imaging techniques, such as cardiac magnetic resonance imaging and fluorine-18 fluorodeoxyglucose positron emission tomography, crucial for early detection. Management involves a complex approach with immunosuppression, antiarrhythmic medications, and catheter ablation, often supplemented by implantable cardioverter-defibrillators to prevent sudden cardiac death. In cardiac sarcoidosis, ventricular arrhythmias are common and cause high mortality. Timely intervention and management are crucial for a better prognosis. The disease's growing prevalence requires further research on refining early detection techniques and developing efficient treatment strategies for these high-risk patients. This review focuses on the etiopathogenesis of arrhythmias in cardiac sarcoidosis, diagnosis, and effective management strategies.

Impact of preanaesthetic electrocardiogram on decision making and modification of anaesthetic protocols in dogs.

This retrospective observational study explored the impact of preanaesthetic electrocardiogram (ECG) assessment on preoperative echocardiography requests and modifications to a standardised anaesthetic protocol in healthy dogs. A total of 228 healthy dogs with no previously diagnosed heart disease that underwent general anaesthesia at Complutense Veterinary Teaching Hospital from December 2017 to June 2018 were included. Preanaesthetic ECGs were assessed for abnormalities, and the findings were documented. The number of dogs requiring echocardiography, based on ECG findings, and the echocardiography results were recorded. All anaesthesia-related decisions were documented. Overall, 72 dogs (31.6%) exhibited ECG abnormalities. Echocardiography was requested for five dogs (2.2%). The anaesthetic protocol was changed in 11 dogs (15.3% of those with ECG abnormalities). P wave disturbances, ventricular premature complexes and impulse conduction issues were abnormalities that prompted echocardiography. Bradycardia and electrical impulse conduction abnormalities influenced protocol modifications. The limited sample size meant that it was not possible to investigate potentialcorrelations between demographics and ECG alterations. Preanaesthetic ECG screening was useful forpromoting echocardiography and influencing anaesthesia plans in a subset of dogs. Despite this, further assessment of the impact of routine use of non-targeted preoperative ECG on anaesthesia-related outcomes is warranted.

Thermodynamic model for memory

A thermodynamic model for memory formation is proposed. Key points include: 1) Any thought or consciousness corresponds to a thermodynamic system of nerve cells. 2) The system concept of nerve cells can only be described by thermodynamics of condensed matter. 3) The memory structure is logically associated with the system structure or the normal structure of biology. 4) The development of our thoughts is processed irreversibly, and numerous states or thoughts can be generated. 5) Memory formation results from the reorganization and change of cellular structures (or memory structures), which are related to nerve cell skeleton and membrane. Their alteration can change the excitability of nerve cells and the pathway of neural impulse conduction. 6) Amnesia results from the loss of thermodynamic stability of the memory structure, which can be achieved by different ways. Some related phenomena and facts are discussed. The analysis shows that thermodynamics can account for the basic properties of memory.

The electrophysiological effects of Tongyang Huoxue granules on the ignition phase during hypoxia/reoxygenation injury in sinoatrial node cells.

This study was undertaken to explore the potential therapeutic effects of Tongyang Huoxue Granules (TYHX) on sinoatrial node (SAN) dysfunction, a cardiac disorder characterized by impaired impulse generation or conduction. The research question addressed whether TYHX could positively influence SAN ion channel function, specifically targeting the sodium-calcium exchanger (I NCX) and L-type calcium channel (I CaL) of the SAN. Sinoatrial node cells (SANCs) were isolated and cultured from neonatal Japanese big-eared white rabbits within 24h of birth. The study encompassed five groups: Control, H/R (hypoxia/reoxygenation), H/R+100μg/mL TYHX, H/R+200μg/mL TYHX, and H/R+400μg/mL TYHX. The H/R model, simulating hypoxia/reoxygenation stress, was induced within 5days of culture. Whole-cell patch clamp technique was employed to record currents following a 3-min perfusion and stabilization period with TYHX. TYHX administration demonstrated improvements in the ignition phase of impaired SANCs. The half-maximal effective dose of TYHX, as determined by SANC beating frequency, was found to be 323.63μg/mL. Inward current density of I NCX increased in response to TYHX (200 and 400μg/mL), while TYHX enhanced I CaL current density in H/R SANCs, with 400μg/mL exhibiting greater efficacy. Additionally, TYHX regulated the gating mechanisms of I CaL by right-shifting the steady-state inactivation curve and accelerating recovery from inactivation. Notably, TYHX increased the activation time constant under 200 and 400μg/mL, prolonged the fast inactivation time constant τ1 with 400μg/mL, and extended the slow inactivation time constant τ2 with 100 and 400μg/mL. The findings suggest that TYHX may hold promise as a therapeutic intervention for sinus node dysfunction, offering potential avenues for drug development aimed at safeguarding SAN function.

Comparison Between Hypnoanesthesia and Local Anesthesia in Minor Surgery

Background: Hypnoanesthesia is a state of anesthesia achieved through hypnosis techniques. Meanwhile, local anesthesia is anesthesia carried out by injecting local anesthetic drugs in or around the surgical site which causes temporary obstruction to the conduction of afferent impulses. Objective: This research was conducted to prove that there is no difference between hypnoanesthesia and local anesthesia in minor surgical procedures, with the indication of pain relief. Methods: The research subjects were patients with benign soft tissue tumors consisting of 40 people who were divided into 2 groups, namely treatment and control. Minor surgical procedures with hypnoanesthesia were performed in the treatment group, while in the control group, minor surgical procedures were performed with local anesthesia using 2% lidocaine. Pain is measured with FPS (Face Pain Scale) and monitored with a vital sign monitor. The intervention process was recorded with camcorder video. Changes in serum levels of excitatory neurotransmitters (Glutamic Acid and Substance P) and inhibitory (Beta Endorphin, Enkephalin, and Serotonin) before and after intervention were analyzed using ELISA (Enzym-Link Immunosorbent Assay) in both groups. Results: In the treatment group, it was discovered that patients did not feel pain after undergoing hypnoanesthesia intervention by providing suggestions for the relief of pain in the area where surgery would be performed. In the control group, patients also did not feel pain after local anesthetic intervention in the area to be operated on. However, the results of research and statistical tests showed that there was no significant difference in changes in Beta Endorphins, Enkephalin, and Serotonin as inhibitory neurotransmitters (p > 0.05) or Glutamic Acid and Substance P as excitatory neurotransmitters (p > 0.05) before and after the intervention in both groups of research subjects. Conclusion: the results of this study show that there is no significant difference between the treatment and control groups, they have equality in the final result, namely the relief of pain.

Chemical and biophysical characterization of novel potassium channel blocker 3-fluoro-5-methylpyridin-4-amine

4-aminopyridine (4AP) is a potassium (K+) channel blocker used clinically to improve walking in people with multiple sclerosis (MS). 4AP binds to exposed K+ channels in demyelinated axons, reducing the leakage of intracellular K+ and enhancing impulse conduction. Multiple derivatives of 4AP capable of blocking K+ channels have been reported including three radiolabeled with positron emitting isotopes for imaging demyelinated lesions using positron emission tomography (PET). However, there remains a demand for novel molecules with suitable physicochemical properties and binding affinity that can potentially be radiolabeled and used as PET radiotracers. In this study, we introduce 3-fluoro-5-methylpyridin-4-amine (5Me3F4AP) as a novel trisubstituted K+ channel blocker with potential application in PET. 5Me3F4AP has comparable potency to 4AP and the PET tracer 3-fluoro-4-aminopyridine (3F4AP). Compared to 3F4AP, 5Me3F4AP exhibits comparable basicity (pKa = 7.46 ± 0.01 vs. 7.37 ± 0.07, P-value = 0.08), greater lipophilicity (logD = 0.664 ± 0.005 vs. 0.414 ± 0.002, P-value < 0.0001) and higher permeability to an artificial brain membrane (Pe = 88.1 ± 18.3 vs. 31.1 ± 2.9 nm/s, P-value = 0.03). 5Me3F4AP is also more stable towards oxidation in vitro by the cytochrome P450 enzyme CYP2E1 (IC50 = 36.2 ± 2.5 vs. 15.4 ± 5.1, P-value = 0.0003); the enzyme responsible for the metabolism of 4AP and 3F4AP. Taken together, 5Me3F4AP has promising properties as a candidate for PET imaging warranting additional investigation.

Vestibular system and human cognitive functions

The article is a review of scientific research on the influence of the vestibular system on human cognitive functions. The vestibular apparatus is well studied. Research in recent decades using functional tomography techniques has shown that it has extensive connections with the subcortical and cortical structures of the brain that provide cognitive activity. Hypotheses are put forward that the conduction and processing of bioelectric impulses by the brain, which are recorded by the vestibular apparatus, creates the necessary background for the course of all cognitive processes. The vestibular apparatus has connections with the limbic system, hippocampus, striatum and neocortex. Therefore, vestibular dysfunctions can reduce the ability to learn, cause impaired attention, memory, executive functions, cause disorientation, and affect stress levels. An urgent area of research is the study of the influence of vestibular sensory reactivity on children’s learning ability. This influence has long been underestimated, since it was generally assumed that motor and cognitive development occur independently of each other. The mechanisms linking vestibular dysfunction with cognitive impairment have not yet been sufficiently studied. Further studies are needed to assess the possible impact of vestibular dysfunctions on attention, memory, and speech. Such studies are already underway. Their results are most relevant for patients with neurodegenerative disorders and for children with special needs.

Early or late phase cardiac remodelling in metabolic syndrome heart characterized with SQT or LQT

Cardiac conduction abnormalities are the main disorders in metabolic syndrome (MetS), however, their mechanisms are not known yet. Although ventricular arrhythmia pathogenesis reflects the time course of cardiomyocyte action potentials (APs) associated with QT-interval duration, recent studies emphasize the role of intercellular crosstalk between cardiomyocytes and nonmyocytes via passive (electrotonic)-conduction. Therefore, considering the possible intercellular interactions between cardiomyocytes and nonmyocytes as electrophysiological contributors to cardiac-conduction, we hypothesized an early-cardiac-remodeling which is characterized by short QT-interval (SQT) via contributions and modulations of changes in the expressions and localizations of nonmyocytes to the ventricular APs in an early-stage MetS hearts. Significant increases in MetS (14-16 weeks) heart rates and SQT, shortened AP duration with a strong response to β-adrenergic stimulation in the contractile activity of the papillary muscles were determined. The patch-clamp analysis of ventricular cardiomyocytes showed that voltage-dependent Na+-channel currents were increased with decreased L-type Ca2+-channel (LTCC) currents and unchanged K+-channel currents. A hemichannel protein of connexin 43 (Cx43) was highly localized into intercalated discs while phospho-Cx43 was densely localized laterally on the sarcolemma and cytosol with increased total expression levels. A marked high-level positively-stained α-SMA and CD68 cells in interfibrillar spaces of the heart were prominently localized and distributed, implying the possible contributions of myofibroblasts and macrophages to both shortened APs and abnormal electrical conduction in an early-stage MetS heart.Our data propose a previously unrecognized pathway for induction of SQT in the heart: This pathway may include not only the contribution of short ventricular-APs via ionic-mechanisms but also increasing contributions of the electrotonic-cardiomyocyte depolarization, spontaneous electrical activity-associated fast heterogeneous impulse conduction in the heart via non-myocytes. Overall, SQT in early cardiac remodeling may arise with increased interactions between cardiomyocytes and non-myocytes, through increasing contributions of passive-conduction by non-myocytes. TUBITAK SBAG-119S661 &amp; 222S502. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Myocardial injury in dogs: a retrospective analysis on etiological, echocardiographic, electrocardiographic, therapeutic, and outcome findings in 102 cases

IntroductionIn dogs, myocardial injury (MI) is a poorly characterized clinical entity; therefore, this study aimed to provide a detailed description of dogs affected by this condition. Animals, materials, and methodsDogs diagnosed with MI according to the concentration of cardiac troponin I (cTnI) were retrospectively searched. Signalment, diagnostic, therapeutic, and outcome data were retrieved. Dogs were divided into six echocardiographic (dilated cardiomyopathy phenotype; hypertrophic cardiomyopathy phenotype; hypertrophic cardiomyopathy phenotype with systolic dysfunction; abnormal echogenicity only; endocarditis; and no echocardiographic abnormalities suggestive of MI), four electrocardiographic (abnormalities of impulse formation; abnormalities of impulse conduction; abnormalities of ventricular repolarization; and no electrocardiographic abnormalities suggestive of MI), and nine etiological (infective; inflammatory; neoplastic; metabolic; toxic; nutritional; immune-mediated; traumatic/mechanical; and unknown) categories. Statistical analysis was performed to compare cTnI values among different categories and analyze survival. ResultsOne hundred two dogs were included. The median cTnI value was 3.71 ng/mL (0.2–180 ng/mL). Echocardiographic and electrocardiographic abnormalities were documented in 86 of 102 and 89 of 102 dogs, respectively. Among echocardiographic and electrocardiographic categories, the dilated cardiomyopathy phenotype (n = 52) and abnormalities of impulse formation (n = 67) were overrepresented, respectively. Among dogs in which a suspected etiological trigger was identified (68/102), the infective category was overrepresented (n = 20). Among dogs belonging to different echocardiographic, electrocardiographic, and etiological categories, cTnI did not differ significantly. The median survival time was 603 days; only eight of 102 dogs died due to MI. ConclusionsDogs with MI often have an identifiable suspected trigger, show various echocardiographic and electrocardiographic abnormalities, and frequently survive to MI-related complications.

Bipolar Patient–Specific In Vitro Diagnostic Test Reveals Underlying Cardiac Arrhythmia Phenotype Caused by Calcium Channel Genetic Risk Factor

A common genetic risk factor for bipolar disorder is CACNA1C, a gene that is also critical for cardiac rhythm. The impact of CACNA1C mutations on bipolar patient cardiac rhythm is unknown. Here, we report the cardiac electrophysiological implications of a bipolar disorder–associated genetic risk factor in CACNA1C using patient induced pluripotent stem cell-derived cardiomyocytes. Results indicate that the CACNA1C bipolar disorder–related mutation causes cardiac electrical impulse conduction slowing mediated by impaired intercellular coupling via connexin 43 gap junctions. In vitro gene therapy to restore connexin 43 expression increased cardiac electrical impulse conduction velocity and protected against thioridazine-induced QT prolongation. Patients positive for bipolar disorder CACNA1C genetic risk factors may have elevated proarrhythmic risk for adverse events in response to psychiatric medications that slow conduction or prolong the QT interval. This in vitro diagnostic tool enables cardiac testing specific to patients with psychiatric disorders to determine their sensitivity to off-target effects of psychiatric medications.

The discrepancy in triggered electromyography responses between fatty filum and normal filum terminale

BackgroundFunctional role of filum terminale (FT) was not well studied though it contains structure basis for nerve impulse conduction. We aimed to explore the possible functions of the FT from the perspective of triggered electromyography (EMG) during surgery.MethodsWe retrospectively reviewed intraoperative neurophysiological monitoring data from pediatric patients who underwent intradural surgeries at the lumbar level in Shanghai Children’s. Hospital from January 2018 to March 2023. Altogether 168 cases with complete intraoperative neurophysiological recordings of the FT were selected for further analysis. Triggered EMG recordings of the filum originated from two main types of surgeries: selective dorsal rhizotomy (SDR) and fatty filum transection.Results96 cases underwent SDR and 72 cases underwent fatty filum transection. Electrical stimulation of the FT with fatty infiltration did not elicit electromyographic activity in the monitored muscles with the maximum stimulus intensity of 4.0 mA, while the average threshold for FT with normal appearance was 0.68 mA, and 89 out of 91 FT could elicit electromyographic responses in monitored channels. The threshold ratio of filum to motor nerve roots at the same surgical segment was significantly higher in patients with fatty filum, and a cut-off point of 21.03 yielded an area under curve of 0.943, with 100% sensitivity and 85.71% specificity.ConclusionFilum with normal appearance can elicit electromyographic activity in the lower limbs/anal sphincter similar to the performance of the cauda equina nerve roots. The threshold of fatty filum is different from that of normal appearing FT. Triggered EMG plays an important role in untethering surgeries.

Principles of the pharmacology of local anesthetics

The development of local anesthetics revolutionized the performance of painful interventions. Local anesthetics have an effect on voltage-gated sodium channels in nerve fibers and modulate the conduction of impulses. With respect to the chemical structure, local anesthetics can be divided into amide and ester types. The structural differences of local anesthetics have an influence on the duration of action, the degradation pathways and specific side effects. Severe adverse events include cardiotoxicity and neurotoxicity. In addition to basic measures, such as the monitoring and securing of vital parameters, lipid infusion represents a treatment option in cases of intoxication. The recent developments of local anesthetics are particularly concerned with the reduction of toxicity and prolonging the duration of action.

Bioenergetics of Axon Integrity and Its Regulation by Oligodendrocytes and Schwann Cells.

Axons are long slender portions of neurons that transmit electrical impulses to maintain proper physiological functioning. Axons in the central nervous system (CNS) and peripheral nervous system (PNS) do not exist in isolation but are found to form a complex association with their surrounding glial cells, oligodendrocytes and Schwann cells. These cells not only myelinate them for faster nerve impulse conduction but are also known to provide metabolic support. Due to their incredible length, continuous growth, and distance from the cell body (where major energy synthesis takes place), axons are in high energetic demand. The stability and integrity of axons have long been associated with axonal energy levels. The current mini-review is thus focused on how axons accomplish their high energetic requirement in a cell-autonomous manner and how the surrounding glial cells help them in maintaining their integrity by fulfilling their energy demands (non-cell autonomous trophic support). The concept that adjacent glial cells (oligodendrocytes and Schwann cells) provide trophic support to axons and assist them in maintaining their integrity comes from the conditional knockout research and the studies in which the metabolic pathways controlling metabolism in these glial cells are modulated and its effect on axonal integrity is evaluated. In the later part of the mini-review, the current knowledge of axon-glial metabolic coupling during various neurodegenerative conditions was discussed, along with the potential lacunae in our current understanding of axon-glial metabolic coupling.