Ageing and the Autonomic Nervous System.

The vertebrate nervous system is divided into central (CNS) and peripheral (PNS) components. In turn, the PNS is divided into the autonomic (ANS) and enteric (ENS) nervous systems. Ageing implicates time-related changes to anatomy and physiology in reducing organismal fitness. In the case of the CNS, there exists substantial experimental evidence of the effects of age on individual neuronal and glial function. Although many such changes have yet to be experimentally observed in the PNS, there is considerable evidence of the role of ageing in the decline of ANS function over time. As such, this chapter will argue that the ANS constitutes a paradigm for the physiological consequences of ageing, as well as for their clinical implications.

Use of Online Resources to Study Cardiology by Clinical Veterinary Students in the United Kingdom.

Online resources are being increasingly used by veterinary students to complement their learning. However, their use by veterinary students, especially for cardiology learning, remains poorly understood. This article investigates the extent to which clinical veterinary students use online resources to study cardiology and whether this is affected by factors of gender, age, year of study, or entry status. This was a questionnaire-based study distributed to clinical veterinary students across eight UK universities and achieved 213 respondents. The lecturer was the most preferred resource except for direct entry students and students aged 27 or more, who preferred recommended textbooks. Some 95.3% of students use search engines to research cardiology topics, and 93.4% indicated that they would first search for answers online rather than contacting their instructor. Online video clips were popular as 71.8% of students accessed them at least once per week for cardiology learning. Of those students, 89.3% found online videos useful for understanding cardiological concepts. Social media was only rarely used (6.6%) to discuss cardiology information. Nonetheless, most students (64.3%) stated that they would enjoy interacting with course material on an instructor-led social media page. Despite most students (62%) not automatically trusting online resources, only 46.9% of students indicated that they verify online cardiology information. Online resources play an important role in complementing traditional resources in cardiology learning and suggest that some level of academic oversight may be necessary to ensure students use these resources in an appropriate manner.

To what extent do preclinical veterinary students in the UK utilize online resources to study physiology.

Online resources are becoming increasingly important in undergraduate education and have been associated with a number of advantages and positive outcomes on students' learning experience. However, online resource use by veterinary students for physiology learning remains poorly understood. Thus the present questionnaire-based study aims to investigate the extent to which first- and second-year veterinary students use online resources, including online video clips and social media, in their physiology learning and if this is influenced by factors of age, gender, entry status, or year of study. One-hundred and twenty-two students across seven UK universities completed the survey. Traditional resources (the lecturer and recommended textbooks) were the most preferred sources for physiology learning. Nonetheless, 97.5% of students used Internet search engines to explore physiology topics. Furthermore, students' tendency to contact their instructor regarding a physiology question was low. Rather, 92.6% said they would first search for an answer online. Particularly popular was the use of online video clips with 91.1% finding them valuable for physiology learning and 34.21% finding them more useful for understanding physiology than university taught material or lecture slides. YouTube was the most common online video clip platform used by students. Most students stated that they would enjoy interacting with course materials on an instructor-led social media page, but only 33.9% currently use social media to discuss physiology-related issues with classmates. Additionally, most students expressed concerns regarding the reliability of online resources but attempts to fact-check these resources were relatively low. Therefore, online resources represent an essential part of veterinary students' physiology learning and this suggests that educators can significantly improve student engagement and understanding of physiology by integrating these resources.

Exploring UK veterinary students' use of online resources as a tool for studying small animal internal medicine.

BACKGROUND: Despite an increase in the use of online resources, their use by veterinary students, especially in the study of small animal internal medicine (SAIM), remains poorly understood. METHODS: A questionnaire-based study consisting of 26 survey items and 263 responses from seven UK universities investigated the use of online resources among clinical veterinary students studying SAIM and whether this was affected by age, gender, year of study or entry status. RESULTS: Random internet searches were the preferred method of clarifying queries, except for graduate-entry students and age categories 18-21 years and 28 years and over who preferred traditional textbooks. Online searches were preferred over emailing instructors or contacting instructors in person. Despite 73.3% of participants not automatically trusting information from online sources, only 47.1% fact-checked, although this was higher among the graduate-entry group (62.5%). Frequent social media use was reported; however, only 44.8% of students reported using social media to discuss SAIM. Video clip usage was high, and 82.9% of students reported video clips were useful for understanding SAIM concepts. CONCLUSION: Online resources are a useful tool to complement traditional resources; however, a level of academic oversight may be required to ensure appropriate and effective use of these resources.

Cardiac ion channel expression in the equine model - In-silico prediction utilising RNA sequencing data from mixed tissue samples.

Understanding cardiomyocyte ion channel expression is crucial to understanding normal cardiac electrophysiology and underlying mechanisms of cardiac pathologies particularly arrhythmias. Hitherto, equine cardiac ion channel expression has rarely been investigated. Therefore, we aim to predict equine cardiac ion channel gene expression. Raw RNAseq data from normal horses from 9 datasets was retrieved from ArrayExpress and European Nucleotide Archive and reanalysed. The normalised (FPKM) read counts for a gene in a mix of tissue were hypothesised to be the average of the expected expression in each tissue weighted by the proportion of the tissue in the mix. The cardiac-specific expression was predicted by estimating the mean expression in each other tissues. To evaluate the performance of the model, predicted gene expression values were compared to the human cardiac gene expression. Cardiac-specific expression could be predicted for 91 ion channels including most expressed Na+ channels, K+ channels and Ca2+ -handling proteins. These revealed interesting differences from what would be expected based on human studies. These differences included predominance of NaV 1.4 rather than NaV 1.5 channel, and RYR1, SERCA1 and CASQ1 rather than RYR2, SERCA2, CASQ2 Ca2+ -handling proteins. Differences in channel expression not only implicate potentially different regulatory mechanisms but also pathological mechanisms of arrhythmogenesis.

Systematic review of renal denervation for the management of cardiac arrhythmias.

BACKGROUND: In the wake of the controversy surrounding the SYMPLICITY HTN-3 trial and data from subsequent trials, this review aims to perform an updated and more comprehensive review of the impact of renal sympathetic denervation on cardiac arrhythmias. METHODS AND RESULTS: A systematic search was performed using the Medline, Scopus and Embase databases using the terms "Renal Denervation" AND "Arrhythmias or Atrial or Ventricular", limited to Human and English language studies within the last 10 years. This search yielded 19 relevant studies (n = 6 randomised controlled trials, n = 13 non-randomised cohort studies) which comprised 783 patients. The studies show RSD is a safe procedure, not associated with increases in complications or mortality post-procedure. Importantly, there is no evidence RSD is associated with a deterioration in renal function, even in patients with chronic kidney disease. RSD with or without adjunctive pulmonary vein isolation (PVI) is associated with improvements in freedom from atrial fibrillation (AF), premature atrial complexes (PACs), ventricular arrhythmias and other echocardiographic parameters. Significant reductions in ambulatory and office blood pressure were also observed in the majority of studies. CONCLUSION: This review provides evidence based on original research that 'second generation' RSD is safe and is associated with reductions in short-term blood pressure and AF burden. However, the authors cannot draw firm conclusions with regards to less prominent arrhythmia subtypes due to the paucity of evidence available. Large multi-centre RCTs investigating the role of RSD are necessary to comprehensively assess the efficacy of the procedure treating various arrhythmias.

Anti-malarial drugs: Mechanisms underlying their proarrhythmic effects.

Malaria remains the leading cause of parasitic death in the world. Artemisinin resistance is an emerging threat indicating an imminent need for novel combination therapy. Given the key role of mass drug administration, it is pivotal that the safety of anti-malarial drugs is investigated thoroughly prior to widespread use. Cardiotoxicity, most prominently arrhythmic risk, has been a concern for anti-malarial drugs. We clarify the likely underlying mechanisms by which anti-malarial drugs predispose to arrhythmias. These relate to disruption of (1) action potential upstroke due to effects on the sodium currents, (2) action potential repolarisation due to effects on the potassium currents, (3) cellular calcium homeostasis, (4) mitochondrial function and reactive oxygen species production and (5) cardiac fibrosis. Together, these alterations promote arrhythmic triggers and substrates. Understanding these mechanisms is essential to assess the safety of these drugs, stratify patients based on arrhythmic risk and guide future anti-malarial drug development.

Mitochondrial Dysfunction Increases Arrhythmic Triggers and Substrates; Potential Anti-arrhythmic Pharmacological Targets.

Incidence of cardiac arrhythmias increases significantly with age. In order to effectively stratify arrhythmic risk in the aging population it is crucial to elucidate the relevant underlying molecular mechanisms. The changes underlying age-related electrophysiological disruption appear to be closely associated with mitochondrial dysfunction. Thus, the present review examines the mechanisms by which age-related mitochondrial dysfunction promotes arrhythmic triggers and substrate. Namely, via alterations in plasmalemmal ionic currents (both sodium and potassium), gap junctions, cellular Ca2+ homeostasis, and cardiac fibrosis. Stratification of patients' mitochondrial function status permits application of appropriate anti-arrhythmic therapies. Here, we discuss novel potential anti-arrhythmic pharmacological interventions that specifically target upstream mitochondrial function and hence ameliorates the need for therapies targeting downstream changes which have constituted traditional antiarrhythmic therapy.

Student perspectives of preparedness characteristics for clinical learning within a fully distributed veterinary teaching model.

The transition into the clinical environment is challenging and associated with significant stress and anxiety. This study aimed to examine the perspectives of students on the characteristics important for preparedness for clinical learning and the influence of gender, age, and graduate status on those perspectives. This descriptive, questionnaire-based study of 62 characteristics categorised into six themes was conducted within the Surrey School of Veterinary Medicine completed by 139 students commencing their final clinical year. The Friedman test and post-hoc Wilcoxon signed rank sum test explored for differences in ranking across the themes. Ordinal logistic regression and Mann-Whitney U pairwise comparisons were utilised to investigate for effects of gender, age, and graduate status on theme ranking. There was a significant difference (P <0.05) between medians for themes of preparedness characteristics with comparisons revealing willingness and communication and interaction as the most highly rated characteristics. Knowledge and understanding were viewed as the least important characteristic. Regression and pairwise Mann-Whitney U comparisons confirmed no significant effects (P >0.05) of gender, age or graduate status on student rating of preparedness characteristics. Integrating learning opportunities of those preparedness characteristics in the pre-clinical curriculum may improve students' preparedness for the clinical environment.

Transcriptional profiles of genes related to electrophysiological function in Scn5a+/- murine hearts.

The Scn5a gene encodes the major pore-forming Nav 1.5 (α) subunit, of the voltage-gated Na+ channel in cardiomyocytes. The key role of Nav 1.5 in action potential initiation and propagation in both atria and ventricles predisposes organisms lacking Scn5a or carrying Scn5a mutations to cardiac arrhythmogenesis. Loss-of-function Nav 1.5 genetic abnormalities account for many cases of the human arrhythmic disorder Brugada syndrome (BrS) and related conduction disorders. A murine model with a heterozygous Scn5a deletion recapitulates many electrophysiological phenotypes of BrS. This study examines the relationships between its Scn5a+/- genotype, resulting transcriptional changes, and the consequent phenotypic presentations of BrS. Of 62 selected protein-coding genes related to cardiomyocyte electrophysiological or homeostatic function, concentrations of mRNA transcribed from 15 differed significantly from wild type (WT). Despite halving apparent ventricular Scn5a transcription heterozygous deletion did not significantly downregulate its atrial expression, raising possibilities of atria-specific feedback mechanisms. Most of the remaining 14 genes whose expression differed significantly between WT and Scn5a+/- animals involved Ca2+ homeostasis specifically in atrial tissue, with no overlap with any ventricular changes. All statistically significant changes in expression were upregulations in the atria and downregulations in the ventricles. This investigation demonstrates the value of future experiments exploring for and clarifying links between transcriptional control of Scn5a and of genes whose protein products coordinate Ca2+ regulation and examining their possible roles in BrS.

Molecular basis of ventricular arrhythmogenicity in a Pgc-1α deficient murine model.

Mitochondrial dysfunction underlying metabolic disorders such as obesity and diabetes mellitus is strongly associated with cardiac arrhythmias. Murine Pgc-1α-/- hearts replicate disrupted mitochondrial function and model the associated pro-arrhythmic electrophysiological abnormalities. Quantitative PCR, western blotting and histological analysis were used to investigate the molecular basis of the electrophysiological changes associated with mitochondrial dysfunction. qPCR analysis implicated downregulation of genes related to Na+-K+ ATPase activity (Atp1b1), surface Ca2+ entry (Cacna1c), action potential repolarisation (Kcnn1), autonomic function (Adra1d, Adcy4, Pde4d, Prkar2a), and morphological properties (Myh6, Tbx3) in murine Pgc-1α-/- ventricles. Western blotting revealed reduced NaV1.5 but normal Cx43 expression. Histological analysis revealed increased tissue fibrosis in the Pgc-1α-/- ventricles. These present findings identify altered transcription amongst a strategically selected set of genes established as encoding proteins involved in cardiac electrophysiological activation and therefore potentially involved in alterations in ventricular activation and Ca2+ homeostasis in arrhythmic substrate associated with Pgc-1α deficiency. They complement and complete previous studies examining such expression characteristics in the atria and ventricles of Pgc-1 deficient murine hearts.

Targeting the ß-adrenergic receptor in the clinical management of congenital long QT syndrome.

The long QT syndrome (LQTS) is largely treated pharmacologically with ß-blockers, despite the role of sympathetic activity in LQTS being poorly understood. Using the trigger-substrate model of cardiac arrhythmias in this review, we amalgamate current experimental and clinical data from both animal and human studies to explain the mechanism of adrenergic stimulation and blockade on LQT arrhythmic risk and hence assess the efficacy of ß-adrenoceptor blockade in the management of LQTS. In LQTS1 and LQTS2, sympathetic stimulation increases arrhythmic risk by enhancing early afterdepolarizations and transmural dispersion of repolarization. ß-Blockers successfully reduce cardiac events by reducing these triggers and substrates; however, these effects are less marked in LQTS2 compared with LQTS1. In LQTS3, clinical and experimental investigations of the effects of sympathetic stimulation and ß-blocker use have produced contradictory findings, resulting in significant clinical uncertainty. We offer explanations for these contradicting results relating to study sample size, the dose of the ß-blocker administered associated with its off-target Na+ channel effects, as well as the type of ß-blocker used. We conclude that the antiarrhythmic efficacy of ß-blockers is a genotype-specific phenomenon, and hence the use of ß-blockers in clinical practice should be genotype dependent.

Protein expression profiles in murine ventricles modeling catecholaminergic polymorphic ventricular tachycardia: effects of genotype and sex.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is associated with mutations in the cardiac ryanodine receptor (RyR2). These result in stress-induced ventricular arrhythmic episodes, with clinical symptoms and prognosis reported more severe in male than female patients. Murine homozygotic RyR2-P2328S (RyR2S/S ) hearts replicate the proarrhythmic CPVT phenotype of abnormal sarcoplasmic reticular Ca2+ leak and disrupted Ca2+ homeostasis. In addition, RyR2S/S hearts show decreased myocardial action potential conduction velocities (CV), all features implicated in arrhythmic trigger and substrate. The present studies explored for independent and interacting effects of RyR2S/S genotype and sex on expression levels of molecular determinants of Ca2+ homeostasis (CASQ2, FKBP12, SERCA2a, NCX1, and CaV 1.2) and CV (NaV 1.5, Connexin (Cx)-43, phosphorylated-Cx43, and TGF-ß1) in mice. Expression levels of Ca2+ homeostasis proteins were not altered, hence implicating abnormal RyR2 function alone in disrupted cytosolic Ca2+ homeostasis. Furthermore, altered NaV 1.5, phosphorylated Cx43, and TGF-ß1 expression were not implicated in the development of slowed CV. By contrast, decreased Cx43 expression correlated with slowed CV, in female, but not male, RyR2S/S mice. The CV changes may reflect acute actions of the increased cytosolic Ca2+ on NaV 1.5 and Cx43 function.

Molecular basis of arrhythmic substrate in ageing murine peroxisome proliferator-activated receptor γ co-activator deficient hearts modelling mitochondrial dysfunction.

INTRODUCTION: Ageing and chronic metabolic disorders are associated with mitochondrial dysfunction and cardiac pro-arrhythmic phenotypes which were recently attributed to slowed atrial and ventricular action potential (AP) conduction in peroxisome proliferator-activated receptor γ co-activator deficient (Pgc-1ß-/-) mice. METHODS: We compared expression levels of voltage-gated Na+ channel (NaV1.5) and gap junction channels, Connexins 40 and 43 (Cx40 and Cx43) in the hearts of young and old, and wild-type (WT) and Pgc-1ß-/- mice. This employed Western blotting (WB) for NaV1.5, Cx40 and Cx43 in atrial/ventricular tissue lysates, and immunofluorescence (IF) from Cx43 was explored in tissue sections. Results were analysed using two-way analysis of variance (ANOVA) for independent/interacting effects of age and genotype. RESULTS: In atria, increased age and Pgc-1ß-/- genotype each independently decreased both Cx40 and Cx43 expression without interacting effects. In IF experiments, both age and Pgc-1ß deletion independently reduced Cx43 expression. In ventricles, age and genotype exerted interacting effects in WB studies of NaV1.5 expression. Young Pgc-1ß-/- then showed greater NaV1.5 expression than young WT ventricles. However, neither age nor Pgc-1ß deletion affected Cx43 expression, independently or through interacting effects in both WB and IF studies. CONCLUSION: Similar pro-arrhythmic atrial/ventricular phenotypes arise in aged/Pgc-1ß-/- from differing contributions of altered protein expression and functional effects that may arise from multiple acute mechanisms.