On the low-frequency dispersion observed in dielectrophoresis spectra.

The foundation of dielectrophoresis (DEP) as a tool for biological investigation is the use of the Clausius-Mossotti (C-M) factor to model the observed behaviour of cells experiencing DEP across a frequency range. Nevertheless, it is also the case that at lower frequencies, the DEP spectrum deviates from predictions; there exists a rise in DEP polarisability, which varies in frequency and magnitude with different cell types and medium conductivities. In order to evaluate the origin of this effect, we have studied DEP spectra from five cell types (erythrocytes, platelets, neurons, HeLa cancer cells and monocytes) in several conditions including medium conductivity and cell treatment. Our results suggest the effect manifests as a low-pass dispersion whose cut-off frequency varies with membrane conductance and capacitance as determined using the DEP spectrum; the effect also varies as a logarithm of medium conductivity and Debye length. These together suggest that the values of membrane capacitance and conductance depend not only on the impedance of the membrane itself, but also of the surrounding double layer. The amplitude of the effect in different cell types compared to the C-M factor was found to correlate with the depolarisation factors for the cells' shapes, suggesting that this ratio may be useful as an indicator of cell shape for DEP modelling.

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.

Cardiac sodium channel complexes and arrhythmia: structural and functional roles of the ß1 and ß3 subunits.

In cardiac myocytes, the voltage-gated sodium channel NaV 1.5 opens in response to membrane depolarisation and initiates the action potential. The NaV 1.5 channel is typically associated with regulatory ß-subunits that modify gating and trafficking behaviour. These ß-subunits contain a single extracellular immunoglobulin (Ig) domain, a single transmembrane α-helix and an intracellular region. Here we focus on the role of the ß1 and ß3 subunits in regulating NaV 1.5. We catalogue ß1 and ß3 domain specific mutations that have been associated with inherited cardiac arrhythmia, including Brugada syndrome, long QT syndrome, atrial fibrillation and sudden death. We discuss how new structural insights into these proteins raises new questions about physiological function.

Comparison of Sodium-Glucose Cotransporter-2 Inhibitor and Dipeptidyl Peptidase-4 Inhibitor on the Risks of New-Onset Atrial Fibrillation, Stroke and Mortality in Diabetic Patients: A Propensity Score-Matched Study in Hong Kong.

OBJECTIVE: To compare the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2Is) and dipeptidyl peptidase-4 inhibitors (DPP4Is) on adverse outcomes in diabetic patients in Hong Kong. METHODS: This was a retrospective population-based cohort study of type 2 diabetes mellitus patients (n = 72,746) treated with SGLT2I or DPP4I between January 1, 2015, and December 31, 2020, in Hong Kong. Patients with exposure to both DPP4I and SGLT2I therapy, without complete demographics or mortality data, or who had prior atrial fibrillation (AF) were excluded. The study outcomes were new-onset AF, stroke/transient ischemic attack, cardiovascular mortality and all-cause mortality. Propensity score matching (1:1 ratio) between SGLT2I and DPP4I users was performed. RESULTS: The unmatched study cohort included 21,713 SGLT2I users and 39,510 DPP4I users (total: n = 61,233 patients; 55.37% males, median age: 62.7 years [interquartile range (IQR): 54.6-71.9 years]). Over a median follow-up of 2030 (IQR: 1912-2117) days, 2496 patients (incidence rate [IR]: 4.07%) developed new-onset AF, 2179 patients (IR: 3.55%) developed stroke/transient ischemic attack, 1963 (IR: 3.20%) died from cardiovascular causes and 6607 patients (IR: 10.79%) suffered from all-cause mortality. After propensity score matching (SGLT2I: n = 21,713; DPP4I: n = 21,713), SGLT2I users showed lower incidence of new-onset AF (1.96% vs. 2.78%, standardized mean difference [SMD] = 0.05), stroke (1.80% vs. 3.52%, SMD = 0.11), cardiovascular mortality (0.47% vs. 1.56%, SMD = 0.11) and all-cause mortality (2.59% vs. 7.47%, SMD = 0.22) compared to DPP4I users. Cox regression found that SGLT2I users showed lower risk of new-onset AF (hazard ratio [HR]: 0.68, 95% confidence interval [CI]: [0.56, 0.83], P = 0.0001), stroke (HR: 0.64, 95% CI: [0.53, 0.79], P < 0.0001), cardiovascular mortality (HR: 0.39, 95% CI: [0.27, 0.56], P < 0.0001) and all-cause mortality (HR: 0.44, 95% CI: [0.37, 0.51], P < 0.0001) after adjusting for significant demographics, past comorbidities, medications and laboratory tests. CONCLUSIONS: Based on real-world data of type 2 diabetic patients in Hong Kong, SGLT2I use was associated with lower risk of incident AF, stroke/transient ischemic attack, and cardiovascular and all-cause mortality outcomes compared to DPP4I use.

Framing Heartaches: The Cardiac ECM and the Effects of Age.

The cardiac extracellular matrix (ECM) is involved in several pathological conditions, and age itself is also associated with certain changes in the heart: it gets larger and stiffer, and it develops an increased risk of abnormal intrinsic rhythm. This, therefore, makes conditions such as atrial arrythmia more common. Many of these changes are directly related to the ECM, yet the proteomic composition of the ECM and how it changes with age is not fully resolved. The limited research progress in this field is mainly due to the intrinsic challenges in unravelling tightly bound cardiac proteomic components and also the time-consuming and costly dependency on animal models. This review aims to give an overview of the composition of the cardiac ECM, how different components aid the function of the healthy heart, how the ECM is remodelled and how it is affected by ageing.

Clinical and Non-Clinical Cardiovascular Disease Associated Pathologies in Parkinson's Disease.

Despite considerable breakthroughs in Parkinson's disease (PD) research, understanding of non-motor symptoms (NMS) in PD remains limited. The lack of basic level models that can properly recapitulate PD NMS either in vivo or in vitro complicates matters. Even so, recent research advances have identified cardiovascular NMS as being underestimated in PD. Considering that a cardiovascular phenotype reflects sympathetic autonomic dysregulation, cardiovascular symptoms of PD can play a pivotal role in understanding the pathogenesis of PD. In this study, we have reviewed clinical and non-clinical published papers with four key parameters: cardiovascular disease risks, electrocardiograms (ECG), neurocardiac lesions in PD, and fundamental electrophysiological studies that can be linked to the heart. We have highlighted the points and limitations that the reviewed articles have in common. ECG and pathological reports suggested that PD patients may undergo alterations in neurocardiac regulation. The pathological evidence also suggested that the hearts of PD patients were involved in alpha-synucleinopathy. Finally, there is to date little research available that addresses the electrophysiology of in vitro Parkinson's disease models. For future reference, research that can integrate cardiac electrophysiology and pathological alterations is required.

Stakeholder perspectives on veterinary student preparedness for workplace clinical training - a qualitative study.

BACKGROUND: The success of workplace clinical training (WCT) is important given that veterinary students are licensed to work independently upon graduation. Considering this, it is perhaps surprising that there is limited published work describing what it means to be prepared for this educational experience, particularly given that the transition to WCT can be stressful for students. This paper reports the results of a qualitative study aiming to generate a rich understanding of veterinary student preparedness for WCT using emic, or insider, perspectives of key stakeholders. METHODS: From a constructivist standpoint, homogenous online group interviews were held with final year veterinary students, recent student alumni, clinical supervisors, faculty, and academic educationalists to discuss what it means to be prepared for WCT. The data was analysed using a template analysis approach. RESULTS: A three-tier taxonomy to describe preparedness for WCT was constructed from the data. At the topmost level, there were seven themes to illuminate different aspects of preparedness: students should be prepared 1) for the transition to learning and working in a clinical and professional environment, 2) for self-directed and experiential learning whilst working, 3) with a growth mindset, 4) with intrinsic motivation and enthusiasm for learning and working, 5) for communication, consultation and clinical reasoning, 6) with the knowledge for work, and 7) with the practical competence and confidence for work. CONCLUSIONS: This study provides a deeper understanding of the tools we can provide, and the attributes we can nurture in, senior veterinary students to facilitate their learning and working during WCT. This improved understanding is a necessary precursor to refining pedagogical support and curriculum design within veterinary schools.

A remote mentorship model for empowering students to undertake electrocardiology research: Effects on gender equity.

Over the past years, there has been increasing awareness on female representation in cardiology, in particular senior academic ranks. Given the gender disparity in cardiology, female talents in cardiovascular academic medicine are significantly under-represented. In addition, whilst women have a slightly higher frequency of earning first authorships, it has been reported that women are 50% less likely to hold a senior authorship position. The drop in female representation in senior ranks of academic medicine may be contributed by a lack of female talent engagement, particularly during their early-career advancement, in high-impact journals and leadership roles. We present a remote, accessible-distributed research team model to help raise the female representation and tackle the challenges faced by female academics in the field of cardiovascular medicine. The group celebrates accessibility through open communication and collaboration, where mentees can seek research advice and ideas virtually from senior members and principal investigators. The decentralized system allows easy access for research guidance and inspirationand break down barriers in the lack of mentorship for early-career female talents. Students are empowered to lead their projects, and be involved in all phases- from the generation of study ideas to publication. The early development of holistic independent research skills equips students to become principal investigators and leaders in the future. The distributive element of the group is demonstrated through the decentralized research approach employed. Authorship is allocated based on intellectual contribution rather than on the acquisition of funding or seniority level.

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.

The cardiac CaMKII-Nav1.5 relationship: From physiology to pathology.

The SCN5A gene encodes Nav1.5, which, as the cardiac voltage-gated Na+ channel's pore-forming α subunit, is crucial for the initiation and propagation of atrial and ventricular action potentials. The arrhythmogenic propensity of inherited SCN5A mutations implicates the Na+ channel in determining cardiomyocyte excitability under normal conditions. Cytosolic kinases have long been known to alter the kinetic profile of Nav1.5 inactivation via phosphorylation of specific residues. Recent substantiation of both the role of calmodulin-dependent kinase II (CaMKII) in modulating the properties of the Nav1.5 inactivation gate and the significant rise in oxidation-dependent autonomous CaMKII activity in structural heart disease has raised the possibility of a novel pathway for acquired arrhythmias - the CaMKII-Nav1.5 relationship. The aim of this review is to: (1) outline the relationship's translation from physiological adaptation to pathological vicious circle; and (2) discuss the relative merits of each of its components as pharmacological targets.

Update on antiarrhythmic drug pharmacology.

Cardiac arrhythmias constitute a major public health problem. Pharmacological intervention remains mainstay to their clinical management. This, in turn, depends upon systematic drug classification schemes relating their molecular, cellular, and systems effects to clinical indications and therapeutic actions. This approach was first pioneered in the 1960s Vaughan-Williams classification. Subsequent progress in cardiac electrophysiological understanding led to a lag between the fundamental science and its clinical translation, partly addressed by The working group of the European Society of Cardiology (1991), which, however, did not emerge with formal classifications. We here utilize the recent Revised Oxford Classification Scheme to review antiarrhythmic drug pharmacology. We survey drugs and therapeutic targets offered by the more recently characterized ion channels, transporters, receptors, intracellular Ca2+ handling, and cell signaling molecules. These are organized into their strategic roles in cardiac electrophysiological function. Following analysis of the arrhythmic process itself, we consider (a) pharmacological agents directly targeting membrane function, particularly the Na+ and K+ ion channels underlying depolarizing and repolarizing events in the cardiac action potential. (b) We also consider agents that modify autonomic activity that, in turn, affects both the membrane and (c) the Ca2+ homeostatic and excitation-contraction coupling processes linking membrane excitation to contractile activation. Finally, we consider (d) drugs acting on more upstream energetic and structural remodeling processes currently the subject of clinical trials. Such systematic correlations of drug actions and arrhythmic mechanisms at different molecular to systems levels of cardiac function will facilitate current and future antiarrhythmic therapy.

Computational approaches for detection of cardiac rhythm abnormalities: Are we there yet?

The analysis of an electrocardiogram (ECG) is able to provide vital information on the electrical activity of the heart and is crucial for the accurate diagnosis of cardiac arrhythmias. Due to the nature of some arrhythmias, this might be a time-consuming and difficult to accomplish process. The advent of novel machine learning technologies in this field has a potential to revolutionise the use of the ECG. In this review, we outline key advances in ECG analysis for atrial, ventricular and complex multiform arrhythmias, as well as discuss the current limitations of the technology and the barriers that must be overcome before clinical integration is feasible.

Chloroquine, hydroxychloroquine, and COVID-19: Systematic review and narrative synthesis of efficacy and safety.

The COVID-19 pandemic has required clinicians to urgently identify new treatment options or the re-purposing of existing drugs. Of particular interest are chloroquine (CQ) and hydroxychloroquine (HCQ). The aims of this systematic review are to systematically identify and collate 24 studies describing the use of CQ and HCQ in human clinical trials and to provide a detailed synthesis of evidence of its efficacy and safety. Of clinical trials, 100% showed no significant difference in the probability of viral transmission or clearance in prophylaxis or therapy, respectively, compared to the control group. Among observational studies employing an endpoint specific to efficacy, 58% concurred with the finding of no significant difference in the attainment of outcomes. Three-fifths of clinical trials and half of observational studies examining an indicator unique to drug safety discovered a higher probability of adverse events in those treated patients suspected of, and diagnosed with, COVID-19. Of the total papers focusing on cardiac side-effects, 44% found a greater incidence of QTc prolongation and/or arrhythmias, 44% found no evidence of a significant difference, and 11% mixed results. The strongest available evidence points towards the inefficacy of CQ and HCQ in prophylaxis or in the treatment of hospitalised COVID-19 patients.

Reduced cardiomyocyte Na+ current in the age-dependent murine Pgc-1ß-/- model of ventricular arrhythmia.

Peroxisome proliferator-activated receptor-γ coactivator-1 deficient (Pgc-1ß-/- ) murine hearts model the increased, age-dependent, ventricular arrhythmic risks attributed to clinical conditions associated with mitochondrial energetic dysfunction. These were accompanied by compromised action potential (AP) upstroke rates and impaired conduction velocities potentially producing arrhythmic substrate. We tested a hypothesis implicating compromised Na+ current in these electrophysiological phenotypes by applying loose patch-clamp techniques in intact young and aged, wild-type (WT) and Pgc-1ß-/- , ventricular cardiomyocyte preparations for the first time. This allowed conservation of their in vivo extracellular and intracellular conditions. Depolarising steps elicited typical voltage-dependent activating and inactivating inward Na+ currents with peak amplitudes increasing or decreasing with their respective activating or preceding inactivating voltage steps. Two-way analysis of variance associated Pgc-1ß-/- genotype with independent reductions in maximum peak ventricular Na+ currents from -36.63 ± 2.14 (n = 20) and -35.43 ± 1.96 (n = 18; young and aged WT, respectively), to -29.06 ± 1.65 (n = 23) and -27.93 ± 1.63 (n = 20; young and aged Pgc-1ß-/- , respectively) pA/µm2 (p < 0.0001), without independent effects of, or interactions with age. Voltages at half-maximal current V*, and steepness factors k in plots of voltage dependences of both Na+ current activation and inactivation, and time constants for its postrepolarisation recovery from inactivation, remained indistinguishable through all experimental groups. So were the activation and rectification properties of delayed outward (K+ ) currents, demonstrated from tail currents reflecting current recoveries from respective varying or constant voltage steps. These current-voltage properties directly implicate decreases specifically in maximum available Na+ current with unchanged voltage dependences and unaltered K+ current properties, in proarrhythmic reductions in AP conduction velocity in Pgc-1ß-/- ventricles.

Age-dependent electrocardiographic changes in Pgc-1ß deficient murine hearts.

Increasing evidence implicates chronic energetic dysfunction in human cardiac arrhythmias. Mitochondrial impairment through Pgc-1ß knockout is known to produce a murine arrhythmic phenotype. However, the cumulative effect of this with advancing age and its electrocardiographic basis have not been previously studied. Young (12-16 weeks) and aged (>52 weeks), wild type (WT) (n = 5 and 8) and Pgc-1ß-/- (n = 9 and 6), mice were anaesthetised and used for electrocardiographic (ECG) recordings. Time intervals separating successive ECG deflections were analysed for differences between groups before and after ß1-adrenergic (intraperitoneal dobutamine 3 mg/kg) challenge. Heart rates before dobutamine challenge were indistinguishable between groups. The Pgc-1ß-/- genotype however displayed compromised nodal function in response to adrenergic challenge. This manifested as an impaired heart rate response suggesting a functional defect at the level of the sino-atrial node, and a negative dromotropic response suggesting an atrioventricular conduction defect. Incidences of the latter were most pronounced in the aged Pgc-1ß-/- mice. Moreover, Pgc-1ß-/- mice displayed electrocardiographic features consistent with the existence of a pro-arrhythmic substrate. Firstly, ventricular activation was prolonged in these mice consistent with slowed action potential conduction and is reported here for the first time. Additionally, Pgc-1ß-/- mice had shorter repolarisation intervals. These were likely attributable to altered K+ conductance properties, ultimately resulting in a shortened QTc interval, which is also known to be associated with increased arrhythmic risk. ECG analysis thus yielded electrophysiological findings bearing on potential arrhythmogenicity in intact Pgc-1ß-/- systems in widespread cardiac regions.

Epac-induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes.

Acute RyR2 activation by exchange protein directly activated by cAMP (Epac) reversibly perturbs myocyte Ca2+ homeostasis, slows myocardial action potential conduction, and exerts pro-arrhythmic effects. Loose patch-clamp studies, preserving in vivo extracellular and intracellular conditions, investigated Na+ current in intact cardiomyocytes in murine atrial and ventricular preparations following Epac activation. Depolarising steps to varying test voltages activated typical voltage-dependent Na+ currents. Plots of peak current against depolarisation from resting potential gave pretreatment maximum atrial and ventricular currents of -20.23 ± 1.48 (17) and -29.8 ± 2.4 (10) pA/µm2 (mean ± SEM [n]). Challenge by 8-CPT (1 µmol/L) reduced these currents to -11.21 ± 0.91 (12) (P < .004) and -19.3 ± 1.6 (11) pA/µm2 (P < .04) respectively. Currents following further addition of the RyR2 inhibitor dantrolene (10 µmol/L) (-19.91 ± 2.84 (13) and -26.6 ± 1.7 (17)), and dantrolene whether alone (-19.53 ± 1.97 (8) and -27.6 ± 1.9 (14)) or combined with 8-CPT (-19.93 ± 2.59 (12) and -29.9 ± 2.5(11)), were indistinguishable from pretreatment values (all P >> .05). Assessment of the inactivation that followed by applying subsequent steps to a fixed voltage 100 mV positive to resting potential gave concordant results. Half-maximal inactivation voltages and steepness factors, and time constants for Na+ current recovery from inactivation in double-pulse experiments, were similar through all the pharmacological conditions. Intracellular sharp microelectrode membrane potential recordings in intact Langendorff-perfused preparations demonstrated concordant variations in maximum rates of atrial and ventricular action potential upstroke, (dV/dt)max . We thus demonstrate an acute, reversible, Na+ channel inhibition offering a possible mechanism for previously reported pro-arrhythmic slowing of AP propagation following modifications of Ca2+ homeostasis, complementing earlier findings from chronic alterations in Ca2+ homeostasis in genetically-modified RyR2-P2328S hearts.

Gene and Protein Expression Profile of Selected Molecular Targets Mediating Electrophysiological Function in Pgc-1α Deficient Murine Atria.

Increases in the prevalence of obesity, insulin resistance, and metabolic syndrome has led to the increase of atrial fibrillation (AF) cases in the developed world. These AF risk factors are associated with mitochondrial dysfunction, previously modelled using peroxisome proliferator activated receptor-γ (PPARγ) coactivator-1 (Pgc-1)-deficient murine cardiac models. We explored gene and protein expression profiles of selected molecular targets related to electrophysiological function in murine Pgc-1α-/- atria. qPCR analysis surveyed genes related to Na⁺-K⁺-ATPase, K⁺ conductance, hyperpolarisation-activated cyclic nucleotide-gated (Hcn), Na⁺ channels, Ca2+ channels, and indicators for adrenergic and cholinergic receptor modulation. Western blot analysis for molecular targets specific to conduction velocity (Nav1.5 channel and gap junctions) was performed. Transcription profiles revealed downregulation of molecules related to Na⁺-K⁺-ATPase transport, Hcn-dependent pacemaker function, Na⁺ channel-dependent action potential activation and propagation, Ca2+ current generation, calsequestrin-2 dependent Ca2+ homeostasis, and adrenergic α1D dependent protection from hypertrophic change. Nav1.5 channel protein expression but not gap junction expression was reduced in Pgc-1α-/- atria compared to WT. Nav1.5 reduction reflects corresponding reduction in its gene expression profile. These changes, as well as the underlying Pgc-1α-/- alteration, suggest potential pharmacological targets directed towards either upstream PGC-1 signalling mechanisms or downstream ion channel changes.

Sodium channel biophysics, late sodium current and genetic arrhythmic syndromes.

Arrhythmias arise from breakdown of orderly action potential (AP) activation, propagation and recovery driven by interactive opening and closing of successive voltage-gated ion channels, in which one or more Na+ current components play critical parts. Early peak, Na+ currents (I Na) reflecting channel activation drive the AP upstroke central to cellular activation and its propagation. Sustained late Na+ currents (I Na-L) include contributions from a component with a delayed inactivation timecourse influencing AP duration (APD) and refractoriness, potentially causing pro-arrhythmic phenotypes. The magnitude of I Na-L can be analysed through overlaps or otherwise in the overall voltage dependences of the steady-state properties and kinetics of activation and inactivation of the Na+ conductance. This was useful in analysing repetitive firing associated with paramyotonia congenita in skeletal muscle. Similarly, genetic cardiac Na+ channel abnormalities increasing I Na-L are implicated in triggering phenomena of automaticity, early and delayed afterdepolarisations and arrhythmic substrate. This review illustrates a wide range of situations that may accentuate I Na-L. These include (1) overlaps between steady-state activation and inactivation increasing window current, (2) kinetic deficiencies in Na+ channel inactivation leading to bursting phenomena associated with repetitive channel openings and (3) non-equilibrium gating processes causing channel re-opening due to more rapid recoveries from inactivation. All these biophysical possibilities were identified in a selection of abnormal human SCN5A genotypes. The latter presented as a broad range of clinical arrhythmic phenotypes, for which effective therapeutic intervention would require specific identification and targeting of the diverse electrophysiological abnormalities underlying their increased I Na-L.