Clinical, Neurophysiological and Histopatological correlations in Pure Neural Leprosy

Although neuropathy remains one of the most problematic issues faced by leprosy patients, the evolving process of its findings continues a challenge particularly in pure neural leprosy (PNL). We evaluated neurological examination, nerve conduction studies and histhopathological data of patients with PNL and ulnar neuropathy. Patients with longer duration of symptoms had reduction in the motor conduction velocities and patients with fibrosis in the biopsy had axonal damage in the nerve conduction studies. This suggests that focal demyelination may be present in leprosy patients at the moment of the diagnosis and be related to the duration of the neuropathy.

ECG and Pacing Criteria for Differentiating Conduction System Pacing from Myocardial Pacing

During His-Purkinje conduction system (HPS) pacing, it is crucial to confirm capture of the His bundle or left bundle branch versus myocardialonly capture. For this, several methods and criteria for differentiation between non-selective (ns) capture – capture of the HPS and the adjacent myocardium – and myocardial-only capture were developed. HPS capture results in faster and more homogenous depolarisation of the left ventricle than right ventricular septal (RVS) myocardial-only capture. Specifically, the depolarisation of the left ventricle (LV) does not require slow cell-to-cell spread of activation from the right side to the left side of the interventricular septum but begins simultaneously with QRS onset as in native depolarisation. These phenomena greatly influence QRS complex morphology and form the basis of electrocardiographic differentiation between HPS and myocardial paced QRS. Moreover, the HPS and the working myocardium are different tissues within the heart muscle that vary not only in conduction velocities but also in refractoriness and capture thresholds. These last two differences can be exploited for the diagnosis of HPS capture using dynamic pacing manoeuvres, namely differential output pacing, programmed stimulation and burst pacing. This review summarises current knowledge of this subject.

Ca2+-dependent modulation of voltage-gated myocyte sodium channels

Voltage-dependent Na+ channel activation underlies action potential generation fundamental to cellular excitability. In skeletal and cardiac muscle this triggers contraction via ryanodine-receptor (RyR)-mediated sarcoplasmic reticular (SR) Ca2+ release. We here review potential feedback actions of intracellular [Ca2+] ([Ca2+]i) on Na+ channel activity, surveying their structural, genetic and cellular and functional implications, translating these to their possible clinical importance. In addition to phosphorylation sites, both Nav1.4 and Nav1.5 possess potentially regulatory binding sites for Ca2+ and/or the Ca2+-sensor calmodulin in their inactivating III–IV linker and C-terminal domains (CTD), where mutations are associated with a range of skeletal and cardiac muscle diseases. We summarize in vitro cell-attached patch clamp studies reporting correspondingly diverse, direct and indirect, Ca2+ effects upon maximal Nav1.4 and Nav1.5 currents (Imax) and their half-maximal voltages (V1/2) characterizing channel gating, in cellular expression systems and isolated myocytes. Interventions increasing cytoplasmic [Ca2+]i down-regulated Imax leaving V1/2 constant in native loose patch clamped, wild-type murine skeletal and cardiac myocytes. They correspondingly reduced action potential upstroke rates and conduction velocities, causing pro-arrhythmic effects in intact perfused hearts. Genetically modified murine RyR2-P2328S hearts modelling catecholaminergic polymorphic ventricular tachycardia (CPVT), recapitulated clinical ventricular and atrial pro-arrhythmic phenotypes following catecholaminergic challenge. These accompanied reductions in action potential conduction velocities. The latter were reversed by flecainide at RyR-blocking concentrations specifically in RyR2-P2328S as opposed to wild-type hearts, suggesting a basis for its recent therapeutic application in CPVT. We finally explore the relevance of these mechanisms in further genetic paradigms for commoner metabolic and structural cardiac disease.

A Computational Study of the Electrophysiological Substrate in Patients Suffering From Atrial Fibrillation

In the context of cardiac electrophysiology, we propose a novel computational approach to highlight and explain the long-debated mechanisms behind atrial fibrillation (AF) and to reliably numerically predict its induction and sustainment. A key role is played, in this respect, by a new way of setting a parametrization of electrophysiological mathematical models based on conduction velocities; these latter are estimated from high-density mapping data, which provide a detailed characterization of patients' electrophysiological substrate during sinus rhythm. We integrate numerically approximated conduction velocities into a mathematical model consisting of a coupled system of partial and ordinary differential equations, formed by the monodomain equation and the Courtemanche-Ramirez-Nattel model. Our new model parametrization is then adopted to predict the formation and self-sustainment of localized reentries characterizing atrial fibrillation, by numerically simulating the onset of ectopic beats from the pulmonary veins. We investigate the paroxysmal and the persistent form of AF starting from electro-anatomical maps of two patients. The model's response to stimulation shows how substrate characteristics play a key role in inducing and sustaining these arrhythmias. Localized reentries are less frequent and less stable in case of paroxysmal AF, while they tend to anchor themselves in areas affected by severe slow conduction in case of persistent AF.

Cardiorespiratory fitness and electroanatomical remodelling in patients with atrial fibrillation

Funding Acknowledgements Type of funding sources: None. Introduction Atrial fibrillation (AF) is the most common clinically-relevant arrhythmia. Its initiation and maintenance is linked to the presence cardiovascular risk factors such as hypertension and obesity. Higher cardiorespiratory fitness (CRF) has been associated with a better prognosis. However, specific electroanatomical features associated with baseline CRF have not been described. Purpose Compare electroanatomical substrate across exercise capacity levels in patients with AF Methods Patients referred for de novo AF radiofrequency ablation at the Centre for Heart Rhythm Disorders from August 2017 until June 2020 were screened for inclusion and CRF was evaluated in metabolic equivalents (METs) by a symptom-limited maximal treadmill exercise test using the standard Bruce protocol prior to ablation. Predicted CRF was calculated based on established equations and patients were categorized according to the percentage of predicted CRF achieved; low (<85%), adequate (85-100%) and high (>100%). Total mean and regional peak-to-peak bipolar voltages, percent of low voltage areas (% LVA), conduction velocity (CV) and percent of complex fractionated electrograms (% CFE) in sinus rhythm were compared across groups. Results There were no between-group differences in baseline characteristics, medication use or echocardiographic features. Total mean voltage was significantly lower in the low CRF group compared to both adequate and high CRF. Compared to the high CRF group, roof (3.25 ± 1.2 mV vs 1.9 ± 1.3 mV, p < 0.05), posterior (3.8 ± 1.8 mV vs 1.7 ± 0.9 mV, p < 0.001) and inferior mean voltages (3.4 ± 2 mV vs 1.6 ± 0.7 mV, p < 0.05) were significantly lower in the low CRF group (figure 1A). Furthermore, compared with the adequate CRF group, mean voltages were significantly lower in the posterior (3.7 ± 1.5 mV vs 1.7 ± 0.9 mV, p < 0.001), inferior (3.4 ± 1 mV vs 1.6 ± 0.7 mV, p < 0.001) and lateral (4.2 ± 2.2 mV vs 2.1 ± 1.4 mV, p < 0.05) walls of the low CRF group. Anterior and septal mean voltages were not significantly different across CRF groups (P for trend = 0.07, 0.3 and 0.15, respectively). Conduction velocities were not significantly different across groups. The inferior %LVA was significantly higher in the low CRF (5.6 ± 6%) compared to adequate CRF group (23 ± 18%) (p < 0.05) (figure 1B). Total and regional % CFE was higher in the low CRF compared to adequate and high CRF. Conclusion Participants in the lower baseline CRF category showed significant reductions in regional voltages along with higher fractionation with preserved conduction velocities. Research on the effect of physical activity and CRF on left atrial arrhythmogenic substrate is required. Abstract Figure. Global and regional mV and % LVA by CRF

Variant Intronic Enhancer Controls SCN10A-Short Expression and Heart Conduction

Background: Genetic variants in SCN10A , encoding the neural voltage-gated sodium channel NaV1.8, are strongly associated with atrial fibrillation, Brugada syndrome, cardiac conduction velocities and heart rate. The cardiac function of SCN10A has not been resolved, however, and diverging mechanisms have been proposed. Here, we investigated the cardiac expression of SCN10A and the function of a variant-sensitive intronic enhancer previously linked to the regulation of SCN5A , encoding the major essential cardiac sodium channel NaV1.5. Methods: The expression of SCN10A was investigated in mouse and human hearts. Using CRISPR/Cas9 genome editing, the mouse intronic enhancer was disrupted, and mutant mice were characterized by transcriptomic and electrophysiological analyses. The association of genetic variants at SCN5A-SCN10A enhancer regions and gene expression were evaluated by GWAS SNP mapping and expression QTL analysis. Results: We found that cardiomyocytes of the atria, sinoatrial node and ventricular conduction system express a short transcript comprising the last 7 exons of the gene ( Scn10a-short ). Transcription occurs from an intronic enhancer-promoter complex, while full length Scn10a transcript was undetectable in the human and mouse heart. Expression QTL analysis revealed that the genetic variants in linkage disequilibrium with genetic variant rs6801957 in the intronic enhancer associate with SCN10A transcript levels in the heart. Genetic modification of the enhancer in the mouse genome led to reduced cardiac Scn10a-short expression in atria and ventricles, reduced cardiac sodium current in atrial cardiomyocytes, atrial conduction slowing and arrhythmia, while expression of Scn5a , the presumed enhancer target gene, remained unaffected. In patch-clamp transfection experiments, expression of Scn10a-short -encoded NaV1.8-short increased NaV1.5-mediated sodium current. We propose that non-coding genetic variation modulates transcriptional regulation of Scn10a-short in cardiomyocytes that impacts on NaV1.5-mediated sodium current and heart rhythm. Conclusions: Genetic variants in and around SCN10A modulate enhancer function and expression of a cardiac-specific SCN10A-short transcript. We propose that non-coding genetic variation modulates transcriptional regulation of a functional C-terminal portion of NaV1.8 in cardiomyocytes that impacts on NaV1.5 function, cardiac conduction velocities and arrhythmia susceptibility.

Essential Oil of Croton zehntneri Prevents Conduction Alterations Produced by Diabetes Mellitus on Vagus Nerve

Autonomic diabetic neuropathy (ADN) is a complication of diabetes mellitus (DM), to which there is no specific treatment. In this study, the efficacy of the essential oil of Croton zehntneri (EOCz) in preventing ADN was evaluated in the rat vagus nerve. For the two fastest conducting myelinated types of axons of the vagus nerve, the conduction velocities and rheobase decreased, whilst the duration of the components of the compound action potential of these fibers increased. EOCz completely prevented these DM-induced alterations of the vagus nerve. Unmyelinated fibers were not affected. In conclusion, this investigation demonstrated that EOCz is a potential therapeutic agent for the treatment of ADN.

Treatment-Induced Neuropathy in Diabetes (TIND)—Developing a Disease Model in Type 1 Diabetic Rats

Treatment-induced neuropathy in diabetes (TIND) is defined by the occurrence of an acute neuropathy within 8 weeks of an abrupt decrease in glycated hemoglobin-A1c (HbA1c). The underlying pathogenic mechanisms are still incompletely understood with only one mouse model being explored to date. The aim of this study was to further explore the hypothesis that an abrupt insulin-induced fall in HbA1c may be the prime causal factor of developing TIND. BB/OKL (bio breeding/OKL, Ottawa Karlsburg Leipzig) diabetic rats were randomized in three groups, receiving insulin treatment by implanted subcutaneous osmotic insulin pumps for 3 months, as follows: Group one received 2 units per day; group two 1 unit per day: and group three 1 unit per day in the first month, followed by 2 units per day in the last two months. We serially examined blood glucose and HbA1c levels, motor- and sensory/mixed afferent conduction velocities (mNCV and csNCV) and peripheral nerve morphology, including intraepidermal nerve fiber density and numbers of Iba-1 (ionized calcium binding adaptor molecule 1) positive macrophages in the sciatic nerve. Only in BB/OKL rats of group three, with a rapid decrease in HbA1c of more than 2%, did we find a significant decrease in mNCV in sciatic nerves (81% of initial values) after three months of treatment as compared to those group three rats with a less marked decrease in HbA1c <2% (mNCV 106% of initial values, p ≤ 0.01). A similar trend was observed for sensory/mixed afferent nerve conduction velocities: csNCV were reduced in BB/OKL rats with a rapid decrease in HbA1c >2% (csNCV 90% of initial values), compared to those rats with a mild decrease <2% (csNCV 112% of initial values, p ≤ 0.01). Moreover, BB/OKL rats of group three with a decrease in HbA1c >2% showed significantly greater infiltration of macrophages by about 50% (p ≤ 0.01) and a decreased amount of calcitonin gene related peptide (CGRP) positive nerve fibers as compared to the animals with a milder decrease in HbA1c. We conclude that a mild acute neuropathy with inflammatory components was induced in BB/OKL rats as a consequence of an abrupt decrease in HbA1c caused by high-dose insulin treatment. This experimentally induced neuropathy shares some features with TIND in humans and may be further explored in studies into the pathogenesis and treatment of TIND.

Electrophysiological properties of maxillary trigeminal Aβ-afferent neurons of rats

Aβ-afferents in maxillary or V2 trigeminal ganglion (TG) neurons are somatosensory neurons that may be involved in both non-nociceptive and nociceptive functions in orofacial regions. However, electrophysiological properties of these V2 trigeminal Aβ-afferent neurons have not been well characterized so far. Here, we used rat ex vivo trigeminal nerve preparations and applied patch-clamp recordings to large-sized V2 TG neurons to characterize their electrophysiological properties. All the cells recorded had afferent conduction velocities in the range of Aβ-afferent conduction speeds. However, these V2 trigeminal Aβ-afferent neurons displayed different action potential (AP) properties. APs showed fast kinetics in some cells but slow kinetics with shoulders in repolarization phases in other cells. Based on the derivatives of voltages in AP repolarization with time (dV/dt), we classified V2 trigeminal Aβ-afferent neurons into four types: type I, type II, type IIIa and type IIIb. Type I V2 trigeminal Aβ-afferent neurons had the largest dV/dt of repolarization, the fastest AP conduction velocities, the shortest AP and afterhyperpolarization (AHP) durations, and the highest AP success rates. In contrast, type IIIb V2 trigeminal Aβ-afferent neurons had the smallest dV/dt of AP repolarization, the slowest AP conduction velocities, the longest AP and AHP durations, and the lowest AP success rates. The type IIIb cells also had significantly lower voltage-activated K+ currents. For type II and type IIIa V2 trigeminal Aβ-afferent neurons, AP parameters were in the range between those of type I and type IIIb V2 trigeminal Aβ-afferent neurons. Our electrophysiological classification of V2 trigeminal Aβ-afferent neurons may be useful in future to study their non-nociceptive and nociceptive functions in orofacial regions.

Assessing Velocity and Directionality of Uterine Electrical Activity for Preterm Birth Prediction Using EHG Surface Records

The aim of the present study was to assess the capability of conduction velocity amplitudes and directions of propagation of electrohysterogram (EHG) waves to better distinguish between preterm and term EHG surface records. Using short-time cross-correlation between pairs of bipolar EHG signals (upper and lower, left and right), the conduction velocities and their directions were estimated using preterm and term EHG records of the publicly available Term–Preterm EHG DataSet with Tocogram (TPEHGT DS) and for different frequency bands below and above 1.0 Hz, where contractions and the influence of the maternal heart rate on the uterus, respectively, are expected. No significant or preferred continuous direction of propagation was found in any of the non-contraction (dummy) or contraction intervals; however, on average, a significantly lower percentage of velocity vectors was found in the vertical direction, and significantly higher in the horizontal direction, for preterm dummy intervals above 1.0 Hz. The newly defined features—the percentages of velocities in the vertical and horizontal directions, in combination with the sample entropy of the EHG signal recorded in the vertical direction, obtained from dummy intervals above 1.0 Hz—showed the highest classification accuracy of 86.8% (AUC=90.3%) in distinguishing between preterm and term EHG records of the TPEHGT DS.