Search

Introduction: Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by the increased number of CTG repeats in 3' UTR of Dystrophia Myotonia Protein Kinase (DMPK) gene. DM1 patients experience conduction abnormalities as well as atrial and ventricular arrhythmias with increased susceptibility to sudden cardiac death. The ionic basis of these electrical abnormalities is poorly understood. Methods: We evaluated the surface electrocardiogram (ECG) and key ion currents underlying the action potential (AP) in a mouse model of DM1, DMSXL, which express over 1000 CTG repeats. Sodium current (INa), L-type calcium current (ICaL), transient outward potassium current (Ito), and APs were recorded using the patchclamp technique. Results: Arrhythmic events on the ECG including sinus bradycardia, conduction defects, and premature ventricular and atrial arrhythmias were observed in DMSXL homozygous mice but not in WT mice. PR interval shortening was observed in homozygous mice while ECG parameters such as QRS duration, and QTc did not change. Further, flecainide prolonged PR, QRS, and QTc visually in DMSXL homozygous mice. At the single ventricular myocyte level, we observed a reduced current density for Ito and ICaL with a positive shift in steady state activation of L-type calcium channels carrying ICaL in DMSXL homozygous mice compared with WT mice. INa densities and action potential duration did not change between DMSXL and WT mice. Conclusion: The reduced current densities of Ito, and ICaL and alterations in gating properties in L-type calcium channels may contribute to the ECG abnormalities in the DMSXL mouse model of DM1. These findings open new avenues for novel targeted therapeutics. [ABSTRACT FROM AUTHOR]

Generating atrial-like cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) is crucial for modeling and treating atrial-related diseases, such as atrial arrythmias including atrial fibrillations. However, it is essential to obtain a comprehensive understanding of the electrophysiological properties of these cells. The objective of the present study was to investigate the molecular, electrical, and biophysical properties of several ion channels, especially NaV1.5 channels, in atrial hiPSC cardiomyocytes. Atrial cardiomyocytes were obtained by the differentiation of hiPSCs treated with retinoic acid (RA). The quality of the atrial specification was assessed by qPCR, immunocytofluorescence, and western blotting. The electrophysiological properties of action potentials (APs), Ca2+ dynamics, K+ and Na+ currents were investigated using patch-clamp and optical mapping approaches. We evaluated mRNA transcript and protein expressions to show that atrial cardiomyocytes expressed higher atrial- and sinoatrial-specific markers (MYL7, CACNA1D) and lower ventricular-specific markers (MYL2, CACNA1C, GJA1) than ventricular cardiomyocytes. The amplitude, duration, and steady-state phase of APs in atrial cardiomyocytes decreased, and had a shape similar to that of mature atrial cardiomyocytes. Interestingly, NaV1.5 channels in atrial cardiomyocytes exhibited lower mRNA transcripts and protein expression, which could explain the lower current densities recorded by patch-clamp. Moreover, Na+ currents exhibited differences in activation and inactivation parameters. These differences could be explained by an increase in SCN2B regulatory subunit expression and a decrease in SCN1B and SCN4B regulatory subunit expressions. Our results show that a RA treatment made it possible to obtain atrial cardiomyocytes and investigate differences in NaV1.5 channel properties between ventricular- and atrial-like cells. [ABSTRACT FROM AUTHOR]

The article is an editorial published in Frontiers in Pharmacology that discusses the importance of studying ion channels and channelopathies in pharmacology. It highlights five review publications from 2023 that have made significant advancements in this field. The reviews cover topics such as the TRPV1 channel, calcium overload-based ion interference therapy, BK channels, reactive astrogliosis, and the voltage-gated sodium channel NaV1.4. The editorial emphasizes the interdisciplinary nature of this research and the potential for collaboration between researchers, clinicians, and industry partners to improve patient outcomes. [Extracted from the article]

P2X receptors are cation-permeable ligand-gated ion channels that open in response to the binding of ATP. These receptors are present in many excitable cells, including neurons, striated muscle cells, epithelial cells, and leukocytes. They mediate fast excitatory neurotransmission in the central and peripheral nervous systems and are thought to be involved in neuropathic pain, inflammation, and cell damage following ischemia-reperfusion injuries. P2X receptors are thus a target for the development of new therapeutics to treat chronic pain and inflammation. In this study, we characterized the inhibition caused by pyridoxal-5'-phosphate, a natural metabolite of vitamin [B.sub.6] (MC- 1), of P2[X.sub.2], P2[X.sub.4], P2[X.sub.7], and P2[X.sub.2/3] receptors stably expressed in HEK293 cells using the patch-clamp technique in the whole-cell configuration. We also tested a new approach using VC6.1, a modified cameleon calcium-sensitive fluorescent protein, to characterize the inhibition of P2[X.sub.2] and P2[X.sub.2/3]. MC-1 blocked these two P2X receptors, with an [IC.sub.50] of 7 and 13 µmol/L, respectively. P2[X.sub.2] exhibited the highest affinity for VC6.1, and the chimeric receptor P2[X.sub.2/3], the lowest. The patch-clamp and imaging approaches gave similar results and indicated that VC6.1 may be useful for high throughput drug screening. Pyridoxal-5'-phosphate is an efficient P2X blocker and can be classified as a P2X antagonist. Key words: P2X receptors, purinergic receptors, patch-clamp, ATP, HEK293 cells, pyridoxal-5'-phosphate, calcium. Les recepteurs P2X sont des canaux ioniques operes par un ligand, permeables aux cations, qui s'ouvrent en reponse a la liaison de l'ATP. Ces recepteurs sont presents chez plusieurs cellules excitables, notamment les neurones, les cellules de muscle strie, les cellules epitheliales et les leucocytes. Ils servent d'intermediaires a la transmission excitatrice rapide dans les systemes nerveux central et peripherique et semblent impliques dans la douleur neuropathique, l'inflammation et le dommage cellulaire qui suit une ischemie-reperfusion. Les recepteurs P2X constituent ainsi des cibles de developpement de nouvelles therapies visant le traitement de la douleur chronique et l'inflammation. Dans cette etude, nous avons caracterise l'inhibition causee par le pyridoxal-5'-phosphate, un metabolite naturel de la vitamine [B.sub.6] (MC-1), des recepteurs P2[X.sub.2], P2[X.sub.4], P2[X.sub.7]et P2[X.sub.2/3] exprimes de facon stable dans les cellules HEK293, grace a la technique de patch-clamp sur cellules entieres. Nous avons aussi teste une nouvelle approche a l'aide de VC6.1, une proteine fluorescente Cameleon modifiee sensible au calcium, afin de caracteriser l'inhibition de P2[X.sub.2] et P2[X.sub.2/3]. Le MC-1 bloquait ces deux recepteur P2X, avec des [CI.sub.50] de 7 µmol/L et 13 µmol/L, respectivement. Le P2[X.sub.2] presentait l'affinite la plus forte pour VC6.1, et le recepteur chimere P2[X.sub.2/3], la plus faible. Les approches en patch-clamp et par imagerie produisaient des resultats similaires et indiquaient que VC6.1 pourrait etre utile lors d'un criblage a haut debit. Le pyridoxal-5'-phosphate est une bloqueur efficace de P2X et peut etre classe parmi les antagonistes de P2X. [Traduit par la Redaction] Mots-cles: recepteurs P2X, recepteurs purinergiques, patch-clamp, ATP, HEK293, pyridoxal-5'-phosphate, calcium., Introduction P2 receptors are a family of receptors that respond to the binding of extracellular ATP, ADP, UTP, and UDP. The family is composed of 2 subfamilies that differ in [...]

Ca2+ plays a crucial role in excitation-contraction coupling in cardiac myocytes. Dysfunctional Ca2+ regulation alters the force of contraction and causes cardiac arrhythmias. Ca2+ entry into cardiomyocytes is mediated mainly through L-type Ca2+ channels, leading to the subsequent Ca2+ release from the sarcoplasmic reticulum. L-type Ca2+ channels are composed of the conventional Cav1.2, ubiquitously expressed in all heart chambers, and the developmentally regulated Cav1.3, exclusively expressed in the atria, sinoatrial node, and atrioventricular node in the adult heart. As such, Cav1.3 is implicated in the pathogenesis of sinoatrial and atrioventricular node dysfunction as well as atrial fibrillation. More recently, Cav1.3 de novo expression was suggested in heart failure. Here, we review the functional role, expression levels, and regulation of Cav1.3 in the heart, including in the context of cardiac diseases. We believe that the elucidation of the functional and molecular pathways regulating Cav1.3 in the heart will assist in developing novel targeted therapeutic interventions for the aforementioned arrhythmias. [ABSTRACT FROM AUTHOR]

Background: The uptake of COVID-19 booster vaccines has been significantly low. Therefore, it is questionable whether combining the COVID-19 booster vaccines with influenza vaccines can increase the population's interest in taking such vaccines and manage the health pandemic effectively. Methodology: In this systematic review and meta-analysis, a synthesis of the findings and summary of a total of 30 research articles based on the topic, 'combining influenza and COVID-19 booster vaccination strategy' was undertaken. The research articles were identified from three databases, namely, PubMed, Cochran Library, and Google Scholar using specific keywords and inclusion criteria. However, research articles that were not peer-reviewed and not published in English were excluded from the systematic review and meta-analysis. The average risk ratio of the intervention group getting a combination of COVID-19 booster and influenza vaccines from the samples of the included studies was 0.78 with regard to a 95% CI. Such risk ratio is based on the null hypothesis of the current study that combining COVID-19 booster and influenza vaccines can increase the uptake of COVID-19 booster vaccines. On the other hand, the heterogeneity between such studies was I2 = 35%, while the statistical significance of their findings occurred at p < 0.05. The average p-value of the included research studies was p = 0.62 with the proportion of studies with significant p-values being 63.33% which is equivalent to 19 out of 30 studies. Therefore, the null hypothesis was not rejected in more than half of the studies. Results: A synthesis of the chosen research articles revealed that when influenza and COVID-19 booster vaccines are combined, there is potential for an increase in the uptake of the latter, mainly because many populations have already been accustomed to taking influenza vaccines on an annual basis. Conclusions: In this way, through such findings, medical health experts can make informed decisions to increase the population's willingness to receive the COVID-19 booster vaccines. [ABSTRACT FROM AUTHOR]

Aims Ventricular fibrillation (VF) occurring in the acute phase of ST-elevation myocardial infarction (STEMI) is the leading cause of sudden cardiac death worldwide. Several studies showed that reduced connexin 43 (Cx43) expression and reduced conduction velocity increase the risk of VF in acute myocardial infarction (MI). Furthermore, genetic background might predispose individuals to primary VF (PVF). The primary objective was to evaluate the presence of GJA1 variants in STEMI patients. The secondary objective was to evaluate the arrhythmogenic impact of GJA1 variants in STEMI patients with VF. Methods and results The MAP-IDM prospective cohort study included 966 STEMI patients and was designed to identify genetic predisposition to VF. A total of 483 (50.0%) STEMI patients with PVF were included. The presence of GJA1 variants increased the risk of VF in STEMI patients [from 49.1 to 70.8%, P = 0.0423; odds ratio (OR): 0.40; 95% confidence interval: 0.16–0.97; P = 0.04]. The risk of PVF decreased with beta-blocker intake (from 53.5 to 44.8%, P = 0.0085), atrial fibrillation (from 50.7 to 26.4%, P = 0.0022), and with left ventricular ejection fraction >50% (from 60.2 to 41.4%, P < 0.0001). Among 16 GJA1 variants, three novel heterozygous missense variants were identified in three patients: V236I, H248R, and I327M. In vitro studies of these variants showed altered Cx43 localization and decreased cellular communication, mainly during acidosis. Conclusion Connexin 43 variants are associated with increased VF susceptibility in STEMI patients. Restoring Cx43 function may be a potential therapeutic target to prevent PVF in patients with acute MI. Clinical trial registration Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00859300 [ABSTRACT FROM AUTHOR]