Search Results (107)

Background and Clinical Significance: Brugada syndrome (BrS) is a rare inherited cardiac channelopathy, often associated with SCN5A loss-of-function mutations. Clinical presentations range from asymptomatic to malignant arrhythmias and sudden cardiac death. Physiological and pharmacological stressors affecting sodium channel function—such as pyrexia, certain medications, and possibly pregnancy—may unmask or exacerbate arrhythmic risk. However, there is limited information regarding pregnancy and obstetric outcomes. Obstetric management remains largely informed by isolated case reports and small case series. A literature review was conducted using OVID Medline and Embase, identifying case reports, case series, and one retrospective cohort study reporting clinical presentation, obstetric management, and outcomes in maternal BrS. A case is presented detailing coordinated multidisciplinary input, antenatal surveillance, and intrapartum and postpartum care to contribute to the growing evidence base guiding obstetric care in this complex setting. Case Presentation: A 30-year-old G2P0 woman with asymptomatic BrS (SCN5A-positive) was referred at 31 + 5 weeks’ gestation for multidisciplinary antenatal care. Regular review and collaborative planning involving cardiology, anaesthetics, maternal–fetal medicine, and obstetrics guided a plan for vaginal delivery with continuous cardiac and fetal monitoring. At 38 + 0 weeks, the woman presented with spontaneous rupture of membranes and underwent induction of labour. A normal vaginal delivery was achieved without arrhythmic events. Epidural block with ropivacaine and local anaesthesia with lignocaine were well tolerated, and 24 h postpartum monitoring revealed no abnormalities. Conclusions: This case adds to the limited but growing literature suggesting that with individualised planning and multidisciplinary care, pregnancies in women with BrS can proceed safely and without complication. Ongoing case reporting is essential to inform future guidelines and optimise maternal and fetal outcomes. Full article

Brugada syndrome is a rare inherited heart disease characterized by ventricular arrhythmias and characteristic ST segment elevation, which increases the risk of sudden death. Studies have shown that the pathogenesis of this disease involves a variety of gene mutations, including abnormal functions of sodium, calcium, and potassium ion channels, resulting in cardiac electrophysiological disorders. These variants affect excitability and conduction of cardiomyocytes, thereby increasing the susceptibility to ventricular arrhythmias and sudden death. However, many genetic variants remain of uncertain significance or are insufficiently characterized, necessitating further investigation. This review summarizes the genetic variants associated with Brugada syndrome and discusses their potential implications for improving diagnosis and therapeutic approaches. Full article

Redox regulation is crucial for the cardiac action potential, coordinating the sodium-driven depolarization, calcium-mediated plateau formation, and potassium-dependent repolarization processes required for proper heart function. Under physiological conditions, low-level reactive oxygen species (ROS), generated by mitochondria and membrane oxidases, adjust ion channel function and support excitation–contraction coupling. However, when ROS accumulate, they modify a variety of important channel proteins in cardiomyocytes, which commonly results in reducing potassium currents, enhancing sodium and calcium influx, and enhancing intracellular calcium release. These redox-driven alterations disrupt the cardiac rhythm, promote after-depolarizations, impair contractile force, and accelerate the development of heart diseases. Experimental models demonstrate that oxidizing agents reduce repolarizing currents, whereas reducing systems restore normal channel activity. Similarly, oxidative modifications of calcium-handling proteins amplify sarcoplasmic reticulum release and diastolic calcium leak. Understanding the precise redox-dependent modifications of cardiac ion channels would guide new possibilities for targeted therapies aimed at restoring electrophysiological homeostasis under oxidative stress, potentially alleviating myocardial infarction and cardiovascular dysfunction. Full article

Background: The two antiepileptic drugs lacosamide and lamotrigine exert their antiepileptic effect by inhibiting sodium channels. Lacosamide enhances the inactivation of sodium channels, while lamotrigine inhibits the activation of the channel. Interactions with sodium channels also play an interesting role in cardiac pro- and antiarrhythmia, with inhibition of inactivation, in particular, being regarded as potentially proarrhythmic. Therefore, the ventricular electrophysiologic effects of lacosamide and lamotrigine were investigated in an established experimental whole-heart model. Methods: A total of 67 rabbit hearts were allocated to four groups. Retrograde aortic perfusion was performed using the Langendorff setup. The action potential duration at 90% repolarization (APD₉₀), QT intervals, spatial dispersion of repolarization, effective refractory period, post-repolarization refractoriness, and VT incidence were determined. The electrophysiological effects of lacosamide and lamotrigine were investigated in increasing concentrations on the natively perfused heart. On the other hand, perfusion with the I_Kr-blocker sotalol was performed to increase arrhythmia susceptibility, followed by perfusion with lacosamide or lamotrigine to investigate the effects of both in a setting of increased arrhythmia susceptibility. Perfusion with lacosamide and lamotrigine tended to decrease APD₉₀ and QT-interval. As expected, perfusion with sotalol led to a significant increase in APD₉₀, QT interval, and arrhythmia incidence. Additive perfusion with lacosamide led to a further increase in arrhythmia incidence, while additive perfusion with lamotrigine led to a decrease in VT incidence. Conclusions: In this model, lacosamide showed proarrhythmic effects, especially in the setting of an additive prolonged QT interval. Lamotrigine showed no significant proarrhythmia under baseline conditions and rather antiarrhythmic effects with additive QT prolongation. Full article

Apelin serves as the endogenous ligand for the APJ receptor and enhances cardiac contractility without significantly affecting potassium currents. However, its short in vivo half-life limits clinical application, prompting the development of metabolically stable APJ receptor agonists. This study employed the patch-clamp technique to investigate the effects of the C-terminally modified apelin-13-2Nal derivative (2Nal) on action potential dynamics, rapid sodium (I_Na), and transient potassium (I_TO) currents in rat cardiomyocytes. We discovered that 2Nal prolongs ventricular action potential duration by selectively blocking I_To. Dose-response analysis indicated that 2Nal acts as a partial antagonist of I_TO, achieving a maximum blockade of 47%, with an apparent EC50 of 0.3 nM, while not affecting I_Na. Our lab previously found that an imbalance between I_To and I_Na currents contributes to the development of cardiac arrhythmias in conditions like Brugada syndrome. Currently, few therapeutic options exist to safely address this imbalance, as sodium channel openers cannot restore it, and most I_To blockers are cardiotoxic. The selective blockade of I_To by 2Nal that we describe here helps restore the balance of electrical currents between I_To and I_Na. Our study presents a novel, safe partial antagonist of I_To that may help prevent arrhythmias associated with Brugada syndrome. Full article

Voltage-gated sodium channels (Navs) are critical for membrane potential depolarisation in cells, with especially important roles in neuronal and cardiomyocyte membranes. Their malfunction results in a range of disorders, and they are the target of many widely used drugs. A rapid yet accurate functional assay is therefore desirable both to probe for novel active compounds and to better understand the many different Nav isoforms. Here, we use fluorescence to monitor Nav function: cells expressing either the cardiac Nav 1.5 or pain-associated Nav 1.7 were loaded with fluorescent membrane potential sensitive dye and then stimulated with veratridine. Cells expressing Nav 1.5 show a concentration-dependent slow rise and then a plateau in fluorescence. In contrast, cells expressing Nav 1.7 show a more rapid rise and then unexpected oscillatory behavior. Inhibition by flecainide and mexiletine demonstrates that these oscillations are Nav-dependent. Thus, we show that this fluorescent membrane potential dye can provide useful functional data and that we can readily distinguish between these two Nav isoforms because of the behavior of cells expressing them when activated by veratridine. We consider these distinct behaviors may be due to different interactions of veratridine with the different Nav isoforms, although more studies are needed to understand the mechanism underlying the oscillations. Full article

Background and Clinical Significance: Mexiletine is a class 1B antiarrhythmic drug commonly prescribed for ventricular arrhythmias and neuropathic pain. It works as a blocker of the sodium channel that modulates cardiac conduction and reduces aberrant nerve signaling. While it is generally well tolerated, gastrointestinal side effects, such as nausea, vomiting, and abdominal pain, are relatively common. Esophagitis and esophageal ulcerations have been described as rare side effects; however, they are poorly documented in the literature. Esophageal ulceration induced by oral medications, termed pill esophagitis, occurs due to prolonged contact between the medication and the esophageal mucosa. Factors contributing to this phenomenon include improper administration, such as swallowing without sufficient water, taking medication before lying down, or inherent irritant properties of the drug itself. Mexiletine-induced esophageal ulceration has not been extensively reported, making such cases clinically significant and worth investigating. In particular, the prompt diagnosis of mexiletine-induced esophageal injury is essential for timely treatment initiation or the discontinuation of the drug, preventing complications such as bleeding, strictures, or perforation. Altogether, these actions are important to prevent the onset of potentially serious complications, such as bleeding, strictures, and the perforation of the esophagus. Case Presentation: Two different patients were included in this case report on mexiletine-induced esophageal ulceration: a 78-year-old woman affected by primary dilated cardiomyopathy and atrial fibrillation with high ventricular response and a 19-year-old man affected by dilated cardiomyopathy and systemic sclerosis. Conclusions: This case report underscores the importance of recognizing mexiletine-induced esophageal ulceration, and it advocates for timely diagnosis and management to optimize patient outcomes. Full article

Several mutations of the uppermost arginine, R219, in the voltage-sensing sliding helix S4_I of cardiac sodium channel Nav1.5 are reported in the ClinVar databases, but the clinical significance of the respective variants is unknown (VUSs). AlphaFold 3 models predicted a significant downshift of S4_I in the R219C VUS. Analogous downshift S4_I, upon its in silico deactivation, resulted in a salt bridge between R219 and the uppermost glutamate, E161, in helix S2_I. To understand how salt bridge elimination affects biophysical characteristics, we generated mutant channel R219E, expressed it in the HEK293-T cells, and employed the patch-clamp method in a whole-cell configuration. Mutation R219E did not change the peak current density but shortened time to the peak current at several potentials, significantly enhanced activation, enhanced steady-state inactivation and steady-state fast inactivation, and slowed recovery from inactivation. Taken together, these data suggest that mutation R219E destabilized the resting state of Nav1.5. Cardiac syndromes associated with mutations R219P/H/C/P or E161Q/K are consistent with the observed changes of biophysical characteristics of mutant channel R219E suggesting pathogenicity of the respective VUSs, as well as ClinVar-reported VUSs involving arginine or glutamate in homologous positions of several Nav1.5 paralogs. Full article

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, highliting the urgent need for new therapeutic strategies. Peptide-based therapies have demonstrated significant potential for treating CVDs; however, their clinical application is hindered by their limited stability in physiological fluids. To overcome this challenge, an effective drug delivery system is essential to protect and efficiently transport peptides to their intended targets. This study introduces two distinct strategies for loading a cardio-specific mimetic peptide (MP), previously designed to modulate L-type calcium channel function in cardiomyocytes, onto calcium phosphate nanoparticles (CaP NPs). MP-loaded CaP NPs were prepared by two different wet precipitation syntheses, one of which involved the use of sodium polyacrylate as a templating agent. Characterization of MP-loaded CaP NPs showed that their crystallinity, size, surface charge, and morphology could be tuned by adjusting the synthesis parameters. In vitro tests on cardiac cells confirmed that both types of MP-loaded CaP NPs are biocompatible with HL-1 cardiomyocytes and restored intracellular calcium flux under stressed conditions, highlighting their therapeutic potential. These results pave the way for further optimization of CaP NP formulations and suggest their potential as a viable nanomaterial for CVD treatment. Full article

Cenobamate is a new and highly effective antiseizure compound used for the treatment of adults with focal onset seizures and particularly for epilepsy resistant to other antiepileptic drugs. It acts on multiple targets, as it is a positive allosteric activator of γ-aminobutyric acid type A (GABA_A) receptors and an inhibitor of neuronal sodium channels, particularly of the late or persistent Na⁺ current. We recently evidenced the inhibitory effects of cenobamate on the peak and late current component of the human cardiac isoform hNav1.5. The determined apparent IC₅₀ values of 87.6 µM (peak) and 46.5 µM (late current) are within a clinically relevant range of concentrations (the maximal plasma therapeutic effective concentration for a daily dose of 400 mg in humans is 170 µM). In this study, we built a 3D model of the canonical hNav1.5 channel (UniProt Q14524-1) in open conformation using AlphaFold2, embedded it in a DPPC lipid bilayer, corrected the residue protonation state (pH 7.2) with H++, and added 2 Na⁺ ions in the selectivity filter. By molecular docking, we found the cenobamate binding site in the central cavity. We identified 10-point mutant variants in the binding site region and explored them via docking and MD. Mutants N1462K/Y (rs1064795922, rs199473614) and M1765R (rs752476527) (by docking) and N932S (rs2061582195) (by MD) featured higher predicted affinity than wild-type. Full article

Wnt/β-catenin signaling has been shown to regulate gene expressions in cardiomyocytes. However, it is not known if this effect is dependent on the sex of cells or the glucose level in the culture medium. In the present study, ventricular myocytes were prepared from male and female neonatal rats and maintained in either a glucose-rich (25 mM) medium or a low-glucose (3 mM), lipid-rich medium. Real-time quantitative PCR was used to measure changes in target genes (Axin2, Scn5a, and Tbx3) after treatment with 1, 3, or 10 µM of CHIR-99021, an activator of Wnt/β-catenin signaling. CHIR induced similar changes in Axin2, Tbx3, and Scn5a transcripts in male and female NRVMs in both media, suggesting the absence of sex difference. However, cells in a high-glucose medium showed greater increases in Axin2 and Tbx3 transcripts than cells in a low-glucose medium. In addition, a low concentration of CHIR (1 µM) reduced the Scn5a transcript in cells in a high-glucose medium but not in a low-glucose medium, suggesting an increased sensitivity to Wnt signaling by high glucose. A non-linear relationship was identified between Axin2 transcript upregulation and Scn5a transcript downregulation in CIHR-treated NRVMs. These data suggest that high glucose sensitizes both male and female cardiomyocytes to Wnt/β-catenin signaling. Full article

Ion channels are essential for mineral ion homeostasis in mammalian cells, and these are activated or inhibited by environmental stimuli such as heat, cold, mechanical, acidic, or basic stresses. These expressions and functions are quite diverse between cell types. The function and importance of ion channels are well-studied in neurons and cardiac cells, while those functions in pluripotent stem cells (PSCs) were not fully understood. Some sodium, potassium, chloride, calcium, transient receptor potential channels and mechanosensitive Piezo channels are found to be expressed and implicated in pluripotency and self-renewal capacity in PSCs. This review summarizes present and previous reports about ion channels and their response to environmental stimuli in PSCs. Furthermore, we compare the expressions and roles between PSCs and their differentiated embryoid bodies. We then discuss those contributions to pluripotency and differentiation. Full article

Background: The aim of this study was to evaluate the performance of the diagnostic pathway proposed by the European Society of Cardiology (ESC) guidelines for identifying the underlying aetiology of sudden cardiac death (SCD) through the screening of first-degree family members of patients with SCD who either had a negative autopsy or no autopsy performed. Methods: To be eligible for enrolment, patients had to meet the following inclusion criteria: a family history of SCD in a first-degree relative under the age of 50 years; the SCD decedents must not have undergone an autopsy, or if an autopsy was performed, non-cardiac and structural cardiac causes must have been excluded. Patients underwent a comprehensive assessment, including the evaluation of family and medical history, electrocardiography (ECG) and ECG with high precordial leads, Holter ECG monitoring, echocardiography, cardiac magnetic resonance imaging, and exercise stress testing. A sodium channel blocker test (i.e., flecainide test) was performed when other clinical investigations were negative and the suspicion of Brugada syndrome was high. Results: Forty-one patients from 25 different families fulfilled the inclusion criteria and represented the final study cohort. After the comprehensive diagnostic work-up, a total of seven patients from five different families (5/25, 20%) were diagnosed with an inherited cardiac condition: two families with arrhythmogenic right ventricular cardiomyopathy, one with dilated cardiomyopathy, one with non-dilated left ventricular cardiomyopathy, and one with long QT syndrome. Conclusions: The comprehensive cardiologic work-up of relatives of mainly young SCD victims results in the diagnosis of inherited cardiac conditions in one-fifth of cases. Full article

Background and objectives: Sudden cardiac death (SCD) is a natural and unexpected death of cardiac origin that occurs within 1 h from the onset of acute symptoms. The major leading causes of SCD are cardiomyopathies and channelopathies. In this review, we focus on channelopathies, inherited diseases caused by mutations affecting genes encoding membrane ion channels (sodium, potassium or calcium channels) or cellular structures that affect Ca²⁺ availability. The diagnosis of diseases such as long QT, Brugada syndrome, short QT and catecholaminergic polymorphic ventricular tachycardia (CPVT) is still challenging. Currently, genetic testing and next-generation sequencing allow us to identify many rare alterations. However, some non-coding variants, e.g., splice-site variants, are usually difficult to interpret and to classify. Methods: In our review, we searched for splice-site variants of genes involved in channelopathies, focusing on variants of unknown significance (VUSs) registered on ClinVar up to now. Results: The research led to a high number of splice-site VUSs of genes involved in channelopathies, suggesting the performance of deeper studies. Conclusions: In order to interpret the correlation between variants and pathologies, we discuss experimental studies, such as RNA sequencing and functional analysis of proteins. Unfortunately, as these in vitro analyses cannot always be performed, we draw attention to in silico studies as future perspectives in genetics. This review has the aim of discussing the potential methods of detection and interpretation of VUSs, bringing out the need for a future reclassification of variants with currently unknown significance. Full article

Elevated blood glucose levels, known as hyperglycemia, play a significant role in sudden cardiac arrest, often resulting in sudden cardiac death, particularly among those with diabetes. Understanding the internal mechanisms has been a challenge for healthcare professionals, leading many research groups to investigate the relationship between blood glucose levels and cardiac electrical activity. Our hypothesis suggests that glucose-sensing biophysics mechanisms in cardiac tissue could clarify this connection. To explore this, we adapted a single-compartment computational model of the human pacemaker action potential. We incorporated glucose-sensing mechanisms with voltage-gated sodium ion channels using ordinary differential equations. Parameters for the model were based on existing experimental studies to mimic the impact of glucose levels on pacemaker action potential firing. Simulations using voltage clamp and current clamp techniques showed that elevated glucose levels decreased sodium ion channel currents, leading to a reduction in the pacemaker action potential frequency. In summary, our mathematical model provides a cellular-level understanding of how high glucose levels can lead to bradycardia and sudden cardiac death. Full article