Abstract Aims SCN5A mutations are associated with various cardiac phenotypes, including long QT syndrome type 3 (LQT3), Brugada syndrome (BrS), and cardiac conduction disease (CCD). Certain mutations, such as SCN5A-1795insD, lead to an overlap syndrome, with patients exhibiting both features of BrS/CCD [decreased sodium current (INa)] and LQT3 (increased late INa). The sodium channel blocker mexiletine may acutely decrease LQT3-associated late INa and chronically increase peak INa associated with SCN5A loss-of-function mutations. However, most studies have so far employed heterologous expression systems and high mexiletine concentrations. We here investigated the effects of a therapeutic dose of mexiletine on the mixed phenotype associated with the SCN5A-1795insD mutation in HEK293A cells and human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs). Methods and results To assess only the chronic effects on trafficking, HEK293A cells transfected with wild-type (WT) SCN5A or SCN5A-1795insD were incubated for 48 h with 10 µm mexiletine followed by wash-out, which resulted in an increased peak INa for both SCN5A-WT and SCN5A-1795insD and an increased late INa for SCN5A-1795insD. Acute re-exposure of HEK293A cells to 10 µm mexiletine did not impact on peak INa but significantly decreased SCN5A-1795insD late INa. Chronic incubation of SCN5A-1795insD hiPSC-CMs with mexiletine followed by wash-out increased peak INa, action potential (AP) upstroke velocity, and AP duration. Acute re-exposure did not impact on peak INa or AP upstroke velocity, but significantly decreased AP duration. Conclusion These findings demonstrate for the first time the therapeutic benefit of mexiletine in a human cardiomyocyte model of SCN5A overlap syndrome.

https://academic.oup.com/europace/article-pdf/25/6/euad154/50725534/euad154.pdf

Beneficial effects of chronic mexiletine treatment in a human model of SCN5A overlap syndrome

ABSTRACT The sinoatrial node (SAN) is the primary pacemaker of the mammalian heart, initiating its electrical activation and ensuring that the heart's functional cardiac output meets physiological demand. SAN dysfunction (SND) can cause complex cardiac arrhythmias that can manifest as severe sinus bradycardia, sinus arrest, chronotropic incompetence and increased susceptibility to atrial fibrillation, among other cardiac conditions. SND has a complex aetiology, with both pre-existing disease and heritable genetic variation predisposing individuals to this pathology. In this Review, we summarize the current understanding of the genetic contributions to SND and the insights that they provide into this disorder's underlying molecular mechanisms. With an improved understanding of these molecular mechanisms, we can improve treatment options for SND patients and develop new therapeutics.

Genetics of sinoatrial node function and heart rate disorders

State-of-the-art innovations in optical cardiac electrophysiology are significantly enhancing cardiac research. A potential leap into patient care is now on the horizon. Optical mapping, using fluorescent probes and high-speed cameras, offers detailed insights into cardiac activity and arrhythmias by analysing electrical signals, calcium dynamics, and metabolism. Optogenetics utilises light-sensitive ion channels and pumps to realise contactless, cell-selective cardiac actuation for modelling arrhythmia, restoring sinus rhythm, and probing complex cell-cell interactions. The merging of optogenetics and optical mapping techniques for 'all-optical' electrophysiology marks a significant step forward. This combination allows for the contactless actuation and sensing of cardiac electrophysiology, offering unprecedented spatial-temporal resolution and control. Recent studies have performed all-optical imaging ex vivo and achieved reliable optogenetic pacing in vivo, narrowing the gap for clinical use. Progress in optical electrophysiology continues at pace. Advances in motion tracking methods are removing the necessity of motion uncoupling, a key limitation of optical mapping. Innovations in optoelectronics, including miniaturised, biocompatible illumination and circuitry, are enabling the creation of implantable cardiac pacemakers and defibrillators with optoelectrical closed-loop systems. Computational modelling and machine learning are emerging as pivotal tools in enhancing optical techniques, offering new avenues for analysing complex data and optimising therapeutic strategies. However, key challenges remain including opsin delivery, real-time data processing, longevity and chronic effects of optoelectronic devices. This review provides a comprehensive overview of recent advances in optical mapping and optogenetics and outlines the promising future of optics in reshaping cardiac electrophysiology and therapeutic strategies.

Optical Mapping and Optogenetics in Cardiac Electrophysiology Research and Therapy: A State-of-the-Art Review.

BACKGROUND AND AIMS
Opioids are associated with increased risk of sudden cardiac death. This may be due to their effects on the cardiac sodium channel (Nav1.5) current. In the present study, we establish whether tramadol, fentanyl, or codeine affect Nav1.5 current.


METHODS
Using whole-cell patch-clamp methodology, we studied the effects of tramadol, fentanyl, and codeine on currents of human Nav1.5 channels stably expressed in HEK293 cells, and on action potential (AP) properties of freshly isolated rabbit ventricular cardiomyocytes.


RESULTS
In fully-available Nav1.5 channels (holding potential -120 mV), tramadol exhibited inhibitory effects on Nav1.5 current in a concentration-dependent manner with an IC50 of 378.5 ± 33.2 μM. In addition, tramadol caused a hyperpolarizing shift of voltage-gated (in)activation, and a delay in recovery from inactivation. These blocking effects occurred at lower concentrations in partially inactivated Nav1.5 channels: during partial fast-inactivation (close-to-physiological holding potential -90 mV), IC50 of Nav1.5 block was 4.5 ± 1.1 μM, while it was 16 ± 4.8 μM during partial slow-inactivation. The tramadol-induced changes on Nav1.5 properties were reflected by a reduction in AP upstroke velocity in a frequency-dependent manner. Fentanyl and codeine had no effect on Nav1.5 current, even when tested at lethal concentrations.


CONCLUSION
Tramadol reduces Nav1.5 currents, in particular, at close-to-physiological membrane potentials. Fentanyl and codeine have no effects on Nav1.5 current.

The opioid tramadol blocks the cardiac sodium channel Nav1.5 in HEK293 cells.

During atrial fibrillation (AF), electrical remodeling occurs, involving ion channels like NaV1.5, KV1.5, and TASK-1. A promising AF treatment encompasses inhibiting these channels. In this study, acetamide compounds were designed based on the local anesthetic pharmacophore as potential NaV1.5, KV1.5, and TASK-1 inhibitors. Compound 6f emerged as the most potent in the series, with IC50 values determined in Xenopus oocytes of approximately 0.3 µM in TASK-1, 81.5 µM in KV1.5, and 21.2 µM in NaV1.5. Unexpectedly, 6f activated at 100 µM another cardiac K2P channel (TASK-4) by about 40%. Next, we performed patch clamp experiments of human atrial cardiomyocytes from sinus rhythm (SR) or AF patients. In SR 6f reduced action potential amplitude (indicating NaV1.5 block) while in AF it increased action potential duration (APD), reflecting high affinity for TASK-1. Additionally, a hyperpolarization in resting membrane potential occurred in AF cardiomyocytes by 6f, consistent with the TASK-4 activation we observed. In a mathematical whole-atria model, 6f prolonged APD and tissue refractoriness, proving efficacious both for AF prevention and cardioversion. Favorable pharmacokinetic properties of 6f in silico, including good absorption and low toxicity, as well as its lack of cytotoxicity in a hemolytic assay, suggest its potential as an AF treatment. 

Polypharmacological Modulation of Atrial Fibrillation: Rational Design, Synthesis, and Evaluation of Novel Compounds Targeting NaV1.5, KV1.5, and K2P Channels

Abstract Aims Atrial fibrillation (AF) is the most common cardiac arrhythmia. Pathogenic variants in genes encoding ion channels are associated with familial AF. The point mutation M1875T in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Nav1.5, has been associated with increased atrial excitability and familial AF in patients. Methods and results We designed a new murine model carrying the Scn5a-M1875T mutation enabling us to study the effects of the Nav1.5 mutation in detail in vivo and in vitro using patch clamp and microelectrode recording of atrial cardiomyocytes, optical mapping, electrocardiogram, echocardiography, gravimetry, histology, and biochemistry. Atrial cardiomyocytes from newly generated adult Scn5a-M1875T+/− mice showed a selective increase in the early (peak) cardiac sodium current, larger action potential amplitude, and a faster peak upstroke velocity. Conduction slowing caused by the sodium channel blocker flecainide was less pronounced in Scn5a-M1875T+/− compared to wildtype atria. Overt hypertrophy or heart failure in Scn5a-M1875T+/− mice could be excluded. Conclusion The Scn5a-M1875T point mutation causes gain-of-function of the cardiac sodium channel. Our results suggest increased atrial peak sodium current as a potential trigger for increased atrial excitability.

/pdf/familial-atrial-fibrillation-mutation-m1875t-scn5a-increases-29dt5zfi.pdf

Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide

11.1Atrial fibrillation (AF) is the most common cardiac arrhythmia. AF often develops due to concomitant cardiovascular conditions combined with a pre-existing atrial substrate. Familial, early onset forms of AF enable identification of this substrate. Pathogenic variants in genes encoding ion channels are associated with familial AF. The point mutation M1875T in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Nav1.5, has been associated with increased atrial excitability and familial AF. Designing a new murine model carrying the Scn5a -M1875T mutation enabled us to study this atrial substrate in detail.1.2Left atrial cardiomyocytes from newly generated Scn5a-M1875T+/- mice showed a selective increase in the early (peak) cardiac sodium current, measured by patch clamp. Microelectrode recordings of intact left atria revealed larger action potential amplitudes and a faster peak upstroke velocity. Conduction was studied using optical mapping. When challenged with the sodium channel blocker flecainide, Scn5a-M1875T+/- left atria showed less conduction slowing than matched wildtype atria. In vivo analysis using electrocardiograms and echocardiography, as well as cardiac histology, excluded overt hypertrophy or heart failure in young adult mice.1.3The Scn5a-M1875T point mutation causes a cardiac sodium channel gain-of-function and suggests increased atrial peak sodium current as a potential trigger for increased atrial excitability and atrial fibrillation.1.4The observed changes highlight a selective increase in peak sodium current as a cause of familial AF. Our findings provide a possible explanation for the variable effectiveness of sodium channel blockers in patients with AF. Carriers of such sodium channel gain-of-function mutations may benefit more from tailored treatments.

https://www.biorxiv.org/content/biorxiv/early/2022/07/12/2022.01.18.476646.full.pdf

Increased early sodium current provokes familial atrial fibrillation and reduces effectiveness of sodium channel block

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Familial atrial fibrillation mutation M1875T-SCN5A increases early sodium current and dampens the effect of flecainide

Increased early sodium current provokes familial atrial fibrillation and reduces effectiveness of sodium channel block