Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels

Brien, Sian O'; Holmes, Andrew P.; Johnson, Dan; Kabir, S. Nashitha; C, Shea; Reilly, M; Avezzu, Adelisa; Reyat, Jasmeet S.; Hall, Amelia Weber; Apicella, Clara; Ellinor, Patrick T.; Niederer, Steven; Tucker, Nathan R.; Fabritz, Larissa; Kirchhof, Paulus; Pavlović, Davor

doi:10.1016/j.yjmcc.2022.01.009

Cited by 13 publications

(11 citation statements)

References 56 publications

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“…It has long been recognized that conduction in the healthy heart is faster in ventricular myocardium than in atrial 32, 59-61, 62, 63 , an observation we recapitulate here. However, these conduction differences have been largely ascribed to differences in myocyte geometry 2 with little known about the functional implications of inter-chamber differences in ID structure.…”

Section: Discussionsupporting

confidence: 65%

Unraveling Chamber-specific Differences in Intercalated Disc Ultrastructure and Molecular Organization and Their Impact on Cardiac Conduction

Struckman

Moise

King

et al. 2023

Preprint

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During each heartbeat, the propagation of action potentials through the heart coordinates the contraction of billions of individual cardiomyocytes and is thus, a critical life process. Unsurprisingly, intercalated discs, which are cell-cell contact sites specialized to provide electrical and mechanical coupling between adjacent cardiomyocytes, have been the focus of much investigation. Slowed or disrupted propagation leads to potentially life-threatening arrhythmias in a wide range of pathologies, where intercalated disc remodeling is a common finding. Hence, the importance and urgency of understanding intercalated disc structure and its influence on action potential propagation. Surprisingly, however, conventional modeling approaches cannot predict changes in propagation elicited by perturbations that alter intercalated disc ultrastructure or molecular organization, owing to lack of quantitative structural data at subcellular through nano scales. In order to address this critical gap in knowledge, we sought to quantify intercalated disc structure at these finer spatial scales in the healthy adult mouse heart and relate them to function in a chamber-specific manner as a precursor to understanding the impacts of pathological intercalated disc remodeling. Using super-resolution light microscopy, electron microscopy, and computational image analysis, we provide here the first ever systematic, multiscale quantification of intercalated disc ultrastructure and molecular organization. By incorporating these data into a rule-based model of cardiac tissue with realistic intercalated disc structure, and comparing model predictions of electrical propagation with experimental measures of conduction velocity, we reveal that atrial intercalated discs can support faster conduction than their ventricular counterparts, which is normally masked by inter-chamber differences in myocyte geometry. Further, we identify key ultrastructural and molecular organization features underpinning the ability of atrial intercalated discs to support faster conduction. These data provide the first stepping stone to elucidating chamber-specific impacts of pathological intercalated disc remodeling, as occurs in many arrhythmic diseases.

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Section: Discussionsupporting

confidence: 65%

Unraveling Chamber-specific Differences in Intercalated Disc Ultrastructure and Molecular Organization and Their Impact on Cardiac Conduction

Struckman

Moise

King

et al. 2023

Preprint

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“… 35 , 62–66 Na V β2 and Na V β4 are Na V 1.5 regulatory subunits differently expressed in atria vs. ventricles, having a higher presence in murine ventricles. 64 , 67 , 68 Hence, in HEK-Na V 1.5 cells expressing Kir2.1 WT and Kir2.1 WT/E299V , we transfected β subunits individually and in combination. The most promising results were obtained in cells expressing Kir2.1 WT/E299V + Na V β4.…”

Section: Resultsmentioning

confidence: 99%

The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of short QT syndrome type 3

Moreno-Manuel,

Macías,

Cruz

et al. 2024

Cardiovascular Research

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Aims Short QT Syndrome Type 3 (SQTS3) is a rare arrhythmogenic disease caused by gain-of-function mutations in KCNJ2, the gene coding the inward rectifier potassium channel Kir2.1. We used a multidisciplinary approach and investigated arrhythmogenic mechanisms in an in-vivo model of de-novo mutation Kir2.1E299V identified in a patient presenting an extremely abbreviated QT interval and paroxysmal atrial fibrillation. Methods and results We used intravenous adeno-associated virus-mediated gene transfer to generate mouse models, and confirmed cardiac-specific expression of Kir2.1WT or Kir2.1E299V. On ECG, the Kir2.1E299V mouse recapitulated the QT interval shortening and the atrial-specific arrhythmia of the patient. The PR interval was also significantly shorter in Kir2.1E299V mice. Patch-clamping showed extremely abbreviated action potentials in both atrial and ventricular Kir2.1E299V cardiomyocytes due to lack of inward-going rectification and increased IK1 at voltages positive to -80 mV. Relative to Kir2.1WT, atrial Kir2.1E299V cardiomyocytes had a significantly reduced slope conductance at voltages negative to -80 mV. After confirming a higher proportion of heterotetrameric Kir2.x channels containing Kir2.2 subunits in the atria, in-silico 3D simulations predicted an atrial-specific impairment of polyamine block and reduced pore diameter in the Kir2.1E299V-Kir2.2WT channel. In ventricular cardiomyocytes, the mutation increased excitability by shifting INa activation and inactivation in the hyperpolarizing direction, which protected the ventricle against arrhythmia. Moreover, Purkinje myocytes from Kir2.1E299V mice manifested substantially higher INa density than Kir2.1WT, explaining the abbreviation in the PR interval. Conclusions The first in-vivo mouse model of cardiac-specific SQTS3 recapitulates the electrophysiological phenotype of a patient with the Kir2.1E299V mutation. Kir2.1E299V eliminates rectification in both cardiac chambers but protects against ventricular arrhythmias by increasing excitability in both Purkinje-fiber network and ventricles. Consequently, the predominant arrhythmias are supraventricular likely due to the lack of inward rectification and atrial-specific reduced pore diameter of the Kir2.1E299V-Kir2.2WT heterotetramer.

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“…Flecainide is a clinically used sodium channel blocker that inhibits cardiac I Na via blocking the pores of open Na v 1.5 channels. 10 , 14 The differential response to flecainide is likely due to the increased early sodium influx through the mutated Na v 1.5 channels, enabling preservation of conduction and activation properties in atrial cardiomyocytes when sodium channels are inhibited, leading to an enhanced activation reserve.…”

Section: Discussionmentioning

confidence: 99%

“…Murine hearts were excised under deep terminal anaesthesia (4% isoflurane inhalation in O 2 , 1.5 L/min) and perfused at 4 mL.min −1 at 37°C on a vertical Langendorff apparatus with the following solutions, equilibrated with 100% O 2 : (i) N-2-hydroxyethylpiperazine-N-2-ethane sulfonic acid (HEPES)-buffered, Ca 2+ -free, modified Tyrode’s solution containing in mM: NaCl 145, KCl 5.4, MgSO 4 0.83, Na 2 HPO 4 0.33, HEPES 5, and glucose 11 (pH 7.4, NaOH)×5 min and (ii) Tyrode’s enzyme solution containing 640 µg/mL collagenase type II (270 U/mg), 600 µg/mL collagenase type IV (270 U/mg) and 50 µg/mL protease (Worthington, Lakewood, NJ), 20 mM taurine and 3 μM CaCl 2 × 8–12 min. 10 The heart was removed from the Langendorff setup and perfused with 5 mL of modified Kraftbruhe (KB) solution containing in mM: DL-potassium aspartate 10, L-potassium glutamate 100, KCl 25, KH 2 PO 4 10, MgSO 4 2, taurine 20, creatine 5, Ethyleneglycol- bis(β-aminoethyl)-N,N,Nʹ,Nʹ-tetraacetic Acid (EGTA) 0.5, HEPES 5, 0.1% BSA, and glucose 20 (pH 7.2, KOH).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2022

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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.

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Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels

Cited by 13 publications

References 56 publications

Unraveling Chamber-specific Differences in Intercalated Disc Ultrastructure and Molecular Organization and Their Impact on Cardiac Conduction

Unraveling Chamber-specific Differences in Intercalated Disc Ultrastructure and Molecular Organization and Their Impact on Cardiac Conduction

The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of short QT syndrome type 3

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

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