Functional modulation of atrio-ventricular conduction by enhanced late sodium current and calcium-dependent mechanisms in Scn5a1798insD/+ mice

Abstract Aims SCN5A mutations are associated with arrhythmia syndromes, including Brugada syndrome, long QT syndrome type 3 (LQT3), and cardiac conduction disease. Long QT syndrome type 3 patients display atrio-ventricular (AV) conduction slowing which may contribute to arrhythmogenesis. We here investigated the as yet unknown underlying mechanisms. Methods and results We assessed electrophysiological and molecular alterations underlying AV-conduction abnormalities in mice carrying the Scn5a1798insD/+ mutation. Langendorff-perfused Scn5a1798insD/+ hearts showed prolonged AV-conduction compared to wild type (WT) without changes in atrial and His-ventricular (HV) conduction. The late sodium current (INa,L) inhibitor ranolazine (RAN) normalized AV-conduction in Scn5a1798insD/+ mice, likely by preventing the mutation-induced increase in intracellular sodium ([Na+]i) and calcium ([Ca2+]i) concentrations. Indeed, further enhancement of [Na+]i and [Ca2+]i by the Na+/K+-ATPase inhibitor ouabain caused excessive increase in AV-conduction time in Scn5a1798insD/+ hearts. Scn5a1798insD/+ mice from the 129P2 strain displayed more severe AV-conduction abnormalities than FVB/N-Scn5a1798insD/+ mice, in line with their larger mutation-induced INa,L. Transverse aortic constriction (TAC) caused excessive prolongation of AV-conduction in FVB/N-Scn5a1798insD/+ mice (while HV-intervals remained unchanged), which was prevented by chronic RAN treatment. Scn5a1798insD/+-TAC hearts showed decreased mRNA levels of conduction genes in the AV-nodal region, but no structural changes in the AV-node or His bundle. In Scn5a1798insD/+-TAC mice deficient for the transcription factor Nfatc2 (effector of the calcium-calcineurin pathway), AV-conduction and conduction gene expression were restored to WT levels. Conclusions Our findings indicate a detrimental role for enhanced INa,L and consequent calcium dysregulation on AV-conduction in Scn5a1798insD/+ mice, providing evidence for a functional mechanism underlying AV-conduction disturbances secondary to gain-of-function SCN5A mutations.

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Abstract 13191: Increased Extracellular Sodium and Intercellular Cleft Separation Synergistically Prolong Repolarization in the Long-qt Syndrome Type 3

Circulation ◽

10.1161/circ.142.suppl_3.13191 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Xiaobo Wu ◽

Gregory HOEKER ◽

David Ryan King ◽

Robert G Gourdie ◽

Seth Weinberg ◽

...

Keyword(s):

Long Qt Syndrome ◽

Sodium Current ◽

Syndrome Type ◽

Long Qt ◽

Late Sodium Current ◽

Individual Effects ◽

Qt Syndrome ◽

The Individual ◽

Extracellular Sodium ◽

Type 3

Introduction: Long-QT syndrome type 3 (LQT3) is caused by a gain-of-function mutation in the cardiac sodium channel that increases the late sodium current and prolongs repolarization. We previously suggested that narrowing the perinexus which is adjacent gap junction conceals the LQT3 phenotype by depleting extracellular sodium ([Na]) within this nanodomain and curtails the late current and repolarization. However, it is unknown if elevating bulk [Na] alone modulates action potential duration (APD) in widened perinexi to unmask LQT3. Hypothesis: Elevated [Na] and widened perinexi synergistically prolong APD in LQT3. Methods: The dependence of APD on [Na] and perinexal width was explored with a computational model and in Langendorff-perfused guinea pig hearts. The late sodium current was induced with ATXII (7nM). Perfusate [Na] changed from 145 (145Na) to 160 mM (160Na). Perinexal expansion was induced with βadp1 (1uM). APD was quantified from whole-heart optical maps. Perinexal width was quantified by transmission electron microscopy. Results: A computational model, including preferential sodium channel location at the intercalated disk, predicts that combination of elevated [Na] and widened perinexus prolongs APD greater than summing the effect of the individual interventions alone. Therefore, the combination is synergistic and not additive. Isolated heart experiments are consistent with the model. Specifically, ATXII+βadp1 significantly widens perinexal width from 27.8±4.1 to 49.7±9.3 nm and prolongs APD by 18.1±5.1ms with 600ms pacing relative to ATXII alone. In the presence of ATXII, 160Na significantly prolongs APD by 12.0±5.8ms relative to 145Na. Furthermore, the combination of both interventions is synergistic. Specifically, in the presence of ATXII, 160Na+βadp1 significantly prolongs APD more than the sum of the individual effects (49.9±7.5ms vs. 30.2±5.4ms). Conclusions: The data demonstrate that in LQT3, enhancing sodium and perinexal width concurrently prolong APD more than the individual effects alone. This synergistic effect suggests that maintaining reduced plasma sodium level can be a simple and effective method to conceal LQT3, even in the presence of perinexal expansion associated with osmotically induced stress.

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