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Aims: Clinical observations in patients with long QT syndrome carrying sodium channel mutations (LQT3) suggest that bradycardia caused by parasympathetic stimulation may provoke torsades de pointes (TdP). β-Adrenoceptor blockers appear less effective in LQT3 than in other forms of the disease. [ABSTRACT FROM PUBLISHER]

Background: Long QT syndrome type 3 (LQT3) is an inherited cardiac disorder caused by gain-of-function mutations in the cardiac voltage-gated sodium channel, Nav1.5. LQT3 is associated with the polymorphic ventricular tachycardia torsades de pointes (TdP), which can lead to syncope and sudden cardiac death. The sea anemone toxin ATX-II has been shown to inhibit the inactivation of Nav1.5, thereby closely mimicking the underlying cause of LQT3 in patients. Objective: The hypothesis for this study was that activation of the IKr current could counteract the proarrhythmic effects of ATX-II. Methods: Two different activators of IKr, NS3623 and mallotoxin (MTX), were used in patch clamp studies of ventricular cardiac myocytes acutely isolated from guinea pig to test the effects of selective IKr activation alone and in the presence of ATX-II. Action potentials were elicited at 1 Hz by current injection and the cells were kept at 32°C to 35°C. Results: NS3623 significantly shortened action potential duration at 90% repolarization (APD90) compared with controls in a dose-dependent manner. Furthermore, it reduced triangulation, which is potentially antiarrhythmic. Application of ATX-II (10 nM) was proarrhythmic, causing a profound increase of APD90 as well as early afterdepolarizations and increased beat-to-beat variability. Two independent IKr activators attenuated the proarrhythmic effects of ATX-II. NS3623 did not affect the late sodium current (INaL) in the presence of ATX-II. Thus, the antiarrhythmic effect of NS3623 is likely to be caused by selective IKr activation. Conclusion: The present data show the antiarrhythmic potential of selective IKr activation in a cellular model of the LQT3 syndrome. [Copyright &y& Elsevier]

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have enormous potential for the study of human cardiac disorders. However, their physiological immaturity severely limits their utility as a model system and their adoption for drug discovery. Here, we describe maturation media designed to provide oxidative substrates adapted to the metabolic needs of human iPSC (hiPSC)-CMs. Compared with conventionally cultured hiPSC-CMs, metabolically matured hiPSC-CMs contract with greater force and show an increased reliance on cardiac sodium (Na + ) channels and sarcoplasmic reticulum calcium (Ca 2+ ) cycling. The media enhance the function, long-term survival, and sarcomere structures in engineered heart tissues. Use of the maturation media made it possible to reliably model two genetic cardiac diseases: long QT syndrome type 3 due to a mutation in the cardiac Na + channel SCN5A and dilated cardiomyopathy due to a mutation in the RNA splicing factor RBM20. The maturation media should increase the fidelity of hiPSC-CMs as disease models., Competing Interests: Declaration of Interests The authors declare no competing interests. A patent application related to this work has been submitted., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

In the heart, voltage-gated sodium (Na v ) channel (Na v 1.5) is defined by its pore-forming α-subunit and its auxiliary β-subunits, both of which are important for its critical contribution to the initiation and maintenance of the cardiac action potential (AP) that underlie normal heart rhythm. The physiological relevance of Na v 1.5 is further marked by the fact that inherited or congenital mutations in Na v 1.5 channel gene SCN5A lead to altered functional expression (including expression, trafficking, and current density), and are generally manifested in the form of distinct cardiac arrhythmic events, epilepsy, neuropathic pain, migraine, and neuromuscular disorders. However, despite significant advances in defining the pathophysiology of Na v 1.5, the molecular mechanisms that underlie its regulation and contribution to cardiac disorders are poorly understood. It is rapidly becoming evident that the functional expression (localization, trafficking and gating) of Na v 1.5 may be under modulation by post-translational modifications that are associated with phosphorylation. We review here the molecular basis of cardiac Na channel regulation by kinases (PKA and PKC) and the resulting functional consequences. Specifically, we discuss: (1) recent literature on the structural, molecular, and functional properties of cardiac Na v 1.5 channels; (2) how these properties may be altered by phosphorylation in disease states underlain by congenital mutations in Na v 1.5 channel and/or subunits such as long QT and Brugada syndromes. Our expectation is that understanding the roles of these distinct and complex phosphorylation processes on the functional expression of Na v 1.5 is likely to provide crucial mechanistic insights into Na channel associated arrhythmogenic events and will facilitate the development of novel therapeutic strategies.