Polyunsaturated fatty acid analogues differentially affect cardiac Na v , Ca v , and K v channels through unique mechanisms

The cardiac ventricular action potential depends on several voltage-gated ion channels, including Nav, Cav, and Kv channels. Mutations in these channels can cause Long QT Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden cardiac death. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics for LQTS because they are modulators of voltage-gated ion channels. Here we demonstrate that PUFA analogues vary in their selectivity for human voltage-gated ion channels involved in the ventricular action potential. The effects of specific PUFA analogues range from selective for a specific ion channel to broadly modulating cardiac ion channels from all three families (Nav, Cav, and KV). In addition, a PUFA analogue selective for the cardiac IKs channel (Kv7.1/KCNE1) is effective in shortening the cardiac action potential in human-induced pluripotent stem cell-derived cardiomyocytes. Our data suggest that PUFA analogues could potentially be developed as therapeutics for LQTS and cardiac arrhythmia.
Source: eLife - Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

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Mutations in the genes encoding the highly conserved Ca2+-sensing protein calmodulin (CaM) cause severe cardiac arrhythmias, including catecholaminergic polymorphic ventricular tachycardia or long QT syndrome and sudden cardiac death. Most of the identified arrhythmogenic mutations reside in the C-terminal domain of CaM and mostly affect Ca2+-coordinating residues. One exception is the catecholaminergic polymorphic ventricular tachycardia–causing N53I substitution, which resides in the N-terminal domain (N-domain). It does not affect Ca2+ coordination and has only a minor impact on binding affinity toward Ca2+ and on...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Molecular Bases of Disease Source Type: research
The cardiac action potential is critical to the production of a synchronized heartbeat. This electrical impulse is governed by the intricate activity of cardiac ion channels, among them the cardiac voltage-gated potassium (Kv) channels KCNQ1 and hERG as well as the voltage-gated sodium (Nav) channel encoded by SCN5A. Each channel performs a highly distinct function, despite sharing a common topology and structural components. These three channels are also the primary proteins mutated in congenital long QT syndrome (LQTS), a genetic condition that predisposes to cardiac arrhythmia and sudden cardiac death due to impaired re...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
ConclusionBoth mutations, KV7.1 A150T and L374H, led to loss of channel function. The degree of loss ‐of‐function may mirror the disease phenotype observed in the patients.This article is protected by copyright. All rights reserved
Source: Pacing and Clinical Electrophysiology : PACE - Category: Cardiology Authors: Tags: ELECTROPHYSIOLOGY Source Type: research
This report highlights a case of QT prolongation with torsades de pointes in a patient with baseline congenital long QT syndrome, believed to be precipitated by metabolic changes associated with the "ketogenic diet." PMID: 32063779 [PubMed]
Source: Baylor University Medical Center Proceedings - Category: Universities & Medical Training Authors: Tags: Proc (Bayl Univ Med Cent) Source Type: research
Conclusion: Video-assisted CSD should be considered as a treatment option for patients with potentially dangerous arrhythmias that do not respond to conventional treatment, especially in recurrent ventricular tachycardia. PMID: 31588139 [PubMed - in process]
Source: Archivos de Cardiologia de Mexico - Category: Cardiology Authors: Tags: Arch Cardiol Mex Source Type: research
KCNH2 encodes the human ether- à-go-go-related gene (hERG) potassium channel, which passes the rapid delayed rectifier potassium current, IKr. Loss-of-function variants in KCNH2 cause long QT syndrome type 2 (LQTS2) which is associated with a markedly increased risk of cardiac arrhythmias. The majority of rare KCNH2 variants how ever are likely to be benign.
Source: Heart Rhythm - Category: Cardiology Authors: Source Type: research
Publication date: 3 September 2019Source: Cell Reports, Volume 28, Issue 10Author(s): Malou van den Boogaard, Jan Hendrik van Weerd, Amira C. Bawazeer, Ingeborg B. Hooijkaas, Harmen J.G. van de Werken, Federico Tessadori, Wouter de Laat, Phil Barnett, Jeroen Bakkers, Vincent M. ChristoffelsSummaryThe human ether-a-go-go-related gene KCNH2 encodes the voltage-gated potassium channel underlying IKr, a current critical for the repolarization phase of the cardiac action potential. Mutations in KCNH2 that cause a reduction of the repolarizing current can result in cardiac arrhythmias associated with long-QT syndrome. Here, we i...
Source: Cell Reports - Category: Cytology Source Type: research
AbstractLong QT syndrome (LQTS) is an inherited primary arrhythmia syndrome that may present with malignant arrhythmia and, rarely, risk of sudden death. The clinical symptoms include palpitations, syncope, and anoxic seizures secondary to ventricular arrhythmia, classicallytorsade de pointes. This predisposition to malignant arrhythmia is from a cardiac ion channelopathy that results in delayed repolarization of the cardiomyocyte action potential. The QT interval on the surface electrocardiogram is a summation of the individual cellular ventricular action potential durations, and hence is a surrogate marker of the abnorma...
Source: Pediatric Cardiology - Category: Cardiology Source Type: research
In conclusion, we identified a novel hERG channel activator HW-0168 that can be used for studying the physiological role of hERG in cardiac myocytes and may be beneficial for treating long QT syndrome.
Source: Journal of Pharmacological Sciences - Category: Drugs & Pharmacology Source Type: research
This article summarizes the diseases that we have learned about, such as the long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. The article examines the diagnosis, genetic screening of patients and their relatives, management, and referral to a specialist for further therapy. PMID: 31378327 [PubMed - in process]
Source: The Medical Clinics of North America - Category: General Medicine Authors: Tags: Med Clin North Am Source Type: research
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