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Acta Physiol (Oxf)
2020 Aug 01;2294:e13471. doi: 10.1111/apha.13471.
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Polyunsaturated fatty acid-derived IKs channel activators shorten the QT interval ex-vivo and in-vivo.
Skarsfeldt MA
,
Liin SI
,
Larsson HP
,
Bentzen BH
.
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AIM: We aimed to assess the ability of natural and modified polyunsaturated fatty acids (PUFAs) to shorten QT interval in ex-vivo and in-vivo guinea pig hearts.
METHODS: The effect of one natural (docosahexaenoic acid [DHA]) and three modified (linoleoyl glycine [Lin-GLY], docosahexaenoyl glycine [DHA-GLY], N-arachidonoyl taurine [N-AT]) PUFAs on ventricular action potential duration (APD) and QT interval was studied in a E4031 drug-induced long QT2 model of ex-vivo guinea pig hearts. The effect of DHA-GLY on QT interval was also studied in in-vivo guinea pig hearts upon intravenous administration. The effect of modified PUFAs on IKs was studied using Xenopus laevis oocytes expressing human KCNQ1 and KCNE1.
RESULTS: All tested PUFAs shortened ADP and QT interval in ex-vivo guinea pig hearts, however, with different ability in restoring baseline APD/QT interval with specific modified PUFAs being most efficacious. Despite comparable ability in activating the human KCNQ1/KCNE1 channel, Lin-GLY was not as effective in shortening APD/QT interval as DHA-GLY in ex-vivo hearts. By constructing a guinea pig-like KCNE1, we found Lin-GLY to induce less activating effect compared with DHA-GLY on human KCNQ1 co-expressed with guinea pig-like KCNE1. Docosahexaenoyl glycine was studied in more detail and was found to shorten QT interval in in-vivo guinea pig hearts.
CONCLUSION: Our results show that specific PUFAs shorten QT interval in guinea pig hearts. The tendency of modified PUFAs with pronounced IKs channel activating effect to better restore QT interval suggests that modifying PUFAs to target the IKs channel is a means to improve the QT-shortening effect.
R01GM109762 NIH HHS , Aase & Ejnar Danielsens Fond, 2017-02040 Swedish Research Council, Ragna Rask-Nielsen Grundforskningsfond, Paula & Axel Nissens Legat, Swedish Society for Medical Research, CF17-0399+CF18-0164 The Carlsberg Foundation, R01 HL131461 NHLBI NIH HHS , R01 GM109762 NIGMS NIH HHS
Albert,
Omega-3 fatty acids, ventricular arrhythmias, and sudden cardiac death: antiarrhythmic, proarrhythmic, or neither.
2012, Pubmed
Albert,
Omega-3 fatty acids, ventricular arrhythmias, and sudden cardiac death: antiarrhythmic, proarrhythmic, or neither.
2012,
Pubmed
Ayad,
Causes and management of drug-induced long QT syndrome.
2010,
Pubmed
Barron,
Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: recommendations for patient information.
2013,
Pubmed
Belevych,
Dietary omega-3 fatty acids promote arrhythmogenic remodeling of cellular Ca2+ handling in a postinfarction model of sudden cardiac death.
2013,
Pubmed
Billman,
The effects of omega-3 polyunsaturated fatty acids on cardiac rhythm: a critical reassessment.
2013,
Pubmed
Billman,
Dietary omega-3 fatty acids and susceptibility to ventricular fibrillation: lack of protection and a proarrhythmic effect.
2012,
Pubmed
Bohannon,
Polyunsaturated fatty acid analogues differentially affect cardiac NaV, CaV, and KV channels through unique mechanisms.
2020,
Pubmed
,
Xenbase
Busch,
The novel class III antiarrhythmics NE-10064 and NE-10133 inhibit IsK channels expressed in Xenopus oocytes and IKs in guinea pig cardiac myocytes.
1994,
Pubmed
,
Xenbase
Bünger,
An isolated guinea pig heart preparation with in vivo like features.
1975,
Pubmed
Carmeliet,
Comparative effects of lignocaine and lorcainide on conduction in the Langendorff-perfused guinea-pig heart.
1979,
Pubmed
Chen,
Charybdotoxin binding in the I(Ks) pore demonstrates two MinK subunits in each channel complex.
2003,
Pubmed
,
Xenbase
Den Ruijter,
Pro- and antiarrhythmic properties of a diet rich in fish oil.
2007,
Pubmed
Elinder,
Actions and Mechanisms of Polyunsaturated Fatty Acids on Voltage-Gated Ion Channels.
2017,
Pubmed
Frishman,
Beta-adrenergic receptor blockers. Adverse effects and drug interactions.
1988,
Pubmed
Goldenberg,
Beta-blocker efficacy in high-risk patients with the congenital long-QT syndrome types 1 and 2: implications for patient management.
2010,
Pubmed
Goldenberg,
Long-term benefit of primary prevention with an implantable cardioverter-defibrillator: an extended 8-year follow-up study of the Multicenter Automatic Defibrillator Implantation Trial II.
2010,
Pubmed
Guo,
Validation of a guinea pig Langendorff heart model for assessing potential cardiovascular liability of drug candidates.
2009,
Pubmed
Kang,
Evidence that free polyunsaturated fatty acids modify Na+ channels by directly binding to the channel proteins.
1996,
Pubmed
Khalifa,
Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine H1 receptor antagonist diphenhydramine.
1999,
Pubmed
Kirchhoff,
The KCa2 Channel Inhibitor AP14145, But Not Dofetilide or Ondansetron, Provides Functional Atrial Selectivity in Guinea Pig Hearts.
2019,
Pubmed
Kügler,
Comparison of in vitro and computational experiments on the relation of inter-beat interval and duration of repolarization in a specific type of human induced pluripotent stem cell-derived cardiomyocytes.
2019,
Pubmed
Larsson,
KCNE1 tunes the sensitivity of KV7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site.
2018,
Pubmed
,
Xenbase
Lee,
In Vitro and In Silico Risk Assessment in Acquired Long QT Syndrome: The Devil Is in the Details.
2017,
Pubmed
Liin,
Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac IKs channel.
2015,
Pubmed
,
Xenbase
Liin,
Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations.
2016,
Pubmed
,
Xenbase
Liin,
Mechanisms Underlying the Dual Effect of Polyunsaturated Fatty Acid Analogs on Kv7.1.
2018,
Pubmed
,
Xenbase
London,
Omega-3 fatty acids and cardiac arrhythmias: prior studies and recommendations for future research: a report from the National Heart, Lung, and Blood Institute and Office Of Dietary Supplements Omega-3 Fatty Acids and their Role in Cardiac Arrhythmogenesis Workshop.
2007,
Pubmed
Lydtin,
Side effects and contraindications of beta-receptor blocking agents.
1977,
Pubmed
Macleod,
The electrical and mechanical response of adult guinea pig and rat ventricular myocytes to omega3 polyunsaturated fatty acids.
1998,
Pubmed
Moreno,
Marine n-3 PUFAs modulate IKs gating, channel expression, and location in membrane microdomains.
2015,
Pubmed
Morin,
Counting membrane-embedded KCNE beta-subunits in functioning K+ channel complexes.
2008,
Pubmed
,
Xenbase
Mozaffarian,
Plasma phospholipid long-chain ω-3 fatty acids and total and cause-specific mortality in older adults: a cohort study.
2013,
Pubmed
Nagasawa,
Sensitivity of inhalation anesthetics isoflurane and sevoflurane for the drug-induced QT-interval prolongation in guinea pigs.
2020,
Pubmed
Nakajo,
Stoichiometry of the KCNQ1 - KCNE1 ion channel complex.
2010,
Pubmed
,
Xenbase
Nerbonne,
Molecular physiology of cardiac repolarization.
2005,
Pubmed
Pepe,
Omega-3 fatty acids for the prevention of myocardial infarction and arrhythmias.
2010,
Pubmed
Persson,
Adverse events following implantable cardioverter defibrillator implantation: a systematic review.
2014,
Pubmed
Persson,
Good publication practice in physiology 2019.
2019,
Pubmed
Priori,
Risk stratification in the long-QT syndrome.
2003,
Pubmed
Roden,
Clinical practice. Long-QT syndrome.
2008,
Pubmed
Roden,
Quinidine delays IK activation in guinea pig ventricular myocytes.
1988,
Pubmed
Saravanan,
Cardiovascular effects of marine omega-3 fatty acids.
2010,
Pubmed
Schwartz,
Prevalence of the congenital long-QT syndrome.
2009,
Pubmed
Schwartz,
Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias.
2001,
Pubmed
Schwartz,
Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome.
2004,
Pubmed
Sun,
Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome.
2017,
Pubmed
,
Xenbase
Suzuki,
The effects of isoflurane on the cardiac slowly activating delayed-rectifier potassium channel in Guinea pig ventricular myocytes.
2003,
Pubmed
Wettwer,
Effects of the new class III antiarrhythmic drug E-4031 on myocardial contractility and electrophysiological parameters.
1991,
Pubmed
Xiao,
Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat ventricular myocytes.
1997,
Pubmed
Xiao,
Blocking effects of polyunsaturated fatty acids on Na+ channels of neonatal rat ventricular myocytes.
1995,
Pubmed
von Schacky,
Omega-3 Fatty acids: anti-arrhythmic, pro-arrhythmic, or both?
2012,
Pubmed
